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Objectives: The objective of this study was to investigate the resistance mechanisms of a multidrug-resistant Salmonella Kentucky ST198 FJ-2064 isolated from a patient in China. Methods: The antimicrobial susceptibility of FJ-2064 was determined by the standard disc dilution and broth microdilution methods. The complete genome of FJ-2064 was sequenced using PacBio and Illumina MiSeq platforms. Polymerase chain reaction (PCR) and S1-PFGE were utilized to confirm the mutation sites and the genomic plasmids, respectively. Results: Isolate FJ-2064 belongs to sequence type ST198 and harboured no visible large plasmids, but was concurrent resistant to 22 detected antimicrobial agents including cefotaxime, ciprofloxacin, and azithromycin. The complete genome sequence identified 20 acquired antibiotic resistance genes (ARGs) and five chromosomal mutations in the gyrA and parC genes of the quinolone resistance determining regions (QRDRs) in FJ-2064. In addition, PCR sequencing confirmed that most of the ARGs were clustered on one multidrug-resistant region and a variant of SGI1-K. In particular, the bla-TEM-1 and bla-CTX−M-55, qnrS1, mph(A) genes, which confer resistance to cephalosporins, quinolones, and macrolides respectively, were all located on the multidrug-resistant region. Conclusions: We have demonstrated one multidrug-resistant region and a variant of SGI1-K in a Salmonella Kentucky ST198 that is co-resistant to cefotaxime, ciprofloxacin, and azithromycin.

Circular RNAs (circRNAs) play a critical regulatory role in degenerative diseases; however, their functions and therapeutic applications in intervertebral disc degeneration (IVDD) have not been explored. Here, we identified that a novel circATXN1 highly accumulates in aging nucleus pulposus cells (NPCs) accountable for IVDD. CircATXN1 accelerates cellular senescence, disrupts extracellular matrix organization, and inhibits mitochondrial respiration. Mechanistically, circATXN1, regulated by heterogeneous nuclear ribonucleoprotein A2B1-mediated splicing circularization, promotes progerin translocation from the cell nucleus to the cytoplasm and inhibits the expression of insulin-like growth factor 1 receptor (IGF-1R). To demonstrate the therapeutic potential of circATXN1, siRNA targeting the backsplice junction of circATNX1 was screened and delivered by tetrahedral framework nucleic acids (tFNAs) due to their unique compositional and tetrahedral structural features. Our siRNA delivery system demonstrates superior abilities to transfect aging cells, clear intracellular ROS, and enhanced biological safety. Using siRNA–tFNAs to silence circATXN1, aging NPCs exhibit reduced mislocalization of progerin in the cytoplasm and up-regulation of IGF-1R, thereby demonstrating a rejuvenated cellular phenotype and improved mitochondrial function. In vivo, administering an aging cell-adapted siRNA nucleic acid framework delivery system to progerin pathologically expressed premature aging mice (zmpste24−/−) can ameliorate the cellular matrix in the nucleus pulposus tissue, effectively delaying IVDD. This study not only identified circATXN1 functioning as a cell senescence promoter in IVDD for the first time, but also successfully demonstrated its therapeutic potential via a tFNA-based siRNA delivery strategy.

Abstract The pumped storage power station (PSPS) is an important measure to achieve the strategic goal of “dual carbon”. As one of the preferred types for the upper reservoir dams of PSPSs, the concrete-faced rockfill dam (CFRD) often has a dam foundation on a steep transverse slop and is prone to produce slip deformation along the slope, resulting in poor anti-sliding stability of the dam slope. It is dangerous for the operation safety of PSPSs. Therefore, the slip deformation of CFRDs on dam foundations with large dip angles is investigated. The mechanism for the initiation of slip deformation is revealed. The design measures of physical mechanic and geometric structure are proposed to reduce slip deformation. The results show that the larger sliding forces and smaller anti-sliding forces are the fundamental reasons that CFRDs on dam foundations with large dip angles are prone to produce slip deformation. The larger the dip angle of the dam foundation, the larger the slip deformation of the dam body and face slab, and the smaller the safety factor of the dam slope. When the dip angle of the dam foundation is greater than 15°, the safety factor of the dam slope is less than the minimum value of 1.5 required by codes. The addition of pressure slopes can effectively reduce the slip deformation of the dam body or face slab and significantly improve the anti-sliding stability of the dam slope. When the height or width of the pressure slope platform is greater and the cohesion or internal friction angle of the pressure slope is larger, the slip deformations of the dam body and face slab are smaller, and the safety factor of the dam slope is greater. It is recommended that the height and width of the pressure slope platform be 1/2 times the maximum height of the main dam, and the density (cohesion and internal friction angle) of the pressure slope be equivalent to that of the main dam’s rockfill material. The research results can provide theoretical and technical support for the design and construction of CFRDs for the upper reservoir of PSPSs.