Clamping enables enhanced electromechanical responses in antiferroelectric thin films.

Thin-film materials with large electromechanical responses are fundamental enablers of next-generation micro-/nano-electromechanical applications. Conventional electromechanical materials (for example, ferroelectrics and relaxors), however, exhibit severely degraded responses when scaled down to submicrometre-thick films due to substrate constraints (clamping). This limitation is overcome, and substantial electromechanical responses in antiferroelectric thin films are achieved through an unconventional coupling of the field-induced antiferroelectric-to-ferroelectric phase transition and the substrate constraints. A detilting of the oxygen octahedra and lattice-volume expansion in all dimensions are observed commensurate with the phase transition using operando electron microscopy, such that the in-plane clamping further enhances the out-of-plane expansion, as rationalized using first-principles calculations. In turn, a non-traditional thickness scaling is realized wherein an electromechanical strain (1.7%) is produced from a model antiferroelectric PbZrO3 film that is just 100 nm thick. The high performance and understanding of the mechanism provide a promising pathway to develop high-performance micro-/nano-electromechanical systems.

Deterministic switching of a perpendicularly polarized magnet using unconventional spin-orbit torques in WTe2.

Spin-orbit torque (SOT)-driven deterministic control of the magnetic state of a ferromagnet with perpendicular magnetic anisotropy is key to next-generation spintronic applications including non-volatile, ultrafast and energy-efficient data-storage devices. However, field-free deterministic switching of perpendicular magnetization remains a challenge because it requires an out-of-plane antidamping torque, which is not allowed in conventional spin-source materials such as heavy metals and topological insulators due to the system's symmetry. The exploitation of low-crystal symmetries in emergent quantum materials offers a unique approach to achieve SOTs with unconventional forms. Here we report an experimental realization of field-free deterministic magnetic switching of a perpendicularly polarized van der Waals magnet employing an out-of-plane antidamping SOT generated in layered WTe2, a quantum material with a low-symmetry crystal structure. Our numerical simulations suggest that the out-of-plane antidamping torque in WTe2 is essential to explain the observed magnetization switching.

TH-302-loaded nanodrug reshapes the hypoxic tumour microenvironment and enhances PD-1 blockade efficacy in gastric cancer.

BACKGROUND: Hypoxia, a common characteristic of the tumour microenvironment, is involved in tumour progression and immune evasion. Targeting the hypoxic microenvironment has been implicated as a promising antitumour therapeutic strategy. TH-302 can be selectively activated under hypoxic conditions. However, the effectiveness of TH-302 in gastric cancer combined immunotherapy remains unclear. METHODS: We designed mPEG-PLGA-encapsulated TH-302 (TH-302 NPs) to target the hypoxic area of tumour tissues. A particle size analyzer was used to measure the average size and zeta potential of TH-302 NPs. The morphology was observed by transmission electron microscopy and scanning electron microscopy. The hypoxic area of tumour tissues was examined by immunofluorescence assays using pimonidazole. Flow cytometry analysis was performed to measure the levels of TNF-α, IFN-γ, and granzyme B. The synergistic antitumour activity of the combination of TH-302 NPs with anti-PD-1 (α-PD-1) therapy was assessed in vitro and in vivo. Haematoxylin and eosin staining of major organs and biochemical indicator detection were performed to investigate the biological safety of TH-302 NPs in vivo. RESULTS: TH-302 NPs inhibited the proliferation and promoted the apoptosis of gastric cancer cells under hypoxic conditions. In vitro and in vivo experiments confirmed that TH-302 NPs could effectively alleviate tumour hypoxia. TH-302 NPs exhibited high bioavailability, effective tumour-targeting ability and satisfactory biosafety. Moreover, the combination of TH-302 NPs with α-PD-1 significantly improved immunotherapeutic efficacy in vivo. Mechanistically, TH-302 NPs reduced the expression of HIF-1α and PD-L1, facilitated the infiltration of CD8+ T cells and increased the levels of TNF-α, IFN-γ, and granzyme B in tumours, thereby enhancing the efficacy of α-PD-1 therapy. CONCLUSION: TH-302 NPs alleviated the hypoxic tumour microenvironment and enhanced the efficacy of PD-1 blockade. Our results provide evidence that TH-302 NPs can be used as a safe and effective nanodrug for combined immunotherapy in gastric cancer treatment.

Synthesis, Magnetic Properties, and Electronic Structure of Magnetic Topological Insulator MnBi2Se4.

The intrinsic magnetic topological insulators MnBi2Te4 and MnBi2Se4 support novel topological states related to symmetry breaking by magnetic order. Unlike MnBi2Te4, the study of MnBi2Se4 has been inhibited by the lack of bulk crystals, as the van der Waals (vdW) crystal is not the thermodynamic equilibrium phase. Here, we report the layer-by-layer synthesis of vdW MnBi2Se4 crystals using nonequilibrium molecular beam epitaxy. Atomic-resolution scanning transmission electron microscopy and scanning tunneling microscopy identify a well-ordered vdW crystal with septuple-layer base units. The magnetic properties agree with the predicted layered antiferromagnetic ordering but disagree with its predicted out-of-plane orientation. Instead, our samples exhibit an easy-plane anisotropy, which is explained by including dipole-dipole interactions. Angle-resolved photoemission spectroscopy reveals the gapless Dirac-like surface state, which demonstrates that MnBi2Se4 is a topological insulator above the magnetic-ordering temperature. These studies show that MnBi2Se4 is a promising candidate for exploring rich topological phases of layered antiferromagnetic topological insulators.

Targeting JMJD3 histone demethylase mediates cardiac fibrosis and cardiac function following myocardial infarction.

Myocardial fibrosis is the pathological consequence of injury-induced fibroblastto-myofibroblast transition, resulting in increased stiffness and diminished cardiac function. Histone modification has been shown to play an important role in the pathogenesis of cardiac fibrosis. Here, we identified H3K27me3 demethylase JMJD3/KDM6B promotes cardiac fibrosis via regulation of fibrogenic pathways. Using neonatal rat cardiac fibroblasts (NRCF), we show that the expression of endogenous JMJD3 is induced by angiotensin II (Ang II), while the principle extracellular matrix (ECM) such as fibronectin, CTGF, collagen I and III are increased. We find that JMJD3 inhibition markedly enhances the suppressive mark (H3K27me3) at the beta (ß)-catenin promoter in activated cardiac fibroblasts, and then substantially decreases expression of fibrogenic gene. Both inhibition of ß-catenin-mediated transcription with ICG-001 and genetic loss of ß-catenin can prevent Ang II-induced ECM deposition. Most importantly, in vivo inhibition of JMJD3 rescues myocardial ischemia-induced cardiac fibrosis and cardiac dysfunction. Collectively, our findings are the first to report a novel role of histone demethylase JMJD3 in the pro-fibrotic cardiac fibroblast phenotype, pharmacological targeting of JMJD3 might represent a promising therapeutic approach for the treatment of human cardiac fibrosis and other fibrotic diseases.

Electrical Switching of Tristate Antiferromagnetic Néel Order in α-Fe_{2}O_{3} Epitaxial Films.

We demonstrate nondecaying, steplike electrical switching of tristate Néel order in Pt/α-Fe_{2}O_{3} bilayers detected by the spin-Hall induced anomalous Hall effect. The as-grown Pt/α-Fe_{2}O_{3} bilayers exhibit sawtooth switching behavior generated by current pulses. After annealing by a high pulse current, the Hall signals reveal single-pulse saturated, nondecaying, steplike switching. Together with control experiments, we show that the sawtooth switching is due to an artifact of Pt while the actual spin-orbit torque induced antiferromagnetic switching is steplike. Our Monte Carlo simulations explain the switching behavior of α-Fe_{2}O_{3} Néel order among three in-plane easy axes.

Interfacial Rashba-Effect-Induced Anisotropy in Nonmagnetic-Material-Ferrimagnetic-Insulator Bilayers.

Interfacial magnetic anisotropy in magnetic insulators has been largely unexplored. Recently, interface-induced skyrmions and electrical control of magnetization have been discovered in insulator-based heterostructures, which demand a thorough understanding of interfacial interactions in these materials. We observe a substantial, tunable interfacial magnetic anisotropy between Tm_{3}Fe_{5}O_{12} epitaxial thin films and fifteen nonmagnetic materials spanning a significant portion of the periodic table, which we attribute to Rashba spin-orbit coupling. Our results show a clear distinction between nonmagnetic capping layers from the d block and the p block. This work offers a new path for controlling magnetic phases in magnetic insulators for low-loss spintronic applications.

Substrate-Dependent Band Structures in Trilayer Graphene/h-BN Heterostructures.

The tight-binding model has been spectacularly successful in elucidating the electronic and optical properties of a vast number of materials. Within the tight-binding model, the hopping parameters that determine much of the band structure are often taken as constants. Here, using ABA-stacked trilayer graphene as the model system, we show that, contrary to conventional wisdom, the hopping parameters and therefore band structures are not constants, but are systematically variable depending on their relative alignment angle between h-BN. Moreover, the addition or removal of the h-BN substrate results in an inversion of the K and K^{'} valley in trilayer graphene's lowest Landau level. Our work illustrates the oft-ignored and rather surprising impact of the substrates on band structures of 2D materials.

Evidence of the Topological Hall Effect in Pt/Antiferromagnetic Insulator Bilayers.

The topological Hall effect has been a primary indicator of nontrivial spin textures in magnetic materials. We observe the evidence of the topological Hall effect in Pt/Cr_{2}O_{3} bilayers grown on Al_{2}O_{3}(0001) and Al_{2}O_{3}(112[over ¯]0), where the Cr_{2}O_{3} epitaxial film is an antiferromagnetic insulator. The Pt/Cr_{2}O_{3} bilayers exhibit topological Hall resistivity for Cr_{2}O_{3} thicknesses below 6 nm near and above room temperature, which is above the Néel temperature of Cr_{2}O_{3}, revealing the key role of thermal fluctuations in the formation of spin textures. The similarity of topological Hall signals in (0001)- and (112[over ¯]0)-oriented Cr_{2}O_{3} films indicates that the emergence of spin textures is insensitive to crystalline orientation.

Downregulation of S100A4 Alleviates Cardiac Fibrosis via Wnt/ß -Catenin Pathway in Mice.

BACKGROUND/AIMS: Cardiac fibrosis is a pathological change leading to cardiac remodeling during the progression of myocardial ischemic diseases, and its therapeutic strategy remains to be explored. S100A4, a calcium-binding protein, participates in fibrotic diseases with an unclear mechanism. This study aimed to investigate the role of S100A4 in cardiac fibrosis. METHODS: Cardiac fibroblasts from neonatal C57BL/6 mouse hearts were isolated and cultured. Myocardial infarction was induced by ligating the left anterior descending coronary artery (LAD). The ligation was not performed in the sham group. A volume of 5×105pfu/g adenovirus or 5 µM/g ICG-001 was intramyocardially injected into five parts bordering the infarction zone or normal region. We used Western blotting, quantitative RT-PCR, immunofluorescence, immunohistochemistry and Masson's trichrome staining to explore the function of S100A4. RESULTS: We found significant increases of S100A4 level and cardiac fibrosis markers, and ß-catenin signaling activation in vitro and in vivo. In addition, knockdown of S100A4 significantly reduced cardiac fibrosis and ß-catenin levels. Moreover, the expression of S100A4 decreased after ICG-001 inhibited ß-catenin signal pathway. CONCLUSION: Downregulation of S100A4 alleviates cardiac fibrosis via Wnt/ß -catenin pathway in mice. S100A4 may be a therapeutic target of cardiac fibrosis.

VSP-17, a New PPARγ Agonist, Suppresses the Metastasis of Triple-Negative Breast Cancer via Upregulating the Expression of E-Cadherin.

Triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer, shows higher metastases and relapse rates than other subtypes. The metastasis of TNBC is the main reason for the death of TNBC patients. Increasing evidence has shown that inhibiting the metastasis of TNBC is a good method for TNBC treatment. Here, VSP-17 was designed and synthesized as an agonist of PPARγ, evidenced by upregulating the expression of CD36 and increasing the activity of PPARγ reporter gene. VSP-17 obviously inhibited the migration and invasion process of MDA-MB-231 cells but showed little effect on the viability of MDA-MB-231 cells. Notably, VSP-17 could selectively promote the expression of E-cadherin without affecting the expression of BRMS1, CXCL12, MMP9, Orai1, Stim1, TGF-ß, and VEGF. In addition, VSP-17 significantly suppressed the metastasis of liver and promoted the expression of E-cadherin in MDA-MB-231 xenograft model. In conclusion, VSP-17 inhibited the metastasis process of TNBC via upregulating the expression of E-cadherin.

Hydrophobic TPU/CNTs-ILs Ionogel as a Reliable Multimode and Flexible Wearable Sensor for Motion Monitoring, Information Transfer, and Underwater Sensing.

Ionogel-based sensors have gained widespread attention in recent years due to their excellent flexibility, biocompatibility, and multifunctionality. However, the adaptation of ionogel-based sensors in extreme environments (such as humid, acidic, alkaline, and salt environments) has rarely been studied. Here, thermoplastic polyurethane/carbon nanotubes-ionic liquids (TPU/CNTs-ILs) ionogels with a complementary sandpaper morphology on the surface were prepared by a solution-casting method with a simple sandpaper as the template, and the hydrophobic flexible TPU/CNTs-ILs ionogel-based sensor was obtained by modification using nanoparticles modified with cetyltrimethoxysilane. The hydrophobicity improves the environmental resistance of the sensor. The ionogel-based sensor exhibits multimode sensing performance and can accurately detect response signals from strain (0-150%), pressure (0.1-1 kPa), and temperature (30-100 °C) stimuli. Most importantly, the hydrophobic TPU/CNTs-ILs ionogel-based sensors can be used not only as wearable strain sensors to monitor human motion signals but also for information transfer, writing recognition systems, and underwater activity monitoring. Thus, the hydrophobic TPU/CNTs-ILs ionogel-based sensor offers a new strategy for wearable electronics, especially for applications in extreme environments.

Hydrogen Sulfide and Functional Therapy: Novel Mechanisms from Epigenetics.

Hydrogen sulfide (H2S) is a gasotransmitter with significant physiological effects, including anti-inflammatory properties, regulation of oxidative stress, and vasodilation, thus regulating body functions. Functional therapy involves using treatments that target the underlying cause of a disease, rather than simply treating symptoms. Epigenetics refers to changes in gene expression that occur through modifications to DNA, to the proteins that package DNA, or to noncoding RNA mechanisms. Recent research advances suggest that H2S may play a role in epigenetic regulation by altering DNA methylation patterns and regulating histone deacetylases, enzymes that modify histone proteins, or modulating microRNA mechanisms. These critical findings suggest that H2S may be a promising molecule for functional therapy in various diseases where epigenetic modifications are dysregulated. We reviewed the relevant research progress in this area, hoping to provide new insights into the epigenetic mechanisms of H2S. Despite the challenges of clinical use of H2S, future research may lead to the progress of new therapeutic approaches. Antioxid. Redox Signal. 40, 110-121.

H2S donor S-propargyl-cysteine for skin wound healing improvement via smart transdermal delivery.

Hydrogen sulfide for wound healing has drawn a lot of attention recently. In this research, the S-propargyl-cysteine (SPRC), an endogenous H2S donor, was loaded on carbomer hydrogel, and a copper sheet rat burn model was developed. Pathological changes in rat skin tissue were examined using hematoxylin-eosin (HE) and Masson staining. The immunohistochemistry (IHC) staining was performed to detect the expression of Collagen I (Col I) and Collagen III (Col III). The mRNA levels of interleukin (IL)-6, Col Iα2, Col IIIα1, tissue inhibitors of metalloproteinase (TIMP)-1, matrix metalloproteinase (MMP)-9, vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)-ß1 were examined by quantitative real-time chain polymerase reaction. The findings demonstrated that the collagen layer was thicker in the SPRC group during the proliferative phase, SPRC hydrogel promoted VEGF expression. In the late stage of wound healing, the expression of IL-6, TIMP-1, MMP-9, and TGF-ß1 was inhibited, and the Col I content was closer to that of normal tissue. These results surface that SPRC hydrogel can promote wound healing and play a positive role in reducing scar formation. Our results imply that SPRC can facilitate wound healing and play a positive role in reducing scar formation.

The 'Other' subfamily of HECT E3 ubiquitin ligases evaluate the tumour immune microenvironment and prognosis in patients with hepatocellular carcinoma.

Primary liver cancer is the sixth most common cancer and the third leading cause of cancer-related death worldwide. The role of the 'Other' subfamily of HECT E3 ligases (E3s) in hepatocellular carcinoma (HCC) remains unknown. The expression of the 'Other' HECT E3s was performed using The Cancer Genome Atlas (TCGA) data, and the authors found that the 'Other' HECT E3s were differentially expressed in HCC. Prognostic values were assessed using the Kaplan-Meier method and indicated that the high expressions of HECTD2, HECTD3, and HACE1 were associated with a worse clinical prognosis of HCC patients. The expression of HECTD2 was significantly correlated with the infiltration of CD4+ T cells and neutrophils. The levels of HECTD3 and HACE1 were notably related to the dendritic cells and memory B cells infiltrated in HCC. In addition, the three previously mentioned genes have shown to be associated with immune checkpoint genes, such as FOXP3, CCR8, STAT5B, TGFB1 and TIM-3. Moreover, HECTD2 could promote the proliferative activity, cell migration and invasive ability of HCC cells. Collectively, the authors' study demonstrated that HECTD2 was a novel immune-related prognostic biomarker for HCC, providing new insight into the treatment and prognosis of HCC.

Structural degeneracy and formation of crystallographic domains in epitaxial LaFeO3 films revealed by machine-learning assisted 4D-STEM.

Structural domains and domain walls, inherent in single crystalline perovskite oxides, can significantly influence the properties of the material and therefore must be considered as a vital part of the design of the epitaxial oxide thin films. We employ 4D-STEM combined with machine learning (ML) to comprehensively characterize domain structures at both high spatial resolution and over a significant spatial extent. Using orthorhombic LaFeO3 as a model system, we explore the application of unsupervised and supervised ML in domain mapping, which demonstrates robustness against experiment uncertainties. The results reveal the consequential formation of multiple domains due to the structural degeneracy when LaFeO3 film is grown on cubic SrTiO3. In situ annealing of the film shows the mechanism of domain coarsening that potentially links to phase transition of LaFeO3 at high temperatures. Moreover, synthesis of LaFeO3 on DyScO3 illustrates that a less symmetric orthorhombic substrate inhibits the formation of domain walls, thereby contributing to the mitigation of structural degeneracy. High fidelity of our approach also highlights the potential for the domain mapping of other complicated materials and thin films.

The cuproptosis-related gene UBE2D2 functions as an immunotherapeutic and prognostic biomarker in pan-cancer.

BACKGROUND: Cuproptosis, as a unique modality of regulated cell death, requires the involvement of ubiquitin-binding enzyme UBE2D2. However, the prognostic and immunotherapeutic values of UBE2D2 in pan-cancer remain largely unknown. METHODS: Using UCSC Xena, TIMER, Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) databases, we aimed to explore the differential expression pattern of UBE2D2 across multiple cancer types and to evaluate its association with patient prognosis, clinical features, and genetic variations. The association between UBE2D2 and immunotherapy response was assessed by gene set enrichment analysis, tumor microenvironment, immune gene co-expression and drug half maximal inhibitory concentration (IC50) analysis. RESULTS: The mRNA and protein levels of UBE2D2 were markedly elevated in most cancer types, and UBE2D2 exhibited prognostic significance in liver hepatocellular carcinoma (LIHC), kidney chromophobe (KICH), uveal melanomas (UVM), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and kidney renal papillary cell carcinoma (KIRP). UBE2D2 expression was correlated with clinical features, tumor mutation burden, microsatellite instability, and anti-tumor drug resistance in several tumor types. Gene enrichment analysis showed that UBE2D2 was significantly associated with immune-related pathways. The expression level of UBE2D2 was correlated with immune cell infiltration, including CD4 + T cells、Macrophages M2、CD8 + T cells in pan-cancer. PDCD1, CD274 and CTLA4 expression levels were positively correlated with UBE2D2 level in multiple cancers. CONCLUSIONS: We comprehensively investigated the potential value of UBE2D2 as a prognostic and immunotherapeutic predictor for pan-cancer, providing a novel insight for cancer immunotherapy.

New Targets and Strategies for Rheumatoid Arthritis: From Signal Transduction to Epigenetic Aspect.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that can lead to joint damage and even permanent disability, seriously affecting patients' quality of life. At present, the complete cure for RA is not achievable, only to relieve the symptoms to reduce the pain of patients. Factors such as environment, genes, and sex can induce RA. Presently, non-steroidal anti-inflammatory drugs, DRMADs, and glucocorticoids are commonly used in treating RA. In recent years, some biological agents have also been applied in clinical practice, but most have side effects. Therefore, finding new mechanisms and targets for treating RA is necessary. This review summarizes some potential targets discovered from the perspective of epigenetics and RA mechanisms.

Signaling pathways in rheumatoid arthritis: implications for targeted therapy.

Rheumatoid arthritis (RA) is an incurable systemic autoimmune disease. Disease progression leads to joint deformity and associated loss of function, which significantly impacts the quality of life for sufferers and adds to losses in the labor force. In the past few decades, RA has attracted increased attention from researchers, the abnormal signaling pathways in RA are a very important research field in the diagnosis and treatment of RA, which provides important evidence for understanding this complex disease and developing novel RA-linked intervention targets. The current review intends to provide a comprehensive overview of RA, including a general introduction to the disease, historical events, epidemiology, risk factors, and pathological process, highlight the primary research progress of the disease and various signaling pathways and molecular mechanisms, including genetic factors, epigenetic factors, summarize the most recent developments in identifying novel signaling pathways in RA and new inhibitors for treating RA. therapeutic interventions including approved drugs, clinical drugs, pre-clinical drugs, and cutting-edge therapeutic technologies. These developments will hopefully drive progress in new strategically targeted therapies and hope to provide novel ideas for RA treatment options in the future.