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关键词： Influenza A virus   SARS-CoV-2   TMPRSS2   inhibitors   entry inhibitors   host-directed-antivirals   broad-spectrum antiviral drugs  

摘要： Human TMPRSS2 is a type II transmembrane serine protease and an essential host factor for SARS-CoV-2 and influenza A virus (IAV H1N1) infections. It facilitates the cleavage of viral surface glycoproteins, which are required for membrane fusion. This importance makes it an attractive target for host-directed antiviral therapies. We previously identified N-0385 and N-0920 as nanomolar TMPRSS2 inhibitors and demonstrated their antiviral potency against several SARS-CoV-2 variants. Here, we screened another twelve N-0385/N-0920 analogs with improved pharmacokinetics. Compounds 9 and 10 showed strong inhibition of TMPRSS2 activity and viral entry: they blocked pseudoviruses and authentic SARS-CoV-2 JN.1 and IAV H1N1 in Calu-3 cells. Compound 9 displayed a synergistic effect with baloxavir during IAV H1N1 infection. Both compounds highly reduced H1N1 infection in air-liquid interface cultures and mouse models, thus highlighting their broad antiviral potential. The discovery of broad-spectrum, host-directed antivirals against current and emerging human viruses is critical in preparing for future pandemics.

关键词： italic>Arabidopsis thaliana   CASEIN KINASE 1   brassinosteroid   transcription   hypocotyl   root   growth  

摘要： The CASEIN KINASE 1 (CK1) family plays diverse roles in the development, physiology, and disease in eukaryotes. In Arabidopsis thaliana, the CASEIN KINASE 1-LIKE (CKL) family has 13 members, but to date, the roles of these kinases remain largely unclear. Here, we characterize several insertion mutants, finding that CKL12 may contribute to hypocotyl and primary root growth. Differential effects of insertions at various parts of the gene suggest that the 3 ' end of the transcript may be important for CKL12 function. We provide evidence that CKL12 may be a transcriptional target of brassinosteroid (BR) signaling. The CKL12 promoter contains in vitro binding sites for BR-related transcription factors. Knock-down of these transcription factors using RNA interference reduces CKL12 transcript. Together, these data suggest that CKL12 may act downstream of BR signaling to regulate seedling growth.

关键词： Syndecan-1   italic>Faecalibacterium prausnitzii   cobalamin biosynthesis   biofilm   heparan sulfate   inflammatory bowel disease  

摘要： Despite the rising global incidence of inflammatory bowel disease (IBD curative therapies remain unavailable. While our previous work implicated the intestinal proteoglycan Syndecan-1 (SDC1) in IBD-associated barrier dysfunction and inflammation, the underlying mechanism was unclear. This study aimed to elucidate how SDC1 maintains intestinal barrier integrity through interactions with the gut microbiome. In DSS-induced colitis, global knockout of Sdc1 (Sdc1-/-) exhibited exacerbated inflammatory infiltration and greater impairment of barrier structure and function than wild-type (WT). Formation of intestinal organoids was independent of genotype, indicating that Sdc1-/- does not impair barrier function via disrupting epithelial development. The heightened colitis susceptibility in Sdc1-/- mice was abolished in the antibiotic-treated pseudo-germ-free models, and transmissible to WT mice via fecal microbiota transplantation. Similar results were reproduced in a germ-free mouse model. Metagenomic sequencing identified Faecalibacterium prausnitzii as the most significantly depleted species upon Sdc1 knockout. In vitro, SDC1-attached glycosaminoglycans (heparan sulfate (HS) and chondroitin sulfate (CS but not the SDC1 core protein promoted F. prausnitzii growth. Prokaryotic transcriptome profiling indicated that HS/CS induces cobalamin biosynthesis in F. prausnitzii. The critical role of cobalamin as a mediator was confirmed, as its synthetic inhibition significantly diminished the growth-promoting effect of HS/CS. Mechanism studies showed that HS/CS enhanced biofilm formation in F. prausnitzii, thereby facilitating cobalamin biosynthesis. Oral administration of HS ameliorated DSS-induced colitis and promoted mucosal colonization of F. prausnitzii, independent of the host genotype. Finally, human IBD biopsies revealed a positive correlation between epithelial SDC1 and mucosal F. prausnitzii, as well as an inverse correlation with bacterial translocation and the number o

关键词： Klebsiella   ST23   hypervirulence   plasmid-mediated resistance   NDM-1   IncFII(K2)  

摘要： The World Health Organization has identified ST23 carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) as a critical public health threat. Through China's national surveillance system (BRICS we identified and characterized ST23 CR-hvKP bloodstream isolates from 2019-2023. Among 1069 CRKP bloodstream isolates, four ST23-K1 strains (0.37%) were detected across two hospitals, including a nosocomial transmission pair (differing by only 2 core SNPs). Clinical outcomes revealed that three of the four patients achieved recovery following appropriate antibiotic therapy, with one mortality case attributed to underlying comorbidities. All four ST23 isolates demonstrated resistance to multiple antibiotics, indicating a pattern of multidrug resistance. Genomic analysis uncovered diverse resistance mechanisms: the nosocomial transmission pair possessed conjugative IncFII(K2) NDM-1 plasmids, while the others harbored conjugative IncFII(K34) KPC-2 plasmids, which exhibited reduced carbapenem resistance attributed to the downregulation of bla(KPC-2) expression. Conjugation assays revealed high transferability (10(-5) for IncFII(K2) NDM-1;10(-4) for IncFII(K34) KPC-2). Whole-plasmid comparative genomics analysis suggested that the IncFII(K2) NDM-1 plasmids shared > 99% identity with historical IncFII(K2) plasmid backbones from Chinese K. pneumoniae isolates (2014-2022 suggesting local evolution. Notably, only 4.4% (26/590) of global IncFII(K2) plasmids carried bla(NDM-1) and all IncFII(K2) NDM-1 plasmids maintain conjugative potential. All strains harbored conserved virulence plasmids and maintained hypervirulence, as indicated by a mouse infection model, with the exception of one strain that exhibited cps mutations. This study reports the first genomic evidence of a high-frequency conjugative IncFII(K2) NDM-1 plasmid in a hospital-transmitted ST23 CR-hvKP clone, highlighting the need for plasmid-focused surveillance to control this potential threat.

关键词： 2D/3D affine projections   geometric accuracy analysis   Jilin-1 satellite   polynomial transformation   rational functions model   sensors orientation  

摘要： Chinese high-resolution Earth observation satellites have developed rapidly over the last two decades and have made continuous progress in terms of their mapping capabilities. In this study, we analyzed the geometric accuracy potential of Jilin-1 satellite imagery covering the area around the Marmara Sea of T & uuml;rkiye. The Jilin-1 image was received as four quadrants, comprising 19 multispectral bands. We used different mathematical models in the accuracy assessment phase, including polynomial transformation, 2D- and 3D-affine projections, projective, DLT, and RFM methods. The reference datasets consisted of the points collected over Jilin-1 images, and their object coordinates were measured on the HGM-K & uuml;re. Then, these image and ground coordinates points were input into the GeoEtrim program, in which various transformation models can be implemented. The findings demonstrate that the highest accuracy values were obtained with the RFM using the panchromatic B0 band with 5 m GSD, reaching the sub-pixel accuracy level in both the row and column directions after applying second-order terms. A similar tendency was observed with the B7 and B15 bands with 10 and 20 m GSD, respectively. Above all, it was shown that it is possible to achieve higher accuracy with Jilin-1 imagery, and this level of accuracy meets the requirements needed for topographic mapping applications.

关键词： Chronic kidney disease   tRFs   mechanism   renal fibrosis   beta-catenin  

摘要： BackgroundRenal fibrosis (RF) is a crucial pathological factor in the progression of chronic kidney disease (CKD) to end-stage renal failure. The role of noncoding RNAs (ncRNAs) in CKD has been researched recently. tRNA-derived fragments (tRFs) constitute a class of small ncRNAs originating from tRNAs. To date, the function of tRFs in RF remains unexplored.MethodsHuman small RNA microarray analysis was performed to identify dysregulated tRFs in urine-derived renal tubular epithelial cells from patients with RF. RT-PCR was used for validation in clinical samples. Hydroxylamine-mediated protein precipitation mass spectrometry (Hypro-MS parallel reaction monitoring (PRM and antisense oligonucleotide (ASO)-mediated knockdown were used to investigate the interaction between tRF-1-ArgTCG-1-1 and beta-catenin and its functional role in TGF-beta 1-treated HK-2 cells.ResultsMicroarray profiling identified tRF-1-ArgTCG-1-1 as an upregulated tRF in urine-derived renal tubular epithelial cells from patients with RF. RT-PCR further confirmed that tRF-1-ArgTCG-1-1 expression was significantly increased in urine samples from patients with CKD and was associated with impaired renal function and a higher risk of RF. Hypro-MS and PRM analyses demonstrated an interaction between tRF-1-ArgTCG-1-1 and beta-catenin. ASO-mediated silencing of tRF-1-ArgTCG-1-1 reduced beta-catenin expression in HK-2 cells. Moreover, silencing of tRF-1-ArgTCG-1-1, alone or together with beta-catenin, attenuated TGF-beta 1-induced expression of RF-related markers in vitro.ConclusionsOverall, these findings suggest that renal tubular epithelial cells tRF-1-ArgTCG-1-1 play a key role in RF and that the tRF-1-ArgTCG-1-1/beta-catenin pathway is a potential therapeutic target for CKD and RF.

关键词： Neutrophils   Interleukin-1 beta   reactive oxygen species   mucin   chronic obstructive pulmonary disease  

摘要： Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and excessive mucin production. Two major gel-forming mucins, MUC5AC and MUC5B, correlate with worsened disease progression and pulmonary function. In COPD, neutrophils are important players in chronic inflammation that contribute to tissue damage through releasing reactive oxygen species (ROS). IL-1 beta, a pro-inflammatory cytokine, plays various roles in COPD disease progression. It is known to recruit and activate neutrophils and is also known to induce mucin production in bronchial epithelium. This study aimed to investigate whether IL-1 beta induces ROS production in neutrophils and whether neutrophil-derived ROS drives mucin secretion in bronchial epithelial cells. HL-60-derived neutrophils were treated with IL-1 beta or vehicle and neutrophil ROS production was assessed through flow cytometry. Using a co-culture system, human bronchial epithelial cells were exposed to IL-1 beta-treated neutrophils, and MUC5AC and MUC5B levels on these cells were evaluated at RNA and protein levels through RT-qPCR, immunofluorescence, and ELISAs. IL-1 beta induced neutrophil ROS production. The elevated ROS production in neutrophils induced MUC5AC and MUC5B production at mRNA and protein levels in bronchial epithelial cells. Inhibition of ROS production in neutrophils using a NOX2 inhibitor reduced MUC5AC and MUC5B secretion in bronchial epithelial cells. IL-1 beta-induced neutrophil-derived ROS is a key driver of mucin hypersecretion in bronchial epithelial cells, potentially contributing to COPD disease progression.Trial registration: Not applicable.

关键词： Obesity   BSH   Ligilactobacillus salivarius   GLP-1   UDCA   gut-liver axis  

摘要： Obesity poses a major global health challenge, necessitating safe and effective therapeutic strategies. Using high-throughput genomic screening for bile salt hydrolase (BSH)-producing strains, we identified Ligilactobacillus salivarius (L. salivarius) XA1416, a strain isolated from the feces of healthy individuals, which exhibits high BSH activity, strong acid resistance, and efficient colonization in the gastrointestinal tract. Oral administration of L. salivarius XA1416 counteracted high-fat diet-induced weight gain in mice, improved glucose homeostasis, and enhanced GLP-1 secretion. The strain modulated the gut microbiota, enriching taxa such as Bacteroides, Alistipes, and Faecalibaculum, and altered bile acid profiles, notably increasing ursodeoxycholic acid (UDCA). Mendelian randomization analysis leveraging large-scale human GWAS data and two cross-sectional cohorts' data, complemented by in vitro fecal microbiota fermentation experiments, collectively supports a key role of UDCA in weight control. The oral administration of UDCA recapitulated the anti-obesity effects and metabolic benefits of XA1416, functioning as an intestinal Farnesoid X receptor antagonist and Takeda G-protein-coupled receptor 5 agonist to stimulate GLP-1 secretion. This mechanism likely involves modulation of the hepatic FXR/SHP/SREBP-1c pathway and concurrent activation of the GLP-1 receptor, contributing to improved metabolic homeostasis. Additionally, we gavaged the mice fed with normal chow or a high-fat diet with GR-7, a specific inhibitor of microbial BSHs, leading to a reduction in UDCA level and GLP-1 production. Using HepG2 cell models and molecular dynamics simulations, we further demonstrated that UDCA directly activates the GLP-1 receptor. Taken together, our findings position L. salivarius XA1416 as a promising anti-obesity probiotic, with UDCA serving as a key microbial metabolite that mediates its beneficial metabolic effects.