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Abstract Rigid solenoid coils have long been indispensable in modern intelligent devices. However, their sparse structure and challenging preparation of flexible coils for soft robots impose limitations. Here, a transformable 3D curved high-density liquid metal coil (HD-LMC) is introduced that surpasses the structural density level of enameled wire. The fabrication technique employed for high-density channels in elastomers is universally applicable. Such HD-LMCs demonstrated excellent performance in pressure, temperature, non-contact distance sensors, and near-field communication. Soft electromagnetic actuators thus achieved significantly improved the electromagnetic force and power density. Moreover, precise control of swinging tail motion enables a bionic pufferfish to swim. Finally, HD-LMC is further utilized to successfully implement a soft rotary robot with integrated sensing and actuation capabilities. This groundbreaking research provides a theoretical and experimental basis for expanding the applications of liquid metal-based multi-dimensional complex flexible electronics and is expected to be widely used in liquid metal-integrated robotic systems.

Cancer is widely regarded as a leading cause of death in humans, with colon adenocarcinoma (COAD) ranking among the most prevalent types. Cuproptosis is a novel form of cell death mediated by protein lipoylation. Cuproptosis-related genes (CRGs) participate in tumourigenesis and development. Their role in pan-cancer and COAD require further investigation. This study comprehensively evaluated the relationship among CRGs, pan-cancer, and COAD. Our research revealed the differential expression of CRGs and the cuproptosis potential index (CPI) between normal and tumour tissues, and further explored the correlation of CRGs or CPI with prognosis, immune infiltration, tumor mutant burden(TMB), microsatellite instability (MSI), and drug sensitivity in pan-cancer. Gene set enrichment analysis (GSEA) revealed that oxidative phosphorylation and fatty acid metabolism pathways were significantly enriched in the high CPI group of most tumours. FDX1 and CDKN2A were chosen for further exploration, and we found an independent association between FDX1 and CDKN2A and prognosis, immune infiltration, TMB, and MSI in pan-cancer. Furthermore, a prognostic risk model based on the association between CRGs and COAD was built, and the correlations between the risk score and prognosis, immune-related characteristics, and drug sensitivity were analysed. COAD was then divided into three subtypes using cluster analysis, and the differences among the subtypes in prognosis, CPI, immune-related characteristics, and drug sensitivity were determined. Due to the level of LIPT1 was notably positive related with the risk score, the cytological identification was carried out to identify the association of LIPT1 with proliferation and migration of colon cancer cells. In summary, CRGs can be used as potential prognostic biomarkers to predict immune infiltration levels in patients with pan-cancer. In addition, the risk model could more accurately predict the prognosis and immune infiltration levels of COAD and better guide the direction of clinical medication. Thus, FDX1, CDKN2A, and LIPT1 may serve as prospective new targets for cancer therapy.

Abstract Background Recently, long non-coding RNAs (lncRNAs) have been demonstrated as essential roles in tumor immune microenvironments (TIME). Nevertheless, researches on the clinical significance of TIME-related lncRNAs are limited in lung adenocarcinoma (LUAD). Methods Single-cell RNA sequencing and bulk RNA sequencing data are integrated to identify TIME-related lncRNAs. A total of 1368 LUAD patients are enrolled from 6 independent datasets. An integrative machine learning framework is introduced to develop a TIME-related lncRNA signature (TRLS). Results This study identified TIME-related lncRNAs from integrated analysis of single‑cell and bulk RNA sequencing data. According to these lncRNAs, a TIME-related lncRNA signature was developed and validated from an integrative procedure in six independent cohorts. TRLS exhibited a robust and reliable performance in predicting overall survival. Superior prediction performance barged TRLS to the forefront from comparison with general clinical features, molecular characters, and published signatures. Moreover, patients with low TRLS displayed abundant immune cell infiltration and active lipid metabolism, while patients with high TRLS harbored significant genomic alterations, high PD-L1 expression, and elevated DNA damage repair (DDR) relevance. Notably, subclass mapping analysis of nine immunotherapeutic cohorts demonstrated that patients with high TRLS were more sensitive to immunotherapy. Conclusions This study developed a promising tool based on TIME-related lncRNAs, which might contribute to tailored treatment and prognosis management of LUAD patients.

In this study, a pattern reconfiguration liquid metal printed antenna is proposed. The antenna, based on the well-known Yagi-Uda antenna, is obtained by directly printing gallium-based liquid metal on a perfluorosulfonic acid ionomer (PFSA) substrate. Since PFSA undergoes two thermally reversible transitions above room temperature, thus exhibiting a triple shape memory effect, the bending state of the antenna substrate can be changed by adjusting the temperature. By changing the operating state of the antenna, the main beam of the antenna can be reconfigured in the E-plane. The proposed E-plane pattern reconfigurable antenna is simple in structure and easy to realize, and its measured results are in good agreement with the simulation results, with the gain and radiation efficiency of 4.4 dBi and 81.2%, respectively. The antenna has the advantages of simple fabrication, light weight, strong E-plane beam switching capability and high gain. These advantages make it possible to be applied in the field of pattern reconfiguration antennas.

Abstract Extracellular matrix (ECM) assembly/disassembly is a critical regulator for airway epithelial development and remodeling. Airway organoid is widely used in respiratory research, yet there is limited study to indicate the roles and mechanisms of ECM organization in epithelial growth and differentiation by using in vitro organoid system. Moreover, most of current Matrigel-based airway organoids are in basal-out orientation where accessing the apical surface is challenging. We present a human apical-out airway organoid using a biochemically defined hybrid hydrogel system. During human nasal epithelial progenitor cells (hNEPCs) differentiation, the gel gradually degrade, leading to the organoid apical surfaces facing outward. The expression and activity of ECM-degrading enzymes, matrix metalloproteinases (MMP7, MMP9, MMP10 and MMP13) increases during organoid differentiation, where inhibition of MMPs significantly suppresses the normal ciliation, resulting in increased goblet cell proportion. Moreover, a decrease of MMPs is found in goblet cell hyperplastic epithelium in inflammatory mucosa. This system reveals essential roles of epithelial-derived MMPs on epithelial cell fate determination, and provides an applicable platform enabling further study for ECM in regulating airway development in health and diseases.

In this study, we propose a novel lightweight detection model for rebar counting, which is rectified mobilenet lightweight feature pyramid network based on YOLO (RM-LFPN-YOLO). The model incorporates a lightweight backbone network that integrates the coordinate attention (CA) mechanism, a lightweight feature pyramid network (LFPN), and a loss function that combines focal loss and efficient intersection over union (EIOU) loss, all meticulously designed to enhance the model’s performance. Experimental results demonstrate that our improved algorithm, with a mere 25.08M parameters, computes efficiently at 7.60G with an input size of 416 pixels. Additionally, it achieves an impressive average precision (AP) of 99.03% at an IOU of 0.5. The proposed lightweight model can be deployed on embedded devices and achieve efficient rebar detection and counting performance.

Summary: The importance of trained immunity in antitumor immunity has been increasingly recognized, but the underlying metabolic regulation mechanisms remain incompletely understood. In this study, we find that squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis, is required for β-glucan-induced trained immunity in macrophages and ensuing antitumor activity. Unexpectedly, the shunt pathway, but not the classical cholesterol synthesis pathway, catalyzed by SQLE, is required for trained immunity induction. Specifically, 24(S),25-epoxycholesterol (24(S),25-EC), the shunt pathway metabolite, activates liver X receptor and increases chromatin accessibility to evoke innate immune memory. Meanwhile, SQLE-induced reactive oxygen species accumulation stabilizes hypoxia-inducible factor 1α protein for metabolic switching into glycolysis. Hence, our findings identify 24(S),25-EC as a key metabolite for trained immunity and provide important insights into how SQLE regulates trained-immunity-mediated antitumor activity.

Inflammatory bowel diseases (IBDs) are commonly associated with dysfunctional intestinal barriers and disturbed gut microbiota. Gastrodin, a major bioactive ingredient of Gastrodia elata Blume, has been shown to exhibit anti-oxidation and anti-inflammation properties and could mitigate non-alcoholic fatty liver disease, but its role in modulating IBD remains elusive. The aim of this study was to investigate the impact of gastrodin on DSS-induced colitis in mice and explore its potential mechanisms. Gastrodin supplementation alleviated clinical symptoms such as weight loss, a shortened colon, and a high disease activity index. Meanwhile, gastrodin strengthened the intestinal barrier by increasing the 0expression of tight junction proteins and mucin. Furthermore, Gastrodin significantly reduced pro-inflammatory cytokine secretion in mice by downregulating the NF-κB and MAPK pathways. Gut microbiota analysis showed that gastrodin improved the DSS-disrupted microbiota of mice. These findings demonstrate that gastrodin could attenuate DSS-induced colitis by enhancing the intestinal barrier and modulating the gut microbiota, providing support for the development of a gastrodin-based strategy to prevent or combat IBD.

Background: We aimed to investigate the clinical and dosimetric factors associated with radiation-induced rhinosinusitis, and further elucidate the optimal dose-volume constraints for nasopharyngeal cancer patients who underwent volumetric-modulated arc therapy (VMAT). Methods: A retrospective review of 196 nasopharyngeal carcinoma (NPC) patients who underwent definitive VMAT between August 2018 and May 2021 was conducted. Both clinical and dose-volume histogram (DVH) data of NPC patients without rhinosinusitis at baseline were selected for analysis. Results: The cumulative incidence of post-RT rhinosinusitis at the 3-, 6-, 9-, and 12-months, and >1 year were 29.6 %, 41.3 %, 42.9 %, and 45.4 %, and 47.4 %, respectively. Nasal irrigation was negatively associated with post-RT rhinosinusitis (p 1.16 % and >1.00 %, respectively (p = 0.027 and p = 0.002). Sphenoid sinusitis was more frequent when Dmax(maxillary sinus) exceeded 69.2Gy (p = 0.005). Conclusions: Regular nasal irrigation may reduce the development of rhinosinusitis. Dose-volume constraints of V70 and Dmax to the maxillary sinus are suggested for VMAT planning. Patients exceeding these thresholds should be closely monitored and potentially offered preventative interventions within 3–6 months post-RT.

Highlights The common performance optimization strategies of smart composite hydrogel are summarized. The recent advanced progress of smart composite hydrogel-based wearable sensors is systematically discussed from the aspect of health monitoring. The current challenges and future prospects of smart composite hydrogel-based wearable sensors are presented.

Summary: Nasopharyngeal carcinoma (NPC) is known for high curability during early stage of the disease, and early diagnosis relies on nasopharyngeal endoscopy and subsequent pathological biopsy. To enhance the early diagnosis rate by aiding physicians in the real-time identification of NPC and directing biopsy site selection during endoscopy, we assembled a dataset comprising 2,429 nasopharyngeal endoscopy video frames from 690 patients across three medical centers. With these data, we developed a deep learning-based NPC detection model using the you only look once (YOLO) network. Our model demonstrated high performance, with precision, recall, mean average precision, and F1-score values of 0.977, 0.943, 0.977, and 0.960, respectively, for internal test set and 0.825, 0.743, 0.814, and 0.780 for external test set at 0.5 intersection over union. Remarkably, our model demonstrated a high inference speed (52.9 FPS), surpassing the average frame rate (25.0 FPS) of endoscopy videos, thus making real-time detection in endoscopy feasible.

ABSTRACT: This study developed and characterized a γ-aminobutyric acid (GABA)-enriched yogurt fermented by Levilactobacillus brevis CGMCC1.5954. The GABA content in the yogurt was 147.36 mg/100 mL, which was 317.06% higher than that of the control group. Furthermore, there was a significant improvement in the aroma, hardness, adhesion, cohesiveness, and gelatinousness of yogurt. The chromatography and metabolomics analyses further confirmed the high GABA content in yogurt and its nutritional value, and the metabolic pathway for GABA production by L. brevis 54 was identified. A total of 58 volatile flavor compounds were identified using headspace solid-phase microextraction-gas chromatography-mass spectrometry, of which 2-nonanone and 2-heptanone may be responsible for the high odor score of GABA-enriched yogurt. This study developed a nutritious and unique GABA-enriched flavored yogurt, summarized the metabolic pathway of GABA, and provided a flavor fingerprint that could guide the production of specifically flavored yogurts.

Abstract Smart sensing fabrics are becoming increasingly attractive in the emerging wearable areas of medical and military so far. Here, for the first time, we present a smart humidity sensing fabric (SHSF) based on a moisture‐sensitive polyacrylamide hydrogel for respiratory monitoring and non‐contact sensing. Fabricated by in situ cross‐linking of the hydrogel precursors on the fibers of the fabric, the flexible SHSF shows excellent sensitivity, outstanding flame retardance, air permeability, water retention capacity, and stability after treatment with lithium bromide solution. Specifically, its conductance increases more than 311 times as humidity increased from 11% to 98%. Besides, the humidity sensor features good repeatability and the ability to work normally under folding due to its flexible nature. As a clothing material, hydrogel–fabric composite exhibits 4.3 times the burning time compared to cotton fabric, illustrating better flame retardance. The SHSF is used to monitor human breathing and non‐contact finger approaching in real time, demonstrating its flexibility in practical applications. This work provides strategies for preparing high‐performance, flame‐retardant SHSF for emerging wearable electronic devices.

Early recognition of patients who may gain benefits from palliative care will help medical service providers to provide such patients with targeted, patient-centered care, therebyreducing the provision of meaningless overtreatment, and improving negative emotional distress and quality of life of patients as well as the quality of life of patients' families. Many tools developed by foreign scholars for early identifying patients with potential palliative care needs, are mostly consisted of predictors of death risk and early warning signs of deterioration. In particular, some of them have been iteratively updated during the process of global application and verification, and could recognize those who could benefit from palliative care, although their applicability and accuracy levels need to be improved further. In contrast, in China, related research is scarce, and the development and application of such tools are still in the preliminary stage. In accordance with the classification of applicable diseases and people, we classified the tools for early identifyingpatients with potential palliative care needs, reviewed their main contents, characteristics and applications, thenmade a comparative analysis of the common tools in terms of basic essentials and application, with a view to providing a reference for the development and localization of such tools, and for accurateassessment and provision of potential palliative care for those who can benefit from such care.

SARS- CoV-2 hijacks ACE2 for cell entry. Here, the authors report that dynamic SUMOylation modulates the TOLLIP-directed selective autophagic degradation of ACE2 and suggest SUMOylation inhibition as a potential intervention against SARS-CoV-2 infection.

Abstract Stretchable hydrogel‐based strain sensors suffer from limited sensitivity, which urgently requires further breakthroughs for precise and stable human‐computer interaction. Here, an efficient microstructural engineering strategy is proposed to significantly enhance the sensitivity of hydrogel‐based strain sensors by sandwiching an emulsion‐polymerized polyacrylamide organohydrogel microsphere membrane between two Ecoflex films, which are accompanied by crack generation and propagation effects upon stretching. Consequently, the as‐developed strain sensor exhibits ultrahigh sensitivity (gauge factor (GF) of 1275), wide detection range (100% strain), low hysteresis, ultralow detection limit (0.05% strain), good fatigue resistance, and low fabrication cost. In addition, the sensor features good water, dehydration, and frost resistance, enabling real‐time strain monitoring in various complex conditions due to the encapsulation of Ecoflex film and the addition of glycerol and KCl. Through further structural manipulation, the device achieves superior response to tiny strains, with a GF value of 98.3 in the strain range of less than 1.5%. Owing to the high strain sensing performance, the sensor is able to detect various human activities from swallowing to finger bending even under water. On this basis, a wireless sensing system with apnea warning and single‐channel gesture recognition capabilities is successfully demonstrated, demonstrating its great promise as wearable electronics.

IntroductionInfluenza susceptibility difference is a widely existing trait that has great practical significance for the accurate prevention and control of influenza.MethodsHere, we focused on the human susceptibility to the seasonal influenza A/H3N2 of healthy adults at baseline level. Whole blood expression data for influenza A/H3N2 susceptibility from GEO were collected firstly (30 symptomatic and 19 asymptomatic). Then to explore the differences at baseline, a suite of systems biology approaches - the differential expression analysis, co-expression network analysis, and immune cell frequencies analysis were utilized.ResultsWe found the baseline condition, especially immune condition between symptomatic and asymptomatic, was different. Co-expression module that is positively related to asymptomatic is also related to immune cell type of naïve B cell. Function enrichment analysis showed significantly correlation with “B cell receptor signaling pathway”, “immune response−activating cell surface receptor signaling pathway” and so on. Also, modules that are positively related to symptomatic are also correlated to immune cell type of neutrophils, with function enrichment analysis showing significantly correlations with “response to bacterium”, “inflammatory response”, “cAMP−dependent protein kinase complex” and so on. Responses of symptomatic and asymptomatic hosts after virus exposure show differences on resisting the virus, with more effective frontline defense for asymptomatic hosts. A prediction model was also built based on only baseline transcription information to differentiate symptomatic and asymptomatic population with accuracy of 0.79.DiscussionThe results not only improve our understanding of the immune system and influenza susceptibility, but also provide a new direction for precise and targeted prevention and therapy of influenza.

Abstract We present green organohydrogel‐based stretchable (up to 700% strain), transparent, and room‐temperature O2 sensors with impressive performance, including drying and freezing tolerances, high sensitivity, broad detection range (100 ppm‐100%), long‐term stability, low theoretical detection limit (0.585 ppm), linearity, and the capability to real‐time monitor human respiration by directly attaching on human skin. A facile solvent replacement approach is employed to partially exchange water with natural and edible xylitol/sorbitol molecules, generating stable, green and tough organohydrogels. Compared with the pristine hydrogel counterpart, the organohydrogel‐based O2 sensors feature higher stability, prolonged life time (140 days) and the ability to work over a wide range of temperatures (−38 to 65°C). The O2 sensing mechanism is elucidated by investigating the redox reactions occurred at the electrode‐hydrogel interface. This work develops a facile strategy to fabricate stretchable, transparent, and high‐performance O2 sensor using stable and green organohydrogels as novel transducing materials for practical wearable applications.

The immune system is highly networked and complex, which is continuously changing as encountering old and new pathogens. However, reductionism-based researches do not give a systematic understanding of the molecular mechanism of the immune response and viral pathogenesis. Here, we present HUMPPI-2022, a high-quality human protein-protein interaction (PPI) network, containing > 11,000 protein-coding genes with > 78,000 interactions. The network topology and functional characteristics analyses of the immune-related genes (IRGs) reveal that IRGs are mostly located in the center of the network and link genes of diverse biological processes, which may reflect the gene pleiotropy phenomenon. Moreover, the virus-human interactions reveal that pan-viral targets are mostly hubs, located in the center of the network and enriched in fundamental biological processes, but not for coronavirus. Finally, gene age effect was analyzed from the view of the host network for IRGs and virally-targeted genes (VTGs) during evolution, with IRGs gradually became hubs and integrated into host network through bridging functionally differentiated modules. Briefly, HUMPPI-2022 serves as a valuable resource for gaining a better understanding of the composition and evolution of human immune system, as well as the pathogenesis of viruses.

Background Stimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic double-stranded DNA originating from microorganisms and host cells. The activation of cytosolic DNA-STING pathway in tumor microenvironments is usually linked to more robust adaptive immune responses to tumors, however the intracellular function of STING in regulatory T cells is largely unknown. In the present study, we aimed to explore the contribution of intracellular STING activation to regulatory T cell induction (iTreg) in cervical cancer (CC) microenvironments.Methods Blood samples and tumor specimens were obtained from patients with CC. The intratumoral STING, CCL22, CD8 and forkhead box P3 (FOXP3) expression levels were measured by immunohistochemistry. T cell-specific STING conditional knockout mice (CD4-Cre/STINGflox/flox, TKO) were generated, and syngeneic TC-1 tumor model were investigated. The differentiation and molecular regulatory pathway of human and murine iTreg under different treatments were investigated by ex vivo assays, immunoblotting and quantitative PCR. Tumor-associated exosomes (T-EXO) were isolated from CC cell lines and exosomal contents were identified by ELISA and Western blot analysis. The impact of T-EXO on T cell differentiation was tested in in vitro cell culture.Results Increased STING, CCL22 level, FOXP3+ cells but decreased CD8+ cells in tumor tissues predicted poor survival. Tumor-bearing CD4-Cre-STINGflox/flox (TKO) mice displayed slower tumor growth tendencies as well as fewer FOXP3+ cells but higher CD8+ cell proportion in tumor tissues than wild-type (WT) mice. Activating of STING signaling cooperated with T cell receptor, interleukin-2 receptor and transforming growth factor-beta (TGF-β) signals to promote CD4+CD25highFOXP3+ iTreg differentiation from both human and murine CD4+-naïve T cells from WT and IFNAR−/− mice but not TKO or IRF3−/− mice in vitro. Ectopic STING, TBK1 or IRF3 expression promoted iTreg differentiation from human CD4+-naïve T cells. T cell-intrinsic STING activation induced FOXP3 transcription through TBK1-IRF3-mediated SMAD3 and STAT5 phosphorylation independent of interferon-β. In CC, tumor-derived exosomes activated STING signaling in tumor-infiltrated T cells by exosomal TGF-β, cyclic GMP-AMP synthase and 2’-3’-cGAMP, leading to iTreg expansion.Conclusions These findings highlight a novel mechanism for iTreg expansion mediated by tumor-derived exosome-activated T cell-intrinsic STING signal, and provide a rationale for developing immunotherapeutic strategies targeting STING signal in CC.

IntroductionKinking of the cervical carotid or vertebral artery is a common structural abnormality in patients with cerebrovascular disease. However, there is no consensus about the relationship between kinking and ischemic stroke/TIA. We aim to determine the effect of arterial kinking on ischemic stroke/TIA.MethodsA retrospective study was performed on patients who underwent cerebral angiography with DSA between January 2014 and December 2018. Demographic information and comorbidities were recorded. Each anatomical circulation system was defined as an observation unit. Kinking and stenosis of each circulation unit were recorded. Ischemia stroke or TIA within 6 months and its location were assessed as an outcome. Logistic regression with a generalized estimating equation approach was used for the analysis.ResultsA total of 1,062 patients (mean age 57.9 ± 14.5 years, 740 males and 322 females) were included in the study. Of the patients, 369 (35%) had kinking and 771 (73%) had ischemic stroke/TIA. There were 110 left anterior, 90 right anterior, and 308 posterior circulation units, among which 343 had mild, 160 had moderate, and 243 had severe kinking. Multivariate regression analysis showed that ischemic stroke/TIA was associated with severe kinking (OR 1.39, 95% CI 1.03–1.88, P = 0.03). Posterior circulation was more vulnerable to acute ischemia than left anterior and right anterior circulation (OR 3.58, 95% CI 2.81–4.56, P < 0.0001).ConclusionSevere kinking of the cervical carotid or vertebral artery may be associated with a higher risk of ischemic stroke/TIA, especially when the kinking is located in the posterior circulation.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by heterogeneous inflammatory endotypes of unknown etiology. Invariant natural killer T (iNKT) cells are multifunctional innate T cells that exhibit Th1-, Th2-, and Th17-like characteristics. We investigated functional relationships between iNKT cells and inflammatory subtypes of CRSwNP. Eighty patients with CRSwNP and thirty-two control subjects were recruited in this study. Flow cytometry was used to analyze the frequencies and functions of iNKT cells and their subsets in peripheral blood mononuclear cells (PBMCs) and tissues. Polyp tissue homogenates were used to study the multifunctionality of iNKT cells. iNKT cells were significantly increased in polyps (0.41%) than in control mucosa (0.12%). iNKT cells were determined in the paucigranunlocytic (n=20), eosinophilic (n=22), neutrophilic (n=23), and mixed granulocytic (n=13) phenotypes of CRSwNP. The percentages of iNKT cells and HLA-DR+PD-1+ subsets were lower in eosinophilic or mixed granulocytic polyps than those of other phenotypes. iNKT cells and subsets were enriched in polyp tissues than in matched PBMCs. The evaluation of surface markers, transcription factors, and signature cytokines indicated that the frequencies of iNKT2 and iNKT17 subsets were significantly increased in eosinophilic and neutrophilic polyps, respectively, than in the paucigranulocytic group. Moreover, the production of type 2 (partially dependent on IL-7) and type 17 (partially dependent on IL-23) iNKT cells could be stimulated by eosinophilic and neutrophilic homogenates, respectively. Our study revealed that type 2 and type 17 iNKT cells were involved in eosinophilic and neutrophilic inflammation, respectively, in CRSwNP, while different inflammatory microenvironments could modulate the functions of iNKT cells, suggesting a role of iNKT cells in feedback mechanisms and local inflammation.

Abstract Background Central nervous system (CNS) hemangioblastomas are the most frequent cause of mortality in patients with Von Hippel–Lindau (VHL) disease, an autosomal dominant genetic disease resulting from germline mutations in the VHL tumor suppressor gene, with most mutations occurring in the exons. To date, there have been no reports of CNS hemangioblastoma cases related to pathogenic variants in intron 2 of VHL, which encodes a tumor suppressor protein (i.e., pVHL) that regulates hypoxia-inducible factor proteins. Case presentation We report the presence of a base substitution of c.464-1G > C and c.464-2A > G in the intron 2 of VHL causing CNS hemangioblastomas in six patients with VHL from two Chinese families. The clinical information about the two pathogentic variants has been submitted to ClinVar database. The ClinVar accession for NM_000551.3(VHL):c.464-1G > C was SCV001371687. This finding may provide a new approach for diagnosing and researching VHL-associated hemangioblastomas. Conclusions This is the first report of a pathogenic variant at intron 2 in VHL-associated hemangioblastomas. Gene sequencing showed that not only exonic but also intronic mutations can lead to the development of CNS hemangioblastomas.

Abstract Objective Central nervous system (CNS) hemangioblastomas (HGBs) are the most frequent cause of mortality in patients with von Hippel-Lindau (VHL) genetic syndrome. However, there is a lack of large studies on the clinical features and optimal management of HGBs in Chinese patients. Methods VHL-related HGB cases treated surgically at our hospital from 2012 to 2019 were evaluated. Patients and family members meeting the clinical diagnostic criteria underwent genetic testing. Clinical, genetic and relevant imaging data were analyzed. Results Eighty-five VHL patients from 34 pedigrees in 16 Chinese provinces who underwent 121 operations for CNS HGBs were enrolled. Multiple operations were associated with a younger age at first operation (OR = 0.926, 95% CI = 0.871–0.985, P = 0.014, threshold: 27.5, sensitivity: 72.2%, specificity: 71.2%) and a longer postoperative period (OR = 1.096, 95% CI = 1.015–1.184, P = 0.019, threshold: 10.5, sensitivity: 66.7%, specificity: 76.3%). The age at first operation was younger in children than in their parents (23 pairs, P

Structural health monitoring (SHM) allows for real-time structural response monitoring and online data acquisition of bridge structures. Thisdata reflectsthe operational and environmental conditions of the bridge, which is important in identification of possible anomalous changes. In order to effortlessly determine the safety condition of the bridge directly through the transferred data without data analysis, a five-level safety standard system will be established for real-time safety warning in this paper. The threshold of each safety levels will be determined through field loading tests results on an external prestressing rehabilitated continuous rigid frame bridge, of which permanent structural health monitoring system was instrumented. After overall evaluation, we cometo the conclusionthat the rehabilitation is successful and that the bridge is under safe operating condition.A novel, simplified safety standard thresholding technique is proposed based on static loading test results as well as ultimate limit state of the bridge. This technique is simple yet very practical in daily bridge monitoring.

Abstract Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

Aim: To explore the relationship between the use of aspirin and the incidence of hepatocellular carcinoma (HCC).Methods: MEDLINE, EMBASE, Web of Science and Cochrane CENTRAL databases were searched systematically from the earliest available date to 13 March 2020. The primary outcome was incidence of HCC, and the secondary outcomes were recurrence and mortality of HCC. The results were expressed as the Hazard Ratio (HR) and 95% confidence interval (CI). Based on the heterogeneity evaluated with the I2 statistic, a meta-analysis was performed using either a random- or fixed-effects model.Results: A total of sixteen articles (2781100 participants) were included. There was lower incidence of HCC in aspirin users than those in non-aspirin users (HR, 0.56; 95% CI, 0.46-0.69; p < 0.001). Subgroup analysis further showed that the incidence of liver cancer in patients with alcoholic cirrhosis (HR, 0.14; 95% CI, 0.09-0.22; p < 0.001) and virus hepatitis (HR, 0.68; 95% CI, 0.62-0.74; p < 0.001) who use aspirin was lower than that of patients who do not use aspirin. In addition, aspirin was found to associate with decreased risk of HCC mortality (HR, 0.71; 95% CI, 0.65-0.78; p < 0.001), not HCC recurrence (HR, 0.52; 95% CI, 0.15-1.76; p = 0.291).Conclusions: Aspirin use is significantly associated with the low incidence rate of liver cancer.

The SYG1, PHO81, and XPR1 (SPX) domain is named after the suppressor of yeast gpa1 (Syg1), yeast phosphatase (Pho81) and the human Xenotropic and Polytrophic Retrovirus receptor1 (XPR1). SPX-domain-containing proteins play pivotal roles in maintaining phosphate ions (Pi) homeostasis in plant. This study was to genome-wide identification and analysis of Solanum lycopersicum SPX-domain-containing protein gene family. The Solanum lycopersicum genome contains 19 SPX-domain-containing protein genes. These SPX-domain-containing protein genes were located in seven of the 12 chromosomes. According to the different conserved domains, the proteins encoded by those genes could be divided into four SPX-domain-containing protein families, which included SPX Family, SPX-ERD1/XPR1/SYG1(SPX-EXS) Family, SPX-Major Facilitator Superfamily (SPX-MFS) Family and SPX-Really Interesting New Gene (SPX-RING) Family. Phylogenetic analysis of SPX-domain-containing protein genes in Arabidopsis thaliana, Solanum tuberosum, Capsicum annuum and Solanum lycopersicum classified these genes into eight clades. Expression profiles derived from transcriptome (RNA-seq) data analysis showed 19 SPX-domain-containing protein genes displayed various expression patterns. SPX-domain-containing protein may play different roles in phosphate nutrition of Solanum lycopersicum different tissues and development stages. And, this study can provide the selection of candidate genes for functional research and genome editing in Solanum lycopersicum phosphate ions (Pi) nutrition.

Background: The ideal treatment for patients who survive from acute vertebrobasilar artery occlusion but develop aggressive ischemic events despite maximal medical therapy in the early non-acute stage is unknown. This paper reports the technical feasibility and outcome of staged endovascular treatment in a series of such patients with symptomatic intracranial vertebral artery occlusion.Methods: Ten consecutive patients who presented with aggressive ischemic events in the early non-acute stage of intracranial vertebral artery occlusion from Jan 2015 to Nov 2020 were retrospectively reviewed. Among them, eight male and two female patients with a mean age of 66.7 years developed aggressive ischemic events, and the NIHSS score was elevated by a median of 7 points despite medical therapy. All patients received staged endovascular treatment 4–21 days from onset, at an average of 11 days. The strategy of staged treatment was as follows: first, a microwire was passed through the portion of the occlusion, which was then dilated with balloon inflation to maintain the perfusion above TICI grade 2b. Then, with the use of antiplatelet drugs, the residual intravascular thrombus was gradually eliminated by the continuous perfusion and an activated fibrinolytic system, leaving the residual stenosis. A second stage of angioplasty with stent implantation was subsequently performed if residual stenosis was ≥50%. The NIHSS scores and mRS scores were compared between pre- and post-endovascular treatment groups and in the follow-up period.Results: Technical success was achieved in 9 patients who received staged endovascular treatment (perforation occurred in one patient during the first stage). The NIHSS scores were significantly improved, with a median score 7 points lower on discharge compared with the scores for the most severe status. Favorable outcomes with mRS score ≤ 2 were achieved in 7 and 9 patients at the 3-month follow-up and the latest follow-up, respectively, which was better than the preoperative status.Conclusion: Staged endovascular treatment might be a safe, efficient, and viable option in carefully selected patients with symptomatic intracranial vertebral artery occlusion in the early non-acute stage. However, this needs to be confirmed by further investigation, preferably in a large, controlled setting.

This article relies on the reinforcement project of the Mulinghe cable-stayed bridge to explore the changes in the mechanical properties of the reinforced concrete cable-stayed bridge before and after reinforcement. The bridge has large cable spacing, large internal force of a single cable, and the main beam is mainly Reinforced Concrete. Therefore, structural calculation, disease analysis, and damage state simulation are carried out. Afterwards, the bridge's commonly used reinforcement methods were compared, and suitable reinforcement schemes were selected. After the reinforcement, the field test was carried out on the cable-stayed bridge, the main beam deflection, the strain of the main beam and the main tower, and the increase in the cable force of the cable- stayed were analyzed. The results show that external prestressed reinforcement is the best way, which can significantly reduce the vertical displacement of the main beam and the horizontal displacement of the main tower, and also improve the stress on the upper and lower edges of the main beam. After the external prestressed reinforcement, the ratio of the observed value to the observed value in the filed load test of the cable-stayed bridge's decreased significantly. It is up to 31% increase in bending capacity of main beams and up to 24% increase in stiffness. This article is instructive for the reinforcement of the early-built sparse-cable reinforced concrete cable-stayed bridge, while also expanding the scope of implementation of external prestressed reinforcement technology.

Goose liver oil (GLO) microcapsules were prepared by konjac glucomannan (KGM) and soybean protein isolate (SPI) for the first time as wall materials. The GLO could be effectively encapsulated, with an encapsulation efficiency of 83.37%, when the ratio of KGM to SPI was 2.9:1, the concentration of the KGM-SPI composite gel layer was 6.28% and the ratio of the GLO to KGM-SPI composite gel layer was 1:6. Fourier transform infrared spectroscopy and X-ray diffraction methods showed electrostatic interactions between KGM and SPI molecules and the formation of hydrogen bonds between the GLO and KGM-SPI wall components. The results of scanning electron microscopy showed a smooth spherical surface morphology of the microcapsules with a dense surface and no cracks. The confocal laser scanning microscopy showed that the microcapsules were homogeneous inside and no coalescence occurred. The encapsulated GLO has a significantly higher thermal and oxidative stability compared to free GLO. In the in vitro digestion experiment, 85.2% of the microcapsules could travel through gastric juice, and 75.2% could be released in the intestinal region. These results suggested that microcapsules prepared by KGM-SPI might be used as a carrier for the controlled release of GLO and could microencapsulate various oil-soluble nutrients in food products.

BackgroundHemangioblastomas are uncommon, benign neoplasms of the central nervous system (CNS). This study aims to evaluate the incidence, demographics, clinical characteristics, and prognosis of CNS hemangioblastomas using the data from the Surveillance, Epidemiology, and End Results (SEER) Program.MethodsUnivariate and multivariate analyses using the Cox proportional hazards model were employed to identify prognostic factors of overall survival. The Kaplan-Meier method was utilized to evaluate overall survival distribution by treatment modality. A nomogram was further built to predict survival at 3 and 5 years.ResultsThe overall incidence rate of CNS hemangioblastomas was 0.141 per 100,000 person-years. Through univariate analysis and multivariate analyses, age between 60 and 79 years (HR = 3.697, p < 0.001), age greater than 80 years (HR = 12.318, p < 0.001), African American race (HR = 1.857, p = 0.003), multiple tumors (HR = 1.715, p < 0.001), and prior surgery (HR = 0.638, p = 0.013) were significantly associated with overall survival. Patients receiving surgery alone had better overall survival compared with patients receiving no treatment (p = 0.008) and patients receiving both surgery and radiotherapy (p = 0.002). The calibration plots demonstrated an excellent agreement between nomogram-predicted and actual survival.ConclusionIn conclusion, age, race, tumor location, number of tumors, and prior surgery are prognostic factors for survival. Surgery was the most common modality and was suggested as an effective and optimal treatment. The proposed nomogram can predict the prognosis of patients with CNS hemangioblastomas and help clinicians in making decisions.

Background: Central nervous system (CNS) hemangioblastomas (HGBs) are the most frequent cause of mortality in patients with von Hippel–Lindau (VHL) disease. Characteristics of multiple and recurrent disease cause certain difficulties in the treatment of CNS HGBs.Methods: VHL-related HGB cases treated surgically at our hospital from September 2015 to February 2019 were analyzed. Patients meeting the clinical diagnostic criteria underwent genetic testing. Real-time PCR and immunohistochemistry were used in HGBs to verify differential expression of mRNAs and proteins, respectively. Furthermore, correlations between the differentially expressed proteins and the histological grading, genetic mutations, and tumor burden were also analyzed.Results: A total of 21 patients with VHL syndrome confirmed by genetic testing (missense group, 9; partial deletion group, 12) were enrolled, and 30 CNS HGBs from these patients were studied. Clinical data showed that men at first operation were significantly younger than females (p = 0.005). Real-time PCR demonstrated that EGFR (p = 0.017) and TGFα (p = 0.017) mRNA expression in VHL-related HGBs was significantly higher than that in the control group. Immunohistochemistry showed that the mean optical density in VHL-related HGBs was significantly higher than that in controls (EGFR, p = 0.007; TGFα, p = 0.021). Finally, the cyst volume was related to the upregulation of EGFR (r = 0.782, p < 0.01).Conclusion: Overexpression of EGFR and TGFα may contribute to tumor growth in VHL-related CNS HGBs. The cyst volume was associated with EGFR overexpression. These results provide information for the management of VHL-related HGBs in the era of targeted therapeutics.

Abstract Circular RNAs (circRNAs) are connected at the 3′ and 5′ ends by exon or intron cyclization, forming a complete ring structure. circRNA is more stable and conservative than linear RNA and abounds in various organisms. In recent years, increasing numbers of reports have found that circRNA plays a major role in the biological functions of a network of competing endogenous RNA (ceRNA). circRNAs can compete together with microRNAs (miRNAs) to influence the stability of target RNAs or their translation, thus, regulating gene expression at the transcriptional level. circRNAs are involved in biological processes such as tumor cell proliferation, apoptosis, invasion, and migration as ceRNAs. circRNAs, therefore, represent promising candidates for clinical diagnosis and treatment. Here, we review the progress in studying the role of circRNAs as ceRNAs in tumors and highlight the participation of circRNAs in signal transduction pathways to regulate cellular functions.

Carbon fiber-reinforced polymer (CFRP) reinforcement technology has been widely used in the reinforcement of reinforced concrete (RC) beams. At this stage, high prestressed CFRP board reinforcement is often used in actual reinforcement. However, most reinforced bridges are designed for a long time, and the design value of the protective layer is low, and it is impossible to achieve a large prestressed tension. Therefore, this paper proposes the reverse-arch method to paste the CFRP board and apply low prestress to strengthen the symmetrical RC beam. Through the three-point forward loading test, the cracking load, ultimate load, crack width, mid-span deflection, strain and failure mode of a reverse-arch method-pasted CFRP board-reinforced beam, a directly pasted CFRP board-reinforced beam and an unreinforced beam are compared. The results show that the load-bearing capacity and stiffness of the test beam can be improved by pasting CFRP plates with anti-arch method, but the ductility of the test beam is reduced. Compared with the unreinforced beam, the maximum cracking load and ultimate load are increased by 56% and 63% respectively. The reverse-arch method can produce low prestress, improve the stiffness and bearing capacity of members, and has a good prospect of engineering application.

The slippage of cable clamps during the long-term operation of suspension bridges is a common and detrimental phenomenon. From an experimental point of view, the cable clamp slippage of a suspension bridge was investigated to reveal the effect of this sliding on the force acting on the full bridge. The forces acting on the bridge before and after the slippage were analyzed using a finite element model. The calculation results showed that the cable clamp slippage directly affects the cable forces of the hangers. The hanger cable force decreased by 19.2% when the slippage reached 10.2 cm, while the maximum increase in the cable force of adjacent hangers was 147.7 kN, an increase of 7.25%. The variation of forces in the hanger cable disrupted the force balance of the main girder, thereby producing a torque effect at the corresponding position in the girder, i.e., increased torque. Meanwhile, the slippage affected the axial tension in the main cable and the main girder. The impact of the tower internal force was less than 1%. Hence, the study concluded that the effect of cable clamp slippage is better understood, ensuring the safety of the suspension bridge.

After publication of the article [1], authors found out that Fig. 1 was inadvertently replaced.

In the fast-evolving landscape of digital networks, the incidence of network intrusions has escalated alarmingly. Simultaneously, the crucial role of time series data in intrusion detection remains largely underappreciated, with most systems failing to capture the time-bound nuances of network traffic. This leads to compromised detection accuracy and overlooked temporal patterns. Addressing this gap, we introduce a novel SSAE-TCN-BiLSTM(STL) model that integrates time series analysis, significantly enhancing detection capabilities. Our approach reduces feature dimensionalitywith a Stacked SparseAutoencoder (SSAE) and extracts temporally relevant features through a Temporal Convolutional Network (TCN) and Bidirectional Long Short-term Memory Network (Bi-LSTM). By meticulously adjusting time steps, we underscore the significance of temporal data in bolstering detection accuracy. On the UNSW-NB15 dataset, ourmodel achieved an F1-score of 99.49%, Accuracy of 99.43%, Precision of 99.38%, Recall of 99.60%, and an inference time of 4.24 s. For the CICDS2017 dataset, we recorded an F1-score of 99.53%, Accuracy of 99.62%, Precision of 99.27%, Recall of 99.79%, and an inference time of 5.72 s. These findings not only confirm the STL model's superior performance but also its operational efficiency, underpinning its significance in real-world cybersecurity scenarios where rapid response is paramount. Our contribution represents a significant advance in cybersecurity, proposing a model that excels in accuracy and adaptability to the dynamic nature of network traffic, setting a new benchmark for intrusion detection systems. [ABSTRACT FROM AUTHOR]