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Abstract Immune checkpoint blockade therapy has revolutionized cancer treatment, but resistance remains prevalent, often due to dysfunctional tumor-infiltrating lymphocytes. A key contributor to this dysfunction is mitochondrial dysfunction, characterized by defective oxidative phosphorylation, impaired adaptation, and depolarization, which promotes T cell exhaustion and severely compromises antitumor efficacy. This review summarizes recent advances in restoring the function of exhausted T cells through mitochondria-targeted strategies, such as metabolic remodeling, enhanced biogenesis, and regulation of antioxidant and reactive oxygen species, with the aim of reversing the state of T cell exhaustion and improving the response to immunotherapy. A deeper understanding of the role of mitochondria in T cell exhaustion lays the foundation for the development of novel mitochondria-targeted therapies and opens a new chapter in cancer immunotherapy.

Although MXene sheets are highly conductive, it is still challenging to prepare MXene complex functional materials for flexible electronics by simple and effective methods. In 3D printing, especially direct ink writing (DIW), different materials are used to create complex 3D shapes by formulating inks with controlled rheological properties. Herein, a printable MXene ink is developed, exhibiting good rheological properties, to print different complex shapes, and potentially manufacture electronic devices such as sensors. Then, we fabricated a highly sensitive hierarchical structure MXene composite materials composed of two layers of bionic micro-spine microstructure and network structure, formed by 3D printing and freeze casting. The obtained MXene composite materials exhibit good pressuring sensing properties with a sensitivity of 17.5 kPa−1, a fast response time (

Abstract In three-dimensional free-bending forming (3D-FBF), the tube is not overly constrained, and the plastic deformation behavior and forming quality of the bent tube are significantly affected by the critical structure of the forming die lining. However, the effects of die-lining structural parameters on the tube quality, and a method to determine the combination of die-lining structural parameters is yet to be devised. This study aims to propose a new framework that allows one to understand the effects of various die-lining structural parameters on tube quality and to propose the best combination of die-lining structural parameters. First, finite-element modeling is performed to simulate 3D-FBF and examine the effects of individual die-lining structures on the quality of tube formation. The simulation results show that the deformation-zone length and die gap are positively correlated with the tube-section distortion and wall-thickness variation, whereas it shows an opposite trend with respect to the bending radius. Additionally, the lining chamfer radius of the bending die and the guide lining chamfer radius minimally affect the tube forming quality. Subsequently, the optimal die-lining structure is obtained using the response-surface method. The tube cross-sectional distortion rate reduced from 2.73 to 2.53% after the die lining is optimized. Additionally, the average inner-wall thickness reduced to 1.06 mm, whereas the average outer-wall thickness increased to 0.97 mm. This paper proposes a method for optimizing the forming-die-lining mechanism and for improving the tube forming quality in 3D-FBF.

Digital light processing (DLP)-based bioprinting technology holds immense promise for the advancement of hydrogel constructs in biomedical applications. However, creating high-performance hydrogel constructs with this method is still a challenge, as it requires balancing the physicochemical properties of the matrix while also retaining the cellular activity of the encapsulated cells. Herein, we propose a facile and practical strategy for the 3D bioprinting of high-performance hydrogel constructs through the in-situ birth of stem cell spheroids. The strategy is achieved by loading the cell/dextran microdroplets within gelatin methacryloyl (GelMA) emulsion, where dextran functions as a decoy to capture and aggregate the cells for bioprinting while GelMA enables the mechanical support without losing the structural complexity and fidelity. Post-bioprinting, the leaching of dextran results in a smooth curved surface that promotes in-situ birth of spheroids within hydrogel constructs. This process significant enhances differentiation potential of encapsulated stem cells. As a proof-of-concept, we encapsulate dental pulp stem cells (DPSCs) within hydrogel constructs, showcasing their regenerative capabilities in dentin and neovascular-like structures in vivo. The strategy in our study enables high-performance hydrogel tissue construct fabrication with DLP-based bioprinting, which is anticipated to pave a promising way for diverse biomedical applications.

Abstract The dual-functional radar-communication (DFRC) integrated system presents an ideal solution to address the challenge of spectrum resource congestion in future networks. This paper explores an adaptive power allocation technique based on beamforming to enhance the word error probability (WEP) performance of the DFRC system. Initially, a joint optimization model is developed to minimize the WEP while adhering to constraints on radar signal-to-interference-noise ratio (SINR), peak-to-average-power ratio, sidelobe level, and total transmit power. This model incorporates dual-function transmit beam, radar, and communication receive beam patterns. Subsequently, the proposed subproblem convex relaxation alternating update (SCRAU) algorithm is introduced to achieve a locally optimal solution for multi-carrier power allocation. This algorithm decomposes the original non-convex optimization problem into three sub-problems with lower complexity and iteratively optimizes them. Simulation experiments validate that the SCRAU algorithm can simultaneously fulfill radar and communication functions. The SCRAU algorithm demonstrates superior WEP performance compared to current advanced algorithms.

Porcine sapelovirus (PSV) is a new pathogen that negatively impacts the pig industry in China. Affected pigs experience severe diarrhea and even death. Vaccination is used to control disease outbreaks, and sensitive diagnostic methods that can distinguish infected animals from vaccinated animals (DIVA) are essential for monitoring the effectiveness of disease control programs. Tests based on the detection of the nonstructural protein (NSP) 3AB are reliable indicators of viral replication in infected and vaccinated animals. In this study, the recombinant PSV 3AB protein was expressed by a prokaryotic expression system, and an indirect ELISA method was established. Serum samples from healthy animals, immunized animals, and infected animals were evaluated. The ELISA method identified 3AB with high sensitivity (99.78%) and specificity (100.0%), and no cross-reaction was observed with serum antibodies against porcine reproductive and respiratory syndrome virus (PRRSV), infection with classical swine fever virus (CSFV), pseudorabies virus (PRV), bovine viral diarrhea virus (BVDV), porcine epidemic diarrhea virus (PEDV), or foot-and-mouth disease virus (FMDV). The ELISA method described here can effectively distinguish infected and vaccinated animals and is an important inexpensive tool for monitoring serum and controlling PSV.

Abstract Aims This study aimed to investigate the impact of different estimated glomerular filtration rate (eGFR) values like cystatin C-based eGFR (eGFRcys), creatinine-based eGFR (eGFRcr), and their difference (eGFRdiff; eGFRcys -eGFRcr), on the incidence of heart failure (HF) in patients with type 2 diabetes(T2D). Methods Being a prospective cohort study, it included 7,967 patients with T2D who underwent serum creatinine and cystatin C tests as part of the Kailuan Group’s 6th annual health examination (2016). Subsequently, eGFRcys, eGFRcr, and eGFRdiff were calculated. Patients were categorized into three groups: negative ( 15 mL/min/1.73 m2) eGFRdiff groups, respectively. Furthermore, the relationship between the various eGFR measurements and new-onset HF were studied using Cox proportional hazards regression, and the potential improvement in predictive capability was evaluated by adding these eGFR metrics to established HF risk models. Results Among 7967 participants with mean age of 60.51 years, there were 20.92% women and 79.08% men. At baseline, eGFRcys and eGFRcr values differed by more than 15 mL/min/1.73m2 in 41.3% of participants. During a median follow-up period of 3.76 years, there were 172 (2.16%) new HF cases and 517 (6.49%) all-cause deaths. The cumulative incidence of HF in the midrange, negative, and positive eGFRdiff groups was 1.74%, 4.10%, and 0.61%, respectively (p

This study investigates the factors that influence municipalities’ decisions to include social equity in their sustainability plans. The theoretical framework commonly used holds that community priority, administrative capacity, governing institutions, and social vulnerability matter. Although there is extensive literature supporting the influence of these factors in sustainability planning concerning economic development and environmental protection, few studies have investigated whether these factors explain decision-making related to the social equity dimension. Using logistic regression, this article tests these four theoretical explanations, to determine their applicability to equity-oriented sustainability planning. Results indicate that community priorities influence decision-making. When officials perceive that their communities prioritize social equity, they are much more likely to pursue equity-focused sustainability plans. Alternatively, when economic development is prioritized, equity strategies are less likely to be included in sustainability plans. The findings suggest possible policy tradeoffs among economic, environmental and equity goals.

Abstract Tunable three-dimensional (3D) electromagnetic metasurfaces are essential for achieving selective modulation of polarized waves, but they usually require complex designs and the use of smart materials, posing great implementation challenges. Here, we propose a novel kirigami-based reconfigurable electromagnetic metasurface, which consists of a kirigami-based deformable thin polyimide substrate and periodically arranged copper split-ring resonators. By simple stretch, the two-dimensional (2D) planar metasurface can be uniformly transformed into a 3D state, enabling it to effectively and selectively modulate linearly and circularly polarized waves. Experimental and numerical results reveal the mechanical deformation and transmission characteristics of the metasurface under applied strains. It is shown that the metasurface exhibits good selective transmission tunability while the resonant frequency remains basically unchanged for both transverse electric and transverse magnetic polarized waves. Furthermore, the selective tuning mechanism and the influence of geometrical parameters are also illustrated by the equivalent circuit analysis.

Abstract Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly understood. In this study, we uncover a critical role for SmD2, a core component of the spliceosome machinery, in modulating DNA damage in HCC through its impact on BRCA1/FANC cassette exons and expression. Our findings reveal that SmD2 depletion sensitizes HCC cells to PARP inhibitors, expanding the potential therapeutic targets. We also demonstrate that SmD2 acetylation by p300 leads to its degradation, while HDAC2-mediated deacetylation stabilizes SmD2. Importantly, we show that the combination of Romidepsin and Olaparib exhibits significant therapeutic potential in multiple HCC models, highlighting the promise of targeting SmD2 acetylation and HDAC2 inhibition alongside PARP inhibitors for HCC treatment.

Purpose: Radiation-induced dermatitis (RD) is a common side-effect of therapeutic ionizing radiation that can severely affect patient quality of life. This study aimed to develop a risk prediction model for the occurrence of RD in patients with cervical carcinoma undergoing chemoradiotherapy using electronic medical records (EMRs). Methods: Using EMRs, the clinical data of patients who underwent simultaneous radiotherapy and chemotherapy at a tertiary cancer hospital between 2017 and 2022 were retrospectively collected, and the patients were divided into two groups: a training group and a validation group. A predictive model was constructed to predict the development of RD in patients who underwent concurrent radiotherapy and chemotherapy for cervical cancer. Finally, the model's efficacy was validated using a receiver operating characteristic curve. Results: The incidence of radiation dermatitis was 89.5% (560/626) in the entire cohort, 88.6% (388/438) in the training group, and 91.5% (172/188) in the experimental group. The nomogram was established based on the following factors: age, the days between the beginning and conclusion of radiotherapy, the serum albumin after chemoradiotherapy, the use of single or multiple drugs for concurrent chemotherapy, and the total dose of afterloading radiotherapy. Internal and external verification indicated that the model had good discriminatory ability. Overall, the model achieved an area under the receiver operating characteristic curve of .66. Conclusions: The risk of RD in patients with cervical carcinoma undergoing chemoradiotherapy is high. A risk prediction model can be developed for RD in cervical carcinoma patients undergoing chemoradiotherapy, based on over 5 years of EMR data from a tertiary cancer hospital.

Abstract Background Mycobacteria bloodstream infections are common in immunocompromised people and usually have disastrous consequences. As the primary phagocytes in the bloodstream, monocytes and neutrophils play critical roles in the fight against bloodstream mycobacteria infections. In contrast to macrophages, the responses of monocytes infected with the mycobacteria have been less investigated. Results In this study, we first established a protocol for infection of non-adherent monocyte-like THP-1 cells (i.e. without the differentiation induced by phorbol 12-myristate 13-acetate (PMA) by bacillus Calmette-Guérin (BCG). Via the protocol, we were then capable of exploring the global transcriptomic profiles of non-adherent THP-1 cells infected with BCG, and found that NF-κB, MAPK and PI3K-Akt signaling pathways were enhanced, as well as some inflammatory chemokine/cytokine genes (e.g. CCL4, CXCL10, TNF and IL-1β) were up-regulated. Surprisingly, the Akt-HIF-mTOR signaling pathway was also activated, which induces trained immunity. In this in vitro infection model, increased cytokine responses to lipopolysaccharides (LPS) restimulation, higher cell viability, and decreased Candida albicans loads were observed. Conclusions We have first characterized the transcriptomic profiles of BCG-infected non-adherent THP-1 cells, and first developed a trained immunity in vitro model of the cells.

ABSTRACT Purpose To compare the efficacy of first‐line regimens based on programmed cell death (or ligand) [PD‐(L)1] blockade in extensive‐stage small‐cell lung cancer (ES‐SCLC) patients with or without liver metastases (LM), and to identify optimal treatment strategies. Methods Network meta‐analysis of randomized controlled trials (RCTs) comparing chemo‐immunotherapy (CIT) and chemotherapy (CT) in ES‐SCLC patients stratified by LM. Overall survival (OS) and progression‐free survival (PFS) were evaluated using hazard ratios (HRs) and 95% confidence intervals (CIs). Results Seven RCTs involving 3658 ES‐SCLC patients (1243 with LM, 2415 without LM) were analyzed. For patients with LM, the combination therapies of anti‐PD‐1 + CT (HR, 0.67; 95% CI, 0.54%–0.82%; p

IntroductionThe trend of human migration to terrestrial high altitudes (HA) has been increasing over the years. However, no published prospective studies exist with follow-up periods exceeding 1 month to investigate the cardiac change. This prospective study aimed to investigate the changes in cardiac structure and function in healthy young male lowlanders following long-term migration to HA.MethodsA total of 122 Chinese healthy young males were divided into 2 groups: those migrating to altitudes between 3600 m and 4000 m (low HA group, n = 65) and those migrating to altitudes between 4000 m and 4700 m (high HA group, n = 57). Traditional echocardiographic parameters were measured at sea level, 1 month and 1 year after migration to HA.ResultsAll 4 cardiac chamber dimensions, areas, and volumes decreased after both 1 month and 1 year of HA exposure. This reduction was more pronounced in the high HA group than in the low HA group. Bi-ventricular diastolic function decreased after 1 month of HA exposure, while systolic function decreased after 1 year. Notably, these functional changes were not significantly influenced by altitude differences. Dilation of the pulmonary artery and a progressive increase in pulmonary artery systolic pressure were observed with both increasing exposure time and altitude. Additionally, a decreased diameter of the inferior vena cava and reduced bicuspid and tricuspid blood flow velocity indicated reduced blood flow following migration to the HA.Discussion1 year of migration to HA is associated with decreased blood volume and enhanced hypoxic pulmonary vasoconstriction. These factors contribute to reduced cardiac chamber size and slight declines in bi-ventricular function.

Free bending forming (FBF) technology is widely used for manufacturing complex-shaped Ti pipes without changing the forming die. Nevertheless, the characteristics of Ti alloys, such as low ductility and high yield stress, pose challenges in achieving high-quality components at room temperature. Therefore, the hot FBF technology is used to manufacture and optimize the process parameters to produce complex-shaped TA18 pipes. Combining theoretical analysis, FE modeling, and experimentation, the forming characteristics of TA18 alloy pipes at elevated temperatures were revealed, and the process parameters were optimized. The Johnson-Cook constitutive model was established in this study and coupled with FE modeling providing accurate simulations of the hot FBF process under various conditions. The FE model of the TA18 alloy pipe was verified by comparing its results with the actual TA18 pipe trials. The hot FBF process can improve the wall thickening and cross-sectional distortion of TA18 bending components and reduce the bending radius of the pipe by weakening the dynamic rebound at the end of the bending and forming of titanium pipes. The increase in heating length is also generally conducive for forming TA18 pipe, and the component's external wall thickness reduction and cross-sectional distortion can be inhibited when the heating length is 250 mm. Moreover, the increase in axial propulsion speed improves the thickening of the inner wall thickness of the TA18 bending components but also increases the thinning of the wall thickness and the distortion of the cross-section. Finally, the process parameters were optimized, and the forming quality of the complex-shape TA18 pipe can be improved. The microstructure of the TA18 pipe hardly changes during the hot FBF process.

Osteoarthritis (OA) is the most common chronic degenerative joint disease in middle‐aged and elderly people, characterized by joint pain and dysfunction. Macrophages are key players in OA pathology, and their activation state has been studied extensively. Various studies have suggested that macrophages might respond to stimuli in their microenvironment by changing their phenotypes to pro‐inflammatory or anti‐inflammatory phenotypes, which is called macrophage polarization. Macrophages accumulate and become polarized (M1 or M2) in many tissues, such as synovium, adipose tissue, bone marrow, and bone mesenchymal tissues in joints, while resident macrophages as well as other stromal cells, including fibroblasts, chondrocytes, and osteoblasts, form the joint and function as an integrated unit. In this study, we focus exclusively on synovial macrophages, adipose tissue macrophages, and osteoclasts, to investigate their roles in the development of OA. We review recent key findings related to macrophage polarization and OA, including pathogenesis, molecular pathways, and therapeutics. We summarize several signaling pathways in macrophage reprogramming related to OA, including NF‐κB, MAPK, TGF‐β, JAK/STAT, PI3K/Akt/mTOR, and NLRP3. Of note, despite the increasing availability of treatments for osteoarthritis, like intra‐articular injections, surgery, and cellular therapy, the demand for more effective clinical therapies has remained steady. Therefore, we also describe the current prospective therapeutic methods that deem macrophage polarization to be a therapeutic target, including physical stimulus, chemical compounds, and biological molecules, to enhance cartilage repair and alleviate the progression of OA.

Abstract Objectives Computed tomographic perfusion (CTP) can play an auxiliary role in the selection of patients with acute ischemic stroke for endovascular treatment. However, data on CTP in non-stroke patients with intracranial arterial stenosis are scarce. We aimed to investigate images in patients with asymptomatic intracranial arterial stenosis to determine the detection accuracy and interpretation time of large/medium-artery stenosis or occlusion when combining computed tomographic angiography (CTA) and CTP images. Methods We retrospectively reviewed 39 patients with asymptomatic intracranial arterial stenosis from our hospital database from January 2021 to August 2023 who underwent head CTP, head CTA, and digital subtraction angiography (DSA). Head CTA images were generated from the CTP data, and the diagnostic performance for each artery was assessed. Two readers independently interpreted the CTA images before and after CTP, and the results were analyzed. Results After adding CTP maps, the accuracy (area under the curve) of diagnosing internal carotid artery (R1: 0.847 vs. 0.907, R2: 0.776 vs. 0.887), middle cerebral artery (R1: 0.934 vs. 0.933, R2: 0.927 vs. 0.981), anterior cerebral artery (R1: 0.625 vs. 0.750, R2: 0.609 vs. 0.750), vertebral artery (R1: 0.743 vs. 0.764, R2: 0.748 vs. 0.846), and posterior cerebral artery (R1: 0.390 vs. 0.575, R2: 0.390 vs. 0.585) occlusions increased for both readers (p

Abstract Superhydrophobic surfaces demonstrate excellent anti-icing performance under static conditions. However, they show a marked decrease in icing time under real flight conditions. Here we develop an anti-icing strategy using ubiquitous wind field to improve the anti-icing efficiency of superhydrophobic surfaces during flight. We find that the icing mass on hierarchical superhydrophobic surface with a microstructure angle of 30° is at least 40% lower than that on the conventional superhydrophobic plate, which is attributed to the combined effects of microdroplet flow upwelling induced by interfacial airflow and microdroplet ejection driven by superhydrophobic characteristic. Meanwhile, the disordered arrangement of water molecules induced by the specific 30° angle also raises the energy barriers required for nucleation, resulting in an inhibition of the nucleation process. This strategy of microdroplet movement manipulation induced by interfacial airflow is expected to break through the anti-icing limitation of conventional superhydrophobic materials in service conditions and can further reduce the risk of icing on the aircraft surface.

Abstract Aims We aimed to explore the associations between urine albumin-to-creatinine ratio (uACR) and cardia-cerebrovascular disease (CVD) in Chinese population with type 2 diabetes(T2D). Methods We included 8975 participants with T2D but free of prevalent CVD (including myocardial infarction, ischemic and hemorrhagic stroke) at baseline from Kailuan study who were assessed with uACR between 2014 and 2016. The participants were divided into three groups based on their baseline uACR: normal (

ObjectivesIn order to formulate an optimization scheme for the torsional vibration parameters of a marine diesel generator shaft system, it is necessary to analyze the transient torsional vibration characteristics of the diesel generator under short-circuit impact.MethodsThe shafting transient torsional vibration characteristics of a 20-cylinder V-type diesel generator set under short-circuit impact are analyzed by the Newmark method, and the effects of different shafting parameters on its shafting transient torsional vibration characteristics under short-circuit conditions are discussed. A new selection scheme of shock absorber stiffness and coupling stiffness is then determined.ResultsThe calculation results show that the shafting torsional vibration characteristics deteriorate significantly when short-circuit impact occurs. After optimization (the stiffness of the torsional shock absorber and coupling are optimized to 90% and 70% of the original value respectively), the maximum transient torque of the motor shaft, maximum transient torque of the coupling and maximum transient stress of each segement of the crankshaft under short-circuit impact conditions are reduced by 13.43%, 10.51% and 5.29% respectively.ConclusionsThe proposed optimized design scheme can effectively reduce the transient torsional vibration level of shaft systems. The results of this study can provide useful references for the vibration and noise reduction design of diesel generator sets.

A large number of sensors are typically installed in industrial plants to collect real-time operational data. These sensors monitor data with time series correlation and spatial correlation over time. In previous studies, GNN has built many successful models to deal with time series data, but most of these models have fixed perspectives and struggle to capture the dynamic correlations in time and space simultaneously. Therefore, this paper constructs a multi-scale dynamic graph neural network (MSDG) for anomaly detection in industrial sensor data. First, a multi-scale sliding window mechanism is proposed to input different scale sensor data into the corresponding network. Then, a dynamic graph neural network is constructed to capture the spatial–temporal dependencies of multivariate sensor data. Finally, the model comprehensively considers the extracted features for sequence reconstruction and utilizes the reconstruction errors for anomaly detection. Experiments have been conducted on three real public datasets, and the results show that the proposed method outperforms the mainstream methods.

Abstract Organic polymer‐based composite materials with favorable mechanical performance and functionalities are keystones to various modern industries; however, the environmental pollution stemming from their processing poses a great challenge. In this study, by finding an autonomous phase separating ability of fungal mycelium, a new material fabrication approach is introduced that leverages such biological metabolism‐driven, mycelial growth‐induced phase separation to bypass high‐energy cost and labor‐intensive synthetic methods. The resulting self‐regenerative composites, featuring an entangled network structure of mycelium and assembled organic polymers, exhibit remarkable self‐healing properties, being capable of reversing complete separation and restoring ≈90% of the original strength. These composites further show exceptional mechanical strength, with a high specific strength of 8.15 MPa g.cm−3, and low water absorption properties (≈33% after 15 days of immersion). This approach spearheads the development of state‐of‐the‐art living composites, which directly utilize bioactive materials to “self‐grow” into materials endowed with exceptional mechanical and functional properties.

IntroductionGastrodia elata Blume is a widely used medicinal and edible herb with a rich chemical composition. Moreover, prescriptions containing Gastrodia elata are commonly used for the prevention and treatment of cardiovascular, cerebrovascular, and aging-related diseases. Recent pharmacological studies have confirmed the antioxidant and neuroprotective effects of Gastrodia elata, and, in recent years, this herb has also been used in the treatment of Alzheimer’s disease (AD) and other neurodegenerative disorders. We have previously shown that 4,4′-methylenediphenol, a key active ingredient of Gastrodia elata, can mitigate amyloid-β (Aβ)-induced paralysis in AD model worms as well as prolong the lifespan of the animals, thus displaying potential as a treatment of AD.MethodsWe investigated the effects of 4,4′-methylenediphenol on AD and aging through paralysis, lifespan, and behavioral assays. In addition, we determined the anti-AD effects of 4,4′-methylenediphenol by reactive oxygen species (ROS) assay, lipofuscin analysis, thioflavin S staining, metabolomics analysis, GFP reporter gene worm assay, and RNA interference assay and conducted in-depth studies on its mechanism of action.Results4,4′-Methylenediphenol not only delayed paralysis onset and senescence in the AD model worms but also enhanced their motility and stress tolerance. Meanwhile, 4,4′-methylenediphenol treatment also reduced the contents of reactive oxygen species (ROS) and lipofuscin, and decreased Aβ protein deposition in the worms. Broad-spectrum targeted metabolomic analysis showed that 4,4′-methylenediphenol administration had a positive effect on the metabolite profile of the worms. In addition, 4,4′-methylenediphenol promoted the nuclear translocation of DAF-16 and upregulated the expression of SKN-1, SOD-3, and GST-4 in the respective GFP reporter lines, accompanied by an enhancement of antioxidant activity and a reduction in Aβ toxicity; importantly, our results suggested that these effects of 4,4′-methylenediphenol were mediated, at least partly, via the activation of DAF-16.ConclusionWe have demonstrated that 4,4′-methylenediphenol can reduce Aβ-induced toxicity in AD model worms, suggesting that it has potential for development as an anti-AD drug. Our findings provide ideas and references for further research into the anti-AD effects of Gastrodia elata and its active ingredients.

Abstract Introduction Intrahepatic cholangiocarcinoma (ICC) is characterized by a dismal prognosis with limited therapeutic alternatives. To explore phosphatase and tension homolog (PTEN) as a biomarker for proteasome inhibition in ICC, we conducted a phase II trial to assess the second‐line efficacy of bortezomib in PTEN‐deficient advanced ICC patients. Methods A total of 130 patients with advanced ICC in our centre were screened by PTEN immunohistochemical staining between 1 July 2017, and 31 December 2021, and 16 patients were ultimately enrolled and treated with single‐agent bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21‐day cycle. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. Results The median follow‐up was 6.55 months (95% confidence interval [CI]: 0.7–19.9 months). Among the 16 enrolled patients, the ORR was 18.75% (3/16) and the disease control rate was 43.75% (7/16). The median progress‐free survival was 2.95 months (95% CI: 2.1–5.1 months) and the median overall survival (mOS) was 7.2 months (95% CI: 0.7–21.6 months) in the intent‐to‐treat‐patients. Treatment‐related adverse events of any grade were reported in 16 patients, with thrombopenia being the most common toxicity. Patients with PTEN staining scores of 0 were more likely to benefit from bortezomib than those with staining scores > 0. Conclusions Bortezomib yielded an encouraging objective response and a favourable OS as a second‐line agent in PTEN‐deficient ICC patients. Our findings suggest bortezomib as a promising therapeutic option for patients with PTEN‐deficient ICC. Highlights There is a limited strategy for the second‐line option of intrahepatic cholangiocarcinoma (ICC). This investigator‐initiated phase 2 study evaluated bortezomib in ICC patients with phosphatase and tension homology deficiency. The overall response rate was 18.75% and the overall survival was 7.2 months in the intent‐to‐treat cohort. These results justify further developing bortezomib in ICC patients with PTEN deficiency.

IntroductionGastrodia elata is the dried tuber of the orchid Gastrodia elata Bl. It is considered a food consisting of a source of precious medicinal herbs, whose chemical composition is relatively rich. Gastrodia elata and its extracted fractions have been shown to have neuroprotective effects. P-hydroxybenzaldehyde (p-HBA), as one of the main active components of Gastrodia elata, has anti-inflammatory, antioxidative stress, and cerebral protective effects, which has potential for the treatment of Alzheimer’s disease (AD). The aim of this study was to verify the role of p-HBA in AD treatment and to investigate its mechanism of action in depth based using the Caenorhabditis elegans (C. elegans) model.MethodsIn this study, we used paralysis, lifespan, behavioral and antistress experiments to investigate the effects of p-HBA on AD and aging. Furthermore, we performed reactive oxygen species (ROS) assay, thioflavin S staining, RNA-seq analysis, qPCR validation, PCR Array, and GFP reporter gene worm experiment to determine the anti-AD effects of p-HBA, as well as in-depth studies on its mechanisms.Resultsp-HBA was able to delay paralysis, improve mobility and resistance to stress, and delay aging in the AD nematode model. Further mechanistic studies showed that ROS and lipofuscin levels, Aβ aggregation, and toxicity were reduced after p-HBA treatment, suggesting that p-HBA ameliorated Aβ-induced toxicity by enhancing antioxidant and anti-aging activity and inhibiting Aβ aggregation. p-HBA had a therapeutic effect on AD by improving stress resistance, as indicated by the down-regulation of NLP-29 and UCR-11 expression and up-regulation of PQN-75 and LYS-3 expression. In addition, the gene microarray showed that p-HBA treatment played a positive role in genes related to AD, anti-aging, ribosomal protein pathway, and glucose metabolism, which were collectively involved in the anti-AD mechanism of p-HBA. Finally, we also found that p-HBA promoted nuclear localization of DAF-16 and increased the expression of SKN-1, SOD-3, and GST-4, which contributed significantly to inhibition of Aβ toxicity and enhancement of antioxidative stress.ConclusionOur work suggests that p-HBA has some antioxidant and anti-aging activities. It may be a viable candidate for the treatment and prevention of Alzheimer’s disease.

IntroductionSwine influenza viruses (SIVs) pose significant economic losses to the pig industry and are a burden on global public health systems. The increasing complexity of the distribution and evolution of different serotypes of influenza strains in swine herds escalates the potential for the emergence of novel pandemic viruses, so it is essential to develop new vaccines based on swine influenza.MethodsHere, we constructed a self-assembling ferritin nanoparticle vaccine based on the hemagglutinin (HA) extracellular domain of swine influenza A (H1N1) virus using insect baculovirus expression vector system (IBEVS), and after two immunizations, the immunogenicities and protective efficacies of the HA-Ferritin nanoparticle vaccine against the swine influenza virus H1N1 strain in mice and piglets were evaluated.ResultsOur results demonstrated that HA-Ferritin nanoparticle vaccine induced more efficient immunity than traditional swine influenza vaccines. Vaccination with the HA-Ferritin nanoparticle vaccine elicited robust hemagglutinin inhibition titers and antigen-specific IgG antibodies and increased cytokine levels in serum. MF59 adjuvant can significantly promote the humoral immunity of HA-Ferritin nanoparticle vaccine. Furthermore, challenge tests showed that HA-Ferritin nanoparticle vaccine conferred full protection against lethal challenge with H1N1 virus and significantly decreased the severity of virus-associated lung lesions after challenge in both BALB/c mice and piglets.ConclusionTaken together, these results indicate that the hemagglutinin extracellular-based ferritin nanoparticle vaccine may be a promising vaccine candidate against SIVs infection.

Abstract The hypothalamic supramammillary nucleus (SuM) plays a crucial role in controlling wakefulness, but the downstream target regions participating in this control process remain unknown. Here, using circuit-specific fiber photometry and single-neuron electrophysiology together with electroencephalogram, electromyogram and behavioral recordings, we find that approximately half of SuM neurons that project to the medial septum (MS) are wake-active. Optogenetic stimulation of axonal terminals of SuM-MS projection induces a rapid and reliable transition to wakefulness from non-rapid-eye movement or rapid-eye movement sleep, and chemogenetic activation of SuMMS projecting neurons significantly increases wakefulness time and prolongs latency to sleep. Consistently, chemogenetically inhibiting these neurons significantly reduces wakefulness time and latency to sleep. Therefore, these results identify the MS as a functional downstream target of SuM and provide evidence for the modulation of wakefulness by this hypothalamic-septal projection.

Actinidia eriantha is one of the species of kiwifruit with a particularly high ascorbic acid (AsA) content. However, the molecular mechanism driving AsA richness in fruit remains unclear. In order to reveal the molecular mechanism of AsA richness in A. eriantha, this study constructed a regulatory network related to AsA metabolism by combining genomics, metabolomics and transcriptomics. We assembled a high-quality genome of A. eriantha ‘Ganlv 1’ with only five remaining gaps. The assembly is comprised of 29 pseudochromosomes with a total size of 615.95 Mb, and contig N50 of 20.35 Mb. Among them, 24 of the pseudochromosomes were obtained directly from telomere-to-telomere. The LTR assembly index score and consensus quality value were 21.34 and 39.90%, respectively. Subsequently, 61 metabolites and 2 092 genes were found to be differentially accumulated/expressed during fruit development by metabolome and transcriptome assays, respectively. AsA metabolism and the cyclic regeneration pathway were found to have high expression levels throughout fruit growth and development, suggesting its crucial role in the regulation of AsA. Furthermore, the AsA contents are highly associated with ascorbate peroxidase genes. The genome obtained in this study provides genomic resources for the genetic and breeding research of A. eriantha, and the constructed regulatory network can provide a public data platform for future research on kiwifruit.

Pitch system can adjust the blade’s pitch angle, control the aerodynamic torque and capture the wind turbine’s aerodynamic power. It is critical guarantee for the turbine’s safety and stability. However, the turbine’s operating environment is harsh and the long-term component abrasion may cause the system failure. Only by the monitoring signals’ instantaneous value, it is difficult to discovery the system fault. Therefore, this paper fuses multiple time sequence signals and uses the multi-channel attention mechanism to improve the long short-time memory networks (MCA-LSTM) for pitch system fault diagnosis. Firstly, the data of SCADA is preprocessed to construct the time sequence ratio vectors and input into MCA-LSTM. Through the attention mechanism, the time sequences ratio vectors are integrated from different channels in MCA-LSTM. Then the MCA-LSTM establishes the logical relationship between the signals and the fault features. Finally, root-mean-square error and the residual fluctuation threshold are used to identify the abnormal states. The experiments utilized the SCADA data of wind farms. The results show that MCA-LSTM can detect the pitch bearing anomalies and hub faults, which are about ten hours earlier than the wind farm fault recording. So, MCA-LSTM can effectively predict pitch system faults and provides an important basis for the WT fault diagnosis.

Laser-induced removal of non-destructive substrates is a continuous pursuit for practical applications. Herein, a strategy of scanning cycle's large adjustment combined with laser energy density's fine tuning was established to achieve precise removal of FeCo-based wave-absorbing coatings. First and foremost, no coating residue was observed on the surface and cross-section of optimized sample E5 with a laser energy density of 61.1 J/cm2 (scanning cycles were seven). CIE LAB color analysis indicated that the surface of sample E5 had the highest coating's removal degree. Through numerical simulation and experimental examination, the oxide layer of the aluminum alloy did not present any damage such as cracking and peeling. In addition, the surface roughness remained unchanged, which verifies the possibility of laser removal towards non-destructive substrates. The multi-perspective evaluations of surface states illustrated that Barite (BaSO4), FeCo and other coating's characteristic substances had disappeared, ensuring the subsequent serviceability of the surface after removal. Furthermore, the vaporization removal mechanism of the wave-absorbing coatings was demonstrated by the plasma captured by a high-speed camera. Notably, the substrate's damage mechanism in laser removal was revealed. The remarkable different thermal expansion behavior of oxide layer and alloy induced extreme stress concentrations at the interface, which led to oxide layer's cracks and exfoliation. In summary, substrate's damage suppression can be achieved through simulation and experimental optimization. The presented research not only benefits the strategy design of laser removal for multilayer materials, but also expands the application potential of laser removal in non-destructive substrates.

This study presents a one-surface plasticity constitutive model combined with phenomenological and micromechanical damage models to be applied to the large plastic deformation during tube hydroforming. These factors lead to simulating the Bauschinger effect and transient behavior in large plastic strain ranges and predicting fracture onset. By using the integration approach, a numerical integration algorithm of implementation by explicit schemes was carried out. A comparison of several cyclic loading tests between experiments and numerical simulation was accomplished. The accuracy of these models is verified, which could be expanded to a large strain range forming process. Adopting the proposed models, finite element modeling is performed in the tube hydroforming process. The simulation and experimental results comparison showed that the proposed framework accurately predicted the tube formability in the hydroforming process.

Abstract Purpose To determine the role and rational application of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) adjuvant therapy in patients with completely resected stage IB-IIIA EGFR-mutant non-small-cell lung cancer (NSCLC). Method Randomized controlled trials (RCTs) that compared the survival outcomes between adjuvant EGFR-TKIs and adjuvant chemotherapy or a placebo, or between different EGFR-TKI treatment durations for resected NSCLC, were eligible for inclusion. Disease-free survival (DFS) and overall survival (OS) with hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated as effective measures using random-effect or fixed-effect models. Subgroup analysis was also performed. Results Eleven RCTs involving 2102 EGFR-mutant NSCLC patients with or without EGFR-TKI adjuvant therapy were included. For all stage IB-IIIA NSCLC patients, EGFR-TKIs adjuvant therapy could not only significantly improve DFS (HR 0.43, 95% CI 0.30–0.63, P

Abstract Biological strong and tough materials have been providing original structural designs for developing bioinspired high‐performance composites. However, new synergistic strengthening and toughening mechanisms from bioinspired structures remain yet to be explored and employed to upgrade current carbon material reinforced polymer composites, which are keystone to various modern industries. In this work, from bamboo, the featured cell face‐bridging fibers, are abstracted and embedded in a cellular network structure, and develop an epoxy resin/carbon composite featuring biomimetic architecture through a fabrication approach integrating freeze casting, carbonization, and resin infusion with carbon fibers (CFs) and carbon nanotubes (CNTs). Results show that this bamboo‐inspired crack‐face bridging fiber reinforced composite simultaneously possesses a high strength (430.8 MPa) and an impressive toughness (8.3 MPa m1/2), which surpass those of most resin‐based nanocomposites reported in the literature. Experiments and multiscale simulation models reveal novel synergistic strengthening and toughening mechanisms arising from the 2D faces that bridge the CFs: sustaining and transferring loads to enhance the overall load‐bearing ability and furthermore, incorporating CNTs pullout that resembles the intrinsic toughening at the molecular to nanoscale and strain delocalization, crack branching, and crack deflection as the extrinsic toughening at the microscale. These constitute a new effective and efficient strategy to develop simultaneously strong and tough composites through abstracting and implenting novel bioinspired structures, which contributes to addressing the long‐standingly challenging attainment of both high strength and toughness for advanced structural materials.

Dengue virus (DENV) infection causes dengue fever, the most prevalent arthropod-transmitted viral disease worldwide. Viruses are acellular parasites and obligately rely on host cell machinery for reproduction. Previous studies have indicated metabolomic changes in endothelial cell models and sera of animal models and patients with dengue fever. To probe the immunometabolic mechanism of DENV infection, here, we report the metabolomic landscape of a human macrophage cell model of DENV infection and its antibody-dependent enhancement. DENV infection of THP-1-derived macrophages caused 202 metabolic variants, of which amino acids occupied 23.7%, fatty acids 21.78%, carbohydrates 10.4%, organic acids 13.37%, and carnitines 10.4%. These metabolomic changes indicated an overall anabolic signature, which was characterized by the global exhaustion of amino acids, increases of cellular fatty acids, carbohydrates and pentoses, but decreases of acylcarnitine. Significant activation of metabolic pathways of glycolysis, pentose phosphate, amino acid metabolism, and tricarboxylic acid cycle collectively support the overall anabolism to meet metabolic demands of DENV replication and immune activation by viral infection. Totally 88 of 202 metabolic variants were significantly changed by DENV infection, 36 of which met the statistical standard (P1.5) of differentially expressed metabolites, which were the predominantly decreased variants of acylcarnitine and the increased variants of fatty acids and carbohydrates. Remarkably, 11 differentially expressed metabolites were significantly distinct between DENV only infection and antibody-dependent enhancement of viral infection. Our data suggested that the anabolic activation by DENV infection integrates the viral replication and anti-viral immune activation.