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Abstract To date, earlier diagnosis of Alzheimer’s disease (AD) is still challenging. Recent studies revealed the elevated expression of connective tissue growth factor (CTGF) in AD brain is an upstream regulator of amyloid-beta (Aβ) plaque, thus CTGF could be an earlier diagnostic biomarker of AD than Aβ plaque. Herein, we develop a peptide-coated gold nanocluster that specifically targets CTGF with high affinity (KD ~ 21.9 nM). The probe can well penetrate the blood-brain-barrier (BBB) of APP/PS1 transgenic mice at early-stage (earlier than 3-month-old) in vivo, allowing non-invasive NIR-II imaging of CTGF when there is no appearance of Aβ plaque deposition. Notably, this probe can also be applied to measuring CTGF on postmortem brain sections by multimodal analysis, including fluorescence imaging, peroxidase-like chromogenic imaging, and ICP-MS quantitation, which enables distinguishment between the brains of AD patients and healthy people. This probe possesses great potential for precise diagnosis of earlier AD before Aβ plaque formation.

Abstract Gliomas are histologically and genetically heterogeneous tumors. However, classical histopathological typing often ignores the high heterogeneity of tumors and thus cannot meet the requirements of precise pathological diagnosis. Here, proximity‐anchored in situ spectral coding amplification (ProxISCA) is proposed for multiplexed imaging of RNA mutations, enabling visual typing of brain gliomas with different pathological grades at the single‐cell and tissue levels. The ligation‐based padlock probe can discriminate one‐nucleotide variations, and the design of proximity primers enables the anchoring of amplicons on target RNA, thus improving localization accuracy. The DNA module‐based spectral coding strategy can dramatically improve the multiplexing capacity for imaging RNA mutations through one‐time labelling, with low cost and simple operation. One‐target‐one‐amplicon amplification confers ProxISCA the ability to quantify RNA mutation copy number with single‐molecule resolution. Based on this approach, it is found that gliomas with higher malignant grades express more genes with high correlation at the cellular and tissue levels and show greater cellular heterogeneity. ProxISCA provides a tool for glioma research and precise diagnosis, which can reveal the relationship between cellular heterogeneity and glioma occurrence or development and assist in pathological prognosis.

As the operating speed of electric multiple units (EMUs) in high-speed railways increases, pantograph–catenary (PC) detachment arcing occurs frequently. The resulting vehicular-grounding electromagnetic transients are related to the dynamic characteristics of the arc length. During large detachment, the processes of arc extinction and arc reignition may occur, resulting in more severe train body (TB) over-voltages and adverse effects on some vehicular electronic devices. As an extension of the previous works, this paper aims to establish a suitable PC arc model to examine the TB transient voltages. To begin with, the arc length dynamic characteristics are reasonably analyzed to deduce the relationship between the detachment distance and the arc length via the chain arc model. Then, the dynamic characteristics of the arc length are introduced, and an arc modeling scheme is proposed to elaborate the vehicle-grid electric power model for EMUs encountering various arcing scenarios. Based on this, the transient over-voltages are analyzed, accounting for both the arc extinction and arc reignition, as well as the mutual influences of multiple detachments in a short time. The influential factors, including arc length characteristics, phase angle, excitation inductance, and grounding parameters, are also involved in the performed analyses.

Peptide-protected gold nanoclusters (AuNCs), possessing exceptional biocompatibility and remarkable physicochemical properties, have demonstrated intrinsic pharmaceutical activity in immunomodulation, making them a highly attractive frontier in the field of nanomedicine exploration. Autoimmune hepatitis (AIH) is a serious autoimmune liver disease caused by the disruption of immune balance, for which effective treatment options are still lacking. In this study, we initially identified glutathione (GSH)-protected AuNCs as a promising nanodrug candidate for AIH alleviating in a Concanavalin A (Con A)-induced mice model. However, to enhance treatment efficiency, liver-targeted delivery needs to be improved. Therefore, human serum albumin (HSA)-encapsulated AuNCs were constructed to achieve enhanced liver targeting and more potent mitigation of Con A-induced elevations in plasma aspartate transaminase (AST), alanine transaminase (ALT), and liver injury in mice. In vivo and in vitro mechanism studies indicated that AuNCs could suppress the secretion of IFN-γ by Con A-stimulated T cells and subsequently inhibit the activation of the JAK2/STAT1 pathway and eventual hepatocyte apoptosis induced by IFN-γ. These actions ultimately protect the liver from immune cell infiltration and damage caused by Con A. These findings suggest that bio-protected AuNCs hold promise as nanodrugs for AIH therapy, with their liver targeting capabilities and therapeutic efficiency being further improved via rational surface ligand engineering.

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with poor prognosis and high recurrence rate. The presence of the blood–brain barrier (BBB) prevents diagnostic and therapeutic drugs from penetrating and working in GBM. In traditional surgical treatment, it is difficult to completely distinguish the boundary between tumor and surrounding normal tissue, resulting in incomplete resection of tumor. Therefore, the diagnosis and treatment of GBM are very challenging. Several molecular probes and nanoprobes have been reported to successfully penetrate the BBB, selectively target and accumulate in GBM to achieve in situ imaging of brain tumors, thus achieving accurate diagnosis and treatment of orthotopic or non‐orthotopic GBM. This paper reviews the advances of molecular probes and nanoprobes in image‐guided diagnosis and treatment of GBM. The design principle, application, and advantages of each probe are enumerated in detail. Finally, the prospects and potential challenges of probes in the diagnosis and treatment of GBM are discussed with a view to further promote the study and application of novel imaging probes in GBM.

Hydrogen sulfide (H2S) is a gaseous signaling molecule that plays an important role in regulating various physiological activities in biological systems. As the fundamental structural and functional unit of organisms, cells are closely related to the homeostasis of their internal environment. The levels of H2S in different organelles maintain a certain balance, and any disruption of this balance will lead to various functional abnormalities that affect the health of organisms. Fluorescent imaging technology provides unique merits, such as simplicity, non-invasiveness, and real-time monitoring, and has become a powerful approach for the detection of molecules in biological systems. Based on the special physicochemical properties of H2S, numerous H2S-specific fluorogenic probes have been designed with different recognition mechanisms that enable rapid and accurate detection of H2S in cells. Therefore, this review briefly illustrates the design strategies, response principles, and biological applications of H2S-specific fluorescent probes and aims to provide relevant researchers with insight for future research.

We study the mobile data offloading problem in cooperative cellular networks, in which the cellular base station can offload a fraction of data traffic to its cooperative Wi-Fi networks. Both user satisfaction and benefit are important for the cellular network. Under the case that the cellular network cannot provide sufficient transmission resources, part of data traffic can be offloaded to its cooperative Wi-Fi networks to guarantee the user satisfaction, even though the benefit loss of the cellular network will be incurred. Meanwhile, considering the users are price sensitive, the operators, including cellular and Wi-Fi, can issue an appreciate unit price to attract more users and more traffic requirements to increase their total benefit. In this paper, we intend to design an optimal pricing scheme to maximize the user satisfaction and minimize the benefit losses of the operators simultaneously. First, we formulate the mobile data offloading problem as a joint optimization of “min–max” problem. Then, we convert the problem into a bi-level optimization problem, in which the lower level is to maximize the user satisfaction and the upper level is to minimize the benefit losses of the operators. Since the lower-level problem is convex, a centralized scheme based on the dynamic coordinate search-based method is employed to find the optimal solution of the bi-level problem. In addition, a distributed method is proposed to obtain the near-optimal solution quickly, where one-third-party agent is used to adjust the data traffic allocation. Simulation results show that the proposed method achieves the near-optimal solutions with limited iterations.

The success of a fluorescent dye as a molecular probe to monitor the intracellular activity of biomolecules depends on its physicochemical characteristics. Here, the authors use a predictive model to identify key features that allow them to design cell permeable, background-free fluorescent probes.

We study the problem of transmitting scalable video coded streams in a hybrid scenario including a global cellular network and a local peer-to-peer network. Given desirable channel condition in cellular downlink, some cellular user equipments can fetch the video chunks via the cellular base station directly, and also provide relay service via the local peer-to-peer network for other user equipments unable to meet their basic video quality. To take the advantage of channel diversity gains, the method of random linear coding is adopted to generate linear combinations of the video chunks for transmission in both the cellular and peer-to-peer networks. To optimize the cellular and peer-to-peer transmission arrangement, we first formulate it as a mixed integer nonlinear programming problem, which becomes more complicated when the number of user equipments increases. Then, we convert it to a quasi-convex optimization problem by approximating the indicator function with a continuous step function, and it can be solved by a centralized approach. Furthermore, a primal-dual decomposition approach is developed and a distributed algorithm is proposed accordingly. Simulation results show that the proposed approach achieves a near-optimal solution.

Complete and accurate spatial magnetic field description is the premise of effectively assessing the power supply capability of a high-speed railway (HSR). Its evaluation indicators are the current distributions and the integrated impedance of traction network. This paper proposes a spatial magnetic-field description method for the auto-transformer (AT) power supply system. Due to the limitations of previous approaches, all the real loop circuits of the AT system are considered for structuring a loop circuit matrix. At first, different description processes are divided, respectively, into those for the right side and the left side of the load. Then, considering that two types of return conductors exist in an AT system, a certain current ratio deduced in existing studies is introduced. As the introduced current ratio of the left side of the load is approximate, an iterative scheme is adopted. By constantly adjusting current ratio to satisfy a constraint condition of circuit voltages, accurate traction network impedance is obtained. Last, in order to verify the effectiveness of the proposed description method, two real-life experiments in a Chinese HSR line are performed, which indicate that the proposed method can not only directly reflect complete and accurate current distribution, but also deduce the exact traction network integrated impedance.

Infectious diseases threaten the health and survival of wildlife populations. Consequently, relationships between host diversity, host abundance, and parasite infection are important aspects of disease ecology and conservation research. Here, we report on the prevalence patterns of avian Plasmodium and Haemoproteus infections and host relative abundance influence based on sampling 728 wild-caught birds representing 124 species at seven geographically widespread sites in southern China. The overall prevalence of two haemoprotozoan parasites, Plasmodium and Haemoproteus, was 29.5%, with 22.0% attributable to Haemoproteus and 7.8% to Plasmodium. Haemoproteus prevalence differed significantly among different avian host families, with the highest prevalence in Nectariniidae, Pycnonotidae and Muscicapidae, whereas Plasmodium prevalence varied significantly among host species. Seventy-nine mitochondrial lineages including 25 from Plasmodium and 54 from Haemoproteus were identified, 80% of which were described here for the first time. The phylogenetic relationships among these parasites indicated stronger host-species specificity for Haemoproteus than Plasmodium. Well-supported host-family (Timaliidae) specific clades were found in both Plasmodium and Haemoproteus. The Haemoproteus tree shows regional subclades, whereas the Plasmodium clades are "scattered" among different geographical regions. Interestingly, there were statistically significant variations in the prevalence of Plasmodium and Haemoproteus among the geographical regions. Furthermore, the prevalence of Plasmodium and Haemoproteus were not significantly correlated with host relative abundance. Further efforts will focus on exploring the relationships between parasite prevalence and sex, age, and immune defense of the host.

Intracellular viscosity is a fundamental physical parameter that indicates the functioning of cells. In this work, we developed a simple boron-dipyrromethene (BODIPY)-based probe, BTV, for cellular mitochondria viscosity imaging by coupling a simple BODIPY rotor with a mitochondria-targeting unit. The BTV exhibited a significant fluorescence intensity enhancement of more than 100-fold as the solvent viscosity increased. Also, the probe showed a direct linear relationship between the fluorescence lifetime and the media viscosity, which makes it possible to trace the change of the medium viscosity. Furthermore, it was demonstrated that BTV could achieve practical applicability in the monitoring of mitochondrial viscosity changes in live cells through fluorescence lifetime imaging microscopy (FLIM).

Objective • Many randomized controlled trials (RCTs) have reported the effect of probiotics on reducing plasma lipids with inconsistent results. An explicit systematic review and meta-analysis were conducted in this study to evaluate the effect of probiotics on the lipid profile of healthy and hyperlipidemia participants. Methods • A comprehensive literature search of RCTs was conducted using PubMed, Embase, World Health Organization (WHO) Global Index Medicus, WHO clinical trial registry, and Clinicaltrials.gov. Inclusion criteria included RCTs comparing the use of any strain of a specified probiotic with the placebo control group. The change in lipid profiles was analyzed. Results • The probiotics can decrease the total cholesterol (TC) level in hyperlipidemia participants but not healthy persons (MD = -0.43, 95% CI -0.60 – -0.25, P < .01; MD = -0.09, 95% CI -0.26 – 0.08, P > .05). Probiotics did not reduce high-density lipoprotein cholesterol (HDL-C) in patients with hyperlipidemia or healthy people (MD = -0.01, 95% CI -0.09 – 0.07, P > .05; MD = 0.02, 95% CI -0.04 – 0.09, P > .05). Furthermore, probiotics can reduce the low-density lipoprotein cholesterol (LDL-C) level both in hyperlipidemia and healthy persons (MD = -0.34, 95% CI -0.43 – -0.26, P < .01; MD = -0.15, 95% CI -0.28 – -0.02, P < .05). Lastly, the effect of probiotics on reducing triglyceride (TG) levels was significant in hyperlipidemia persons but not in the healthy population (MD = -0.20, 95% CI -0.37 – -0.04, P < .01; MD = -0.01, 95% CI -0.02 – 0.04, P > .05). Conclusions • Through our analysis, the effect of probiotics on lowering plasma lipid was more obvious in hyperlipidemia participants than healthy population. However, further studies are required to confirm the findings due to pronounced clinical heterogeneity [ABSTRACT FROM AUTHOR]

Copper-based nanomaterials demonstrate promising potential in cancer therapy. Cu+ efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione, initiating chemical dynamic therapy (CDT) and ferroptosis. Cuproptosis, a newly identified cell death modality that represents a great prospect in cancer therapy, is activated. However, active homeostatic systems rigorously keep copper levels within cells exceptionally low, which hinders the application of cooper nanomaterials-based therapy. Herein, a novel strategy of CRISPR-Cas9 RNP nanocarrier to deliver cuprous ions and suppress the expression of copper transporter protein ATP7A for maintaining a high level of copper in cytoplasmic fluid is developed. The Cu2O and organosilica shell would degrade under the high level of glutathione and weak acidic environment, further releasing RNP and Cu+. The liberated Cu+ triggered a Fenton-like reaction for CDT and partially transformed to Cu2+, consuming intracellular GSH and initiating cuproptosis and ferroptosis efficiently. Meanwhile, the release of RNP effectively reduced the expression of copper transporter ATP7A, subsequently increasing the accumulation of cooper and enhancing the efficacy of CDT, cuproptosis, and ferroptosis. Such tumor microenvironment responsive multimodal nanoplatform opens an ingenious avenue for colorectal cancer therapy based on gene editing enhanced synergistic cuproptosis/CDT/ferroptosis.

To investigate the impact of different seedling transplanting times on rice growth, the present study evaluated seedling age and root pruning using treatments consisting of root pruning (RC20, RC30, and RC40) and no root pruning (CK20, CK30, and CK40). Quantitative analysis using curve fitting of the changes in dry matter accumulation (DMA) during the seedling and field stages was performed, and the changes in root parameters during the re-greening stage were observed. The results showed that the seedling stage could be divided into a gradual increase period, a rapid increase period, and a slow increase period. Transplanting at different time periods resulted in different transplanting shock effects. During the field stage, the DMA exhibited a slow-fast-slow "S" shaped curve as the developmental time progressed. However, significant differences were observed in growth parameters among the different treatments. Root injury promoted early maturity in young seedlings but also prolonged the whole growth period in older seedlings. The inhibitory effect of root pruning on rice root growth increased with young seedling age. The present results provide a theoretical basis for the design of seedling needle structure and the optimisation of rice seedling cultivation practices.

The construction of municipal road engineering is a complex system engineering, and its internal components are interconnected and mutually restricted, and the relationship is intricate. The quality of its construction plan directly affects the realization of the project's quality, safety, environment, progress, cost, and other goals, and the project construction plan occupies an important position in the construction of the project. The selection of construction plans for municipal road projects involves a wide range of areas. According to the characteristics of specific municipal road engineering projects, it is very important to establish a scientific construction scheme intelligent generation model and select the optimal construction scheme suitable for the project from many feasible construction schemes, which has very important theoretical research value and practical application value. After analyzing the knowledge characteristics of road construction technology and the content of road construction schemes, this study decomposes the knowledge of road construction schemes into two parts: case characteristics and solutions. Then, according to the needs of case retrieval technology, the data storage form of each subdivision index is proposed and the value range is explained, and a complete structure form of the road construction scheme case database is formed. Combined with actual engineering cases, the feasibility and applicability of the intelligent generation method of the road construction scheme based on the KNN algorithm is confirmed, which provides a new idea for the automation of road construction scheme preparation and the improvement of the scheme application effect. [ABSTRACT FROM AUTHOR]

Abstract Background Non‐apoptotic cell death is presently emerging as a potential direction to overcome the apoptosis resistance of cancer cells. In the current study, a natural plant agent α‐hederin (α‐hed) induces caspase‐independent paraptotic modes of cell death. Purpose The present study is aimed to investigate the role of α‐hed induces paraptosis and the associated mechanism of it. Methods The cell proliferation was detected by CCK‐8. The cytoplasm organelles were observed under electron microscope. Calcium (Ca2+) level was detected by flow cytometry. Swiss Target Prediction tool analyzed the potential molecule targets of α‐hed. Molecular docking methods were used to evaluate binding abilities of α‐hed with targets. The expressions of genes and proteins were analyzed by RT‐qPCR, western blotting, immunofluorescence, and immunohistochemistry. Xenograft models in nude mice were established to evaluate the anticancer effects in vivo. Results α‐hed exerted significant cytotoxicity against a panel of CRC cell lines by inhibiting proliferation. Besides, it induced cytoplasmic vacuolation in all CRC cells. Electron microscopy images showed the aberrant dilation of endoplasmic reticulum and mitochondria. Both mRNA and protein expressions of Alg‐2 interacting proteinX (Alix), the marker of paraptosis, were inhibited by α‐hed. Besides, both Swiss prediction and molecular docking showed that the structure of α‐hed could tightly target to GPCRs. GPCRs were reported to activate the phospholipase C (PLC)‐β3/ inositol 1,4,5‐trisphosphate receptor (IP3R)/ Ca2+/ protein kinase C alpha (PKCα) pathway, and we then found all proteins and mRNA expressions of PLCβ3, IP3R, and PKCα were increased by α‐hed. After blocking the GPCR signaling, α‐hed could not elevate Ca2+ level and showed less CRC cell cytotoxicity. MAPK cascade is the symbol of paraptosis, and we then demonstrated that α‐hed activated MAPK cascade by elevating Ca2+ flux. Since non‐apoptotic cell death is presently emerging as a potential direction to overcome chemo‐drug resistance, we then found α‐hed also induced paraptosis in 5‐fluorouracil‐resistant (5‐FU‐R) CRC cells, and it reduced the growth of 5‐FU‐R CRC xenografts. Conclusions Collectively, our findings proved α‐hed as a promising candidate for inducing non‐apoptotic cell death, paraptosis. It may overcome the resistance of apoptotic‐based chemo‐resistance in CRC.

Abstract Lipid metabolism disorders are considerably involved in the pathology of atherosclerosis; nevertheless, the fundamental mechanism is still largely unclear. This research sought to examine the function of lipophagy in lipid metabolism disorder-induced atherosclerosis and its fundamental mechanisms. Previously, Sirt6 has been reported to stimulate plaque stability by promoting macrophage autophagy. However, its role in macrophage lipophagy and its relationship with Wnt1 remains to be established. In this study, ApoE−/−: Sirt6−/− and ApoE−/−: Sirt6Tg mice were used and lipid droplets were analysed via transmission electron microscopy and Bodipy 493/503 staining in vitro. Atherosclerotic plaques in ApoE−/−: Sirt6−/− mice showed greater necrotic cores and lower stability score. Reconstitution of Sirt6 in atherosclerotic mice improved lipid metabolism disorder and prevented the progression of atherosclerosis. Furthermore, macrophages with Ac-LDL intervention showed more lipid droplets and increased expression of adipophilin and PLIN2. Reconstitution of Sirt6 recruited using SNF2H suppressed Wnt1 expression and improved lipid metabolism disorder by promoting lipophagy. In addition, downregulation of Sirt6 expression in Ac-LDL-treated macrophages inhibited lipid droplet degradation and stimulated foam cell formation. Innovative discoveries in the research revealed that atherosclerosis is caused by lipid metabolism disorders due to downregulated Sirt6 expression. Thus, modulating Sirt6’s function in lipid metabolism might be a useful therapeutic approach for treating atherosclerosis.

Abstract Developing more extensive methods to understand the underlying structure-property relationship of mechanochromic luminescent molecules is demanding but remains challenging. Herein, the effect of host-guest interaction on the mechanochromic properties of organic molecules is illustrated. A series of pyridinium-functionalized triphenylamine derivatives show bathochromic-shifted emission upon mechanical stimulation. These derivatives bind to cucurbit[8]uril to form homoternary host-guest inclusion complexes through host-stabilized intermolecular charge transfer interactions. Remarkably, the homoternary complexes exhibit longer emission than that of free guests in the solid state (even longer than ground guests), and a further bathochromic-shifted emission is observed upon grinding. Additionally, a heteroternary complex constructed through the encapsulation of pyrene (donor) and pyridinium (acceptor) guest pair in cucurbit[8]uril also displays the mechanochromic luminescent property. This work not only discloses the effect of host-guest inclusion on the mechanochromic property of organic molecules, but also provides a principle and a facile way to design the sequentially red-shifted mechanochromic materials.

Olfaction is critical for guiding the physiological activities of insects, with antennae being the primary olfactory organs. However, recent evidence suggests that other tissues may also participate in olfactory recognition. Among these, the genitalia of moths have received attention due to their roles in mating and oviposition. Sensilla and odorant receptors (ORs) in moth genitalia highlight the potential olfactory function of these structures. In this study, we examined the olfactory sensing capacity of the genitalia in Helicoverpa armigera by analyzing their structure in males and females and characterizing the expressed ORs. Scanning electron microscopy uncovered many sensilla distributed throughout the male and female genitalia. Transcriptome sequencing identified 20 ORs in the genitalia, with HarmOR68 exhibiting significant responses to methyl esters: methyl benzoate and salicylate. Our findings provide theoretical evidence that H. armigera genitalia may have significant olfactory perception functions.

Multifunctional bioimaging probes based on metal clusters have multiple characteristics of metal clusters and functional conjugates, and their development has broad application prospects in the fields of biomedical imaging and tumor diagnosis. However, current bioconjugation methods on metal clusters are time-consuming and have low reaction efficiency, which hinders the construction of bioimaging probes with multifunctional components. Here, we report a concise and promising design strategy to realize the simple and efficient introduction of functional conjugates through bioorthogonal reactions based on azido-functionalized metal clusters. Based on this strategy, taking the probe FA-CuC@BSA-Cy5 as an example, we demonstrated the design of a copper cluster-based multifunctional near-infrared (NIR) fluorescent probe and its real-time imaging application in vivo. Through the strain-promoted azide–alkyne cycloaddition (SPAAC) reaction, the tumor-specific targeting ligand folic acid (FA) and fluorophore (Cy5) can be chemically conjugated to azido-functionalized CuC@BSA-N3 quickly and efficiently under biocompatible conditions. The prepared probe showed numerous advantages of metal clusters, including good stability, ultra-small particle size and low toxicity and rapid renal clearance. At the same time, FA-modified FA-CuC@BSA-Cy5 can specifically target KB cells with high FR expression, and in vivo fluorescence imaging shows higher tumor accumulation. The construction of the azido functional metal cluster platform can be extended to various metal clusters with functional probes and prodrugs, thereby providing more promising candidates for future medical diagnoses. [ABSTRACT FROM AUTHOR]

Abstract Background Microvascular complications are associated with an overtly increased risk of adverse outcomes in patients with diabetes including coronary microvascular injury which manifested as disruption of adherens junctions between cardiac microvascular endothelial cells (CMECs). However, particular mechanism leading to diabetic coronary microvascular hyperpermeability remains elusive. Methods Experimental diabetes was induced in mice with adipose tissue-specific Adipsin overexpression (AdipsinLSL/LSL-Cre) and their respective control (AdipsinLSL/LSL). In addition, cultured CMECs were subjected to high glucose/palmitic acid (HG + PA) treatment to simulate diabetes for a mechanistic approach. Results The results showed that Adipsin overexpression significantly reduced cardiac microvascular permeability, preserved coronary microvascular integrity, and increased coronary microvascular density. Adipsin overexpression also attenuated cardiac dysfunction in diabetic mice. E/A ratio, an indicator of cardiac diastolic function, was improved by Adipsin. Adipsin overexpression retarded left ventricular adverse remodeling, enhanced LVEF, and improved cardiac systolic function. Adipsin-enriched exosomes were taken up by CMECs, inhibited CMECs apoptosis, and increased CMECs proliferation under HG + PA treatment. Adipsin-enriched exosomes also accelerated wound healing, rescued cell migration defects, and promoted tube formation in response to HG + PA challenge. Furthermore, Adipsin-enriched exosomes maintained adherens junctions at endothelial cell borders and reversed endothelial hyperpermeability disrupted by HG + PA insult. Mechanistically, Adipsin blocked HG + PA-induced Src phosphorylation (Tyr416), VE-cadherin phosphorylation (Tyr685 and Tyr731), and VE-cadherin internalization, thus maintaining CMECs adherens junctions integrity. LC-MS/MS analysis and co-immunoprecipitation analysis (Co-IP) unveiled Csk as a direct downstream regulator of Adipsin. Csk knockdown increased Src phosphorylation (Tyr416) and VE-cadherin phosphorylation (Tyr685 and Tyr731), while abolishing Adipsin-induced inhibition of VE-cadherin internalization. Furthermore, Csk knockdown counteracted Adipsin-induced protective effects on endothelial hyperpermeability in vitro and endothelial barrier integrity of coronary microvessels in vivo. Conclusions Together, these findings favor the vital role of Adipsin in the regulation of CMECs adherens junctions integrity, revealing its promises as a treatment target against diabetic coronary microvascular dysfunction. Graphical Abstract Graphical abstract depicting the mechanisms of action behind Adipsin-induced regulation of diabetic coronary microvascular dysfunction.

Abstract Background As the main pathological basis for various cardiovascular and cerebrovascular diseases, atherosclerosis has become one of the leading causes of death and disability worldwide. Emerging evidence has suggested that Rho GTPase Rnd3 plays an indisputable role in cardiovascular diseases, although its function in atherosclerosis remains unclear. Here, we found a significant correlation between Rnd3 and pyroptosis of aortic endothelial cells (ECs). Methods ApoeKO mice were utilized as a model for atherosclerosis. Endothelium‐specific transgenic mice were employed to disrupt the expression level of Rnd3 in vivo. Mechanistic investigation of the impact of Rnd3 on endothelial cell pyroptosis was carried out using liquid chromatography tandem mass spectrometry (LC‐MS/MS), co‐immunoprecipitation (Co‐IP) assays, and molecular docking. Results Evidence from gain‐of‐function and loss‐of‐function studies denoted a protective role for Rnd3 against ECs pyroptosis. Downregulation of Rnd3 sensitized ECs to pyroptosis under oxidized low density lipoprotein (oxLDL) challenge and exacerbated atherosclerosis, while overexpression of Rnd3 effectively prevented these effects. LC‐MS/MS, Co‐IP assay, and molecular docking revealed that Rnd3 negatively regulated pyroptosis signaling by direct interaction with the ring finger domain of tumor necrosis factor receptor‐associated factor 6 (TRAF6). This leads to the suppression of K63‐linked TRAF6 ubiquitination and the promotion of K48‐linked TRAF6 ubiquitination, inhibiting the activation of NF‐κB and promoting the degradation of TRAF6. Moreover, TRAF6 knockdown countered Rnd3 knockout‐evoked exacerbation of EC pyroptosis in vivo and vitro. Conclusions These findings establish a critical functional connection between Rnd3 and the TRAF6/NF‐κB/NLRP3 signaling pathway in ECs, indicating the essential role of Rnd3 in preventing pyroptosis of ECs.

Abstract Cardiovascular disease is the leading cause of death worldwide. Reperfusion therapy is vital to patient survival after a heart attack but can cause myocardial ischemia/reperfusion injury (MI/RI). Nitric oxide (NO) can ameliorate MI/RI and is a key molecule for drug development. However, reactive oxygen species (ROS) can easily oxidize NO to peroxynitrite, which causes secondary cardiomyocyte damage. Herein, L‐arginine‐loaded selenium‐coated gold nanocages (AAS) are designed, synthesized, and modified with PCM (WLSEAGPVVTVRALRGTGSW) to obtain AASP, which targets cardiomyocytes, exhibits increased cellular uptake, and improves photoacoustic imaging in vitro and in vivo. AASP significantly inhibits oxygen glucose deprivation/reoxygenation (OGD/R)‐induced H9C2 cell cytotoxicity and apoptosis. Mechanistic investigation revealed that AASP improves mitochondrial membrane potential (MMP), restores ATP synthase activity, blocks ROS generation, and prevents NO oxidation, and NO blocks ROS release by regulating the closing of the mitochondrial permeability transition pore (mPTP). AASP administration in vivo improves myocardial function, inhibits myocardial apoptosis and fibrosis, and ultimately attenuates MI/RI in rats by maintaining mitochondrial function and regulating NO signaling. AASP shows good safety and biocompatibility in vivo. This findings confirm the rational design of AASP, which can provide effective treatment for MI/RI.

Colorectal cancer (CRC) is the third most common malignancy in terms of global tumor incidence, and the rates of morbidity and mortality due to CRC are rising. Experimental models of CRC play a vital role in CRC research. Clinical studies aimed at investigating the evolution and mechanism underlying the formation of CRC are based on cellular and animal models with broad applications. The present review classifies the different experimental models used in CRC research, and describes the characteristics and limitations of these models by comparing the research models with the clinical symptoms. The review also discusses the future prospects of developing new experimental models of CRC.

Abstract tRNA-derived fragments (tRFs) are a class of small RNAs that occur when tRNAs are broken down by enzymes due to stress. Increasing reports have shown that tRFs are associated with multiple physiological and pathological processes, especially in cancers; however, very little is known of the effects and mechanisms of tRFs. Therefore, further investigation on the biological roles and clinical value of tRFs is required. In this study, we utilized whole-transcriptome sequencing to profile tRFs expression in the tissues and plasma exosomes of patients with colorectal cancer (CRC). Three tRFs (tRF-3022b, tRF-3030b and tRF-5008b) showed an increasing trend in CRC tissues compared to adjacent normal tissues. They also tended to be elevated in plasma exosomes of CRC patients compared to healthy controls. These results indicated that they may be upregulated in cancer cells and then secreted by exosomes. The knockdown of tRF-regulated factors such as AlkB homolog 3 (ALKBH3), tRNA aspartic acid methyltransferase 1 (DNMT2), angiogenin (ANG), and argonaute RISC catalytic component 2 (AGO2) could affect the expression of tRFs. Notably, we found that the decrease in the three tRFs arrests the progression of the CRC cell cycle and induces cell apoptosis. Silencing tRF-3022b could facilitate M2 macrophage polarization. Mechanistically, we found that tRF-3022b binds to galectin 1 (LGALS1) and macrophage migration inhibitory factor (MIF) in CRC cells and reduces polarization by regulating MIF in M2 macrophages. In conclusion, our study revealed the expression pattern of tRFs in both tissue and plasma exosomes and identified a novel tRF, tRF-3022b, which may affect CRC tumor growth and M2 macrophage polarization by binding to LGALS1 and MIF.

Abstract Fenugreek seeds (Trigonella foenum‐graecum L.), one kind of traditional Chinese medicine, are reported to be of great potential as a new alternative in terms of their bioactive components. In our present study, an ultrasonic‐assisted method was applied in the extraction of antioxidative components from fenugreek seeds. Four factors: ethanol concentration, liquid–solid ratio, sonication time, and sonication power were selected and multiple responses were studied using the response surface methodology (RSM). The effects of factors along with the correlation between all responses (flavonoids content, 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) assay, OH− assay) were studied. The regression model indicated that all four factors are of significant effect on all responses. The model predicted that the ethanol concentration of 72%, solvent‐to‐material ratio of 35 ml/g, ultrasonic time of 41 min, and 500 W of power would provide a flavonoid yield of 9.10 mg/g, DPPH clearance of 80.33%, and OH− clearance of 24.28%, respectively. The confirmation test showed the closeness of the predicted results with those of experimental values. And AB‐8 resin was successfully used to purify the fenuellus hulusi seed extract, and the flavonoid concentration of 78.14% was obtained. Six flavonoids (Swertisin, Puerarin apioside, Jasminoside B, Astragalin, Apigenin‐7‐O‐beta‐D‐glucoside, and Apiin) were successfully identified by the liquid chromatography–mass spectrometry (LC–MS) analysis.

The drug pair consisting of Sophora flavescens Aiton (Sophorae flavescentis radix, Kushen) and Coptis chinensis Franch. (Coptidis rhizoma, Huanglian), as described in Prescriptions for Universal Relief (Pujifang), is widely used to treat laxation. Matrine and berberine are the major active components of Kushen and Huanglian, respectively. These agents have shown remarkable anti-cancer and anti-inflammatory effects. A mouse model of colorectal cancer was used to determine the most effective combination of Kushen and Huanglian against anti-colorectal cancer. The results showed that the combination of Kushen and Huanglian at a 1:1 ratio exerted the best anti-colorectal cancer effect versus other ratios. Moreover, the anti-colorectal cancer effect and potential mechanism underlying the effects of matrine and berberine were evaluated by the analysis of combination treatment or monotherapy. In addition, the chemical constituents of Kushen and Huanglian were identified and quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 67 chemical components were identified from the Kushen–Huanglian drug pair (water extraction), and the levels of matrine and berberine were 129 and 232 µg/g, respectively. Matrine and berberine reduced the growth of colorectal cancer and relieved the pathological conditions in mice. In addition, the combination of matrine and berberine displayed better anti-colorectal cancer efficacy than monotherapy. Moreover, matrine and berberine reduced the relative abundance of Bacteroidota and Campilobacterota at phylum level and that of Helicobacter, Lachnospiraceae_NK4A136_group, Candidatus_Arthromitus, norank_f_Lachnospiraceae, Rikenella, Odoribacter, Streptococcus, norank_f_Ruminococcaceae, and Anaerotruncus at the genus level. Western blotting results demonstrated that treatment with matrine and berberine decreased the protein expressions of c-MYC and RAS, whereas it increased that of sirtuin 3 (Sirt3). The findings indicated that the combination of matrine and berberine was more effective in inhibiting colorectal cancer than monotherapy. This beneficial effect might depend on the improvement of intestinal microbiota structure and regulation of the RAS/MEK/ERK-c-MYC-Sirt3 signaling axis.

In this paper, we first study the uniqueness and symmetry of solution of nonlinear Schrödinger–Kirchhoff equations with constant coefficients. Then, we show the uniqueness of the solution of nonlinear Schrödinger–Kirchhoff equations with the polynomial potential. In the end, we investigate the asymptotic behaviour of the positive least energy solutions to nonlinear Schrödinger–Kirchhoff equations with vanishing potentials. The vanishing potential means that the zero set of the potential is non-empty. The uniqueness results of Schrödinger equations and the scaling technique are used in our proof. The elliptic estimates and energy analysis are applied in the proof of the asymptotic behaviour of the above Schrödinger–Kirchhoff-type equations.

In this paper, we deal with the following Schrödinger-Kirchhoff equation with potentials vanishing at infinity: −ε2a+εb∫ℝ3∇u2Δu+Vxu=Kxup−1u in ℝ3and u>0,u∈H1ℝ3, where Vx~x−α and Kx~x−β with 00. We first prove the existence of positive ground state solutions uε∈H1ℝ3 under the assumption that σ

Colorectal cancer (CRC), a malignant tumor worldwide consists of microsatellite instability (MSI) and stable (MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing was performed to explore the role of SHP2 in all cell types of tumor microenvironment (TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING–TBK1–IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68+ macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively, our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy.

BackgroundThe activation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) stimulates the transcription of the downstream target proteins, mitochondrial transcription factor A (TFAM) and nuclear respiratory factor 1 (NRF1), which induces mitochondrial biogenesis and promotes colorectal tumorigenesis. Agrimol B (Agr) is a constituent of Agrimonia pilosa Ledeb. that exerts anticancer effects. Herein, we aimed to investigate the antitumor activity of Agr and its mechanism of action.MethodsThe interaction between Agr and PGC-1α was predicted by molecular docking. After the treatment with different concentrations of Agr (0, 144, 288, and 576 nM), the cell viability, migration rate, proliferation rate, and apoptosis rate of human colon cancer HCT116 cells were determined. Mitochondrial activity, cellular reactive oxygen species (ROS), and mitochondrial membrane potential were assessed to measure the regulatory effect of Agr on mitochondrial function. Western blotting (WB) assay was used to examine the expression of PGC-1α, NRF1, and TFAM, as well as of the pro-apoptotic proteins, Bax and Caspase-3, and the antiapoptotic protein (Bcl-2). Finally, subcutaneous tumor xenograft model mice were used to evaluate the effect of Agr on colorectal cancer (CRC) in vivo.ResultsThe molecular docking results revealed a high likelihood of Agr interacting with PGC-1α. Agr inhibited the proliferation and migration of HCT116 cells, promoted ROS production and mitochondrial oxidative stress, inhibited mitochondrial activity, and decreased mitochondrial membrane potential. Agr induced cell apoptosis and, in combination with PGC-1α, impaired mitochondrial biogenesis and suppressed the expression of NRF1 and TFAM. Agr also suppressed the expression of Bcl-2 and Cleaved-Caspase-3 and increased the expression of Bax and Caspase-3. In addition, the in vivo antitumor effect and mechanism of Agr were confirmed by using a subcutaneous tumor xenograft mouse model.ConclusionsOur findings demonstrated that Agr regulates the expression of PGC-1α, thereby inducing mitochondrial dysfunction and promoting tumor cell apoptosis. This work highlights the potential of Agr as a promising therapeutic candidate in CRC.

Background The loss of tumor antigens and depletion of CD8 T cells caused by the PD-1/PD-L1 pathway are important factors for tumor immune escape. In recent years, there has been increasing research on traditional Chinese medicine in tumor treatment. Cycloastragenol (CAG), an effective active molecule in Astragalus membranaceus, has been found to have antiviral, anti-aging, anti-inflammatory, and other functions. However, its antitumor effect and mechanism are not clear.Methods The antitumor effect of CAG was investigated in MC38 and CT26 mouse transplanted tumor models. The antitumor effect of CAG was further analyzed via single-cell multiomics sequencing. Target responsive accessibility profiling technology was used to find the target protein of CAG. Subsequently, the antitumor mechanism of CAG was explored using confocal microscopy, coimmunoprecipitation and transfection of mutant plasmids. Finally, the combined antitumor effect of CAG and PD-1 antibodies in mice or organoids were investigated.Results We found that CAG effectively inhibited tumor growth in vivo. Our single-cell multiomics atlas demonstrated that CAG promoted the presentation of tumor cell-surface antigens and was characterized by the enhanced killing function of CD8+ T cells. Mechanistically, CAG bound to its target protein cathepsin B, which then inhibited the lysosomal degradation of major histocompatibility complex I (MHC-I) and promoted the aggregation of MHC-I to the cell membrane, boosting the presentation of the tumor antigen. Meanwhile, the combination of CAG with PD-1 antibody effectively enhanced the tumor killing ability of CD8+ T cells in xenograft mice and colorectal cancer organoids.Conclusion Our data reported for the first time that cathepsin B downregulation confers antitumor immunity and explicates the antitumor mechanism of natural product CAG.

As a vital adipokine, Adipsin is closely associated with cardiovascular risks. Nevertheless, its role in the onset and development of cardiovascular diseases remains elusive. This study was designed to examine the effect of Adipsin on survival, cardiac dysfunction and adverse remodeling in the face of myocardial infarction (MI) injury. In vitro experiments were conducted to evaluate the effects of Adipsin on cardiomyocyte function in the face of hypoxic challenge and the mechanisms involved. Our results showed that Adipsin dramatically altered expression of proteins associated with iron metabolism and ferroptosis. In vivo results demonstrated that Adipsin upregulated levels of Ferritin Heavy Chain (FTH) while downregulating that of Transferrin Receptor (TFRC) in peri-infarct regions 1 month following MI. Adipsin also relieved post-MI-associated lipid oxidative stress as evidenced by decreased expression of COX2 and increased GPX4 level. Co-immunoprecipitation and immunofluorescence imaging prove a direct interaction between Adipsin and IRP2. As expected, cardioprotection provided by Adipsin depends on the key molecule of IRP2. These findings revealed that Adipsin could be efficiently delivered to the heart by exosomes derived from pericardial adipose tissues. In addition, Adipsin interacted with IRP2 to protect cardiomyocytes against ferroptosis and maintain iron homeostasis. Therefore, Adipsin-overexpressed exosomes derived from pericardial adipose tissues may be a promising therapeutic strategy to prevent adverse cardiac remodeling following ischemic heart injury.

The surrounding rock of a coal mine roof fractures with the excavation of the underground working face in coal mining. These mining-induced fractures are connected and extended upward to form water inrush channels. A water inrush accident may occur when there is a sufficiently large water source. To elucidate the formation mechanisms of the roof water inrush channel and the characteristics of water inrush in goafs, we performed a case study of No.18401 Panel of Xiqu Coal Mine in China and determined whether the roof water inrush channel is connected by theoretical calculation and microseismic monitoring. The modified mechanical parameters of rock masses were embedded into the numerical model based on microseismic data. Microseismic monitoring and numerical simulation were organically combined to analyze the connection process of the water inrush channel, after which the roof water inrush channel is calibrated on the No.18401 Panel. We established a non-Darcy flow model for water inrush in the water-conducting fractured zone of mines by coupling the Darcy, Forchheimer, and Navier–Stokes equations. Finite element language and its compiler (FELAC) was used to study the water inrush mechanism of non-Darcy seepage. The results show that the pressure, velocity, and porosity in the water-conducting fractured zone are non-uniform in water inrush occurrence and development, and the mixed fluid mainly passes through the “dominant channel.” The development of water inrush is accompanied by the release of the hydrostatic pressure in the aquifer, the sudden increase of the velocity at the water inrush position, and the increase in fluid concentration. Hence, the underground water inrush can be predicted and prevented by monitoring the aforementioned indicators. This research is of great significance for the calibration of the water inrush channel of the roof and the prediction of water inrush disasters.

Amoxicillin appears to be clinically drug-resistant due to the presence of β-lactamase in bacteria. Here, we designed and prepared a hollow Prussian Blue (HPB)-based therapeutic nanoplatform that was constructed by encapsulating amoxicillin into polyethyleneimine with β-lactamase inhibitor 4-carboxyphenylboronic acid (4-Cpba) decorated HPB nanoparticles (CPA NPs). The antibacterial effect of the CPA NPs on drug-resistant bacteria was observed by in vitro colony-forming unit, minimum inhibitory concentration, scanning electron microscopy, and fluorescence tests. The results show that amoxicillin effectively inhibited Escherichia coli and Staphylococcus aureus-resistant bacteria in the presence of 4-Cpba. The in vivo experimental results show that the CPA NPs exhibited a synergistic anti-infective effect in vivo, which inhibited the inflammatory response and apoptosis induced by the drug-resistant bacterial infection, and promoted wound healing in mice. The hematoxylin and eosin staining and blood biochemical experiments revealed that the acute toxicity of the material was negligible and it had good biocompatibility. Our results verify our design that CPA NPs can restore the antibacterial activity of amoxicillin.

Abstract Background Some natural compounds inhibit cancer cell growth in various cancer cell lines with fewer side effects than traditional chemotherapy. Here, we explore the pharmacological effects and mechanisms of worenine (isolated from Coptis chinensis) against colorectal cancer. Methods The effects of worenine on colorectal cancer cell proliferation, colony formation and cell cycle distribution were measured. Glycolysis was investigated by examining glucose uptake and consumption, lactate production, and the activities and expressions of glycolysis enzymes (PFK-L, HK2 and PKM2). HIF-1α was knocked down and stimulated in vitro to investigate the underlying mechanisms. Results Worenine somewhat altered the glucose metabolism and glycolysis (Warburg effect) of cancer cells. Its anti-cancer effects and capability to reverse the Warburg effect were similar to those of HIF-1α siRNA and weakened by deferoxamine (an HIF-1α agonist). Conclusion It is suggested that worenine targets HIF-1α to inhibit colorectal cancer cell growth, proliferation, cell cycle progression and the Warburg effect.

Abstract Background Nano-Fenton reactors as novel strategy to selectively convert hydrogen peroxide (H2O2) into active hydroxyl radicals in tumor microenvironment for cancer therapy had attracted much attention. However, side effects and low efficiency remain the main drawbacks for cancer precise therapy. Results Here, ruthenium-loaded palmitoyl ascorbate (PA)-modified mesoporous silica (Ru@SiO2-PA) was successfully fabricated and characterized. The results indicated that Ru@SiO2-PA under pH6.0 environment displayed enhanced growth inhibition against human cancer cells than that of pH7.4, which indicated the super selectivity between cancer cells and normal cells. Ru@SiO2-PA also induced enhanced cancer cells apoptosis, followed by caspase-3 activation and cytochrome-c release. Mechanism investigation revealed that Ru@SiO2-PA caused enhanced generation of superoxide anion, which subsequently triggered DNA damage and dysfunction of MAPKs and PI3K/AKT pathways. Moreover, Ru@SiO2-PA effectively inhibited tumor spheroids and tumor xenografts growth in vivo by induction of apoptosis. The real-time imaging by monitoring Ru fluorescence in vitro and in vivo revealed that Ru@SiO2-PA mainly accumulated in cell nucleus and tumor xenografts. Importantly, Ru@SiO2-PA showed no side effects in vivo, predicting the safety and potential application in clinic. Conclusions Our findings validated the rational design that Ru@SiO2-PA can act as novel tumor microenvironment-response nano-Fenton reactors for cancer precise therapy. Graphic Abstract

Objective(s): Physical exercise has emerged as an effective therapy to mitigate cardiac remodelling in diabetic cardiomyopathy (DCM). The results of our previous studies revealed mammalian sterile 20-like kinase 1 (Mst1) is a key regulator of the progression of DCM. However, the precise molecular mechanism of physical exercise-induced cardiac protection and its association with Mst1 inhibition remain unclear. Materials and Methods: Wildtype and Mst1 transgenic mice were challenged with streptozotocin (STZ) to induce experimental diabetes and were divided into sedentary and exercise groups. The DCM phenotype was evaluated by echocardiography, Masson’s trichrome staining, TUNEL and immunoblotting analyses. The exercise-regulated miRNAs targeting Mst1 were predicted by bioinformatic analysis and later confirmed by RT-qPCR, immunoblotting, and dual-luciferase reporter assays. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulate diabetes to elucidate the underlying mechanisms. Results: Compared to the sedentary diabetic control, physical exercise inhibited Mst1 and alleviated cardiac remodelling in mice with DCM, as evidenced by decreases in the left ventricular end-systolic internal dimension (LVESD) and left ventricular end-diastolic internal dimension (LVEDD), increases in the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), attenuation of collagen deposition, and the suppression of apoptosis. Bioinformatic analysis and apoptosis assessments revealed exercise exerted protective effects against DCM through miR-486a-5p release. Moreover, luciferase reporter assays confirmed miR-486a-5p directly suppressed the expression of Mst1, thereby inhibiting the apoptosis of cardiomyocytes subjected to high glucose treatment. Conclusion: Physical exercise inhibits cardiac remodelling in DCM, and the mechanism is associated with miR-486a-5p release-induced Mst1 inhibition.

Microseismic (MS) monitoring technology has been widely used to monitor ground pressure disasters. However, the underground mining environment is complex and contains many types of noise sources. Furthermore, the traditional recognition method entails a complex process with low recognition accuracy for MS signals, so it is difficult to serve for the safe production of mines. Therefore, this study established a hybrid model combining the singular spectrum analysis (SSA) method, convolutional neural networks (CNN), and long short-term memory networks (LSTM). First, the principal components of monitoring signals were extracted with the SSA method, and then spatial and temporal features of monitoring signals were separately extracted with the CNN and LSTM. Based on actual field data collected from Xiadian Gold Mine, the hybrid model was compared with the CNN, LSTM, and back-propagation networks (BP), as well as commonly used recognition methods including the support vector machine (SVM), decision tree (DT), K-nearest neighbor (KNN), and linear discriminant analysis (LDA). The results show that the proposed hybrid model can accurately extract data features of monitoring signals and further improve MS signals' recognition performance. Furthermore, the recognition accuracy of mechanical signals in monitoring signals is particularly increased using the hybrid model, which avoids confusion with MS signals.

AimsYes-associated protein (YAP), a downstream protein in the Hippo signaling pathway, plays an important role in tumor proliferation, including in hepatocellular carcinoma (HCC). α-hederin, a monodesmosidic triterpenoid saponin isolated from Fructus akebiae, displayed anti-cancer effects on several cancer cell lines but the precise mechanism has not been ascertained. In the present study, we explored the effects of α-hederin on cell proliferation and apoptosis in human HCC cell lines and the underlying mechanisms.Main MethodCell proliferation and apoptosis were assessed using 5-ethynyl-2’-deoxyuridine staining, colony formation, flow cytometry. The expression patterns of components of Hippo signaling pathway and apoptotic genes were further examined via RT-qPCR and immunoblotting. A xenograft tumor model in nude mice was used to evaluate the anti-HCC effects of α-hederin in vivo.Resultsα-hederin promoted the apoptosis and inhibited the proliferation of SMMC-7721 and HepG2 cells in vitro, and remarkably inhibited the tumor size and weight in the xenograft mouse model. Additionally, α-hederin increased the expression of pro-apoptosis proteins and suppressed the expression of anti-apoptosis proteins. Moreover, α-hederin treatment upregulated the expression of Hippo signaling pathway-related proteins and genes, while, effectively reduced the level of nuclear YAP, which resulted in the inhibition of proliferation and the induction of apoptosis of HCC cells. Finally, the effects of α-hederin on HCC cell proliferation and apoptosis were alleviated by XMU-MP-1, a Mst1/2 inhibitor in vitro.SignificanceWe identified α-hederin is a novel agonist of Hippo signaling pathway and possesses an anti-HCC efficacy through inhibiting YAP activity.

BackgroundExosomes are extracellular vesicles secreted by most cells to deliver functional cargoes to recipient cells. MicroRNAs (miRNAs) constitute a significant part of exosomal contents. The ease of diffusion of exosomes renders them speedy and highly efficient vehicles to deliver functional molecules. Cancer cells secrete more exosomes than normal cells. Reports have showed that exosomal miRNAs of cancer cells facilitate cancer progression. Yet the complexity of cancer dictates that many more functional exosomal miRNAs remain to be discovered.MethodsIn this study, we analyzed miRNA expression profiles of tissue and plasma exosome samples collected from 10 colorectal cancer (CRC) patients and 10 healthy individuals. We focused on hsa-miR-101-3p (101-3p), a profoundly up-regulated miRNA enriched in plasma exosomes of patients bearing CRC. We performed target analysis of 101-3p and pursued functional studies of this microRNA in two colorectal cancer cell lines, namely HCT116 and SW480.ResultsOur results indicated that inhibiting 101-3p slowed cell growth and retarded cell migration in vivo in two colorectal cancer cell lines. Target analysis showed that Homeodomain-interacting protein kinase (HIPK3) is a target of miR-101-3p. HCT116 and SW480 cells stably overexpressing HIPK3 showed increased level of phosphorylated FADD, as well as retarded cell growth, migration, and increased sensitivity to 5-FU. In-depth analysis revealed increased mitochondrial membrane potential upon HIPK3 overexpression along with increased production of reactive oxygen species, number of mitochondria, and expression of respiratory complexes. Measurements of glycolytic parameters and enzymes revealed decreased level of glycolysis upon HIPK3 overexpression in these two cell lines. Xenograft model further confirmed a profoundly improved potency of the synergistic treatment combining both 5-FU and 101-3p inhibitor compared to 5-FU alone.ConclusionThis study unraveled an oncogenic nature of the exosomal 101-3p and suggested a relationship between the 101-3p-HIPK3 axis and metabolic homeostasis in colorectal cancer. Expression level of 101-3p is positively correlated with glycolytic capacity in CRC and therefore 101-3p itself is an oncomiR. Combining 101-3p inhibitor with chemotherapeutic agents is an effective strategy against CRC.