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The cycloaddition of aziridines with unsaturated compounds is a valuable method for synthesizing nitrogen heterocycles. However, this process is predominantly substrate-controlled, posing significant challenges in regulating the regioselectivity of the C-N bond cleavage. In this study, we report a nickel-catalyzed dynamic kinetic activation strategy that enables catalyst-controlled activation of aziridines. Various types of aziridines, including 2-phenyl, 2-carbonyl, 2-alkyl, and disubstituted aziridines, consistently cleave their more sterically hindered C-N bonds to generate 1,3-radical anion intermediates. These intermediates participate in a highly regioselective 1,4-Heck/allylic substitution cascade with aromatic branched 1,3-dienes, resulting in a radical-polar crossover (4 + 3) cycloaddition that produces seven-membered azepine products. This approach not only complements traditional dipolar cycloaddition, in which aziridines typically act as zwitterionic 1,3-dipoles, but also introduces an unusual cycloaddition mode for 1,3-dienes. Experimental investigations and density functional theory (DFT) calculations provide insight into the reaction mechanism.

Objective: To evaluate the therapeutic effects of Kuanxiong Aerosol (KXA) on ischemic stroke with reperfusion and elucidate the underlying pharmacological mechanisms., Methods: In vivo pharmacological effects on ischemic stroke with reperfusion was evaluated using the transient middle cerebral artery occlusion (t-MCAO) mice model. To evaluate short-term outcome, 30 mice were randomly divided into vehicle group (n=15) and KXA group (n=15). Mice in KXA and vehicle groups received 69 mg KXA and vehicle for 1 day, respectively. To evaluate long-term outcome, 35 mice were randomly divided into sham group (n=5), vehicle group (n=15), and KXA group (n=15). Mice in KXA and vehicle groups received 69 mg KXA and vehicle for 7 days, respectively. Pathological changes in the brain were observed by 2,3,5-triphenyltetrazolium chloride or Nissl stainings, and behavioral assessments, including the Modified Neurologic Severity Score, Bederson score, rotarod test, and adhesive removal test were conducted. The penetration ability of KXA and KX (KXA without propellants) through the blood-brain barrier was assessed both in vitro using a transwell model and in vivo. Furthermore, in vitro effects of KX (5, 10, and 20 µL/L) on oxygen and glucose deprivation/re-oxygenation (OGD/R)-induced injury, transient receptor potential vanilloid type 1 (TRPV1) modulation, calcium influx, and mitochondrial function were explored through Western blot, CCK-8 assay, JC-1 staining, calcium imaging, adenosine triphosphate (ATP) and antioxidant measurements., Results: In in vivo experiments, KXA reduced brain infarct volume and neuron loss in t-MCAO mice. Behavioral assessments showed marked improvement in the neurological deficit of t-MCAO mice with KXA treatment (P<0.05 or P<0.01). Additionally, in vitro findings indicated that KX ameliorated OGD/R-induced injury through TRPV1 channel modulation. KX increased cell viability in OGD/R-treated SH-SY5Y cells and prevented OGD/R-induced calcium overload by downregulating TRPV1 expression and constraining calcium influx through TRPV1 (P<0.05 or P<0.01). Furthermore, KXA maintained the membrane potential and function of mitochondria in OGD/R-treated SH-SY5Y cells., Conclusions: KXA could attenuate ischemic stroke injury through TRPV1 channel modulation, indicating its potential as a promising therapeutic option for stroke in clinical practice., Competing Interests: Conflict of Interest. Dr. CHEN Hong-jian and Dr. CHEN Ye-feng are in the joint postdoctoral program of Zhejiang University and Zhejiang SuKean Pharmaceutical Co., Ltd. Dr. QIAN Kai, ZHU Yang-yang, FANG Lei, and YANG Tao are employed by Zhejiang SuKean Pharmaceutical Co., Ltd. The study was conducted in accordance with rigorous scientific standards to ensure the objectivity and reliability of the results. The data was analyzed and interpreted by authors without relationships relevant to the company. The company had no influence on the data analysis or interpretation of the results. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Two new polyacetylenes, (5 Z ,12 E )-14-hydroxytetradeca-5,12-dien-8,10-diyn-1-yl 3-methylbut-2-enoate ( 1 ) and 5 S , 1' R -(6 E ,12 E )-1-hydroxytetradeca-6,12-dien-8,10-diyn-5-yl 2-methylbutanoate ( 2 ), together with two known ones, (2 E ,8 E )-12- β -methylbutyryltetradeca-2,8-diene-4,6-diyne-1,14-diol ( 3 ), and ( E )-5-[5-(but-3-en-1-yn-1-yl)thiophen-2-yl]pent-2-en-4-yn-1-yl acetate ( 4 ) were isolated from the ethyl acetate extract of the roots of Atractylodes macrocephala by various chromatographic methods, such as normal phase silica gel column, MPLC, and semi-preparative HPLC. Their structures were identified by kinds of spectroscopic methods including 1D NMR, 2D NMR, IR, UV, HR-ESI-MS, and ECD. Compound 1 exhibited cytotoxic activities in HepG2 and Huh7 cells with IC 50 values of 20.50 ± 2.07 and 19.99 ± 1.35 μM, respectively.

Oocytes are the largest cell type in multicellular animals. Here, we show that mRNA transporter 4 (MTR4) is indispensable for oocyte growth and functions as part of the RNA surveillance mechanism, which is responsible for nuclear waste RNA clearance. MTR4 ensures the normal post-transcriptional processing of maternal RNAs, their nuclear export to the cytoplasm, and the accumulation of properly processed transcripts. Oocytes with Mtr4 knockout fail to accumulate sufficient and normal transcripts in the cytoplasm and cannot grow to normal sizes. MTR4-dependent RNA surveillance has a previously unrecognized function in maintaining a stable nuclear environment for the establishment of non-canonical histone H3 lysine-4 trimethylation and chromatin reorganization, which is necessary to form a nucleolus-like structure in oocytes. In conclusion, MTR4-dependent RNA surveillance activity is a checkpoint that allows oocytes to grow to a normal size, undergo nuclear and cytoplasmic maturation, and acquire developmental competence., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: This retrospective study aimed to explore the association and clinical value of sequential organ failure assessment (SOFA) score on the predictors of adverse events in patients with unruptured abdominal aortic aneurysms (AAA)., Methods: A total of 322 patients from Medical Information Mart for Intensive Care IV database were enrolled. Logistic regression was conducted to explore the association between SOFA and primary outcome (need for surgery, NFS). Receiver operating characteristic (ROC) and nomogram analyses were used to assess its performance for predicting NFS. We also explored the association and clinical value of SOFA on secondary outcomes including hospital length of stay (LOS), ICU-LOS, and in-hospital mortality by linear and logistic regression analyses, generalized additive model, ROC, and decision curve analysis., Results: Totally 291 patients underwent the surgery. High SOFA score significantly correlated with NFS both in crude and adjusted models (all P<0.05). SOFA had a relatively favorable prediction performance on NFS (AUC = 0.701, 95%CI: 0.596-0.802). After adjusting for related diseases, its prediction performance was increased. When SOFA was combined with lactate and gender, the model showed an AUC of 0.888 (95%CI: 0.759-1.000) and 0.3-0.9 prediction possibility. Further, the SOFA also showed significant relationship with hospital-LOS, ICU-LOS, and in-hospital mortality (all P<0.05), and exerted some value in the prediction of 7-day hospital-LOS (AUC = 0.637, 95%CI: 0.575-0.686) and in-hospital mortality (AUC = 0.637, 95%CI: 0.680-0.845)., Conclusions: SOFA score was related to the NFS and can be regarded as a useful indicator for predicting the NFS in patients with AAA., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Weng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aptamers are attractive recognition ligands for sensing proteins due to their favorable affinity, specificity, stability, and easy synthesis. However, it is difficult to detect proteins directly in complex biological samples without sophisticated equipment or tedious sample pretreatment. Herein, we developed a portable electrophoretic mobility shift assay (EMSA) platform for direct protein aptasensing in complex biological samples. This portable EMSA consists of a mini agarose gel apparatus and a simple blue light transmission instrument integrated a smartphone camera. Lactoferrin (LF), which plays critical roles in food quality and dry eye diagnosis, was selected for feasibility verification. The successful direct determination of LF in dairy samples revealed that agarose gel not only provides separation power for the LF-aptamer complex but also functions as a physical barrier, excluding milk fat globules and casein micelles and further eliminating their interference. In addition, this pretreatment-free approach also exhibits good generality and multiplexity for other proteins assay by altering aptamer sequences. Therefore, the portable EMSA could be a reliable, affordable, user-friendly and pretreatment-free tool for protein aptasensing in biological and clinical samples for point-of-need diagnostics as well as food quality and safety., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In recent years, magnetic particle imaging (MPI) has emerged as a promising imaging technique depicting high sensitivity and spatial resolution. It originated in the early 2000s where it proposed a new approach to challenge the low spatial resolution achieved by using relaxometry in order to measure the magnetic fields. MPI presents 2D and 3D images with high temporal resolution, non-ionizing radiation, and optimal visual contrast due to its lack of background tissue signal. Traditionally, the images were reconstructed by the conversion of signal from the induced voltage by generating system matrix and X-space based methods. Because image reconstruction and analyses play an integral role in obtaining precise information from MPI signals, newer artificial intelligence-based methods are continuously being researched and developed upon. In this work, we summarize and review the significance and employment of machine learning and deep learning models for applications with MPI and the potential they hold for the future. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 1., (© 2024 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Objective: To explore weight-bearing stability of Pilon fracture fixed by external fixator., Methods: Six ankle bone models (right side) and 4 pairs (8 ankle cadaver specimens) were selected. Pilon fracture model was prepared by using the preset osteotomy line based on Ruedi Allgower Pilon fracture type. Pilon fracture model was built by using a minimally invasive osteotomy. After ankle bone model and cadaver specimen model were fixed with external fixator, axial load was carried out on mechanical loading machine. After ankle bone model and cadaver specimen model were fixed with external fixator, axial load was carried out on mechanical loading machine. Axial loads of 150, 300 and 450 N were applied to ankle bone model, and displacements of fibula fracture blocks, lateral tibia fracture blocks and medial tibia fracture blocks in three-dimensional space (X, Y and Z axes) were recorded by dynamic capture instrument. Axial loads of 300, 600 and 900 N were applied to ankle cadaver model fixed by external fixator. X-ray films of Pilon fracture cadaver model fixed by external fixator under different loading conditions were taken. The anterior tibial angle, tibial malleolar point angle, talus shift value, talus tilt angle, lateral malleolar shift value, lateral malleolar shift value, medial malleolar separation shift value and articular surface step displacement value were measured under different loads by digimizer software., Results: After 150, 300 and 450 N axial loads were applied to Pilon fracture models fixed by external fixator, no loosening or fracture of external fixator was observed, and no loosening, fracture or irreversible plastic deformation of Kirschner needle were observed. The displacement values of fibular fracture pieces on X-axis(around) were 0.032 (-0.022, 0.269), 0.061 (-0.002, 0.427), 0.212(-0.016, 1.223) mm, and the displacement values on Y-axis(above and below) were 0.002(-0.031, 0.103), 0.051(-1.133, 0.376), 0.128 (-1.394, 0.516) mm, and displacement values on Z-axis (front and rear) were -0.003 (-0.130, 0.171), 0.137 (-0.076, 0.433), 0.030(-0.487, 0.478) mm;the displacement values of lateral tibial fractures on X-axis were 0.000(-0.108, 0.027), 0.083(-0.364, 0.050), -0.121(-0.289, 0.165) mm, and displacement values on Y-axis were -0.009(-0.200, 0.025), -0.179(-0.710, 0.084), -0.257(-0.799, 0.027) mm, and displacement values on Z-axis were 0.112(-0.024, 0.256), 0.157(-0.068, 0.293), -0.210(-0.035, 0.430) mm;the displacement values of medial tibial fracture block on X-axis were -0.010(-0.060, 0.013), -0.165(-0.289, 0.056), -0.181(-0.395, 0.013) mm, and the displacement values on Y-axis were -0.036(-0.156, 0.007), -0.104(-0.269, 0.178), -0.245(-0.380, -0.011) mm, and displacement values on Z-axis were -0.005(-0.372, 0.189), -0.012 (-1.774, 0.380), 0.200 (-1.963, -0.540) mm. After 300, 600 and 900 N axial loads were applied to Pilon fracture cadaverous models fixed with external fixators, there were no significant difference in anterior tibial angles, angles of malleolar points of tibia, oblique angles of talus, fracture steps, shift values of talus, lateral shift values of lateral malleolus, lateral shift values of medial malleolus, lateral shift values of medial malleolus between under different loading conditions and those without loading ( P >0.05). No loosening or fracture of external fixator as a whole, loosening, fracture or irreversible deformation of Kirschner needle at the local fixed fracture end occurred., Conclusion: The early weight-bearing external fixator could maintain stability of fracture end and ankle joint, and the maximum weight is not more than 300 N. In clinical practical application, material characteristics of the implant and type of fracture should be selected.

Traumatic brain injury (TBI) remains a principal factor in neurological disorders, often resulting in significant morbidity due to secondary neuroinflammatory and oxidative stress responses. While circular RNAs are recognized for their high expression levels in the nervous system and play crucial roles in various neurological processes, their specific contributions to the pathophysiology of TBI remain underexplored. In this study, the possible molecular mechanisms through which circMETTL9 modulated oxidative stress and neurological outcomes following TBI were investigated. In vitro model of oxidative stress utilizing SH-SY5Y cells revealed that circMETTL9 knockdown significantly attenuated H₂O₂-induced reactive oxygen species (ROS) production, reduced apoptosis, and preserved mitochondrial function. Additionally, CCAR2 has been identified as a circMETTL9-binding protein by mass spectrometry and RNA immunoprecipitation, with circMETTL9 positively regulating CCAR2 expression. Meanwhile, on the basis of silencing CCAR2, it was verified that the regulation of oxidative stress in SH-SY5Y cells by circMETTL9 was mediated by CCAR2. In vivo experiments using a TBI rat model further confirmed that CCAR2 knockdown alleviated central nervous system (CNS) injury, reduced oxidative stress and apoptosis, and protected mitochondrial integrity following TBI. These findings suggest a novel mechanism by which circMETTL9 targets CCAR2 via mitochondria-mediated Bax/Bcl-2/caspase-3 signaling to regulate apoptosis. CircMETTL9 may provide a viable therapeutic target for mitigating neurological dysfunction following TBI, offering new insights into potential interventions aimed at reducing secondary brain injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

CD8 + T cell spatial distribution in the context of tumor microenvironment (TME) dictates the immunophenotypes of tumors, comprised of immune-infiltrated, immune-excluded and immune-desert, discriminating "hot" from "cold" tumors. The infiltration of cytotoxic CD8 + T cells is associated with favorable therapeutic response. Hitherto, the immunophenotypes of esophageal squamous cell carcinoma (ESCC) have not yet been comprehensively delineated. Herein, we comprehensively characterized the immunophenotypes of ESCC and identified a subset of ESCC, which was defined as cold tumor and characterized with CD8 + T cell-desert TME. However, the mechanism underlying the defect of CD8 + T cells in TME is still pending. Herein, we uncovered that tumor cell-intrinsic EZH2 with high expression was associated with the immunophenotype of immune-desert tumors. Targeted tumor cell-intrinsic EZH2 rewired the transcriptional activation of CXCL9 mediated by NF-κB and concomitantly reinvigorated DC maturation differentiation via inducing the reduction of VEGFC secretion, thereby enhancing the infiltration of cytotoxic CD8 + T cells into TME and inhibiting tumor immune evasion. Our findings identify EZH2 as a potential therapeutic target and point to avenues for targeted therapy applied to patients with ESCC characterized by CD8 + T cell-desert tumors., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval statement and patient consent statement: The collected human tumor tissue samples were approved by the Ethical Committee of cancer Hospital of Shantou university medical college and the Medical College of Shantou University, (2024019) and all patients have signed informed consent forms. Animal care guidelines approved by the Animal Policy and Welfare Committee of Shantou University Medical College (SUMCSY2024-003) were followed while animal experiments were conducted., (© 2024. The Author(s).)

Background: Endoscopic assessment for the diagnosis of gastric cancer is limited by interoperator variability and lack of real-time capability. Recently, Raman spectroscopy-based artificial intelligence (AI) has been proposed as a solution to overcome these limitations., Objective: To compare the performance of the AI-enabled Raman spectroscopy with that of high-definition white light endoscopy (HD-WLE) for the risk classification of gastric lesions., Methods: This was a randomized double-arm feasibility proof-of-concept trial in which participants with suspected gastric neoplasia underwent endoscopic assessment using either the Raman spectroscopy-based AI (SPECTRA IMDx™) or HD-WLE performed by expert endoscopists. Identified lesions were classified in real time as having either low or high risk for neoplasia. Diagnostic outcomes were compared between the two groups using histopathology as the reference., Results: A total of 20 patients with 25 lesions were included in the study. SPECTRA, in real-time, performed at a statistically similar level to that of HD-WLE performed by expert endoscopists, achieving an overall sensitivity, specificity, and accuracy of 100%, 80%, and 89.0%, respectively, by patient; and 100%, 80%, and 92%, respectively, by lesion, while expert endoscopists using HD-WLE attained a sensitivity, specificity, and accuracy of 100%, 80%, and 90%, respectively, by patient; and 100%, 83.3%, and 91.7%, respectively, by lesion, in differentiating high-risk from low-risk gastric lesions., Conclusions: The SPECTRA's comparable performance with that of HD-WLE suggests that it can potentially be a valuable adjunct for less experienced endoscopists to attain accurate and real-time diagnoses of gastric lesions. Larger-scale prospective randomized trials are recommended to validate these promising results further.

Surface-enhanced Raman spectroscopy (SERS) offers a distinctive vibrational fingerprint of the molecules and has led to widespread applications in medical diagnosis, biochemistry, and virology. With the rapid development of artificial intelligence (AI) technology, AI-enabled Raman spectroscopic techniques, as a promising avenue for biosensing applications, have significantly boosted bacteria identification. By converting spectra into images, the dataset is enriched with more detailed information, allowing AI to identify bacterial isolates with enhanced precision. However, previous studies usually suffer from a trade-off between high-resolution spectrograms for high-accuracy identification and short training time for data processing. Here, we present an efficient bacteria identification strategy that combines deep learning models with a spectrogram encoding algorithm based on wavelet packet transform and Gramian angular field techniques. In contrast to the direct analysis of raw Raman spectra, our approach utilizes wavelet packet transform techniques to compress the spectra by a factor of 1/15, while concurrently maintaining state-of-the-art accuracy by amplifying the subtle differences via Gramian angular field techniques. The results demonstrate that our approach can achieve a 99.64 % and a 90.55 % identification accuracy for two types of bacterial isolates and thirty types of bacterial isolates, respectively, while a 90 % reduction in training time compared to the conventional methods. To verify the model's stability, Gaussian noises were superimposed on the testing dataset, showing a specific generalization ability and superior performance. This algorithm has the potential for integration into on-site testing protocols and is readily updatable with new bacterial isolates. This study provides profound insights and contributes to the current understanding of spectroscopy, paving the way for accurate and rapid bacteria identification in diverse applications of environment monitoring, food safety, microbiology, and public health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: This study delves into the complex interplay between genetics, 25-hydroxyvitamin D (25OHD), and schizophrenia (SCZ). It leverages extensive sample data derived from Genome-Wide Association Studies (GWAS) to uncover genetic correlations., Methods: Employing Linkage Disequilibrium Score Regression (LDSC) and S-LDSC, this study investigates genetic connections between 25OHD and SCZ. It examines Single Nucleotide Polymorphism (SNP) heritability in specific tissues and incorporates diverse immune cell datasets for genetic enrichment analysis. Local genetic correlations were analyzed using HESS software, and pleiotropy analysis identified shared genetic loci in brain tissues. Hyprcoloc analysis was used to explore shared genetic factors between 25OHD, immune cells, and SCZ, complemented by a bidirectional Mendelian Randomization (MR) to probe potential causal links., Results: We identified a significant negative genetic correlation between 25OHD levels and SCZ. PLACO analysis revealed 35 pleiotropic loci with strong enrichment in brain regions, particularly the cerebellum, frontal cortex, and hippocampus. Eight loci (1p34.2, 2p23.3, 3p21.1, 5q31.2, 12q23.2, 14q32.33, 16p13.3, and 16q24.3) exhibited strong colocalization, highlighting potential drug targets. Gene and tissue enrichment analyses emphasized neurological and immune-related mechanisms, including hyaluronan metabolism. Bidirectional MR analysis supported a causal effect of SCZ on 25OHD levels., Conclusion: Our study identifies NEK4 as a potential therapeutic target and highlights the involvement of hyaluronan metabolism in the genetic association between 25OHD and SCZ. These findings provide valuable insights into shared genetic pathways, immune-related connections, and causal interactions in the context of SCZ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer Y-QY declared a shared parent affiliation with the author H-ML to the handling editor at the time of review., (Copyright © 2024 Rong, Li, Lu, Su and Jin.)

Single-cell RNA sequencing (scRNA-seq) is widely used to reveal heterogeneity in cells, which has given us insights into cell-cell communication, cell differentiation, and differential gene expression. However, analyzing scRNA-seq data is a challenge due to sparsity and the large number of genes involved. Therefore, dimensionality reduction and feature selection are important for removing spurious signals and enhancing downstream analysis. Correlated clustering and projection (CCP) was recently introduced as an effective method for preprocessing scRNA-seq data. CCP utilizes gene-gene correlations to partition the genes and, based on the partition, employs cell-cell interactions to obtain super-genes. Because CCP is a data-domain approach that does not require matrix diagonalization, it can be used in many downstream machine learning tasks. In this work, we utilize CCP as an initialization tool for uniform manifold approximation and projection (UMAP) and t-distributed stochastic neighbor embedding (tSNE). By using 21 publicly available datasets, we have found that CCP significantly improves UMAP and tSNE visualization and dramatically improve their accuracy. More specifically, CCP improves UMAP by 22% in ARI, 14% in NMI and 15% in ECM, and improves tSNE by 11% in ARI, 9% in NMI and 8% in ECM., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hozumi, Wei. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Terrestrial animal intestines are hotspots for the enrichment of micro/nano plastics (M/NPs) and antibiotic-resistant genes (ARGs). However, little is known about the further impact of M/NPs on the spread of ARGs in animal guts. This study investigates the role of M/NPs (polystyrene) with varying particle sizes (0.082, 42, and 182 μm), concentrations (10 and 100 mg/L), and exposure durations (4 and 16 days) in the ARGs dissemination via conjugation in the edible snail (Achatina fulica) gut. Combination of qPCR with 16S rRNA-based sequencing, we found that PS exposure caused intestinal cell impairment and shifts in the gut microbial community of snails. Conjugation rate increased with PS particle sizes in the snail gut. After 4 days of exposure, significantly higher conjugation rates were observed in the gut exposed to 100 mg/L PS compared to 10 mg/L, however, this trend reversed after 16 days. Consistently, the abundances of conjugation relevant genes trfA and trbB shared similar trends to the conjugation ratios in the snail gut after PS exposure. Transconjugant diversity was much lower in 10 mg/L PS groups than in 100 mg/L PS treatments. Therefore, this study suggests that the presence of M/NPs would complicate management of ARG spread. The selection pressure exerted by M/NPs may sustain or even amplify the spread of ARGs in the gut of terrestrial animals even in the absence of antibiotics. It highlights the necessity of avoiding M/NPs intake as a part of comprehensive strategy for cubing ARG dissemination in the gut of animals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Congenital tracheal stenosis (CTS) is a rare but life-threatening malformation of the trachea. Surgical reconstruction is the treatment of choice in symptomatic cases which is highly risky and is rarely performed in extremely premature infants. With this, reporting a case of CTS managed by tracheal reconstructive surgery under ECMO in a baby weighing 1.47 kg at 32 + 1 WOG was the first ever case in China., Case Presentation: A premature newborn with a very low birth weight (VLBW) was admitted to our institute for breathing difficulties, requiring mechanical ventilation, and experienced two unsuccessful attempts of extubation. The team performed tracheal reconstructive surgery supported by ECMO after identifying lower tracheal stenosis through a bronchoscopy examination. One month after the surgery, oxygen support was able to discontinue. The patient's entire hospitalization was incredibly challenging, marked by hemodynamic instability with persistent anemia, and disseminated intravascular coagulation (DIC), which were managed with great care. Despite the difficult stay, a follow-up bronchoscopy revealed no obstruction or tracheal stenosis, leading to a successful discharge., Conclusion: Advancements in diagnostic techniques and innovative management methods have made diagnosing and treating CTS easier, even in premature infants. Our case is the first in China to successfully undergo tracheal reconstructive surgery supported by ECMO, inspiring future achievements in the medical field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Xu, Sapana, Qi, Fu, Guo, Ma, Wang, Zhao, Wang and Zhang.)

To explore whether red blood cell distribution width-albumin ratio (RAR) is relevant to in-hospital mortality among abdominal aortic aneurysm (AAA). This is a retrospective study retrieving data from the MIMIC-IV database. Patients were divided into survivor or non-survivor groups by the in-hospital mortality. Receiver operating characteristic curve analysis, logistic regression models, subgroup analysis, interaction analysis, and restricted cubic spline analysis were conducted to analyze the correlation between RAR and in-hospital mortality. Then, we divided patients into 2 groups by an optimal cutoff value of RAR to identify the factors independently linked to RAR. Following this, the mediation analysis was conducted to reveal the potential regulatory path. Finally, we assessed the clinical value of RAR in secondary outcomes containing length of hospital stay, intensive care unit (ICU) admission, and ICU stay. Totally 770 participants with AAA were enrolled: 722 survivors and 48 non-survivors. Higher RAR was observed in the non-survivor group and its level performed satisfactorily in predicting in-hospital mortality. AAA patients were more likely to die during in-hospital with the increase of RAR (P < .05) and this linear correlation was revealed by restricted cubic spline (P non-linear > .05). Additionally, urea nitrogen and creatinine were independently related to RAR. RAR served as a mediator in the association of urea nitrogen/creatinine with in-hospital mortality. Finally, the length of hospital stay and ICU stay were longer in the RAR ≥ 4.658 group (P < .05). RAR is a potential risk predictor for in-hospital mortality in AAA patients. Further, RAR upregulation was significantly correlated with prolonged length of hospital stay and ICU stay., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Neuropsychiatric symptoms (NPS) such as depression, anxiety, apathy and aggression affect up to 90% of Alzheimer's disease (AD) patients. These symptoms significantly increase caregiver stress and institutionalization rates, and more importantly they are correlated with faster cognitive decline. However, the neuronal basis of NPS in AD remains largely unknown. Here, we review current understanding of NPS and related pathology in studies of AD patients and AD mouse models. Clinical studies indicate that NPS prevalence and severity vary across different AD stages and types. Neuroimaging and postmortem studies have suggested that pathological changes in the anterior cingulate cortex, hippocampus, prefrontal cortex, and amygdala are linked to NPS, although the precise mechanisms remain unclear. Studies of AD mouse models have indicated that amyloid-beta and tau-related neurodegeneration in the hippocampus, prefrontal cortex, and anterior cingulate cortex are correlated with NPS-like behavioral deficits. A better understanding of the NPS phenotypes and related pathological changes will pave the way for developing a better management strategy for NPS in AD patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Zhang, Zhang, Zhang, Tao and Zhang.)

Introduction: The meticulous management of risk factors is paramount in the effective control of allergic rhinitis (AR), playing a significant role in diminishing both the direct medical expenditures and the indirect economic impacts associated with the condition. Presently, there is a notable deficiency in research concerning the risk factors for severe AR, as well as the correlation between serum allergen-specific immunoglobulin E (sIgE) levels and the severity of AR symptoms., Methods: The study utilized data from a cross-sectional epidemiological survey conducted in Guangzhou, China, from April 2023 to March 2024, involved 638 AR patients. We used Visual Analogue Scale (VAS) scores to assess the severity of AR. Data of daily risk factors were collected through face-to-face questionnaires, and serum sIgE levels were measured using the AllergyScreen assay (Mediwiss Analytic GmbH, Moers, Germany). A generalized linear model was used to investigate the associations., Results: Our findings indicate that patients with severe AR exhibited more unhealthy lifestyle habits and lived in high-risk environments compared to non-severe patients. Physical activity more than three times per week was associated with a reduced risk of severe symptoms (OR: 0.55, 95% CI: 0.36, 0.82). Frequent indoor cleaning also lowered the risk of severe AR (OR: 0.70, 95% CI: 0.56, 0.87). Additionally, a one-level increase in serum sIgE was linked to higher odds of severe AR (OR: 1.26, 95% CI: 1.11, 1.43) after adjusting for risk factors., Conclusion: Severe AR is associated with poor household cleaning and less exercise. Higher serum sIgE levels correspond to a higher risk of severe AR., (© 2024 S. Karger AG, Basel.)

Salmonella is a critical group of zoonotic pathogens that are widely spread in poultry, causing avian salmonellosis. This disease usually leads to significant reductions in poultry performance, including reduced egg production in laying hens, decreased hatchability in chicks, and retarded growth in broilers. As a result, worldwide poultry industry suffers serious economic losses. Vaccination serves as an essential strategy for preventing Salmonella infection in poultry, effectively reducing susceptibility and alleviating disease symptoms, while also minimizing fecal shedding and environmental contamination. This subsequently diminishes public health risks. Various Salmonella vaccines can induce humoral and cellular immune responses to different extents. Therefore, a thorough understanding of the immune defense mechanisms, especially adaptive immune responses in poultry infected with Salmonella, is crucial for the development of Salmonella vaccines. This review summarizes the progress in the application of Salmonella vaccines in poultry, including adaptive immune responses induced by Salmonella and vaccines targeting the predominant circulating serotypes in poultry. It also provides an insight into the future of poultry-origin Salmonella vaccines., Competing Interests: Declaration of competing interests The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Recreating natural organisms' dynamic shape-morphing and adaptive color-changing capabilities in a compact structure poses significant challenges but unlocks unprecedented hybridized robotic-visual applications. Overcoming programmability and predictability obstacles is key to achieving real-time, responsive changes in appearance and functionality, enhancing robot-environment-user interactions in ways previously unattainable. Herein, a Soft Magneto-Mechano-Chromic (SoMMeC) structure comprising a magnetic actuating and a synthetic photonic film, mirroring the intricate color-tuning mechanism of chameleons is devised. A model combining numerical simulation and a strain-dependent color evolution map enables precise predictions and controllable shape-color alterations across various geometrical and magnetization profiles. The SoMMeC exhibits rapid (0.1s), broad (full-visible spectrum), tether-free (remote magnetic manipulation), and programmable (model-guided control) color transformations, surpassing traditional limitations with its real-time response, broad and omnidirectional coloration for enhanced visibility, and robustness against external disturbances. The SoMMeC translates into dynamic advertising iridescence, adaptive camouflage, self-sensing, and multi-level encryption, and transcends traditional robotics by seamlessly blending dynamic movement with nuanced visual changes. It opens up a spectrum of applications that redefine robotic functionality through dynamic appearance modulation, making robotic systems more versatile, adaptive, and suitable for unexplored integrative functions., (© 2024 Wiley‐VCH GmbH.)

Topological data analysis (TDA) has made significant progress in developing a new class of fundamental operators known as the Dirac operator, particularly in topological signals and molecular representations. However, the current approaches being used are based on the classical case of chain complexes. The present study establishes Mayer Dirac operators based on N -chain complexes. These operators interconnect an alternating sequence of Mayer Laplacian operators, providing a generalization of the classical result D 2 = L . Furthermore, the research presents an explicit formulation of the Laplacian for N -chain complexes induced by vertex sequences on a finite set. Weighted versions of Mayer Laplacian and Dirac operators are introduced to expand the scope and improve applicability, showcasing their effectiveness in capturing physical attributes in various practical scenarios. The study presents a generalized version for factorizing Laplacian operators as an operator's product and its 'adjoint'. Additionally, the proposed persistent Mayer Dirac operators and extensions are applied to biological and chemical domains, particularly in the analysis of molecular structures. The study also highlights the potential applications of persistent Mayer Dirac operators in data science., (© 2024 The Author(s). Published by IOP Publishing Ltd.)

Bacterial operons often contain intergenic transcription terminators that terminate some, but not all, RNA polymerase molecules. In these operons, the level of terminator readthrough determines downstream gene expression and helps establish protein ratios among co-regulated genes. Despite its critical role in maintaining stoichiometric gene expression, terminator strength remains difficult to predict from DNA sequence. The necessary features of a major class of bacterial terminators - intrinsic terminators - have been known for half a century, but a strong sequence-function model has yet to be developed. Here, we summarize high-throughput approaches for probing the sequence determinants of intrinsic termination efficiency and discuss the impact of trans-acting factors on this sequence-function relationship. Building on the main lessons from these studies, we map out the experimental challenges that must be circumvented to establish a quantitative model for termination efficiency., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: Sciatica is commonly caused by herniated lumbar disc and contributes to severe pain and prolonged disability. Although acupuncture is widely used by patients with chronic sciatica, the evidence of its efficacy is scarce., Objective: To investigate the efficacy and safety of acupuncture compared with sham acupuncture in patients with chronic sciatica from herniated disk., Design, Settings, and Participants: This was a multicenter 2-arm randomized clinical trial conducted in 6 tertiary-level hospitals in China of patients with chronic sciatica from herniated disk. Participants were recruited from March 25, 2021, to September 23, 2021, with a final follow-up through September 22, 2022. Data analyses were performed from December 2022 to March 2023., Interventions: Participants were randomly assigned to receive 10 sessions of acupuncture (n = 110) or sham acupuncture (n = 110) over 4 weeks. Participants, outcome assessors, and statisticians were blinded., Main Outcomes and Measures: The 2 coprimary outcomes were changes in visual analog scale (VAS) for leg pain and Oswestry Disability Index (ODI) from baseline to week 4. Secondary outcomes were adverse events., Results: A total of 216 patients (mean [SD] age, 51.3 [15.2] years; 147 females [68.1%] and 69 males [31.9%]) were included in the analyses. The VAS for leg pain decreased 30.8 mm in the acupuncture group and 14.9 mm in the sham acupuncture group at week 4 (mean difference, -16.0; 95% CI, -21.3 to -10.6; P < .001). The ODI decreased 13.0 points in the acupuncture group and 4.9 points in the sham acupuncture group at week 4 (mean difference, -8.1; 95% CI, -11.1 to -5.1; P < .001). For both VAS and ODI, the between-group difference became apparent starting in week 2 (mean difference, -7.8; 95% CI, -13.0 to -2.5; P = .004 and -5.3; 95% CI, -8.4 to -2.3; P = .001, respectively) and persisted through week 52 (mean difference, -10.8; [95% CI, -16.3 to -5.2; P < .001; and -4.8; 95% CI, -7.8 to -1.7; P = .003, respectively). No serious adverse events occurred., Conclusions and Relevance: This randomized clinical trial found that in patients with chronic sciatica from herniated disk, acupuncture resulted in less pain and better function compared with sham acupuncture at week 4, and these benefits persisted through week 52. Acupuncture should be considered as a potential treatment option for patients with chronic sciatica from a herniated disk., Trial Registration: Chictr.org Identifier: ChiCTR2100044585.

Background: Changes in K + channel expression/function are associated with disruption of vascular reactivity in several pathological conditions, including hypertension, diabetes, and atherosclerosis. Gasotransmitters achieve part of their effects in the organism by regulating ion channels, especially K + channels. Their involvement in hydrogen sulfide (H 2 S)-mediated vasorelaxation is still unclear, and data about human vessels are limited., Objective: To determine the role of K + channel subtypes in the vasorelaxant mechanism of H 2 S donor, sodium-hydrosulfide (NaHS), on isolated human internal mammary artery (HIMA)., Results: NaHS (1 × 10 -6 -3 × 10 -3  mol/L) induced a concentration-dependent relaxation of HIMA pre-contracted by phenylephrine and high K + . Among K + channel blockers, iberiotoxin, glibenclamide, 4-aminopyridine (4-AP), and margatoxin significantly inhibited NaHS-induced relaxation of phenylephrine-contracted HIMA (P < 0.01), whereas in the presence of apamin/1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) combination, the HIMA relaxation was partially reduced (P < 0.05). The effect of NaHS was antagonized by NO pathway inhibitors, L-NAME and KT5823, and by cyclo-oxygenase inhibitor, indomethacin (P < 0.01). Under conditions of blocked NO/prostacyclin synthesis and release, apamin/TRAM-34 and glibenclamide caused further decrease in NaHS-induced vasorelaxation (P < 0.01), while iberiotoxin, 4-AP, and margatoxin were without additional effect (P > 0.05). In the presence of nifedipine, NaHS induced partial relaxation of HIMA (P < 0.01)., Conclusion: Our results demonstrated that H 2 S donor, NaHS, induced concentration-dependent relaxation of isolated HIMA. Vasorelaxant mechanisms of H 2 S included direct or indirect opening of different K + channel subtypes, K ATP , BK Ca , SK Ca /IK Ca , and K V (subtype K V 1.3), in addition to NO pathway activation and interference with extracellular Ca 2+ influx., (© 2024 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Developing sensor arrays capturing comprehensive fluorescence (FL) spectra from a single probe is crucial for understanding sugar structures with very high similarity in biofluids. Therefore, the analysis of highly similar sugar' structures in biofluids based on the entire FL of a single nanozyme probe needs more concern, which makes the development of novel alternative approaches highly wanted for biomedical and other applications. Herein, a well-designed deep learning model with intrinsic information of 3D FL of CuO nanoparticles (NPs)' oxidase-like activity was developed to classify and predict the concentration of a group of sugars with very similar chemical structures in different media. The findings presented that the overall accuracy of the developed model in classifying the nine selected sugars was (99-100 %), which prompted us to transfer the developed model to predict the concentration of the selected sugars at a concentration range of (1-100 μM). The transferred model also gave excellent results (R 2  = 97-100 %). Therefore, the model was extended to other more complex applications, namely the identification of mixtures of sugars in serum and the detection of polysaccharides in different media such as serum and lake water. Notably, LOD for fructose was determined at 4.23 nM, marking a 120-fold decrease compared to previous studies. Our developed model was also compared with other deep learning-based models, and the results have demonstrated remarkable progress. Moreover, the identification of other possible coexisting interference substances in lake water samples was considered. This work marks a significant advancement, opening avenues for the widespread application of sensor arrays integrating nanozymes and deep learning techniques in biomedical and other diverse fields., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fluorescence of cyanine dyes is often quenched in aqueous solution, limiting their application in water or biological system. In this work, a novel strategy of host-guest interaction based on cyanine derivatives containing auxochromes was proposed to enhance fluorescence in aqueous solution and cell imaging. By using the host (methylated β-cyclodextrin, M-β-CD) to inclusion and suppress the TICT effect of the dye, the fluorescence was significantly enhanced at lower host concentration. Cyanine and hemicyanine dyes (Ad-NH-1a, Ad-NH-1b and Ad-NH-2) with adamantyl group as auxochrome were designed and prepared by using host-guest complexation to inhibit the TICT effect of dyes, thus realizing the purpose of significantly enhancing the fluorescence of dyes at lower concentration. After adding M-β-CD, the fluorescence quantum yields of these dyes increased to 15.9 %, 21.8 %, and 6.08 %, respectively. In comparison, the fluorescence quantum yield of the dyes Ad-CONH-1 and Ad-CONH-2 containing adamantyl groups, increased only modestly from 1.78 to 2.83 times. Encouraged by these satisfactory results, further cell experiments were conducted with Ad-NH-1a, Ad-NH-1b, and Ad-NH-2. The experiment showed that adding a lower concentration of M-β-CD significantly reduced the clear imaging dosage of the probe (0.3 μM) without altering the organelle targeting of the probes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We report a step-economic strategy for the direct synthesis of novel polycyclic N -heterocycle-fused naphthoquinones by merging intramolecular oxidative coupling and cascade [4 + 2] cycloaddition. In the protocol, mechanistic investigations suggest that the cascade reaction involves the intermediate spiro polycyclic N -heterocycles and [4 + 2] cycloaddition processes. This protocol is featured with moderate to excellent yields, wide substrate scope, and divergent structures of products. In addition, the photophysical properties of the synthesized products were evaluated. These products exhibit interesting fluorescence properties, and surprisingly, the compounds have the ability to selectively recognize trifluoroacetic acid.

Objectives: This study aims to evaluate the organ-protective efficacy of postoperative glucocorticoid in patients with type A aortic dissection., Methods: Postoperative type A aortic dissection patients were randomly allocated to receive either postoperative glucocorticoid or standard-of-care treatment. Intravenous methylprednisolone was administered for 3 days. The primary outcome was the reduction of Sequential Organ Failure Assessment score on postoperative day 4 compared to baseline (on postoperative day 1 before methylprednisolone administration)., Results: Two hundred twelve patients were included in the intention-to-treat analysis. The primary outcome was significantly different between groups: 3.16 ± 2.52 in the control group versus 4.36 ± 2.82 in the glucocorticoid group (absolute difference 1.20 [95% CI 0.52-1.93], P = 0.001). The glucocorticoid group showed markedly lower median high-sensitivity C-reactive protein levels compared to the control group (91.0 mg/l vs 182.0 mg/l; absolute difference: -91 (95% CI -122 to -57), P = 0.009) on postoperative day 4. Fewer patients in the glucocorticoid group required continuous renal replacement therapy (8.5% vs 19.8% in the control group; absolute difference: -10.4 [95% CI -19.1 to -1.3], P = 0.03)., Conclusions: This trial demonstrates that postoperative glucocorticoid in patients with type A aortic dissection significantly reduces postoperative inflammation and improves recovery of early organ dysfunction. These findings advocate for the implementation of glucocorticoid in the early phase after surgery for enhanced organ protection., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

The stereoselectivity of enzymes plays a central role in asymmetric biocatalytic reactions, but there remains a dearth of evolution-driven biochemistry studies investigating the evolutionary trajectory of this vital property. Imine reductases (IREDs) are one such enzyme that possesses excellent stereoselectivity, and stereocomplementary members are pervasive in the family. However, the regulatory mechanism behind stereocomplementarity remains cryptic. Herein, we reconstruct a panel of active ancestral IREDs and trace the evolution of stereoselectivity from ancestors to extant IREDs. Combined with coevolution analysis, we reveal six historical mutations capable of recapitulating stereoselectivity evolution. An investigation of the mechanism with X-ray crystallography shows that they collectively reshape the substrate-binding pocket to regulate stereoselectivity inversion. In addition, we construct an empirical fitness landscape and discover that epistasis is prevalent in stereoselectivity evolution. Our findings emphasize the power of ASR in circumventing the time-consuming large-scale mutagenesis library screening for identifying mutations that change functions and support a Darwinian premise from a molecular perspective that the evolution of biological functions is a stepwise process., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Many structures in science, engineering, and art can be viewed as curves in 3-space. The entanglement of these curves plays a crucial role in determining the functionality and physical properties of materials. Many concepts in knot theory provide theoretical tools to explore the complexity and entanglement of curves in 3-space. However, classical knot theory primarily focuses on global topological properties and lacks the consideration of local structural information, which is critical in practical applications. In this work, two localized models based on the Jones polynomial, namely the multiscale Jones polynomial and the persistent Jones polynomial, are proposed. The stability of these models, especially the insensitivity of the multiscale and persistent Jones polynomial models to small perturbations in curve collections, is analyzed, thus ensuring their robustness for real-world applications.

Background: Helicobacter pylori (H. pylori) stands as the predominant infectious agent linked to the onset of gastritis, peptic ulcer diseases, and gastric cancer (GC). Identified as the exclusive bacterial factor associated with the onset of GC, it is classified as a group 1 carcinogen by the World Health Organization. The elimination of H. pylori plays a crucial role in the primary prevention of GC. While the prevalence has declined in recent decades, H. pylori infection is still highly prevalent in China, accounting for a significant part of the disease burden of GC. Therefore, updated prevalence information for H. pylori infection, especially regional and demographic variations in China, is an important basis for the design of targeted strategies that will be effective for the prevention of GC and application of policies for H. pylori control., Aim: To methodically evaluate the occurrence of H. pylori infection throughout China and establish a reference point for subsequent investigations., Methods: A systematic review and meta-analysis was conducted following established guidelines, as detailed in our methodology section., Results: Our review synthesized data from 152 studies, covering a sample of 763827 individuals, 314423 of whom were infected with H. pylori . We evaluated infection rates in mainland China and the combined prevalence of H. pylori was 42.8% (95%CI: 40.7-44.9). Subgroup analysis indicated the highest prevalence in Northwest China at 51.3% (95%CI: 45.6-56.9), and in Qinghai Province, the prevalence reached 60.2% (95%CI: 46.5-73.9). The urea breath test, which recorded the highest infection rate, showed a prevalence of 43.7% (95%CI: 41.4-46.0). No notable differences in infection rates were observed between genders. Notably, the prevalence among the elderly was significantly higher at 44.5% (95%CI: 41.9-47.1), compared to children, who showed a prevalence of 27.5% (95%CI: 19.58-34.7)., Conclusion: Between 2014 and 2023, the prevalence of H. pylori infection in China decreased to 42.8%, down from the previous decade. However, the infection rates vary considerably across different geographical areas, among various populations, and by detection methods employed., Competing Interests: Conflict-of-interest statement: The authors disclose that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

The fast evolution of SARS-CoV-2 and other infectious viruses poses a grand challenge to the rapid response in terms of viral tracking, diagnostics, and design and manufacture of monoclonal antibodies (mAbs) and vaccines, which are both time-consuming and costly. This underscores the need for efficient computational approaches. Recent advancements, like topological deep learning (TDL), have introduced powerful tools for forecasting emerging dominant variants, yet they require deep mutational scanning (DMS) of viral surface proteins and associated three-dimensional (3D) protein-protein interaction (PPI) complex structures. We propose an AlphaFold 3 (AF3)-assisted multi-task topological Laplacian (MT-TopLap) strategy to address this need. MT-TopLap combines deep learning with topological data analysis (TDA) models, such as persistent Laplacians (PL) to extract detailed topological and geometric characteristics of PPIs, thereby enhancing the prediction of DMS and binding free energy (BFE) changes upon virus mutations. Validation with four experimental DMS datasets of SARS-CoV-2 spike receptor-binding domain (RBD) and the human angiotensin-converting enzyme-2 (ACE2) complexes indicates that our AF3 assisted MT-TopLap strategy maintains robust performance, with only an average 1.1% decrease in Pearson correlation coefficients (PCC) and an average 9.3% increase in root mean square errors (RMSE), compared with the use of experimental structures. Additionally, AF3-assisted MT-TopLap achieved a PCC of 0.81 when tested with a SARS-CoV-2 HK.3 variant DMS dataset, confirming its capability to accurately predict BFE changes and adapt to new experimental data, thereby showcasing its potential for rapid and effective response to fast viral evolution.

β-Branched chiral amines with contiguous stereocenters are valuable building blocks for preparing various biologically active molecules. However, their asymmetric synthesis remains challenging. Herein, we report a highly diastereo- and enantioselective biocatalytic approach for preparing a broad range of β-branched chiral amines starting from their corresponding racemic ketones. This involves a dynamic kinetic resolution-asymmetric reductive amination process catalyzed using only an imine reductase. Four rounds of protein engineering endowed wild-type PocIRED with higher reactivity, better stereoselectivity, and a broader substrate scope. Using the engineered enzyme, various chiral amine products were synthesized with up to >99.9 % ee, >99 : 1 dr, and >99 % conversion. The practicability of the developed biocatalytic method was confirmed by producing a key intermediate of tofacitinib in 74 % yield, >99.9 % ee, and 98 : 2 dr at a challenging substrate loading of 110 g L -1 . Our study provides a highly capable imine reductase and a protocol for developing an efficient biocatalytic dynamic kinetic resolution-asymmetric reductive amination reaction system., (© 2024 Wiley-VCH GmbH.)

Chemical weathering is a pivotal geochemical process that shapes the carbon cycling and climates in the critical zone. Among its critical drivers, river discharge holds a particular significance, especially in the orogenic landscapes. Here, we examined the impact of discharge on mineral weathering in southwestern (SW) Taiwan by analyzing river water chemistry across a wide discharge range. Current observations indicated that carbonate contributes significantly to total weathering (50-80 %), with sulfuric acid accounting for one-half to two-thirds of carbonate weathering. A statistically strong correlation between river discharge and sulfuric acid-mediated carbonate weathering was highlighted, while the silicate weathering remained constant. This relationship suggests an increased influx of fresh minerals, such as pyrite, into the weathering regime as water flow increases. Our model identifies a critical discharge threshold of 4.6 m 3  s -1 , determining whether mineral weathering acts as a net source or sink of CO 2 . Consequently, mineral weathering in SW Taiwan acts as a net CO 2 sink during dry periods but turns into a net source during wet periods. Through analyzing a decade of daily discharge data, we found mineral weathering in SW Taiwan is a net CO 2 source, with a 2.6-fold increase in annual mean discharge causing a 3.8-fold increase in net CO 2 flux. This pattern is likely to be applicable to other similar minerals containing mountain-building regions, highlighting the significant role of hydrology in determining weathering sources and their potential impact on the carbon cycle balance., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hou-Chun Liu reports financial support was provided by National Science and Technology Council. Chen-Feng You reports financial support was provided by National Science and Technology Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Tetralogy of Fallot (TOF) is a common congenital heart disease (CHD) but the impact of the variants of the HAND1 gene promoter region has not been explored., Methods: DNA from blood samples of 612 subjects (300 sporadic TOF patients and 312 healthy controls) was sequenced to identify variants in the HAND1 gene promoter region that were further tested by cellular function experiments including dual-luciferase reporter gene assays, electrophoretic mobility shift analysis (EMSA), and bioinformatics analysis using JASPAR, a transcription factor binding site database., Results: Eight variants in HAND1 gene promoter region were identified with 3 only found in TOF patients including one novel g.3639 G > T. All 3 variants significantly reduced the transcriptional activity of HAND1 gene promoter in an in vitro reporter assay (p < 0.05). JASPAR analysis indicated that these variants may alter the binding sites of transcription factors, potentially associated with TOF formation., Conclusions: In the promoter region of HAND1gene of TOF patients, 3 variants were found only in the patients including one found for the first time. These variants decreased transcription factor activity. Therefore, the present study implies the role of HAND1 gene in the pathogenesis of TOF and further provides new insights into the genetic basis of TOF formation., Impact: Sequencing of DNA from 612 human subjects (300 TOF patients and 312 healthy controls) identified 8 variants in the promoter region of HAND1 gene with 3 found only in TOF including 1 newly identified. Reduced transcriptional activity at these 3 variants was confirmed by dual-luciferase reporter gene assay and EMSA assay. Predictions from the JASPAR database suggest altered binding sites of transcription factors by the variants. We for the first time demonstrate variants in the HAND1 promoter and that cause cellular dysfunction. The variants identified may have a pathological role in the formation of TOF., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of TEDA International Cardiovascular Hospital (Clinical Research Ethics Review Number: [2021]-0715-4). All subjects participating in the study have obtained written informed consent from their parents or guardians., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objectives: Metagenomic next-generation sequencing (mNGS) is emerging as a novel diagnostic technology for various infectious diseases; however, limited studies have investigated its application in etiological diagnosis of early onset pneumonia (EOP) among patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR) following in-hospital cardiac arrest (IHCA), The clinical significance of early mNGS in predicting short-term prognosis of IHCA patients after ECPR remains unclear., Methods: This retrospective study included 76 patients with IHCA who underwent ECPR at the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2022. Baseline characteristics and etiological data of all patients during their hospitalization were collected and statistically analyzed. The primary outcome of this study was the diagnosis of EOP, while the secondary outcomes included successful extracorporeal membrane oxygenation (ECMO) weaning and survival at discharge. Additionally, the characteristics of bronchoalveolar lavage fluid (BALF) flora in these patients were compared by analyzing both mNGS results and culture results., Results: Multivariate logistic regression were employed to analyze the predictors of ECMO weaning failure, mortality at discharge, and the incidence of EOP. Ultimately, patients with lower SOFA scores on admission [OR (95%CI): 1.447 (1.107-1.890), p=0.007] and those who underwent early mNGS testing within 48 hours after ECPR [OR (95%CI): 0.273 (0.086-0.865), p=0.027] demonstrated a higher probability of successful weaning from ECMO. Patients with higher SOFA scores on admission [OR (95%CI): 2.404 (1.422-4.064), p=0.001], and elevated lactate levels [OR (95%CI): 1.176 (1.017-1.361), p=0.029] exhibited an increased likelihood of mortality at discharge. Furthermore, early mNGS detection [OR (95%CI): 0.186 (0.035-0.979), p=0.047], and lower CRP levels (48h-7d after ECMO) [OR (95%CI):1.011 (1.003-1.019), p=0.006] were associated with a reduced incidence of EOP. In addition, the pathogens detected by mNGS within 48 hours after ECPR were mainly oral colonizing bacteria and viruses, and viruses were in the majority, while all BALF cultures were negative. In contrast, between 48 hours and 7 days after ECPR, BALF cultures were positive in all EOP patients., Conclusions: Early mNGS testing to identify microbial flora facilitates timely adjustment of antibiotic regimens, thereby reducing the incidence of EOP and improving short-term prognosis in patients undergoing ECPR following IHCA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Guo, Li, Zhou, Liu, Li, Fu, Zhao, Zhang and Zhao.)

Background: Internet hospitals (IHs) have rapidly developed as a promising strategy to address supply-demand imbalances in China's medical industry, with their capabilities directly dependent on information platform functionality. Furthermore, a novel theory of "Trinity" smart hospital has provided advanced guidelines on IH constructions., Objective: This study aimed to explore the construction experience, construction models, and development prospects based on operational data from IHs., Methods: Based on existing information systems and internet service functionalities, our hospital has built a "Smart Hospital Internet Information Platform (SHIIP)" for IH operations, actively to expand online services, digitalize traditional health care, and explore health care services modes throughout the entire process and lifecycle. This article encompasses the platform architecture design, technological applications, patient service content and processes, health care professional support features, administrative management tools, and associated operational data., Results: Our platform has presented a set of data, including 82,279,669 visits, 420,120 online medical consultations, 124,422 electronic prescriptions, 92,285 medication deliveries, 6,965,566 prediagnosis triages, 4,995,824 offline outpatient appointments, 2025 medical education articles with a total of 15,148,310 views, and so on. These data demonstrate the significant role of IH as an indispensable component of our physical hospital services, with deep integration between online and offline health care systems., Conclusions: The upward trends in various data metrics indicate that our IH has gained significant recognition and usage among both the public and healthcare workers, and may have promising development prospects. Additionally, the platform construction approach, which prioritizes comprehensive service digitization and the 'Trinity' of the public, healthcare workers, and managers, serves as an effective means of promoting the development of Internet Hospitals. Such insights may prove invaluable in guiding the development of IH and facilitating the continued evolution of the Internet healthcare sector., (©Guang-Wei Zhang, Bin Li, Zheng-Min Gu, Wei-Feng Yang, Yi-Ran Wang, Hui-Jun Li, Han-Bing Zheng, Ying-Xu Yue, Kui-Zhong Wang, Mengchun Gong, Da-Xin Gong. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 08.11.2024.)

Benign prostatic hyperplasia(BPH) is a common disease in middle-aged and elderly men, with lower urinary tract symptoms as the main manifestation, severely affecting the quality of life of patients. The pathogenesis of BPH is not yet fully understood, and there are still some challenges and limitations in western medicine treatment for BPH. Therefore, finding new and more effective treatment strategies is urgent. In recent years, many basic and clinical studies have confirmed the important role of traditional Chinese medicine in the treatment of BPH. This article reviews the progress of basic and clinical research in the treatment of BPH with traditional Chinese medicine, and believes that basic research mainly focuses on the active ingredients of Chinese medicine [regulating pathways such as NF-E2-related factor 2(Nrf2)/antioxidant response element(ARE), nuclear factor κB(NF-κB), epidermal growth factor receptor(EGFR)/signal transducer and activator of transcription 3(STAT3), phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR), p38 mitogen-activated protein kinase(p38 MAPK)/forkhead box O subtype(FOXO3a), etc.], single Chinese herbs(regulating inflammatory factors, oxidative stress-related proteins, cell cycle-related proteins, and apoptotic factors, etc.), and Chinese herbal compounds and patent medicines [regulating extracellular signal-regulated kinase(ERK1/2), transforming growth factor-β(TGF-β)/Smad, mitogen-activated protein kinase(MAPK), PI3K/Akt, Nrf2, trefoil factor 2(TFF2)/Wnt, interleukin-6(IL-6)/Janus kinase 2(JAK2)/STAT3, hypoxia-inducible factor 1α(HIF-1α)/vascular endothelial growth factor receptor(VEGFR), etc.], and then play a therapeutic role by inhibiting BPH cell proliferation, oxidative stress, inflammatory response, promoting apoptosis, and inhibiting epithelial-mesenchymal transition. Clinical studies mainly focus on internal treatment, external treatment, combined internal and external treatment, and integrated Chinese and western medicine treatment as the main methods, aiming to improve traditional Chinese medicine syndrome scores, prostate symptom scores, residual urine volume, effective bladder volume, sexual quality of life, increase average urine flow rate, maximum urine flow rate, and promote balance of sex hormone secretion. Through this research, it is hoped to provide some reference ideas for clinical research and drug development for BPH.

The advancement of soft bioelectronics hinges critically on the electromechanical properties of hydrogels. Despite ongoing research into diverse material and structural strategies to enhance these properties, producing hydrogels that are simultaneously tough, resilient, and highly conductive for long-term, dynamic physiological monitoring remains a formidable challenge. Here, a strategy utilizing scalable layered heterogeneous hydrogel fibers (LHHFs) is introduced that enables synergistic electromechanical modulation of hydrogels. High toughness (1.4 MJ m -3 ) and resilience (over 92% recovery from 200% strain) of LHHFs are achieved through a damage-free toughening mechanism that involves dense long-chain entanglements and reversible strain-induced crystallization of sodium polyacrylate. The unique symmetrical layered structure of LHHFs, featuring distinct electrical and mechanical functional layers, facilitates the mixing of multi-walled carbon nanotubes to significantly enhance electrical conductivity (192.7 S m -1 ) without compromising toughness and resilience. Furthermore, high-performance LHHF capacitive iontronic strain/pressure sensors and epidermal electrodes are developed, capable of accurately and stably capturing biomechanical and bioelectrical signals from the human body under long-term, dynamic conditions. The LHHF offers a promising route for developing hydrogels with uniquely integrated electromechanical attributes, advancing practical wearable healthcare applications., (© 2024 Wiley‐VCH GmbH.)

Background: Aortic dissection (AD) is a life-threatening cardiovascular emergency that is often misdiagnosed as other chest pain conditions. Physiologically, AD may cause abnormalities in peripheral blood flow, which can be detected using pulse oximetry waveforms., Purpose: This study aimed to assess the feasibility of identifying AD based on pulse oximetry waveforms and to highlight the key waveform features that play a crucial role in this diagnostic method., Methods: This prospective study employed high-risk chest pain cohorts from two emergency departments. The initial cohort was enriched with AD patients (n = 258, 47% AD) for model development, while the second cohort consisted of chest pain patients awaiting angiography (n = 71, 25% AD) and was used for external validation. Pulse oximetry waveforms from the four extremities were collected for each patient. After data preprocessing, a recognition model based on the random forest algorithm was trained using patients' gender, age, and waveform difference features extracted from the pulse oximetry waveforms. The performance of the model was evaluated using receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA). The importance of features was also assessed using Shapley Value and Gini importance., Results: The model demonstrated strong performance in identifying AD in both the training and external validation sets. In the training set, the model achieved an area under the ROC curve of 0.979 (95% CI: 0.961-0.990), sensitivity of 0.918 (95% CI: 0.873-0.955), specificity of 0.949 (95% CI: 0.912-0.985), and accuracy of 0.933 (95% CI: 0.904-0.959). In the external validation set, the model attained an area under the ROC curve of 0.855 (95% CI: 0.720-0.965), sensitivity of 0.889 (95% CI: 0.722-1.000), specificity of 0.698 (95% CI: 0.566-0.812), and accuracy of 0.794 (95% CI: 0.672-0.878). Decision curve analysis (DCA) further showed that the model provided a substantial net benefit for identifying AD. The median mean and median variance of the four limbs' signals were the most influential features in the recognition model., Conclusions: This study demonstrated the feasibility and strong performance of identifying AD based on peripheral pulse oximetry waveforms in high-risk chest pain populations in the emergency setting. The findings also provided valuable insights for future human fluid dynamics simulations to elucidate the impact of AD on blood flow in greater detail., (© 2024 American Association of Physicists in Medicine.)

The COVID-19 pandemic has driven substantial evolution of the SARS-CoV-2 virus, yielding subvariants that exhibit enhanced infectiousness in humans. However, this adaptive advantage may not universally extend to zoonotic transmission. In this work, we hypothesize that viral adaptations favoring animal hosts do not necessarily correlate with increased human infectivity. In addition, we consider the potential for gain-of-function mutations that could facilitate the virus's rapid evolution in humans following adaptation in animal hosts. Specifically, we identify the SARS-CoV-2 receptor-binding domain (RBD) mutations that enhance human-animal cross-transmission. To this end, we construct a multitask deep learning model, MT-TopLap trained on multiple deep mutational scanning datasets, to accurately predict the binding free energy changes upon mutation for the RBD to ACE2 of various species, including humans, cats, bats, deer, and hamsters. By analyzing these changes, we identified key RBD mutations such as Q498H in SARS-CoV-2 and R493K in the BA.2 variant that are likely to increase the potential for human-animal cross-transmission., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Developing high-performance porous materials to separate ethane from ethylene is an important but challenging task in the chemical industry, given their similar sizes and physicochemical properties. Herein, a new type of ultra-strong C 2 H 6 nano-trap, CuIn(3-ain) 4 is presented, which utilizes multiple guest-host interactions to efficiently capture C 2 H 6 molecules and separate mixtures of C 2 H 6 and C 2 H 4 . The ultra-strong C 2 H 6 nano-trap exhibits the high C 2 H 6 (2.38 mmol g -1 ) uptake at 6.25 kPa and 298 K and demonstrates a remarkable selectivity of 3.42 for C 2 H 6 /C 2 H 4 (10:90). Additionally, equimolar C 2 H 6 /C 2 H 4 exhibited a superior high separation potential ∆Q (2286 mmol L -1 ) at 298 K. Kinetic adsorption tests demonstrated that CuIn(3-ain) 4 has a high adsorption rate for C 2 H 6 , establishing it as a new benchmark material for the capture of C 2 H 6 and the separation of C 2 H 6 /C 2 H 4 . Notably, this exceptional performance is maintained even at a higher temperature of 333 K, a phenomenon not observed before. Theoretical simulations and single-crystal X-ray diffraction provide critical insights into how selective adsorption properties can be tuned by manipulating pore dimensions and geometry. The excellent separation performance of CuIn(3-ain) 4 has been confirmed through breakthrough experiments for C 2 H 6 /C 2 H 4 gas mixtures., (© 2024 Wiley‐VCH GmbH.)

Translational pharmacological research on traditional medicines lays the foundation for precisely understanding how the medicines function in the body to deliver therapeutic benefits. Borneolum syntheticum (Bingpian) is commonly used in Chinese herbal medicines for coronary heart disease, but its specific cardiovascular impact remains poorly understood. Isoborneol, a constituent of Bingpian, has been found to reduce lipid accumulation in macrophages in vitro, but its oral bioavailability is limited. This investigation aimed to evaluate anti-atherosclerotic effects of Bingpian, based on understanding its first-pass metabolism. Human subjects orally received an herbal medicine containing Bingpian and their plasma samples were analyzed to identify the major circulating compounds of Bingpian, with the metabolism that was also characterized in vitro and in mice. The identified compounds were evaluated for their ability to inhibit macrophage foam-cell formation induced by oxidized low-density lipoprotein. Furthermore, the anti-atherosclerotic effect of repeatedly dosed Bingpian was assessed in ApoE -/- mice fed a high-fat diet. In human subjects, the major circulating compounds of Bingpian were metabolites, rather than their precursor constituents borneol and isoborneol. These constituents were efficiently absorbed in the intestinal tract but underwent significant first-pass metabolism, involving UGT2B7-mediated glucuronidation into borneol-2-O-glucuronide and isoborneol-2-O-glucuronide, respectively, and CYP2A6/2B6/3A-mediated oxidation both into camphor. Despite their poor membrane permeability, hepatic efflux of borneol-2-O-glucuronide and isoborneol-2-O-glucuronide into the systemic circulation was enhanced by MRP3/4. The circulating metabolites, particularly their combinations, markedly inhibited macrophage foam-cell formation induced by oxidized low-density lipoprotein in vitro. Sub-chronic administration of Bingpian (30 mg·kg -1 ·d - 1 , i.g.) for 12 weeks significantly decreased atherosclerotic lesion size and enhanced plaque stability in ApoE -/- mice. Systemic exposure to Bingpian metabolites in mice closely resembles that in humans, suggesting that the pharmacodynamic effects of Bingpian in mice are likely applicable to humans. Overall, the cardiovascular benefits of Bingpian involve reducing atherosclerosis by inhibiting foam-cell formation through its metabolites. This investigation supports that oral Bingpian could be a druggable agent for reducing atherosclerosis., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Objectives: To observe the effect of manual acupuncture stimulation on changes of behavior and hippocampal signaling pathways of AMP-activated kinase (AMPK)/UNC-51-like kinase 1 (ULK1) in rats with chronic unpredictable mild stress (CUMS)-induced depression, so as to explore its molecular mechanism underlying improvement of depression., Methods: Thirty-two male SD rats were randomly divided into normal control, model, acupuncture and medication (fluoxetine) groups, with 8 rats in each group. The depression model was established by using CUMS (fasting, water depredation, restraint, swimming in cold water, crowding, stroboscope stimulation, and tail clipping, each of which was used once a week) for 6 weeks. Manual acupuncture stimulation was applied to "Baihui"(GV20) and "Yintang"(EX-HN3) for 10 min, once daily, 6 times a week for 6 weeks before every-day modeling. Rats of the medication group received gavage of fluoxetine (10 mg/kg) once a day for 6 weeks before every-day modeling. The percentage of sucrose preference, and the percentages of open arm times and open arm time in the elevated plus maze experiments were detected. The expression levels of AMPK, phosphorylated (p)-AMPK, ULK1, p-ULK1, mammalian target of rapamycin (mTOR) and p-mTOR proteins in the hippocampus tissue were detected by Western blot, and the expression of autophagy effecting protein (Beclin-1) and the selective autophagy receptors (p62) mRNA in the hippocampal tissue was detected using real-time fluorescence quantitative PCR, respectively., Results: Compared with the normal group, the percentage of sucrose preference, percentage of times of entering the open arm and percentage of open arm time, the expression levels of p-AMPK /AMPK ratio, p-ULK1 /ULK1 ratio of proteins, and Beclin-1 mRNA were significantly decreased ( P <0.01, P <0.05), and the expression levels of p-mTOR /mTOR ratio and p62 mRNA were significantly increased ( P <0.01, P <0.05) in the model group. In comparison with the model group, the percentage of sucrose preference, percentage of open arm times and open arm time, the expression levels of p-AMPK /AMPK ratio, p-ULK1/ULK1 ratio of proteins, and Beclin-1 mRNA were significantly increased in both acupuncture and medication groups ( P <0.01, P <0.05), while the expression levels of p-mTOR /mTOR ratio of proteins, and p62 mRNA were markedly decreased only in the medication group ( P <0.05)., Conclusions: Acupuncture treatment can alleviate depression-like behavior in CUMS rats, which may be related to its functions in up-regulating AMPK/ULK1 signaling pathway to induce cellular autophagy in the hippocampus.

Sleeping animals can be woken up rapidly by external threat signals, which is an essential defense mechanism for survival. However, neuronal circuits underlying the fast transmission of sensory signals for this process remain unclear. Here, we report in mice that alerting sound can induce rapid awakening within hundreds of milliseconds and that glutamatergic neurons in the pontine central gray (PCG) play an important role in this process. These neurons exhibit higher sensitivity to auditory stimuli in sleep than wakefulness. Suppressing these neurons results in reduced sound-induced awakening and increased sleep in intrinsic sleep/wake cycles, whereas their activation induces ultra-fast awakening from sleep and accelerates awakening from anesthesia. Additionally, the sound-induced awakening can be attributed to the propagation of auditory signals from the PCG to multiple arousal-related regions, including the mediodorsal thalamus, lateral hypothalamus, and ventral tegmental area. Thus, the PCG serves as an essential distribution center to orchestrate a global auditory network to promote rapid awakening., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)