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ABSTRACT: Objectives: This study reports identification of the carbapenemase-encoding gene from carbapenem-resistant Enterobacterales from food animals. Methods: A total of 40 bacterial isolates recovered from 475 faecal swabs obtained on one farm were tested for the presence of the blaNDM-1 gene by PCR. Species identification of three blaNDM-1-positive strains was conducted by MALDI-TOF/MS. Antimicrobial susceptibility testing was performed by broth microdilution. Transferability of the blaNDM-1 and cfr genes was determined by filter mating. The genetic environment of blaNDM-1 and cfr was analysed by whole-genome sequencing. Results: Two Proteus mirabilis (JPM24 and YPM35) and one Providencia rettgeri (YPR25) carried blaNDM-1. The blaNDM-1 genes were located on conjugable pPrY2001-like plasmids often reported to carry important antimicrobial resistance genes (ARGs). YPR25 and YPM35 shared two almost identical conjugable plasmids, one carrying blaNDM-1 and the other cfr. The blaNDM-1 gene in YPR25 (same as YPM35) and JPM24 was located in two novel transposons, designated Tn6922 and Tn6923, respectively. Tn6922 and Tn6923 carried 14 and 7 ARGs, respectively, and both contained multiple copies of IS26 in the same direction, with a high degree of similarity. Additionally, cfr was located on a plasmid with an unreported high frequency of conjugative transfer in YPR25 (same as YPM35). Conclusion: We identified two novel blaNDM-1-containing transposons (Tn6922 and Tn6923) present on pPrY2001-like plasmids. The pPrY2001-like blaNDM-1 plasmids coexisted with a novel cfr plasmid, and both could transfer at high frequency, highlighting the importance of continuous surveillance of multiresistant Enterobacterales of animal origin that can serve as a reservoir for ARGs.

The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biological, nonbiological, biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clinical products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic.

ABSTRACT Understanding the fitness costs associated with plasmid carriage is a key to better understanding the mechanisms of plasmid maintenance in bacteria. In the current work, we performed multiple serial passages (63 days, 627.8 generations) to identify the compensatory mechanisms that Salmonella enterica serovar Typhimurium ATCC 14028 utilized to maintain the multidrug-resistant (MDR) IncHI2 plasmid pJXP9 in the presence and absence of antibiotic selection. The plasmid pJXP9 was maintained for hundreds of generations even without drug exposure. Endpoint evolved (the endpoint of evolution) S. Typhimurium bearing evolved plasmids displayed decreased growth lag times and a competitive advantage over ancestral pJXP9 plasmid-carrying ATCC 14028 strains. Genomic and transcriptomic analyses revealed that the fitness costs of carrying pJXP9 were derived from both specific plasmid genes and particularly the MDR regions and conjugation transfer region I and conflicts resulting from chromosome-plasmid gene interactions. Correspondingly, plasmid deletions of these regions could compensate for the fitness cost that was due to the plasmid carriage. The deletion extent and range of large fragments on the evolved plasmids, as well as the trajectory of deletion mutation, were related to the antibiotic treatment conditions. Furthermore, it is also adaptive evolution that chromosomal gene mutations and altered mRNA expression correlated with changed physiological functions of the bacterium, such as decreased flagellar motility, increased oxidative stress, and fumaric acid synthesis but increased Cu resistance in a given niche. Our findings indicated that plasmid maintenance evolves via a plasmid-bacterium adaptative evolutionary process that is a trade-off between vertical and horizontal transmission costs along with associated alterations in host bacterial physiology. IMPORTANCE The current idea that compensatory evolution processes can account for the “plasmid paradox” phenomenon associated with the maintenance of large costly plasmids in host bacteria has attracted much attention. Although many compensatory mutations have been discovered through various plasmid-host bacterial evolution experiments, the basis of the compensatory mechanisms and the nature of the bacteria themselves to address the fitness costs remain unclear. In addition, the genetic backgrounds of plasmids and strains involved in previous research were limited and clinical drug resistance such as the poorly understood compensatory evolution among clinically dominant multidrug-resistant plasmids or clones was rarely considered. The IncHI2 plasmid is widely distributed in Salmonella Typhimurium and plays an important role in the emergence and rapid spread of its multidrug resistance. In this study, the predominant multidrug-resistant IncHI2 plasmid pJXP9 and the standard Salmonella Typhimurium ATCC 14028 bacteria were used for evolution experiments under laboratory conditions. Our findings indicated that plasmid maintenance through experimental evolution of plasmid-host bacteria is a trade-off between increasing plasmid vertical transmission and impairing its horizontal transmission and bacterial physiological phenotypes, in which compensatory mutations and altered chromosomal expression profiles collectively contribute to alleviating plasmid-borne fitness cost. These results provided potential insights into understanding the relationship of coexistence between plasmids encoding antibiotic resistance and their bacterial hosts and provided a clue to the adaptive forces that shaped the evolution of these plasmids within bacteria and to predicting the evolution trajectory of antibiotic resistance.

ABSTRACT Types 1 and 3 fimbriae in Enterobacteriaceae play versatile roles in bacterial physiology including attachment, invasion, cell motility as well as with biofilm formation and urinary tract infections. Herein, we investigated the prevalence and transmission of plasmid-mediated types 1 and 3 fimbriae from 1753 non-duplicate Enterobacteriaceae from diseased food Animals. We identified 123 (7.01%) strong biofilm producers and all was identified as E. coli. WGS analysis of 43 selected strong biofilm producers revealed that they harbored multiple ARGs, including ESBLs, PMQR and mcr-1. The gene clusters mrkABCDF and fimACDH encoding types 1 and 3 fimbriae, respectively, were identified among 43 (34.96%) and 7 (5.7%) of 123 strong biofilm isolates, respectively. These two operons were able to confer strong biofilm-forming ability to an E. coli weak-biofilm forming laboratory strain. Plasmid analysis revealed that mrk and fim operons were found to co-exist with ARGs and were primarily located on IncX1 and IncFII plasmids with similar backbones, respectively. mrkABCDF operons was present in all of 9457 Klebsiella pneumoniae using archived WGS data, and shared high homology to those on plasmids of 8 replicon types and chromosomes from 6 Enterobacteriaceae species from various origins and countries. In contrast, fimACDH operons was present in most of Enterobacter cloacae (62.15%), and shared high homology to those with only a small group of plasmids and Enterobacteriaceae species. This is the first comprehensive report of the prevalence, transmission and homology of plasmid-encoded type 1 and 3 fimbriae among the Enterobacteriaceae. Our findings indicated that plasmid-encoded mrkABCDF and fimACDH were major contributors to enhanced biofilm formation among E. coli and these two operons, in particular mrk could be as a potential anti-biofilm target. IMPORTANCE Biofilms allow bacteria to tolerate disinfectants and antimicrobials, as well as mammalian host defenses, and are therefore difficult to treat clinically. Most research concerning biofilm-related infections is typically focused on chromosomal biofilm-associated factors, including types 1 and 3 fimbriae of biofilm-forming Enterobacterium. However, the transmission and homology of the mobile types 1 and 3 fimbriae among Enterobacteriaceae is largely unknown. The findings revealed that the plasmid-encoded type 3 fimbriae encoded by mrkABCDF and type 1 fimbriae encoded by fimACDH were major contributors to enhancing biofilm formation among strong biofilm E. coli from diseased food producing animals. Additionally, mrk operon with high homology at an amino acid sequence was present both on plasmids of various replicon types and on chromosomes from diverse Enterobacteriaceae species from numerous origins and countries. These findings provide important information on the transmission of the mobile types 1 and 3 fimbriae among Enterobacteriaceae, indicating a potential antibiofilm target.

ObjectiveThis study aimed to explore the expression and effect of the nuclear receptor subfamily 2 group F member 6 (NR2F6) gene in non-small cell lung cancer (NSCLC) and provide an experimental basis for the targeted therapy of NSCLC.MethodFirst, the expression of NR2F6 in lung cancer tissues was analyzed using the Gene Expression Omnibus and the Cancer Genome Atlas (TCGA) databases, and the expression of NR2F6 in lung cancer tissues and cells was verified by Western blotting and quantitative polymerase chain reaction. Next, the relationship between NR2F6 expression and the clinicopathological features of lung cancer was analyzed via immunohistochemistry, and the relationship between NR2F6 expression and prognosis was analyzed using the Kaplan–Meier Plotter. The influence of NR2F6 knockdown on the proliferation capacity of lung cancer cells was then verified at cell level. Finally, the expression of heterogeneous nuclear ribonucleoprotein D (HNRNPD) in lung cancer tissue was analyzed using the TCGA database and immunohistochemistry. The impact of HNRNPD knockdown on the proliferation capacity of lung cancer cells was verified at cell level, and the relationship between NR2F6 and HNRNPD was verified by co-immunoprecipitation.ResultsNR2F6 was highly expressed in lung cancer tissues and cells, and its expression was positively correlated with the depth of invasion, lymphatic metastasis, and clinical stage of lung cancer. High expression of NR2F6 in lung cancer was also significantly associated with poor prognosis. At cell level, NR2F6 knockdown was found to inhibit the proliferation of H460 and H358 in lung cancer cells. Furthermore, the TCGA database and immunohistochemical results showed that HNRNPD was highly expressed in lung cancer tissues and was highly consistent with NR2F6 expression in these tissues. Knockdown of HNRNPD also inhibited the proliferation of lung cancer cells. The co-immunoprecipitation experiment verified that NR2F6 interacted with HNRNPD.ConclusionNR2F6 may interact with HNRNPD to jointly regulate the progression of lung cancer, and this conclusion provides a new experimental basis for the study of the molecular targeted therapy of NSCLC.

BackgroundKidney cancer (KC) is one of the most challenging cancers due to its delayed diagnosis and high metastasis rate. The 5-year survival rate of KC patients is less than 11.2%. Therefore, identifying suitable biomarkers to accurately predict KC outcomes is important and urgent.MethodsCorresponding data for KC patients were obtained from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) databases. Systems biology/bioinformatics/computational approaches were used to identify suitable biomarkers for predicting the outcome and immune landscapes of KC patients.ResultsWe found two ferroptosis- and immune-related differentially expressed genes (FI-DEGs) (Klotho (KL) and Sortilin 1 (SORT1)) independently correlated with the overall survival of KC patients. The area under the curve (AUC) values of the prognosis model using these two FI-DEGs exceeded 0.60 in the training, validation, and entire groups. The AUC value of the 1-year receiver operating characteristic (ROC) curve reached 0.70 in all the groups.ConclusionsOur present study indicated that KL and SORT1 could be prognostic biomarkers for KC patients. Whether this model can be used in clinical settings requires further validation.

Background: Ferroptosis and immunity are novel treatments that target several cancers, including kidney renal clear cell carcinoma (KIRC). Long noncoding RNAs (lncRNAs) are an important class of gene expression regulators that play fundamental roles in the regulation of ferroptosis and immunity. We aimed to identify ferroptosis- and immune-related lncRNAs as biomarkers in patients with KIRC.Methods: Corresponding data for each patient with KIRC were obtained from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate Cox regression analyses were used to identify candidate biomarkers followed by least absolute shrinkage and selection operator (LASSO) regression analyses, weighted gene coexpression network analysis (WGCANA), and gene set enrichment analysis (GSEA).Results: Three ferroptosis- and immune-related differentially expressed lncRNAs (FI-DELs) (AC124854.1, LINC02609, and ZNF503-AS2) were markedly and independently correlated with the overall survival (OS) of patients with KIRC. The area under the curve (AUC) value of the prognostic model in the entire group using the three FI-DELs was > 0.70. The sensitivity and specificity of the diagnostic model using the three FI-DELs were 0.8586 and 0.9583, respectively.Conclusion: The present study found that AC124854.1, LINC02609, and ZNF503-AS2 were considerably and independently correlated with the OS of patients with KIRC, suggesting that the three FI-DELs could be used as prognostic and diagnostic biomarkers for patients with KIRC.

Highly stretchable aerogel films are attractive for advanced next‐generation stretchable electronics. However, it is a great challenge to achieve high stretchability for aerogel films. Here, several types of unprecedented ultra‐stretchable semiconducting polymer‐based aerogel films with crimpled porous structures are developed via crosslinking and template methods combined with uniaxial and biaxial pre‐stretching strategies. The semiconducting aerogel films obtained by uniaxial pre‐stretching exhibit ultrahigh stretchability up to 100–200%, while those obtained by biaxial pre‐stretching show high biaxial stretchability up to 50%. The resulting aerogel films show strain‐insensitive electrical and joule heating properties. A prototype of the aerogel film‐based stretchable organic electrochemical transistor (OECT) is developed for the first time. Benefiting from their unique porous structures, the aerogel film‐based OECTs exhibit enhanced on/off ratio and transconductance compared with corresponding dense film‐based OECTs, high stretchability up to 100%, and high stretching stability with 10 000 stretching cycles under 30% strain. It is demonstrated that the aerogel film‐based OECTs can be applied as high‐performance stretchable artificial synapses and biosensors. This work gives a versatile strategy toward highly stretchable aerogel films promising for flexible electronics. [ABSTRACT FROM AUTHOR]

Abstract Background Colorectal cancer (CRC) is the second most prevalent cancer, as it accounts for approximately 10% of all annually diagnosed cancers. Studies have indicated that DNA methylation is involved in cancer genesis. The purpose of this study was to investigate the relationships among DNA methylation, gene expression and the tumor-immune microenvironment of CRC, and finally, to identify potential key genes related to immune cell infiltration in CRC. Methods In the present study, we used the ChAMP and DESeq2 packages, correlation analyses, and Cox regression analyses to identify immune-related differentially expressed genes (IR-DEGs) that were correlated with aberrant methylation and to construct a risk assessment model. Results Finally, we found that HSPA1A expression and CCRL2 expression were positively and negatively associated with the risk score of CRC, respectively. Patients in the high-risk group were more positively correlated with some types of tumor-infiltrating immune cells, whereas they were negatively correlated with other tumor-infiltrating immune cells. After the patients were regrouped according to the median risk score, we could more effectively distinguish them based on survival outcome, clinicopathological characteristics, specific tumor-immune infiltration status and highly expressed immune-related biomarkers. Conclusion This study suggested that the risk assessment model constructed by pairing immune-related differentially expressed genes correlated with aberrant DNA methylation could predict the outcome of CRC patients and might help to identify those patients who could benefit from antitumor immunotherapy.

Abstract Background Kidney renal clear cell carcinoma (KIRC) is the most common type of kidney cell carcinoma which has the worst overall survival rate. Almost 30% of patients with localized cancers eventually develop to metastases despite of early surgical treatment carried out. MicroRNAs (miRNAs) play a critical role in human cancer initiation, progression, and prognosis. The aim of our study was to identify potential prognosis biomarkers to predict overall survival of KIRC. Methods All data were downloaded from an open access database The Cancer Genome Atlas. DESeq2 package in R was used to screening the differential expression miRNAs (DEMs) and genes (DEGs). RegParallel and Survival packages in R was used to analysis their relationships with the KIRC patients. David version 6.8 and STRING version 11 were used to take the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Results We found 2 DEGs (TIMP3 and HMGCS1) and 3 DEMs (hsa-miR-21-5p, hsa-miR-223-3p, and hsa-miR-365a-3p) could be prognosis biomarkers for the prediction of KIRC patients. The constructed prognostic model based on those 2 DEGs could effectively predict the survival status of KIRC. And the constructed prognostic model based on those 3 DEMs could effectively predict the survival status of KIRC in 3-year and 5-year. Conclusion The current study provided novel insights into the miRNA related mRNA network in KIRC and those 2 DEGs biomarkers and 3 DEMs biomarkers may be independent prognostic signatures in predicting the survival of KIRC patients.

IntroductionThe aim of this work was to determine the feasibility of using a deep learning approach to predict occult lymph node metastasis (OLM) based on preoperative FDG-PET/CT images in patients with clinical node-negative (cN0) lung adenocarcinoma.Materials and MethodsDataset 1 (for training and internal validation) included 376 consecutive patients with cN0 lung adenocarcinoma from our hospital between May 2012 and May 2021. Dataset 2 (for prospective test) used 58 consecutive patients with cN0 lung adenocarcinoma from June 2021 to February 2022 at the same center. Three deep learning models: PET alone, CT alone, and combined model, were developed for the prediction of OLM. The performance of the models was evaluated on internal validation and prospective test in terms of accuracy, sensitivity, specificity, and areas under the receiver operating characteristic curve (AUCs).ResultsThe combined model incorporating PET and CT showed the best performance, achieved an AUC of 0.81 [95% confidence interval (CI): 0.61, 1.00] in the prediction of OLM in internal validation set (n = 60) and an AUC of 0.87 (95% CI: 0.75, 0.99) in the prospective test set (n = 58). The model achieved 87.50% sensitivity, 80.00% specificity, and 81.00% accuracy in the internal validation set and achieved 75.00% sensitivity, 88.46% specificity, and 86.60% accuracy in the prospective test set.ConclusionThis study presented a deep learning approach to enable the prediction of occult nodal involvement based on the PET/CT images before surgery in cN0 lung adenocarcinoma, which would help clinicians select patients who would be suitable for sublobar resection.

Salmonella enterica can lead to intestinal diarrhea, and the emergence and spread of cephalosporin-resistant Salmonella have brought great challenges to clinical treatment. Therefore, this study investigated the prevalence and transmission of blaCTX-M genes among S. Typhimurium from diarrhoeal outpatients in Guangdong, China, from 2010 to 2017. A total of 221 blaCTX-M-positive isolates were recovered from 1,263 S. Typhimurium isolates from the facal samples of diarrhoea patients in 45 general hospitals from 11 cities. The most popular CTX-M gene was blaCTX-M-55 (39.6%, 72/182) in the CTX-M-1 group, followed by blaCTX-M-14 (22.5%, 41/182) and blaCTX-M-65 (19.2%, 35/182) in the CTX-M-9 group. The isolates that carried blaCTX-M-9G had significantly higher resistance rates to multiple antibacterials compared with blaCTX-M-1G (p 50%, and it first reported the emergence of blaTEM-141 in S. Typhimurium. This study underscores the importance of surveillance for blaCTX-M-positive microbes in diarrhea patients.

BackgroundAlmost 40% of patients with kidney renal clear cell carcinoma (KIRC) with advanced cancers eventually develop to metastases, and their 5-year survival rates are approximately 10%. Aberrant DNA methylations are significantly associated with the development of KIRC. The aim of our present study was to identify suitable ferroptosis- and immune-related (FI) biomarkers correlated with aberrant methylations to improve the prognosis and diagnosis of KIRC.MethodsChAMP and DESeq2 in R (3.6.2) were used to screen the differentially expressed methylation probes and differentially expressed genes, respectively. Univariate and multivariate Cox regression were used to identify the overall survival (OS)–related biomarkers.ResultsWe finally identified five FI biomarkers (CCR4, CMTM3, IFITM1, MX2, and NR3C2) that were independently correlated with the OS of KIRC. The area under the curve value of the receiver operating characteristic value of prognosis model was 0.74, 0.68, and 0.72 in the training, validation, and entire cohorts, respectively. The sensitivity and specificity of the diagnosis model were 0.8698 and 0.9722, respectively. In addition, the prognosis model was also significantly correlated with several immune cells and factors.ConclusionOur present study suggested that these five FI-DEGs (CCR4, CMTM3, IFITM1, MX2, and NR3C2) could be used as prognosis and diagnosis biomarkers for patients with KIRC, but further cross-validation clinical studies are still needed to confirm them.