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Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that bone-borne TGF-β induces the acetylation of transcription factor KLF5 in PCa bone metastases, and acetylated KLF5 (Ac-KLF5) causes osteoclastogenesis and bone metastatic lesions by activating CXCR4, which leads to IL-11 secretion, and stimulating SHH/IL-6 paracrine signaling. While essential for maintaining the mesenchymal phenotype and tumorigenicity, Ac-KLF5 also causes resistance to docetaxel in tumors and bone metastases, which is overcome by targeting CXCR4 with FDA-approved plerixafor. Establishing a mechanism for bone metastasis and chemoresistance in PCa, these findings provide a rationale for treating chemoresistant bone metastasis of PCa with inhibitors of Ac-KLF5/CXCR4 signaling. The therapies for bone metastatic prostate cancer are limited and the underlying mechanisms are unclear. Here, the authors show that bone derived TGF-β induces acetylation of KLF5 (Ac-KLF5), and Ac-KLF5 promotes prostate cancer bone metastasis and resistance to docetaxel by upregulating CXCR4.

Two-dimensional (2D) materials have been identified as promising candidates for future electronic devices. However, high dielectric constant (κ) materials, which can be integrated with 2D semiconductors, are still rare. Here, we report a hydrate-assisted thinning chemical vapor deposition (CVD) technique to grow manganese oxide (Mn 3 O 4 ) single crystal nanosheets, enabled by a strategy to minimize the substrate lattice mismatch and control the growth kinetics. The material demonstrated a dielectric constant up to 135, an equivalent oxide thickness (EOT) as low as 0.8 nm, and a breakdown field strength ( E bd ) exceeding 10 MV/cm. MoS 2 field-effect transistors (FETs) integrated with Mn 3 O 4 thin films through mechanical stacking method operate under low voltages (<1 V), achieving a near 10 8 I on /I off ratio and a subthreshold swing (SS) as low as 84 mV/dec. The MoS 2 FET exhibit nearly zero hysteresis (<2 mV/MV cm⁻¹) and a low drain-induced barrier lowering (~20 mV/V). This work further expands the family of 2D high- κ dielectric materials and provides a feasible exploration for the epitaxial growth of single-crystal thin films of non-layered materials. High dielectric constant (κ) materials compatible with van der Waals materials are desired to promote the development of 2D electronics. Here, the authors report a method to grow Mn 3 O 4 nanosheets exhibiting κ up to 135 and equivalent oxide thickness down to 0.8 nm, enabling the fabrication of high-performance 2D MoS 2 transistors.

To reduce traffic congestion and meet the demand for rail transportation, the diameters of shield tunnels are constantly expanded. The super-large diameter, deep depth and long distance of super-large-diameter shield tunnels, coupled with the limitation of existing structures on underground construction space, cause many problems in the construction of these tunnels, such as affecting existing structures. This study takes a shield project in Wuhan as the research object, uses the finite element method to simulate the influence of super-large-diameter shield tunnelling on the displacement of the existing Line 5 tunnel segments, and analyzes the influence of the isolation pile arrangement and length on the isolation effect. The analysis indicates that (1) the displacement of Line 5 decreases with an increasing horizontal center distance between the tunnels and increases with an increasing vertical center distance between the tunnels, with a maximum displacement of 17.9 mm; (2) the displacement direction and position of the maximum displacement of Line 5 vary with changes in the vertical center distance between the tunnels, but remain essentially constant with changes in the horizontal center distance; and (3) the isolation piles closer to the shield tunnel improve support, with its isolation effect on the Line 5 segment becoming limited.

Salt stress, as a principal abiotic stress, harms the growth and metabolism of rice, thus affecting its yield and quality. The tillering stage is the key growth period that controls rice yield. Prohexadione-calcium (Pro-Ca) can increase the lodging resistance of plants by reducing plant height, but its effects on rice leaves and roots at the tillering stage under salt stress are still unclear. This study aimed to evaluate the ability of foliar spraying of Pro-Ca to regulate growth quality at the rice tillering stage under salt stress. The results showed that salt stress reduced the tillering ability of the rice and the antioxidant enzyme activity in the roots. Salt stress also reduced the net photosynthetic rate (Pn), stomatal conductance (Gs) and intercellular CO 2 concentration (Ci) of the rice leaves and increased the contents of osmotic regulatory substances in the leaves and roots. The application of exogenous Pro-Ca onto the leaves increased the tiller number of the rice under salt stress and significantly increased the photosynthetic capacity of the leaves. Additionally, it increased the activities of antioxidant enzymes and the AsA content. The contents of an osmotic regulation substance, malondialdehyde (MDA), and H 2 O 2 in the leaves and roots also decreased. These results suggested that Pro-Ca can increase the tillering ability, photosynthetic capacity, osmotic adjustment substance content levels and antioxidant enzyme activity levels in rice and reduce membrane lipid peroxidation, thus improving the salt tolerance of rice at the tillering stage.

Accurate crop mapping can represent the fundamental data for digital agriculture and ecological security. However, current crop classification methods perform poorly in mountainous areas with small cropland field parcel areas and multiple crops under cultivation. This study proposed a new object-oriented classification method to address this issue, using multi-source data and object features to achieve multi-crop classification in mountainous areas. Firstly, a deep learning method was employed to extract cropland field parcels in mountainous areas. Subsequently, the fusion of multi-source data was carried out based on cropland field parcels, while object features tailored for mountainous crops were designed for crop classification. Comparative analysis indicates that the proposed classification method demonstrates exceptional performance, enabling accurate mapping of various crops in mountainous regions. The F1 score and overall accuracy (OA) of the proposed method are 0.8449 and 0.8502, representing a 10% improvement over the pixel-based random forest classification results. Furthermore, qualitative analysis reveals that the proposed method exhibits higher classification accuracy for smaller plots and more precise delineation of crop boundaries. Finally, meticulous crop mapping of corn, sorghum, rice, and other crops in Xishui County, Guizhou Province, demonstrates the significant potential of the proposed method in crop classification within mountainous scenarios.

PTEN inactivation is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer associated fibroblasts (CAFs) play a pivotal role in tumor progression, but it remains elusive whether and how PTEN-deficient prostate cancers reprogram CAFs to overcome the barriers for tumor progression. Herein, we report that PTEN deficiency induces KLF5 acetylation; and interruption of KLF5 acetylation orchestrates intricate interactions between cancer cells and CAFs that enhance FGFR1 signaling and promote tumor growth. Deacetylated KLF5 promotes tumor cells to secrete TNF-α, which stimulates inflammatory CAFs to release FGF9. CX3CR1 inhibition blocks FGFR1 activation triggered by FGF9 and sensitizes PTEN-deficient prostate cancer to AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rational for combined therapies using inhibitors of AKT and CX3CR1.

Background Coronary microvascular dysfunction (CMD) is a leading cause of ischemic heart disease. Over the past few decades, considerable progress has been made with respect to research on CMD. The present study summarized the current research hotspots and trends on CMD by applying a bibliometric approach. Methods Relevant publications between 2002 and 2022 were extracted from the Web of Science Core Collection. Visualization network maps of countries, institutions, authors, and co-cited authors were built using VOSviewer. CiteSpace was used for keyword analysis and the construction of a dual-map overlay of journals and a timeline view of co-cited references. Results 1539 CMD-related publications were extracted for bibliometric analysis. The annual publications generally showed an upward trend. The United States of America was the most prolific country, with 515 publications (33.5%). Camici P. G. was the most influential author, whereas the European Heart Journal , Circulation , and Journal of the American College of Cardiology were the most authoritative journals. Research hotspot analysis revealed that endothelial dysfunction as well as reduced nitric oxide production or bioavailability played critical roles in CMD development. Positron emission tomography was the most widely used imaging method for diagnosis. In addition, microvascular angina, hypertrophic cardiomyopathy, and heart failure have attracted much attention as the main clinical implications. Furthermore, international standards for CMD diagnosis and management may be the future research directions. Conclusions This study offers a comprehensive view about the hotspots and development trends of CMD, which can assist subsequent researchers and guide future directions.

Background Nanoscale drug delivery systems have emerged as broadly applicable approach for chemo-photothermal therapy. However, these nanoscale drug delivery systems suffer from carrier-induced toxicity, uncontrolled drug release and low drug carrying capacity issues. Thus, to develop carrier-free nanoparticles self-assembled from amphiphilic drug molecules, containing photothermal agent and anticancer drug, are very attractive. Results In this study, we conjugated camptothecin (CPT) with a photothermal agent new indocyanine green (IR820) via a redox-responsive disulfide linker. The resulting amphiphilic drug–drug conjugate (IR820-SS-CPT) can self-assemble into nanoparticles (IR820-SS-CPT NPs) in aqueous solution, thus remarkably improving the membrane permeability of IR820 and the aqueous solubility of CPT. The disulfide bond in the IR820-SS-CPT NPs could be cleaved in GSH rich tumor microenvironment, leading to the on demand release of the conjugated drug. Importantly, the IR820-SS-CPT NPs displayed an extremely high therapeutic agent loading efficiency (approaching 100%). Besides, in vitro experimental results indicated that IR820-SS-CPT NPs displayed remarkable tumor cell killing efficiency. Especially, the IR820-SS-CPT NPs exhibited excellent anti-tumor effects in vivo. Both in vitro and in vivo experiments were conducted, which have indicated that the design of IR820-SS-CPT NPs can provide an efficient nanotherapeutics for chemo-photothermal therapy. Conclusion A novel activatable amphiphilic small molecular prodrug IR820-SS-CPT has been developed in this study, which integrated multiple advantages of GSH-triggered drug release, high therapeutic agent content, and combined chemo-photothermal therapy into one drug delivery system. Graphical Abstract

Alogliptin is a commonly prescribed drug treating patients with type 2 diabetes. Here, we show that long‐term intervention with alogliptin (0.03% w/w in diet) improves survival and health of mice on a high‐fat diet. Alogliptin intervention takes beneficial effects associated with longevity, including increased insulin sensitivity, attenuated functionality decline, decreased organ pathology, preserved mitochondrial function, and reduced oxidative stress. Autophagy activation is proposed as an underlying mechanism of these beneficial effects. We conclude that alogliptin intervention could be considered as a potential strategy for extending lifespan and healthspan in obesity and overweight.

Some small cell lung cancers (SCLCs) are highly sensitive to inhibitors of the histone demethylase LSD1. LSD1 inhibitors are thought to induce their anti-proliferative effects by blocking neuroendocrine differentiation, but the mechanisms by which LSD1 controls the SCLC neuroendocrine phenotype are not well understood. To identify genes required for LSD1 inhibitor sensitivity in SCLC, we performed a positive selection genome-wide CRISPR/Cas9 loss of function screen and found that ZFP36L1 , an mRNA-binding protein that destabilizes mRNAs, is required for LSD1 inhibitor sensitivity. LSD1 binds and represses ZFP36L1 and upon LSD1 inhibition, ZFP36L1 expression is restored, which is sufficient to block the SCLC neuroendocrine differentiation phenotype and induce a non-neuroendocrine “inflammatory” phenotype. Mechanistically, ZFP36L1 binds and destabilizes SOX2 and INSM1 mRNAs, two transcription factors that are required for SCLC neuroendocrine differentiation. This work identifies ZFP36L1 as an LSD1 target gene that controls the SCLC neuroendocrine phenotype and demonstrates that modulating mRNA stability of lineage transcription factors controls neuroendocrine to non-neuroendocrine plasticity. LSD1 inhibition blocks the neuroendocrine phenotype of some small cell lung cancers (SCLCs). Here, a genome-wide CRISPR/Cas9 LSD1 inhibitor resistance screen identifies the mRNA-binding protein ZFP36L1 as a gene repressed by LSD1 that when restored inhibits SCLC neuroendocrine differentiation.