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Abstract Liquid biopsy is a minimally invasive method that uses biofluid samples instead of tissue samples for cancer diagnosis. Exosomes are small extracellular vesicles secreted by donor cells and act as mediators of intercellular communication in human health and disease. Due to their important roles, exosomes have been considered as promising biomarkers for liquid biopsy. However, traditional methods for exosome isolation and cargo detection methods are time-consuming and inefficient, limiting their practical application. In the past decades, many new strategies, such as microfluidic chips, nanowire arrays and electrochemical biosensors, have been proposed to achieve rapid, accurate and high-throughput detection and analysis of exosomes. In this review, we discussed about the new advance in exosome-based liquid biopsy technology, including isolation, enrichment, cargo detection and analysis approaches. The comparison of currently available methods is also included. Finally, we summarized the advantages and limitations of the present strategies and further gave a perspective to their future translational use. Graphical Abstract

Abstract Tumor cells remodel the phenotype and function of tumor microenvironment (TME) cells to favor tumor progression. Previous studies have shown that neutrophils in TME are polarized to N2 tumor-associated neutrophils (TANs) by tumor derived factors, thus promoting tumor growth and metastasis, angiogenesis, therapy resistance, and immunosuppression. Exosomes act as critical intercellular messengers in human health and diseases including cancer. So far, the biological roles of exosomes from N2 TANs in gastric cancer have not been well characterized. Herein, we represented the first report that exosomes from N2 TANs promoted gastric cancer metastasis in vitro and in vivo. We found that exosomes from N2 TANs transferred miR-4745-5p/3911 to gastric cancer cells to downregulate SLIT2 (slit guidance ligand 2) gene expression. Adenovirus-mediated overexpression of SLIT2 reversed the promotion of gastric cancer metastasis by N2 TANs derived exosomes. We further revealed that gastric cancer cells induced glucose metabolic reprogramming in neutrophils through exosomal HMGB1 (high mobility group protein B1)/NF-κB pathway, which mediated neutrophil N2 polarization and miR-4745-5p/3911 upregulation. We further employed ddPCR (droplet digital PCR) to detect the expression of miR-4745-5p/3911 in N2 TANs exosomes from human serum samples and found their increased levels in gastric cancer patients compared to healthy controls and benign gastric disease patients. Conclusively, our results indicate that N2 TANs facilitate cancer metastasis via regulation of SLIT2 in gastric cancer cells by exosomal miR-4745-5p/3911, which provides a new insight into the roles of TME cells derived exosomes in gastric cancer metastasis and offers a potential biomarker for gastric cancer diagnosis.

Abstract Background Our previous genome‑wide association studies (GWAS) have suggested rs912304 in 14q12 as a suggestive risk variant for type 1 diabetes (T1D). However, the association between this risk region and T1D subgroups and related clinical risk features, the underlying causal functional variant(s), putative candidate gene(s), and related mechanisms are yet to be elucidated. Methods We assessed the association between variant rs912304 and T1D, as well as islet autoimmunity and islet function, stratified by the diagnosed age of 12. We used epigenome bioinformatics analyses, dual luciferase reporter assays, and expression quantitative trait loci (eQTL) analyses to prioritize the most likely functional variant and potential causal gene. We also performed functional experiments to evaluate the role of the causal gene on islet function and its related mechanisms. Results We identified rs912304 as a risk variant for T1D subgroups with diagnosed age ≥ 12 but not

Abstract WNT signaling is fundamental in development and homeostasis, but how the Frizzled receptors (FZDs) propagate signaling remains enigmatic. Here, we present the cryo-EM structure of FZD4 engaged with the DEP domain of Dishevelled 2 (DVL2), a key WNT transducer. We uncover a distinct binding mode where the DEP finger-loop inserts into the FZD4 cavity to form a hydrophobic interface. FZD4 intracellular loop 2 (ICL2) additionally anchors the complex through polar contacts. Mutagenesis validates the structural observations. The DEP interface is highly conserved in FZDs, indicating a universal mechanism by which FZDs engage with DVLs. We further reveal that DEP mimics G-protein/β-arrestin/GRK to recognize an active conformation of receptor, expanding current GPCR engagement models. Finally, we identify a distinct FZD4 dimerization interface. Our findings delineate the molecular determinants governing FZD/DVL assembly and propagation of WNT signaling, providing long-sought answers underlying WNT signal transduction.

Hydrodynamic separators are commonly used to control the total suspended solid concentration in stormwater before being discharged to natural water bodies. The separator studied in this paper, featuring a swirling flow generated by tangential inlet and outlet connections, was analyzed for its sediment removal efficiency in relation to sediment and flow rates. For the separator studied in this paper, the numerical model showed that the flow field was favorable for the sediments to gather at the center and settle. A higher flow rate or a smaller sediment diameter corresponded to a lower removal rate and vice versa. The dimension improvement for increasing the sediment removal rate was also studied. It was found that increasing the diameter of the separator showed a higher sediment removal rate compared with corresponding increase in the height of the separator. A dimensionless parameter J was proposed to assess the sediment removal rate of a separator, which may be used for designing and optimizing such a device. The removal rate is positively correlated with the J value. When the J value reaches 0.5 or above, the sediment removal rate exceeds 80%, which is a good initial target value for designing this type of separator. HIGHLIGHTS Provided an experimentally validated computational fluid dynamics model.; Changing the diameter has a greater impact on the removal rate of hydrodynamic separators than changing the height.; The J value can be used to evaluate the solids removal efficiency of a hydrodynamic separator.;

Abstract Objectives Patients with traumatic brain injury (TBI) often suffer memory and cognitive impairments, and oxiracetam‐like drugs are considered to have a positive impact on these symptoms potentially. However, the efficacy and safety of L‐oxiracetam and oxiracetam in TBI patients have not been sufficiently investigated. Methods The study adopts a multicenter, randomized, double‐blind, parallel‐group, phase 3 clinical trial design in 74 centers across 51 hospitals in China. A total of 590 TBI patients meeting criteria will be randomly allocated into three groups in a 2:2:1 ratio: L‐oxiracetam group, oxiracetam group, and placebo group. The treatment period is 14 days, with a follow‐up period of 90 days. The primary outcome measure is the change in the Loewenstein Occupational Therapy Cognitive Assessment score at 90 days after treatment. Secondary outcomes include changes in other cognitive assessments, neurological function, activities of daily living, and safety assessments. Discussion There is no robust evidence to suggest that L‐oxiracetam and oxiracetam can enhance memory and cognitive function in patients with mild to moderate TBI. This study has the potential to answer this crucial clinical question. Trial registration chinadrugtrials.org.cn, identifier CTR20192539; ClinicalTrials.gov, identifier NCT04205565.

Objective·To establish the early symptom network of adult intensive care unit (ICU) patients after transfer (post-ICU patients), identify the core symptoms and bridge symptoms, compare the symptom networks of two subgroups, i.e. mixed ICU and coronary care unit (CCU), and analyze the occurrence of symptoms.Methods·From December 2022 to August 2023, a total of 328 adult patients transferred to wards from mixed ICU and CCU of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine were selected by convenience sampling. The general situation and clinical data questionnaire, and symptom questionnaires (including Hospital Anxiety and Depression Scale, Fatigue Severity Scale, Richards-Campbell Sleep Questionnaire, and Pain Numeric Rating Scale) were used. Based on Spearman correlation analysis and GLASSO algorithm, contemporaneous symptom network was built, and centrality indices and differences between subgroup symptom networks were computed. The edge accuracy and the stability of centrality indices of the network were tested.Results·A total of 302 valid questionnaires were collected, and the effective rate was 92.1%. The results of the centrality indices computations showed that in the early symptom network of post-ICU patients, the highest strength was “feel cheerful” (rS=1.145), the highest closeness was “enjoy something” (rC=1.851×10-3), and the highest expected influence was “（fatigue） interferes with physical function” (rE=1.143). The top three highest bridge strengths of symptoms were “worrying thoughts” (rb=10.392), “enjoy something” (rb=10.359), and pain (rb=10.221). There were no significant differences in network structure (M=0.289) and overall connection strength (GSmixed ICU=13.876, GSCCU=13.838; S=0.039) of the early symptom networks between mixed ICU and CCU patients after being transferred to wards. When comparing the centrality indices, apart from the strength and expected influence of five symptoms showing statistically significant differences (all P

Abstract Background Pediatric acute transverse myelitis (ATM) accounts for 20–30% of children presenting with a first acquired demyelinating syndrome (ADS) and may be the first clinical presentation of a relapsing ADS such as multiple sclerosis (MS). B cells have been strongly implicated in the pathogenesis of adult MS. However, little is known about B cells in pediatric MS, and even less so in pediatric ATM. Our lab previously showed that plasmablasts (PB), the earliest B cell subtype producing antibody, are expanded in adult ATM, and that these PBs produce self-reactive antibodies that target neurons. The goal of this study was to examine PB frequency and phenotype, immunoglobulin selection, and B cell receptor reactivity in pediatric patients presenting with ATM to gain insight to B cell involvement in disease. Methods We compared the PB frequency and phenotype of 5 pediatric ATM patients and 10 pediatric healthy controls (HC) and compared them to previously reported adult ATM patients using cytometric data. We purified bulk IgG from the plasma samples and cloned 20 recombinant human antibodies (rhAbs) from individual PBs isolated from the blood. Plasma-derived IgG and rhAb autoreactivity was measured by mean fluorescence intensity (MFI) in neurons and astrocytes of murine brain or spinal cord and primary human astrocytes. We determined the potential impact of these rhAbs on astrocyte health by measuring stress and apoptotic response. Results We found that pediatric ATM patients had a reduced frequency of peripheral blood PB. Serum IgG autoreactivity to neurons in EAE spinal cord was similar in the pediatric ATM patients and HC. However, serum IgG autoreactivity to astrocytes in EAE spinal cord was reduced in pediatric ATM patients compared to pediatric HC. Astrocyte-binding strength of rhAbs cloned from PBs was dependent on somatic hypermutation accumulation in the pediatric ATM cohort, but not HC. A similar observation in predilection for astrocyte binding over neuron binding of individual antibodies cloned from PBs was made in EAE brain tissue. Finally, exposure of human primary astrocytes to these astrocyte-binding antibodies increased astrocytic stress but did not lead to apoptosis. Conclusions Discordance in humoral immune responses to astrocytes may distinguish pediatric ATM from HC.

Abstract Background Circular RNAs (circRNAs) play important roles in cancer progression and metastasis. However, the expression profiles and biological roles of circRNAs in non-small cell lung cancer (NSCLC) remain unclear. Methods In this study, we identified a novel circRNA, hsa_circ_0006834 (termed circ6834), in NSCLC by RNA-seq and investigated the biological role of circ6834 in NSCLC progression in vitro and in vivo. Finally, the molecular mechanism of circ6834 was revealed by tagged RNA affinity purification (TRAP), western blot, RNA immunoprecipitation, dual luciferase reporter gene assays and rescue experiments. Results Our results showed that circ6834 was downregulated in NSCLC tumor tissues and cell lines. Circ6834 overexpression inhibited NSCLC cell growth and metastasis both in vitro and in vivo, while circ6834 knockdown had the opposite effect. We found that TGF-β treatment decreased circ6834 expression, which was associated with the QKI reduction in NSCLC cells and circ6834 antagonized TGF-β-induced EMT and metastasis in NSCLC cells. Mechanistically, circ6834 bound to AHNAK protein, a key regulator of TGF-β/Smad signaling, and inhibited its stability by enhancing TRIM25-mediated ubiquitination and degradation. In addition, circ6834 acted as a miRNA sponge for miR-873-5p and upregulated TXNIP gene expression, which together inactivated the TGF-β/Smad signaling pathway in NSCLC cells. Conclusion In conclusion, circ6834 is a tumor-suppressive circRNA that inhibits NSCLC progression by forming a negative regulatory feedback loop with the TGF-β/Smad signaling pathway and represents a novel therapeutic target for NSCLC.

In light of the significant presence of liquefiable sandy silt layers in the foundation of the airfield area at the Beijing Daxing airport, this study employed a low-energy, small spacing, and low blow count dynamic compaction method to treat it.To assess the compaction effects and determin the parameters of the compaction process, two energy levels of 1 000 kN·m and 2 000 kN·m were selected, with each energy level tested at 4, 6, 8, 10, and 12 blow counts. Additionally, the effect of the surface frozen soil layer on compaction was investigated using 1 000 kN·m energy level with 4, 6, and 8 blow counts. The full depth standard penetration, surface wave and dry density tests were carried out in the dynamic compaction test area. The experimental results revealed that the sandy silt soil foundation exhibited increased compaction, propagation wave velocity, and enhanced liquefaction resistance after dynamic compaction. Optimal blow counts were determined as 10 and 8 for energy levels of 1 000 kN·m and 2 000 kN·m, the corresponding dynamic consolidation depth is 4.5m and 5.5m, and the eliminating liquefaction depth is 4.3m and 5.3m, respectively. Besides, the standard penetration test requires a minimum of 10 and 12 blows in the depth range of 4.5 m and 5.5 m for energy levels of 1 000 kN·m and 2 000 kN·m. At the optimal blow counts, the dry density of the surface layer of the original foundation should not be less than 1.45 g/cm3. The experimental results suggest that, for foundation treatment in the runway area, the dynamic compaction level of 2 000 kN·m is suitable, and 1 000 kN·m dynamic compaction level is used for foundation treatment in the apron and taxiway area.

The space environment strongly affects the on-orbit performance of spacecraft，and ultraviolet（UV） radiation is one of the important factors，which can lead to charge accumulation and charge discharge of spacecraft surface materials. The photoelectron emission yield（PEEY）of spacecraft surface materials is measured to obtain the basic data of photoemission and perform surface charging simulation analysis，which is an important method to study the charging problem of spacecraft surface materials. The paper firstly introduces the development of PEEY theoretical models，including the Fowler-Dubridge（FD） model，the one-step model，the three-step model（TSM）/Monte carlo（MC） model based on the three-step photoelectron emission theory，and the Moments-based （MB） emission model and quantum model（QM）. The research methods and applicable conditions of each model are analyzed and compared，and the development of PEEY model is sorted out. Then the experimental test applications of PEEY，including the development of domestic and foreign ultraviolet photoelectron yield spectroscopy （UV-PEEY） instruments，the experimental study of PEEY for typical space materials are introduced，and the influence of external conditions and surface conditions on PEEY is focused on. Finally，the suggestions for in-depth research on PEEY for space surface materials are put forward.

Abstract Cyanobacteria bloom and the secondary metabolites released by the microorganism are extremely harmful to aquatic animals, yet study on their adverse effects in zoobenthos is rare. Corbicula fluminea widely distributed in freshwater environment with algal blooms. It is a typical filter feeding zoobenthos that may be affected by the secondary metabolites of cyanobacteria due to its high filtering rate. In this study, C. fluminea was exposed to Microcystis aeruginosa exudates (MaE) for 96 h, which was obtained from 5 × 105 cells/mL and 2.5 × 106 cells/mL exponential stage M. aeruginosa culture solution that represented cyanobacteria cell density needs environmental risk precaution control and emergent control, respectively. The responses of C. fluminea critical organs to MaE were analyzed and evaluated based on histopathological sections, antitoxicity biomarkers, and organ function biomarkers. The results showed that all the organs underwent structural disorders, cell vacuolization, apoptosis, and necrosis, and the damage levels increased as MaE concentration increased. The detoxification and antioxidant defense systems biomarkers in each organ response to MaE exposure differently and the level of reaction improved when MaE concentration increased. The siphon rate and acetylcholinesterase activity showed that the filtration function decreased significantly as the MaE concentration increased. Increased activity of glutathione S-transferase and amylase in the digestive gland indicate that it is the major detoxification organ of C. fluminea. Increased vitellogenin concentration and enlarged oocytes in the gonad indicate that MaE may have an estrogenic effect on C. fluminea. This study demonstrates that cyanobacteria threat benthic bivalves by inducing oxidative stress, inhibiting filtering feeding system, and disturbing digestion system and reproduction potential of C. fluminea.

Abstract Background The purpose of this research is to study the sonographic and clinicopathologic characteristics that associate with axillary lymph node metastasis (ALNM) for pure mucinous carcinoma of breast (PMBC). Methods A total of 176 patients diagnosed as PMBC after surgery were included. According to the status of axillary lymph nodes, all patients were classified into ALNM group (n = 15) and non-ALNM group (n = 161). The clinical factors (patient age, tumor size, location), molecular biomarkers (ER, PR, HER2 and Ki-67) and sonographic features (shape, orientation, margin, echo pattern, posterior acoustic pattern and vascularity) between two groups were analyzed to unclose the clinicopathologic and ultrasonographic characteristics in PMBC with ALNM. Results The incidence of axillary lymph node metastasis was 8.5% in this study. Tumors located in the outer side of the breast (upper outer quadrant and lower outer quadrant) were more likely to have lymphatic metastasis, and the difference between the two group was significantly (86.7% vs. 60.3%, P = 0.043). ALNM not associated with age (P = 0.437). Although tumor size not associated with ALNM(P = 0.418), the tumor size in ALNM group (32.3 ± 32.7 mm) was bigger than non-ALNM group (25.2 ± 12.8 mm). All the tumors expressed progesterone receptor (PR) positively, and 90% of all expressed estrogen receptor (ER) positively, human epidermal growth factor receptor 2 (HER2) were positive in two cases of non-ALNM group. Ki-67 high expression was observed in 36 tumors in our study (20.5%), and it was higher in ALNM group than non-ALNM group (33.3% vs. 19.3%), but the difference wasn’t significantly (P = 0.338). Conclusions Tumor location is a significant factor for ALNM in PMBC. Outer side location is more easily for ALNM. With the bigger size and/or Ki-67 higher expression status, the lymphatic metastasis seems more likely to present.

The study of specific physiological processes from the perspective of network physiology has gained recent attention. Modeling the global information integration among the separated functionalized modules in structural and functional brain networks is a central problem. In this article, the preferentially cutting–rewiring operation (PCRO) is introduced to approximatively describe the above physiological process, which consists of the cutting procedure and the rewiring procedure with specific preferential constraints. By applying the PCRO on the classical Erdös–Rényi random network (ERRN), three types of isolated nodes are generated, based on which the common leaves (CLs) are formed between the two hubs. This makes the initially homogeneous ERRN experience drastic changes and become heterogeneous. Importantly, a statistical analysis method is proposed to theoretically analyze the statistical properties of an ERRN with a PCRO. Specifically, the probability distributions of these three types of isolated nodes are derived, based on which the probability distribution of the CLs can be obtained easily. Furthermore, the validity and universality of our statistical analysis method have been confirmed in numerical experiments. Our contributions may shed light on a new perspective in the interdisciplinary field of complexity science and biological science and would be of great and general interest to network physiology.

The traditional evaluation method of student pilots ' manual manipulation level relies too much on teachers' subjective judgment. A quantitative evaluation method based on flight data is proposed to compensate for the shortcoming of the traditional method. According to the theory of the core competence of a pilot, the evaluation index system of manual manipulation level of student pilots in a typical scene is constructed. The Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) categorizes pilot manipulation levels into four grades. The improved support vector machine (SVM) model with particle swarm optimization (PSO) is trained using index data and rank labels as inputs. The data is split into training and verification sets with the cross-validation method. The training data for Guanghan Airport are taken as an example to verify the model's reliability. The model's prediction accuracy is compared with that of K-nearest neighbor and random forest models. The results show that the PSO-SVM model has higher prediction accuracy. The research can provide a theoretical reference for quantitatively evaluating manual manipulation levels and improving flight training quality.

Background: Traumatic brain injury (TBI) is a common neurosurgical disease in emergency rooms with poor prognosis, imposing severe burdens on patients and their families. Evidence indicates that piracetam and compound porcine cerebroside and ganglioside injection (CPCGI) can improve cognitive levels in TBI patients to enhance functional prognosis, but there is still a research gap regarding the efficacy of CPCGI. This study aims to determine the effectiveness and safety of CPCGI in improving cognitive and functional outcomes in TBI patients. Methods: This study is a multicenter, randomized, parallel-group, double-blind trial aiming to recruit 900 adult patients with mild to moderate TBI. After providing informed consent, 600 patients will be randomly assigned to the CPCGI group (20 ml/d, for 14 days), and 300 patients will be randomized to the piracetam group as a control (20 ml/d, for 14 days), followed up for 3 months after treatment. The primary outcome is the change in the Montreal Cognitive Assessment (MoCA) score from baseline after 3 months. The main secondary outcome measures include Mini-Mental State Examination (MMSE) scores, Glasgow Outcome Scale-Extended (GOS-E), and the Barthel Index at 1 and 3 months. Discussion: This multi-center clinical trial aims to provide high-quality evidence on the efficacy and safety of CPCGI in improving cognitive and functional outcomes in mild to moderate TBI patients. Trial registration: ChiCTR2000040466, date of registration: November 28, 2020.

Abstract Background Polycystic ovary syndrome (PCOS) is an endocrinological and metabolic disorder that can lead to female infertility. Lipid metabolomics and proteomics are the new disciplines in systems biology aimed to discover metabolic pathway changes in diseases and diagnosis of biomarkers. This study aims to reveal the features of PCOS to explore its pathogenesis at the protein and metabolic level. Methods We collected follicular fluid samples and granulosa cells of women with PCOS and normal women who underwent in vitro fertilization(IVF) and embryo transfer were recruited. The samples were for the lipidomic study and the proteomic study based on the latest metabolomics and proteomics research platform. Results Lipid metabolomic analysis revealed abnormal metabolism of glycerides, glycerophospholipids, and sphingomyelin in the FF of PCOS. Differential lipids were strongly linked with the rate of high-quality embryos. In total, 144 differentially expressed proteins were screened in ovarian granulosa cells in women with PCOS compared to controls. Go functional enrichment analysis showed that differential proteins were associated with blood coagulation and lead to follicular development disorders. Conclusion The results showed that the differential lipid metabolites and proteins in PCOS were closely related to follicle quality,which can be potential biomarkers for oocyte maturation and ART outcomes.

Abstract Background Despite substantial research revealing that patients with rheumatoid arthritis (RA) have excessive morbidity and mortality of cardiovascular disease (CVD), the mechanism underlying this association has not been fully known. This study aims to systematically investigate the phenotypic and genetic correlation between RA and CVD. Methods Based on UK Biobank, we conducted two cohort studies to evaluate the phenotypic relationships between RA and CVD, including atrial fibrillation (AF), coronary artery disease (CAD), heart failure (HF), and stroke. Next, we used linkage disequilibrium score regression, Local Analysis of [co]Variant Association, and bivariate causal mixture model (MiXeR) methods to examine the genetic correlation and polygenic overlap between RA and CVD, using genome-wide association summary statistics. Furthermore, we explored specific shared genetic loci by conjunctional false discovery rate analysis and association analysis based on subsets. Results Compared with the general population, RA patients showed a higher incidence of CVD (hazard ratio [HR] = 1.21, 95% confidence interval [CI]: 1.15–1.28). We observed positive genetic correlations of RA with AF and stroke, and a mixture of negative and positive local genetic correlations underlying the global genetic correlation for CAD and HF, with 13 ~ 33% of shared genetic variants for these trait pairs. We further identified 23 pleiotropic loci associated with RA and at least one CVD, including one novel locus (rs7098414, TSPAN14, 10q23.1). Genes mapped to these shared loci were enriched in immune and inflammatory-related pathways, and modifiable risk factors, such as high diastolic blood pressure. Conclusions This study revealed the shared genetic architecture of RA and CVD, which may facilitate drug target identification and improved clinical management.

Ex vivo liver resection combined with autologous liver transplantation offers the opportunity to treat otherwise unresectable hepatobiliary malignancies and has been applied in clinic. The implementation of enhanced recovery after surgery (ERAS) program improves the outcome of surgical procedures. This is a retrospective single-center study including 11 cases of patients with liver cancer that underwent autologous liver transplantation and received ERAS: cholangiocarcinoma of the hilar region (n = 5), intrahepatic cholangiocarcinoma (n = 3), gallbladder cancer (n = 1), liver metastasis from colorectal cancer (n = 1), and liver metastasis from gastrointestinal mesenchymal tumor (n = 1). There were no deaths within 30 days and major complications occurred in two patients, and four patients were readmitted upon the first month after the surgery. Median hospital stay was 20 days (range 13–44) and median open diet was Day 4 (range 2–9) after surgery and median early post-operative activity was Day 5 (range 2–9) after surgery. In conclusion, autologous liver transplantation is feasible in the treatment of otherwise unresectable hepatobiliary malignancies, and our study showed favorable results with autologous liver transplantation in ERAS modality. ERAS modality provides a good option for some patients whose tumors cannot be resected in situ and offers a chance for rapid recovery.

Photonic reservoir computing (RC) is a simple and efficient neuromorphic computing framework for human cortical circuits, which is featured with fast training speed and low training cost. Photonic time delay RC, as a simple hardware implementation method of RC, has attracted widespread attention. In this paper, we present and experimentally demonstrate a time delay RC system based on a Fabry Perot (FP) laser for multiple tasks processing. Here, the various tasks are attempted to perform in parallel in the multiple longitudinal modes of the FP laser. It is found that the time delay RC system based on the FP laser can successfully handle different tasks across multiple longitudinal modes simultaneously. The experimental results demonstrate the potential of the time delay RC system based on the FP laser to achieve multiple tasks processing, providing various possibilities for improving the information processing ability of neural morphology RC systems, and promoting the development of RC systems.

Aiming to address power consumption issues of various equipment in metro stations and the inefficiency of peak shaving and valley filling in the power supply system, this study presents an economic optimization scheduling method for the multi-modal “source-network-load-storage” system in metro stations. The proposed method, called the Improved Gray Wolf Optimization Algorithm (IGWO), utilizes objective evaluation criteria to achieve economic optimization. First, construct a mathematical model of the “sourcenetwork- load-storage” joint system with the metro station at its core. This model should consider the electricity consumption within the station. Secondly, a two-layer optimal scheduling model is established, with the upper model aiming to optimize peak elimination and valley filling, and the lower model aiming to minimize electricity consumption costs within a scheduling cycle. Finally, this paper introduces the IGWO optimization approach, which utilizes meta-models and the Improved Gray Wolf Optimization Algorithm to address the nonlinearity and computational complexity of the two-layer model. The analysis shows that the proposed model and algorithm can improve the solution speed and minimize the cost of electricity used by about 5.5% to 8.7% on the one hand, and on the other hand, it improves the solution accuracy, and at the same time effectively realizes the peak shaving and valley filling, which provides a proof of the effectiveness and feasibility of the new method.

Abstract The histamine H4 receptor (H4R) plays key role in immune cell function and is a highly valued target for treating allergic and inflammatory diseases. However, structural information of H4R remains elusive. Here, we report four cryo-EM structures of H4R/Gi complexes, with either histamine or synthetic agonists clobenpropit, VUF6884 and clozapine bound. Combined with mutagenesis, ligand binding and functional assays, the structural data reveal a distinct ligand binding mode where D943.32 and a π-π network determine the orientation of the positively charged group of ligands, while E1825.46, located at the opposite end of the ligand binding pocket, plays a key role in regulating receptor activity. The structural insight into H4R ligand binding allows us to identify mutants at E1825.46 for which the agonist clobenpropit acts as an inverse agonist and to correctly predict inverse agonism of a closely related analog with nanomolar potency. Together with the findings regarding receptor activation and Gi engagement, we establish a framework for understanding H4R signaling and provide a rational basis for designing novel antihistamines targeting H4R.

Abstract Computationally hard combinatorial optimization problems (COPs) are ubiquitous in many applications. Various digital annealers, dynamical Ising machines, and quantum/photonic systems have been developed for solving COPs, but they still suffer from the memory access issue, scalability, restricted applicability to certain types of COPs, and VLSI-incompatibility, respectively. Here we report a ferroelectric field effect transistor (FeFET) based compute-in-memory (CiM) annealer for solving larger-scale COPs efficiently. Our CiM annealer converts COPs into quadratic unconstrained binary optimization (QUBO) formulations, and uniquely accelerates in-situ the core vector-matrix-vector (VMV) multiplication operations of QUBO formulations in a single step. Specifically, the three-terminal FeFET structure allows for lossless compression of the stored QUBO matrix, achieving a remarkably 75% chip size saving when solving Max-Cut problems. A multi-epoch simulated annealing (MESA) algorithm is proposed for efficient annealing, achieving up to 27% better solution and ~ 2X speedup than conventional simulated annealing. Experimental validation is performed using the first integrated FeFET chip on 28nm HKMG CMOS technology, indicating great promise of FeFET CiM array in solving general COPs.

Abstract Transcortical vessels (TCVs) provide effective communication between bone marrow vascular system and external circulation. Although osteocytes are in close contact with them, it is not clear whether osteocytes regulate the homeostasis of TCVs. Here, we show that osteocytes maintain the normal network of TCVs by transferring mitochondria to the endothelial cells of TCV. Partial ablation of osteocytes causes TCV regression. Inhibition of mitochondrial transfer by conditional knockout of Rhot1 in osteocytes also leads to regression of the TCV network. By contrast, acquisition of osteocyte mitochondria by endothelial cells efficiently restores endothelial dysfunction. Administration of osteocyte mitochondria resultes in acceleration of the angiogenesis and healing of the cortical bone defect. Our results provide new insights into osteocyte-TCV interactions and inspire the potential application of mitochondrial therapy for bone-related diseases.

AIM: To identify the differential methylation sites (DMS) and their according genes associated with diabetic retinopathy (DR) development in type 1 diabetes (T1DM) children. METHODS: This study consists of two surveys. A total of 40 T1DM children was included in the first survey. Because no participant has DR, retina thinning was used as a surrogate indicator for DR. The lowest 25% participants with the thinnest macular retinal thickness were included into the case group, and the others were controls. The DNA methylation status was assessed by the Illumina methylation 850K array BeadChip assay, and compared between the case and control groups. Four DMS with a potential role in diabetes were identified. The second survey included 27 T1DM children, among which four had DR. The methylation patterns of the four DMS identified by 850K were compared between participants with and without DR by pyrosequencing. RESULTS: In the first survey, the 850K array revealed 751 sites significantly and differentially methylated in the case group comparing with the controls (|Δβ|>0.1 and Adj.P0.05) between participants with and without DR. CONCLUSION: The hypermethylation of the TCERG1L gene is a risk factor for DR development in Chinese children with T1DM.

Abstract M2‐polarized tumor‐associated macrophages (M2 TAMs) promote cancer progression. Exosomes mediate cellular communication in the tumor microenvironment (TME). However, the roles of exosomes from M2 TAMs in gastric cancer progression are unclear. Herein, it is reported that M2 TAMs‐derived exosomes induced aerobic glycolysis in gastric cancer cells and enhanced their proliferation, metastasis, and chemoresistance in a glycolysis‐dependent manner. It is identified that MALAT1 (metastasis‐associated lung adenocarcinoma transcript 1) is enriched in M2 TAM exosomes and confirmed that MALAT1 transfer from M2 TAMs to gastric cancer cells via exosomes mediates this effect. Mechanistically, MALAT1 interacted with the δ‐catenin protein and suppressed its ubiquitination and degradation by β‐TRCP. In addition, MALAT1 upregulated HIF‐1α expression by acting as a sponge for miR‐217‐5p. The activation of β‐catenin and HIF‐1α signaling pathways by M2 TAM exosomes collectively led to enhanced aerobic glycolysis in gastric cancer cells. Finally, a dual‐targeted inhibition of MALAT1 in both gastric cancer cells and macrophages by exosome‐mediated delivery of siRNA remarkably suppressed gastric cancer growth and improved chemosensitivity in mouse tumor models. Taken together, these results suggest that M2 TAMs‐derived exosomes promote gastric cancer progression via MALAT1‐mediated regulation of glycolysis. The findings offer a potential target for gastric cancer therapy.

The transcription factor, signal transducer, and stimulator of transcription 3 (STAT3) is a potential target in osteoarthritis (OA) treatment. Although xanthatin (XA), a biologically active substance derived from Xanthium strumarium L, specifically inhibits STAT3 phosphorylation at Tyr705, the mechanism underlying its inhibitory effect on OA progression remains unclear. In this study, our objective was to explore the therapeutic effects exerted by XA on OA and the underlying molecular mechanisms. The effects of XA treatment on mouse OA models subjected to destabilization of the medial meniscus using medial collateral ligament transection, as well as on interleukin-1β (IL-1β)-induced mouse chondrocytes, were examined. Histological changes in cartilage and subchondral bone (SCB), as well as changes in the expression levels of osteophytes, cartilage degeneration- and osteoclast differentiation-related factors, and the role of XA-related signaling pathways in human cartilage tissue, were studied using different techniques. XA inhibited STAT3 phosphorylation at Tyr705 and further attenuated the activity of nuclear factor-κB (NF-κB) in chondrocytes and osteoclasts. In vitro, XA administration alleviated pro-inflammatory cytokine release, extracellular matrix catabolism, and RANKL-mediated osteoclast differentiation. In vivo, intraperitoneal injection of XA exerted a protective effect on cartilage degeneration and SCB loss. Similarly, XA exerted a protective effect on human cartilage tissue by inhibiting the STAT3/NF-κB signaling pathway. Overall, our study elucidated the therapeutic potential of XA as a small-molecule inhibitor of STAT3-driven OA progression. This discovery may help enhance innovative clinical interventions against OA.

Due to the low oxidation potential and high electrochemiluminescence (ECL) quantum yield, Luminol has been widely applied in analytical and detection fields, especially in immunoassay, food safety and environmental monitoring. However, there is a lack of sufficient experimental evidence on the ECL mechanism of Luminol, which affects the further improvement of its ECL efficiency. Herein, an electrochemistry-micro tube-mass spectrometry (EC-MT-MS) device was constructed for on-line monitoring of Luminol ECL reaction. In this EC-MT-MS device, a high borosilicate glass tube with a nano tip was used as electrochemical cell and electrospray ionization source, a platinum working electrode and a platinum counter electrode were inserted into the tube and connected to a customized power station, which could simultaneously input a low voltage (volt level) for the ECL reaction and a high voltage (kilovolt level) for the formation of electrospray. Prior to the EC-MT-MS experiment, the composition of the reaction solution was optimized to obtain the highest MS signal response, and Luminol was dissolved in acetonitrile-water (4:1, V/V) solvent with ammonium acetate as the electrolyte. The concentrations of Luminol and ammonium acetate in the prepared solution were both 0.1 mmol/L, and the pH was adjusted to 11 using ammonium aqueous. The oxidation potential of Luminol was subsequently studied using a traditional three-electrode system by cyclic voltammetry in the same solution, and the determined oxidation potential for ECL reaction was 0.87 V. During the EC-MT-MS measurements, (2.5 kV+0.87 V) and 2.5 kV were input to the working and counter through the power station, respectively. A series of short-lived intermediates and products such as L1 (m/z 198) and the luminescent precursor AP- (m/z 180) in the Luminol ECL reaction process were successfully captured and analyzed by MS. The molecular structures of these products were characterized by tandem mass spectrometry (MSn) technique. There are mainly two fragments of m/z 163, 136 present in the MS2 spectrum of luminescent precursor AP-, attributed to the (NH2+H) and COO losses, respectively. In addition, the promotion mechanism of hydrogen peroxide (H2O2) for the ECL performance of Luminol was also investigated. A key reaction intermediate LO2H- was found in the MS spectrum at m/z 208. Meanwhile, the peak intensity of luminescent precursor AP- significantly increased from 1.3% to 15.7%, proving that the presence of H2O2 effectively promoted the generation of key luminescent intermediate. Finally, by adding 1,4-benzoquinone to the Luminol-H2O2 system, the central role of the superoxide anion radical (O2·-) derived from H2O2 in the Luminol ECL process was confirmed. The relevant results provide a direct data reference for the study of the Luminol ECL mechanism.

Abstract Background Despite its prevalence, there is ongoing debate regarding the optimal management strategy for chronic subdural hematoma (CSDH), reflecting the variability in clinical presentation and treatment outcomes. This ambidirectional, nationwide, multicenter registry study aims to assess the efficacy and safety of multimodality treatment approaches for CSDH in the Chinese population. Methods/design A multicenter cohort of CSDH patients from 59 participating hospitals in mainland China was enrolled in this study. The treatment modalities encompassed a range of options and baseline demographics, clinical characteristics, radiographic findings, and surgical techniques were documented. Clinical outcomes, including hematoma resolution, recurrence rates, neurological status, and complications, were assessed at regular intervals during treatment, 3 months, 6 months, 1 year, and 2 years follow-up. Result Between March 2022 and August 2023, a comprehensive cohort comprising 2173 individuals who met the criterion was assembled across 59 participating clinical sites. Of those patients, 81.1% were male, exhibiting an average age of 70.12 ± 14.53 years. A historical record of trauma was documented in 48.0% of cases, while headache constituted the predominant clinical presentation in 58.1% of patients. The foremost surgical modality employed was the burr hole (61.3%), with conservative management accounting for 25.6% of cases. Notably, a favorable clinical prognosis was observed in 88.9% of CSDH patients at 3 months, and the recurrence rate was found to be 2.4%. Conclusion This registry study provides critical insights into the multimodality treatment of CSDH in China, offering a foundation for advancing clinical practices, optimizing patient management, and ultimately, improving the quality of life for individuals suffering from this challenging neurosurgical condition. Trial registration ChiCTR2200057179

A 16-month monitoring program was conducted on a prototype sanitary system in a coastal city in China. The groundwater infiltration (GWI) on dry weather days and the rain-derived inflow and infiltration (RDII) on wet weather days were quantified and analyzed. The proportion of monthly averaged GWI to total flow can be as high as 70% during the observation period mainly due to the high groundwater level. The results also show that the ratio of RDII volume to total rainfall volume (defined as R-value) reaches a limited value of approximately 10% for the studied system when the total rainfall depth increases. A reference indicator Rlim for the limited R-value was proposed for assessing the conditions of sewer systems in terms of RDII. The Rlim value depends on local sewer conditions and in general, a lower Rlim value represents a better performance on RDII and vice versa. This study enriches the case studies on the performance of a specific sanitary sewer system on inflow and infiltration in a typical coastal city with exceptionally high groundwater levels, excess rainfall events in the monitoring season and possible typhoon events, which addresses the unique locational and hydrological properties of a representative coastal city. HIGHLIGHTS The time-period for the ‘minimum night flow method’ should be adjusted accordingly.; High infiltration due to high groundwater levels was observed specifically for the study site.; The ratio of RDII volume to total rainfall volume (R-value) tends to be limited as rainfall increases for all RDII events.; The limited R-value for high rainfall events was proposed for assessing the performance of sewer systems.;

Abstract KMT2A-rearranged acute myeloid leukemia (KMT2Ar-AML) is an aggressive subtype of AML with poor response and prognosis. KMT2Ar-AML has been demonstrated to be sensitive to BCL2 inhibitor venetoclax (VEN), but these patients are unable to benefit from current VEN-based regimen (VEN plus azacitidine or low dose-cytarabine), so a novel and KMT2A rearrangement-specific targeting partner is required, and MENIN inhibitor (MEN1i) is a promising one. Herein, we investigated the effect and mechanism of VEN plus MEN1i in KMT2Ar-AML. Our results showed that VEN and MEN1i exhibited a striking synergistic effect in KMT2Ar-AML cell lines (in vitro), primary KMT2Ar-AML cells (ex vivo), and MOLM13 xenotransplantation model (in vivo). Furthermore, we found that VEN plus MEN1i significantly enhanced apoptotic induction in KMT2Ar-AML cell lines. VEN or MEN1i monotherapy disrupted balance of BCL-2/BCL-XL or down-regulated HOXA9/MEIS1, respectively, but these mechanisms were not further strengthened by their combination. RNA-Sequencing identified that HDAC9 was specifically repressed by VEN plus MEN1i rather than monotherapy. We demonstrated that HDAC9 was indispensable for KMT2Ar-AML proliferation and its repression contributed to proliferation inhibition of VEN plus MEN1i. Moreover, we found that hypoxia induced HDAC9 expression in KMT2Ar-AML, and VEN plus MEN1i inhibited hypoxia pathway, especially HIF-1A, and its target HDAC9. As our results indicated, VEN plus MEN1i-mediated HDAC9 down-regulation was partially dependent on HIF-1A repression in KMT2Ar-AML. Hypoxia induction sensitized KMT2Ar-AML to VEN plus MI-503-mediated proliferation inhibition and apoptosis induction. Therefore, repressing HIF-1A-induced HDAC9 contributed to the synergistic effect of VEN and MEN1i in KMT2Ar-AML.

The oxidation of almonds during the storage and processing would seriously affect their nutrition and quality. The purpose of this study was to establish a sensitive and reliable method for rapid detection of the oxidation of almonds. A rapid and simple phase-transfer of gold nanoparticles (AuNPs) from aqueous solution to toluene was achieved via a strategy of surface ligand exchange. The results of UV-Vis and transmission electron microscopy showed that the morphology of AuNPs after phase-transfer changed no obvious. The AuNPs in toluene could be successfully used as an efficient SERS substrate for detecting the oxidation of almond oil. The characteristic Raman signal of the cis-double bond at 1655 cm−1 of almonds oil gradually decreased during oxidation. Raman signal at 1747 cm−1 of the ester bond was selected as the reference, and the relative intensity of I1655/I1747 showed a good linear relationship with the time of accelerated ageing of almonds (R2=0.98). By virtue of principal component analysis, the developed method was able to quickly and accurately distinguish the almonds with different oxidation levels. This study also provided a new strategy for the preparation and application of SERS substrates for fatty foods.

This study observed the effect of salidroside on improving oxidative aging induced by D-galactose in mice by enhancing aerobic swimming. In this study, the oxidative aging model of mice was established by D-galactose, and the changes of organ index, histopathological changes, and mRNA expression in serum and tissue of oxidative aging mice after aerobic swimming and aerobic swimming+salidroside were detected. The results showed that aerobic swimming and aerobic swimming+salidroside inhibited the decline of heart index, liver index, spleen index and kidney index caused by oxidative aging in mice. Aerobic swimming and aerobic swimming+salidroside increased the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione (GSH) in serum, liver and spleen of oxidative aging mice, and decreased the level of malondialdehyde (MDA). The study also found that aerobic swimming and aerobic swimming+salidroside can reduce the damage of oxidative aging to liver and spleen tissues. Quantitative polymerase chain reaction (qPCR) showed that aerobic swimming and aerobic swimming+salidroside could up-regulate the mRNA expression of CAT, GSH, Cu/Zn-SOD, Mn-SOD and GSH-PX in mouse liver tissue. The results showed that aerobic swimming could effectively inhibit the oxidative aging of mice induced by D-galactose, and the effect of aerobic swimming+salidroside was better than that of aerobic swimming alone. It can be seen that salidroside can enhance the improvement of aerobic swimming on oxidative aging and can be used as a sports supplement.

Abstract Traditional Chinese Medicines (TCMs) have been used for centuries for the treatment and management of various diseases. However, their effective delivery to targeted sites may be a major challenge due to their poor water solubility, low bioavailability, and potential toxicity. Nanocarriers, such as liposomes, polymeric nanoparticles, inorganic nanoparticles and organic/inorganic nanohybrids based on active constituents from TCMs have been extensively studied as a promising strategy to improve the delivery of active constituents from TCMs to achieve a higher therapeutic effect with fewer side effects compared to conventional formulations. This review summarizes the recent advances in nanocarrier-based delivery systems for various types of active constituents of TCMs, including terpenoids, polyphenols, alkaloids, flavonoids, and quinones, from different natural sources. This review covers the design and preparation of nanocarriers, their characterization, and in vitro/vivo evaluations. Additionally, this review highlights the challenges and opportunities in the field and suggests future directions for research. Nanocarrier-based delivery systems have shown great potential in improving the therapeutic efficacy of TCMs, and this review may serve as a comprehensive resource to researchers in this field. Graphical abstract

The action-to-reaction dynamics of next-generation nanofertilizers (NFs) towards field crops are currently being addressed in precision and sustainable agriculture. Therefore, our aim was to evaluate the effects of foliar application of ZnO nanoparticles (ZnO-NPs) or their combination with hybrid nanoporous biosilica mixed with yeast (ZnSi-bio) for soybean plants’ selected production and physiological indices in comparison to an NF-free control. The experiment was conducted at eco-friendly concentrations in Veľký Krtíš, Slovakia, a location within the Central European agronomical region. The ZnSi-bio variant had an improved number of pods, seed count, and yield, while the ZnO-NPs variant had an enhanced seed bulk density compared to the NF-free control, which had a greater effect on thousand-seed weight (TSW). Significant differences were found in the final quality components of soybeans with respect to phosphorus content without ZnO-NP biofortification. In the case of the ZnSi-bio variant, soybeans were biofortified with zinc. Both leaf-applied NFs markedly improved nutritional and energetic values for soybeans. NFs continued to positively affect seasonal physiology, such as the stomatal conductance (Ig) and crop water stress index (CWSI), compared to the control. The results suggest that the ZnO-NPs, especially when combined with hybrid biosilica and yeast, open new avenues for interdisciplinary research in agro-food science.

Abstract Background Acute myeloid leukaemia (AML) is a haematological malignancy with unfavourable prognosis. Despite the effectiveness of chemotherapy and targeted therapy, relapse or drug resistance remains a major threat to AML patients. N6‐methyladenosine (m6A) RNA methylation and super‐enhancers (SEs) are extensively involved in the leukaemogenesis of AML. However, the potential relationship between m6A and SEs in AML has not been elaborated. Methods Chromatin immunoprecipitation (ChIP) sequencing data from Gene Expression Omnibus (GEO) cohort were analysed to search SE‐related genes. The mechanisms of m6 A‐binding proteins IGF2BP2 and IGF2BP3 on DDX21 were explored via methylated RNA immunoprecipitation (MeRIP) assays, RNA immunoprecipitation (RIP) assays and luciferase reporter assays. Then we elucidated the roles of DDX21 in AML through functional assays in vitro and in vivo. Finally, co‐immunoprecipitation (Co‐IP) assays, RNA sequencing and ChIP assays were performed to investigate the downstream mechanisms of DDX21. Results We identified two SE‐associated transcripts IGF2BP2 and IGF2BP3 in AML. High enrichment of H3K27ac, H3K4me1 and BRD4 was observed in IGF2BP2 and IGF2BP3, whose expression were driven by SE machinery. Then IGF2BP2 and IGF2BP3 enhanced the stability of DDX21 mRNA in an m6A‐dependent manner. DDX21 was highly expressed in AML patients, which indicated a poor survival. Functionally, knockdown of DDX21 inhibited cell proliferation, promoted cell apoptosis and led to cell cycle arrest. Mechanistically, DDX21 recruited transcription factor YBX1 to cooperatively trigger ULK1 expression. Moreover, silencing of ULK1 could reverse the promoting effects of DDX21 overexpression in AML cells. Conclusions Dysregulation of SE‐IGF2BP2/IGF2BP3‐DDX21 axis facilitated the progression of AML. Our findings provide new insights into the link between SEs and m6A modification, elucidate the regulatory mechanisms of IGF2BP2 and IGF2BP3 on DDX21, and reveal the underlying roles of DDX21 in AML.

Railways are essential to the global transportation infrastructure, providing eco-friendly and economical solutions for the movement of freight and passengers. Inspecting and maintaining extensive rail networks timely poses significant challenges. My group and collaborators have focused on automated railroad inspection technologies, emphasizing the use of deep learning and computer vision to overcome the limitations of traditional manual inspections. Our research introduces groundbreaking real-time inspection methods, leveraging a specialized dataset of railroad components for enhanced instance segmentation models, achieving unprecedented accuracy and inference speeds. The developed computer vision systems efficiently detect track components and their changes over time, and also quantify rail surface defects. Additionally, our work extends to improving railroad crossing safety, utilizing deep learning frameworks for the detection of unusual pedestrian behaviors and object identification, aimed at reducing crossing incidents and improving emergency response times. Our future research directions aim to further refine the cost-effectiveness and autonomy of railroad inspection systems. Through these innovations, we hope to aid in the inspection and maintenance of railroads, offering practical solutions for railroad and other civil engineering applications.

The ‘diabetic bone paradox’ suggested that type 2 diabetes (T2D) patients would have higher areal bone mineral density (BMD) but higher fracture risk than individuals without T2D. In this study, we found that the genetically predicted T2D was associated with higher BMD and lower risk of fracture in both weighted genetic risk score (wGRS) and two-sample Mendelian randomization (MR) analyses. We also identified ten genomic loci shared between T2D and fracture, with the top signal at SNP rs4580892 in the intron of gene RSPO3. And the higher expression in adipose subcutaneous and higher protein level in plasma of RSPO3 were associated with increased risk of T2D, but decreased risk of fracture. In the prospective study, T2D was observed to be associated with higher risk of fracture, but BMI mediated 30.2% of the protective effect. However, when stratified by the T2D-related risk factors for fracture, we observed that the effect of T2D on the risk of fracture decreased when the number of T2D-related risk factors decreased, and the association became non-significant if the T2D patients carried none of the risk factors. In conclusion, the genetically determined T2D might not be associated with higher risk of fracture. And the shared genetic architecture between T2D and fracture suggested a top signal around RSPO3 gene. The observed effect size of T2D on fracture risk decreased if the T2D-related risk factors could be eliminated. Therefore, it is important to manage the complications of T2D to prevent the risk of fracture.

IntroductionPatient satisfaction is a crucial metric to gauge the quality of medical services, but the psychological factors influencing patient satisfaction remain insufficiently explored.MethodsThis study examines these psychological factors by applying the theory of bounded rationality to 1,442 inpatients in Hangzhou, China, whose data were collected using a questionnaire. One-way ANOVA, correlation analysis, and hierarchical regression were used to analyze patient satisfaction and its associated factors. Additionally, the path analysis of the structural equation model revealed the mechanisms behind the key psychological factors that influenced patient satisfaction.ResultsMedical risk perception, the social cognition of the medical environment, and social desirability bias had significant positive impacts on patient satisfaction. By contrast, negative emotions had a significant negative impact on patient satisfaction. Notably, patients’ negative emotions had both a suppressive effect and a positive moderating effect on the relationship between medical risk perception and patient satisfaction. Similarly, social desirability bias had a suppressive effect on the correlation between the social cognition of the medical environment and patient satisfaction, albeit with a negative moderating effect.DiscussionThese results suggest that when evaluating and improving patient satisfaction, accounting only for the factors that directly influence medical service quality is insufficient, as the indirect and moderating effects of patients’ negative emotions and the social cognition of the medical environment must also be considered. Medical service providers should thus address patients’ negative emotions, establish good doctor–patient relationships, optimize service environments, provide managers with medical risk education and training on negative emotions, and prioritize patient-centered care. Additionally, the government and relevant health departments should optimize medical policies, enhance fairness and accessibility, and create a positive social cognitive environment through public education and awareness campaigns.

Background and purposeIrregular pulsation of the aneurysmal wall has been suggested as a novel predictor for aneurysm rupture. Aneurysm volume variations during the cardiac cycle and the association between irregular pulsation and morphological features have been discussed, but the clinical significance remains unclear. The purpose of this study was to quantify changes in morphological characteristics over the cardiac cycle and examine their correlation with irregular pulsation to facilitate comprehension of aneurysm dynamics.Materials and methodsFourteen unruptured intracranial aneurysms (UIAs) from 11 patients were included in this study, and each of them underwent 4D-CTA after diagnosis by DSA. The R-R intervals were divided into 20-time phases at 5% intervals to determine whether an aneurysm had irregular pulsation throughout the cardiac cycle. CT images from the 20-time phases were used to reconstruct 3D aneurysm models, measure 14 morphological parameters, and quantify each parameter’s absolute change and relative rates of change during the cardiac cycle.ResultsSeven of 14 UIAs exhibited irregular pulsation over the cardiac cycle by 4D-CTA, 5 of which were small aneurysms (< 7 mm). The UIAs with irregular pulsation exhibited greater changes in morphological characteristics. As aneurysm size increased, the absolute change in aneurysm volume increased (p = 0.035), but the relative rates of change in aneurysm size (p = 0.013), height (p = 0.014), width (p = 0.008), height-to-width ratio (p = 0.009), dome-to-neck ratio (p = 0.019) and bottleneck factor (p = 0.012) decreased.ConclusionAlthough the larger the aneurysm, the greater the amplitude of its volumetric variation, small aneurysms are prone to irregular pulsation during the cardiac cycle and have more pronounced and dramatic morphological changes during the cardiac cycle that may increase the risk of rupture. This proof-of-concept study could help to explain the importance of dynamic changes using 4D-CTA in assessing the rupture risk of UIAs.

Purpose: Through this study, we assess whether night shift work increases the risk of osteoporosis, and explore the effects of age, gender, or lifestyle differences. Methods: This cross-sectional study included the collection of data from a sample of the US adults who participated in the National Health and Nutrition Examination Survey (NHANES) over a 7.3-year period (2007–2008, 2009–2010, 2017–March2020), including 4408 participants (2351[52.8%] men and 2057[47.2%] women), with an age range of 20–80 years. The primary variables, health status, nutrition, harmful lifestyle habits, and bone mineral density (BMD), were segregated, and analyzed according to different work schedules. Linear regression models were conducted to evaluate correlations of night shift work and T-scores. Associations between night shift work and osteoporosis were examined using logistic regression analyses. All regression models were stratified by gender and age ≥50 years. Osteoporosis was defined as BMD at the femoral neck or total spine equal to or less than 2.5 standard deviations below the mean for youthful people of the same gender. All data were obtained using questionnaires and examinations collected in mobile examination center (MEC) from NHANES. Results: After multivariate adjustment, night shift work was related to statistically significant decreases of the total spine in T-scores of females aged ≥50 years. Furthermore, night shift work of the overall population (OR = 2.31 [95% CI, 1.03–5.18]; P = 0.043) and females aged ≥50 years (OR = 4.6 [95% CI, 1.21–17.54]; P = 0.025) was related to an increased prevalence of osteoporosis. Conclusion: Night shift work correlates with a higher risk of osteoporosis in the population of the US adults, with the combined effect of age, gender, and harmful lifestyle.

Coronary heart disease (CHD) is the leading cause of death globally, posing a serious threat to human health. However, the current treatment approaches available for CHD fall short of the ideal results. Tongxinluo (TXL) is a traditional Chinese medicine (TCM) that has been employed in the clinical treatment of cardiovascular and cerebrovascular diseases (such as angina pectoris, stroke, etc.) in China for many years and holds great potential as a prospective treatment. TXL either as a standalone treatment or in combination with interventions recommended in CHD guidelines has been shown to be effective and well tolerated in clinical trials for CHD. Drawing on the evidence from clinical trials and experimental studies, this review will focus on the cardiovascular protective properties and related mechanisms of TXL. By searching 8 Chinese and English databases, more than 4000 articles were retrieved. These articles were categorized, then read, and finally written into this review. In this review, the pharmacological properties of TXL include regulation of blood lipids, improvement of endothelial function, anti-inflammatory, antioxidant, inhibition of apoptosis and regulation of autophagy, anti-fibrosis, promotion of angiogenesis, and modulation of exosome communication. The information provided in this review will help the reader to comprehend better the insights that TCM has developed over time in practice and provide new perspectives for the treatment of CHD.

Traumatic Brain Injury (TBI) is a prevalent form of neurological damage that may induce varying degrees of cognitive dysfunction in patients, consequently impacting their quality of life and social functioning. This article provides a mini review of the epidemiology in Chinese TBI patients and etiology of cognitive impairment. It analyzes the risk factors of cognitive impairment, discusses current management strategies for cognitive dysfunction in Chinese TBI patients, and summarizes the strengths and limitations of primary testing tools for TBI-related cognitive functions. Furthermore, the article offers a prospective analysis of future challenges and opportunities. Its objective is to contribute as a reference for the prevention and management of cognitive dysfunction in Chinese TBI patients.

Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN5−HT) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN5−HT neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α–P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α–P2X2 signaling in DRN5−HT neurons as a potential avenue for screening novel therapeutic treatments for MDD.

Abstract Background Microbiome changes on the ocular surface may cause dry eyes. A metagenome assay was used to compare the microbiome composition and function of the ocular surface between diabetic children and adolescents with dry eye, diabetic children and adolescents without dry eye, and normal children. Materials and methods Twenty children and adolescents aged 8 to 16 with diabetes were selected from the Shanghai Children and Adolescent Diabetes Eye Study. Ten healthy children and adolescents belonging to the same age group were selected from the outpatient clinic during the same period. The participants were classified into the dry eye group (DM-DE group, n = 10), the non-dry eye group (DM-NDE group, n = 10) and the normal group (NDM group, n = 10). A conjunctival sac swab was collected for metagenomic sequencing, and the relationship between the microbiome composition and functional gene differences on the ocular surface with dry eye was studied. Results The classification composition and metabolic function of the microorganisms on the ocular surface of children in the 3 groups were analyzed. It was found that children’s ocular microbiota was composed of bacteria, viruses and fungi. There were significant differences in α diversity and β diversity of microbial composition of ocular surface between DM-DE group and NDM group(P

Abstract Purpose A randomized controlled double-blind trial was conducted to evaluate the effects of adding dexamethasone to the local infiltration analgesia (LIA) mixture on frequency of patient controlled analgesia (PCA) and opioids consumption after simultaneous bilateral total hip or knee arthroplasty (THA or TKA). Methods 108 patients who received simultaneous bilateral THA or TKA were randomly divided into dexamethasone group and normal saline (NS) group. The main difference between two groups was whether or not dexamethasone was added to the LIA mixture. The main outcome was the cumulative consumption of opioids within 24 h. The secondary outcome were the total cumulative consumption of opioids during postoperative hospitalization, consumption of opioids drug for rescue analgesia, frequency of PCA, postoperative Visual Analogue Scale (VAS), and complications. Results Cumulative consumption of opioids in the 24 h was similar between two groups (P = 0.17). Total cumulative consumption of opioids in the dexamethasone group during postoperative hospitalization was significantly lower (P = 0.03). No significant difference in the consumption of opioids drug for rescue analgesia between two groups within 24 h, while the frequency of PCA was significantly different (P = 0.04). VAS of dexamethasone group and NS group were similar during postoperative hospitalization, while the incidence of postoperative nausea and vomiting (PONV) in dexamethasone group was lower than that in NS group. Conclusions Adding dexamethasone to LIA in the simultaneous bilateral THA or TKA can effectively reduce the total cumulative consumption of opioids and the frequency of PCA, as well as reduce the incidence of PONV. Trial Registration The trial has been registered in the Chinese Clinical Trial Registry (Registration Number: ChiCTR2100042551, Date: 23/01/2021).

Our previous studies have shown physiological and yield intensification of selected crops with the application of nanoparticles (NPs). However, the impact on the quantitative, qualitative, and yield parameters of maize (Zea mays L.) in field conditions remains highly debated. This study aimed to evaluate the effects of zinc oxide (ZnO-NPs), gold NPs anchored to meso-biosilica (Au-NP-bioSi), and titanium dioxide (TiO2-NPs) as biological stimulants under field conditions during the vegetation season of 2021 in the Central European region. The study assessed the effects on the number of plants, yield, yield components, and nutritional quality, including mineral nutrients, starch, and crude protein levels. The potential translocation of these chemically–physically stable NPs, which could pose a hazard, was also investigated. The results indicate that Au-NP-bioSi and ZnO-NPs-treatments were the most beneficial for yield and yield components at a statistically significant level. Mineral nutrient outcomes were varied, with the NP-free variant performing the best for phosphorus-levels, while Au-NP-bioSi and ZnO-NPs were optimal for crude protein. Starch content was comparable across the TiO2-NPs, Au-NP-bioSi, and control variants. Importantly, we observed no hazardous translocation of NPs or negative impacts on maize grain quality. This supports the hypothesis that NPs can serve as an effective tool for precise and sustainable agriculture.

In paced excitable systems, a traditional viewpoint on signal transmission is that an excitable pacing signal should propagate from the source to its excited neighbors in a sequential rule, which is known as the normal sequential response mode (SRM). However, in our present paper, by extensively exploring the response modes emerged on the paced excitable C. elegans network, we found that, besides the normal SRM, a response mode that breaks the sequence rule and contains isolated excited clusters or even isolated excited nodes on the propagation path of the response structure can be detected. Such remote response nodes and clusters are excited discontinuously from the source node, forming the phenomenon of the remote response mode (RRM). An effective-driving analysis approach (EDAA) is proposed to theoretically study the mechanism of the RRM, based on which key role played by the excited nodes possessing nonexcited upstream driving neighbors is confirmed in the formation of the RRM. We further verify the applicability and the universality of the EDAA in identifying the RRM on general paced excitable networks. These contributions are expected to shed light on the study of complex response modes in paced excitable systems and to have great impact in related topics.

Power shift tractors have been widely used in agricultural tractors in recent years because of their advantages of uninterrupted power during shifting, high transmission efficiency and high stability. As one of the indispensable driving states of the power shift tractor, the starting process requires a small impact and a starting speed that meets the driver’s requirements. In this paper, aiming at such contradictory requirements, the starting control strategy of a power shift tractor is formulated with the goal of starting quality and the driver’s intention. Firstly, the identification characteristics of the driver under three starting intentions are obtained by a real vehicle test. An extreme learning machine with fast identification speed and short training time is used to establish the basic driver’s intention identification model. For the instability of the identification results of the Extreme Learning Machine (ELM), the particle swarm optimization algorithm (PSO) is used to optimize the ELM. The optimized extreme learning machine model has an accuracy of 96.891% for driver’s intention identification. The wet clutch is an important part of the power shift gearbox. In this paper, the starting control strategy knowledge base of the starting clutch is established by a combination of bench tests and simulation tests. Through the fuzzy algorithm, the driver’s intention is combined with the starting control strategy. Different drivers’ intentions will affect the comprehensive evaluation model of the clutch (the single evaluation index of the clutch is: the maximum sliding power, the sliding power, the speed stability time, the impact degree), thus affecting the final choice of the starting clutch control strategy considering the driver’s intention. On this basis, this paper studies and establishes the MPC starting controller for the power shift gearbox. Compared with the linear control strategy, the PSO-ELM-fuzzy weight starting strategy proposed in this paper can reduce the maximum sliding friction power by 45%, the sliding friction power by 69.45%, and the speed stabilization time by 0.11 s. The effectiveness of the starting control strategy considering the driver’s intention proposed in this paper to improve the starting quality of the power shift tractor is verified.