Tick-borne encephalitis virus (TBEV) has been classified into three subtypes, namely the European (Eu-TBEV), Far Eastern (FE-TBEV), and Siberian (Sib-TBEV). In this study, we discovered a new subtype of TBEV in wild rodent Marmota himalayana in Qinghai-Tibet Plateau in China, proposed as subtype Himalayan (Him-TBEV). Two complete genomes of TBEV were obtained from respiratory samples of 200 marmots. The phylogenetic analysis using the E protein and polyprotein demonstrated that the two strains of Him-TBEV formed an independent branch, separated from Eu-TBEV, Sib-TBEV, and FE-TBEV. The nomenclature of Him-TBEV as a new subtype was also supported by comparative analysis using nucleotide and amino acid sequences of E protein and polyprotein. For E protein, The Him-TBEV showed 82.6–84.6% nucleotide identities and 92.7–95.0% amino acid identities with other three subtypes. For polyprotein, the Him-TBEV showed 83.5–85.2% nucleotide identities and 92.6–94.2% amino acids identities with other three subtypes. Furthermore, of 69 amino acid substitutions profiles detected in complete polyprotein of 112 strains of TBEV, Him-TBEV subtype displayed unique amino acids in the 36 positions. Notably, for the subtype-specific amino acid position 206 of E protein, Him-TBEV shared the Val with Eu-TBEV, but differed from FE-TBEV and Sib-TBEV. The evolutionary analysis with BEAST suggested that Him-TBEV diverged from other subtypes of eastern TBEV group about 2469 years ago. It should be mentioned that Qinghai-Tibet Plateau in China is the plague endemic region where Marmota himalayana is the primary host. The public health significance of discovery of Him-TBEV in Marmota himalayana must be carefully evaluated.

The emergence and spread of mobilized colistin resistance (mcr) genes have triggered extensive concerns worldwide. Here, we characterized the global distribution of mcr-9, a newly-identified variant of mcr, by assembling the data set of mcr-9-positive isolates from GenBank database and the literature available. Genetic features of all the mcr-9-harboring plasmids were determined by bioinformatic analysis. We showed that mcr-9 is globally distributed in 21 countries across six continents, with a wide dissemination among various species of Enterobacteriaceae strains from human, animal, food and environment. IncHI2-ST1 plasmids were found to be the predominant replicon type carrying mcr-9. Comparative genomics highlighted that IncHI2-type plasmids may also serve as a critical reservoir of mcr-9, from which different types of circulating plasmids acquired the mcr-9. Results revealed that the rcnR-rcnA-pcoE-pcoS-IS903-mcr-9-wbuC structure was consistent in most mcr-9 cassettes, suggesting a relatively unitary model involved in the mobilization of mcr-9. It is most likely that the spread of mcr-9 was mainly attributed to the conjugation and recombination events of mcr-9-carrying plasmids. In summary, our results provide a comprehensive picture of the distribution and genetic environment of mcr-9, and demonstrate the central roles played by IncHI2 plasmids in the worldwide dissemination of mcr-9. Antibiotic resistance poses a great threat to global public health and carbapenem-resistant Enterobacteriaceae is triggering a health crisis worldwide 1,2. Colistin, a cationic cyclic-peptide, is one of the last-resort antibiotics to defend against severe infections caused by carbapenem-resistant Enterobacteriaceae 3. However, since the initial discovery of a plasmid-mediated mobilized colistin resistance gene (mcr-1) in China in late 2015 4 , a number of diversified bacterial strains carrying mcr-1 have been detected across over 50 countries covering six continents 5. The prevalent plasmid-borne MCR enzyme can catalyze chemical addition of phosphoethanolamine to lipid A moiety of bacterial lipopolysaccharides, the target of colistin, which consequently promotes colistin resistance 6. In recent years, a growing number of mcr-like genes (namely, from mcr-2 to mcr-10) have been identified 7-14. These ongoing discoveries indicate a rapid evolution of MCR family under selective pressures, which raise global health concerns. mcr-9 is a newly emerging variant of the mobilized colistin resistance determinants, which was first identified in a clinical Salmonella enterica isolate in the USA in May, 2019 13. Since its initial identification, mcr-9 has been reported in several other countries, such as China 15 , Sweden 16 , and France 17. Not only that, in silico analysis using the GenBank database indicated that mcr-9 had already been presented in a number of Enterobacteriaceae isolates recovered worldwide 13,17. The high prevalence of mcr-9 suggests one more threat to public health. However, little information is available about the glo...

Esophageal cancer micro environment factor WNT2 was critical in cancer metastasis. However, very little is known about WNT2 receptors and their role in the malignant progression of ESCC. The clinical significance and underlying molecular mechanisms of FZD2, one of the receptors of WNT2, was further investigated in ESCC. We found that FZD2 expression was positively correlated with WNT2 levels in clinical ESCC specimens through database analysis. Upregulated FZD2 expression was detected in 69% (69/100) of the primary ESCC cases examined, and increased FZD2 expression was significantly correlated with poor prognosis (P < 0.05). Mechanistically, FZD2 induced the migration and invasion of ESCC cells by regulating the FZD2/STAT3 signaling. In vivo xenograft experiments further revealed the metastasis-promoting role of FZD2 in ESCC. Moreover, we found that the WNT2 ligand could stabilize and phosphorylate the FZD2 receptor by attenuating FZD2 ubiquitination, leading to the activation of STAT3 signaling and the initiation of ESCC cell metastasis. Collectively, our data revealed that a novel non-canonical WNT2/FZD2/STAT3 signaling axis is critical for ESCC progression. Strategies targeting this specific signaling axis might be developed to treat patients with ESCC.

Raoultella planticola is an emerging pathogen causing several infections in humans, and its roles in the propagation of antibiotic resistance genes (ARGs) remain uncharacterized. In this study, a carbapenem and tigecycline-resistant R. planticola isolate was recovered from hospital sewage. It carried nine plasmids, bearing 30 ARGs, including one blaKPC-2 and two blaNDM-1. It also contained a plasmid-borne efflux pump gene cluster, tmexCD1-toprJ, conferring resistance to tigecycline. Analysis of plasmid sequences revealed that both blaNDM-1-carrying plasmids were highly similar to those recovered from humans, reinforcing the close relatedness of environmental and clinical isolates. We also identified that plasmid bearing blaNDM-1 or tmexCD1-toprJ1 was transferable, and can be stabilized in the host bacteria, indicating that the R. planticola isolate has a considerable potential in the dissemination of ARGs. Besides, we found that this isolate could produce biofilm and was virulent in a Galleria mellonella infection model. In conclusion, our study shows the convergence of virulence and multidrug resistance in a R. planticola isolate. This potentially virulent superbug may disseminate into its receiving rivers, and finally to humans through cross-contamination during recreation activities or daily use of water, which poses a risk to public health.

Shear stress exerted by the blood stream modulates endothelial functions through altering gene expression. KLF2 and KLF4, the mechanosensitive transcription factors, are promoted by laminar flow to maintain endothelial homeostasis. However, how the expression of KLF2/4 is regulated by shear stress is poorly understood. Here, we showed that the activation of PIEZO1 upregulates the expression of KLF2/4 in endothelial cells. Mice with endothelial-specific deletion of Piezo1 exhibit reduced KLF2/4 expression in thoracic aorta and pulmonary vascular endothelial cells. Mechanistically, shear stress activates PIEZO1, which results in a calcium influx and subsequently activation of CaMKII. CaMKII interacts with and activates MEKK3 to promote MEKK3/MEK5/ERK5 signaling and ultimately induce the transcription of KLF2/4. Our data provide the molecular insight into how endothelial cells sense and convert mechanical stimuli into a biological response to promote KLF2/4 expression for the maintenance of endothelial function and homeostasis.