查看更多>>摘要：G protein-coupled receptors(GPCRs)are crucial players in various physiological processes,making them attractive candidates for drug discovery.However,traditional approaches to GPCR ligand discovery are time-consuming and resource-intensive.The emergence of artificial intelligence(AI)methods has revo-lutionized the field of GPCR ligand discovery and has provided valuable tools for accelerating the identi-fication and optimization of GPCR ligands.In this study,we provide guidelines for effectively utilizing AI methods for GPCR ligand discovery,including data collation and representation,model selection,and specific applications.First,the online resources that are instrumental in GPCR ligand discovery were sum-marized,including databases and repositories that contain valuable GPCR-related information and ligand data.Next,GPCR and ligand representation schemes that can convert data into computer-readable for-mats were introduced.Subsequently,the key applications of AI methods in the different stages of GPCR drug discovery were discussed,ranging from GPCR function prediction to ligand design and agonist identification.Furthermore,an AI-driven multi-omics integration strategy for GPCR ligand discovery that combines information from various omics disciplines was proposed.Finally,the challenges and future directions of the application of Al in GPCR research were deliberated.In conclusion,continued advance-ments in AI techniques coupled with interdisciplinary collaborations will offer great potential for improv-ing the efficiency of GPCR ligand discovery.
查看更多>>摘要：Transplantation represents the most effective treatment for end-stage liver diseases but is limited by the shortage of healthy donor organs.Extended criteria donor(ECD)liver grafts are increasingly utilized in clinical practice to mitigate this challenge.However,impaired ischemic tolerance of these grafts jeopar-dizes organ viability during cold storage.Machine perfusion(MP)was designed to improve organ preser-vation and reduce posttransplant complications.Nevertheless,it is increasingly evident that MP alone may not preserve ECD grafts optimally.Increasing emphasis has thus been placed on modified MP strate-gies,including the use of different perfusates,modified perfusion modalities,and different therapeutic interventions.Here,we introduce a novel term,"MP Plus,"denoting these additional strategies that are designed to restore organ function and potentially enable regeneration of ECD grafts.In this review,we summarize the existing and potential modified MP strategies and discuss their advantages in recon-ditioning different ECD grafts in clinical settings.
查看更多>>摘要：A universal vaccine is in high demand to address the uncertainties of antigenic drift and the reduced effectiveness of current influenza vaccines.In this study,a strategy called computationally optimized broadly reactive antigen(COBRA)was used to generate a consensus sequence of the hemagglutinin glob-ular head portion(HA1)of influenza virus samples collected from 1918 to 2021 to trace evolutionary changes and incorporate them into the designed constructs.Constructs carrying different HA1 regions were delivered into eukaryotic cells by Salmonella-mediated bactofection using a Semliki Forest virus RNA-dependent RNA polymerase(RdRp)-based eukaryotic expression system,pJHL204.Recombinant protein expression was confirmed by Western blot and immunofluorescence assays.Mice immunized with the designed constructs produced a humoral response,with a significant increase in immunoglob-ulin G(IgG)levels,and a cell-mediated immune response,including a 1.5-fold increase in CD4+and CD8+T cells.Specifically,constructs #1 and #5 increased the production of interferon-y(IFN-y)producing CD4+and CD8+T cells,skewing the response toward the T helper type 1 cell(Th1)pathway.Additionally,interleukin-4(IL-4)-producing T cells were upregulated 4-fold.Protective efficacy was demonstrated,with up to 4-fold higher production of neutralizing antibodies and a hemagglutination inhibition titer＞40 against the selected viral strains.The designed constructs conferred a broadly pro-tective immune response,resulting in a notable reduction in viral titer and minimal inflammation in the lungs of mice challenged with the influenza A/PR8/34,A/Brisbane/59/2007,A/California/07/2009,KBPV VR-92,and NCCP 43021 strains.This discovery revolutionizes influenza vaccine design and deliv-ery;Salmonella-mediated COBRA-HA1 is a highly effective in vivo antigen presentation strategy.This approach can effectively combat seasonal H1N1 influenza strains and potential pandemic outbreaks.
查看更多>>摘要：Hepatocyte nuclear factor 1 alpha(HNF1 A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A,and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.
查看更多>>摘要：This paper presents a systematic investigation and demonstration of a K-band circularly polarized liquid-crystal-based phased array(LCPA),including the design,over-the-air(OTA)in-array calibration,and experimental validation.The LCPA contains 16 phase-shifting radiating channels,each consisting of a cir-cularly polarized stacked patch antenna and a liquid-crystal-based phase shifter(LCPS)based on a loaded differential line structure.Thanks to its slow-wave properties,the LCPS exhibits a maximum phase-shifting range of more than 360° with a figure of merit of 78.3(°)·dB-1 based on a liquid crystal layer with a thickness of only 5 pm.Furthermore,an automatic OTA calibration based on a state ergodic method is proposed,which enables the extraction of the phase-voltage curve of every individual LCPA channel.The proposed LCPA is manufactured and characterized with a total profile of only 1.76 mm,experimentally demonstrating a scanned circularly polarized beam from-40° to+40° with a measured peak gain of 12.5 dBic and a scanning loss of less than 2.5 dB.The bandwidth of the LCPA,which satisfies the require-ments of port reflection(|S11|)＜-15 dB,an axial ratio(AR)＜3 dB,beam squinting＜3°,and a gain vari-ation＜2.2 dB,spans from 25.5 to 26.0 GHz.The total efficiency is about 34％,which represents a new state of the art.The use of the demonstrated low-profile LCPA to support circularly polarized scanning beams,along with the systematic design and calibration methodology,holds potential promise for a vari-ety of millimeter-wave applications.
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