circNEIL3 inhibits tumor metastasis through recruiting the E3 ubiquitin ligase Nedd4L to degrade YBX1.

Distant metastasis is a major contributor to cancer-related mortality. However, the role of circRNAs in this process remains unclear. Herein, we profiled the circRNA expression in a cohort of 68 colorectal carcinoma (CRC) primary tumors and their paired liver metastatic lesions. By overlapping with the TGFß-responsive circRNAs, circNEIL3 (hsa_circ_0001460) was identified as a TGFß-repressive and metastasis-related circRNA. Functionally, circNEIL3 effectively inhibited tumor metastasis in both and in vivo and in vivo models of various cancer types. Mechanistically, circNEIL3 exerts its metastasis-repressive function through its direct interaction with oncogenic protein, Y-box-binding protein 1 (YBX1), which consequently promotes the Nedd4L-mediated proteasomal degradation of YBX1. Importantly, circNEIL3 expression was negatively correlated to YBX1 protein level and metastatic tendency in CRC patient samples. Collectively, our findings indicate the YBX1-dependent antimetastatic function of circNEIL3 and highlight the potential of circNEIL3 as a biomarker and therapeutic option in cancer treatment.

Narrowing Signal Distribution by Adamantane Derivatization for Amino Acid Identification Using an α-Hemolysin Nanopore.

The rapid progress in nanopore sensing has sparked interest in protein sequencing. Despite recent notable advancements in amino acid recognition using nanopores, chemical modifications usually employed in this process still need further refinements. One of the challenges is to enhance the chemical specificity to avoid downstream misidentification of amino acids. By employing adamantane to label proteinogenic amino acids, we developed an approach to fingerprint individual amino acids using the wild-type α-hemolysin nanopore. The unique structure of adamantane-labeled amino acids (ALAAs) improved the spatial resolution, resulting in distinctive current signals. Various nanopore parameters were explored using a machine-learning algorithm and achieved a validation accuracy of 81.3% for distinguishing nine selected amino acids. Our results not only advance the effort in single-molecule protein characterization using nanopores but also offer a potential platform for studying intrinsic and variant structures of individual molecules.

Macrophage KLF15 prevents foam cell formation and atherosclerosis via transcriptional suppression of OLR-1.

BACKGROUND: Macrophage-derived foam cells are a hallmark of atherosclerosis. Scavenger receptors, including lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (OLR-1), are the principal receptors responsible for the uptake and modification of LDL, facilitating macrophage lipid load and the uptake of oxidized LDL by arterial wall cells. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates the expression of genes by binding to the promoter during transcription. Therefore, this study aimed to investigate the precise role of macrophage KLF15 in atherogenesis. METHODS: We used two murine models of atherosclerosis: mice injected with an adeno-associated virus (AAV) encoding the Asp374-to-Tyr mutant version of human PCSK9, followed by 12 weeks on a high-fat diet (HFD), and ApoE-/-- mice on a HFD. We subsequently injected mice with AAV-KLF15 and AAV-LacZ to assess the role of KLF15 in the development of atherosclerosis in vivo. Oil Red O, H&E, and Masson's trichome staining were used to evaluate atherosclerotic lesions. Western blots and RT-qPCR were used to assess protein and mRNA levels, respectively. RESULTS: We determined that KLF15 expression was downregulated during atherosclerosis formation, and KLF15 overexpression prevented atherosclerosis progression. KLF15 expression levels did not affect body weight or serum lipid levels in mice. However, KLF15 overexpression in macrophages prevented foam cell formation by reducing OLR-1-meditated lipid uptake. KLF15 directly targeted and transcriptionally downregulated OLR-1 levels. Restoration of OLR-1 reversed the beneficial effects of KLF15 in atherosclerosis. CONCLUSION: Macrophage KLF15 transcriptionally downregulated OLR-1 expression to reduce lipid uptake, thereby preventing foam cell formation and atherosclerosis. Thus, our results suggest that KLF15 is a potential therapeutic target for atherosclerosis.

Reduction of Cofed Carbon Dioxide Modifies the Local Coordination Environment of Zeolite-Supported, Atomically Dispersed Chromium to Promote Ethane Dehydrogenation.

The reduction of CO2 is known to promote increased alkene yields from alkane dehydrogenations when the reactions are cocatalyzed. The mechanism of this promotion is not understood in the context of catalyst active-site environments because CO2 is amphoteric, and even general aspects of the chemistry, including the significance of competing side reactions, differ significantly across catalysts. Atomically dispersed chromium cations stabilized in highly siliceous MFI zeolite are shown here to enable the study of the role of parallel CO2 reduction during ethylene-selective ethane dehydrogenation. Based on infrared spectroscopy and X-ray absorption spectroscopy data interpreted through calculations using density functional theory (DFT), the synthesized catalyst contains atomically dispersed Cr cations stabilized by silanol nests in micropores. Reactor studies show that cofeeding CO2 increases stable ethylene-selective ethane dehydrogenation rates over a wide range of partial pressures. Operando X-ray absorption near-edge structure (XANES) and extended X-ray absorption fine-structure (EXAFS) spectra indicate that during reaction at 650 °C the Cr cations maintain a nominal 2+ charge and a total Cr-O coordination number of approximately 2. However, CO2 reduction induces a change, correlated with the CO2 partial pressure, in the population of two distinct Cr-O scattering paths. This indicates that the promotional effect of parallel CO2 reduction can be attributed to a subtle change in Cr-O bond lengths in the local coordination environment of the active site. These insights are made possible by simultaneously fitting multiple EXAFS spectra recorded in different reaction conditions; this novel procedure is expected to be generally applicable for interpreting operando catalysis EXAFS data.

Nuclear miR-204-3p mitigates metabolic dysfunction-associated steatotic liver disease in mice.

BACKGROUND & AIMS: Accumulating evidence has indicated the presence of mature microRNAs (miR) in the nucleus, but their effects on steatohepatitis remain elusive. We have previously demonstrated that the intranuclear miR-204-3p in macrophages protects against atherosclerosis, which shares multiple risk factors with metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we aimed to explore the functional significance of miR-204-3p in steatohepatitis. METHODS: miR-204-3p levels and subcellular localization were assessed in the livers and peripheral blood mononuclear cells of patients with MASLD. Wild-type mice fed high-fat or methionine- and choline-deficient diets were injected with an adeno-associated virus system containing miR-204-3p to determine the effect of miR-204-3p on steatohepatitis. Co-culture systems were applied to investigate the crosstalk between macrophages and hepatocytes or hepatic stellate cells (HSCs). Multiple high-throughput epigenomic sequencings were performed to explore miR-204-3p targets. RESULTS: miR-204-3p expression decreased in livers and macrophages in mice and patients with fatty liver. In patients with MASLD, miR-204-3p levels in peripheral blood mononuclear cells were inversely related to the severity of hepatic inflammation and damage. Macrophage-specific miR-204-3p overexpression reduced steatohepatitis in high-fat or methionine- and choline-deficient diet-fed mice. miR-204-3p-overexpressing macrophages inhibited TLR4/JNK signaling and pro-inflammatory cytokine release, thereby limiting fat deposition and inflammation in hepatocytes and fibrogenic activation in HSCs. Epigenomic profiling identified miR-204-3p as a specific regulator of ULK1 expression. ULK1 transcription and VPS34 complex activation by intranuclear miR-204-3p improved autophagic flux, promoting the anti-inflammatory effects of miR-204-3p in macrophages. CONCLUSIONS: miR-204-3p inhibits macrophage inflammation, coordinating macrophage actions on hepatocytes and HSCs to ameliorate steatohepatitis. Macrophage miR-204-3p may be a therapeutic target for MASLD. IMPACT AND IMPLICATIONS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic inflammatory disease ranging from simple steatosis to steatohepatitis. However, the molecular mechanisms underlying the progression of MASLD remain incompletely understood. Here, we demonstrate that miR-204-3p levels in circulating peripheral blood mononuclear cells are negatively correlated with disease severity in patients with MASLD. Nuclear miR-204-3p activates ULK1 transcription and improves autophagic flux, limiting macrophage activation and hepatic steatosis. Our study provides a novel understanding of the mechanism of macrophage autophagy and inflammation in steatohepatitis and suggests that miR-204-3p may act as a potential therapeutic target for MASLD.

Nanozyme-Enhanced Electrochemical Biosensors: Mechanisms and Applications.

Nanozymes, as innovative materials, have demonstrated remarkable potential in the field of electrochemical biosensors. This article provides an overview of the mechanisms and extensive practical applications of nanozymes in electrochemical biosensors. First, the definition and characteristics of nanozymes are introduced, emphasizing their significant role in constructing efficient sensors. Subsequently, several common categories of nanozyme materials are delved into, including metal-based, carbon-based, metal-organic framework, and layered double hydroxide nanostructures, discussing their applications in electrochemical biosensors. Regarding their mechanisms, two key roles of nanozymes are particularly focused in electrochemical biosensors: selective enhancement and signal amplification, which crucially support the enhancement of sensor performance. In terms of practical applications, the widespread use of nanozyme-based electrochemical biosensors are showcased in various domains. From detecting biomolecules, pollutants, nucleic acids, proteins, to cells, providing robust means for high-sensitivity detection. Furthermore, insights into the future development of nanozyme-based electrochemical biosensors is provided, encompassing improvements and optimizations of nanozyme materials, innovative sensor design and integration, and the expansion of application fields through interdisciplinary collaboration. In conclusion, this article systematically presents the mechanisms and applications of nanozymes in electrochemical biosensors, offering valuable references and prospects for research and development in this field.

Assessing the effects of climate and human activity on vegetation change in Northern China.

Fractional vegetation cover (FVC) has changed significantly under various disturbances over northern China in recent decades. This research examines the dynamics of FVC and how it is affected by climate and human activity during the period of 1990-2018 in northern China. The effects of climate change (i.e., temperature, precipitation, solar radiation, and soil moisture) and human activity (socioeconomic data and land use) on vegetation coverage change in northern China from 1990 to 2018 were quantified using the Sen + Mann-Kendall test, partial correlation analysis, and structural equation modelling (SEM) methods. The findings of this research indicate the following: (1) From 1990 to 2018, the overall trend in FVC in northern China was increased. The areas with obvious increases were mainly situated on the northern slope of Tianshan Mountains, Xinjiang, the Loess Plateau, the Northeast China Plain, and the Sanjiang Plain, while the areas with distinct degradation were located in the Inner Mongolia Plateau, the Changbai Mountain and the eastern part of north China. (2) In the past 29 years, the FVC in northern China has been mainly affected by precipitation and soil moisture. (3) Based on structural equation modelling, we discovered that certain variables impacted the main factors influencing the amount of FVC in northern China. Human activity has had a larger impact on FVC than climate change. Our findings can accelerate the comprehension of vegetation dynamics and their underlying mechanisms and provide a theoretical basis for regional ecological environmental protection.

Ferroptosis: a potential target for the treatment of atherosclerosis.

Atherosclerosis (AS), the main contributor to acute cardiovascular events, such as myocardial infarction and ischemic stroke, is characterized by necrotic core formation and plaque instability induced by cell death. The mechanisms of cell death in AS have recently been identified and elucidated. Ferroptosis, a novel iron-dependent form of cell death, has been proven to participate in atherosclerotic progression by increasing endothelial reactive oxygen species (ROS) levels and lipid peroxidation. Furthermore, accumulated intracellular iron activates various signaling pathways or risk factors for AS, such as abnormal lipid metabolism, oxidative stress, and inflammation, which can eventually lead to the disordered function of macrophages, vascular smooth muscle cells, and vascular endothelial cells. However, the molecular pathways through which ferroptosis affects AS development and progression are not entirely understood. This review systematically summarizes the interactions between AS and ferroptosis and provides a feasible approach for inhibiting AS progression from the perspective of ferroptosis.

Synergistic Enhancement of Photocatalytic CO2 Reduction by Built-in Electric Field/Piezoelectric Effect and Surface Plasmon Resonance via PVDF/CdS/Ag Heterostructure.

Photocatalytic reduction of CO2 using solar energy is an effective means to achieve carbon neutrality. However, the photocatalytic efficiency still requires improvements. In this study, polyvinylidene fluoride (PVDF) ferroelectric/piezoelectric nanofiber membranes are prepared by electrospinning. Cadmium sulfide (CdS) nanosheets are assembled in situ on the surface of PVDF based on coordination between F- and Cd2+ , and then Ag nanoparticles are deposited on CdS. Because of the synergistic effect between localized surface plasmon resonance of Ag nanoparticles and the built-in electric field of PVDF, the CO2 photocatalytic reduction efficiency using PVDF/CdS/Ag under visible light irradiation is significantly higher than that of any combination of CdS, CdS/Ag, or PVDF/CdS. Under micro-vibration to simulate air flow, the CO2 reduction efficiency of PVDF/CdS/Ag is three times higher than that under static conditions, reaching 240.4 µmol g-1 h-1 . The piezoelectric effect caused by micro-vibrations helps prevent the built-in electric field from becoming saturated with carriers and provides a continuous driving force for carrier separation.

Image distortion by ambiguous multiple-photon detections in a superconducting nanowire single-photon imager and the correction method.

Scaling up superconducting nanowire single-photon detectors (SNSPDs) into a large array for imaging applications is the current pursuit. Although various readout architectures have been proposed, they cannot resolve multiple-photon detections (MPDs) currently, which limits the operation of the SNSPD arrays at high photon flux. In this study, we focused on the readout ambiguity of a superconducting nanowire single-photon imager applying time-of-flight multiplexing readout. The results showed that image distortion depended on both the incident photon flux and the imaging object. By extracting multiple-photon detections on idle pixels, which were virtual because of the incorrect mapping from the ambiguous readout, a correction method was proposed. An improvement factor of 1.3~9.3 at a photon flux of µ = 5 photon/pulse was obtained, which indicated that joint development of the pixel design and restoration algorithm could compensate for the readout ambiguity and increase the dynamic range.

RANKL from bone marrow adipose lineage cells promotes osteoclast formation and bone loss.

Receptor activator of NF-κB ligand (RANKL) is essential for osteoclast formation and bone remodeling. Nevertheless, the cellular source of RANKL for osteoclastogenesis has not been fully uncovered. Different from peripheral adipose tissue, bone marrow (BM) adipose lineage cells originate from bone marrow mesenchymal stromal cells (BMSCs). Here, we demonstrate that adiponectin promoter-driven Cre expression (AdipoqCre ) can target bone marrow adipose lineage cells. We cross the AdipoqCre mice with ranklfl/fl mice to conditionally delete RANKL from BM adipose lineage cells. Conditional deletion of RANKL increases cancellous bone mass of long bones in mice by reducing the formation of trabecular osteoclasts and inhibiting bone resorption but does not affect cortical bone thickness or resorption of calcified cartilage. AdipoqCre ; ranklfl/fl mice exhibit resistance to estrogen deficiency and rosiglitazone (ROS)-induced trabecular bone loss but show bone loss induced by unloading. BM adipose lineage cells therefore represent an essential source of RANKL for the formation of trabecula osteoclasts and resorption of cancellous bone during remodeling under physiological and pathological conditions. Targeting bone marrow adiposity is a promising way of preventing pathological bone loss.

Transaldolase inhibits CD36 expression by modulating glutathione-p38 signaling, exerting protective effects against macrophage foam cell formation.

In atherosclerosis, macrophage-derived foam cell formation is considered to be a hallmark of the pathological process; this occurs via the uptake of modified lipoproteins. In the present study, we aim to determine the role of transaldolase in foam cell formation and atherogenesis and reveal the mechanisms underlying its role. Bone marrow-derived macrophages (BMDMs) isolated from mice successfully form foam cells after treatment with oxidized low-density lipoprotein (80 µg/mL). Elevated transaldolase levels in the foam cell model are assessed by quantitative polymerase chain reaction and western blot analysis. Transaldolase overexpression and knockdown in BMDMs are achieved via plasmid transfection and small interfering RNA technology, respectively. We find that transaldolase overexpression effectively attenuates, whereas transaldolase knockdown accelerates, macrophage-derived foam cell formation through the inhibition or activation of cholesterol uptake mediated by the scavenger receptor cluster of differentiation 36 (CD36) in a p38 mitogen-activated protein kinase (MAPK) signaling-dependent manner. Transaldolase-mediated glutathione (GSH) homeostasis is identified as the upstream regulator of p38 MAPK-mediated CD36-dependent cholesterol uptake in BMDMs. Transaldolase upregulates GSH production, thereby suppressing p38 activity and reducing the CD36 level, ultimately preventing foam cell formation and atherosclerosis. Thus, our findings indicate that the transaldolase-GSH-p38-CD36 axis may represent a promising therapeutic target for atherosclerosis.

Multifaceted role of ferroptosis in cardiovascular disease.

Ferroptosis is a newly identified form of non-apoptotic cell death characterised primarily by iron-dependent lipid peroxidation. It differs morphologically, biochemically, and genetically from other forms of cell death, such as apoptosis, autophagy, and necrosis. Although the molecular mechanism underlying ferroptosis remains unclear, multiple biological processes, such as iron metabolism, lipid peroxides, and systems, such as the glutathione system and the tetrahydrobiopterin/coenzyme Q10 system, appear to be involved. While the contribution of ferroptotic mechanisms to human diseases is not clear, recent studies have identified a number of ferroptosis-related genes. Cardiovascular diseases are the main cause of death globally. In this review, we outline the progress regarding the emerging role of ferroptosis in the pathogenesis of cardiac pathophysiological conditions and the association of ferroptosis with cardiomyopathy, myocardial ischemia-reperfusion injury, heart failure, and atherosclerosis. We further summarise newly discovered ferroptotic targets for the development of therapies for cardiovascular diseases. Finally, we discuss the current challenges and future research directions in cardiovascular disease treatments.

Probabilistic Energy-to-Amplitude Mapping in a Tapered Superconducting Nanowire Single-Photon Detector.

A spectrum-resolved photon detector is crucial for cutting-edge quantum optics, astronomical observation, and spectroscopic sensing. However, such an ability is rarely obtained because a direct linear conversion from weak single-photon energy to a readable electrical signal above the noise level without causing an avalanche is challenging. Here, we overcame these difficulties by building a probabilistic energy-to-amplitude mapping in a tapered superconducting nanowire single-photon detector and combining a computational reconstruction to obtain equivalent spectral resolving capacity. Distinguished dependence of pulse amplitude distributions on varied input spectra has been observed experimentally. As the energy-to-amplitude mapping is probabilistic, statistical measurements are required. By collecting around a few hundred photons, we have demonstrated wavelength perception over a wide spectral range from 600 to 1700 nm with a resolution of 100 nm. These findings represent a new approach to designing spectrum-sensitive SNSPDs for low-light spectroscopic applications.

Hydrochemical characteristics and driving factors of travertine deposition in Huanglong, Sichuan, SW, China.

The hydrochemical characteristics were analyzed by mathematical statistics, the hydrochemical types were analyzed by Piper three line diagram, and the sources and influencing factors of main ions in surface water were discussed by Gibbs diagram and ion correlation analysis. The results show that the TDS of surface water in the study area is 109-559 mg·L-1, and the average value is 318.67 mg·L-1; The pH value is 6.81-8.62, and the average value is 7.85. Most of them belong to weakly alkaline water. The surface water cation is mainly Ca2+ and Mg2+, the anion is mainly HCO3- and the hydrochemical type is HCO3-Ca. Through the correlation analysis of the main ions, it can be seen that TDS has a significant positive correlation with Na+, K+, Mg2+, Ca2+ and HCO3-, and these ions contribute to TDS. HCO3- has a significant correlation with Na+, K+ and Mg2+ and comes from carbonate rocks. According to the analysis of water-rock model, the hydrochemical genesis of surface water in the study area is mainly controlled by rock weathering, most ions are weathered and dissolved by carbonate rock and evaporated salt rock and a few cations are affected by water ion exchange.

A Molybdenum Disulfide Nanozyme with Charge-Enhanced Activity for Ultrasound-Mediated Cascade-Catalytic Tumor Ferroptosis.

The deficient catalytic activity of nanozymes and insufficient endogenous H2 O2 in the tumor microenvironment (TME) are major obstacles for nanozyme-mediated catalytic tumor therapy. Since electron transfer is the basic essence of catalysis-mediated redox reactions, we explored the contributing factors of enzymatic activity based on positive and negative charges, which are experimentally and theoretically demonstrated to enhance the peroxidase (POD)-like activity of a MoS2 nanozyme. Hence, an acidic tumor microenvironment-responsive and ultrasound-mediated cascade nanocatalyst (BTO/MoS2 @CA) is presented that is made from few-layer MoS2 nanosheets grown on the surface of piezoelectric tetragonal barium titanate (T-BTO) and modified with pH-responsive cinnamaldehyde (CA). The integration of pH-responsive CA-mediated H2 O2 self-supply, ultrasound-mediated charge-enhanced enzymatic activity, and glutathione (GSH) depletion enables out-of-balance redox homeostasis, leading to effective tumor ferroptosis with minimal side effects.

RNA-Seq analysis reveals the important co-expressed genes associated with polyphyllin biosynthesis during the developmental stages of Paris polyphylla.

BACKGROUND: Plants synthesize metabolites to adapt to a continuously changing environment. Metabolite biosynthesis often occurs in response to the tissue-specific combinatorial developmental cues that are transcriptionally regulated. Polyphyllins are the major bioactive components in Paris species that demonstrate hemostatic, anti-inflammatory and antitumor effects and have considerable market demands. However, the mechanisms underlying polyphyllin biosynthesis and regulation during plant development have not been fully elucidated. RESULTS: Tissue samples of P. polyphylla var. yunnanensis during the four dominant developmental stages were collected and investigated using high-performance liquid chromatography and RNA sequencing. Polyphyllin concentrations in the different tissues were found to be highly dynamic across developmental stages. Specifically, decreasing trends in polyphyllin concentration were observed in the aerial vegetative tissues, whereas an increasing trend was observed in the rhizomes. Consistent with the aforementioned polyphyllin concentration trends, different patterns of spatiotemporal gene expression in the vegetative tissues were found to be closely related with polyphyllin biosynthesis. Additionally, molecular dissection of the pathway components revealed 137 candidate genes involved in the upstream pathway of polyphyllin backbone biosynthesis. Furthermore, gene co-expression network analysis revealed 74 transcription factor genes and one transporter gene associated with polyphyllin biosynthesis and allocation. CONCLUSIONS: Our findings outline the framework for understanding the biosynthesis and accumulation of polyphyllins during plant development and contribute to future research in elucidating the molecular mechanism underlying polyphyllin regulation and accumulation in P. polyphylla.

Interconversion of Atomically Dispersed Platinum Cations and Platinum Clusters in Zeolite ZSM-5 and Formation of Platinum gem-Dicarbonyls.

Catalysts composed of platinum dispersed on zeolite supports are widely applied in industry, and coking and sintering of platinum during operation under reactive conditions require their oxidative regeneration, with the platinum cycling between clusters and cations. The intermediate platinum species have remained only incompletely understood. Here, we report an experimental and theoretical investigation of the structure, bonding, and local environment of cationic platinum species in zeolite ZSM-5, which are key intermediates in this cycling. Upon exposure of platinum clusters to O2 at 700 °C, oxidative fragmentation occurs, and Pt2+ ions are stabilized at six-membered rings in the zeolite that contain paired aluminum sites. When exposed to CO under mild conditions, these Pt2+ ions form highly uniform platinum gem-dicarbonyls, which can be converted in H2 to Ptδ+ monocarbonyls. This conversion, which weakens the platinum-zeolite bonding, is a first step toward platinum migration and aggregation into clusters. X-ray absorption and infrared spectra provide evidence of the reductive and oxidative transformations in various gas environments. The chemistry is general, as shown by the observation of platinum gem-dicarbonyls in several commercially used zeolites (ZSM-5, Beta, mordenite, and Y).

64-Pixel Mo80Si20 superconducting nanowire single-photon imager with a saturated internal quantum efficiency at 1.5 µm.

A superconducting nanowire single-photon imager (SNSPI) uses a time-multiplexing method to reduce the readout complexity. However, due to the serial connection, the nanowire should be uniform so that a common bias can set all segments of the nanowire to their maximum detection efficiency, which becomes more challenging as the scalability (i.e., the length of the nanowire) increases. Here, we have developed a 64-pixel SNSPI based on amorphous Mo80Si20 film, which yielded a uniform nanowire and slow transmission line. Adjacent detectors were separated by delay lines, giving an imaging field of 270 µm × 240 µm. Benefiting from the high kinetic inductance of Mo80Si20 films, the delay line gave a phase velocity as low as 4.6 µm/ps. The positions of all pixels can be read out with a negligible electrical cross talk of 0.02% by using cryogenic amplifiers. The timing jitter was 100.8 ps. Saturated internal quantum efficiency was observed at a wavelength of 1550 nm. These results demonstrate that amorphous film is a promising material for achieving SNSPIs with large scalability and high efficiency.

Diterbutyl phthalate attenuates osteoarthritis in ACLT mice via suppressing ERK/c-fos/NFATc1 pathway, and subsequently inhibiting subchondral osteoclast fusion.

Osteoarthritis (OA) is the most common arthritis with a rapidly increasing prevalence. Disease progression is irreversible, and there is no curative therapy available. During OA onset, abnormal mechanical loading leads to excessive osteoclastogenesis and bone resorption in subchondral bone, causing a rapid subchondral bone turnover, cyst formation, sclerosis, and finally, articular cartilage degeneration. Moreover, osteoclast-mediated angiogenesis and sensory innervation in subchondral bone result in abnormal vascularization and OA pain. The traditional Chinese medicine Panax notoginseng (PN; Sanqi) has long been used in treatment of bone diseases including osteoporosis, bone fracture, and OA. In this study we established two-dimensional/bone marrow mononuclear cell/cell membrane chromatography/time of flight mass spectrometry (2D/BMMC/CMC/TOFMS) technique and discovered that diterbutyl phthalate (DP) was the active constituent in PN inhibiting osteoclastogenesis. Then we explored the therapeutic effect of DP in an OA mouse model with anterior cruciate ligament transaction (ACLT). After ACLT was conducted, the mice received DP (5 mg·kg-1·d-1, ip) for 8 weeks. Whole knee joint tissues of the right limb were harvested at weeks 2, 4, and 8 for analysis. We showed that DP administration impeded overactivated osteoclastogenesis in subchondral bone and ameliorated articular cartilage deterioration. DP administration blunted aberrant H-type vessel formation in subchondral bone marrow and alleviated OA pain assessed in Von Frey test and thermal plantar test. In RANKL-induced RAW264.7 cells in vitro, DP (20 µM) retarded osteoclastogenesis by suppressing osteoclast fusion through inhibition of the ERK/c-fos/NFATc1 pathway. DP treatment also downregulated the expression of dendritic cell-specific transmembrane protein (DC-STAMP) and d2 isoform of the vacuolar (H+) ATPase V0 domain (Atp6v0d2) in the cells. In conclusion, we demonstrate that DP prevents OA progression by inhibiting abnormal osteoclastogenesis and associated angiogenesis and neurogenesis in subchondral bone.