M6A RNA methylation-mediated dysregulation of AGAP2-AS1 promotes trastuzumab resistance of breast cancer.

INTRODUCTION: Trastuzumab is commonly used in the treatment of human epidermal growth factor receptor-2 positive (HER-2+) breast cancer patients, but its efficacy is often limited by chemotherapy resistance. Recent studies indicate that long noncoding RNAs (lncRNAs) play important roles in tumor progression and response to therapy. However, the regulatory mechanism of lncRNAs in trastuzumab resistance is still unknown to date. METHODS: qPCR was performed to detect the expression of related genes. Western blot and immunofluorescence assays were used for the evaluation of protein expression levels. A series of gain- or loss-functional assays confirmed the function of AGAP2-AS1 in trastuzumab resistance, both in vitro and in vivo. RNA immunoprecipitation and pulldown analysis was conducted to verify the interaction between METTL3/YTHDF2 and lncRNA AGAP2-AS1. , Results: AGAP2-AS1 was upregulated in trastuzumab-resistant cells and SKBR-3R-generated xenograft in nude mice. Silence of AGAP2-AS1 significantly decreased trastuzumab-induced cell cytotoxicity both in vitro and in vivo. The m6A methylation of AGAP2-AS1 was found to be reduced in trastuzumab resistant cells compared to parental cells. In addition, METTL3 increased the m6A methylation of AGAP2-AS1, which finally induced the suppression of AGAP2-AS1 expression. Moreover, YTHDF2 was essential for METTL3-mediated m6A methylation of AGAP2-AS1. Functionally, AGAP2-AS1 regulated trastuzumab resistance via inducing autophagy and increasing ATG5 protein level. CONCLUSION: Taken together, we proved that METTL3/YTHDF2-mediated m6A methylation indued the increased expression AGAP2-AS1, which could promote the trastuzumab resistance of breast cancer. In addition, AGAP2-AS1 also regulates trastuzumab resistance via inducing autophagy. Therefore, AGAP2-AS1 may be promising predictive biomarker and therapeutic target breast cancer patients.

Engineering anisotropy in 2D transition metal dichalcogenides via heterostructures.

Two-dimensional (2D) semiconductors featuring low-symmetry crystal structures hold an immense potential for the design of advanced optoelectronic devices, leveraging their inherent anisotropic attributes. While the synthesis techniques for transition metal dichalcogenides (TMDs) have matured, a promising avenue emerges: the induction of anisotropy within symmetric TMDs through interlayer van der Waals coupling engineering. Here, we unveil the creation of heterostructures (HSs) by stacking highly symmetric MoSe2 with low-symmetry ReS2, introducing artificial anisotropy into monolayer MoSe2. Through a meticulous analysis of angle-dependent photoluminescence (PL) spectra, we discern a remarkable anisotropic intensity ratio of approximately 1.34. Bolstering this observation, the angle-resolved Raman spectra provide unequivocal validation of the anisotropic optical properties inherent to MoSe2. This intriguing behavior can be attributed to the in-plane polarization of MoSe2, incited by the deliberate disruption of lattice symmetry within the monolayer MoSe2 structure. Collectively, our findings furnish a conceptual blueprint for engineering both isotropic and anisotropic HSs, thereby unlocking an expansive spectrum of applications in the realm of high-performance optoelectronic devices.

Enhanced Homogeneity of Moiré Superlattices in Double-Bilayer WSe2 Homostructure.

Moiré superlattices have emerged as a promising platform for investigating and designing optically generated excitonic properties. The electronic band structure of these systems can be qualitatively modulated by interactions between the top and bottom layers, leading to the emergence of new quantum phenomena. However, the inhomogeneities present in atomically thin bilayer moiré superlattices created by artificial stacking have hindered a deeper understanding of strongly correlated electron properties. In this work, we report the fabrication of homogeneous moiré superlattices with controllable twist angles using a 2L-WSe2/2L-WSe2 homostructure. By adding extra layers, we provide additional degrees of freedom to tune the optical properties of the moiré superlattices while mitigating the nonuniformity problem. The presence of an additional bottom layer acts as a buffer, reducing the inhomogeneity of the moiré superlattice, while the encapsulation effect of the additional top and bottom WSe2 monolayers further enhances the localized moiré excitons. Our observations of alternating circularly polarized photoluminescence confirm the existence of moiré excitons, and their characteristics were further confirmed by theoretical calculations. These findings provide a fundamental basis for studying moiré potential correlated quantum phenomena and pave the way for their application in quantum optical devices.

Adhesion-regulating molecule 1 (ADRM1) can be a potential biomarker and target for bladder cancer.

Adhesion-regulating molecule 1 (ADRM1) has been implicated in tumor development, yet its specific role in bladder cancer (BC) remains undefined. This study aimed to elucidate the function of ADRM1 in BC through a combination of bioinformatics analysis and immunohistochemical analysis (IHC). Utilizing R version 3.6.3 and relevant packages, we analyzed online database data. Validation was conducted through IHC data, approved by the Institutional Ethics Committee (Approval No. K20220830). In both paired and unpaired comparisons, ADRM1 expression was significantly elevated in BC tissues compared to adjacent tissues, as evidenced by the results of TCGA dataset and IHC data. Patients with high ADRM1 expression had statistically worse overall survival than those with low ADRM1 expression in TCGA dataset, GSE32548 dataset, GSE32894 dataset, and IHC data. Functional analysis unveiled enrichment in immune-related pathways, and a robust positive correlation emerged between ADRM1 expression and pivotal immune checkpoints, including CD274, PDCD1, and PDCD1LG2. In tumor microenvironment, samples with the high ADRM1 expression contained statistical higher proportion of CD8 + T cells and Macrophage infiltration. Meanwhile, these high ADRM1-expressing samples displayed elevated tumor mutation burden scores and stemness indices, implying potential benefits from immunotherapy. Patients with low ADRM1 expression were sensitive to cisplatin, docetaxel, vinblastine, mitomycin C, and methotrexate. According to the findings from bioinformatics and IHC analyses, ADRM1 demonstrates prognostic significance for BC patients and holds predictive potential for both immunotherapy and chemotherapy responses. This underscores its role as a biomarker and therapeutic target in BC.

Pressure-Induced Dynamic Tuning of Interlayer Coupling in Twisted WSe2/WSe2 Homobilayers.

Moiré superlattices induced by twisted van der Waals (vdW) heterostructures or homostructures have recently gained significant attention due to their potential to generate exotic strong-correlation electronic and phonon phenomena. However, the lack of dynamic tuning for interlayer coupling of moiré superlattices hinders a thorough understanding and development of the moiré correlation state. Here, we present a dynamic tuning method for twisted WSe2/WSe2 homobilayers using a diamond anvil cell (DAC). We demonstrate the powerful tuning of interlayer coupling and observe an enhanced response to pressure for interlayer breathing modes and the rapid descent of indirect excitons in twisted WSe2/WSe2 homobilayers. Our findings indicate that the introduction of a moiré superlattice for WSe2 bilayers gives rise to hybridized excitons, which lead to the different pressure-evolution exciton behaviors compared to natural WSe2 bilayers. Our results provide a novel understanding of moiré physics and offer an effective method to tune interlayer coupling of moiré superlattices.

Observation of optical anisotropy and a linear dichroism transition in layered silicon phosphide.

The investigation of in-plane two-dimensional (2D) anisotropic materials has garnered significant attention due to their exceptional electronic, optical, and mechanical characteristics. The anisotropic optical properties and angle-dependent photodetectors based on 2D anisotropic materials have been extensively studied. However, novel in-plane anisotropic materials still need to be explored to satisfy for distinct environments and devices. Here, we report the remarkable anisotropic behavior of excitons and demonstrate a unique linear-dichroism transition of absorption between ultraviolet and visible light in layered silicon phosphide (SiP) through the analysis of polarization photoluminescence (PL) and absorbance spectra. Its high absorption linear dichroism ratio of 1.16 at 388 nm, 1.15 at 532 nm, and 1.19 at 733 nm is revealed, suggesting the brilliant non-isotropic responses. The robust periodic variation of the A1 and A2 Raman modes in 2D SiP materials allows for the determination of their crystal orientation. Furthermore, the presence of indirect excitons with phonon sidebands in the temperature-dependent PL spectra exhibits non-monotonic energy shifts with increasing temperature, which is attributed to an enhanced electron-phonon interaction and thermal expansion. Our findings provide valuable insights into the fundamental physical properties of layered SiP and offer guidelines for designing polarization-sensitive photodetectors and angle-dependent devices based on 2D anisotropic materials.

Localization-enhanced moiré exciton in twisted transition metal dichalcogenide heterotrilayer superlattices.

The stacking of twisted two-dimensional (2D) layered materials has led to the creation of moiré superlattices, which have become a new platform for the study of quantum optics. The strong coupling of moiré superlattices can result in flat minibands that boost electronic interactions and generate interesting strongly correlated states, including unconventional superconductivity, Mott insulating states, and moiré excitons. However, the impact of adjusting and localizing moiré excitons in Van der Waals heterostructures has yet to be explored experimentally. Here, we present experimental evidence of the localization-enhanced moiré excitons in the twisted WSe2/WS2/WSe2 heterotrilayer with type-II band alignments. At low temperatures, we observed multiple excitons splitting in the twisted WSe2/WS2/WSe2 heterotrilayer, which is manifested as multiple sharp emission lines, in stark contrast to the moiré excitonic behavior of the twisted WSe2/WS2 heterobilayer (which has a linewidth 4 times wider). This is due to the enhancement of the two moiré potentials in the twisted heterotrilayer, enabling highly localized moiré excitons at the interface. The confinement effect of moiré potential on moiré excitons is further demonstrated by changes in temperature, laser power, and valley polarization. Our findings offer a new approach for localizing moiré excitons in twist-angle heterostructures, which has the potential for the development of coherent quantum light emitters.

Strain-tunable valley polarization and localized excitons in monolayer WSe2.

Monolayer transition metal dichalcogenides (TMDs) have a crystalline structure with broken spatial inversion symmetry, making them promising candidates for valleytronic applications. However, the degree of valley polarization is usually not high due to the presence of intervalley scattering. Here, we use the nanoindentation technique to fabricate strained structures of WSe2 on Au arrays, thus demonstrating the generation and detection of strained localized excitons in monolayer WSe2. Enhanced emission of strain-localized excitons was observed as two sharp photoluminescence (PL) peaks measured using low-temperature PL spectroscopy. We attribute these emerging sharp peaks to excitons trapped in potential wells formed by local strains. Furthermore, the valley polarization of monolayer WSe2 is modulated by a magnetic field, and the valley polarization of strained localized excitons is increased, with a high value of up to approximately 79.6%. Our results show that tunable valley polarization and localized excitons can be realized in WSe2 monolayers, which may be useful for valleytronic applications.

Moiré Enhanced Potentials in Twisted Transition Metal Dichalcogenide Trilayers Homostructures.

The exploration of moiré superlatticesholds promising potential to uncover novel quantum phenomena emerging from the interplay of atomic structure and electronic correlation . However, the impact of the moiré potential modulation on the number of twisted layers has yet to be experimentally explored. Here, this work synthesizes a twisted WSe2 homotrilayer using a dry-transfer method and investigates the enhancement of the moiré potential with increasing number of twisted layers. The results of the study reveal the presence of multiple exciton resonances with positive or negative circularly polarized emission in the WSe2 homostructure with small twist angles, which are attributed to the excitonic ground and excited states confined to the moiré potential. The distinct g-factor observed in the magneto-optical spectroscopy is also shown to be a result of the confinement of the exciton in the moiré potential. The moiré potential depths of the twisted bilayer and trilayer homostructures are found to be 111 and 212 meV, respectively, an increase of 91% from the bilayer structure. These findings demonstrate that the depth of the moiré potential can be manipulated by adjusting the number of stacked layers, providing a promising avenue for exploration into highly correlated quantum phenomena.

A novel endothelial-related prognostic index by integrating single-cell and bulk RNA sequencing data for patients with kidney renal clear cell carcinoma.

Background: Endothelial cells in the tumor microenvironment play an important role in the development of kidney renal clear cell carcinoma (KIRC). We wanted to further identify the function of endothelial cells in KIRC patients by integrating single-cell and bulk RNA sequencing data. Methods: Online databases provide the original data of this study. An endothelial-related prognostic index (ERPI) was constructed and validated by R version 3.6.3 and relative packages. Results: The ERPI consisted of three genes (CCND1, MALL, and VWF). Patients with high ERPI scores were significantly correlated with worse prognosis than those with low ERPI scores in the TCGA training group, TCGA test group, and GSE29609 group. A positive correlation was identified between the ERPI score and poor clinical features. The results of functional analysis indicated that ERPI was significantly associated with immune-related activities. We suggested that patients with high ERPI scores were more likely to benefit from immunotherapy based on the results of immune checkpoints, tumor microenvironment, stemness index, and TCIA, while patients with low ERPI scores were sensitive to gemcitabine, docetaxel, paclitaxel, axitinib, pazopanib, sorafenib, and temsirolimus according to the results of the "pRRophetic" algorithm. Therefore, this ERPI may help doctors choose the optimal treatment for patients with KIRC. Conclusion: By integrating single-cell and bulk RNA sequencing data from KIRC patients, we successfully identified the key genes from the perspective of endothelial cells in the tumor microenvironment and constructed ERPIs that had positive implications in precision medicine.

PSMB1 Inhibits the Replication of Porcine Reproductive and Respiratory Syndrome Virus by Recruiting NBR1 To Degrade Nonstructural Protein 12 by Autophagy.

The nonstructural proteins (Nsps) of porcine reproductive and respiratory syndrome virus (PRRSV) play essential roles in virus replication-a multistep process that requires the participation of host factors. It is of great significance for the development of antiviral drugs to characterize the host proteins that interact with PRRSV Nsps and their functions in PRRSV replication. Here, we determined that proteasome subunit ß type 1 (PSMB1) interacted with viral Nsp12 to inhibit PRRSV replication in target and permissive cells. PSMB1 could be downregulated by PRRSV infection through interaction with the transcription factor EBF1. Proteasome and autophagy inhibitor assays showed that PSMB1 was regulated by the autophagic pathway to degrade Nsp12. Cotransfection of PSMB1 and Nsp12 increased the level of intracellular autophagy; both molecules were colocated in lysosomes. We also found that the selective autophagy cargo receptor protein NBR1 and E3 ubiquitin ligase STUB1 interacted with PSMB1 and Nsp12, respectively, in the autophagic degradation of Nsp12. Furthermore, the degradation of Nsp12 by PSMB1 was mainly dependent on the ubiquitination of Nsp12 at lysine site 130. Our results indicate for the first time that PSMB1 is an anti-PRRSV host protein that inhibits the replication of PRRSV by degradation of Nsp12 through the selective autophagy pathway. IMPORTANCE PRRS is a major threat to the global pig industry and urgently requires an effective and sustainable control strategy. PRRSV Nsps have important roles in viral RNA synthesis, proteinase activity, induction of replication-associated membrane rearrangements, replicative endoribonuclease activity, determination of virulence, and regulation of host immune response. Research associated with PRRSV Nsps can provide vital guidance to modify the PRRSV genome through reverse genetics in the development of vaccines and diagnostics. The function of Nsp12, which generally plays essential roles in virus replication, remains unclear. We demonstrated that PSMB1 interacted with and degraded Nsp12 through an autophagic pathway to inhibit PRRSV replication. Our data confirmed a novel antiviral function of PSMB1 and allowed us to elaborate on the roles of Nsp12 in PRRSV pathogenesis. These findings suggest a valid and highly conserved candidate target for the development of novel therapies and more effective vaccines and demonstrate the complex cross talk between selective autophagy and PRRSV infection.

Strong Interlayer Coupling in Twisted Transition Metal Dichalcogenide Moiré Superlattices.

Moiré superlattices in twisted van der Waals materials offer a powerful platform for exploring light-matter interactions. The periodic moiré potentials in moiré superlattices can induce strongly correlated quantum phenomena that depend on the moiré potential associated with interlayer coupling at the interface. However, moiré superlattices are primarily prepared by mechanical exfoliation and manual stacking, where the transfer methods easily cause interfacial contamination, and the preparation of high-quality bilayer 2D materials with small twist angles by growth methods remains a significant challenge. In this work, WSe2 /WSe2 homobilayers with different twist angles by chemical vapor deposition (CVD), using a heteroatom-assisted growth technique, are synthesized. Using low-frequency Raman scattering, the uniformity of the moiré superlattices is mapped to demonstrate the strong interfacial coupling of the CVD-fabricated twist-angle homobilayers. The moiré potential depths of the CVD-grown and artificially stacked homostructures with twist angles of 1.5° are 115 and 45 meV (an increase of 155%), indicating that the depth of moiré potential can be modulated by the interfacial coupling. These results open a new avenue to study the modulation of moiré potential by strong interlayer coupling and provide a foundation for the development of twistronics.

Development of a novel nomogram for predicting clinically significant prostate cancer with the prostate health index and multiparametric MRI.

Introduction: On prostate biopsy, multiparametric magnetic resonance imaging (mpMRI) and the Prostate Health Index (PHI) have allowed prediction of clinically significant prostate cancer (csPCa). Methods: To predict the likelihood of csPCa, we created a nomogram based on a multivariate model that included PHI and mpMRI. We assessed 315 males who were scheduled for prostate biopsies. Results: We used the Prostate Imaging Reporting and Data System version 2 (PI-RADS V2) to assess mpMRI and optimize PHI testing prior to biopsy. Univariate analysis showed that csPCa may be identified by PHI with a cut-off value of 77.77, PHID with 2.36, and PI-RADS with 3 as the best threshold. Multivariable logistic models for predicting csPCa were developed using PI-RADS, free PSA (fPSA), PHI, and prostate volume. A multivariate model that included PI-RADS, fPSA, PHI, and prostate volume had the best accuracy (AUC: 0.882). Decision curve analysis (DCA), which was carried out to verify the nomogram's clinical applicability, showed an ideal advantage (13.35% higher than the model that include PI-RADS only). Discussion: In conclusion, the nomogram based on PHI and mpMRI is a valuable tool for predicting csPCa while avoiding unnecessary biopsy as much as possible.

Clinical outcomes of endoscopic versus laparoscopic resection for senile patients with gastric gastrointestinal stromal tumours (2 to 4 cm) originating from the muscularis propria layer.

Introduction: Currently, there still are no selection criteria for endoscopic resection (ER) versus laparoscopic resection (LR) of gastric gastrointestinal stromal tumours (GIST) (2 to 4 cm) originating from the muscularis propria layer (MP-GISTs). Aim: To investigate and compare the long-term prognosis of ER and LR for resecting gastric MP-GISTs, with at least 5 years of follow-up. Material and methods: Between January 2010 and December 2015, 134 patients with gastric MP-GISTs were consecutively enrolled in this study. The main comparison measurements included the short-term and long-term outcomes between the ER group (n = 89) and the LR group (n = 45). Results: In this study, there were no significant differences in the rates of complete resection (p = 0.220) and short-term complications (p = 0.663) between the ER group and the LR group. The ER group had a shorter operation time (50.1 ±18.2 min vs. 120.6 ±32.5 min, p < 0.001), shorter hospital stays (5.1 ±1.9 days vs. 6.4 ±3.7 days, p = 0.026), and lower hospitalization costs (16639.5 ±5091.3 CNY vs. 24030.4 ±6803.1 CNY, p < 0.001) than the LR group. The ER group had a lower rate of long-term complications than the LR group (p = 0.001) during the follow-up period (84.2 ±17.9 months vs. 89.0 ±16.8 months, p = 0.207). Conclusions: Our results showed that ER was a more feasible treatment approach than LR when the gastric MP-GIST was located in or near the cardia/pylorus. ER also had several other advantages over LR, such as a shorter procedure time, shorter hospital stay, and lower hospitalization costs.

Establishment and Application of a Quantitative PCR Method for E248R Gene of African Swine Fever Virus.

ASF has caused huge economic losses to China's swine industry. As clinical symptoms of ASF were difficult to distinguish from classical swine fever and porcine reproductive and respiratory syndrome (PRRS), rapid and effective differential diagnosis of ASFV seems very important to control the spread of the disease. In this study, the ASFV E248R gene was selected to be the target for establishing a real-time PCR method. TaqMan real-time PCR for the detection of ASFV E248R gene did not cross-react with other porcine viruses that could cause similar symptoms. The results of the repeatability test showed that the coefficients of variation between and within groups were lower than 1.977%. This method can be used for the rapid detection and early diagnosis of ASF. Meanwhile, the recombinant PRRS virus (PRRSV)-expressing E248R gene of ASFV was constructed and rescued by using the reverse genetic platform of live-attenuated PRRSV vaccine. The ASFV E248R gene can be detected by using this real-time PCR detection method, confirming that the ASFV E248R gene could be stably amplified in PRRSV genome at least 20 cell passages. The detection methods can be used for the efficient detection of the ASFV infection and recombinant PRRSV live vector virus-expressing ASFV antigen protein.

Observation of moiré excitons in the twisted WS2/WS2 homostructure.

Moiré superlattices offer a fascinating platform for designing the properties of optical excitons. The moiré pattern can generate an ordered exciton array in space, making it possible for topological excitons and quantum emitters. Recently, evidence of moiré excitons in the twisted heterostructures of TMDs has been widely reported. However, to date, the capture and investigation of moiré excitons in the twisted homostructure (T-HS) remain elusive. Here, we report the observation of moiré excitons in the WS2/WS2 T-HS with a twist angle of about 1.5°. The PL spectrum of the T-HS region shows many small peaks with nearly constant peak spacing, which is attributed to the reconstructed moiré potential generated by the reconstructed moiré pattern to confine the intralayer excitons, thereby forming an ordered moiré exciton array. Furthermore, we have studied the influence of temperature and laser power on the moiré excitons as well as the valley polarization of the moiré excitons. Our results provide a promising prospect for further exploration of artificial excitonic crystals and quantum emitters of TMD moiré patterns.