Search

Abstract Background Thyroid eye disease (TED) is a vision-threatening autoimmune disorder. Orbital tissue fibrosis leading to intractable complications remains a troublesome issue in TED management. Exploration of novel therapeutic targets and agents to ameliorate tissue fibrosis is crucial for TED. Recent work suggests that Ca2+ signaling participates in tissue fibrosis. However, whether an alteration of Ca2+ signaling has a role in fibrogenesis during TED remains unclear. In this study, we aimed to investigate the role of Ca2+ signaling in the fibrogenesis process during TED and the potential therapeutic effects of a highly selective inhibitor of the L-type calcium channel (LTCC), nimodipine, through a TGF-β1 induced in vitro TED model. Methods Primary culture of orbital fibroblasts (OFs) were established from orbital adipose connective tissues of patients with TED and healthy control donors. Real-time quantitative polymerase chain reaction (RT-qPCR) and RNA sequencing were used to assess the genes expression associated with LTCC in OFs. Flow cytometry, RT-qPCR, 5-ethynyl-2′-deoxyuridine (EdU) proliferation assay, wound healing assay and Western blot (WB) were used to assess the intracellular Ca2+ response on TGF-β1 stimulation, and to evaluate the potential therapeutic effects of nimodipine in the TGF-β1 induced in vitro TED model. The roles of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and signal transducer and activator of transcription 1 (STAT1) in fibrogenesis during TED were determined by immunohistochemistry, WB, flow cytometry and co-immunoprecipitation assay. Selective inhibitors were used to explore the downstream signaling pathways. Results LTCC inhibitor nimodipine blocked the TGF-β1 induced intracellular Ca2+ response and further reduced the expression of alpha-smooth muscle actin (α-SMA), collagen type I alpha 1 (Col1A1) and collagen type I alpha 2 (Col1A2) in OFs. Besides, nimodipine inhibited cell proliferation and migration of OFs. Moreover, our results provided evidence that activation of the CaMKII/STAT1 signaling pathway was involved in fibrogenesis during TED, and nimodipine inhibited the pro-fibrotic functions of OFs by down-regulating the CaMKII/STAT1 signaling pathway. Conclusions TGF-β1 induces an LTCC-mediated Ca2+ response, followed by activation of CaMKII/STAT1 signaling pathway, which promotes the pro-fibrotic functions of OFs and participates in fibrogenesis during TED. Nimodipine exerts potent anti-fibrotic benefits in vitro by suppressing the CaMKII/STAT1 signaling pathway. Our work deepens our understanding of the fibrogenesis process during TED and provides potential therapeutic targets and alternative candidate for TED.

The corrosion features of 20# carbon steel, the base material of sour water stripper, in NH4Cl solution were examined in this research. The anatomical samples of the corroded parts were characterized by an X-ray diffractometer and other analytical tools. It was found to be a localized perforation caused by pitting, and the corrosion product was FeCl2. 20# steel was subjected to electrochemical testing using Tafel polarization and Electrochemical impedance spectroscopy. The studies showed that the 20# steel’s cathodic depolarization reaction rate speeds as density rises, and that the concentration polarization gets more marked as temperature rises. The corrosion rate of 20# steel is the fastest when temperature hits its highest point of 80°C, measuring 4.7142 mm/a. When density rose from 5 to 20%, corrosion rate grew from 1.6378 to 7.2430 mm/a.

The traffic loading is a typical cyclic loading with variable confining pressure and always lasts long, and is believed to have a significant effect on the subgrade soil, especially for the subgrade filled with soft clay. However, the mechanics have yet to be fully understood. Given that the duration of traffic loading lasts long enough, the partially drained conditions should be considered for the soft clay under the long-term cyclic loading, rather than the undrained conditions adopted commonly by most previous researches. In this study, 28 cyclic tests were conducted on the remolded saturated soft clay, utilizing both constant confining pressure and variable confining pressure under partially drained and undrained conditions. The effect of cyclic confining pressure and different drainage conditions is analyzed in relation to the evolution of pore pressure and deformation behaviors. Incorporating both the cyclic confining pressure and cyclic stress ratio, a concise pre-diction model of permanent strain is proposed and validated by the experimental results.

Cardiovascular disease (CVD) is one of the leading causes of mortality in humans, and oxidative stress plays a pivotal role in disease progression. This phenomenon typically arises from weakening of the cellular antioxidant system or excessive accumulation of peroxides. This review focuses on a specialized form of oxidative stress—disulfide stress—which is triggered by an imbalance in the glutaredoxin and thioredoxin antioxidant systems within the cell, leading to the accumulation of disulfide bonds. The genesis of disulfide stress is usually induced by extrinsic pathological factors that disrupt the thiol-dependent antioxidant system, manifesting as sustained glutathionylation of proteins, formation of abnormal intermolecular disulfide bonds between cysteine-rich proteins, or irreversible oxidation of thiol groups to sulfenic and sulfonic acids. Disulfide stress not only precipitates the collapse of the antioxidant system and the accumulation of reactive oxygen species, exacerbating oxidative stress, but may also initiate cellular inflammation, autophagy, and apoptosis through a cascade of signaling pathways. Furthermore, this review explores the detrimental effects of disulfide stress on the progression of various CVDs including atherosclerosis, hypertension, myocardial ischemia-reperfusion injury, diabetic cardiomyopathy, cardiac hypertrophy, and heart failure. This review also proposes several potential therapeutic avenues to improve the future treatment of CVDs.

Abstract Background To investigate serum irisin levels in girls at different developmental status and explore the significance of irisin for the diagnosis of central precocious puberty (CPP) in girls. Methods In this cross-sectional study 111 girls were enrolled, including 43 cases of CPP, 44 cases of peripheral precocious puberty (PPP) and 24 cases of girls with normal sexual development as controls. The data on age, weight and height, measured blood levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, and irisin were collected. Pelvic Doppler ultrasound was performed to evaluate uterine length, transverse diameter, anteroposterior diameter. The girls were divided into non-CPP group and CPP group according to gonadotropin-releasing hormone (GnRH) stimulation test. Results Serum irisin levels were significantly higher in CPP group than in PPP group and normal control group. Serum irisin level was positively correlated with basal LH level, basal FSH level, peak LH level, peak LH /FSH ratio, uterine volume, bone age, and bone age index. The area under the curve, cut-off value, sensitivity and specificity of serum irisin were 0.958, 219.255 pg/ml, 100% and 80.6%. The combined diagnosis of CPP in girls by serum irisin and serum basal LH combined with uterine volume had an AUC, sensitivity, and specificity of 0.994, 97.6%, and 100%, superior to that of the single index. Conclusions Serum irisin level in girls with CPP is significantly increased. An irisin combined index could help the diagnosis of CPP in girls.

With the increasing demand for personalized and customized home products, how to realize the innovative design of furniture and improve the design efficiency has become a research hotspot for related professionals. Aiming at these problems, the study extracts the main color of furniture images by optimizing the K-mean clustering algorithm, uses the simulated annealing algorithm to color-match the furniture, and reconstructs the image by edge detection to design a furniture design method based on image color extraction. The results revealed that in the foreground part, the correct rate of color match based on the design method was 95.7%, and in the background part, the correct rate of color match based on the design method was 94.81 %, which proved its effectiveness. The average feature point extraction time and the average feature point matching time of the design-based algorithm were 5.45 ms and 9.83 ms, respectively, which proved its high computational efficiency. In furniture color edge detection and overall color match, the image obtained based on the design method was significantly clearer, and the overall coherence, saturation and brightness were closer to the input image. In addition to raising the standard of furniture design, the study's design methodology increases design efficiency and offers solid technical support for the area.

This study explores the reduction of carbamates (CAs) and pyrethroids (PYs) − commonly used pesticides − in lettuce using various immersion solutions and ultrasonic processing. It also examines the role of machine learning and molecular docking in understanding the mechanisms of pesticide reduction. The results revealed that the highest reduction of both CAs and PYs exceeded 80 % on lettuce leaves. In most samples, the reduction increased with the power of ultrasonic processing and processing time. The results of machine learning models (XGBoost and SHAP) showed that during the immersion cleaning of CAs and PYs, as well as during both immersion cleaning and ultrasonic processing of CAs + PYs, the reduction was most influenced by the initial pesticide levels and immersion time. Gas Chromatography-Mass Spectrometry (GC–MS) analysis of lettuce’s wax layer identified 24 compounds, including fatty alcohols, fatty acids, fatty acid esters, and triterpenoids. Despite the absence of active sites, the lipophilic nature of long-chain aliphatic compounds aids in pesticide binding, while triterpenoids form strong hydrogen bonds with pesticides, indicating a robust adsorption on the lettuce surface. This study aims to offer insights into the efficient removal of chemical pesticide residues from fruits and vegetables, addressing critical concerns for food safety and human health.

Abstract Two-dimensional (2D) superlattices, formed by stacking sublattices of 2D materials, have emerged as a powerful platform for tailoring and enhancing material properties beyond their intrinsic characteristics. However, conventional synthesis methods are limited to pristine 2D material sublattices, posing a significant practical challenge when it comes to stacking chemically modified sublattices. Here we report a chemical synthesis method that overcomes this challenge by creating a unique 2D graphene superlattice, stacking graphene sublattices with monodisperse, nanometer-sized, square-shaped pores and strategically doped elements at the pore edges. The resulting graphene superlattice exhibits remarkable correlations between quantum phases at both the electron and phonon levels, leading to diverse functionalities, such as electromagnetic shielding, energy harvesting, optoelectronics, and thermoelectrics. Overall, our findings not only provide chemical design principles for synthesizing and understanding functional 2D superlattices but also expand their enhanced functionality and extensive application potential compared to their pristine counterparts.

Rydberg atom receiver attracts much research interest for promising applications in communications and sensing. Generally, Rydberg atomic receiver is utilized with microwave frequency comb (MFC) to expand its detectable frequency range. MFC consists of a set of equally spaced discrete frequency lines, resembling a comb in frequency space. In such receives, the mixing of RF signal and its closest MFC component excites the atoms into the desired Rydberg state. Since the mixing rather than RF signal is detected, there exists inevitable ambiguity of frequency estimation. In this paper, we provide a novel frequency ambiguity resolution based on improved Chinese remainder theorem (I-CRT). It realizes the instantaneous frequency estimation of RF signal with the MFC-based Rydberg atomic receiver. The effectiveness of proposed resolution in this paper is verified by both simulation experiments and theoretical analysis.

Abstract AXIN1, has been initially identified as a prominent antagonist within the WNT/β-catenin signaling pathway, and subsequently unveiled its integral involvement across a diverse spectrum of signaling cascades. These encompass the WNT/β-catenin, Hippo, TGFβ, AMPK, mTOR, MAPK, and antioxidant signaling pathways. The versatile engagement of AXIN1 underscores its pivotal role in the modulation of developmental biological signaling, maintenance of metabolic homeostasis, and coordination of cellular stress responses. The multifaceted functionalities of AXIN1 render it as a compelling candidate for targeted intervention in the realms of degenerative pathologies, systemic metabolic disorders, cancer therapeutics, and anti-aging strategies. This review provides an intricate exploration of the mechanisms governing mammalian AXIN1 gene expression and protein turnover since its initial discovery, while also elucidating its significance in the regulation of signaling pathways, tissue development, and carcinogenesis. Furthermore, we have introduced the innovative concept of the AXIN1-Associated Phosphokinase Complex (AAPC), where the scaffold protein AXIN1 assumes a pivotal role in orchestrating site-specific phosphorylation modifications through interactions with various phosphokinases and their respective substrates.

Aiming at the problem that in the hybrid visible light and RF network, such as the traditional user switching scheme leveraging received signal strength and ignoring the user switching error rate, a location-based user switching scheme was proposed.Specifically, an integrated communication and positioning system built upon low-cost IoT chip ESP32 was designed, which could fuse both visible light communication downlink and Wi-Fi uplink signals for accurate user location.A communication and positioning integration framework utilizing time-frequency multiplexing was designed, which used a neural network to estimate the user’s position, and the user completed the switching based on the estimated position.In terms of communication, the throughput of the system can reach up to 35 kbit/s.In terms of positioning, the positioning accuracy of the system can reach 2.8 cm, making a 33% improvement over traditional system.Compared with the switching scheme relying on received signal strength, user switching error rate of the proposed scheme is reduced by 4%.

Abstract Background Hepatocellular carcinoma (HCC) has a high incidence and mortality rate despite various treatment options, including 125I seed implantation. However, recurrence and radiation resistance remain challenging issues. Hsa_circ_0007895 (circEYA3)—derived from exons 2–6 of EYA3–facilitates the proliferation and progression of pancreatic ductal adenocarcinoma. However, the role of circEYA3 in HCC 125I radiation resistance remains unclear. Thus, we aimed to investigate the functions and underlying molecular mechanisms of circEYA3 in HCC under 125I and X-ray irradiation conditions. Methods CircEYA3 was identified by RNA-seq in patients with HCC before and after 125I seed implantation treatment, followed by fluorescence in situ hybridization and RNase R assays. The radiosensitivity of HCC cell lines irradiated with 125I seeds or external irradiation were evaluated using the Cell Counting Kit 8, flow cytometry, γH2A.X immunofluorescence and comet assays. RNA pull-down and RNA immunoprecipitation assays were performed to explore the interactions between circEYA3 and IGF2BP2. DTX3L mRNA was identified by RNA-seq in PLC/PRF/5 cells with overexpressed circEYA3. The corresponding in vitro results were verified using a mouse xenograft model. Results CircEYA3 decreased the radiosensitivity of HCC cells both in vitro and in vivo. Notably, using a circRNA pulldown assay and RNA-binding protein immunoprecipitation, we identified IGF2BP2 as a novel and robust interacting protein of circEYA3. Mechanistically, circEYA3 binds to IGF2BP2 and enhances its ability to stabilize DTX3L mRNA, thereby specifically alleviating radiation-induced DNA damage in HCC cells. Conclusions Our findings demonstrate that circEYA3 increases the radioresistance of HCC to 125I seeds and external irradiation via the IGF2BP2/DTX3L axis. Thus, circEYA3 might be a predictive indicator and intervention option for 125I brachytherapy or external radiotherapy in HCC.

Artificial spin systems are used to solve combinatorial optimization problems by mapping them to the ground state search of the Ising model. Ising machines of various designs, in fields as diverse as photonics and electronics, have been proposed and demonstrated in recent years. One important mathematical operation required in photonic Ising machines for nearly all Hamiltonian minimization algorithms is repeated matrix–vector multiplication with the vector size limited by the physical size of the optical system. Herein, an integrated photonic Ising machine based on matrix partitioning and phase encoding, which effectively allows the use of physically small optical circuits to handle arbitrarily large spin vectors, is proposed. All the complicated calculations are carried out optically, rather than electronically, in this approach. How the required surface area of a hypothetical chip‐based photonic Ising machine can be resized according to convenience, with the trade‐off being the solution time, and that this trade‐off can be done in a way that does not impact the algorithm's efficacy, is shown. Through simulation, the system is predicted to have a high success rate, high noise tolerance, and high error tolerance.

Peri-urban areas are vitally important to the function and value of our communities, our environment, and the economy. They often epitomise the relationship between a community and the landscape, providing essential eco-system services for the receiving settlement. With the expansion of cities and the resulting urban sprawl, the ability of peri-urban zones to sustain food provision is threatened in Aotearoa New Zealand. This study reports and reflects on a workshop facilitated by the Centre of Excellence: Designing Future Productive Landscapes, Te Whare Wānaka o Aoraki | Lincoln University, with the Canterbury Mayoral Forum, to explore alternative land use topologies for the peri-urban areas of Waitaha | Canterbury region. The focus of this paper is on the application of a ‘design-thinking methodology’, to explore this issue, and the opportunities for engagement and solution ideation that it promoted. Workshop participants were engaged in three activities designed to provoke alternative and innovative thinking about the spatial relationship between urban growth (housing) and agricultural land (production). Key findings illustrate the strengths of the methodology to elicit alternative responses to land use within the peri-urban zone, with results indicating a desire to rethink how we plan and design the edges of cities to better protect and enhance their ability to produce food and support other essential eco-system services alongside urban expansion.

Aluminosilicate zeolites are widely recognized as an industrially important crystalline microporous material. Among them, small-pore SSZ-13 stands out as an artificial aluminosilicate zeolite with CHA topology. Since its invention in 1985, SSZ-13 zeolite has garnered significant attention in both academia and industry due to its exceptional performance in heterogeneous catalysis, gas adsorption and separation. Modification of its physicochemical properties to meet the diverse requirements of various application scenarios has become a prominent topic in zeolite research. Considerable efforts have been devoted to alleviating the diffusion limitations inherent in micropores by downsizing crystal size or introducing additional mesopores and/or macropores to construct hierarchical structures. Regulating framework Al atoms in isolation or pairing introduces remarkable catalytic or adsorptive diversity into compositionally similar SSZ-13 zeolites. The conventional synthesis of SSZ-13 zeolite, which involves the use of expensive and toxic N,N,N-trimethyl-1-adamantylammonium hydroxide (TMAdaOH) as an organic structure-directing agent (OSDA) and a hydrothermal crystallization process lasting typically more than four days, severely hinders its cost-effective utilization. In response, extensive research endeavors have been dedicated to developing innovative synthetic approaches for SSZ-13 zeolites aimed at greener, more efficient, and economically viable production. This article presents a comprehensive overview of recent research developments in the field of SSZ-13 zeolites, encompassing novel synthetic methods, hierarchical engineering, nanocrystal technology, Al distribution, fast synthesis, and cost reduction techniques, aiming to provide valuable insights and guidance to relevant researchers.

Developing new therapeutic agents for cancer immunotherapy is highly demanding due to the low response ratio of PD-1/PD-L1 blockade in cancer patients. Here, we discovered that the novel immune checkpoint VISTA is highly expressed on a variety of tumor-infiltrating immune cells, especially myeloid derived suppressor cells (MDSCs) and CD8+ T cells. Then, peptide C1 with binding affinity to VISTA was developed by phage displayed bio-panning technique, and its mutant peptide VS3 was obtained by molecular docking based mutation. Peptide VS3 could bind VISTA with high affinity and block its interaction with ligand PSGL-1 under acidic condition, and elicit anti-tumor activity in vivo. The peptide DVS3-Pal was further designed by d-amino acid substitution and fatty acid modification, which exhibited strong proteolytic stability and significant anti-tumor activity through enhancing CD8+ T cell function and decreasing MDSCs infiltration. This is the first study to develop peptides to block VISTA/PSGL-1 interaction, which could act as promising candidates for cancer immunotherapy.

Zeolite-based catalysts efficiently catalyze the selective catalytic reduction of NOx with methane (CH4-SCR) for the environmentally friendly removal of nitrogen oxides, but suffer severe deactivation in high-temperature SO2- and H2O-containing flue gas. In this work, SSZ-39 zeolite (AEI topology) with high hydrothermal stability is reported for preparing CH4-SCR catalysts. Mild acid leaching with oxalic acid (OA) not only modulates the Si/Al ratio of commercial SSZ-39 to a suitable value, but also removes some extra-framework Al atoms, introducing a small number of mesopores into the zeolite that alleviate diffusion limitation. Additional Co3O4 modification during indium exchange further enhances the catalytic activity of the resulting In-Co3O4/H-SSZ-39(OA). The optimized sample exhibits remarkable performance in CH4-SCR under a gas hourly space velocity (GHSV) of 24,000 h−1 and in the presence of 5 vol% H2O. Even under harsh SO2- and H2O-containing high-temperature conditions, it shows satisfactory stability. Catalysts containing Co3O4 components demonstrate much higher CH4 conversion. The strong mutual interaction between Co3O4 and Brønsted acid sites, confirmed by the temperature-programmed desorption of NO (NO-TPD), enables more stable NxOy species to be retained in In-Co3O4/H-SSZ-39(OA) to supply further reactions at high temperatures.

Monitoring ships on water surfaces encounters obstacles such as weather conditions, sunlight, and water ripples, posing significant challenges in accurately detecting target ships in real time. Synthetic Aperture Radar (SAR) offers a viable solution for real-time ship detection, unaffected by cloud coverage, precipitation, or light levels. However, SAR images are often affected by speckle noise, salt-and-pepper noise, and water surface ripple interference. This study introduces LCAS-DetNet, a Multi-Location Cross-Attention Ship Detection Network tailored for the ships in SAR images. Modeled on the YOLO architecture, LCAS-DetNet comprises a feature extractor, an intermediate layer (“Neck”), and a detection head. The feature extractor includes the computation of Multi-Location Cross-Attention (MLCA) for precise extraction of ship features at multiple scales. Incorporating both local and global branches, MLCA bolsters the network’s ability to discern spatial arrangements and identify targets via a cross-attention mechanism. Each branch utilizes Multi-Location Attention (MLA) and calculates pixel-level correlations in both channel and spatial dimensions, further combating the impact of salt-and-pepper noise on the distribution of objective ship pixels. The feature extractor integrates downsampling and MLCA stacking, enhanced with residual connections and Patch Embedding, to improve the network’s multi-scale spatial recognition capabilities. As the network deepens, we consider this structure to be cascaded and multi-scale, providing the network with a richer receptive field. Additionally, we introduce a loss function based on Wise-IoUv3 to address the influence of label quality on the gradient updates. The effectiveness of our network was validated on the HRSID and SSDD datasets, where it achieved state-of-the-art performance: a 96.59% precision on HRSID and 97.52% on SSDD.

Malignant tumors are major causes of morbidity and mortality in China. Despite advances in surgical, radiological, chemotherapeutic, molecular targeting, and immunotherapeutic treatments, patients with malignant tumors still have poor prognoses. Low-dose-rate brachytherapy, specifically 125I seed implantation, is beneficial because of its high local delivery dose and minimal damage to surrounding tissues. Consequently, it has gained increasing acceptance as a treatment modality for various malignant tumors. In this study, we explored the fundamental principles, clinical applications, and new technologies associated with 125I radioactive seed implantation.

The research on the management and distribution of renewable water resources mostly adopts the method of combining the intelligent optimization algorithm and the target planning model. In this paper, four water distribution users are used as categories, and the problem of renewable water resources allocation is transformed into a classification problem, which is included in the category of wireless virtualization processing problems, and wireless virtualization is selected to support the allocation of renewable water resources. Experiments show that the water shortage of the water distribution scheme obtained by the method in this paper is lower than that of the optimal water distribution scheme of the traditional intelligent optimization algorithm. It can also be seen from the water distribution cost and water shortage of a single user that the water distribution effect of the method in this paper is better than that of the traditional intelligent optimization algorithm (P

Abstract Recent years have witnessed significant progress in quantum communication and quantum internet with the emerging quantum photonic chips, whose characteristics of scalability, stability, and low cost, flourish and open up new possibilities in miniaturized footprints. Here, we provide an overview of the advances in quantum photonic chips for quantum communication, beginning with a summary of the prevalent photonic integrated fabrication platforms and key components for integrated quantum communication systems. We then discuss a range of quantum communication applications, such as quantum key distribution and quantum teleportation. Finally, the review culminates with a perspective on challenges towards high-performance chip-based quantum communication, as well as a glimpse into future opportunities for integrated quantum networks.

Single-atom catalysts (SACs) have been widely recognized as state-of-the-art catalysts in environment remediation because of their exceptional performance, 100% metal atomic utilization, almost no secondary pollution, and robust structures. Most recently, the activation of persulfate with carbon-based SACs in advanced oxidation processes (AOPs) raises tremendous interest in the degradation of emerging contaminants in wastewater, owning to its efficient and versatile reactive oxidant species (ROS) generation. However, the comprehensive and critical review unraveling the underlying relationship between structures of carbon-based SACs and the corresponding generated ROS is still rare. Herein, we systematically summarize the fundamental understandings and intrinsic mechanisms between single metal atom active sites and produced ROS during AOPs. The types of emerging contaminants are firstly elaborated, presenting the prior pollutants that need to be degraded. Then, the preparation and characterization methods of carbon-based SACs are overviewed. The underlying material structure–ROS type relationship in persulfate-based AOPs is discussed in depth to expound the catalytic mechanisms. Finally, we briefly conclude the current development of carbon-based SACs in AOPs and propose the prospects for rational design and synthesis of carbon-based SACs with on-demand catalytic performances in AOPs in future research.

With the advancement of computer-based testing, log file data has drawn considerable attention from researchers. Although emerging studies have begun to explore log file data, there is a gap in the exploitation of log file data for capturing and understanding participants' cognitive processes. The debate on how to maximize insights from log file data has not yet reached a consensus. Therefore, we present this protocol for a scoping review that aims to characterize the application of log file data in current publications, including the data pre-processing techniques, analytical methodologies, and theoretical frameworks used by researchers. This review will also aim to illuminate how log file data can enhance psychological and educational assessments. Our findings will highlight the opportunities and challenges presented by log file data as an emerging and essential source of evidence for future advancements in psychological and educational assessment.

In order to accurately and efficiently assess the impact of tunnel excavation on overlying existing pipeline, an analytical method is proposed to solve this problem. First, the vertical free displacement of the surrounding soil due to tunnel excavation can be derived by the Loganathan formula. Next, the overlying existing pipeline can be treated as a Timoshenko beam resting on the Vlasov foundation model, and the influence of the surrounding soil on the both sides of the existing pipeline is taken into consideration. Finally, an analytical solution for the longitudinal deformation of the existing pipeline can be obtained by using the integral method. Case analysis results demonstrate that the calculated results of this method closely in line with measured data. Compared to the degenerate analytical solution given by this method, the result from this method is more consistent with the measured data. Further parameter studies show that the volume loss rate, diameter of new tunnel, skew angle, and vertical distance between tunnel and pipeline are significant factors affecting the existing pipeline response due to tunneling underlying.

Thin‐film lithium niobate (TFLN) modulators have garnered significant attention in the field of integrated photonics due to their ability to manipulate light. Numerous TFLN modulators have been demonstrated over the past few years, with speed records consistently being broken. However, due to the low refractive index contrast and anisotropic properties of TFLN, modulators based on this material feature larger device sizes and lower efficiency. A more compact and efficient modulator is important, as it is required for future dense integration and low power consumption applications. There have been some reports on how to reduce device size, and research is ongoing. A comprehensive summary can help individuals understand the current state of research and existing problems. In this review, we provide an overview of recent advancements in TFLN modulator technology, focusing on compactness and efficiency. Herein, various types of modulators, such as the Mach–Zehnder interferometer, Michelson interferometer, resonator cavity, and Z‐cut type modulators, are discussed. Moreover, potential improvement strategies and applications for compact and efficient TFLN modulators in advanced photonic systems are explored. In conclusion, in this review, the recent achievements in compact and efficient TFLN modulators are summarized and their significance in various optoelectronic applications is emphasized.

Abstract Bone metastasis is the main cause of death in patients with prostate cancer (PCa), but there lacks effective treatment method. Immunotherapy shows new hopes for bone metastatic PCa patients, while the efficacy is still unsatisfactory and limited by the unique immunosuppressive microenvironment in metastatic bone site. Here, we developed a bone-targeted nano-delivery system as a nano-regulator to enhance the immunotherapy of bone metastatic PCa. The nanosystem was assembled via coordination between phytic acid (PA) and Fe3+ to form nano-sized metal–organic framework (MOF), through which mitoxantrone (MTO) was encapsulated. At cellular level, the nanosystem showed selective cytotoxicity towards RM-1 PCa cells over immune cells, and could induce tumor cells immunogenic cell death (ICD) to improve the immunogenicity of the tumor. Moreover, the nanosystem was able to induce ubiquitination of TGFβ receptor (TβR) on immune cells to promote its degradation, thus serving as a nano-regulator to block the functions of TGF-β, an abundant cytokine that has a systematically immunosuppressive effect in the tumor microenvironment. Upon intravenous injection, the nanoparticle showed pro-longed blood circulation and targeting accumulation into bone metastatic site, and imposed robust anti-tumor effect in combination with αCTLA-4. In addition, bone destruction was significantly alleviated after treatment to reduce the skeletal-related events. Overall, this work provides a biocompatible nanomedicine to restore immune sensitivity of bone metastatic tumor for enhanced immunotherapy by blocking TGF-β signaling pathway.

Gemcitabine is a nucleoside analog effective against a number of cancers. However, it has an oral bioavailability of less than 10%, due to its high hydrophilicity and low permeability through the intestinal epithelium. Therefore, the aim of this project was to develop a novel nanoparticulate drug delivery system for the oral delivery of gemcitabine to improve its oral bioavailability. In this study, gemcitabine-loaded β-glucan NPs were fabricated using a film-casting method followed by a freezer-milling technique. As a result, the NPs showed a small particle size of 447.6 ± 14.2 nm, and a high drug entrapment efficiency of 64.3 ± 2.1%. By encapsulating gemcitabine into β-glucan NPs, a sustained drug release profile was obtained, and the anomalous diffusion release mechanism was analyzed, indicating that the drug release was governed by diffusion through the NP matrix as well as matrix erosion. The drug-loaded NPs had a greater ex vivo drug permeation through the porcine intestinal epithelial membrane compared to the plain drug solution. Cytotoxicity studies showed a safety profile of the β-glucan polymers, and the IC50s of drug solution and drug-loaded β-glucan NPs were calculated as 228.8 ± 31.2 ng·mL−1 and 306.1 ± 46.3 ng·mL−1, respectively. Additionally, the LD50 of BALB/c nude mice was determined as 204.17 mg/kg in the acute toxicity studies. Notably, pharmacokinetic studies showed that drug-loaded β-glucan NPs could achieve a 7.4-fold longer T1/2 and a 5.1-fold increase in oral bioavailability compared with plain drug solution. Finally, in vivo pharmacodynamic studies showed the promising capability of gemcitabine-loaded β-glucan NPs to inhibit the 4T1 breast tumor growth, with a 3.04- and 1.74-fold reduction compared to the untreated control and drug solution groups, respectively. In conclusion, the presented freezer-milled β-glucan NP system is a suitable drug delivery method for the oral delivery of gemcitabine and demonstrates a promising potential platform for oral chemotherapy.

The genus Stictochironomus (Diptera: Chironomidae) has an almost worldwide distribution, with more than 30 species. However, species delimitation and identification based on the markings on the wings and legs are controversial and uncertain. In this study, we focused on color patterns to review the adults of the genus from China, and two new species (S. trifuscipes sp. nov. and S. quadrimaculatus sp. nov.) are described and figured. DNA barcodes can accurately separate the two new species with specific color patterns. However, heterospecific individuals form a monophyletic cluster in the phylogeny tree. For example, S. maculipennis (Meigen) and S. pictulus (Meigen), which have a lower interspecific genetic divergence, form a single clade. Sequences with the same species name but with high intraspecific distance form more than one phylogenetic clade, such as S. sticticus (Fabricius) of three clades, S. pictulus of four clades, S. akizukii (Tokunaga) and S. juncaii Qi, Shi, and Wang of two clades, might have potential cryptic species diversity. Species delimitation analysis using ASAP, PTP, and GMYC clearly delineated them as separate species. Consequently, color patterns are a good diagnostic characteristic for species delimitation in Stictochironomus. The distance-based analysis shows that a threshold of 4.5–7.7% is appropriate for species delimitation in Stictochironomus. Additionally, an updated key including color pattern variation for male adults of known Stictochironomus species from China is provided.

Abstract Background Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal malignancy with poor patient prognosis. Current treatment for ESCC, including immunotherapy, is only beneficial for a small subset of patients. Better characterization of the tumor microenvironment (TME) and the development of novel therapeutic targets are urgently needed. Methods In the present study, we hypothesized that integration of single-cell transcriptomic sequencing and large microarray sequencing of ESCC biopsies would reveal the key cell subtypes and therapeutic targets that determine the prognostic and tumorigenesis of ESCC. We characterized the gene expression profiles, gene sets enrichment, and the TME landscape of a microarray cohort including 84 ESCC tumors and their paired peritumor samples. We integrated single-cell transcriptomic sequencing and bulk microarray sequencing of ESCC to reveal key cell subtypes and druggable targets that determine the prognostic and tumorigenesis of ESCC. We then designed and screened a blocking peptide targeting Chemokine C–C motif ligand 18 (CCL18) derived from tumor associated macrophages and validated its potency by MTT assay. The antitumor activity of CCL18 blocking peptide was validated in vivo by using 4-nitroquinoline-1-oxide (4-NQO) induced spontaneous ESCC mouse model. Results Comparative gene expression and cell–cell interaction analyses revealed dysregulated chemokine and cytokine pathways during ESCC carcinogenesis. TME deconvolution and cell interaction analyses allow us to identify the chemokine CCL18 secreted by tumor associated macrophages could promote tumor cell proliferation via JAK2/STAT3 signaling pathway and lead to poor prognosis of ESCC. The peptide Pep3 could inhibit the proliferation of EC-109 cells promoted by CCL18 and significantly restrain the tumor progression in 4-NQO-induced spontaneous ESCC mouse model. Conclusions For the first time, we discovered and validated that CCL18 blockade could significantly prevent ESCC progression. Our study revealed the comprehensive cell–cell interaction network in the TME of ESCC and provided novel therapeutic targets and strategies to ESCC treatment.

ObjectivesThis study aims to explore the crashworthiness of a nuclear power platform's double-skin side structure.MethodsFinite element models of the full platform and partial double-skin side structure are established respectively, and the collision is carried out using LS-DYNA software. Based on the simulation analysis, a scale quasi-static squeeze test model is designed, and the quasi-static squeeze test of the double-skin side structure is carried out and compared with the numerical simulation. ResultsThe results show that for low-speed ship collisions, the structural response calculated using the local double-skin side structure model is basically consistent with that calculated using the whole ship model; thus, the quasi-static scaled test results are in good agreement with the numerical simulation results and can reflect the characteristics and structural deformation mode, thereby verifying the numerical simulation method. Meanwhile, the test results show that the double-skin side structure of the nuclear power platform remains intact when colliding with a 5 000 ton class ship at a speed of 2 m/s, which means that it has good crashworthiness. ConclusionsThis study shows that using a local double-skin side structure model to calculate collision response has high accuracy and greatly reduces the modelling and calculation workloads. The results of this study can provide valuable references for structural crashworthiness design in marine engineering.

As one of the important parts of Neural Network, activation function plays a very important role in model training in Neural Network. In this paper, the status quo, advantages and disadvantages of the existing common activation functions are analysed, and a new activation function is proposed and applied to target detection. To test the performance of the new activation function, this paper compares it with the ReLU activation functions on a variety of Neural Networks and data sets, and not only analyses the performance of the activation function itself but also verifies the effectiveness of the activation function in target detection.

Large-scale silicon-based integrated artificial neural networks lack of silicon-integrated optical neurons. Here, Yu et al, report a self-monitored all-optical neural network enabled by nonlinear germanium-silicon photodiodes, making the photonic neural network more versatile and compact.

Understanding the functions of enzymes in various physiological processes is important, but the design of signaling probes for fast analysis of enzymatic activity is particularly challenging. Herein, a fluorescence-enhanced probe, 10-methyl-2-nitro-acridone (MNA), was synthesized and applied to analyze nitroreductase (NTR) activity in vitro and in vivo. The detection mechanism is based on the nitro group in MNA reacting toward NTR with high reactivity and generating 10-methyl-2-amino- acridone (MAA) accompanied by an obvious fluorescence signal enhancement at 525 nm emission. The probe shows low cytotoxicity, fast response, and high selectivity and sensitivity with a limit of detection as low as 150 ng·mL−1. The probe was also employed for two-photon fluorescence imaging of NTR in zebrafish in vivo revealing the distribution of NTR. Versus existing NTR probes, the proposed probe shows favorable analytical performance including near-infrared light excitation with no other byproducts produced after the reaction. The superior properties of this signaling probe allow it to become a fluorescence imaging candidate in other biosystems.

Background Aside from immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1), intervention of CD47/Sirpα mediated ‘don’t eat me’ signal between macrophage and tumor cell is considered as a promising therapeutic approach for cancer immunotherapy. Compared with CD47, the novel immune checkpoint CD24/Siglec-10 can also deliver ‘don’t eat me’ signal and CD24 shows much lower expression level in normal tissue which might avoid unwanted side effects.Methods Cell-based phage display biopanning and D-amino acid modification strategy were used to identify the CD24/Siglec-10 blocking peptide. Cell-based blocking assay and microscale thermophoresis assay were used to validate the blocking and binding activities of the peptide. Phagocytosis and co-culture assays were used to explore the in vitro function of the peptide. Flow cytometry was performed to assess the immune microenvironment after the peptide treatment in vivo.Results A CD24/Siglec-10 blocking peptide (CSBP) with hydrolysis-resistant property was identified. Surprisingly, we found that CSBP could not only block the interaction of CD24/Siglec-10 but also PD-1/PD-L1. CSBP could induce the phagocytosis of tumor cell by both the macrophages and monocytic myeloid-derived suppressor cells (M-MDSCs), which can further activate CD8+ T cells. Besides, combination of radiotherapy and CSBP synergistically reduced tumor growth and altered the tumor microenvironment in both anti-PD-1-responsive MC38 and anti-PD-1-resistant 4T1 tumor models.Conclusions In summary, this is the first CD24/Siglec-10 blocking peptide which blocked PD-1/PD-L1 interaction as well, functioned via enhancing the phagocytosis of tumor cells by macrophages and M-MDSCs, and elevating the activity of CD8+ T cells for cancer immunotherapy.

IntroductionMarine ferromanganese crusts are potentially important metal resources.The deep-ocean research and survey ships often need to carry out rapid chemical element component analysis of mineral resources, so as to plan for the geological resource exploration mission.MethodsThe laser-induced breakdown spectroscopy can obtain the spectrum of chemical elements by the plasma excited by high-energy laser irradiation on the surface of the sample. A laser induced breakdown spectroscopy optical system for the detection of deepocean ferromanganese crusts is designed and built, which can meet the requirements of near-insitu chemical component detection of deep-ocean mineral resources on ocean-going survey ships.ResultsHyperspectral data of Fe-Mn crusts are carried out by the Laser-induced breakdown spectroscopy (LIBS) system during a deep-sea exploration mission at a depth of 2,490 m in the South China Sea. The experimental parameters of laser energy and spectral acquisition delay are optimized to improve the spectral measurement accuracy. Based on the calibration-free method, the significant spectral features of the chemical elements Fe and Mn were obtained through proper alignment with the National Institute of Standards and Technology (NIST) chemical element spectral library.DiscussionThe LIBS instrument can be placed on board long-range survey vessels in the future to provide a fast, convenient, accurate, and economical detection method for deep-ocean resource exploration.

Abstract Background Melatonin, an indoleamine produced by the pineal gland, plays a pivotal role in maintaining circadian rhythm homeostasis. Recently, the strong antioxidant and anti-inflammatory properties of melatonin have attracted attention of researchers. We evaluated the therapeutic efficacy of melatonin in experimental autoimmune uveitis (EAU), which is a representative animal model of human autoimmune uveitis. Methods EAU was induced in mice via immunization with the peptide interphotoreceptor retinoid binding protein 1–20 (IRBP1–20). Melatonin was then administered via intraperitoneal injection to induce protection against EAU. With EAU induction for 14 days, clinical and histopathological scores were graded to evaluate the disease progression. T lymphocytes accumulation and the expression of inflammatory cytokines in the retinas were assessed via flow cytometry and RT-PCR, respectively. T helper 1 (Th1), T helper 17 (Th17), and regulatory T (Treg) cells were detected via flow cytometry for both in vivo and in vitro experiments. Reactive-oxygen species (ROS) from CD4 + T cells was tested via flow cytometry. The expression of thioredoxin-interacting protein (TXNIP) and hypoxia-inducible factor 1 alpha (HIF-1α) proteins were quantified via western blot. Results Melatonin treatment resulted in notable attenuation of ocular inflammation in EAU mice, evidenced by decreasing optic disc edema, few signs of retinal vasculitis, and minimal retinal and choroidal infiltrates. Mechanistic studies revealed that melatonin restricted the proliferation of peripheral Th1 and Th17 cells by suppressing their transcription factors and potentiated Treg cells. In vitro studies corroborated that melatonin restrained the polarization of retina-specific T cells towards Th17 and Th1 cells in addition to enhancing the proportion of Treg cells. Pretreatment of retina-specific T cells with melatonin failed to induce EAU in naïve recipients. Furthermore, the ROS/ TXNIP/ HIF-1α pathway was shown to mediate the therapeutic effect of melatonin in EAU. Conclusions Melatonin regulates autoimmune T cells by restraining effector T cells and facilitating Treg generation, indicating that melatonin could be a hopeful treatment alternative for autoimmune uveitis.

The loss of productive soils and food-producing landscapes on the edges of cities is an increasing issue facing Aotearoa New Zealand. Like many countries globally, New Zealand’s largest cities are facing rapid expansion because of increasing urbanisation, with high levels of low-density residential sprawl into the productive peri-urban hinterlands and increasing rates of ‘reverse sensitivity’. Food production, as a result, is being pushed further away, disconnected from the communities it serves, and often onto less productive soil. This paper explores the perceptions and attitudes of both peri-urban residents and food producers living and working within the peri-urban zone of Ōtautahi Christchurch. Conducting two surveys, one with residents and another with producers, respondents’ perceptions of food growing within this peri-urban landscape are explored to better understand the enablers and barriers of growing food close to cities. Overall, the results indicated that peri-urban residents appreciate food being produced close to where they live, with over 90% of residential respondents feeling either ‘mostly positive’ or ‘extremely positive’ towards food being grown close to their homes. Of greatest concern for peri-urban residents were issues relating to negative impacts on the environment and human health, with particular concern for water quality. The lack of accessibility to locally produced food was also identified as an area of concern to residents. Food producers felt less positive towards operating their food-production enterprises within the peri-urban zone, identifying a range of issues impacting their experience. The information rendered from these surveys provides a base for future land-use planning consideration within the peri-urban zone, where both food production and housing can co-exist.

Ga(III) can mimic Fe(III) in the biological system due to its similarities in charge and ionic radius to those of Fe(III) and can exhibit antimicrobial activity by disrupting the acquisition and metabolism of Fe in bacterial cells. For example, Ga(NO3)3 has been proven to be effective in treating chronic lung infections by Pseudomonas aeruginosa (P. aeruginosa) in cystic fibrosis patients in a recent phase II clinical trial. However, Ga(NO3)3 is an ionic compound that can hydrolyze to form insoluble hydroxides at physiological pH, which not only reduces its bioavailability but also causes potential renal toxicity when it is used as a systemic drug. Although complexion with suitable chelating agents has offered a varying degree of success in alleviating the hydrolysis of Ga(III), the use of nanotechnology to deliver this metallic ion should constitute an ultimate solution to all the above-mentioned problems. Thus far, the development of Ga-based nanomaterials as metalloantibiotics is an underexploited area of research. We have developed two different synthetic routes for the preparation of biocompatible Ga2(HPO4)3 NPs and shown that both the PVP- or PEG-coated Ga2(HPO4)3 NPs exhibit potent antimicrobial activity against P. aeruginosa. More importantly, such polymer-coated NPs do not show any sign of Ga-resistant phenotype development after 30 passes, in sharp contrast to Ga(NO3)3, which can rapidly develop Ga-resistant phenotypes of P. aeruginosa, indicating the potential of using Ga2(HPO4)3 NPs a new antimicrobial agent in place of Ga(NO3)3.

Nowadays, task allocation has attracted increasing attention in the Internet of Vehicles. To efficiently allocate tasks to suitable workers, users usually need to publish their task interests to the service provider, which brings a serious threat to users' privacy. Existing task allocation schemes either cannot comprehensively preserve user privacy (i.e., requester privacy and worker privacy) or introduce tremendous resource overhead. In this paper, we propose an efficient and privacy-preserving versatile task allocation scheme (PPVTA) for the Internet of vehicles. Specifically, we utilize the randomizable matrix multiplication technique to preserve requester privacy and worker privacy. Then, the polynomial fitting technique is leveraged to enrich the randomizable matrix multiplication to support versatile task allocation functions, such as threshold-based task allocation (PPVTA-I), conjunctive task allocation (PPVTA-II), and task allocation with bilateral access control (PPVTA-III). We formally analyze the security of our constructions to prove the security under the chosen-plain attack. Based on a prototype, experimental results demonstrate that our constructions have acceptable efficiency in practice.

ObjectiveThe widespread use of antibiotics has inevitably led to the emergence of multidrug-resistant bacterial strains, such as methicillin-resistant Staphylococcus aureus (MRSA), making treatment of this infection a serious challenge. This study aimed to explore new treatment strategies for MRSA infection.MethodsThe structure of Fe3O4 NPs with limited antibacterial activity was optimized, and the Fe2+ ↔ Fe3+ electronic coupling was eliminated by replacing 1/2 Fe2+ with Cu2+. A new type of copper-containing ferrite nanoparticles (hereinafter referred to as Cu@Fe NPs) that fully retained oxidation–reduction activity was synthesized. First, the ultrastructure of Cu@Fe NPs was examined. Then, antibacterial activity was determined by testing the minimum inhibitory concentration (MIC) and safety for use as an antibiotic agent. Next, the mechanisms underlying the antibacterial effects of Cu@Fe NPs were investigated. Finally, mice models of systemic and localized MRSA infections was established for in vivo validation.ResultsIt was found that Cu@Fe NPs exhibited excellent antibacterial activity against MRSA with MIC of 1 μg/mL. It effectively inhibited the development of MRSA resistance and disrupted the bacterial biofilms. More importantly, the cell membranes of MRSA exposed to Cu@Fe NPs underwent significant rupture and leakage of the cell contents. Cu@Fe NPs also significantly reduced the iron ions required for bacterial growth and contributed to excessive intracellular accumulation of exogenous reactive oxygen species (ROS). Therefore, these findings may important for its antibacterial effect. Furthermore, Cu@Fe NPs treatment led to a significant reduction in colony forming units within intra-abdominal organs, such as the liver, spleen, kidney, and lung, in mice with systemic MRSA infection, but not for damaged skin in those with localized MRSA infection.ConclusionThe synthesized nanoparticles has an excellent drug safety profile, confers high resistant to MRSA, and can effectively inhibit the progression of drug resistance. It also has the potential to exert anti-MRSA infection effects systemically in vivo. In addition, our study revealed a unique multifaceted antibacterial mode of Cu@Fe NPs: (1) an increase in cell membrane permeability, (2) depletion of Fe ions in cells, (3) generation of ROS in cells. Overall, Cu@Fe NPs may be potential therapeutic agents for MRSA infections.

Compared with quartz sand, recycled aggregate sand is characterized by the high liquefaction and shear resistance because of its irregular particle shape. However, the interrelationship between its particle shape and shear behaviors is seldom investigated. This paper investigates the role of the particle shape on the shear behaviors of recycled aggregate sand by conducting a series of monotonic and cyclic simple shear tests under undrained constant volume conditions. The particles’ morphology parameters are assessed in terms of sphericity, roundness and regularity with microscopic observation and image processing. According to the experimental results, the recycled aggregate sand with irregular shapes mobilizes greater gradients of the flow liquefaction lines under monotonic shear conditions. The irregularity of the particle shape also leads to greater peak shear stress and dynamic shear modulus, indicating stronger shear and liquefaction resistances under the cyclic shearing. Furthermore, the interrelationships between the peak shear stress, dynamic shear modulus and particle shape of the samples are revealed and established by well fitted functions, which could serve as references for the selection of recycled aggregate sand and corresponding designs of the foundation.

Abstract Background Cancer is one of the devastating diseases in the world. The development of nanocarrier provides a promising perspective for improving cancer therapeutic efficacy. However, the issues with potential toxicity, quantity production, and excessive costs limit their further applications in clinical practice. Results Herein, we proposed a nanocarrier obtained from aloe with stability and leak-proofness. We isolated nanovesicles from the gel and rind of aloe (gADNVs and rADNVs) with higher quality and yield by controlling the final centrifugation time within 20 min, and modulating the viscosity at 2.98 mPa S and 1.57 mPa S respectively. The gADNVs showed great structure and storage stability, antioxidant and antidetergent capacity. They could be efficiently taken up by melanoma cells, and with no toxicity in vitro or in vivo. Indocyanine green (ICG) loaded in gADNVs (ICG/gADNVs) showed great stability in both heating system and in serum, and its retention rate exceeded 90% after 30 days stored in gADNVs. ICG/gADNVs stored 30 days could still effectively damage melanoma cells and inhibit melanoma growth, outperforming free ICG and ICG liposomes. Interestingly, gADNVs showed prominent penetrability to mice skin which might be beneficial to noninvasive transdermal administration. Conclusions Our research was designed to simplify the preparation of drug carrier, and reduce production cost, which provided an alternative for the development of economic and safe drug delivery system. Graphical Abstract

Abstract Chemotherapy-induced intestinal mucositis (CIM) is a common adverse reaction to antineoplastic treatment with few appropriate, specific interventions. We aimed to identify the role of the G protein coupled estrogen receptor (GPER) in CIM and its mechanism. Adult male C57BL/6 mice were intraperitoneally injected with 5-fluorouracil to establish the CIM model. The selective GPER agonist G-1 significantly inhibited weight loss and histological damage in CIM mice and restored mucosal barrier dysfunction, including improving the expression of ZO-1, increasing the number of goblet cells, and decreasing mucosal permeability. Moreover, G-1 treatment did not alter the antitumor effect of 5-fluorouracil. In the CIM model, G-1 therapy reduced the expression of proapoptotic protein and cyclin D1 and cyclin B1, reversed the changes in the number of TUNEL+ cells, Ki67+ and bromodeoxyuridine+ cells in crypts. The selective GPER antagonist G15 eliminated all of the above effects caused by G-1 on CIM, and application of G15 alone increased the severity of CIM. GPER was predominantly expressed in ileal crypts, and G-1 inhibited the DNA damage induced by 5-fluorouracil in vivo and vitro, as confirmed by the decrease in the number of γH2AX+ cells in the crypts and the comet assay results. Referring to the data from GEO dataset we verified GPER activation restored ERK1/2 activity in CIM and 5-fluorouracil-treated IEC-6 cells. Once the effects of G-1 on ERK1/2 activity were abolished with the ERK1/2 inhibitor PD0325901, the effects of G-1 on DNA damage both in vivo and in vitro were eliminated. Correspondingly, all of the manifestations of G-1 protection against CIM were inhibited by PD0325901, such as body weight and histological changes, the mucosal barrier, the apoptosis and proliferation of crypt cells. In conclusion, GPER activation prevents CIM by inhibiting crypt cell DNA damage in an ERK1/2-dependent manner, suggesting GPER might be a target preventing CIM.

Tryptophan 2,3-dioxygnease 2 (TDO2) is specific for metabolizing tryptophan to kynurenine (KYN), which plays a critical role in mediating immune escape of cancer. Although accumulating evidence demonstrates that TDO2 overexpression is implicated in the development and progression of multiple cancers, its tumor-promoting role in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we observed that TDO2 was overexpressed in ESCC tissues and correlated significantly with lymph node metastasis, advanced clinical stage, and unfavorable prognosis. Functional experiments showed that TDO2 promoted tumor cell proliferation, migration, and colony formation, which could be prevented by inhibition of TDO2 and aryl hydrocarbon receptor (AHR). Further experimentation demonstrated that TDO2 could promote the tumor growth of KYSE150 tumor-bearing model, tumor burden of C57BL/6 mice with ESCC induced by 4-NQO, enhance the expression of phosphorylated AKT, with subsequent phosphorylation of GSK3β, and polarization of M2 macrophages by upregulating interleukin-8 (IL-8) to accelerate tumor progression in the tumor microenvironment (TME). Collectively, our results discovered that TDO2 could upregulate IL-8 through AKT/GSK3β to direct the polarization of M2 macrophages in ESCC, and suggested that TDO2 could represent as an attractive therapeutic target and prognostic marker to ESCC.

A new species of fossil cockroach, Fragosublatta pectinata gen. et sp. nov., is described from mid-Cretaceous Burmese amber. The new species is assigned to the family Corydiidae based on the following combination of characters: pronotum with tubercles, tegmina obovate with smallish anal region and spinules on the antero-ventral margin of the front femur (type C1). The new species is the second reported cockroach with ramified antennae. This finding broadens the diversity of Blattodea in mid-Cretaceous Burmese amber and provides further evidence of convergent evolution for antennal structures among different insect lineages.

Background The development of cancer is largely dependent on the accumulation of somatic mutations, indicating the potential to develop cancer chemoprevention agents targeting mutation drivers. However, ideal cancer chemoprevention agents that can effectively inhibit the mutation drivers have not been identified yet.Methods The somatic mutation signatures and expression analyses of APOBEC3B were performed in patient with pan-cancer. The computer-aided screening and skeleton-based searching were performed to identify natural products that can inhibit the activity of APOBEC3B. 4-nitroquinoline-1-oxide (4-NQO)-induced spontaneous esophageal squamous cell carcinoma (ESCC) and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced spontaneous colon cancer mouse models were conducted to investigate the influences of APOBEC3B inhibitor on the prevention of somatic mutation accumulation and cancer progression.Results Here, we discovered that the cytidine deaminase APOBEC3B correlated somatic mutations were widely observed in a variety of cancers, and its overexpression indicated poor survival. SMC247 (3, 5-diiodotyrosine), as a source of kelp iodine without side effects, could strongly bind APOBEC3B (KD=65 nM) and effectively inhibit its deaminase activity (IC50=1.69 µM). Interestingly, 3, 5-diiodotyrosine could significantly reduce the clusters of mutations, prevent the precancerous lesion progression, and prolong the survival in 4-NQO-induced spontaneous ESCC and AOM/DSS-induced spontaneous colon cancer mouse models. Furthermore, 3, 5-diiodotyrosine could reduce colitis, increase the proportion and function of T lymphocytes via IL-15 in tumor microenvironment. The synergistic cancer prevention effects were observed when 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade.Conclusions This is the first prove-of-concept study to elucidate that the natural product 3, 5-diiodotyrosine could prevent somatic mutation accumulation and cancer progression through inhibiting the enzymatic activity of APOBEC3B. In addition, 3, 5-diiodotyrosine could reduce the colitis and increase the infiltration and function of T lymphocytes via IL-15 in tumor microenvironment. 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade could elicit synergistic cancer prevention effects, indicating a novel strategy for both prevent the somatic mutation accumulation and the immune-suppressive microenvironment exacerbation.

In order to solve the problem of multiple aircraft formation transformation to a designated formation, a distributed formation transformation algorithm that decomposes the formation transformation problem into target-matching problems and trajectory-planning problems was studied. According to the actual formation transformation requirements, the target allocation index was proposed, and the improved genetic algorithm which is 23% better than other algorithms was used to achieve target matching. The adaptive cross-mutation probability was designed, and the population was propagated without duplicates by the hash algorithm. The multi-objective algorithm of distributed model predictive control was used to design smooth and conflict-free trajectories for the UAVs in formation transformation, and the trajectory-planning problem was transformed into a quadratic programming problem under inequality constraints. Finally, point-to-point collision-free offline trajectory planning was realized by simulation.

ObjectiveThe study aims to discuss the longitudinal impact of the parent-teacher relationship on students’ academic achievements in China.MethodBased on the China Education Panel Survey, covering the data from 438 classes of 112 schools in 28 county-level administrative areas in China, we used the hierarchical linear model to analyze the data.ResultsWe found that the parents’ active communication with teachers, parents’ participation in parent meetings, teachers’ active contact, whether parents are afraid to communicate with teachers, and parents’ willingness to participate in parent meetings have significant relationships with students’ academic achievements. At the class level, the extent of teachers’ stress from parents’ requests and teachers’ perception of respect from parents also affected students’ academic achievements significantly in the Chinese context.ConclusionThere was a longitudinal association between the parent-teacher relationship and students’ academic achievements. The practical implication was discussed in the paper.

BackgroundLiver hepatocellular carcinoma (LIHC), one of the most common primary malignancies, exhibits high levels of molecular and clinical heterogeneity. Increasing evidence has confirmed the important roles of some RNA helicase families in tumor development, but the function of the DEAH-box RNA helicase family in LIHC therapeutic strategies has not yet been clarified.MethodsThe LIHC dataset was downloaded from The Cancer Genome Atlas (TCGA). Consensus clustering was applied to group the patients. Least absolute shrinkage and selection operator Cox regression and univariate and multivariate Cox regression were used to develop and validate a prognostic risk model. The Tumor Immune Estimation Resource and Tumor Immune Single Cell Hub databases were used to explore the role of DEAH-box RNA helicases in LIHC immunotherapy. In vitro experiments were performed to investigate the role of DHX9 in LIHC radiosensitivity.ResultsTwelve survival-related DEAH-box RNA helicases were identified. High helicase expression levels were associated with a poor prognosis and clinical features. A prognostic model comprising six DEAH-box RNA helicases (DHX8, DHX9, DHX34, DHX35, DHX38, and DHX57) was constructed. The risk score of this model was found to be an independent prognostic indicator, and LIHC patients with different prognosis were distinguished by the model in the training and test cohorts. DNA damage repair pathways were also enriched in patients with high-risk scores. The six DEAH-box RNA helicases in the risk model were substantially related to innate immune cell infiltration and immune inhibitors. In vitro experiments showed that DHX9 knockdown improved radiosensitivity by increasing DNA damage.ConclusionThe DEAH-box RNA helicase signature can be used as a reliable prognostic biomarker for LIHC. In addition, DHX9 may be a definitive indicator and therapeutic target in radiotherapy and immunotherapy for LIHC.

8-Hydroxyquinoline (8-hq) exhibits potent antimicrobial activity against Staphylococcus aureus (SA) bacteria with MIC = 16.0–32.0 µM owing to its ability to chelate metal ions such as Mn2+, Zn2+, and Cu2+ to disrupt metal homeostasis in bacterial cells. We demonstrate that Fe(8-hq)3, the 1:3 complex formed between Fe(III) and 8-hq, can readily transport Fe(III) across the bacterial cell membrane and deliver iron into the bacterial cell, thus, harnessing a dual antimicrobial mechanism of action that combines the bactericidal activity of iron with the metal chelating effect of 8-hq to kill bacteria. As a result, the antimicrobial potency of Fe(8-hq)3 is significantly enhanced in comparison with 8-hq. Resistance development by SA toward Fe(8-hq)3 is considerably delayed as compared with ciprofloxacin and 8-hq. Fe(8-hq)3 can also overcome the 8-hq and mupirocin resistance developed in the SA mutant and MRSA mutant bacteria, respectively. Fe(8-hq)3 can stimulate M1-like macrophage polarization of RAW 264.7 cells to kill the SA internalized in such macrophages. Fe(8-hq)3 exhibits a synergistic effect with both ciprofloxacin and imipenem, showing potential for combination therapies with topical and systemic antibiotics for more serious MRSA infections. The in vivo antimicrobial efficacy of a 2% Fe(8-hq)3 topical ointment is confirmed by the use of a murine model with skin wound infection by bioluminescent SA with a reduction of the bacterial burden by 99 ± 0.5%, indicating that this non-antibiotic iron complex has therapeutic potential for skin and soft tissue infections (SSTIs).