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Abstract Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.

Abstract Background Triglyceride and glucose (TyG) index, a surrogate marker of insulin resistance, has been validated as a predictor of cardiovascular disease. However, effects of TyG-related indices combined with obesity markers on cardiovascular diseases remained unknown. We aimed to investigate the associations between TyG index and modified TyG indices with new-onset cardiovascular disease and the time-dependent predictive capacity using a national representative cohort. Methods This study is a retrospective observational cohort study using data from China Health and Retirement Longitudinal Study (CHARLS) of 7 115 participants. The TyG index was calculated as Ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. The modified TyG indices were developed combining TyG with body mass index (BMI), waist circumference (WC) and waist-to‐height ratio (WHtR). We used adjusted Cox proportional hazards regression to analyze the association and predictive capacity based on hazard ratio (HR) and Harrell’s C‐index. Results Over a 7-year follow‐up period, 2136 participants developed cardiovascular disease, including 1633 cases of coronary heart disease and 719 cases of stroke. Compared with the lowest tertile group, the adjusted HR (95% CI) for new-onset cardiovascular disease in the highest tertile for TyG, TyG-BMI, TyG-WC, and TyG-WHtR were 1.215 (1.088–1.356), 1.073 (0.967–1.191), 1.078 (0.970–1.198), and 1.112 (1.002–1.235), respectively. The C‐indices of TyG index for cardiovascular disease onset were higher than other modified TyG indices. Similar results were observed for coronary heart disease and stroke. Conclusion TyG and TyG-WhtR were significantly associated with new-onset cardiovascular diseases, and TyG outperformed the modified TyG indices to identify individuals at risk of incident cardiovascular event.

Abstract Chemotherapeutic agents can inhibit the proliferation of malignant cells due to their cytotoxicity, which is limited by collateral damage. Dihydroartemisinin (DHA), has a selective anti-cancer effect, whose target and mechanism remain uncovered. The present work aims to examine the selective inhibitory effect of DHA as well as the mechanisms involved. The findings revealed that the Lewis cell line (LLC) and A549 cell line (A549) had an extremely rapid proliferation rate compared with the 16HBE cell line (16HBE). LLC and A549 showed an increased expression of NRAS compared with 16HBE. Interestingly, DHA was found to inhibit the proliferation and facilitate the apoptosis of LLC and A549 with significant anti-cancer efficacy and down-regulation of NRAS. Results from molecular docking and cellular thermal shift assay revealed that DHA could bind to epidermal growth factor receptor (EGFR) molecules, attenuating the EGF binding and thus driving the suppressive effect. LLC and A549 also exhibited obvious DNA damage in response to DHA. Further results demonstrated that over-expression of NRAS abated DHA-induced blockage of NRAS. Moreover, not only the DNA damage was impaired, but the proliferation of lung cancer cells was also revitalized while NRAS was over-expression. Taken together, DHA could induce selective anti-lung cancer efficacy through binding to EGFR and thereby abolishing the NRAS signaling pathway, thus leading to DNA damage, which provides a novel theoretical basis for phytomedicine molecular therapy of malignant tumors.

Abstract Background Both the triglyceride-glucose (TyG) index, as a surrogate marker of insulin resistance, and systemic inflammation are predictors of cardiovascular diseases; however, little is known about the coexposures and relative contributions of TyG index and inflammation to cardiovascular diseases. Using the nationally representative data from the China Health and Retirement Longitudinal Study (CHARLS), we conducted longitudinal analyses to evaluate the joint and mutual associations of the TyG index and high-sensitivity C-reactive protein (hsCRP) with cardiovascular events in middle-aged and older Chinese population. Methods This study comprised 8 658 participants aged at least 45 years from the CHARLS 2011 who are free of cardiovascular diseases at baseline. The TyG index was calculated as Ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Cardiovascular events were defined as the presence of physician-diagnosed heart disease and/or stroke followed until 2018.We performed adjusted Cox proportional hazards regression and mediation analyses. Results The mean age of the participants was 58.6 ± 9.0 years, and 3988 (46.1%) were females. During a maximum follow-up of 7.0 years, 2606 (30.1%) people developed cardiovascular diseases, including 2012 (23.2%) cases of heart diseases and 848 (9.8%) cases of stroke. Compared with people with a lower TyG index (

Flexible electronic devices with mechanical properties like the soft tissues of human organs have great potential for the next generation of wearable and implantable electronic devices. Self-healing hydrogel composites typically have high tensile strength, high electrical conductivity and damage repair properties and have wide applications in flexible electronics, such as human-computer interaction, health detection and soft robots. Various self-healing hydrogel composites have been developed to produce new stretchable conductive materials with satisfactory mechanical and self-healing properties. This paper presents the fabrication of self-healing hydrogel composites and their application in flexible electronic devices. Firstly, the repair mechanism of physically cross-linked and chemically cross-linked self-healing hydrogel composites is presented. Secondly, self-healing double network hydrogels, self-healing nanocomposite hydrogels and double crosslinked self-healing hydrogel composites and their applications in flexible sensors, energy harvesting devices, energy storage devices and optical devices are presented and discussed. Finally, the challenges and prospects of self-healing hydrogel composites in flexible electronic devices in the future are presented.

The process data in computer-based problem-solving evaluation is rich in valuable implicit information. However, its diverse and irregular structure poses challenges for effective feature extraction, leading to varying degrees of information loss in existing methods. Process-response behavior exhibits similarities to textual data in terms of the key units and contextual relationships. Despite the scarcity of relevant research, exploring text analysis methods for feature recognition in process data is significant. This study investigated the efficacy of Term Frequency-Inverse Document Frequency (TF-IDF) and Word to Vector (Word2vec) in extracting response behavior features and compared the predictive, analytical, and clustering effects of classical machine learning methods (supervised and unsupervised) on response behavior. An analysis of the PISA 2012 computer-based problem-solving dataset revealed that TF-IDF effectively extracted key response behaviors, whereas Word2vec captured effective features from sequenced response behaviors. In addition, in supervised machine learning using both methods, the random forest model based on TF-IDF performed the best, followed by the SVM model based on Word2vec. Word2vec-based models outperformed TF-IDF-based ones in the F1-score, accuracy, and recall (except for precision) across the logistic regression, k-nearest neighbor, and support vector machine algorithms. In unsupervised machine learning, the k-means algorithm effectively clustered different response behavior patterns extracted by these methods. The findings underscore the theoretical and methodological transferability of these text analysis methods in educational and psychological assessment contexts. This study offers valuable insights for research and practice in similar domains by yielding rich feature representations, supplementing fine-grained assessment evidence, fostering personalized learning, and introducing novel insights for educational assessment.

Background: Mycobacterium tilburgii is a nonculturable, nontuberculous mycobacterium that occasionally causes serious infections in individuals with immune deficiencies. Owing to its nonculturable nature, its antimicrobial susceptibility has not been assessed, and the optimal treatment regimen is unclear. Herein, we report a case of disseminated M. tilburgii infection in a person with AIDS, identified using metagenomics next-generation sequencing (mNGS) and polymerase chain reaction (PCR). Case presentation: A 33-year-old man presented with a 3-month history of abdominal pain, lymphadenopathy, intermittent night hot flashes, night sweats, and weight loss. No pathogen was detected during initial routine investigations. M. tilburgii was subsequently identified in a left cervical lymph node sample using mNGS. Furthermore, M. tilburgii infection was detected in a bone marrow sample based on PCR of 16S rRNA and hsp65 gene sequencing. The person was treated with a combination of moxifloxacin, clarithromycin, ethambutol, rifabutin, and amikacin. The laboratory results improved, and the patient's symptoms resolved. Conclusion: M. tilburgii may be missed in diagnostic tests because it cannot be grown using routine culture techniques. Early diagnosis and timely and effective treatment are critical in patients with M. tilburgii infection; therefore, molecular techniques are recommended for patients with suspected M. tilburgii infection.

Timely and accurate mapping of paddy rice cultivation based on remote sensing technology is crucial and valuable for ensuring food security and sustainable environmental management. In most relevant studies, rice mapping was conducted using time-series images, but conventional rice mapping methods are not specifically designed for time-series data, making it difficult to extract the deep information contained in these data. To address these problems, in this paper, an automatic rice mapping method based on an integrated time-series gradient boosting tree (Auto-ITSGBT) is proposed using GF-6 WFV and Sentinel-2 MSI data. This method accounts for the local and overall shape features of time-series curves, and fully exploits the information related to phenological characteristics between time-series data. The proposed rice mapping method is tested and validated in three typical rice-producing areas, which are located in different provinces of China characterized by diverse climate conditions, planting times or topographies. The results show that the overall accuracy and Kappa coefficient of the method exceeded 95% and 0.93, respectively, at all study sites, respectively. Our method performs better than the existing competing methods, with an overall accuracy improvement of 2% to 4%. To identify the rice planting areas as early as possible, rice mapping was conducted by reducing the number of images one by one. The rice distribution map was obtained in mid-July with an overall accuracy of at least 90%, thus obtaining a spatial distribution map of rice with high accuracy before harvesting.

PurposeThe debate over the causal and longitudinal association between cystatin C and stroke in older adults persists. Our aim was to assess the link between cystatin C levels, both measured and genetically predicted, and stroke risk.MethodsThis study employed a retrospective cohort design using samples of the China Health and Retirement Longitudinal Study (CHARLS), which is a nationally representative cohort recruiting individuals aged 45 years or above. A multivariate logistic model and the two-sample Mendelian randomization framework were used to investigate the longitudinal and genetically predicted effect of serum cystatin C on stroke.ResultsThe study population had a mean age of 59.6 (SD ±9.5), with 2,996 (46.1%) women. After adjusting for confounding factors, compared to those in the first quartile of cystatin C, those in the last quartile had the greatest risk of stroke incidence [odds ratio (OR), 1.380; 95% confidence interval (CI), 1.046–1.825]. The Mendelian randomization analysis showed that a genetically predicted cystatin C level was positively associated with total stroke (OR by inverse variance-weighted method, 1.114; 95% CI, 1.041–1.192).ConclusionsThis national cohort study suggests that higher serum cystatin C is associated with an increased risk of total stroke, which is further supported by Mendelian randomization.

Abstract In recent years, the development of photocatalysts based on noncovalent strategies has shown an important role in medical and organic materials. Herein, an organic fluorescent dye benzothiazole derivative (2‐(N,N‐diethylanilin‐4‐yl)‐4,6‐bis(3‐methylpyrazol‐1‐yl)‐1,3,5‐triazine [MPBT]) was designed and synthesized. It was encapsulated in the cavity of cucurbit[8]uril (CB[8]) to form a supramolecular dimer through host–guest interaction, which converted the dye into a highly efficient photocatalyst. With the formation of 2MPBT‐CB[8] supramolecular dimer, the emergence of host‐enhanced charge transfer interactions could significantly facilitate singlet to triplet through intersystem crossing. At the same time, the alternating structure of 2MPBT‐CB[8] facilitated the triplet states for further energy transfer and electron transfer. In addition, the electron transfer process with electron donor generated cationic free radical and photocatalyst negative ion free radical (PC⋅−), which in turn reacted with oxygen (O2) to form superoxide anion radical (O2⋅−). The generated O2⋅− could be used to catalyze the oxidative hydroxylation of aryl boronic acid. Therefore, the 2MPBT‐CB[8] had become a highly efficient photocatalyst for the oxidative hydroxylation of aryl boronic acid. This strategy of supramolecular dimerization provides a new strategy for the development of new photocatalysts based on noncovalent interactions.

Abstract Background Homogentisate phytyltransferase (HPT) is the critical enzyme for the biosynthesis of tocopherols (vitamin E), which are the major lipid-soluble antioxidants and help plants adapt to various stress conditions. HPT is generally strictly conserved in various plant genomes; however, a divergent lineage HPT2 was identified recently in some Triticeae species. The molecular function and transcriptional profiles of HPT2 remain to be characterized. Results In this study, we performed comprehensive transcriptome data mining of HPT1 and HPT2 in different tissues and stages of barley (Hordeum vulgare), wheat (Triticum aestivum), and oat (Avena sativa), followed by qRT-PCR experiments on HPT1 and HPT2 in different tissues of barley and wheat. We found that the common HPT1 genes (HvHPT1, TaHPT1s, and AsHPT1s) displayed a conserved transcriptional pattern in the three target species and were universally transcribed in various tissues, with a notable preference in leaf. In contrast, HPT2 genes (HvHPT2, TaHPT2, and AsHPT2) were specifically transcribed in spike (developmentally up-regulated) and shoot apex tissues, displaying a divergent tissue-specific pattern. Cis-regulatory elements prediction in the promoter region identified common factors related to light-, plant hormone-, low temperature-, drought- and defense- responses in both HPT1s and HPT2s. We observed the transcriptional up-regulation of HvHPT1 and HvHPT2 under various stress conditions, supporting their conserved function in environmental adaption. We detected a clear, relaxed selection pressure in the HPT2 lineage, consistent with the predicted evolution pattern following gene duplication. Protein structural modelling and substrate docking analyses identified putative catalytic amino acid residues for HvHPT1 and HvHPT2, which are strictly conserved and consistent with their function in vitamin E biosynthesis. Conclusions We confirmed the presence of two lineages of HPT in Triticeae and Aveninae, including hexaploid oat, and characterized their transcriptional profiles based on transcriptome and qRT-PCR data. HPT1s were ubiquitously transcribed in various tissues, whilst HPT2s were highly expressed in specific stages and tissue. The active transcription of HPT2s, together with its conserved cis-elements and protein structural features, support HPT2s’ role in tocopherol production in Triticeae. This study is the first protein structural analysis on the membrane-bound plant HPTs and provides valuable insights into its catalytic mechanism.

Abstract Higher-order Weyl semimetals are a family of recently predicted topological phases simultaneously showcasing unconventional properties derived from Weyl points, such as chiral anomaly, and multidimensional topological phenomena originating from higher-order topology. The higher-order Weyl semimetal phases, with their higher-order topology arising from quantized dipole or quadrupole bulk polarizations, have been demonstrated in phononics and circuits. Here, we experimentally discover a class of higher-order Weyl semimetal phase in a three-dimensional photonic crystal (PhC), exhibiting the concurrence of the surface and hinge Fermi arcs from the nonzero Chern number and the nontrivial generalized real Chern number, respectively, coined a real higher-order Weyl PhC. Notably, the projected two-dimensional subsystem with k z = 0 is a real Chern insulator, belonging to the Stiefel-Whitney class with real Bloch wavefunctions, which is distinguished fundamentally from the Chern class with complex Bloch wavefunctions. Our work offers an ideal photonic platform for exploring potential applications and material properties associated with the higher-order Weyl points and the Stiefel-Whitney class of topological phases.

Background: We aim to investigate the characteristics of invasive pulmonary aspergillosis (IPA) in patients with HBV-related acute on chronic liver failure (HBV-ACLF). Methods: A total of 44 patients with probable IPA were selected as the case group, and another 88 patients without lung infections were chosen as the control group. Results: HBV-ACLF patients with probable IPA had more significant 90-day mortality (38.6% vs. 15.9%, p = 0.0022) than those without. The white blood cell (WBC) count was the independent factor attributed to the IPA development [odds ratio (OR) 1.468, p = 0.027]. Respiratory failure was associated with the mortality of HBV-ACLF patients with IPA [OR 26, p = 0.000]. Twenty-seven patients received voriconazole or voriconazole plus as an antifungal treatment. Plasma voriconazole concentration measurements were performed as therapeutic drug monitoring in 55.6% (15/27) of the patients. The drug concentrations exceeded the safe range with a reduced dosage. Conclusions: The WBC count might be used to monitor patients’ progress with HBV-ACLF and IPA. The presence of IPA increases the 90-day mortality of HBV-ACLF patients mainly due to respiratory failure. An optimal voriconazole regimen is needed for such critical patients, and voriconazole should be assessed by closely monitoring blood levels.

Background:The rapid spread of bacteria with plasmid-mediated resistance to antibiotics poses a serious threat to public health. The search for potential compounds that can increase the antibacterial activity of existing antibiotics is a promising strategy for addressing this issue.Methods:Synergistic activity of the FDA-approved agent oxethazine combined with colistin was investigated in vitro using checkerboard assays and time-kill curves. The synergistic mechanisms of their combination of oxethazine and colistin was explored by fluorescent dye, scanning electron microscopy (SEM) and LC-MS/MS. The synergistic efficacy was evaluated in vivo by the Galleria mellonella and mouse sepsis models.Results:In this study, we found that oxethazine could effectively enhance the antibacterial activity of colistin against both mcr-positive and -negative pathogens, and mechanistic assays revealed that oxethazine could improve the ability of colistin to destruct bacterial outer membrane and cytoplasmic membrane permeability. In addition, their combination triggered the accumulation of reactive oxygen species causing additional damage to the membrane structure resulting in cell death. Furthermore, oxethazine significantly enhanced the therapeutic efficacy of colistin in two animal models.Conclusion:These results suggested that oxethazine, as a promising antibiotic adjuvant, can effectively enhance colistin activity, providing a potential strategy for treating multidrug-resistant bacteria.

Summary: Exploring high-efficiency catalysts for oxygen reduction reactions (ORRs) is essential for the development of large-scale applications of fuel cell and metal-air batteries technology. The as-prepared Fe-NC-800 via polymerization-pyrolysis strategy exhibited superior ORR activity with onset potential of 1.030 V vs. reversible hydrogen electrode (RHE) and half-wave potential of 0.908 V vs. RHE, which is higher than that of the Pt/C catalyst and most of other Fe-based catalysts. The different d-band center values can be attributed to the influence of different N-doped carbon, leading to the adjustment in the ORR activity. In addition, Fe-NC-800-based Zn-air battery showed better electrochemical performance with a high discharge specific capacity of 806 mA h g−1 and a high-power density of 220 mW cm−2 than that of the Pt/C-based battery. Therefore, the biomass Fe-NC-800 catalyst may become a promising substitute for Pt/C catalysts in energy storage and conversion devices.

Topological photonics is a rapidly developing field that leverages geometric and topological concepts to engineer and control the characteristics of light. Currently, the research on topological photonics has expanded from traditional one-dimensional (1D) and two-dimensional (2D) to three-dimensional (3D) and higher-dimensional spaces. However, most reviews on topological photonics focus on 1D and 2D systems, and a review that provides a detailed classification and introduction of 3D and higher-dimensional systems is still missing. Here, we review the photonic topological states in 3D and higher-dimensional systems on different platforms. Moreover, we discuss internal connections between different photonic topological phases and look forward to the future development direction and potential applications of 3D and higher-dimensional systems.

Two novel two-dimensional (2D) supramolecular organic frameworks were fabricated in water based on the encapsulation-enhanced donor-acceptor interaction between the methyl viologen (MV) units, methoxy naphthyl (MN) units, and CB [8]. The tetraphenylethylene (TPE) derivatives 1 with four MV units were employed as rigid building blocks and the two MN units modified oligoethylene glycol derivatives 2 and 3 served as flexible edges, respectively. The obtained two SOFs have obvious sheet-like structures and exhibit fluorescence emission at 350–500 ​nm. In addition, these two SOFs were employed for the luminescent detection of Cr(VI) and Mn(VII) in aqueous solutions, and the detection limits of CrO42−, Cr2O72−, and MnO4− were calculated in a very low concentration range, indicating that these two SOFs can serve as a potential sensor for Cr(VI) and Mn(VII) detection in water. This work constructs two SOFs in an aqueous solution through a facile method and further enriches the applications of SOFs.

Abstract Background Internal fixation of the femoral neck carries a risk of perforation due to the presence of the isthmus of the femoral neck. At present, there are few studies on the safe and risk zones of the femoral neck system (FNS) implantation. This study aimed to recommend the safe range of injection of FNS in the lateral wall of the proximal femur, parallel to the axis of the femoral neck, during FNS treatment of femoral neck fracture (FNF). Methods Femoral computed tomography (CT) data of 80 patients (male: 40; female: 40) who met the inclusion criteria were collected. Mimics 21.0 software was used to complete the modeling. 3-Matic 13.0 software was used to establish the axis of the femoral neck and its vertical plane, perform the cutting of the femoral neck, and project it on the vertical plane of the femoral neck axis. After matching a rectangle for each projection map, all sample sizes (80 cases) were standardized and superimposed to obtain gradient maps of the safe zone (SZ) and dangerous zone (RZ), thereby securing edge key points and safe FNS insertion range. Results In the 80 samples, the mean diameter of the smallest femoral neck section was 33.87 ± 2.32 mm for men and 29.36 ± 1.92 mm for women. All 80 femoral necks had safe and risky areas. The SZ/S × 100% was 77.59 (± 2.22%), and the RS/S × 100% was 22.39% (± 2.22%). The risk area was composed of four parts: (1), (2), (3), and (4), respectively, corresponding to 3.45 ± 1.74%, 5.51 ± 2.63%, 6.22 ± 1.41%, and 7.22 ± 1.39%. Four marginal key points, perforation risk, and safe ranges (SR) of FNS were analyzed on the lateral wall of the femoral neck. Conclusions The SR of FNS placement was recommended by digital simulation. In addition, Regions (3) and (4) posed a higher risk of penetrating the cortex. Using the gradient map of RZ for preoperative evaluation is recommended to avoid iatrogenic perforation.

Highlights Fundamental principles underlying the design of oxide catalysts, including the influence of crystal structure, and electronic structure on their performance are summarized and analyzed. Challenges associated with developing oxide catalysts and the potential strategies are discussed.

A novel method, ECWS, is proposed for measuring soil initial salinity content (b), based on the soil electrical conductivity EC and soil moisture content WS. This pioneering model rigorously establishes and incorporates the inherent potential correlation among soil bulk conductivity (ECa), soil solution conductivity (ECw), volume water content (θc), and soil salinity content (SSC). First of all, in order to delve the deeper relationship between ECa, ECw, θc and SSC, the soil salinity conductivity conversion coefficient ρa and soil leaching solution salinity conductivity conversion coefficient ρw were employed based on the formula of parallel conducting channels of the soil–water system, and a new measurement model of salinity content was constructed. After that, a mathematical analysis method was used to transform the coefficients of multiple sets of regression equations into matrices to solve ρa, ρw and b. Finally, to validate the accuracy of the proposed ECWS method, verification tests were conducted by utilizing TDR and PWMER sensors. The results with different salinity contents showed that the b size obtained by ECWS model were K2SO4 (1.84 g/kg), NaCl (1.91 g/kg), and KCl (1.92 g/kg). The maximum deviation was less than 0.08 g/kg (relative error less than 5%). The results showed that the influence of different anions and cations on the measurement of salinity content Cl− is greater than that of SO42−, and K+ is greater than that of Na+. This study revealed the relationship between soil electrical conductivity and soil salinity content to a certain extent, and realized the transformation between them, which provided a new method for the measurement of soil salinity content, and also provided a reference for related research on the measurement of soil salinization.

Carrier-free nanoparticulate formulations are an advantageous platform for the oral administration of insoluble drugs with the expectation of improving their bioavailability. However, the key limitation of exploiting carrier-free nanoparticulate formulations is the controlled preparation of drug nanoparticles on the basis of rational prescription design. In the following study, we used curcumin (Cur) and piperine (Pip) as model water-insoluble drugs and developed a new method for the controlled preparation of carrier-free drug nanoparticles via multidrug co-assembly in a high-gravity environment. Encouraged by the controlled regulation of the nucleation and crystal growth rate of high-gravity technology accomplished by a rotating packed bed, co-amorphous Cur-Pip co-assembled multidrug nanoparticles with a uniform particle size of 130 nm were successfully prepared, exhibiting significantly enhanced dissolution performance and in vitro cytotoxicity. Moreover, the hydrogen bonding interactions between Cur and Pip in nanoparticles provide them with excellent re-dispersibility and storage stability. Moreover, the oral bioavailability of Cur was dramatically enhanced as a result of the smaller particle size of the co-assembled nanoparticles and the effective metabolic inhibitory effect of Pip. The present study provides a controlled approach to preparing a carrier-free nanoparticulate formulation through a multidrug co-assembly process in the high-gravity field to improve the oral bioavailability of insoluble drugs.

Methionine dipeptide (Met-Met) could improve milk protein synthesis in bovine epithelia mammary cells and lactating mice, while the effects of Met-Met on lactation performance, rumen fermentation and microbiota profile in lactating dairy cows have not been explored. For this reason, 60 Chinese lactating Holstein cows were allocated into three treatment groups: control group (CON), 6 g/d methionine dipeptide group (MM), and 6.12 g/d rumen-protected methionine dipeptide group (RPMM). The experiment lasted for 10 weeks to monitor lactation performance, plasma amino acid profile and rumen fermentation parameters and microbiota profile. Results showed that MM increased the energy-corrected milk (ECM), and RPMM increased both milk yield and ECM (p < 0.05). The milk protein concentration and yield were increased by MM and RPMM (p < 0.05). The rumen fermentation showed that RPMM increased total volatile fatty acids, acetate and valerate concentrations (p < 0.05). The relative abundance of Firmicutes, including Succiniclasticum, Selenomonas and Clostridium_XlVa, were enriched and the Prevotella was decreased by RPMM (p < 0.05). In summary, daily supplementing with 6 g of MM or RPMM in lactating dairy cows could improve milk yield and both percentage and yield of milk protein, and RPMM benefited the rumen fermentation and altered the bacterial composition. These results provided the first evidence that Met-Met supplementation can improve lactation performance of dairy cows.

The threat of ozone in indoor spaces and other enclosed environments is receiving increasing attention. Among numerous ozone catalytic decomposition technologies, copper catalytic material has a superior performance and relatively low cost, making it one of the ideal catalyst materials. This review presents the recent Cu catalyst studies on ozone decomposition, particularly morphological design, the construction of heterostructures, and monolithic catalyst design used to improve their performance. Moreover, this review proposes further improvement directions based on Cu materials’ inherent limitations and practical needs. On this basis, in the foreseeable future, Cu materials will play a greater role.

Abstract Electrochemical oxidation of small molecules (e.g., water, urea, methanol, hydrazine, and glycerol) has gained growing scientific interest in the fields of electrochemical energy conversion/storage and environmental remediation. Designing cost‐effective catalysts for the electrooxidation of small molecules (ESM) is thus crucial for improving reaction efficiency. Recently, earth‐abundant amorphous transition metal (TM)‐based nanomaterials have aroused souring interest owing to their earth‐abundance, flexible structures, and excellent electrochemical activities. Hundreds of amorphous TM‐based nanomaterials have been designed and used as promising ESM catalysts. Herein, recent advances in the design of amorphous TM‐based ESM catalysts are comprehensively reviewed. The features (e.g., large specific surface area, flexible electronic structure, and facile structure reconstruction) of amorphous TM‐based ESM catalysts are first analyzed. Afterward, the design of various TM‐based catalysts with advanced strategies (e.g., nanostructure design, component regulation, heteroatom doping, and heterostructure construction) is fully scrutinized, and the catalysts’ structure‐performance correlation is emphasized. Future perspectives in the development of cost‐effective amorphous TM‐based catalysts are then outlined. This review is expected to provide practical strategies for the design of next‐generation amorphous electrocatalysts.

Highlights This review systematically analyzes the effect of the electrolyte-to-sulfur ratios on battery energy density and the challenges for sulfur reduction reactions under lean electrolyte conditions. The strengths and limitations of different transition metal compounds are systematically presented and discussed from a fundamental perspective. Three promising strategies for sulfur hosts that act as anchors and catalysts are proposed to boost lean electrolyte Li–S battery performance.

Abstract Dihydroartemisinin (DHA), a natural product derived from the herbal medicine Artemisia annua, is recently used as a novel anti-cancer agent. However, some intrinsic disadvantages limit its potential for clinical management of cancer patients, such as poor water solubility and low bioavailability. Nowadays, the nanoscale drug delivery system emerges as a hopeful platform for improve the anti-cancer treatment. Accordingly, a metal-organic framework (MOF) based on zeolitic imidazolate framework-8 was designed and synthesized to carry DHA in the core (ZIF-DHA). Contrast with free DHA, these prepared ZIF-DHA nanoparticles (NPs) displayed preferable anti-tumor therapeutic activity in several ovarian cancer cells accompanied with suppressed production of cellular reactive oxygen species (ROS) and induced apoptotic cell death. 4D-FastDIA-based mass spectrometry technology indicated that down-regulated reactive oxygen species modulator 1 (ROMO1) might be regarded as potential therapeutic targets for ZIF-DHA NPs. Overexpression of ROMO1 in ovarian cancer cells significantly reversed the cellular ROS-generation induced by ZIF-DHA, as well as the pro-apoptosis effects. Taken together, our study elucidated and highlighted the potential of zeolitic imidazolate framework-8-based MOF to improve the activity of DHA to treat ovarian cancer. Our findings suggested that these prepared ZIF-DHA NPs could be an attractive therapeutic strategy for ovarian cancer.

Abstract Objective The safety and efficacy of drug-eluting balloon on the treatment of intracranial atherosclerotic stenosis (ICAS) remain unclear. Here, we present our observation in a cohort study on the safety and efficacy of rapamycin-eluting balloon for patients with ICAS. Methods A total of 80 ICAS patients with stenosis degree of 70–99% were included. All patients were treated with rapamycin-eluting balloon and were followed up for 12 months after operation. Results All patients were successfully treated, where the mean stenosis severity reduced from 85.1 ± 7.6 to 6 ± 4.9%. 8 patients experienced immediate post-operational complications. Two patients passed away during the first month of the follow-up period. Recurrent ischemic syndrome and angiographic restenosis only appeared 7 days after operation. During later follow-up period, none of the patients had clinical angiographic restenosis or needed target vessel revascularization. Conclusion Our data suggest that intracranial stenting with rapamycin-eluting balloon seems to be safe and effective, although more clinical data are needed to support this notion.

Abstract In rice (Oryza sativa) tissue culture, callus can be induced from the scutellum in embryo or from the vasculature of non-embryonic organs such as leaves, nodes, or roots. Here we show that the auxin signaling pathway triggers cell division in the epidermis of the scutellum to form an embryo-like structure, which leads to callus formation. Our transcriptome data show that embryo-, stem cell-, and auxin-related genes are upregulated during scutellum-derived callus initiation. Among those genes, the embryo-specific gene OsLEC1 is activated by auxin and involved in scutellum-derived callus initiation. However, OsLEC1 is not required for vasculature-derived callus initiation from roots. In addition, OsIAA11 and OsCRL1, which are involved in root development, are required for vasculature-derived callus formation but not for scutellum-derived callus formation. Overall, our data indicate that scutellum-derived callus initiation is regulated by an embryo-like development program, and this is different from vasculature-derived callus initiation which borrows a root development program.

With the improving life expectancy of patients with human immunodeficiency virus (HIV), there is an increasing health concern of potential toxicity and drug interactions of long-term antiretroviral therapies. We describe a female patient with HIV, who was admitted to the emergency department following an unexplained loss of consciousness. This patient had been on antiretroviral therapy comprising tenofovir disoproxil fumarate, lamivudine, and lopinavir/ritonavir for 12 years. Coincidentally, she had been prescribed terfenadine for urticaria recently. After 3 days on this medication, she suddenly lost her consciousness, with a distinctive electrocardiogram alteration characterized by QT prolongation and torsade de pointes. This symptom recurred several times over a span of 2 days. We postulate that the primary instigator was an elevated concentration of terfenadine, which can be traced back to her antiretroviral therapy regimen comprising lopinavir/ritonavir. This drug is known to impede the metabolism of cytochrome P450 3A4 substrates and consequently elevate terfenadine concentrations.

Ultra-high molecular weight polyethylene (UHMWPE) fiber is a new kind of high-performance fiber. Due to its excellent physical and chemical characteristics, it is widely used in various fields. However, the surface UHMWPE fiber is smooth and demonstrates no-polar groups. The weak interfacial adhesion between fiber and resin seriously restricts the applications of UHMWPE fiber. Therefore, the surface modification treatments of UHMWPE fiber are used to improve the interfacial adhesion strength. The modified method by adding nanomaterials elucidates the easy fabrication, advanced equipment and proper technology. Thus, the progress of UHMWPE nanocomposite fibers prepared via adding various nanofillers are reviewed. Meanwhile, the effects of other various methods on surface modification are also reviewed. This work advances the various design strategies about nano technologies on improving interfacial adhesion performance via treatment methodologies.

MXenes are emerging transition metal carbides and nitrides-based 2D conductive materials. They have found wide applications in sensors due to their excellent valuable properties. This paper reviews the recent research status of MXene-based electrochemical (bio) sensors for detecting biomarkers, pesticides, and other aspects. The first part of this paper introduced the synthesis strategy and the effect of surface modification on various properties of MXenes. The second part of this paper discussed the application of MXenes as electrode modifiers for detecting pesticides, environmental pollutants, and biomarkers such as glucose, hydrogen peroxide, etc. Hope this review will inspire more efforts toward research on MXene-based sensors to meet the growing requirements.

Abstract Background Gene duplication is a prevalent phenomenon and a major driving force underlying genome evolution. The process leading to the fixation of gene duplicates following duplication is critical to understand how genome evolves but remains fragmentally understood. Most previous studies on gene retention are based on gene duplicate analyses in single reference genome. No population-based comparative gene retention analysis has been performed to date. Results Taking advantage of recently published genomic data in Triticeae, we dissected a divergent homogentisate phytyltransferase (HPT2) lineage caught in the middle stage of gene fixation following duplication. The presence/absence of HPT2 in barley (diploid), wild emmer (tetraploid), and bread wheat (hexaploid) pangenome lines appears to be associated with gene dosage constraint and environmental adaption. Based on these observations, we adopted a phylogeny-based orthology inference approach and performed comparative gene retention analyses across barley, wild emmer, and bread wheat. This led to the identification of 326 HPT2-pattern-like genes at whole genome scale, representing a pool of gene duplicates in the middle stage of gene fixation. Majority of these HPT2-pattern-like genes were identified as small-scale duplicates, such as dispersed, tandem, and proximal duplications. Natural selection analyses showed that HPT2-pattern-like genes have experienced relaxed selection pressure, which is generally accompanied with partial positive selection and transcriptional divergence. Functional enrichment analyses showed that HPT2-pattern-like genes are over-represented with molecular-binding and defense response functions, supporting the potential role of environmental adaption during gene retention. We also observed that gene duplicates from larger gene family are more likely to be lost, implying a gene dosage constraint effect. Further comparative gene retention analysis in barley and bread wheat pangenome lines revealed combined effects of species-specific selection and gene dosage constraint. Conclusions Comparative gene retention analyses at the population level support gene dosage constraint, environmental adaption, and species-specific selection as three factors that may affect gene retention following gene duplication. Our findings shed light on the evolutionary process leading to the retention of newly formed gene duplicates and will greatly improve our understanding on genome evolution via duplication.

Crop leaf length, perimeter, and area serve as vital phenotypic indicators of crop growth status, the measurement of which is important for crop monitoring and yield estimation. However, processing a leaf point cloud is often challenging due to cluttered, fluctuating, and uncertain points, which culminate in inaccurate measurements of leaf phenotypic parameters. To tackle this issue, the RKM-D point cloud method for measuring leaf phenotypic parameters is proposed, which is based on the fusion of improved Random Sample Consensus with a ground point removal (R) algorithm, the K-means clustering (K) algorithm, the Moving Least Squares (M) method, and the Euclidean distance (D) algorithm. Pepper leaves were obtained from three growth periods on the 14th, 28th, and 42nd days as experimental subjects, and a stereo camera was employed to capture point clouds. The experimental results reveal that the RKM-D point cloud method delivers high precision in measuring leaf phenotypic parameters. (i) For leaf length, the coefficient of determination (R2) surpasses 0.81, the mean absolute error (MAE) is less than 3.50 mm, the mean relative error (MRE) is less than 5.93%, and the root mean square error (RMSE) is less than 3.73 mm. (ii) For leaf perimeter, the R2 surpasses 0.82, the MAE is less than 7.30 mm, the MRE is less than 4.50%, and the RMSE is less than 8.37 mm. (iii) For leaf area, the R2 surpasses 0.97, the MAE is less than 64.66 mm2, the MRE is less than 4.96%, and the RMSE is less than 73.06 mm2. The results show that the proposed RKM-D point cloud method offers a robust solution for the precise measurement of crop leaf phenotypic parameters.

The emergence of plasmid-mediated colistin resistance threatens the efficacy of colistin as a last-resort antibiotic used to treat infection caused by Gram-negative bacteria (GNB). Given the shortage of new antibiotics, the discovery of adjuvants to existing antibiotics is a promising strategy to combat infections caused by multidrug-resistant (MDR) GNB. This study was designed to investigate the potential synergistic antibacterial activity of bavachin, a bioactive compound extracted from the Psoralea Fructus, combined with colistin against MDR GNB. Herein, the synergistic efficacy in vitro and the therapeutic efficacy of colistin combined with bavachin in vivo were evaluated. The synergistic mechanism was detected by fluorescent probe and the transcript levels of mcr-1. Bavachin combined with colistin showed an excellent synergistic activity against GNB, as the FICI ≤ 0.5. In contrast to colistin alone, combination therapy dramatically increased the survival rate of Galleria mellonella and mice in vivo. Moreover, the combination of bavachin and colistin significantly reduced the amount of bacterial biofilm formation, improved the membrane disruption of colistin and inhibited mcr-1 transcription. These findings show that bavachin is a potential adjuvant of colistin, which may provide a new strategy to combat colistin-resistant bacteria infection with lower doses of colistin.

Topological photonics offers a powerful platform for next-generation nanophotonic chips, capitalizing on their remarkable resilience to disorder and defects. Among the two-dimensional (2D) photonic topological insulators, valley-Hall (VH) and pseudo-spin-Hall (PSH) topological insulators have emerged as the most practical designs, as they do not require breaking time-reversal symmetry. These photonic topological insulators support robust edge states, demonstrating promising potential for a wide range of applications, from on-chip communication to optical computing and sensing. However, the conversion between distinct topological phases (VH and PSH) in terahertz (THz) band has not been achieved. Here we experimentally demonstrate a THz on-chip spin–valley converter through adiabatic evolution in 2D parameter space without closing the bulk bandgap. By leveraging the adiabatic phase transition, we confirm the high-efficiency conversion between two valley states in a valley–spin–valley converter. In addition, we verify the robustness of THz PSH topological energy transport through sharply twisted corners. Our findings not only advance the understanding of topological phases in photonics but also hold promise for the development of innovative photonic devices with enhanced performance and functionality.

Flotation machines and flotation columns are widely used as separation equipment for coal sludge. In order to obtain better flotation results for different particle sizes, the bubble distribution and size in the flow field need to be studied. In this paper, a novel three-phase fluidized bed flotation column (TFC) was designed, and the shear effect of liquid velocity (0.198 m/s, 0.226 m/s, and 0.254 m/s) and static bed height (0.1 m, 0.2 m, and 0.3 m) on the bubbles in the mineralized flow field region was investigated and evaluated for the formation of bubbles by shear in laboratory and semi-industrial experiments. The results show that the increase in filling bed height has a very obvious strengthening effect on the reduction of bubble diameter, and after the filling bed height reaches a certain value, the filling bed height will weaken the effect of apparent gas velocity on bubble diameter. The apparent gas velocity has different influencing effects on bubble diameter, and under conditions of low water velocity, the increase in the apparent gas velocity contributes to the reduction of bubble diameter. The conclusions of this study are expected to optimize the operating parameters of the flotation mineralization process and enrich the study of TFC, which can provide a reference for the design of future TFC studies.

Abstract Background We aimed to explore the predictive value of retinol binding protein (RBP) for outcomes of hip fractures. Methods Patients with hip fractures who underwent hip surgeries between December 2017 and February 2021 and met the inclusion criteria were analyzed. Propensity score matching was used to reduce the bias of co-factors and ROC curves based on matched populations were created to determine the optimal cutoff point of RBP. The outcomes between patients with low levels of RBP and high levels of RBP were compared. Results Four hundred eighty patients were enrolled in this study and 69 patients died within one year. After a 1:1 PSM, patients with more than 1-year survival had significantly higher RBP (p = 0.013) than those who died within one year, as well as patients divided by 6-months survival (p = 0.012). Logistics analysis showed that low RBP may be an independent risk factor for 3-month survival, 6-month survival, 1-year survival, and 3-month free walking ability. Conclusion RBP may be associated with the survival and 3-month walking abilities of patients with hip fractures.

Highlights Critical strategies for converting wastes to catalysts are summarized. Applications of waste-derived catalysts in hydrogen evolution reaction, oxygen evolution reaction, and overall water electrolysis are comprehensively reviewed. Perspectives in the development of waste-derived catalysts are analyzed.

The present work aims to prove the concept of tumor-targeted drug delivery mediated by platelets. Doxorubicin (DOX) attached to nanodiamonds (ND-DOX) was investigated as the model payload drug of platelets. In vitro experiments first showed that ND-DOX could be loaded in mouse platelets in a dose-dependent manner with a markedly higher efficiency and capacity than free DOX. ND-DOX-loaded platelets (Plt@ND-DOX) maintained viability and ND-DOX could be stably held in the platelets for at least 4 hr. Next, mouse Lewis lung cancer cells were found to activate Plt@ND-DOX and thereby stimulate cargo unloading of Plt@ND-DOX. The unloaded ND-DOX was taken up by co-cultured cancer cells which consequently exhibited loss of viability, proliferation suppression and apoptosis. In vivo, Plt@ND-DOX displayed significantly prolonged blood circulation time over ND-DOX and DOX in mice, and Lewis tumor grafts demonstrated infiltration, activation and cargo unloading of Plt@ND-DOX in the tumor tissue. Consequently, Plt@ND-DOX effectively reversed the growth of Lewis tumor grafts which exhibited significant inhibition of cell proliferation and apoptosis. Importantly, Plt@ND-DOX displayed a markedly higher therapeutic potency than free DOX but without the severe systemic toxicity associated with DOX. Our findings are concrete proof of platelets as efficient and efficacious carriers for tumor-targeted nano-drug delivery with the following features: 1) large loading capacity and high loading efficiency, 2) good tolerance of cargo drug, 3) stable cargo retention and no cargo unloading in the absence of stimulation, 4) prolonged blood circulation time, and 5) excellent tumor distribution and tumor-activated drug unloading leading to high therapeutic potency and few adverse effects. Platelets hold great potential as efficient and efficacious carriers for tumor-targeted nano-drug delivery.

Photosynthesis is the basis for the survival of organisms in nature; consequently, the fabrication of artificial light-harvesting systems (LHSs) that simulate natural photosynthesis is of significant interest. Recently, a variety of artificial LHSs have been successfully constructed using fluorescence resonance energy transfer (FRET). However, it is crucial to fabricate artificial LHSs with a sequential energy transfer process when considering that the natural photosynthetic process involves a multistep sequential energy transfer process rather than a simple one-step energy transfer. Moreover, many previously reported LHSs have been used as imaging agents for cell labeling and bioimaging or as catalysts in photocatalytic reactions, showing promise for applications simulating natural photosynthesis. In this review, we have summarized recently published representative work on artificial LHSs. In addition, the application of LHSs in photocatalysis and cell labeling has been described in detail.

The rapid development of artificial intelligence and 5G network technology has opened a new era of interconnection of all things.The great improvement of computing power has threatened the traditional cryptographic algorithm based on the theory of computational difficulty.Data security and communication security have become key problems to be solved urgently in the era of Internet of things,hence cryptology has entered an intelligence era.The new generation of intelligent cryptology mainly consists of two core technologies:intelligent cryptographic algorithm based on neural network and intelligent cryptanalysis based on machine learning.The former uses the nonlinear characteristics of neural network to design the encryption process and improve the security of ciphertext.The latter trains the machine learning model through the clear ciphertext set to obtain the ciphertext features and improve the ciphertext decoding efficiency.This paper briefly reviews the development of cryptographic algorithms,discusses machine learning methods on intelligent cryptology,focuses on combing the latest progress of cryptographic algorithms and cryptanalysis intelligence at home and abroad,analyzes the advantages and disadvantages of intelligent cryptology at present,and discusses the research direction and challenges in the future.

Based on the hourly observation data of 79 automatic weather stations in Shanghai from 2010 to 2020 and the rainstorm warning signal data issued by the Shanghai Meteorological Center and District Meteorological Centers from 2016 to 2020, the spatial and temporal distribution characteristics of the rainstorm in Shanghai are analyzed using statistical metrics such as trend analysis and cumulative frequency. On the basis of statistical analysis of the frequency and timeliness of rainstorm warning signals at different levels, the difference of the timeliness of rainstorm warning signals under different synoptic conditions was studied. The results show that the rainstorm meeting the 6-h rainfall standard presents a significantly increasing trend, particularly for the rainstorm with the "Blue " warning. The rainstorm meeting the 6-h rainfall standard is the minimum in July, while the rainstorm meeting the 1-h rainfall standard is mroe in July than in June, which indicates that the frequency of short-time rainstorm in Shanghai is higher in July due to the control of subtropical high. The rainstorm in Shanghai usually lasts relatively short in the afternoon, while the longer rainstorm usually occurs in the morning. The frequency of heavy rainstorm is the highest in the urban area and Pudong near the Huangpu River, which may be related to the urban heat island effect. The release time of early warning signal in Shanghai presents a feature of bimodal distribution. The first peak appears at 12:00, and the release of early warning signals from 12:00 to 17:00 is relatively concentrated. The second peak appears at 6:00 in the morning.The average duration of early warning signals of all levels is 5.9 hours. The average hit rate of rainstorm early warning in Shanghai is 82.4%, and the average rainstorm warning time is 1.3 hours. The severe convective rainstorm at the edge of the subtropical high has the shortest warning timeliness, and the rainstorm near the typhoon body or the peripheral spiral rain belt is easy to be missed, which requires special attention in future.

Abstract Although the oxygen reduction process to hydrogen peroxide (H2O2) is a green option for H2O2 generation, the low activity and selectivity hindered the industry's process. In recent years, the electrochemical synthesis of H2O2 through a 2e– transfer method of oxygen reduction reaction (ORR) has piqued the interest of both academics and industry. Metal oxide catalysts have emerged as a novel family of electrochemical catalysts due to their unusual physical, chemical, and electrical characteristics. In this work, we first developed a Ruddlesden–Popper perovskite oxide (Pr2NiO4+δ) as a highly selective and active catalyst for 2e– ORR to produce H2O2. Molybdenum was introduced here to adjust the oxidation states of these transition metals with successful substitution into Ni‐site to prepare Pr2Ni1‐xMoxO4+δ, and the molybdenum substitution improves the H2O2 selectivity during the ORR process, in 0.1 M KOH, from 60% of Pr2NiO4+δ to 79% of Pr2Ni0.8Mo0.2O4+δ at 0.55 V versus RHE. A limiting H2O2 concentration of 0.24 mM for Pr2NiO4+δ and 0.42 mM for Pr2Ni0.8Mo0.2O4+δ was obtained at a constant current of 10 mA/cm2 using a flow‐cell reactor using a gas‐diffusion electrode.

This article aims to fill a gap in existing studies by examining methanol's prospects as a cleaner marine vessel fuel and addressing the industry's challenges in reducing pollution from ship oil. The analysis focuses on methanol as a decarbonization fuel option, following its advantages compared to others through data triangulation that uses both bottom-up and top-down approaches to examine the safety concerns and environmental impacts of methanol. The findings support its use as a promising alternative to conventional marine fuels, considering regulations and safety codes related to low-flashpoint fuels and specifying key safety measures. Also, container vessels (6% of the global fleet) consume 23% of all annual bunker volume and require nearly two-thirds of the global bunker demand, along with liquid bulk tankers and dry bulk carriers. These findings, along with the current regulatory landscape and infrastructure requirements for methanol fuel distribution, pose the greatest challenges to its widespread adoption, despite successes by MAN and Wärtsilä engine manufacturers in offering high-pressure diesel combustion technology engines for burning methanol. This study provides insights that can help ASEAN adopt methanol fuel while complying with emission standards and reducing its environmental impacts.

Background Immune cell infiltration (ICI) has a close relationship with the progression of atherosclerosis (AS). Therefore, the current study was aimed to explore the role of genes related to ICI and to investigate potential mechanisms in AS. Methods Single-sample gene set enrichment analysis (ssGSEA) was applied to explore immune infiltration in AS and controls. Genes related to immune infitration were mined by weighted gene co-expression network analysis (WGCNA). The function of those genes were analyzed by enrichment analyses of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). The interactions among those genes were visualized in the protein-protein interaction (PPI) network, followed by identification of hub genes through Cytoscape software. A receiver operating characteristic (ROC) plot was generated to assess the performance of hub genes in AS diagnosis. The expressions of hub genes were measured by reverse transcription quantitative real-time PCR (RT-qPCR) in human leukemia monocyticcell line (THP-1) derived foam cells and macrophages, which mimic AS and control, respectively. Results We observed that the proportions of 27 immune cells were significantly elevated in AS. Subsequent integrative analyses of differential expression and WGCNA identified 99 immune cell-related differentially expressed genes (DEGs) between AS and control. Those DEGs were associated with tryptophan metabolism and extracellular matrix (ECM)-related functions. Moreover, by constructing the PPI network, we found 11 hub immune cell-related genes in AS. The expression pattern and receiver ROC analyses in two independent datasets showed that calsequestrin 2 (CASQ2), nexilin F-Actin binding protein (NEXN), matrix metallopeptidase 12 (MMP12), C-X-C motif chemokine ligand 10 (CXCL10), phospholamban (PLN), heme oxygenase 1 (HMOX1), ryanodine receptor 2 (RYR2), chitinase 3 like 1 (CHI3L1), matrix metallopeptidase 9 (MMP9), actin alpha cardiac muscle 1 (ACTC1) had good performance in distinguishing AS from control samples. Furthermore, those biomarkers were shown to be correlated with angiogenesis and immune checkpoints. In addition, we found 239 miRNAs and 47 transcription factor s (TFs), which may target those biomarkers and regulate their expressions. Finally, we found that RT-qPCR results were consistent with sequencing results.

Abstract Background Chemodynamic therapy (CDT) relying on intracellular iron ions and H2O2 is a promising therapeutic strategy due to its tumor selectivity, which is limited by the not enough metal ions or H2O2 supply of tumor microenvironment. Herein, we presented an efficient CDT strategy based on Chinese herbal monomer-dihydroartemisinin (DHA) as a substitute for the H2O2 and recruiter of iron ions to amplify greatly the reactive oxygen species (ROS) generation for synergetic CDT-ferroptosis therapy. Results The DHA@MIL-101 nanoreactor was prepared and characterized firstly. This nanoreactor degraded under the acid tumor microenvironment, thereby releasing DHA and iron ions. Subsequent experiments demonstrated DHA@MIL-101 significantly increased intracellular iron ions through collapsed nanoreactor and recruitment effect of DHA, further generating ROS thereupon. Meanwhile, ROS production introduced ferroptosis by depleting glutathione (GSH), inactivating glutathione peroxidase 4 (GPX4), leading to lipid peroxide (LPO) accumulation. Furthermore, DHA also acted as an efficient ferroptosis molecular amplifier by direct inhibiting GPX4. The resulting ROS and LPO caused DNA and mitochondria damage to induce apoptosis of malignant cells. Finally, in vivo outcomes evidenced that DHA@MIL-101 nanoreactor exhibited prominent anti-cancer efficacy with minimal systemic toxicity. Conclusion In summary, DHA@MIL-101 nanoreactor boosts CDT and ferroptosis for synergistic cancer therapy by molecular amplifier DHA. This work provides a novel and effective approach for synergistic CDT-ferroptosis with Chinese herbal monomer-DHA and Nanomedicine. Graphical Abstract