Government of the People's Republic of China

Background and Aims Hepatitis C virus (HCV) vaccines are urgently needed to achieve WHO's goal for the elimination of viral hepatitis by 2030. The lack of suitable animal models for evaluating vaccine efficacy has greatly hindered the development of HCV vaccines. By using the rat model chronically infected with rodent hepacivirus from Rattus norvegicus (RHV‐rn1), a hepacivirus homologously close to HCV as a surrogate model of HCV infection, we assessed the protective effectiveness of the RHV‐rn1 vaccine Sad23L‐RHVns. Methods Sad23L‐RHVns vaccine was constructed with the nonstructural proteins (NS) 3–5B genes of RHV‐rn1. SD rats were immunised with Sad23L‐RHVns by prime or prime‐boost regimen via intramuscular injection, then challenged 4 weeks post vaccination by RHV‐rn1. A part of the rats were rechallenged with a variant 15 weeks post the first challenge of RHV‐rn1. Results The specific T‐cell responses to NS3‐5B antigens were induced by prime immunisation, which were significantly enhanced by boost vaccination. The inoculated rats and controls were challenged by wild‐type RHV‐rn1, of all the primed and control rats having persistently high levels of viremia, whereas 7 of 9 (77.8%) boosted rats cleared RHV‐rn1 infection. Interestingly, the resolver acquired immune protection against re‐challenging with variant and showed significantly higher T‐cell responses than the nonresolver in 25 weeks post rechallenge. Conclusions Sad23L‐RHVns with prime‐boost regimen protected 77.8% of rats against wild‐type RHV‐rn1 infection, and resolvers showed high levels and maintenance of T cell immunity against the variant. Our findings that maintenance of effective T cell immunity is required for RHV‐rn1 resolution may provide insight to develop the HCV vaccine in humans.

Background Anastomotic leak (AL) is a common complication in patients with operable esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (NCRT) and radical esophagectomy. Therefore, this study aimed to establish and validate a nomogram to predict the occurrence of AL. Methods Between March 2016 and December 2022, ESCC patients undergoing NCRT and radical esophagectomy were retrospectively collected in China. Clinicopathologic and radiomics characteristics were included in the univariate logistic regression analysis, and statistically significant factors were enrolled to develop the nomogram, which was evaluated by the area under the curve (AUC) of the receiver operating characteristic curve, calibration curve, and decision curve analysis (DCA). Results 231 eligible patients were divided into training (n = 159) and validation cohorts (n = 72). Univariate and multivariate analyses revealed that dose at the anastomosis ≥ 24 Gy, gross tumor volume ≥ 60 cm3, postoperative albumin < 35 g/L, comorbidities, duration of surgery ≥ 270 min, and computed tomography-based radiomics characteristics were independent predictors of AL. The nomogram AUC in the training and validation cohorts was 0.845 (95% confidence interval [CI]: 0.770–0.920) and 0.839 (95% CI: 0.718–0.960), respectively, indicating good discriminatory ability. The calibration curves showed good agreement between the predicted and actual AL occurrence and the DCA demonstrated favorable clinical outcomes. Conclusions We developed and validated a nomogram based on radiomics and clinicopathologic characteristics. This predictive model could be a powerful tool to predict AL occurrence in patients with ESCC treated with NCRT.

Background Sepsis remains a leading cause of global morbidity and mortality, yet early diagnosis is hindered by the limited specificity and sensitivity of current biomarkers. Aim The aim of this study was to identify lncRNAs that play a key role in sepsis and provide potential biomarkers for the diagnosis and treatment of sepsis. Methods Transcriptomic data from sepsis patients were retrieved from the Chinese National Genebank (CNGBdb). Differential expression analysis identified 2,348 LncRNAs and 5,125 mRNAs (|FC|≥2, FDR < 0.05). Weighted gene co-expression network analysis (WGCNA) and meta-analysis were applied to screen core genes. Gene set enrichment analysis (GSEA) explored functional pathways, while single-cell sequencing and qPCR validated cellular localization and expression patterns. Results WGCNA identified three key genes: LINC02363 (LncRNA), DYNLT1, and FCGR1B. Survival and meta-analyses revealed strong correlations between these genes and sepsis outcomes. GSEA highlighted LINC02363’s involvement in “herpes simplex virus type 1 infection,” “tuberculosis,” and ribosome pathways. Single-cell sequencing showed FCGR1B’s broad distribution across immune cells, while DYNLT1 localized predominantly in macrophages. qPCR confirmed significant upregulation of LINC02363 (p < 0.01), FCGR1B (p < 0.05), and DYNLT1 (p < 0.05) in sepsis patients compared to controls. Conclusion LINC02363 may serve as a new biomarker for the diagnosis and treatment of sepsis.

Objective. Seizure onset zone (SOZ) localization and SOZ resection outcome prediction are critical for the surgical treatment of drug-resistant epilepsy but have mainly relied on manual inspection of intracranial electroencephalography (iEEG) monitoring data, which can be both inaccurate and time-consuming. Therefore, automating SOZ localization and surgical outcome prediction by using appropriate iEEG neural features and machine learning models has become an emerging topic. However, current channel-wise local features, graph-theoretic network features, and system-theoretic network features cannot fully capture the spatial, temporal, and neural dynamical aspects of epilepsy, hindering accurate SOZ localization and surgical outcome prediction. Approach. Here, we develop a method for computing dynamical functional network controllability from multi-channel iEEG signals, which from a control-theoretic viewpoint, has the ability to simultaneously capture the spatial, temporal, functional, and dynamical aspects of epileptic brain networks. We then apply multiple machine learning models to use iEEG functional network controllability for localizing SOZ and predicting surgical outcomes in drug-resistant epilepsy patients and compare with existing neural features. We finally combine iEEG functional network controllability with representative local, graph-theoretic, and system-theoretic features to leverage complementary information for further improving performance. Main results. We find that iEEG functional network controllability at SOZ channels is significantly higher than that of other channels. We further show that machine learning models using iEEG functional network controllability successfully localize SOZ and predict surgical outcomes, significantly outperforming existing local, graph-theoretic, and system-theoretic features. We finally demonstrate that there exists complementary information among different types of neural features and fusing them further improves performance. Significance. Our results suggest that iEEG functional network controllability is an effective feature for automatic SOZ localization and surgical outcome prediction in epilepsy treatment.

Orbital angular momentum (OAM) provides a new high-dimensional degree-of-freedom for lasers enabling high-dimensional shift keying, thus showing huge potential in free-space optical data-transmissions. Ensuring the accuracy of data transmission is of concern in any communication system. However, in the free-space OAM shift keying link, interferences from environmental occlusions will broaden the OAM spectrum and thus affect the correctness of information received. In this paper, the occlusion immunities of two commonly used OAM shift keying strategies—OAM-encoding-symbols and OAM-encoding-bits—are evaluated under different occlusion scenarios. We introduce radial, azimuthal, and random occlusions into the link and then analyze the bit error rate (BER) of various OAM shift keying strategies. The results illustrate that the strategy of OAM-encoding-symbols exhibits stronger occlusion immunity with zero BER than OAM-encoding-bits. Moreover, proof-of-concept experiments are done to transmit grayscale images under occlusions. The final decoding results show identical data-transmission performance with simulations.

Background Uniparental disomy (UPD) is a specific type of chromosomal variation in which both chromosomes of a homologous pair are inherited from the same parent. It is responsible for a wide range of disorders. Monosomy rescue and trisomy rescue are the two main hypotheses of UPD generation. Methods An older parturient woman with a positive noninvasive prenatal screening (NIPS) test but a negative prenatal diagnosis was referred to the hospital. Trio whole exome sequencing (trio‐WES) and ddPCR were further performed. Results Utilizing Trio‐WES analysis, our research identified a maternal segmental UPD on chromosome 16, characterized by isodisomic genomic segments at the ends of the chromosome arms and heterodisomic genomic segments near the centromere. Moreover, several nuanced signs pointing to the paternal chromosome 16 were discovered, suggesting a low level of trisomy 16 mosaicism. A homozygous missense mutation (c.1499C>T; p.Ala500Val) was also detected in the fetal TBC1D24 gene, passed down from the heterozygous carrier mother. Furthermore, ddPCR analysis verified a 3% mosaic level of trisomy 16. Conclusion We have quantitatively verified for the first time a combination of trisomy 16 mosaicism and maternal segmental UPD 16 due to incomplete trisomy rescue, illuminating the cause of the mismatch between positive NIPS and negative prenatal diagnoses.

Aims The body mass index (BMI), as an easy‐to‐calculate measure of body fatness, is closely associated with all‐cause mortality, but few studies with a large enough scale have examined the relationship between BMI and quality of life. A comprehensive and precise insight into a new range is needed. Materials and Methods Based on the ChinaHEART (Health Evaluation And risk Reduction through nationwide Teamwork), a nationwide, population‐based cohort study, 4,485,773 participants living in 20,159 communities or villages were passively followed for death records, through a linkage of data with the National Mortality Surveillance System and Vital Registration. Firstly, we conducted Cox proportional‐hazards regression models to assess the hazard ratios (HRs) of BMI on the risk of all‐cause and cause‐specific mortality. Secondly, we used logistic regression models to examine associations between BMI and health‐related quality of life (HRQL). Fully adjusted models were adjusted for age, sex, annual household income, occupation, education level, marriage, medical insurance, urbanity, tobacco smoking, alcohol consumption and the history of hypertension, diabetes mellitus, dyslipidaemia and cardiovascular disease (CVD). Results Among the 4 485 773 included participants with an average age of 56.4 ± 10.0 years, 59.0% were female. During the follow‐up period, which had a median duration of 5.3 years, a total of 142 004 cases of all‐cause mortality were confirmed. After adjusting for participant characteristics and lifestyles, we observed the U‐shaped association between BMI and all‐cause mortality with an inflection of 26–27 kg/m ² , and the estimated HR per 1 kg/m ² increase in BMI was 0.92 (95% CI 0.92–0.93) and 1.03 (95% CI 1.03–1.04) below and above the turning point, respectively. An inverted J‐shape pattern between BMI and HRQL with a peak of 22–23 kg/m ² was found, in which the odd ratio per 1 kg/m ² increase in BMI was 0.98 (95% CI 0.98, 0.99) below 22–23 kg/m ² and 1.03 (95% CI 1.03–1.03) above this point. Conclusions We found distinct ranges of BMI for minimized mortality risk and maximized HRQL. The BMI range corresponding to the HRQL is lower than the BMI range corresponding to the lowest risk of death generally. Therefore, it is worth considering how to define the new recommended range for a new BMI based on the goal of ‘living a longer and healthier life’.

This paper investigates an adaptive optimal admittance control scheme for robot manipulators interacting with unknown environment. To resolve the optimized interaction performance considering tracking error and interaction force, an impedance adaptation approach is developed without the initial stabilizing policy. Based on the gradient‐based updating method, the online solution can exponentially converge to the optimal impedance gain without prior knowledge of environment dynamics. A nonlinear mapping method is integrated into the admittance control, transforming the constrained system into an equivalent system without state constraints. By eliminating feasibility conditions, the tracking controller can achieve the full‐state asymmetric time‐varying constraints under a broad range of initial conditions. Through the Lyapunov analysis, it is proven that the closed‐loop signals are bounded. Finally, simulation and experiment results demonstrate the effectiveness of the proposed methods.

Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. Circular RNAs (circRNAs), a novel class of endogenous noncoding RNA with a covalently closed continuous loop that lacks the 5′-cap structure and the 3′-poly A tail, are more stable than linear RNAs and less susceptible to degradation by nucleases. CircRNAs are widespread in multiple mammalian genomes and have been detected in various tissues, cells and body fluids. Increasing evidence shows that abnormal expression of circRNAs is involved in the development of a variety of diseases, including breast cancer. Numerous studies have explored the potential of circRNAs as biomarkers in various malignant tumors. In this review, we aim to provide a comprehensive overview of the latest advances in circRNAs as promising biomarkers in the early diagnosis, prognosis, molecular type, metastasis and drug resistance of breast cancer.

Background and Aims The impact of low‐level viremia(LLV) on the efficacy of immune checkpoint inhibitors (ICIs) in unresectable hepatocellular carcinoma(uHCC) patients remains unclear. This study aims to investigate the effect of LLV on the outcomes of ICIs‐based therapy in patients with uHCC. Methods In this multicenter retrospective study, we included patients with uHCC who received ICIs‐based therapy at four centres between January 2019 and December 2022. All patients were positive for HBsAg and were on nucleos(t)ide analogues (NAs) antiviral therapy. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to balance baseline characteristics between the LLV and maintained virological response (MVR) groups. Proteomic analysis was performed on a subset of patients to identify differential protein expression. Results A total of 329 patients (mean age 56 years; 92.4% male; 70.8% BCLC stage C) were included, with 170 patients in the LLV group and 159 in the MVR group. The objective response rate (ORR) was significantly lower in the LLV group compared to the MVR group (21.2% vs. 36.5%, p = 0.002), as was the disease control rate (DCR) (78.8% vs. 92.5%, p < 0.001). Median progression‐free survival (mPFS) was shorter in the LLV group (7.6 vs. 12.6 months, p < 0.001), as was median overall survival (mOS) (22.8 vs. 40.0 months, p < 0.001). These differences remained consistent after PSM and IPTW adjustments. Multivariate analysis identified LLV as the only independent risk factor for overall survival (hazard ratio [HR] 0.522, 95% CI 0.348–0.781; p = 0.002). Proteomic analysis revealed significant differences in the expression of Flt3L, SLAMF1 and FGF‐5 proteins between the LLV and MVR groups. Conclusion LLV is associated with poorer responses to ICIs‐based therapy and reduced survival in patients with HBV‐related uHCC.

Coordination serves as a crucial metric for analysing collective behaviour in complex systems. Given the prevalence of biological diversity, this study re-evaluated the coordination issue in strictly metric-free (SMF) swarms, incorporating both limited perceptual ranges and hierarchical dynamics. Initially, the study introduced a single-layer hierarchical SMF model that was optimized using differential evolution strategies. Our empirical findings suggest that the leader–follower set-up marginally enhances coordination uniformity, with larger groups requiring a subtler leadership gradient than smaller groups. In addition, a global perspective may not be necessary for effective swarming because a high level of coordination and consistency can be achieved regardless of the population size, as long as the visual angle is not less than 105∘. Furthermore, we examine how varying leadership layers influence collective behaviour. The results demonstrate that smaller groups benefit from uniform directional strategies, whereas larger groups (over 600 individuals) favour stochastic leadership patterns. Notably, for all group sizes, multi-layered frameworks incorporating stochastic components surpassed traditional SMF models in terms of coordination efficiency. These observations reinforce the importance of biological diversity for the formation of natural groups.

Four‐dimensional flow cardiovascular magnetic resonance (4D Flow cardiac MRI) is an advanced non‐invasive imaging technology, and its derived kinetic energy (KE) blood flow parameters have been confirmed as a potential biomarkers for assessing ventricular hemodynamics. This review synthesizes details on the methodology, clinical significance, and current status of studies focused on quantifying KE parameters of the ventricle using 4D Flow cardiac MRI, providing an objective foundation for further exploration of the value of KE in cardiac diseases. Study Type: retrospective. Subjects: This review includes studies that utilized 4D Flow cardiac MRI in human subjects, focusing on the changes in KE parameters. Field Strength: 1.5T or 3T. Assessment: A systematic review was conducted to assess the literature on the intracardiac clinical applications of 4D Flow cardiac MRI. In September 2024, searches were performed in PubMed, Web of Science, SCIENCEDIRECT, and Springer Link databases using the keywords “4D Flow cardiac MRI,” “ventricular kinetic energy,” and “intraventricular hemodynamics,” covering a period of 10 years. The inclusion criteria for the literature were: (1) clinical trials with human subjects; (2) studies that addressed the value of 4D Flow cardiovascular magnetic resonance and its derived blood flow KE parameters in quantifying ventricular blood flow. The exclusion criteria were: (1) animal experimental studies; (2) non‐English core journal articles. Out of the 195 articles screened, 62 studies met the criteria for the systematic review. The included literature comprised 26 (41.9%) studies on 4D Flow cardiac MRI technology and blood flow parameter research, and 36 (58.1%) clinical application studies. KE measurement using 4D Flow cardiac MRI is a promising tool for evaluating ventricular hemodynamics. It provides clinicians with deeper insights into the physiological and pathological dynamics of ventricular blood flow, from healthy states to disease.

Background Acute ischemic stroke (AIS) initiates secondary injuries that worsen neurological damage and hinder recovery. While peripheral immune responses play a key role in stroke outcomes, clinical results from immunotherapy have been suboptimal, with limited focus on T-cell dynamics. Umbilical mesenchymal stem cells (UMSCs) offer therapeutic potential due to their immunomodulatory properties. They can regulate immune responses and reduce neuroinflammation, potentially enhancing recovery by fostering a pro-regenerative peripheral immune environment. However, the effect of UMSCs on T-cell dynamics in AIS remains underexplored. This study investigates T-cell dynamics following AIS and examines how UMSCs may mitigate immune dysregulation to develop better treatment strategies. Methods AIS patients (NIHSS scores 0–15) were recruited within 72 h of stroke onset, with peripheral blood samples collected on Day 0 (enrollment) and Day 7. T-cell compartments were identified by flow cytometry, and plasma cytokine levels were quantified using a cytometric bead array (CBA). Mitochondria in UMSCs were labeled with MitoTracker. Peripheral blood mononuclear cells from patients were isolated, treated with lipopolysaccharide (LPS), and cocultured with UMSCs in both direct contact and Transwell systems. Flow cytometry, CBA, RT-qPCR, and immunofluorescence assays were used to detect T-cell compartments, gene expression markers for helper T (Th) cell differentiation, cytokine profiles, mitochondrial transfer, reactive oxygen species (ROS) production, and mitochondrial membrane potential. Additionally, mitochondrial DNA in UMSCs was depleted. The effects of UMSCs and mitochondria-depleted UMSCs on ischemic stroke mice were compared through behavioral assessments and analysis of the peripheral immune microenvironment. Results In AIS, T-cell compartments underwent a phenotypic shift from naïve to effector or memory states, with a specific increase in Th17 cells and a decrease in regulatory T cells, leading to alterations in T-cell-mediated immune functions. In an ex vivo co-culture system, LPS stimulation further amplified these disparities, inducing mitochondrial dysfunction and oxidative stress in T cells. Notably, UMSCs restored mitochondrial function and reversed the shift in T-cell compartments through mitochondrial transfer. Critically, UMSC treatment significantly improved both neurological deficits and peripheral immune disorders in ischemic stroke mice, whereas mitochondria-depleted UMSCs failed to produce this effect. Conclusions Our comprehensive insights into the key attributes of T-cell compartments in acute ischemic stroke and the immune regulatory mechanisms of UMSCs provide a crucial theoretical foundation for understanding peripheral immune disorders in ischemic stroke and the therapeutic potential of UMSC treatment. Graphical abstract

Joubert syndrome (JS) is a rare neurodevelopmental disorder associated with mutations in genes involved in ciliary function. Germline variants in CPLANE1 have been implicated in JS. In this study, we investigated a family with three adverse pregnancies characterised by fetal malformations consistent with JS. Whole‐exome sequencing (WES) identified compound heterozygous variants in CPLANE1: c.8893C>T (p.Gln2965*) and c.203C>T (p.Thr68Ile). Sanger sequencing confirmed the variants in the family. Bioinformatics analysis predicted that the c.203C>T variant affects mRNA splicing and protein function. Functional studies using PBMCs demonstrated that the c.203C>T variant causes exon 3 skipping, resulting in a frameshift and premature termination codon, leading to potential nonsense‐mediated mRNA degradation (NMD). The mRNA transcription and translation inhibition experiment, by treatment with actinomycin D and puromycin, indicated that the c.203C>T variant leads to accelerated mRNA degradation. Notably, the inhibition of SMG1, a key marker of the NMD pathway, partially rescued mRNA expression in mutated cells, providing further evidence of NMD activation. Based on these findings and ACMG guidelines, the c.203C>T variant was reclassified from a variant of uncertain significance (VUS) to likely pathogenic. This is the first report of novel CPLANE1 compound heterozygous variants contributing to JS in this family. Our study expands the known pathogenic variant spectrum of CPLANE1 in JS and provides new insights into the molecular mechanisms of this ciliopathy.

This study investigated the effects of long-term method of fertilization on growth and yield formation in early-season rice. Based on a 42-year field experiment initiated in 1981, three treatments: chemical N, P, and K (NPK), a double dose of chemical NPK (HNPK), and a combination of chemical and organic fertilizers (NPKM) were selected for comparison. Measurements included rice yield, yield components, tiller dynamic, dry matter accumulation, chlorophyll content (SPAD values), and transcriptome analysis of leaves at full heading stage in 2022. Results showed that rice yield followed the order NPKM > HNPK > NPK. The HNPK and NPKM treatments increased by 56.64% and 90.33%, respectively (p < 0.05). Spikelet density and 1000-grain weight increased by 9.16–22.89% and 3.74–4.28%, respectively. Both HNPK and NPKM enhanced the tillering rate by 43.84–72.73%, leading to an 18.95–57.54% increase in effective panicles. Dry matter accumulation from heading to filling stages was highest in NPKM-treated rice, with an increase of 3.31–4.25 g/plant in dry matter transport from leaves and stems to spikes during the filling to maturity stages. The SPAD values of NPKM-treated plants were consistently higher than those of HNPK and NPK treatments, with a smaller decline (6.94%) from heading to filling stages compared to 18.23% and 26.29% for HNPK and NPK, respectively. Correlation analysis indicated a positive relationship between yield and SPAD values or dry matter accumulation and a negative correlation with the decline in SPAD values from full heading to filling stage. Transcriptome analysis revealed significant enrichment of photosynthesis and plant senescence pathways among treatments. Overall, long-term combined application of chemical and organic fertilizers (NPKM) improved yield components, delayed chlorophyll degradation, promoted dry matter accumulation and transport, and regulated the expression of photosynthesis-related and senescence-related genes, ultimately optimizing growth and yield in early-season rice.