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It is widely accepted that the next lepton collider beyond a Higgs factory would require center-of-mass energy of the order of up to 15 TeV. Since, given reasonable space and cost restrictions, conventional accelerator technology reaches its limits near this energy, high-gradient advanced acceleration concepts are attractive. Advanced and novel accelerators (ANAs) are leading candidates due to their ability to produce acceleration gradients on the order of 1-100 GV/m, leading to compact acceleration facilities. However, intermediate energy facilities (IEF) are required to test the critical technology elements on the way towards multi-TeV-class collliders. Here a science case for a 20-100 GeV center-of-mass energy ANA-based lepton collider that can be a candidate for an intermediate energy facility is presented. The IEF can provide numerous opportunities for high energy physics studies including precision Quantum Chromodynamics and Beyond the Standard Model physics measurements, investigation of charged particle interactions with extreme electromagnetic fields, and exploring muon and proton beam acceleration. Possible applications of this collider include the studies of γγ and electron beam-fixed target/beamdump collider designs. Thus, the goal of the proposed IEF is to both carry out particle physics measurements in the 20-100 GeV ranges as well as to serve as an ANA demonstrator facility.

Hongmei Xu,1 Ningning Wu,2 Hui Yu,3 Chuanqing Wang,4 Jikui Deng,5 Hongmei Wang,5 Chunzhen Hua,6 Yinghu Chen,6 Xuejun Chen,7 Ting Zhang,8 Hong Zhang,9 Yiping Chen,10 Shifu Wang,11 Qing Cao,12 Huiling Deng,13 Sancheng Cao,14 Jianhua Hao,15 Wei Gao,16 Chunmei Jing2 1Infectious Disease Department, Children’s Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, People’s Republic of China; 2Department of Clinical Laboratory, Children’s Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, People’s Republic of China; 3Infectious Disease Department, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, People’s Republic of China; 4Department of Clinical Microbiology Laboratory, Nosocomial Infection Control Department, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, People’s Republic of China; 5Infectious Disease Department, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 6Infectious Disease Department, Children’s Hospital of Zhejiang University, Zhejiang, People’s Republic of China; 7Department of Medical Laboratory, Children’s Hospital of Zhejiang University, Zhenjiang, People’s Republic of China; 8Digestive and Infectious Disease Department, Children’s Hospital of Shanghai Jiaotong University, Shanghai, People’s Republic of China; 9Department of Medical Laboratory, Children’s Hospital of Shanghai Jiaotong University, Shanghai, People’s Republic of China; 10Pediatric Infectious Disease Department, Second Affiliated Hospital, and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 11Department of Medical Laboratory, Qilu Children’s Hospital, Shandong University, Shandong, People’s Republic of China; 12Infectious Disease Department, Shanghai Children’s Medical Center, Shanghai, People’s Republic of China; 13Infectious Disease Department, Xi’an Children’s Hospital, Xi’an, People’s Republic of China; 14Department of Medical Laboratory, Xi’an Children’s Hospital, Xi’an, People’s Republic of China; 15Infectious Disease Department, Children’s Hospital of Kaifeng City, Kaifeng, People’s Republic of China; 16Department of Medical Laboratory, Children’s Hospital of Kaifeng City, Kaifeng, People’s Republic of ChinaCorrespondence: Chunmei Jing, Department of Clinical Laboratory, Children’s Hospital of Chongqing Medical University, Chongqing Medical University, No. 136 Zhongshan Er Road, Yu Zhong District, Chongqing, 400014, People’s Republic of China, Email jcm791203@163.comObjective: Aim to investigate the pathogens distribution and drug resistance of gram-negative bacteria causing bloodstream infection (BSIs) in Infectious Disease Surveillance of Pediatric from 2016 to 2022. The prevalence of four important drug resistance phenotypes was studied: difficult-to-treat resistance, fluoroquinolone resistance, carbapenem resistance, and extended-spectrum cephalosporin resistance, and to provide reference basis for preventing and treating BSIs diseases in children.Methods: Strain identification and antimicrobial susceptibility tests were independently performed at each hospital. Data were analyzed using Whonet 5.6 and GraphPad Prism 8 software. The Mann–Whitney U-test was used to examine and compare temporal changes.Results: A total of 39977 BSIs strains were isolated, with 27.1% of the negative bacteria causing BSIs (10824 strains). The highest bacteria detected were E. coli and S. maltophilia in the neonatal and pediatric groups. The detection rate of carbapenem-resistant-K. pneumoniae (CRKPN) in neonate group was 31.4%, significantly increased compared with pediatric group, whose detection rate was 24.7%. The rates of resistance to levofloxacin and trimethoprim/sulfamethoxazole were significantly lower in neonatal groups than pediatric groups in BSIs caused by K. pneumoniae. To imipenem and meropenem were 3.6% and 3.9% among neonatal isolates, which was lower than 4.7% and 5.8 among pediatric BSIs caused by E. coli. Isolated from neonatal BSIs caused by A. baumannii showed lower resistance ratios to all the agents tested than those from pediatric. However, only the prevalence of piperacillin/tazobactam resistance was statistically lower than that in pediatric BSIs caused by P. aeruginosa. The average detection rates of carbapenem resistance, extended-spectrum cephalosporin resistance, and fluoroquinolone resistance for K. pneumoniae and E. coli were 28.1%,41.4%,11.6% and 4.0%,24.3%,31.1%, respectively.Conclusion: The detection rate of gram-negative pathogens showed an increasing trend among the bloodstream infection. The detection rate of CRKPN assumed a downward trend in 2018. There are differences types of pathogens between the neonatal group and the pediatric group, The detection rate of CRKPN in the neonate group was significantly higher than pediatric group. The first average detection rates for carbapenem resistance, extended-spectrum cephalosporin resistance, and fluoroquinolone resistance were obtained for A. baumannii, K. pneumoniae, and Escherichia coli, respectively. Those data showed a high level of antimicrobial resistance, which has posed an urgent threat to Children’s health, suggested that effective monitoring of antimicrobial resistance and antimicrobial stewardship among children in China are required.Keywords: bloodstream infection, pathogenic bacterium, difficult-to-treat resistance, carbapenem resistance, extended-spectrum cephalosporin resistance, fluoroquinolone resistance

Our earth is immersed in the near-earth space plasma environment, which plays a vital role in protecting our planet against the solar-wind impact and influencing space activities. It is significant to investigate the physical processes dominating the environment, for deepening our scientific understanding of it and improving the ability to forecast the space weather. As a crucial part of the National Major Scientific and Technological Infrastructure–Space Environment Simulation Research Infrastructure (SESRI) in Harbin, the Space Plasma Environment Research Facility (SPERF) builds a system to replicate the near-earth space plasma environment in the laboratory. The system aims to simulate the three-dimensional (3-D) structure and processes of the terrestrial magnetosphere for the first time in the world, providing a unique platform to reveal the physics of the 3-D asymmetric magnetic reconnection relevant to the earth's magnetopause, wave–particle interaction in the earth's radiation belt, particles' dynamics during the geomagnetic storm, etc. The paper will present the engineering design and construction of the near-earth space plasma simulation system of the SPERF, with a focus on the critical technologies that have been resolved to achieve the scientific goals. Meanwhile, the possible physical issues that can be studied based on the apparatus are sketched briefly. The earth-based system is of great value in understanding the space plasma environment and supporting space exploration. [ABSTRACT FROM AUTHOR]

Tris(2-chloroethyl) phosphate (TCEP), emerging as a predominant substitute for brominated flame retardants (BFRs), is now increasingly recognized as a prevalent contaminant in aquatic ecosystems. The extent of its reproductive toxicity in aquatic species, particularly in zebrafish (Danio rerio), remains insufficiently characterized. This study subjected zebrafish embryos to various concentrations of TCEP (0, 0.8, 4, 20, and 100 μg/L) over a period of 120 days, extending through sexual maturation, to assess its impact on female reproductive health. Notable reductions in body weight (0.59- and 0.76-fold) and length (0.71- and 0.77-fold) were observed at concentrations of 20 and 100 μg/L, with a concomitant decrease by 0.21- to 0.61-fold in the gonadal somatic index across all treatment groups. The reproductive output, as evidenced by egg production and hatchability, was adversely affected. Histopathological analysis suggested that TCEP exposure impedes ovarian development. Endocrine alterations were also evident, with testosterone and 11-ketotestosterone levels significantly diminished by 0.38- and 0.08-fold at the highest concentration tested, while 17β-estradiol was elevated by 0.09- to 0.14-fold in all exposed groups. Transcriptomic profiling illuminated numerous differentially expressed genes (DEGs) integral to reproductive processes, including hormone regulation, neuroactive ligand-receptor interactions, oocyte meiosis, and progesterone-mediated maturation pathways. Collectively, these findings indicate that lifelong exposure to TCEP disrupts ovarian development and maturation in female zebrafish, alters gene expression within the hypothalamic-pituitary-gonadal axis, and perturbs sex hormone synthesis, culminating in pronounced reproductive toxicity., 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.)

Key Message: A stable QTL, GW3, controlling grain width was identified in two populations. Its causal gene LOC_Os03g04680 was verified by gene-based haplotype analysis, expression analysis, gene knockout and complementation transgenic tests. Grain width (GW) is one of the key traits affecting grain size and determines grain yield and appearance quality in rice. Mining gene loci and elite alleles controlling GW is necessary. The GW phenotypes of the two populations were investigated in three environments, which showed abundant phenotypic variation. GW3, encoding a P450 subfamily protein, was identified and validated as a causal gene by gene-based haplotype analysis, expression analysis, gene knockout and complementation transgenic tests. The accessions with large GW values had high gene expression levels. In addition, the GW of the accessions with the GG allele was significantly greater than that of the accessions with the AA allele. The Hap 1 and Hap 3 were identified as elite haplotypes, which can increase GW. The expression levels of OsKO1, OsGA3ox1, OsGA20ox1 and OsGA20ox2 in the young panicle of A7444 were significantly greater than those in the young panicle of the mutants, indicating that GW3 may be involved in the gibberellins (GA) biosynthesis pathway to regulate GW. GA 4 content detection and electron scanning analysis revealed that GA 4 regulates GW by affecting glume cell size. These results provide new insights for studying the genetic mechanism of rice GW and provide a material basis for breeding high-yield rice varieties., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The study was outlined to develop and approve a nomogram and chance stratification demonstrate for foreseeing overall survival of Chinese patients with at first metastatic small-cell lung cancer (SCLC). We collected information from the Surveillance, Epidemiology, and End Results (SEER) database approximately Chinese SCLC patients with at first distant metastases between 2010 and 2015. Patients with incomplete data about the follow-up time or clinicopathological information were excluded. The included patients were randomized into the training and validation set. Univariate and multivariate Cox proportional hazard regression models were performed. By integrating the significant variables screened, a prescient nomogram and risk stratification model were developed. In addition, we collected 198 small-cell lung cancer patients with metastasis at diagnosis from the case database of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine as an external validation cohort. In all, 421 patients were screened from the SEER database. Multivariate examination showed that age (P = .049), sex (P = .001), grade (P = .008), chemotherapy (P = .001), liver metastasis (P = .001), and pleural invasion (P = .012) were independent prognostic factors. The C-indicator of the nomogram to anticipate overall survival was higher than that of the eighth edition of the American Joint Committee on Cancer Tumor Node Metastasis classification system (0.75 vs 0.543; P < .001). A risk stratification model was encouraged to be created to precisely classify patients into 2 prognostic bunches. The survival rates anticipated by the nomogram appeared to have critical qualifications from the Kaplan-Meier curves in the entire SEER cohort. Calibration curves and survival predictions also showed strong accuracy and consistency in the external validation cohort. The nomogram provided a clear prognostic superiority over the traditional Tumor Node Metastasis system. It could help clinicians make individual risk predictions for initially metastatic Chinese SCLC cancer patients and give necessary treatment recommendations., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

We present a Cu/PTFE electrode for the CO 2 reduction reaction with a high coverage of *OH which facilitates both the activation of CO 2 and the C-C coupling, leading to a faradaic efficiency for ethylene exceeding 50% at an exceptionally low potential of -246 mV vs. RHE, with the maximum FE C 2 H 4 reaching 60.3%.

Diffusive gradients in thin films (DGT) technique is renowned for in situ passive sampling but not for rapid on-site analysis, whereas surface-enhanced Raman spectroscopy (SERS) excels in ultrasensitive on-site detection but is limited by substrate contamination from complex matrices. Here, a hierarchical nanostructure of silver (Ag) mirror-supported large Ag nanoparticles (∼120 nm) was grown in situ in polyacrylamide hydrogel with a restricted pore size (PAM/Ag mirror/AgNPs) to serve as both the DGT binding phase and the SERS substrate. The substrate exhibited a maximum electric field enhancement factor of 9.9 × 10 8 and a signal relative standard error of 4.8%. Using the DGT-SERS sensor, As(III) and As(V) in freshwater were simultaneously detected at limits of 0.9 and 0.8 μg L -1 , respectively, applicable across a wide range of environmental conditions. The DGT-SERS effectively mitigated the interfacial reduction of As(V) caused by humic acid by excluding it from plasmonic hotspots through size exclusion of the diffusive layer. The Raman analysis of a DGT sample in the field requires only 2 s using a portable spectrometer without DGT device disassembly. More importantly, the DGT-SERS captured the first two-dimensional image of As(III) and As(V) in one DGT at the micron scale resolution, revealing their spatially supplementary distribution patterns at the sediment-water interface. This study paves the way for next-generation speciation imaging DGT and the application of SERS in complex environments.

Organic matter (OM) plays an important role in the biogeochemical cycles of carbon, nitrogen, and other elements, shaping the structure of the microbiome and vice versa. However, the molecular composition of OM and its impact on the microbial community in terrestrial geothermal environments remain unclear. In this study, we characterized the OM in water and sediment from a typical geothermal field using ultra-high-resolution Fourier transform ion cyclotron resonance mass spectrometry. By combining high-throughput amplicon sequencing and multivariate analyses, we deciphered the association between OM components and microbial community. A surprisingly high chemodiversity of OM was observed in the waters (11,088 compounds) and sediments (7772 compounds) in geothermal springs. Sulfur-containing organic compounds, a characteristic molecular signature of geothermal springs, accounted for 21 % ± 5 % in waters and 33 % ± 4 % in sediments. Multivariate analyses revealed that both labile and recalcitrant fractions of OM (e.g., carbohydrates intensity and tannins chemodiversity) influenced the structure and function of the microbial community. Co-occurrence networks showed that Proteobacteria and Crenarchaeota accounted for most of the connections with OM in waters (33 % and 15 %, respectively) and sediments (15 % and 12 %, respectively), highlighting their key roles in carbon cycling. This study expands our understanding of the molecular compositions of OM in geothermal springs and highlights its potentially important role in global climate change through microbial carbon cycling., 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: While p53 mutations occur early in Barrett's oesophagus (BE) progression to oesophageal adenocarcinoma (EAC), their role in gastric cardia stem cells remains unclear., Objective: This study investigates the impact of p53 mutation on the fate and function of cardia progenitor cells in BE to EAC progression, particularly under the duress of chronic injury., Design: We used a BE mouse model (L2-IL1β) harbouring a Trp53 mutation (R172H) to study the effects of p53 on Cck2r + cardia progenitor cells. We employed lineage tracing, pathological analysis, organoid cultures, single-cell RNA sequencing (scRNA-seq) and computational analyses to investigate changes in progenitor cell behaviour, differentiation patterns and tumour progression. Additionally, we performed orthotopic transplantation of sorted metaplastic and mutant progenitor cells to assess their tumourigenic potential in vivo., Results: The p53 mutation acts as a switch to expand progenitor cells and inhibit their differentiation towards metaplasia, but only amidst chronic injury. In L2-IL1β mice, p53 mutation increased progenitors expansion and lineage-tracing with a shift from metaplasia to dysplasia. scRNA-seq revealed dysplastic cells arise directly from mutant progenitors rather than progressing through metaplasia. In vitro, p53 mutation enhanced BE progenitors' organoid-forming efficiency, growth, DNA damage resistance and progression to aneuploidy. Sorted metaplastic cells grew poorly with no progression to dysplasia, while mutant progenitors gave rise to dysplasia in orthotopic transplantation. Computational analyses indicated that p53 mutation inhibited stem cell differentiation through Notch activation., Conclusions: p53 mutation contributes to BE progression by increasing expansion and fitness of undifferentiated cardia progenitors and preventing their differentiation towards metaplasia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The role of complement in cancer remains controversial. Whether immune cells and inflammatory factors mediate the pathway from complement to cancer has not been fully elucidated., Methods: We conducted bidirectional Mendelian randomization (MR) analysis to explore the causal association between complement components and cancer. Meta-analysis was conducted to enhance the robustness of the results. We further explored the mediation roles of immune cells and inflammatory factors in these associations., Results: Our study identified causal associations between 11 complement components and 12 types of cancer. Furthermore, we identified five immune cells as potential mediators: BAFF-R on IgD + CD38- naive B cell mediated 7.434% of the increased risk for liver cancer from C3; CD4 on CD39 + activated CD4 regulatory T cell mediated 12.384% of the increased risk for biliary tract cancer from CD93; CD25 +  + CD45RA + CD4 not regulatory T cell and Basophil %CD33dim HLA DR- CD66b- mediated 7.721% and 7.986% of the increased risk of colorectal cancer from MASP1, respectively; CD45RA on resting CD4 regulatory T cell mediated 11.444% of the increased risk of skin cancer from MASP1., Conclusion: This study revealed the causal relationships between complement components and certain cancers, with five immune cells as potential mediators., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Purpose: Thromboxane A 2 (TXA 2 ) is a prostanoid produced during platelet activaton, important in enhancing platelet reactivity by activation of TP receptors. However, due to the short half-life, studying TXA 2 signalling is challenging. To enhance our understanding of TP receptor-mediated platelet biology, we therefore synthesised mono and difluorinated TXA 2 analogues and explored their pharmacology on heterologous and endogenously expressed TP receptor function., Experimental Approach: Platelet functional and signalling responses were studied using aggregometry, Ca 2+ mobilisation experiments and immunoblotting and compared with an analogue of the TXA 2 precursor prostaglandin H 2 , U46619. Gα q /Gα s receptor signalling was determined using a bioluminescence resonance energy transfer (BRET) assay in a cell line overexpression system., Key Results: BRET studies revealed that F-TXA 2 and F 2 -TXA 2 promoted receptor-stimulated TP receptor G-protein activation similarly to U46619. Unexpectedly, F 2 -TXA 2 caused reversible aggregation in platelets, whereas F-TXA 2 and U46619 induced sustained aggregation. Blocking the IP receptor switched F 2 -TXA 2 -mediated reversible aggregation into sustained aggregation. Further BRET studies confirmed F 2 -TXA 2 -mediated IP receptor activation. F 2 -TXA 2 rapidly and potently stimulated platelet TP receptor-mediated protein kinase C/P-pleckstrin, whereas IP-mediated protein kinase A/P-vasodilator-stimulated phosphoprotein was more delayed., Conclusion and Implications: F-TXA 2 is a close analogue to TXA 2 used as a selective tool for TP receptor platelet activation. In contrast, F 2 -TXA 2 acts on both TP and IP receptors differently over time, resulting in an initial wave of TP receptor-mediated platelet aggregation followed by IP receptor-induced reversibility of aggregation. This study reveals the potential difference in the temporal aspects of stimulatory and inhibitory pathways involved in platelet activation., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Arbuscular mycorrhizal fungi (AMF) and Chitooligosaccharide (COS) can increase the resistance of plants to disease. COS can also promote the symbiosis between AMF and plants. However, the effects of AMF & COS combined application on the rhizosphere soil microbial community of tobacco and the improvement of tobacco's resistance to black shank disease are poorly understood.·We treated tobacco with AMF, COS, and combined application of AMF & COS (AC), respectively. Then studied the incidence, physio-biochemical changes, root exudates, and soil microbial diversity of tobacco seedling that was inoculated with Phytophthora nicotianae. The antioxidant enzyme activity and root vigor of tobacco showed a regular of AC > AMF > COS > CK, while the severity of tobacco disease showed the opposite regular. AMF and COS enhance the resistance to black shank disease by enhancing root vigor, and antioxidant capacity, and inducing changes in the rhizosphere microecology of tobacco. We have identified key root exudates and critical soil microorganisms that can inhibit the growth of P. nicotianae. The presence of caprylic acid in root exudates and Bacillus (WdhR-2) in rhizosphere soil microorganisms is the key factor that inhibits P. nicotianae growth. AC can significantly increase the content of caprylic acid in tobacco root exudates compared to AMF and COS. Both AMF and COS can significantly increase the abundance of Bacillus in tobacco rhizosphere soil, but the abundance of Bacillus in AC is significantly higher than that in AMF and COS. This indicates that the combined application of AMF and COS is more effective than their individual use. These findings suggest that exogenous stimuli can induce changes in plant root exudates, regulate plant rhizosphere microbial community, and then inhibit the growth of pathogens, thereby improving plant resistance to diseases., 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 Masson SAS. All rights reserved.)

Antimony (Sb) pollution has raised increasing public concerns and its rapid on-site screening is central for the risk assessment. Herein, we proposed two gel-based methods based on colorimetric diffusive equilibrium in thin films (DET) and surface-enhanced Raman scattering (SERS), for two-dimensional imaging and sensitive detection of Sb(III) by revisiting the phenylfluorone (PhF) complexation reaction. PhF was well dispersed in the polyvinyl alcohol (PVA) hydrogel and reacted with Sb(III) in the DET gel to form a strong PhF-Sb(III) complex. The distribution of Sb(III) was easily visualized at a submillimeter resolution using computer imaging densitometry, with a detection limit (LOD) of ∼100 nmol L -1 . Field application in the Sb mine area reveals limited dissolved Sb(III) penetrating the redox barrier below the sediment-water interface by 20 mm in rivers and tailing pond sediments. To improve the detection sensitivity and apply the principle to trace Sb quantification, a SERS platform was established by anchoring PhF on the hydrogel-stabilized Ag nanoparticles via C-O-Ag bonding to specifically detect Raman-inactive Sb(III). Benefiting from the high SERS activity of PhF and enrichment ability of hydrogel, Sb(III) was quantified with a LOD of 1.2-10.7 nmol L -1 depending on the sample volume. The coexisting ions at a 100-fold higher concentration than Sb(III) resulted in only 3.3-10.4 % variation in SERS intensity, indicating a negligible interference on the SERS platform. The platform exhibited a RSD of 6.6-13.1 % and acceptable recoveries for various environmental matrices, highlighting its promise in on-site application., 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.)

Cardiovascular diseases are major diseases, and there is lack of artificial blood vessels with small diameters which can be applied in coronary artery bypass surgery. The conventional vascular scaffold preparation techniques in tissue engineering have shortcomings in regulating the diameter, geometric shape, and interconnectivity of the scaffold. 3D bioprinting can simulate the natural structure of the vascular tissue, accurately print live cells and biomaterials, and regulate the microstructure and porosity of scaffolds on the nanoscale, providing new ideas for vascular tissue engineering. This article systematically evaluates the classification of 3D bioprinting technologies and reviews the latest research progress of 3D bioprinting in vascular tissue engineering. It summarizes the advantages of 3D bioprinting and points out the problems that need to be solved, such as the immune rejection of blood vessel materials, providing reference for the further research.

We designed and synthesized 27 new amide and dipeptide derivatives containing a substituted phenylalanine as negative allosteric modulators (NAMs) for the beta-2 adrenergic receptor (β2AR). These analogs aimed to improve the activity of our lead compound, Cmpd-15, by introducing variations in three key regions: the meta-bromobenzyl methylbenzamide (S1), para-formamidophenylalanine (S2), and 1-cyclohexyl-1-phenylacetyl (S3) groups. The synthesis involved the Pd-catalyzed β-C(sp3)-H arylation of N-acetylglycine with 1-iodo-4-substituent-benzenes as the key step. GloSensor cAMP accumulation assay revealed that six analogs (A1, C5, C6, C13, C15 and C17) surpass Cmpd-15 in β2AR allosteric function. This highlights the crucial role of the S1 region (meta-bromobenzyl methylbenzamide) in β2AR allostery while suggesting potential replaceability of the S2 region (para-formamidophenylalanine). These findings serve as a valuable springboard for further optimizing Cmpd-15, potentially leading to smaller, more active, and more stable β2AR-targeting NAMs., (© 2024 Wiley‐VCH GmbH.)

Metal micro-droplet ejection technology has attracted attention for its potential applications in the rapid prototyping of micro-metal parts and microelectronic packaging. The current micro-droplet ejection device developed based on this technology faces challenges such as the requirement of a micro-oxygen ejection environment, a complex feeding structure, and high costs. Therefore, a drop-on-demand droplet generator for metallic pellets with impact feed ejection is designed in this paper. This device has a simple and compact structure, does not require a high-cost heat source, and can perform drop-on-demand ejection of metallic pellets in an atmospheric environment. A micro-channel feeding method based on piezoelectric ceramic actuator drives is proposed. A rigid dynamics metallic pellet flight trajectory model is established to analyze the relationships between the driving voltage and the flight trajectory of the pellets. With the help of Fluent to simulate and analyze the melting and ejection processes of the pellets inside the nozzle, the changes in the variable parameters of the flow field in the process of the melting and flight of a single molten drop are studied. The droplet generator produces stable droplets with a 500 µs pulse width and 1100 mm/s initial velocity of the projectile. The simulation results show that a single projectile has to go through three stages including feeding, melting, and ejecting, which take 39.5 ms, 7.85 ms, and 17.65 ms. The total simulation time is 65.0 ms. It is expected that the injection frequency of the metal projectile droplet-generating device will reach 15 Hz.

The automated and autonomous cryogenic transmission electron microscopy (Cryo-EM) demands a sample holder capable of maintaining temperatures below 10 K with precise control, long holding times, and minimal helium use. Rising to this challenge, we initiated an ambitious project to develop a novel closed-cycle cryocooler-based cryogenic sample holder that operates without the use of liquid helium and the consumption of gaseous helium. This article presents the design, construction, and experimental testing of the initial prototype, which achieves an ultimate temperature of 5.6 K with exceptional stability close to 1mK, while providing a wide temperature control range from 295 K to 5.6 K, marking a clear advancement in cryo-EM holder development. While the prototype was not designed for atomic resolution imaging and thus lacks a sturdy support system to mitigate mechanical vibrations from the cryocooler's pulsed tube, this innovative approach successfully demonstrates proof of concept. It offers unprecedented capabilities for state-of-the-art cryogenic microscopy and microanalysis in materials and biological sciences., 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: We aimed to examine how electroacupuncture and manual acupuncture affect treatment results, pain levels, and joint function in individuals with knee osteoarthritis., Methods: Research was carried out in various databases including PubMed, Medline, Embase, CENTRAL, and CNKI. Following the "Cochrane manual", the risk of bias of included RCTs was assessed. A funnel plot was utilized to evaluate any potential bias in the publications. The impact size was indicated by the average discrepancy along with its 95% confidence interval., Results: The EA group showed a higher effectiveness rate ( P = 0.001) and a lower WOMAC pain score ( P < 0.00001) compared to the control group. The EA group had a lower WOMAC pain score compared to the SA/exercise group and the group that received manual acupuncture. The WOMAC pain score was significantly lower in the EA group compared to the manual acupuncture group under intense electroacupuncture stimulation ( P < 0.0001). The WOMAC pain score was significantly lower in the EA group compared to the manual acupuncture group when weak current acupuncture was applied ( P = 0.0001). However, no significant difference in WOMAC function score between EA and control group., Conclusion: Comparison to manual acupuncture, placebo acupuncture, and exercise training, electroacupuncture enhanced the effectiveness of treating KOA and decreased the WOMAC pain score in patients with KOA. The level of pain relief achieved may be linked to the strength of the current stimulation. However, electroacupuncture had no significant effect on WOMAC function score., (Copyright© 2024 Luo et al. Published by Tehran University of Medical Sciences.)

The study of nicotine addiction mechanism is of great significance in both nicotine withdrawal and brain science. The detection of addiction-related brain connectivity using functional magnetic resonance imaging (fMRI) is a critical step in study of this mechanism. However, it is challenging to accurately estimate addiction-related brain connectivity due to the low-signal-to-noise ratio of fMRI and the issue of small sample size. In this work, a prior-embedding graph generative adversarial network (PG-GAN) is proposed to capture addiction-related brain connectivity accurately. By designing a dual-generator-based scheme, the addiction-related connectivity generator is employed to learn the feature map of addiction connection, while the reconstruction generator is used for sample reconstruction. Moreover, a bidirectional mapping mechanism is designed to maintain the consistency of sample distribution in the latent space so that addiction-related brain connectivity can be estimated more accurately. The proposed model utilizes prior knowledge embeddings to reduce the search space so that the model can better understand the latent distribution for the issue of small sample size. Experimental results demonstrate the effectiveness of the proposed PG-GAN.

Objectives: This study aims to analyze the efficacy of transcatheter arterial chemoembolization (TACE) combined with radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation (CA) in hepatocellular carcinoma (HCC)., Methods: A retrospective analysis was conducted on 632 patients with HCC at Barcelona Clinic Liver Cancer Staging (BCLC) System stages 0, A, and B from Beijing You'an Hospital affiliated with Capital Medical University. The primary outcomes analyzed were overall survival (OS) and progression-free survival (PFS), while the secondary outcomes included one-, three-, and five-year OS rates among different groups., Results: The median follow-up period for 632 cases identified with HCC was 52.1 months (range: 3-162 months), while 127 patients died during follow-up. The one-, three-, and five-year OS rates were 97.1 %, 89.5 %, and 80.4 %, respectively. Moreover, the one-, three-, and five-year PFS rates were 58.1 %, 29.3 %, and 19.8 %, respectively. Multivariate analysis revealed that the BCLC stages and complete ablation were independent predictors of OS and PFS (all p < 0.05). Subgroup analysis showed no difference in OS rate among TACE-RFA, TACE-MWA, and TACE-CA groups, but TACE-CA showed better efficacy in improving the PFS rate (all p < 0.05)., Conclusions: The combination of TACE and ablation is effective in early-stage HCC and BCLC stage B. Complete ablation and BCLC stages are significant prognostic factors for PFS and OS. Further research, including randomized controlled trials, is needed to validate these findings., 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 Authors. Published by Elsevier B.V. All rights reserved.)

Ionic polymer metal composite (IPMC) is regarded as the mainstream application material for achieving flexible driving technology in various engineering fields. In this article, aiming at the non-independence of the current IPMC electric driving method, an IPMC optical-controlled flexible driving method based on the photoinduced effects of lanthanum-modified lead zirconate titanate (PLZT) ceramic is proposed. To this end, a mathematical model for IPMC optical controlled flexible driving is built on the basis of the photovoltaic characteristic of PLZT ceramic, and the driving performance is experimentally analyzed through different lengths of IPMC under the excitation of different direct currents and light intensities. From the analysis and experimental results, when PLZT ceramic is irradiated by different light intensities, the output deformation of IPMC increases with increases in light intensity, and finally reaches a stable state. Moreover, the actuation curves obtained by light excitation and direct current excitation are consistent, and the motion coefficient reflects the driving performance more accurately. In addition, using light energy as an excitation source to drive IPMC not only provides new ideas for its development in the flexible driving field, but also provides a theoretical basis for its practical application.

Aim: To explore the association between Processed red meat (PRM) consumption and cardiovascular risk factors in Chinese adults with type 2 diabetes mellitus (T2DM)., Methods: Dietary survey, physical measurement, and blood biochemical examination were conducted on 316 patients with type 2 diabetes in Bengbu, China from May to July 2019. Possible confounding factors were identified by comparing between-group variability in the baseline table. To eliminate the effect of confounding factors, subgroup analysis was used to explore whether there were differences in the correlation between PRM intake status and the indicators in cardiovascular disease risk factors. A logistic regression model was used to analyze the association between PRM and the risk of abnormal levels of cardiovascular risk factors in T2DM patients. Restricted cubic spline plots were used to analyze the dose-response relationship between PRM intake and the indicators of cardiovascular disease risk factors., Results: A total of 316 subjects were included in the study, of whom 139 (44.0%) were male and 177 (56.0%) were female. In the multiplicative interaction, there was an effect modifier for smoking (Pinteraction = 0.033) on the association between PRM intake and the risk of substandard FPG level control; sex (Pinteraction = 0.035), smoking status (Pinteraction = 0.017), and alcohol consumption (Pinteraction = 0.046) had effect modifying effects on the association between PRM intake and risk of abnormal systolic blood pressure. Sex (Pinteraction = 0.045) had an effect modifier on the association of PRM intake status with the risk of diastolic blood pressure abnormality. In addition, age had an effect modifier on the association of PRM intake status with risk of abnormal triglyceride index (Pinteraction = 0.004) and risk of abnormal HDL index (Pinteraction = 0.018). After adjusting for potential confounding variables, logistic regression showed that the OR for substandard HbA1c control in patients in the highest PRM intake group, T3 (3.4 ~ 57.2 g/d), was 1.620-fold higher than in the lowest intake, i.e., the no-intake group, T1 (0.0 ~ 0.0 g/d; OR = 2.620; 95% CI 1.198 ~ 5.732; p  = 0.016). Whereas the OR for abnormal control of systolic blood pressure levels was 1.025 times higher (OR = 2.025; 95% CI 1.033 ~ 3.968; p  = 0.040) in patients in the PRM low intake group T2 (0.1 ~ 3.3 g/d) than in the non-intake group T1 (0.0 ~ 0.0 g/d), the OR for substandard control of systolic blood pressure in patients in the highest group T3 (3.4 ~ 57.2 g/d) was 1.166 times higher than in the no-intake group T1 (OR = 2.166; 95% CI 1.007 ~ 4.660; p  = 0.048). The OR for abnormal TG levels in patients in the highest PRM intake group T3 (3.4 ~ 57.2 g/d) was 1.095 times higher than in the no-intake group T1 (OR = 2.095; 95% CI 1.076 ~ 4.078; p  = 0.030). Restricted cubic spline plots presented a nonlinear dose-response relationship between PRM intake and risk of substandard HbA1c and SBP control (P nonlinear <0.05), and an atypical inverted U-shaped association between PRM intake and TC and LDL-C levels (P nonlinear <0.05). The strength of the associations between PRM intake and the control levels of FPG, DBP, HDL-C, and TG were not statistically significant ( p  > 0.05)., Conclusion: PRM intake was generally low in patients with T2DM, but a nonlinear dose-response relationship between PRM intake and the risk of suboptimal control of HbA1c and SBP, with an atypical inverted U-shaped association with TC and LDL-C levels, was observed. Appropriate control of PRM intake may be important for tertiary prevention of T2DM and cardiovascular disease prevention. We need to better understand these relationships to promote improved cardiometabolism and global health., 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 Zhang, Chai, Ren, Xu, Jing, Zhang, Jiang and Xie.)

Background: The combination of anti-programmed death 1 (PD-1) inhibitors and tyrosine kinase inhibitors is an effective treatment strategy in endometrial cancer. We aimed to explore the efficacy and safety of camrelizumab plus apatinib as an alternative therapeutic option in patients with previously treated endometrial cancer., Methods: This single-arm Simon's two-stage phase II trial was conducted at the Fudan University Shanghai Cancer Center. Patients with advanced or recurrent endometrial cancer who had failed at least one prior systemic therapy were screened for potential participation. Eligible patients were treated with intravenous camrelizumab (200 mg d1 q2w) and oral apatinib (250 mg qd) every 4 weeks. The primary end point was the objective response rate (ORR) per RECIST v1.1 in the intention-to-treat principle., Results: Between January 20, 2020, and October 14, 2022, 36 patients (29 with microsatellite stability/mismatch repair proficient [MSS/pMMR] tumors; two with microsatellite instability-high/mismatch repair deficient [MSI-H/dMMR] tumors) were enrolled and treated. The confirmed ORR was 44.4% (95% CI: 27.9, 61.9) and the disease control rate was 91.7% (95% CI: 77.5, 98.2). The median duration of response was 9.3 (95% CI: 4.3, not reached) months, the median progression-free survival was 6.2 (95% CI: 5.3, 11.1) months, and the median overall survival was 21.0 (95% CI: 13.4, not reached) months during a median follow-up of 14.2 (interquartile range: 10.3, 27.6) months. Treatment-related adverse events of grade 3 or 4 occurred in 20 (55.6%) patients, with the most common being increased γ-glutamyl transferase (27.8%), alanine aminotransferase (16.7%) and aspartate aminotransferase (13.9%), and hypertension (11.1%). No treatment-related death occurred., Conclusions: Camrelizumab plus apatinib showed promising antitumor activity with manageable toxicity in patients with advanced or recurrent endometrial cancer who had failed at least one prior systemic therapy. The findings of this study support further investigation of camrelizumab plus apatinib as an alternative therapeutic option, especially for patients with MSS/pMMR tumors., Trial Registration: This trial was retrospectively registered with ChiCTR.org.cn, number ChiCTR2000031932., (© 2024. The Author(s).)

This study aimed to investigate whether fetal growth trajectories (FGTs) could predict early childhood development, indicate intrauterine metabolic changes, and explore potential optimal and suboptimal FGTs. FGTs were developed by using an unsupervised machine-learning approach. Children's neurodevelopment, anthropometry, and respiratory outcomes in the first 6 years of life were assessed at different ages. In a subgroup of participants, we conducted a metabolomics analysis of cord blood to reveal the metabolic features of FGTs. We identified 6 FGTs: early decelerating, early decelerating with late catch-up growth, early accelerating, early accelerating with late medium growth, late decelerating, and late accelerating. The early accelerating with late medium growth pattern might be the optimal FGT due to its associations with better psychomotor development, mental development, intelligence quotient, and lung function and a lower risk of behaviour and respiratory problems. Compared with the optimal FGT, early decelerating and late decelerating FGTs were associated with poor neurodevelopment and lung function, while early accelerating FGT was associated with more severe autistic symptoms, poor lung function, and increased risks of overweight/obesity. Metabolic alterations were enriched in amino acid metabolism for early decelerating and late decelerating FGTs, whereas altered metabolites were enriched in lipid metabolism for early accelerating FGT. These findings suggest that FGTs are predictors of early life development and may indicate intrauterine adaptive metabolism. The discovery of optimal and suboptimal FGTs provides potential clues for the early identification and intervention of fetal origin dysplasia or disease, but further research on related mechanisms is still needed., (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)

Despite observational studies suggesting a link between psoriatic disease (including psoriasis and psoriatic arthritis) and migraine, it is unclear whether there is a shared genetic etiology or a causal relationship between the two conditions. We aimed to reveal the genetic overlap and causality using the Mendelian randomization (MR) framework. The genetic analysis utilized summary data from the most extensive European genome-wide association study (GWAS) of migraine. Well-powered psoriatic disease GWAS data were obtained from two independent cohort studies, which served as discovery and validation datasets. Global and regional genetic correlations between psoriatic disease and migraine were assessed, and pleiotropic regions identified by pairwise GWAS analysis were further annotated. We further applied a two-sample MR multivariate MR to investigate the potential causal relationship between them. The global genetic correlation test indicated weak correlations between psoriatic disease and migraine, while regional correlation analyses delineated one significant shared locus between psoriasis and migraine. Pathway enrichment analysis revealed that shared genes were involved biological processes to the major histocompatibility and antigen processing and presentation. In terms of causality estimates, genetically predicted psoriasis (P meta = 0.003) and psoriatic arthritis (P meta = 0.028) were associated with an increased risk of migraine. Multivariate MR analysis indicated that psoriasis was an independent risk factor for migraine (P < 0.05). No significant associations were found in the reverse direction. Our study supported the causal role of psoriasis on migraine, and the central role for immunomodulatory etiology. These findings have significant implications for the management of migraine and clinical practice in patients with psoriasis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The modulation recognition technology for acoustic signals holds significant research importance in signal demodulation and communication signal reconnaissance, serving as a crucial component and key aspect. This paper investigates the modulation recognition technology for acoustic signals (< 20 kHz) from the perspectives of signal preprocessing and feature extraction. Firstly, it selects seven modulation signals 2ASK, 4ASK, 2FSK, 4FSK, 2PSK, 4PSK, and OFDM as recognition targets and systematically compares the effectiveness of four different endpoint detection algorithms in modulation signal recognition. To further enhance the performance of the short-time energy entropy ratio algorithm, this study introduces three different noise reduction algorithms for optimization. Finally, to accurately identify and distinguish between 2 and 4FSK signals, this study optimizes the related algorithms of the cyclic spectrum by using the kurtosis coefficient value Kur of the cyclic spectrum parameter matrix when the cyclic frequency α = 0 to differentiate between these two signals. The results show that at SNR of 4 dB, the proposed modulation recognition algorithm can effectively distinguish between these two signals, achieving a recognition accuracy of over 99%., (© 2024. The Author(s).)

Psoriasis is considered a chronic inflammatory skin disorder characterized by keratinocytes hyperproliferation. The IL-23/IL-17 immune pathway has been substantiated in numerous studies to be closely associated with psoriasis progression. Yinxie I Formula is a traditional Chinese medicine made from 9 herbal medicines, which has excellent clinical efficacy in psoriasis. However, to date, the mechanism of action of Yinxie I Formula against psoriasis remains unknown. In this perspective, we discuss the efficacy of Yinxie I Formula in mice with imiquimod (IMQ) induced psoriasis. Yinxie I Formula significantly reduced the area of skin lesions and the inflammatory response in mice with psoriasis. Furthermore, Yinxie I Formula alleviated the expression levels of inflammation-related genes IL-6, IL-17 A, IL-22, IL-23, TNF-α and IL-23, IL-18, IL-6 and IL-1β-related proteins and alleviated the abnormal surge of dendritic cells, macrophages and T cells in the skin and spleen. Meanwhile we found that Yinxie I Formula reduced the release of NO, TNF-α, IL-1β and IL-23 in lipopolysaccharide-induced mouse macrophage RAW264.7 cell line. The results suggest that the therapeutic mechanism of Yinxie I Formula may also be correlated with the STAT signaling pathway. We further analyzed the active ingredient of Yinxie I Formula, Buddleoside, which may be the main substance that exerts the therapeutic effect. In conclusion, we have investigated that Yinxie I Formula attenuates the IMQ-induced inflammatory response in psoriasis by inhibiting the IL-23/IL-17 axis, which lays the foundation for the antipsoriasis mechanism and provides a theoretical basis for the clinical promotion of Yinxie I Formula., (© 2024. The Author(s).)

Background: The tumor microenvironment (TME) of colorectal cancer (CRC) mainly comprises immune cells, stromal cells, tumor cells, as well as the extracellular matrix (ECM), which holds a pivotal position. The ECM affects cancer progression, but its regulatory roles and predictive potential in CRC are not fully understood., Methods: We analyzed transcriptomes from CRC tumors and paired normal tissues to study ECM features. Up-regulated ECM components were examined through functional enrichment analysis, and single-cell sequencing identified cell types producing collagen, regulators, and secreted factors. Transcription factor analysis and cell-cell interaction studies were conducted to identify potential regulators of ECM changes. Additionally, a prognostic model was developed using TCGA-CRC cohort data, focusing on up-regulated core ECM components., Results: Bulk RNA-seq analysis revealed a unique ECM pattern in tumors, with ECM abundance and composition significantly related to patient survival. Up-regulated ECM components were linked to various cancer-related pathways. Fibroblasts and non-fibroblasts interactions were crucial in forming the TME. Key potential regulators identified included ZNF469, PRRX2, TWIST1, and AEBP1. A prognostic model based on five ECM genes (THBS3, LAMB3, ESM1, SPRX, COL9A3) demonstrated strong associations with immune suppression and tumor angiogenesis., Conclusions: The ECM components were involved in various cell-cell interactions and correlated with tumor development and poor survival outcomes. The ECM prognostic model components could be potential targets for novel therapeutic interventions in colorectal cancer., Competing Interests: 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., (© 2024 The Authors.)

Diabetic nephropathy (DN) is an important cause of death in diabetes patients, which is mainly due to its complex pathogenesis. Here, we explored the role of N6-methyladenosine (m6A) RNA methylation in DN development. Renal tubular epithelial cells from DN patients and experimental DN mice treated with streptozotocin (STZ) exhibited a considerable increase in METTL14 and WTAP expression as well as overall m6A methylation. Knocking down the expression of METTL14 and WTAP inhibited the migration and proliferation of tubular epithelial cells. MeRIP-seq analysis of the renal tissues of DN patients revealed that the genes with elevated m6A methylation were concentrated in the Wnt/β-Catenin signaling pathway. Dickkopf homolog 3 (DKK3) was screened out as the gene with the most significant increase in m6A methylation. In addition, the expression change pattern of DKK3 under DN circumstances is in line with those of METTL14 and WTAP. DKK3's m6A methylation sites were confirmed to be located in the 3'UTR region, which is how METTL14 and WTAP improved DKK3's mRNA stability. Finally, YTHDF1, a m6A reader, was demonstrated to recognize m6A-methylated DKK3 and promote DKK3 expression., 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 Inc. All rights reserved.)

Background: Biliary tract cancer (BTC) is a highly malignant tumor, with limited therapy regimens and short response duration. In this study, we aim to assess the efficacy and safety of the combination of camrelizumab, apatinib, and capecitabine as the first- or second-line treatment in patients with advanced BTC., Methods: In this phase 2, nonrandomized, prospective study, eligible patients received camrelizumab (200 mg, d1, Q3W), apatinib (250 mg, qd, d1-d21, Q3W), and capecitabine (1000 mg/m², bid, d1-d14, Q3W) until trial discontinued. The primary endpoint was the objective response rate (ORR). The secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and safety., Results: From July 2019 to April 2023, we enrolled a total of 28 patients, of whom 14 patients were in the first-line treatment setting and 14 patients were in the second-line setting. At the data cutoff (April 30, 2023), the median follow-up duration was 18.03 months. Eight of 28 patients reached objective response (ORR: 28.57%), with an ORR of 50% and 7.1% for first-line and second-line treatment patients (P = .033). The median PFS was 6.30 months and the median OS was 12.80 months. Grade 3 or 4 adverse events (AEs) occurred in 9 (32.14%) patients, including elevated transaminase, thrombocytopenia, etc. No serious treatment-related AEs or treatment-related deaths occurred., Conclusions: In this trial, the combination of camrelizumab, apatinib, and capecitabine showed promising antitumor activity and manageable toxicity in patients with advanced BTC, especially in the first-line setting., Clinical Trial Registration: NCT04720131., (© The Author(s) 2024. Published by Oxford University Press.)

The obstacle to effectively treating Diffuse Large B-cell Lymphoma (DLBCL) lies in the resistance observed toward standard therapies. Identifying therapeutic targets that prove effective for relapsed or refractory patients poses a significant challenge. OTUD3, a deubiquitinase enzyme, is overexpressed in DLBCL tissues. However, its role in DLBCL has not been investigated. Our study has brought to light the multifaceted impact of OTUD3 in DLBCL. Not only does it enhance cell survival through the deubiquitination of MYL12A, but it also induces CD8+ T cell exhaustion within the local environment by deubiquitinating PD-L1. Our findings indicate that the OTUD3 inhibitor, Rupatadine, exerts its influence through competitive binding with OTUD3. This operation diminishes the deubiquitination of both MYL12A and PD-L1 by OTUD3. This research unveils the central and oncogenic role of OTUD3 in DLBCL and highlights the potential clinical application value of the OTUD3 inhibitor, Rupatadine. These findings contribute valuable insights into addressing the challenges of resistant DLBCL cases and offer a promising avenue for further clinical exploration., (© 2024. The Author(s).)

Anionic redox allows the direct formation of O─O bonds from lattice oxygens and provides higher catalytic in the oxygen evolution reaction (OER) than does the conventional metal ion mechanism. While previous theories have predicted and experiments have suggested the possible O─O bond, it has not yet been directly observed in the OER process. In this study, operando soft X-ray absorption spectroscopy (sXAS) at the O K-edge and the operando Raman spectra is performed on layered double CoFe hydroxides (LDHs) after intercalation with [Cr(C 2 O 4 ) 3 ] 3- , and revealed a three-step oxidation process, staring from Co 2+ to Co 3+ , further to Co 4+ (3d6L), and ultimately leading to the formation of O─O bonds and O 2 evolution above a threshold voltage (1.4 V). In contrast, a gradual oxidation of Fe is observed in CoFe LDHs. The OER activity exhibits a significant enhancement, with the overpotential decreasing from 300 to 248 mV at 10 mA cm -2 , following the intercalation of [Cr(C 2 O 4 ) 3 ] 3- into CoFe LDHs, underscoring a crucial role of anionic redox in facilitating water splitting., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Objective: Rheumatoid arthritis (RA) and thyroid dysfunction are frequently observed in the same patient. However, whether they co-occur or exhibit a causal relationship remains uncertain. We aimed to systematically investigate the causal relationship between RA and thyroid function using a large sample and advanced methods., Methods: Bidirectional two-sample Mendelian randomization (MR) analysis was performed based on RA and six thyroid function trait data sets from the European population. The robustness of the results was demonstrated using multiple MR methods and a series of sensitivity analyses. Multivariable MR using Bayesian model averaging (MR-BMA) was performed to adjust for possible competing risk factors. A sensitivity data set, which included data from patients with seropositive RA and controls, was used to repeat the analyses. Furthermore, enrichment analysis was employed to discover the underlying mechanism between RA and thyroid functions., Results: A significantly positive causal effect was identified for RA on autoimmune thyroid disease (AITD) as well as for AITD on RA (P < 0.001). Further sensitivity analyses showed consistent causal estimates from a variety of MR methods. After removing the outliers, MR-BMA results showed that RA and AITD were independent risk factors in their bidirectional causality, even in the presence of other competing risk factors (adjusted P < 0.05). Enrichment analysis showed immune cell activation and immune response play crucial roles in them., Conclusion: Our results illustrate the significant bidirectional causal effect of RA and AITD, which holds even in multiple competing risk factors. Clinical screening for thyroid dysfunction in patients with RA deserves further attention, and vice versa., (© 2024 American College of Rheumatology.)

The core of clinic treatment of Parkinson's disease (PD) is to enhance dopamine (DA) signaling within the brain. The regulation of dopamine transporter (DAT) is integral to this process. This study aims to explore the regulatory mechanism of glial cell line-derived neurotrophic factor (GDNF) on DAT, thereby gaining a profound understanding its potential value in treating PD. In this study, we investigated the effects of GDNF on both cellular and mouse models of PD, including the glycosylation and membrane transport of DAT detected by immunofluorescence and immunoblotting, DA signal measured by neurotransmitter fiber imaging technology, Golgi morphology observed by electron microscopic, as well as cognitive ability assessed by behavior tests. This study revealed that in animal trials, MPTP-induced Parkinson's Disease (PD) mice exhibited a marked decline in cognitive function. Utilizing ELISA and neurotransmitter fiber imaging techniques, we observed a decrease in dopamine levels and a significant reduction in the intensity of dopamine signal release in the Prefrontal Cortex (PFC) of PD mice induced by MPTP. Intriguingly, these alterations were reversed by Glial Cell Line-Derived Neurotrophic Factor (GDNF). In cellular experiments, following MPP + intervention, there was a decrease in Gly-DAT modification in both the cell membrane and cytoplasm, coupled with an increase in Nongly-DAT expression and aggregation of DAT within the cytoplasm. Conversely, GDNF augmented DAT glycosylation and facilitated its membrane transport in damaged dopaminergic neurons, concurrently reversing the effects of GRASP65 depletion and Golgi fragmentation, thereby reducing the accumulation of DAT in the Golgi apparatus. Furthermore, overexpression of GRASP65 enhanced DAT transport in PD cells and mice, while suppression of GRASP65 attenuated the efficacy of GDNF on DAT. Additionally, GDNF potentiated the reutilization of neurotransmitters by the PFC presynaptic membrane, boosting the effective release of dopamine following a single electrical stimulation, ultimately ameliorating the cognitive impairments in PD mice.Therefore, we propose that GDNF enhances the glycosylation and membrane trafficking of DAT by facilitating the re-aggregation of the Golgi apparatus, thereby amplifying the utilization of DA signals. This ultimately leads to the improvement of cognitive abilities in PD mouse models. Our study illuminates, from a novel angle, the beneficial role of GDNF in augmenting DA utilization and cognitive function in PD, providing fresh insights into its therapeutic potential., (© 2024. The Author(s).)

Background: Moringa oleifera leaves are rich in bioactive substances., Purpose: The purpose of this study was to evaluate the effects of Moringa oleifera leaf aqueous extract supplements on energy metabolism and antioxidant function in young male adults., Methods: Forty-four young male adults (26.3 ± 3.5 years) were randomly assigned to two groups: a supplement group (n = 23) receiving aqueous extract of Moringa oleifera leaves and a placebo group (n = 21). The supplementation period lasted for 30 days. Baseline measurements were taken at the beginning of the study, and further measurements were taken at the end of the supplementation period. Changes in upper- and lower-body strength, treadmill endurance, and certain blood biochemical parameters were evaluated., Results: After 30 days of supplementation, participants in the supplement group exhibited enhanced performance in push-ups and treadmill exhaustion tests compared to the placebo group. Levels of glucose, urea, malondialdehyde, and glutathione peroxidase activity in serum were also improved in the supplement group., Conclusion: The findings suggest that Moringa oleifera leaf aqueous extracts have the potential to improve post-exercise energy metabolism and antioxidant function in young male adults., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations. There is no professional or other personal interest of any nature or kind in any product, service and/or company., (Copyright © 2024. Published by Elsevier GmbH.)

The Bacillus genus is widely distributed in nature, has bacteriostatic and growth-promoting activities, and has broad application potential in agriculture. An exopolysaccharide (EPS) was extracted and purified from Bacillus velezensis HY23. Structural characterisation of the EPS was performed by chemical and spectroscopic analyses. Methylation analysis showed that the EPS of HY23 was composed of mannose and glucose at a ratio of 82:18 and was identified as glucomannan. Combined with the nuclear magnetic resonance (NMR) analysis, EPS from HY23 had a backbone of →2)-α-D-Manp-(1 → and →2,6)-α-D-Manp-(1 → branched at C-6 with terminal α-(3-O-Me)-D-Manp-(1 → and →6)-α-D-Manp-(1 → residues as the side chain. A certain amount of β-D-Glcp residues were also present in backbone. Moreover, EPS significantly improved the nitrogen-fixing activity and salt resistance of soybean seedlings by regulating the antioxidant pool and expression of ion transporters. These findings indicate that EPS from B. velezensis HY23 is a potential biostimulant for enhancing plant resistance to salt stress., 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: Migraine is a common primary headache that has a significant impact on patients' quality of life. The co-occurrence of migraine and depression is frequent, resulting in more complex symptoms and a poorer prognosis. The evidence suggests that depression and migraine comorbidity share a polygenic genetic background., Objective: The aim of this study is to identify related genetic variants that contribute to genetic susceptibility to migraine with and without depression in a Chinese cohort., Methods: In this case-control study, 263 individuals with migraines and 223 race-matched controls were included. Eight genetic polymorphism loci selected from the GWAS were genotyped using Sequenom's MALDI-TOF iPLEX platform., Results: In univariate analysis, ANKDD1B rs904743 showed significant differences in genotype and allele distribution between migraineurs and controls. Furthermore, a machine learning approach was used to perform multivariate analysis. The results of the Random Forest algorithm indicated that ANKDD1B rs904743 was a significant risk factor for migraine susceptibility in China. Additionally, subgroup analysis by the Boruta algorithm showed a significant association between this SNP and migraine comorbid depression. Migraineurs with depression have been observed to have worse scores on the Beck Anxiety Inventory (BAI) and the Migraine Disability Assessment Scale (MIDAS)., Conclusion: The study indicates that there is an association between ANKDD1B rs904743 and susceptibility to migraine with and without depression in Chinese 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., (Copyright © 2024 An, Zhao, Fang, Li, Yue, Jing, Zhang, Zhang, Zhou, Chen, Qu, Ma and Lin.)

Background: There is a scarcity of large randomized clinical trials on the efficacy and safety of high-dose amino acid supplementation (AAS) in patients with gastrointestinal tumors undergoing surgical treatment., Methods: This pragmatic, randomized, controlled, single-center, open-label, parallel-group AMIGITS trial was performed in a tertiary care teaching hospital. Patients with gastrointestinal tumors were randomly assigned to receive either AAS or standard care (SC). Amino acid targets were 2.0 g/kg per day in the AAS group and 1.2 g/kg per day in the SC group. The AAS group received additional amino acids intravenously, while the SC group received an iso-energetic 5% glucose intravenously., Results: Overall, 407 patients (AAS group, 204; SC group, 203) were included in this study. During the intervention, the actual mean daily energy intake did not differ significantly between the AAS and SC groups (25.53 vs. 25.16 kcal/kg per day, P=0.493). However, the actual mean daily amino acid intake was significantly higher in the AAS group than that in the SC group (1.81 vs. 0.94 g/kg per day, P<0.001). The infection incidence during hospitalization and that within 30 days of surgery was significantly lower in the AAS group than that in the SC group (P=0.031 and P=0.024, respectively). The 30-day postoperative incidence of amino acid treatment-related adverse events and other complications did not significantly differ between the two groups. The postoperative hospital stay was significantly different between the two groups (P<0.001)., Conclusions: AAS was associated with a reduced infection incidence within 30 days of major surgery in patients with gastrointestinal tumors and can be a promising strategy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

This patient was an elderly patient with abdominal distension and shortness of breath. According to relevant examinations, his condition was initially considered to be related to cirrhosis, but pathological biopsy confirmed the diagnosis of noncirrhotic portal hypertension of unknown etiology. The portal vein pressure was significantly reduced after transjugular intrahepatic portosystemic shunt (TIPS). Nevertheless, the relief of the hydrothorax and ascites was not significant, and the numbness in both lower limbs gradually worsened. POEMS syndrome was ultimately diagnosed following a comprehensive examination. After two courses of bortezomib combined with dexamethasone, the patient died due to a systemic infection. The clinical symptoms of the patient were atypical, as was the presence of portal hypertension, which hindered the diagnosis of POEMS. Due to the patient's advanced age, the diagnosis was delayed, and the prognosis was poor. This case reminds clinicians that POEMS patients can also have portal hypertension as the main manifestation., 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 Xu, Jing, Zhu, Jiang, Fu, Xie, Li and Meng.)

Metabolic reprogramming dictates tumor molecular attributes and therapeutic potentials. However, the comprehensive metabolic characteristics in gastric cancer (GC) remain obscure. Here, metabolic signature-based clustering analysis identifies three subtypes with distinct molecular and clinical features: MSC1 showed better prognosis and upregulation of the tricarboxylic acid (TCA) cycle and lipid metabolism, combined with frequent TP53 and RHOA mutation; MSC2 had moderate prognosis and elevated nucleotide and amino acid metabolism, enriched by intestinal histology and mismatch repair deficient (dMMR); and MSC3 exhibited poor prognosis and enhanced glycan and energy metabolism, accompanied by diffuse histology and frequent CDH1 mutation. The Shandong Provincial Hospital (SDPH) in-house dataset with matched transcriptomic, metabolomic, and spatial-metabolomic analysis also validated these findings. Further, we constructed the metabolic subtype-related prognosis gene (MSPG) scoring model to quantify the activity of individual tumors and found a positive correlation with cuproptosis signaling. In conclusion, comprehensive recognition of the metabolite signature can enhance the understanding of diversity and heterogeneity in GC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: This study aims to examine the nutritional status of individuals diagnosed with esophageal cancer and compare the nutritional indicators and intestinal flora between malnourished and non-malnourished patients. The findings aim to contribute to the early prevention of malnutrition and the development of interventions targeting the intestinal flora to treat esophageal cancer., Methods: An 80-patient sample of hospitalized individuals with esophageal cancer was selected from the radiotherapy department of our hospital between July 2021 and July 2022 to evaluate NRS2002 scores and PG-SGA scores. This cross-sectional analysis aimed to examine the disparities in dietary nutrient intake, blood indicators, body composition, and fecal intestinal flora between malnourished and non-malnourished patients with esophageal cancer. Additionally, we randomly selected 40 cases to predict and analyze the relationship between intestinal flora and malnutrition., Results: The incidence of nutritional risk and malnutrition in patients with esophageal cancer was 62.5% and 60%, respectively. The low intake of carbohydrates and dietary fiber in the malnutrition group was statistically significant compared to those in the non-malnutrition group ( P < 0.05). The albumin (ALB) level was lower in the malnutrition group than in the non-malnutrition group, while the C-reactive protein (CRP) level was higher; these differences were also statistically significant ( P < 0.05). The basal metabolic rate, phase angle, body cell mass, muscle mass, skeletal muscle index, and fat-free mass index in the malnutrition group all decreased compared to the non-malnutrition group. The extracellular water/total body water was higher than that in the non-malnutrition group, which was also statistically significant ( P < 0.05). As shown by 16S rDNA sequencing of fecal intestinal flora, there was no significant difference in α and β diversity between the malnutrition and non-malnutrition groups; at the genus level, significant differences were observed for Selimonas, Clostridioides, Dielma, Lactobacillus, and [Eubacterium]&#95;siraeum&#95;group. However, Dielma, Sellimonas, and Clostridioides were significantly lower in the malnutrition group than in the non-malnutrition group, while Anaerococcus, Atopobium, Eubacterium&#95;siraeum&#95;group, and Lactobacillus were significantly higher in the malnutrition group. Correlation analysis between different genera and clinical indicators showed that Lactobacillus was positively correlated with ALB, dietary energy, intracellular water/total body water (ICW/TBW), phase angle (PA), muscle mass (MM), skeletal muscle mass (SMM), body cell mass (BCM), basal metabolic rate (BMR), appendicular skeletal muscle mass (ASMM), total body water (TBW), fat-free mass index (FFMI), skeletal muscle index (SMI), fat-free mass (FFM), Weight, body mass index (BMI) ( r > 0, P < 0.05), but negatively correlated with PG-SGA score, NRS2002 score, and extracellular water/total body water (ECW/TBW) ( r < 0 , P < 0.05). Based on PG-SGA, there was only a low accuracy for identifying nutrient deficiency (most areas under curve (AUC) values fell within 0.5 to 0.7, or even lower), with Lachnoclostridium's AUC being 0.688 (CI = 0.518-0.858) and Lactobacillus&#95;salivarius&#95;g&#95;Lactobacillus's AUC being 0.257 (CI = 0.098-0.416). A KEGG functional analysis based on 16S data indicated potential differences affecting glucose metabolism pathways and the synthesis or division of DNA, influencing the onset, development, and prognosis of esophageal cancer patients., Conclusion: Esophageal cancer patients are more likely to be malnourished. The nutritional status of these patients is closely linked to the intake of carbohydrates and fiber, albumin levels, inflammation levels, and lean body mass. Furthermore, the patient's intestinal flora composition plays a significant role in their nutritional well-being. Consequently, modulating the intestinal flora holds promise as a potential therapeutic approach for addressing malnutrition in esophageal cancer patients., Clinical Trial Registration: ChiCTR2100048141., 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 LiYa, XinSheng, Xiang, Zhao, Lu, XiuMing, Ye, Jing, KeMing, HongChi, Jing, Yang, Xiu, HongBo, ShuQin, Fang and YingHua.)

Background: Fibroblasts play an important role in the development of idiopathic pulmonary fibrosis (IPF)., Methods: We employed single-cell RNA-sequencing data obtained from the Gene Expression Omnibus database to perform cell clustering and annotation analyses. We then performed secondary clustering of fibroblasts and conducted functional enrichment and cell trajectory analyses of the two newly defined fibroblast subtypes. Bulk RNA-sequencing data were used to perform consensus clustering and weighted gene co-expression network analysis. We constructed a fibroblast-related prognostic model using least absolute shrinkage, selection operator regression, and Cox regression analysis. The prognostic model was validated using a validation dataset. Immune infiltration and functional enrichment analyses were conducted for patients in the high- and low-risk IPF groups., Results: We characterized two fibroblast subtypes that are active in IPF (F3+ and ROBO2+). Using fibroblast-related genes, we identified five genes ( CXCL14 , TM4SF1 , CYTL1 , SOD3 , and MMP10 ) for the prognostic model. The area under the curve values of our prognostic model were 0.852, 0.859, and 0.844 at one, two, and three years in the training set, and 0.837, 0.758, and 0.821 at one, two, and three years in the validation set, respectively., Conclusion: This study annotates and characterizes different subtypes of fibroblasts in IPF., Competing Interests: The authors have no conflict of interest., (© 2024 The Authors.)

Grain chalkiness directly affects the commercial value of rice. Genes related to chalkiness reported thus far have been discovered in mutants, but it has not been identified whether these genes can be used to improve rice quality by breeding. Therefore, discovering more quantitative trait loci (QTLs) or genes related to chalkiness in the rice germplasm is necessary. This study entails a genome-wide association study on the degree of endosperm chalkiness (DEC) and percentage of grains with chalkiness (PGWC) by combining 1.2 million single-nucleotide polymorphisms (SNPs) with the phenotypic data of 173 rice accessions. Thirteen QTLs for DEC and nine for PGWC were identified, of which four were detected simultaneously for both DEC and PGWC; further, qDEC11/qPGWC11 was identified as the major QTL. By combining linkage disequilibrium analysis and SNP information, LOC&#95;Os11g10170 was identified as the candidate gene for DEC. There were significant differences among the haplotypes of LOC&#95;Os11g10170 , and the Hap 1 of LOC&#95;Os11g10170 was observed to reduce the DEC by 6.19%. The qRT-PCR results showed that the gene expression levels in accessions with high DEC values were significantly higher than those in accessions with low DEC values during days 21-42 after flowering, with a maximum at 28 days. These results provide molecular markers and germplasm resources for genetic improvement of the chalkiness-related traits in rice., 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 Xu, Jiang, Jing, Hu, Zhang, Li, Shen, Hai, Zhang, Wang and Dang.)

Pediatric ankle injuries are common; ankle epiphyseal fractures are also common in children. But isolated distal epiphyseal fibular fractures of the distal fibula are clinically rare. We describe one unusual case of an adolescent with a completely displaced Salter-Harris type II distal fibular epiphyseal fracture. The attempt of closed reduction failed, and the patient required open reduction and internal fixation. The localized periosteum and the superior peroneal retinaculum were avulsed from the distal fibular metaphysis, with the peroneal tendons underneath exposed but no obvious subluxation. To the best of our knowledge, this combination of injuries has not been previously reported., (© 2024. The Author(s).)

Background: Accurate estimation of reference crop evapotranspiration (ET 0 ) is crucial for farmland hydrology, crop water requirements, and precision irrigation decisions. The Penman-Monteith (PM) model has high accuracy in estimating ET 0 , but it requires many uncommon meteorological data inputs. Therefore, an ideal method is needed that minimizes the number of input data variables without compromising estimation accuracy. This study aims to analyze the performance of various methods for estimating ET 0 in the absence of some meteorological indicators. The Penman-Monteith (PM) model, known for its high accuracy in ET 0 estimation, served as the standard value under conditions of adequate meteorological indicators. Comparative analyses were conducted for the Priestley-Taylor (PT), Hargreaves (H-A), McCloud (M-C), and FAO-24 Radiation (F-R) models. The Bayesian estimation method was used to improve the ET estimation model., Results: Results indicate that, compared to the PM model, the F-R model performed best with inadequate meteorological indicators. It demonstrates higher average correlation coefficients (R 2 ) at daily, monthly, and 10-day scales: 0.841, 0.937, and 0.914, respectively. The corresponding root mean square errors (RMSE) are 1.745, 1.329, and 1.423, and mean absolute errors (MAE) are 1.340, 1.159, and 1.196, with Willmott's Index (WI) values of 0.843, 0.862, and 0.859. Following Bayesian correction, R 2 values remained unchanged, but significant reductions in RMSE were observed, with average reductions of 15.81%, 29.51%, and 24.66% at daily, monthly, and 10-day scales, respectively. Likewise, MAE decreased significantly, with average reductions of 19.04%, 34.47%, and 28.52%, respectively, and WI showed improvement, with average increases of 5.49%, 8.48%, and 10.78%, respectively., Conclusion: Therefore, the F-R model, enhanced by the Bayesian estimation method, significantly enhances the estimation accuracy of ET 0 in the absence of some meteorological indicators., 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 Sun, Zhang, Dai, Gao, Jing, Ma, Gu, Gu, Zhen and Gu.)