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Objectives To investigate the molecular characteristics and transferability of plasmid-borne linezolid resistance genes optrA, cfr, poxtA2 and cfr(D) genes in one linezolid-resistant Enterococcus faecalis DM86 from retail meat. Methods E. faecalis DM86 was screened for the presence of known linezolid resistance genes via PCR analysis. Conjugation experiments were used to evaluate the transferability of the resistance genes. The complete genome of E. faecalis DM86 was obtained using both the Illumina and Nanopore platforms. Results Analysis of the complete sequence showed that E. faecalis DM86 belonged to sequence type 116 (ST116). Four linezolid resistance genes were identified on three plasmids, designated as pDM86-2-cfr, pDM86-3-optrA and pDM86-4-poxtA [cfr(D) co-located]. IS1216 mobile elements were found to flank the cfr and optrA locus on these two plasmids. pDM86-3-optrA encoded the RDK-type OptrA protein and a common genetic array of ‘IS1216-fexA-optrA-erm(A)-IS1216’ was identified on this plasmid. The cfr(D) gene was closely associated with the poxtA2 gene on pDM86-4-poxtA, and similar plasmids and structures were reported recently in the E. faecalis of animal origin. The intra- and inter-species horizontal transferability of this plasmid to E. faecalis JH2-2, Enterococcus faecium BM4105RF and Staphylococcus aureus RN4220 was also proved, with a frequency of 2.8 × 10−3, 1.7 × 10−3 and 3.4 × 10−5, respectively. Conclusions This was the first report of the co-existence of up to four plasmid-borne linezolid resistance genes in one E. faecalis. Thus, efficient actions should be exerted to circumvent the microbiota contamination of food and the further spread of these antimicrobial resistance reservoirs.

Pseudomonas aeruginosa is one of the most common opportunistic pathogens causing severe nosocomial infections for its patterns of multidrug resistance, particularly for carbapenems. Timely epidemiological surveillance could greatly facilitate infection control of P. aeruginosa and many deadly pathogens alike. IR Biotyper (IRBT), is a novel real-time typing tool, based on a Fourier-transform infrared (FTIR) spectroscopy system. It is critical to comprehensively establish and evaluate the feasibility of IRBT in P. aeruginosa strain typing. In the current study, we first established standards and schemes for its routine laboratory application, and we found that Mueller–Hinton agar plates give better discriminatory power than blood agar plates. Data showed that the cut-off value of 0.15 with an additional 0.025 range was optimal. Secondly, 27 clinically isolated carbapenem-resistant P. aeruginosa (CRPA) strains collected from October 2010 to September 2011 were evaluated for typing effectiveness by comparing IRBT to the other commonly used typing methods, such as multi-locus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing (WGS)-based typing. When using WGS-based typing as the reference method, the typing method of FTIR spectroscopy (AR = 0.757, SID = 0.749) could better cluster P. aeruginosa strains than MLST and in silico serotyping (AR = 0.544, SID = 0.470). Though PFGE showed the highest discriminatory power, low concordance was observed between PFGE and the other methods. Above all, this study demonstrates the utility of the IRBT as a quick, low-cost, real-time typing tool for the detection of CRPA strains.

This study represented an optimized screening approach for the optrA gene, which is an important mechanism of antimicrobial resistance to linezolid as a last resort for the treatment of infections caused by multiresistant Gram-positive bacteria. We revealed a high fecal carriage rate of the optrA gene among adults by this method and reported the first identification of optrA in Lactococcus formosensis as well as the identification of this gene in Vagococcus lutrae and of the poxtA gene in Ligilactobacillus salivarius of human origin, suggesting the wide spread of the optrA gene in the Gram-positive bacterial community.

The linezolid resistance mediated by

Dissemination of the Klebsiella pneumoniae carbapenemase (KPC)-encoding gene among Enterobacterales is common but relatively rare in Aeromonas spp. In this study, we characterized two KPC-2-producing Aeromonas hydrophila strains (Ah2101 and Ah2111), each isolated from a patient in different intensive care units (ICUs) of a Chinese hospital. Whole-genome sequencing (WGS) revealed simultaneous carriage of the blaKPC−2 and imiH genes, both of which encode high-level carbapenem resistance in these two A. hydrophila isolates. The two isolates were shown to be clonally related and each isolate harbored two distinguishable blaKPC−2-bearing plasmids, only one of which was transferrable to A. hydrophila, but not Escherichia coli EC600 via conjugation. The genetic element that contains blaKPC−2 in these two plasmids, namely ISKpn27-ΔblaTEM−1-blaKPC−2-ISKpn6, was structurally identical, commonly detected in Enterobacterales, and associated with Tn3-based transposons. In addition, more than sixty putative genes that encode various virulence factors were identified in these two A. hydrophila isolates. This is the first study that reports clonal dissemination of carbapenem-resistant A. hydrophila strains carrying structurally different blaKPC−2-bearing plasmids. Further investigation is warranted to monitor the future transmission of blaKPC−2-bearing plasmids in A. hydrophila in clinical settings.

Linezolid resistance has represented a global concern with its wide dissemination among nosocomial pathogens in recent years. One hundred and two linezolid-resistant

Cholesterol gallstone disease is a common global condition. This study investigated the role of plant sterols (PS) in the prevention of gallstone formation and the underlying mechanisms. Adult male mice were fed a lithogenic diet (LD) alone or supplemented with PS (LD-ps), phospholipids (LD-pl) or both PS and phospholipids (LD-ps/pl) for 8 weeks. Incidences of gallstone formation were compared among the groups. Lipids in the bile, liver and serum were analyzed. The expression of genes involved in cholesterol absorption, transport and metabolism in the liver and small intestine was determined. The incidences of gallstone formation were 100% (10/10), 20% (2/10), 100% (10/10) and 40% (4/10) in the LD, LD-ps, LD-pl and LD-ps/pl groups, respectively. Serum cholesterol and intestinal cholesterol absorption were decreased in PS-supplemented mice. The expression of genes related to cholesterol transport and metabolism in the liver was down-regulated by dietary PS. PS supplementation decreased Niemann-Pick C1-like 1 expression in the small intestine and reduced intestinal cholesterol absorption. Our results demonstrated that PS could inhibit intestinal cholesterol absorption and thus prevent cholesterol gallstone formation.

This study reported the identification of a novel ceftazidime-avibactam-resistant KPC-2 variant, KPC-123, in a

Dissemination of the

BackgroundHepatic lipid metabolism regulates biliary composition and influences the formation of cholesterol gallstones. The genes Hmgcr and Cyp7a1, which encode key liver enzymes, are regulated by circadian rhythm-related transcription factors. We aimed to investigate the effect of circadian rhythm disruption on hepatic cholesterol and bile acid metabolism and the incidence of cholesterol stone formation.MethodsAdult male C57BL/6J mice were fed either a lithogenic diet (LD) only during the sleep phase (time-restricted lithogenic diet feeding, TRF) or an LD ad libitum (non-time-restricted lithogenic diet feeding, nTRF) for 4 weeks. Food consumption, body mass gain, and the incidence of gallstones were assessed. Circulating metabolic parameters, lipid accumulation in the liver, the circadian expression of hepatic clock and metabolic genes, and the gut microbiota were analyzed.ResultsTRF caused a dysregulation of the circadian rhythm in the mice, characterized by significant differences in the circadian expression patterns of clock-related genes. In TRF mice, the circadian rhythms in the expression of genes involved in bile acid and cholesterol metabolism were disrupted, as was the circadian rhythm of the gut microbiota. These changes were associated with high biliary cholesterol content, which promoted gallstone formation in the TRF mice.ConclusionDisordered circadian rhythm is associated with abnormal hepatic bile acid and cholesterol metabolism in mice, which promotes gallstone formation.

Recently, there has been an increase in the incidence of malignant tumors among the older population. Moreover, there is an association between aging and cancer. During the process of senescence, the human body suffers from a series of imbalances, which have been shown to further accelerate aging, trigger tumorigenesis, and facilitate cancer progression. Therefore, exploring the junctions of aging and cancer and searching for novel methods to restore the junctions is of great importance to intervene against aging-related cancers. In this review, we have identified the underlying pathogenetic mechanisms of aging-related cancers by comparing alterations in the human body caused by aging and the factors that trigger cancers. We found that the common mechanisms of aging and cancer include cellular senescence, alterations in proteostasis, microbiota disorders (decreased probiotics and increased pernicious bacteria), persistent chronic inflammation, extensive immunosenescence, inordinate energy metabolism, altered material metabolism, endocrine disorders, altered genetic expression, and epigenetic modification. Furthermore, we have proposed that aging and cancer have common means of intervention, including novel uses of common medicine (metformin, resveratrol, and rapamycin), dietary restriction, and artificial microbiota intervention or selectively replenishing scarce metabolites. In addition, we have summarized the research progress of each intervention and revealed their bidirectional effects on cancer progression to compare their reliability and feasibility. Therefore, the study findings provide vital information for advanced research studies on age-related cancers. However, there is a need for further optimization of the described methods and more suitable methods for complicated clinical practices. In conclusion, targeting aging may have potential therapeutic effects on aging-related cancers.

Background and Aim: Chronic atrophic gastritis is a common gastric disease which shows a positive correlation with the occurrence of gastric cancer. Traditional chinese medicines have been used in the treatment of chronic atrophic gastritis. There is no solid evidence for the curative effects of traditional chinese medicines. This study aimed to investigate the clinical efficacy of Weifuchun tablets on patients with chronic atrophic gastritis. Methods 97 patients of chronic atrophic gastritis without current H. pylori infection were divided into two groups: an experiment group treated with Weifuchun and a control group treated with teprenone and folic acid for six months. Pathological examination of gastric biopsies and clinical symptoms assessment were performed for all patients before and after treatments. Primary outcome was the pathological response rate in each group evaluated by changes of histological scores.Secondary outcome was the clinical symptom scores. Results Twenty four patients in the Weifuchun group and twenty eight patients in the control group completed the study. The pathological response rates for atrophy and intestinal metaplasia were 66.7% and 45.8% in the Weifuchun group and 66.7% and 42.9% in the folic acid group, respectively, without statistical significance between groups.Clinical symptoms failed to improve after treatments in either group. Conclusions Weifuchun is effective to improve pathological changes of chronic atrophic gastritis in patients without current H. pylori infection. Monotherapy of Weifuchun had a similar efficacy to the combined therapy by teprenone and folic acid in the treatment of chronic atrophic gastritis. Trial registration: Evaluation of Weifuchun Pills on chronic atrophic gastritis, ChiCTR-IPR-17013939, Registered 15 December 2017, http://www.chictr.org.cn/ showproj.aspx?proj = 23910.

We report herein the design and synthesis of “novel imidazo [1,2- a ]pyridine-3-carboxamides (IPAs)” bearing a variety of different linkers, based on the structure of IMB-1402 discovered in our lab. Results reveal that 2,6-dimethyl- N -[2-(phenylamino)ethyl] IPAs with an electron-donating group on the benzene ring as a potent scaffold. Compounds 26g and 26h have considerable activity (MIC: 0.041–2.64 μM) against drug-sensitive/resistant MTB strains, and they have acceptable safety indices against MTB H37Rv with the SI values of 4395 and 1405, respectively. Moreover, N -[2-(piperazin-1-yl)ethyl] moiety was also identified as a potentially alternative linker (compound 31 ), opening a new direction for further SAR studies.

Background: MicroRNAs (miRNAs) play important roles in post-transcriptional regulation and may serve as targets for the diagnosis and treatment of cancers. Nevertheless, a comprehensive understanding of miRNAs profiles in gastric cancer (GC) progression is still lacking. Methods: Bioinformatics analyses, qRT-PCR, western blotting, and immunohistochemistry were applied for detecting miR-129-5p, HOXC10 and Cyclin D1 expression in GC tissues. Kaplan-Meier analysis with log-rank test was used for survival analyses. ChIP assay was performed for identifying potential gene regulated by HOXC10. Series in vitro and in vivo assays were used for exploring the function of miR-129-5p, HOXC10 and Cyclin D1 in the progression of GC. Findings: MiR-129-5p is downregulated in gastric cancer tissues and inhibits gastric cancer proliferation by inducing cycle cell arrest. MiR-129-5p directly targeted the 3’ untranslated regions (3’ UTR) of HOXC10 mRNA and downregulated its expression. Importantly, miR-129-5p could reverse the oncogenic effect induced by HOXC10. We systemically screened the downstream target of HOXC10 by ChIP-sequencing, and found that HOXC10 could transcriptionally regulate the expression of Cyclin D1 and facilitate G1/S cell cycle transition. Interpretation: MiR-129-5p/HOXC10/Cyclin D1 axis modulates cell cycle and gastric tumorigenesis, which might provide potential prognostic biomarkers and therapeutic targets for gastric cancer patients. Funding Statement: This work was supported by National Natural Science Foundation of China (31771540, 81802348, 81972276); Natural Science Foundation of Zhejiang Province (LY18H160011, LYY19H310011); Fundamental Research Funds for the Central Universities (2017QNA7005); Zhejiang Provincial Medical and Health Science and Technology Project (2018KY464). Declaration of Interests: The authors declare no potential conflicts of interest. Ethical Approval Statement: Animal experimental protocols were approved by the Committee of Animal Ethics of Zhejiang University. Informed written consent was obtained from all participants, and the study was approved by the ethics committee of Sir Run Run Shaw Hospital and The First Affiliated Hospital in Zhejiang University.

The design and synthesis of novel chiral ligands plays an important role in asymmetric catalysis. In this feature article, we describe our recent studies of synthesis, characteration and application of novel chiral macrocyclic ligands. Novel chiral 22-membered macrocyclic ligands have been synthesized and the structures have been determined by an X-ray diffraction study. The catalytic systems in situ generated from the chiral macrocyclic ligand ( R , R , R , R )- 22 and the cheap, readily available Fe3(CO)12 exhibited high activity and excellent enantioselectivity with up to 99% ee in the asymmetric transfer hydrogenation as well as asymmetric hydrogenation of a wide variety of ketones.

A series of novel fluoroquinolone derivatives containing an 3-alkoxyimino-4-(cyclopropylanimo)methylpyrrolidine moiety were designed, synthesized and evaluated for their biological activity. Our results revealed that 19b2 shows good activity against MTB H37Rv ATCC 27294 (MIC