Spatial transcriptomics of gastric cancer brain metastasis reveals atypical vasculature strategies with supportive immune profiles.

Background: Gastric cancer brain metastasis (GCBM) represents a rare but highly aggressive malignancy. Metastatic cancer cells are highly heterogeneous and differentially remodels brain vasculature and immune microenvironments, which affects the treatment effectiveness and patient outcome. This study aimed to investigate the spatial interactions among different cell components, especially the vasculature system and the brain microenvironment of GCBM patients. Methods: We used digital spatial profiling to examine 140 regions composing tumor, immune, and brain tissues from three GCBM patients. Transcriptomic data with spatial information were analyzed for tissue areas related to different blood recruitment strategies. For validation, independent analysis of patient bulk transcriptomic data and in vivo single-cell transcriptomic data were performed. Results: Angiogenesis and blood vessel co-option co-existed within the same GCBM lesion. Tumors with high epithelial-mesenchymal transition and an enhanced transcriptomic gene signature composed of CTNNB1, SPARC, VIM, SMAD3, SMAD4, TGFB1, TGFB2, and TGFB3 were more prone to adopt blood vessel co-option than angiogenesis. Enriched macrophage infiltration, angiogenic chemokines, and NAMPT were found in angiogenic areas, while increased T cells, T cell activating cytokines, and reduced NAMPT were found in vessel co-option regions. Spatially, angiogenesis was enriched at the tumor edge, which showed higher DMBT1 expression than the tumor center. Conclusions: This study mapped the orchestrated spatial characteristics of tumor and immunological compositions that support the conventional and atypical vascularization strategies in GCBM. Our data provided molecular insights for more effective combinations of anti-vascular and immune therapies.

Recombinant human adenovirus type 5 promotes anti-tumor immunity via inducing pyroptosis in tumor endothelial cells.

Recombinant human type 5 adenovirus (H101) is an oncolytic virus used to treat nasopharyngeal carcinoma. Owing to the deletion of the E1B-55kD and E3 regions, H101 is believed to selectively inhibit nasopharyngeal carcinoma. Whether H101 inhibits other type of tumors via different mechanisms remains unclear. In this study we investigated the effects of H101 on melanomas. We established B16F10 melanoma xenograft mouse model, and treated the mice with H101 (1 × 108 TCID50) via intratumoral injection for five consecutive days. We found that H101 treatment significantly inhibited B16F10 melanoma growth in the mice. H101 treatment significantly increased the infiltration of CD8+ T cells and reduced the proportion of M2-type macrophages. We demonstrated that H101 exhibited low cytotoxicity against B16F10 cells, but the endothelial cells were more sensitive to H101 treatment. H101 induced endothelial cell pyroptosis in a caspase-1/GSDMD-dependent manner. Furthermore, we showed that the combination of H101 with the immune checkpoint inhibitor PD-L1 antibody (10 mg/kg, i.p., every three days for three times) exerted synergic suppression on B16F10 tumor growth in the mice. This study demonstrates that, in addition to oncolysis, H101 inhibits melanoma growth by promoting anti-tumor immunity and inducing pyroptosis of vascular endothelial cells.

Scalable Fabrication of Black Phosphorous Films for Infrared Photodetector Arrays.

Bulk black phosphorous (bP) exhibits excellent infrared (IR) optoelectronic properties, but most reported bP IR photodetectors are fabricated from single exfoliated flakes with lateral sizes of < 100 µm. Here, scalable thin films of bP suitable for IR photodetector arrays are realized through a tailored solution-deposition method. The properties of the bP film and their protective capping layers are optimized to fabricate bP IR photoconductors exhibiting specific detectivities up to 4.0 × 108 cm Hz1/2 W-1 with fast 30/60 µs rise/fall times under λ = 2.2 µm illumination. The scalability of the bP thin film fabrication is demonstrated by fabricating a linear array of 25 bP photodetectors and obtaining 25 × 25 pixel IR images at ≈203 ppi with good spatial fidelity. This research demonstrates a commercially viable method of fabricating scalable bP thin films for optoelectronic devices including room temperature-operable IR photodetector arrays.

Myeloid-specific Hdac10 deletion protects against LPS-induced acute lung injury via P62 acetylation at lysine 165.

BACKGROUND: Aberrant activation of macrophages is associated with pathogenesis of acute lung injury (ALI). However, the potential pathogenesis has not been explored. OBJECTIVES: We aimed to identify whether histone deacetylase (HDAC) 10 is involved in lipopolysaccharide (LPS)-exposed ALI and reveal the underlying pathogenesis by which it promotes lung inflammation in LPS-exposed ALI via modifying P62 with deacetylation. METHODS: We constructed an ALI mice model stimulated with LPS to determine the positive effect of Hdac10 deficiency. Moreover, we cultured murine alveolar macrophage cell line (MH-S cells) and primary bone marrow-derived macrophages (BMDMs) to explore the pro-inflammatory activity and mechanism of HDAC10 after LPS challenge. RESULTS: HDAC10 expression was increased both in mice lung tissues and macrophage cell lines and promoted inflammatory cytokines production exposed to LPS. Hdac10 deficiency inhibited autophagy and inflammatory response after LPS stimulation. In vivo, Hdac10fl/fl-LysMCre mice considerably attenuated lung inflammation and inflammatory cytokines release exposed to LPS. Mechanistically, HDAC10 interacts with P62 and mediates P62 deacetylation at lysine 165 (K165), by which it promotes P62 expression and increases inflammatory cytokines production. Importantly, we identified that Salvianolic acid B (SAB), an HDAC10 inhibitor, reduces lung inflammatory response in LPS-stimulated ALI. CONCLUSION: These results uncover a previously unknown role for HDAC10 in regulating P62 deacetylation and aggravating lung inflammation in LPS-induced ALI, implicating that targeting HDAC10 is an effective therapy for LPS-exposed ALI.

Vaporchromic Domino Transformation and Polarized Photonic Heterojunctions of Organoplatinum Microrods.

Photonic heterostructures with codable properties have shown great values as versatile information carriers at the micro and nanoscale. These heterostructures are typically prepared by a step-by-step growth or post-functionalization method to achieve varied emission colors among different building blocks. In order to realize high-throughput and multivariate information loading, we report here a strategy to integrate polarization signals into photonic heterojunctions. A U-shaped di-Pt(II) complex is assembled into highly-polarized yellow-phosphorescent crystalline microrods (Y-rod) by strong intermolecular Pt···Pt interaction. Upon end-initiated desorption of the incorporated CH2Cl2 solvents, Y-rod is transformed in a domino fashion into tri-block polarized photonic heterojunctions (PPHs) with alternate red-yellow-red emissions or red-phosphorescent microrods (R-rod). The red emissions of these structures are also highly polarized; however, their polarization directions are just orthogonal to those of the yellow phosphorescence of Y-rod. With the aid of a patterned mask, R-rod is further programmed into multi-block PPHs with precisely-controlled block sizes by side-allowed adsorption of CH2Cl2 vapor. X-ray diffraction analysis and theoretical calculations suggest that the solvent-regulated modulation of intramolecular and intermolecular excited states is critical for the construction of these PPHs.

Evidence Construction of Chuankezhi Injection Against Chronic Obstructive Pulmonary Disease: A Systematic Review and Network Pharmacology.

Objective: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease with high prevalence, morbidity, and mortality. Chuankezhi (CKZ) injection, a Chinese patent medicine, has been commonly used for treating COPD. This study evaluated the clinical efficacy of CKZ injections in COPD patients and explored potential underlying mechanisms by integrating meta-analysis and network pharmacology. Research Methods: Randomized controlled trials (RCTs) were search in database by Web of Science, Cochrane Library and PubMed as of November 2022 for literature collection, and the Review Manager 5.4 was used to analyze the data. Through the network pharmacology method, the chemical components and their targets, as well as the disease targets were further analyzed. Results: A total of 15 RCTs including 1212 patients were included. The results of meta-analysis showed that CKZ injection can significantly improve the clinical effective rate (RR = 1.25, 95% CI: 1.14 to 1.36), and the clinical advantage was that it can significantly reduced acute exacerbation rate (RR = 0.29, 95% CI: 0.12 to 0.70) and COPD assessment test (CAT) scores (MD =-4.62, 95% CI:-8.966 to-0.28). A total of 31 chemical compounds and 178 potential targets for CKZ injection were obtained from the online databases. Molecular docking revealed that most key components and targets could form stable structure. Conclusion: This systematic review with meta-analysis and network pharmacology demonstrates that CKZ could effectively improve the clinical efficacy and safety in the treatment of COPD. Such efficacy may be related to an anti-inflammatory effect and immunoregulation of CKZ via multiple components, multiple targets and multiple pathways.

Recognition on pharmacodynamic ingredients of natural products.

Natural products (NPs) play an irreplaceable role in the intervention of various diseases and have been considered a critical source of drug development. Many new pharmacodynamic compounds with potential clinical applications have recently been derived from NPs. These compounds range from small molecules to polysaccharides, polypeptides, proteins, self-assembled nanoparticles, and extracellular vesicles. This review summarizes various active substances found in NPs. The investigation of active substances in NPs can potentiate new drug development and promote the in-depth comprehension of the mechanism of action of NPs that can be beneficial in the prevention and treatment of human diseases.

Efficacy of Repetitive Transcranial Magnetic Stimulation over the Supplementary Motor Area on Motor Function in Parkinson's Disease: A Meta-Analysis.

OBJECTIVES: The objective of this study was to assess the effect of repetitive transcranial magnetic stimulation (rTMS) on the supplementary motor area (SMA) in motor function in Parkinson's disease (PD) patients. METHOD: Databases searched included 5 databases from October 7,2022 to January 4, 2023. The Cochrane Bias Risk Assessment Tool was used for quality assessment. Standardized mean differences (SMDs) were calculated using a random-effects model. Outcome measure is the motor function examination of the motor part of Unified Parkinson's Disease Rating Scale (UPDRS-III). RESULTS: Seven studies totaling 374 patients were included. Meta-analysis showed that stimulation of SMA significantly improved motor function in PD patients compared with sham stimulation (SMD = -1.24; 95% CI, -2.24 to -0.24; P = 0.02; I 2 = 93%). Stimulation of the same target (SMA), subgroup analysis showed that high-frequency rTMS (HF-rTMS) is more effective than low-frequency rTMS (LF-rTMS) in improving motor function in PD (SMD = -1.39; 95% CI, -2.21 to -0.57; P = 0.04; I 2 = 77.2%). CONCLUSIONS: Overall, rTMS over SMA had a statistically significant improvement in motor function in PD patients, and HF-rTMS is statistically significantly more effective than LF-rTMS.

Enzyme-activatable charge transfer in gold nanoclusters.

Surface-protecting ligands, as a major component of metal nanoclusters (MNCs), can dominate molecular characteristics, performance behaviors, and biological properties of MNCs, which brings diversity and flexibility to the nanoclusters and largely promotes their applications in optics, electricity, magnetism, catalysis, biology, and other fields. We report herein the design of a new kind of water-soluble luminescent gold nanoclusters (AuNCs) for enzyme-activatable charge transfer (CT) based on the ligand engineering of AuNCs with 6-mercaptopurine ribonucleoside (MPR). This elaborately designed cluster, Au5(MPR)2, can form a stable intramolecular CT state after light excitation, and exhibits long-lived color-tunable phosphorescence. After the cleavage by purine nucleoside phosphorylase (PNP), the CT triplet state can be easily directed to a low-lying energy level, leading to a bathochromic shift of the emission band accompanied by weaker and shorter-lived luminescence. Remarkably, these ligand-engineered AuNCs show high affinity towards PNP as well as decent performance for analyzing and visualizing enzyme activity and related drugs. The work of this paper provides a good example for diversifying physicochemical properties and application scenarios of MNCs by rational ligand engineering, which will facilitate future interest and new strategies to precisely engineer solution-based nanocluster materials.

Comparison of the Effects of Combined Femoral and Sciatic Nerves Block versus General Anesthesia on Hemodynamic Stability and Postoperative Complication in Patients with Diabetic Foot: A Prospective, Double-Blind and Randomized Controlled Trial.

Background: Perioperative anesthetic management of patients with diabetic foot undergoing surgical treatment is challenging due to their poor cardiovascular health status. According to previous literature, general anesthesia and peripheral nerve block have their own advantages and disadvantages for such patients. We reported the effect of these two anesthesia techniques on perioperative hemodynamics and prognosis in these patients. Methods: This study employed a prospective randomized controlled design, where patients meeting the inclusion criteria were assigned to two groups: the general anesthesia group (GA group) and the peripheral nerve block group (PNB group). The primary outcomes were the differences in intraoperative hemodynamic stability and the incidence of postoperative complications between the two groups. The second outcomes were postoperative numerical rating scale scores, analgesic drug remedies, postoperative sleep conditions monitored by sleep bracelets and health status assessed by EQ-5D-5 L scores. Results: One hundred and nine subjects were enrolled in this study, including 54 in the GA group and 55 in the PNB group. The baseline parameters of the two groups were comparable. The GA group exhibited a significantly higher incidence of hypotension, and Colloid intake and total fluid intake were significantly higher in the GA group than in the PNB group. Additionally, a larger proportion of patients in the GA group. The scores of postoperative pain during the 48 hours after surgery were significantly higher, and more patients needed tramadol for postoperative analgesia during the 24 h after surgery in the GA group than in the PNB group. Patients in the PNB group slept better, first feeding time, earlier out-of-bed activity and earlier discharge from the hospital, compared to the GA group. However, there was no obvious difference in postoperative complications between the two groups except pharyngeal pain. Conclusion: Peripheral nerve block is a better option in patients with diabetes undergoing elective below-knee surgery than general anesthesia.

Divergent Synthesis of Enantioenriched Silicon-Stereogenic Benzyl-, Vinyl- and Borylsilanes via Asymmetric Aryl to Alkyl 1,5-Palladium Migration.

Functionalization of Si-bound methyl group provides an efficient access to diverse organosilanes. However, the asymmetric construction of silicon-stereogenic architectures by functionalization of Si-bound methyl group has not yet been described despite recent significant progress in producing chiral silicon. Herein, we disclosed the enantioselective silylmethyl functionalization involving the aryl to alkyl 1,5-palladium migration to access diverse naphthalenes possessing an enantioenriched stereogenic silicon center, which are inaccessible before. It is worthy to note that the realization of asymmetric induction at the step of metal migration itself remains challenging. Our study constitutes the first enantioselective aryl to alkyl 1,5-palladium migration reaction. The key to the success is the discovery and fine-tuning of the different substituents of α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL)-based phosphoramidites, which ensure the enantioselectivity and desired reactivity.

Plasma Coupled Electrolyte Additive Strategy for Construction of High-Performance Solid Electrolyte Interphase on Li Metal Anodes.

High-performance lithium metal anodes are crucial for the development of advanced Li metal batteries. Herein, this work reports a novel plasma coupled electrolyte additive strategy to prepare high-quality composite solid electrolyte interphase (SEI) on Li metal to achieve enhanced performance and stability. With the guidance of calculations, this work selects diethyl dibromomalonate (DB) as an additive to optimize the solvation structure of electrolytes to modify the SEI. Meanwhile, this work groundbreakingly develops DB plasma technology coupled with DB electrolyte additive to construct a combinatorial SEI: inner plasma-induced SEI layer composed of LiBr and Li2CO3 plus additive-reduced SEI containing LiBr/Li2CO3/organic lithium compounds as an outer compatible layer. The optimized hybrid SEI has strong affinity toward Li+ and good mechanical properties, thereby inducing horizontal dispersion and uniform deposition of Li+ and keep structure stable. Accordingly, the symmetrical cells exhibit enhanced cycling stability for 1200 h at an overpotential of 23.8 mV with average coulombic efficiency (99.51%). Additionally, the full cells with LiNi0.8Co0.1Mn0.1O2 cathode deliver a capacity retention of 81.7% after 300 cycles at 0.5 C, and the pouch cell achieves a volumetric specific energy of ≈664 Wh L‒1. This work provides new enlightenment on plasma technology for fabrication of advanced metal anodes for energy storage.

Prussian blue nanoparticles coated with tumor cell membranes for precise photothermal therapy and subsequent inflammation reduction.

The utilization of photothermal agents (PTAs) in photothermal therapy (PTT) is faced with challenges such as immune clearance and inadequate concentration, which consequently result in residual tumors and an increased risk of recurrence and metastasis. Conversely, excessive treatment can lead to heightened inflammation and inevitable harm to adjacent healthy tissues. To address these issues, we developed a nanosystem (M@PB) consisting of Prussian blue coated with tumor cell membrane for precise photothermal therapy (PTT) and subsequent reduction of inflammation. This system not only evades immune attack due to the homologous biological characteristics of the encapsulating cell membrane but also exhibits active targeting capabilities towards homologous tumors. Furthermore, it effectively reduces excessive phototoxicity by leveraging the distinctive photothermal and anti-inflammatory characteristics of PB nanoparticles. The resulting M@PB nanosystem demonstrates effective photothermal ablation under 808 nm laser irradiation while mitigating the inflammatory response through inhibiting of local production of inflammatory mediators. Our study provides valuable insights into achieving targeted PTT with high efficiency while minimizing post-treatment inflammatory responses.

Global emergence of double and multi-carbapenemase producing organisms: epidemiology, clinical significance, and evolutionary benefits on antimicrobial resistance and virulence.

Redundant carbapenemase-producing (RCP) bacteria, which carry double or multiple carbapenemases, represent a new and concerning phenomenon. The objective of this study is to conduct a comprehensive analysis of the epidemiology and genetic mechanisms of RCP strains to support targeted surveillance and control measures. A retrospective analysis was conducted using surveillance data from 277 articles. Statistical analysis was performed to determine and evaluate species prevalence, proportions of carbapenemases, antibiotic susceptibility profiles, sample information, and patient outcomes. Complete plasmid sequencing data were utilized to investigate potential antimicrobial resistance or virulence advantages that strains may gain from acquiring redundant carbapenemases. RCP bacteria are widely distributed globally, and their prevalence is increasing over time. Several countries, including China, India, Iran, Turkey, and South Korea, have reported more than 100 RCP strains. The most commonly reported RCP species are Klebsiella pneumoniae and Acinetobacter baumannii, which exhibit varying proportions of carbapenemase combinations. Certain species-carbapenemase combinations, such as K. pneumoniae carrying New Delhi metallo-ß-lactamase (NDM) + oxacillinase (OXA) (56.76%) and K. pneumoniae carbapenemase (KPC) + Verona integron-encoded metallo-ß-lactamase (VIM) (50.00%) carbapenemases, are associated with high mortality rates. In patients with RCP strains isolated from the bloodstream and respiratory system, the mortality rates are 58.70% and 69.23%, respectively. Analysis of plasmids from RCP strains suggests that they may acquire additional antibiotic resistance phenotypes and virulence factors. Carbapenem-resistant bacteria carrying redundant carbapenemases pose a significant global health threat. This study provides valuable insights into the epidemiology and genetic mechanisms of these bacteria, supporting the development of effective control and prevention strategies to mitigate their transmission.IMPORTANCEThis study examined the global distribution patterns of 1,780 bacteria with double or multiple carbapenemases from 277 articles and assessed their clinical impact. The presence of multiple carbapenemases increases the chances of co-resistance to other classes of antibiotics and more virulence factors, further complicating the clinical management of infections.

Plasma EBV quantification is associated with the efficacy of immune checkpoint blockade and disease monitoring in patients with primary pulmonary lymphoepithelioma-like carcinoma.

Objectives: Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein-Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation. Methods: We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB-treated PLELC. Viral EBNA-1 and BamHI-W DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction. Results: Progression-free survival (PFS) was significantly longer in EBNA-1 high or BamHI-W high groups. A longer PFS was also observed in patients with both high plasma EBNA-1 or BamHI-W and PD-L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with EBNA-1 and BamHI-W. Plasma EBV load was negatively associated with intratumoral CD8+ immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months. Conclusions: Plasma EBV DNA could be a useful and easy-to-use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging.

Charting facial growth and development for Bantu Africans: Central tendencies, variational properties and sexual dimorphisms.

Current studies on facial growth and development have been largely based on European populations. Less studied are African populations, who because of their distinct genetic makeup and environmental conditions, provide deeper insights into patterns of facial development. Patterns of facial shape development in African populations remain largely uncharacterised. Our study aimed to establish facial growth and development trajectories based on a cohort of 2874 Bantu Africans from Tanzania aged 6-18 years, with particular focus on identifying morphogenetic processes that lead to observed developmental shape changes. Procrustes ANCOVA suggested sexually dimorphic patterns of facial shape development (p = 0.0036). The forehead was relatively contracted during development in both sexes. The glabella region was more anteriorly displaced in females due to expansion in the region laterosuperior to the eyes. Nasal protrusion increased with development, which was found to arise from local expansion in the nasal alae and columella. Local expansion in the upper and lower labial regions resulted in forward displaced lips in both sexes, with the effect more pronounced in males. The mentum was displaced more anteriorly in females due to comparatively more expanded mental regions with development. The lateral facial region corresponding to the underlying body of the mandible were developmentally expanded but were posteriorly positioned due to protrusive growth of surrounding structures. Generalised additive modelling of Procrustes variance suggested that facial variation decreased non-linearly with age (p < 0.05). Relative principal component analysis suggested that variations in facial outline shape were developmentally constrained, whereas nasolabial and mental regions, where developmental changes were significant, became morphologically diversified with development. In contrast to simple descriptive illustration of facial shape development, we gained transformative insights into patterns of facial shape development by analysing morphogenetic processes and variational properties. Our analytical framework is broadly applicable to morphometric studies on ontogenetic shape changes.

Nylons with Highly-Bright and Ultralong Organic Room-Temperature Phosphorescence.

Endowing the widely-used synthetic polymer nylon with high-performance organic room-temperature phosphorescence would produce advanced materials with a great potential for applications in daily life and industry. One key to achieving this goal is to find a suitable organic luminophore that can access the triplet excited state with the aid of the nylon matrix by controlling the matrix-luminophore interaction. Herein we report highly-efficient room-temperature phosphorescence nylons by doping cyano-substituted benzimidazole derivatives into the nylon 6 matrix. These homogeneously doped materials show ultralong phosphorescence lifetimes of up to 1.5 s and high phosphorescence quantum efficiency of up to 48.3% at the same time. The synergistic effect of the homogeneous dopant distribution via hydrogen bonding interaction, the rigid environment of the matrix polymer, and the potential energy transfer between doped luminophores and nylon is important for achieving the high-performance room-temperature phosphorescence, as supported by combined experimental and theoretical results with control compounds and various polymeric matrices. One-dimensional optical fibers are prepared from these doped room-temperature phosphorescence nylons that can transport both blue fluorescent and green afterglow photonic signals across the millimeter distance without significant optical attenuation. The potential applications of these phosphorescent materials in dual information encryption and rewritable recording are illustrated.

Contemporary multimodality non-invasive cardiac imaging protocols for tetralogy of Fallot.

Tetralogy of Fallot is the most prevalent cyanotic congenital heart disease, requiring lifelong multimodality non-invasive cardiac imaging, such as echocardiography, cardiothoracic computed tomography, and cardiac magnetic resonance imaging. As imaging techniques continuously evolve and are gradually integrated into clinical practice, there is a critical need to update multimodality imaging protocols. Over the last two decades, cardiothoracic computed tomography imaging techniques have advanced remarkably, significantly enhancing its role in evaluating patients with tetralogy of Fallot. In this review, we describe contemporary multimodality non-invasive cardiac imaging protocols for tetralogy of Fallot, emphasizing the expanding role of cardiothoracic computed tomography. Additionally, we present standardized reporting forms designed to facilitate the clinical adoption of these protocols.

TGIN: Document-level event extraction with two-phase graph inference network.

Document-level event extraction aims to extract event records from a whole document that contain numerous entities scattered across multiple sentences. Efficiently modeling the interactions among these entities is crucial. However, previous methods suffer from two main shortcomings. Firstly, they tend to implicitly model key information, which can result in representations with higher levels of noise. Secondly, they excessively consider irrelevant entities, thereby reducing extraction efficiency and precision. To address these issues, we propose a novel Two-phase Graph Inference Network (TGIN) approach for extracting document-level events. In the first phase, TGIN constructs a heterogeneous document-level graph to capture complex interactions among nodes of different granularity, enabling the acquisition of document-aware features. Subsequently, a dedicated module is developed to extract relevant entity pairs within the same event record. This module utilizes a key information aggregator with an attention mechanism to explicitly aggregate key sentences for entity pairs. In the second phase, the entity links predicted in the first phase serve as prior information to construct the entity-level graph, which focuses on modeling interactions between entity pairs that potentially share the same event link, effectively reducing error propagation. Experimental results on the publicly available document-level event extraction dataset ChFinAnn demonstrate the superiority of our framework over most existing models.

A randomized, double-blind, placebo-controlled phase I clinical trial of rotavirus inactivated vaccine (Vero cell) in a healthy adult population aged 18-49 years to assess safety and preliminary observation of immunogenicity.

We conducted a phase I, randomized, double-blind, placebo-controlled trial including healthy adults in Sui County, Henan Province, China. Ninety-six adults were randomly assigned to one of three groups (high-dose, medium-dose, and low-dose) at a 3:1 ratio to receive one vaccine dose or placebo. Adverse events up to 28 days after each dose and serious adverse events up to 6 months after all doses were reported. Geometric mean titers and seroconversion rates were measured for anti-rotavirus neutralizing antibodies using microneutralization tests. The rates of total adverse events in the placebo group, low-dose group, medium-dose group, and high-dose group were 29.17 % (12.62 %-51.09 %), 12.50 % (2.66 %-32.36 %), 50.00 % (29.12 %-70.88 %), and 41.67 % (22.11 %-63.36 %), respectively, with no significant difference in the experimental groups compared with the placebo group. The results of the neutralizing antibody assay showed that in the adult group, the neutralizing antibody geometric mean titer at 28 days after full immunization in the low-dose group was 583.01 (95 % confidence interval [CI]: 447.12-760.20), that in the medium-dose group was 899.34 (95 % CI: 601.73-1344.14), and that in the high-dose group was 1055.24 (95 % CI: 876.28-1270.75). The GMT of serum-specific IgG at 28 days after full immunization in the low-dose group was 3444.26 (95 % CI: 2292.35-5175.02), that in the medium-dose group was 6888.55 (95 % CI: 4426.67-10719.6), and that in the high-dose group was 7511.99 (95 % CI: 3988.27-14149.0). The GMT of serum-specific IgA at 28 days after full immunization in the low-dose group was 2332.14 (95 % CI: 1538.82-3534.45), that in the medium-dose group was 4800.98 (95 % CI: 2986.64-7717.50), and that in the high-dose group was 3204.30 (95 % CI: 2175.66-4719.27). In terms of safety, adverse events were mainly Grades 1 and 2, indicating that the safety of the vaccine is within the acceptable range in the healthy adult population. Considering the GMT and positive transfer rate of neutralizing antibodies for the main immunogenicity endpoints in the experimental groups, it was initially observed that the high-dose group had higher levels of neutralizing antibodies than the medium- and low-dose groups in adults aged 18-49 years. This novel inactivated rotavirus vaccine was generally well-tolerated in adults, and the vaccine was immunogenic in adults (ClinicalTrials.gov number, NCT04626856).