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Background Leukemia is a group of hematopoietic malignancies characterized by the accumulation and infiltration of abnormal hematopoietic stem cells or early progenitor cells. T cell acute lymphoblastic leukemia (T-ALL) is a hematologic malignancy occurring in 15 % of pediatric and 25 % of adult ALL cases. Infiltration and metastasis of leukemic cells to specific organs are consequences of disease relapse and dismal prognosis. Long non-coding RNAs (lncRNAs) have been identified to function in the migration, invasion and infiltration of tumors by regulating gene expression. Our previous studies showed that CC chemokine receptor 9 (CCR9), which specifically bind to CC chemokine ligand 25 (CCL25), promotes T-ALL infiltration. Methods Bioinformatic methods were used to screen LINC00853 in gene expression omnibus (GEO) datasets. RT-qPCR, western bolt and flow cytometry were applied to detect the expression of LINC00853 and CCR9. Transwell and martrigel-transwell were employed to assess the cells migration and invasion abilities. Fluorescence microscope was applied to observed the green fluorescence protein positive (GFP+) cells. Lentivirus and adenovirus were packed to construct nc-blank, sh-LINC00853-blank and sh-LINC00853-rescue jurkat cell lines. Results In this study, we found out the negative correlation of LINC00853 and CCR9 expression. LINC00853 was downregulated while CCR9 was upregulated in GEO datasets, T-ALL cell lines and clinical samples. Moreover, LINC00853 suppressed jurkat cells migration and invasion in vitro and restrained infiltration in liver, spleen, kidney, lung, brain, ovary of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Conclusions These findings indicate that LINC00853 restrains T-ALL cell invasion and infiltration by regulating CCR9/CCL25.

Background Stress urinary incontinence (SUI), which causes involuntarily leakage of urine, has an impact on many women and may affect self-efficacy, which, in turn, can lead to poor health-related quality of life (QOL). This study aimed to explore the effects of sociodemographic and health information, symptom distress, self-efficacy, and positive thinking on the health-related QOL (general QOL and urinary incontinence-specific QOL) of women with SUI. Methods A cross-sectional study design was used. Women with SUI were recruited from the obstetrics and gynecology outpatient department and urodynamics examination room of a hospital by convenience sampling from August 2021 to March 2022. Participants were surveyed on the following questionnaires: Urogenital Distress Inventory, Geriatric Self-efficacy Index for Urinary Incontinence, Positive Thinking Scale, 12-Item Short-Form Health Survey (SF-12), and Incontinence Impact Questionnaire Short Form. Results Participants (N = 135) had a mean age of 53.76 years old. The mean SF-12 physical component summary score was 48.48 (physical QOL), and the mental component summary score was 46.56 (mental QOL). The urinary incontinence-specific QOL score was 16.01. Women with greater positive thinking and higher self-efficacy for urinary incontinence had better physical and mental QOL. Women with less symptom distress of urinary incontinence and higher self-efficacy for urinary incontinence had better urinary incontinence-specific QOL. Conclusion The health-related QOL of women with SUI is affected by many factors, including positive thinking, self-efficacy, and symptom distress. Healthcare professionals can provide multifaceted programs to improve the health-related QOL of women with SUI.

Background The increasing use of colistin causes a serious breach in our last line of defence against MDR Gram-negative pathogens. Our previous study showed that CpxR overexpression increases the susceptibility of acrB and cpxR double-deleted Salmonella enterica serovar Typhimurium to colistin. Objectives To identify the mechanism of CpxAR and efflux pumps that synergistically enhance the susceptibility of S. Typhimurium to colistin. Methods A series of cpxR- and tolC-deleted mutants and a cpxR-complemented strain from a multidrug-susceptible standard strain of S. Typhimurium (JS) were generated in our previous study. Herein, we investigated the susceptibility of these strains to colistin through the broth microdilution method, time–kill curves and survival assays. Growth curves were measured by OD600 in LB broth, tryptone-soy broth (TSB) and M9-glucose (0.2%) minimal media. Finally, molecular mechanisms underlying the mode of action were elucidated by transcriptomic analysis. Results We found that in contrast to JS (0.8 mg/L), the MIC of colistin for JSΔtolC::kan showed a 16-fold decrease (0.05 mg/L). Notably, JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR were associated with a 256-fold decrease (0.0031 mg/L) compared with JS. Growth curves identified that JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR displayed a markedly lower growth rate and poorer adaptability. In addition, time–kill curves and survival assays showed that JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR were more susceptible to colistin. Lastly, double deletion of cpxR and tolC enhanced oxidative damage through promoting oxidative phosphorylation, the tricarboxylic acid (TCA) cycle and trimethylamine N-oxide (TMAO) respiration. Conclusions Our findings revealed that double deletion of cpxR and tolC significantly increases the susceptibility of S. Typhimurium to colistin.

Exercise preconditioning (EP) provides protective effects for acute cardiovascular stress; however, its mechanisms need to be further investigated. Autophagy is a degradation pathway essential for myocardium health. Therefore, we investigated whether intermittent myocardial ischemia-hypoxia affected Beclin1 and whether the changes in autophagy levels contribute to EP-induced early myocardial protective effects. Rats were trained on a treadmill using an EP model (four cycles of 10 minutes of running/10 minutes of rest). Exhaustive exercise (EE) was performed to induce myocardial injury. Cardiac troponin I (cTnI) and ischemia-hypoxia staining were used to evaluate myocardial injury and protection. Double-labeled immunofluorescence staining and western blot analysis were employed to examine related markers. EP attenuated the myocardial ischemic-hypoxic injury induced by EE. Compared with the control (C) group, the dissociations of Beclin1/Bcl-2 ratio and Beclin1 expression were both higher in all other groups. Compared with the C group, PI3KC3 and the LC3-II/LC3-I ratio were higher in all other groups, whereas LC3-II was higher in the EE and EEP + EE groups. p62 was higher in the EE group than in the C group but lower in the EEP + EE group than in the EE group. We concluded that EP increases Beclin1 via intermittent myocardial ischemia-hypoxia and induces autophagy, which exerts early myocardial protective effects and reduces the myocardial ischemic-hypoxic injury induced by exhaustive exercise.

The emergence and rapid spread of multidrug resistant (MDR) Gram-negative bacteria have posed a serious threat to global health and security. Because of the time-consuming, high cost and high risk of developing new antibiotics, a significant method is to use antibiotic adjuvants to revitalize the existing antibiotics. The purpose of the study is to research the traditional Chinese medicine baicalin with the function of inhibiting the efflux pump and EDTA whether their single or combination can increase the activity of colistin against colistin-resistant Salmonella in vitro and in vivo, and to explore its molecular mechanisms. In vitro antibacterial experiments, we have observed that baicalin and EDTA alone could enhance the antibacterial activity of colistin. At the same time, the combination of baicalin and EDTA also showed a stronger synergistic effect on colistin, reversing the colistin resistance of all Salmonella strains. Molecular docking and RT-PCR results showed that the combination of baicalin and EDTA not only affected the expression of mcr-1, but also was an effective inhibitor of MCR-1. In-depth synergistic mechanism analysis revealed that baicalin and EDTA enhanced colistin activity through multiple pathways, including accelerating the tricarboxylic acid cycle (TCA cycle), inhibiting the bacterial antioxidant system and lipopolysaccharide (LPS) modification, depriving multidrug efflux pump functions and attenuating bacterial virulence. In addition, the combinational therapy of colistin, baicalin and EDTA displayed an obvious reduction in bacterial loads cfus of liver and spleen compared with monotherapy and 2-drug combination therapy. In conclusion, our study indicates that the combination of baicalin and EDTA as a novel colistin adjuvant can provide a reliable basis for formulating the therapeutic regimen for colistin resistant bacterial infection.

To investigate the genetic features and biological costs of the plasmid pTW4 harboring tet(M) in an isolate of Escherichia coli ST162 from a duck. The complete nucleotide sequence of plasmid pTW4 was determined. The characteristics of plasmid pTW4 in E. coli were investigated by stability and direct competition assays. pTW4 is an IncHI2-type plasmid that contained the resistant genes tet(M), floR, strAB, sul2, rmtB, and blaCMY-2. Tet(M) is located in the composite transposon Tn6539 within the multidrug resistant (MDR) region on this plasmid. Furthermore, the resistance gene rmtB and blaCMY-2 were found outside the MDR region. The plasmid pTW4 remained stable in the host strain E. coli J53 after passage under an antibiotic-free environment for 7 days. However, the strain E. coli J53/pTW4 showed a fitness disadvantage of 6% per ten generations in the process of growth competition with E. coli J53. In conclusion, the plasmid pTW4, a mobile MDR vehicle, may promote the dissemination of tet(M), floR, rmtB, strAB, sul2, and blaCMY-2 among bacteria and then, but it appears to confer growth disadvantage to the host.

China’s Chang’E-4 (CE-4) probe has started its exploration on the far side of the Moon thanks to the relay satellite---Queqiao---which is around the Earth-Moon collinear libration point L 2 and provides continuous communication links between the lander and ground stations. The triangular libration points of the Earth-Moon system, L 4 and L 5 , have long been considered as potential locations for future space applications. As a possible extension of Queqiao or other future missions around L 2 , the work presented here contributes to constructing transfers from the collinear libration point ( L 2 ) to the triangular libration points. Taking the L 4 point as an example, two types of two-maneuver transfers from a planar Lyapunov orbit around L 2 to the periodic orbit around L 4 are investigated in the planar Earth-Moon system and compared with each other, including the type-I transfer utilizing invariant manifolds along with powered lunar gravity assist and the type-II transfer using the Jacobi integral. Our studies indicate that type-I transfer saves more Δ v cost than type-II transfer. For the cases studied by us, the minimum Δ v cost is about 0.1636 km/s for type-I transfer, with a corresponding transfer time of 169.84 days. For type-II transfer and the cases studied by us, the corresponding values are 0.4745 km/s and 137.19 days. At the end of the paper, the type-I transfer is generalized (with some modifications) to the ephemeris model and some example transfer trajectories are given. Although only the transfer from L 2 to L 4 is studied in this paper, the same orbit design strategy can be generalized to the transfer to the triangular libration point L 5 , and the transfers from the collinear libration point L 1 to triangular libration points.

The relationship between wage difference and relative employment is a very important issue in the field of economic structural change. An M-sector economic growth model is constructed in this paper to investigate the relationship between wage difference, price difference, technology gap, relative employment and sectoral dynamic change from the perspective of technologies. Labor flow is regarded as a decision-making behavior to maximize the benefits of economic agents. The benefits of labor flow mainly come from sectoral wage difference, and the costs of labor flow mainly come from the social resource expenditure during labor flow process. Our model illustrates that: (i) the relative employment is positively correlated with the real wage difference and technology gap; (ii) the sectoral dynamic changes coexist with the aggregate economic growth; (iii) increases in technology gap, and price and wage differences will stimulate labor migration, exacerbate the unbalanced growth of sectoral economies, and lead to faster and more effective aggregate economic growth.

Background Gastric cancer (GC) is among the most common forms of cancer affecting the digestive system. This study sought to identify hub genes regulating early GC (EGC) in order to explore their potential for early diagnosis and prognosis of patients. Methods We utilized a publically available dataset from the Gene Expression Omnibus database (GSE55696). Differences between EGC and LGIN with respect to gene expression were compared using the limma software. Identified differentially expressed genes (DEGs) were subjected to gene ontology (GO) and pathway enrichment analyses with the DAVID application, and the STRING website and Cytoscape software were used to construct a protein-protein interaction (PPI) network incorporating these DEGs. This network was in turn used to identify hub genes among selected DEGs, which were analyzed with the Kaplan-Meier Plotter database. In addition, Western blotting, qRT-PCR, immunohistochemistry, and UALCAN were all employed to validate the relationship between the expression of these genes and GC patient prognosis. Results A total of 482 DEGs were identified, with GO analyses indicating an increase in the expression of genes linked with the development of cancer. Pathway analyses also indicated that these genes play a role in certain cancer-related pathways. The PPI network highlighted four potential hub genes, of which only ICAM1 was linked to a poor GC patient prognosis. This link between ICAM1 and GC patient outcomes was confirmed via UALCAN, Western blotting, immunohistochemistry, and qRT-PCR. Conclusion ICAM1 may therefore modulate tumor progression in GC, thus potentially representing a valuable prognostic and diagnostic biomarker of EGC.

Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid cells, are characterized by their immunosuppressive abilities through the secretion of various cytokines such as inducible nitric oxide synthase, nitric oxide, reactive oxygen species, transforming growth factor-β, and arginase-1. Accumulating evidence highlights its potential role in maintaining immune tolerance in solid organ and hematopoietic stem cell transplantation. Mechanistically, MDSCs-induced transplant tolerance is mainly dependent on direct suppression of allogeneic reaction or strengthened cross-talk between MDSCs and Treg or NKT cells. Adopted transfer of in vitro- or in vivo-induced MDSCs by special drugs therefore becomes a potential strategy for maintaining transplantation tolerance. In this review, we will summarize the previously published data about the role of MDSCs in the biology of transplantation tolerance and gain insights into the possible molecular mechanism governing this process.

Objectives To characterize a novel tigecycline resistance gene, tet(X6), and a novel SXT-related integrative and conjugative element (ICE), ICEPgs6Chn1, found in a tigecycline-resistant Proteus genomospecies 6 strain, T60. Methods Strain T60 was identified by the VITEK 2 system, biochemical reactions and an SNP-based approach. The genetic profile of strain T60 was determined by WGS analysis. ICEPgs6Chn1 was analysed by PCR, conjugation experiments and bioinformatics tools. tet(X6) was characterized by cloning and protein structure prediction. Results Strain T60 was resistant to ampicillin, tetracycline, tigecycline, florfenicol, colistin and kanamycin, but susceptible to cefotaxime; it also exhibited high MICs of eravacycline (32 mg/L) and omadacycline (>64 mg/L). Only one chromosome was identified and tet(X6) was located in chromosomal ICEPgs6Chn1, a member of the SXT/R391 ICE family, of 114 368 bp and encoding the antimicrobial resistance genes floR, strB, strA, aph(3′)-Ia, aac(3)-IV, aph(4)-Ia, tet(X6) and sul2. The circular intermediate of ICEPgs6Chn1 was detected by PCR and sequencing, but conjugation experiments showed that it was not self-transmissible. Cloning of the novel gene tet(X6) and protein structure prediction revealed that Tet(X6) confers tigecycline resistance. Conclusions To our knowledge, this is the first report of a novel SXT/R391 ICE in a Proteus genomospecies 6 strain. Importantly, a novel high-level tigecycline resistance gene, tet(X6), emerged for the first time in the SXT/R391 element of Proteus genomospecies 6, revealing that ICEs may serve as an important platform for the accumulation of antibiotic resistance genes.

This study aims to investigate the prevalence of islet autoantibodies and other organ-specific autoantibodies in type 1 diabetes mellitus (T1DM) patients and characterize their clinical features. Glutamic acid decarboxylase antibody (GADA), insulinoma antigen 2 antibody (IA-2A), zinc transporter 8 antibody (ZnT8A) and tetraspanin7 antibody (TSPAN7A) were assayed by radioligand or luciferase immunoprecipitation system assays in 205 newly diagnosed acute-onset T1DM patients and 170 healthy controls. Other organ-specific autoantibodies, including thyroid peroxidase antibody (TPOA), thyroglobulin antibody (TGA), tissue transglutaminase antibody (tTGA) and 21-hydroxylase antibody (21-OHA), were also measured. The prevalence of GADA, IA-2A, ZnT8A, TSPAN7A, TPOA, TGA and 21-OHA was higher in T1DM patients than in healthy controls. The combinational assay of various islet autoantibodies could increase the frequency of autoantibody positivity in T1DM to 85.4%. GADA+ IA-2A+ T1DM patients preferentially had TPOA and TGA, while IA-2A+ patients often had tTGA. Patients positive for two or more islet autoantibodies often had TPOA and TGA. BMI of multiple islet autoantibody-positive patients was lower than that of patients with single or no islet autoantibodies, and there were no significant differences in C-peptide and glycated hemoglobin between patients positive for islet autoantibodies combined with other organ-specific antibodies and noncombined patients. Younger female patients who were islet autoantibody positive were more likely to have TPOA and TGA. The frequency of Graves' disease was much higher in T1DM patients than in healthy controls. T1DM usually occurs together with other organ-specific autoantibodies. Measuring of other organ-specific autoantibodies will be beneficial for T1DM patients.

Exercise preconditioning (EP) has a good myocardial protective effect. This study explored whether EP improves electrocardiographic (ECG) signs of myocardial ischemic/hypoxic injury and the occurrence of malignant arrhythmia after exhaustive exercise. A total of 120 male SD rats were randomly divided into the control group (group C), early exercise preconditioning group (group EEP), late exercise preconditioning group (group LEP), exhaustive exercise group (group EE), early exercise preconditioning + exhaustive exercise group (group EEP + EE) and late exercise preconditioning + exhaustive exercise group (group LEP + EE). Changes in heart rate (HR), ST segment, T wave and QT corrected (QTc) intervals on ECG; hematoxylin-basic fuchsin-picric acid (HBFP) staining; and cTnI levels were used to study myocardial injury and the protective effect of EP. Compared with those in group C, the levels of plasma markers of myocardial injury, HBFP staining and ECG in group EE were significantly increased (P P

The architecture, engineering, and construction (AEC) industry globally has a long history of prudently adopting novel technologies to improve products and services. Yet the rapid development of digital technology currently taking place is threatening to produce a more disruptive inflection, or substantial jolt. This paper explores the state of readiness of the AEC industry for such anticipated transformation. We illustrate our conceptual arguments with evidence from an explorative study across a sample of AEC organizations in Australia. At the core of this paper, we offer six provocations that highlight what we consider major challenges for the AEC industry-across multiple levels of analysis-related to the increasing role of digital technology. We then turn to lessons learned from other industries in order to propose a framework consisting of four leadership thinking schemas to enable digital transformation readiness: future thinking, strategic thinking, capability thinking, and experimental thinking. For these four schemas, we present practices and initiatives that may help AEC firms to better adapt-or to proactively create and shape a sustainable future.

Background. Ferredoxin 1 (FDX1) is a newly discovered gene regulating cuprotosis. However, the effect of FDX1 expression on clear renal cell carcinoma (ccRCC) is unknown. Methods. Gene expression profiles and clinical data of ccRCC patients were downloaded from the Cancer Genome Atlas (TCGA) database. The differences in FDX1 expression between ccRCC and nonneoplastic tissues adjacent to cancer were analyzed by R software. The results were validated by GEO data, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting (WB), and immunohistochemistry (IHC). Chi-square test was used to analyze the clinical pathological parameters. Kaplan-Meier survival analysis and Cox proportional hazard regression model selection were used to evaluate the effect of FDX1 expression on overall survival. Protein interaction networks were used to analyze other proteins that interact with FDX1. Signal pathway analysis was performed for possible FDX1 enrichment using GSEA and ssGSEA algorithms. Pan-cancer analysis of FDX1 was carried out through TCGA database. Results. The FDX1 expression in nontumor tissues was significantly higher than that in ccRCC, and the expression difference was verified by GEO data, qRT-PCR, WB, and IHC. The high expression of FDX1 was significantly related to the well overall survival rate ( P < 0.05 ). The chi-square test showed that the high expression of FDX1 was related to gender, TNM stage, T stage, lymph node metastasis, and pathological grade. Additionally, the FDX1 expression level was different in groups classified based on pathological grade, gender, TNM stage, T stage, lymph node metastasis, and distant metastasis ( P < 0.05 ). The multivariate analysis revealed the high expression of FDX1 as an important independent predictor for overall survival. STRING database results showed that LIAS and LIPT1 may interact with FDX1 in the PPI network, which are also involved in the regulation of cuprotosis. The GSEA and ssGSEA results showed that the FDX1 was enriched in the anticancer pathway. The FDX1 high expression is associated with better prognosis in many cancers, as revealed by pan-cancer analysis. Conclusion. FDX1 may play a role in the progression of ccRCC as a tumor suppressor gene. It can be used as a potential prognostic indicator and therapeutic target of ccRCC. However, the cuprotosis regulatory role in the development of ccRCC needs to be further verified.

Objective To investigate the patient safety culture regarding intravenous therapy in parts of tertiary hospitals in Guangzhou, China. Methods A cross-sectional survey was conducted. A total of 333 medical staffs members from eight hospitals in Guangzhou were included in our study using convenience sampling. An evaluation about the patient safety culture regarding intravenous therapy was conducted. Results The summarized results show that the total and level one items’ scores are greater than 4.3 points (the full mark is 5 points). The lowest scoring of the five level one items is for the hospital’s security resources (4.53±0.526), and the highest is for the hospital’s safety management commitment (4.65±0.445). Among the 25 secondary entries, the four lowest-scoring entries are “doctors who can master the knowledge of drug efficacy and adverse reactions” (4.44±0.622), “doctors who can master the knowledge of the choice of medicine” (4.45±0.621), “a guarantee of sufficient human resources” (4.46±0.647), and “doctors who can master the knowledge related to the observation and complications with the treatment of intravenous therapy operation” (4.435±0.634). Conclusions The patient safety culture regarding intravenous treatment in parts of tertiary hospitals in Guangzhou is promising, but there are still shortcomings, including the need to increase relevant resources, such as equipment facilities, training resources, and especially human input.

The NAD-dependent deacetylase Sirtuin 1 (SIRT1) plays a vital role in leukemogenesis. Nicotinamide (NAM) is the principal NAD+ precursor and a noncompetitive inhibitor of SIRT1. In our study, we showed that NAM enhanced the sensitivity of chronic myeloid leukemia (CML) to doxorubicin (DOX) via SIRT1. We found that SIRT1 high expression in CML patients was associated with disease progression and drug resistance. Exogenous NAM efficiently repressed the deacetylation activity of SIRT1 and induced the apoptosis of DOX-resistant K562 cells (K562R) in a dose-dependent manner. Notably, the combination of NAM and DOX significantly inhibited tumor cell proliferation and induced cell apoptosis. The knockdown of SIRT1 in K562R cells enhanced NAM+DOX-induced apoptosis. SIRT1 rescue in K562R reduced the NAM+DOX-induced apoptosis. Mechanistically, the combinatory treatment significantly increased the cleavage of caspase-3 and PARP in K562R in vitro and in vivo. These results suggest the potential role of NAM in increasing the sensitivity of CML to DOX via the inhibition of SIRT1.

Lung cancer has the highest morbidity and mortality among all cancers. Discovery of early diagnostic and prognostic biomarkers of lung cancer can greatly facilitate the survival rate and reduce its mortality. In our study, by analyzing Gene Expression Omnibus and Oncomine databases, we found a novel potential oncogene uridine‐cytidine kinase 2 (UCK2), which was overexpressed in lung tumor tissues compared to adjacent nontumor tissues or normal lung. Then we confirmed this finding in clinical samples. Specifically, UCK2 was identified as highly expressed in stage IA lung cancer with a high diagnostic accuracy (area under the receiver operating characteristic curve > 0.9). We also found that high UCK2 expression was related to poorer clinicopathological features, such as higher T stage and N stage and higher probability of early recurrence. Furthermore, we found that patients with high UCK2 expression had poorer first progression survival and overall survival than patients with low UCK2 expression. Univariate and multivariate Cox regression analyses showed that UCK2 was an independent risk factor related with worse DFS and OS. By gene set enrichment analysis, tumor‐associated biological processes and signaling pathways were enriched in the UCK2 overexpression group, which indicated that UCK2 might play a vital role in lung cancer. Furthermore, in cytology experiments, we found that knockdown of UCK2 could suppress the proliferation and migration of lung cancer cells. In conclusion, our study indicated that UCK2 might be a potential early diagnostic and prognostic biomarker for lung cancer.

Objectives To characterize the complete sequences of four plasmids in MCR-1-producing clinical Escherichia coli strain D72, and to depict the formation mechanism and characteristics of the cointegrate plasmid derived from the pD72-mcr1 and pD72-F33 plasmids. Methods The genetic profiles of plasmids in strain D72 and its transconjugant were determined by conjugation, S1-PFGE, Southern hybridization, WGS analysis and PCR. Plasmid sequences were analysed with bioinformatic tools. The traits of the fusion plasmid were characterized by cointegration, stability and conjugation assays. Results Strain D72, belonging to ST1114, contained four plasmids, including mcr-1-carrying pD72-mcr1, blaCTX-M-55-carrying pD72-F33, blaTEM-238-bearing pD72-IncP and pD72-IncX1 carrying aph(3′)-Ia, qnrS2 and floR. A single plasmid, pD72C, in the transconjugant was found to be larger than any plasmid in the original strain D72. Sequence analysis showed that pD72C was the fusion product of pD72-mcr1 and pD72-F33, and the recombinant event involved an intermolecular replicative mechanism. Plasmid fusion occurred at a frequency of 1.75 × 10−4 cointegrates per transconjugant. The fusion plasmid presented a high stability and conjugation frequency of 8.00 × 10−3. Conclusions To our knowledge, this is the first report of the IS26-mediated fusion of an IncN1-F33:A−:B− plasmid and an mcr-1-carrying phage-like plasmid, providing evidence for the important role of IS26 in the recombination of plasmids. The biological advantages of the fusion plasmid indicated that the fusion event presumably plays a potential role in the dissemination of mcr-1.

Physiologically based pharmacokinetic (PBPK) models are an important type of systems model used commonly in drug development before commencement of first-in-human studies. Due to structural complexity, these models are not easily utilised for future data-driven population pharmacokinetic (PK) analyses that require simpler models. In the current study we aimed to explore and automate methods of simplifying PBPK models using a proper lumping technique. A linear 17-state PBPK model for fentanyl was identified from the literature. Four methods were developed to search the optimal lumped model, including full enumeration (the reference method), non-adaptive random search (NARS), scree plot plus NARS, and simulated annealing (SA). For exploratory purposes, it was required that the total area under the fentanyl arterial concentration–time curve (AUC) between the lumped and original models differ by 0.002% at maximum. In full enumeration, a 4-state lumped model satisfying the exploratory criterion was found. In NARS, a lumped model with the same number of lumped states was found, requiring a large number of random samples. The scree plot provided a starting lumped model to NARS and the search completed within a short time. In SA, a 4-state lumped model was consistently delivered. In simplify an existing linear fentanyl PBPK model, SA was found to be robust and the most efficient and may be suitable for general application to other larger-scale linear systems. Ultimately, simplified PBPK systems with fundamental mechanisms may be readily used for data-driven PK analyses. Electronic supplementary material The online version of this article (10.1007/s10928-019-09644-5) contains supplementary material, which is available to authorized users.

Aims Rituximab is a chimeric IgG-1 monoclonal antibody that depletes B cells, aiding in the treatment of several conditions including autoimmune diseases. It is not licensed for use in children. This study aimed to quantify the B cell-related pharmacodynamics of rituximab in children with autoimmune disease. Methods Routine electronic health record data were collected at a large paediatric tertiary hospital in London, UK. Dosing protocols were either 2 × 750 mg/m2 intravenous infusions of rituximab on days 1 and 15, or 4 × 375 mg/m2 infusions on days 1, 8, 15 and 22. Rituximab pharmacokinetics (PK) were not measured but CD19+ lymphocyte counts were taken before and after rituximab treatment. A dose-response model was constructed describing the life cycle of CD19+ lymphocytes, with rituximab assumed to increase the death rate. Rituximab effect was assumed to decay by first-order kinetics. Results In total, 258 measurements of CD19+ lymphocyte counts were collected from 39 children with 8 autoimmune diseases. The elimination rate constant (% relative standard error) of rituximab effect decay was 0.036 (22.7%) days-1 and CD19+ turnover was 0.02 (41%) days-1 corresponding to half-lives of 19 and 35 days respectively. Rituximab increased CD19+ death rate 35-fold, with methotrexate and cyclophosphamide associated with further increases. Simulations suggested that a single infusion of 750 mg/m2 provides similar 6-month suppression of CD19+ lymphocytes to current dosing. Conclusions Rituximab pharmacodynamics (PD) in paediatric autoimmune diseases has been described. Compared with rituximab alone, the additional effect of methotrexate or cyclophosphamide was statistically significant but small.

To characterize IncI1 and IncF18:A-:B1 multidrug-resistance plasmids from an avian Escherichia coli isolate, antibiotic susceptibility testing, conjugation assays, transformation assays, S1-PFGE, and WGS analysis were performed. The 119,457-bp plasmid pEC014-1 with a multidrug-resistance region (MRR) containing four different segments interspersed with six IS26 elements, belonged to incompatibility group I1 and sequence type 71. The 154,516-bp plasmid pEC014-2 with two replicons, typed as FII-18 and FIB-1, carried 14 resistance determinants including bla

Objectives Secondary spinal cord injury (SCI), a reversible pathological change, involves neural inflammation and apoptosis. This study explored how microRNA (miR)-488, an inflammatory regulator as reported affected secondary SCI. Methods In vivo, Wistar rats were clipped on the spinal cord for SCI induction. In vitro, PC-12 cells were treated with lipopolysaccharide (LPS) to induce cell injuries to mimic the environment during the secondary SCI. Cell viability and apoptosis were measured by CCK-8 assay and flow cytometry. The levels of inflammation-related factors (interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α) in the serum and PC-12 cells were determined by ELISA. The expressions of miR-488, high mobility group box 1 (HMGB1), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), cleaved caspase-3, toll-like receptor 4 (TLR4), phosphorylated (p)-p65 and total-p65 in rat spinal cord or PC-12 cells were analyzed by quantitative reverse transcription PCR or western blot. Results After SCI induction, rats exhibited low Basso-Beattie-Bresnahan scores, promoted the release of inflammation-related factors and downregulated miR-488. LPS treatment decreased cell viability, enhanced apoptosis and downregulated miR-488. Upregulating miR-488 neutralized LPS-induced releases of inflammation-related factors and expressions of Bax and cleaved caspase-3 and counteracted LPS-induced inhibition on Bcl-2 expression. MiR-488 directly targeted HMGB1 and miR-488 mimic decreased LPS-induced HMGB1 expression. Overexpressing HMGB1 counteracted miR-488 mimic-induced decreases in the expressions of TLR4 and p-p65 and the ratio of p-p65 to Total-p65 in LPS-treated PC-12 cells. Conclusion MiR-488 inhibited neural inflammation and apoptosis in SCI via its binding with HMGB1-mediated restraint on the TLR4/NF-κB signaling pathway.

To characterize the formation mechanism and characteristics of two cointegrate plasmids in Salmonella enterica serotype Enteritidis strain S13, plasmids from strain S13 and three corresponding transconjugants were subjected to whole genome sequencing and analyzed using bioinformatics tools. The traits of two fusion plasmids in transconjugants were characterized by stability and conjugation experiments. Sequence analysis indicated that strain S13 contained four plasmids, including mcr-1-bearing pS13-1, blaCTX–M–55-carrying pS13-2, tet(M)-bearing pS13-3, and floR-carrying pS13-4. IncN1-F33:A–:B– plasmid pS13-2, respectively, fused with IncFI:A–:B– plasmid pS13-3 and IncX1 plasmid pS13-4, which generated two cointegrate plasmids, designated pS13D and pS13F, which involved in two intermolecular replicative mechanisms mediated by IS26 and the novel transposon Tn6952 (ΔTnAS3-IS26-ΔISEcp1-ramA-ΔIS26-ΔTnAS1), respectively. This is the first report of the fusion of the IncN1-F33:A–:B– plasmid and IncFI:A–:B– plasmid mediated by IS26, and with IncX1 plasmid mediated by Tn6952. The formation and evolution of cointegrate plasmids could expand the resistance and host spectrum of fusion plasmids.

The cardioprotection of exercise preconditioning (EP) has been well documented. EP can be divided into two phases that are the induction of exercise preconditioning (IEP) and the protection of exercise preconditioning (PEP). PEP is characterized by biphasic protection, including early exercise preconditioning (EEP) and late exercise preconditioning (LEP). LC3 lipidation-mediated autophagy plays a pivotal role in cardioprotection. This study aimed to investigate the alterations of LC3 lipidation-associated proteins during EP-induced cardioprotection against myocardial injury induced by exhaustive exercise (EE) was used in a rat model of EP. These rats were subjected to an intermittent exercise consisting of four periods, with each period including 10 min of running at 30 m/min and 0% grade (approximately 75% VO2max) followed by 10 min of intermittent rest. A model of EE-induced myocardial injury was developed by subjecting rats to a consecutive running (30 m/min, 0% grade) till exhaustion. Following EEP, the colocalization of LC3 with Atg7 was significantly increased, and LC3-I, LC3-II, LC3-II/LC3-I, Atg7, Atg4B, and Atg3 levels were significantly increased. Atg7, Atg4B, and Atg3 mRNAs were all significantly upregulated, and LC3 mRNAs tended to be higher. Following LEP, Atg4B, and Atg3 levels were significantly increased. Atg7, Atg4B, and Atg3 mRNAs were all significantly upregulated, and LC3 mRNAs tended to be higher. A group of rats were subjected to EEP followed by EE, and the co-localization of LC3 with Atg7 was significantly increased, while LC3-I, LC3-II, LC3-II/LC3-I, Atg7, Atg4B, and Atg3 levels were also significantly increased. Moreover, there was a significant increase in the co-localization of LC3 with Atg7, LC3-I, LC3-II, Atg7, and Atg4B levels during LEP followed by EE. The formation of autophagosome during LEP followed by EE may have been weaker than that during EEP followed by EE due to the lower lipidation of LC3. EP may promote autophagy to maintain cell homeostasis and survival, which cooperates for cardioprotection of alleviating exhaustive exercise-induced myocardial injury by increasing LC3 lipidation-associated proteins. There is a difference between EEP and LEP in terms of the mechanisms of cardioprotection afforded by these respective conditions. The positive regulation of transcription and translation level of LC3 lipidation-associated proteins may all be involved in the mechanism of EEP and LEP, while compared with LEP, the regulation of translation level of EEP is more positively to promote autophagy.

To characterize the formation mechanism and characteristics of two cointegrate plasmids in Salmonella enterica serotype Enteritidis strain S13, plasmids from strain S13 and three corresponding transconjugants were subjected to whole genome sequencing and analyzed using bioinformatics tools. The traits of two fusion plasmids in transconjugants were characterized by stability and conjugation experiments. Sequence analysis indicated that strain S13 contained four plasmids, including mcr-1-bearing pS13-1, blaCTX–M–55-carrying pS13-2, tet(M)-bearing pS13-3, and floR-carrying pS13-4. IncN1-F33:A–:B– plasmid pS13-2, respectively, fused with IncFI:A–:B– plasmid pS13-3 and IncX1 plasmid pS13-4, which generated two cointegrate plasmids, designated pS13D and pS13F, which involved in two intermolecular replicative mechanisms mediated by IS26 and the novel transposon Tn6952 (ΔTnAS3-IS26-ΔISEcp1-ramA-ΔIS26-ΔTnAS1), respectively. This is the first report of the fusion of the IncN1-F33:A–:B– plasmid and IncFI:A–:B– plasmid mediated by IS26, and with IncX1 plasmid mediated by Tn6952. The formation and evolution of cointegrate plasmids could expand the resistance and host spectrum of fusion plasmids.

Background Since the winter of 2018 to the end of 2019, there has been an epidemic of Adenovirus infection in southern China, including Zhejiang province, and the number of children suffering from adenovirus pneumonia has increased significantly. Adenovirus pneumonia is often accompanied by other infections in children[3,4], but the effect of other Pathogenic coinfection on the AP has been reported few. Mycoplasma pneumoniae is also an important pathogen of community-acquired pneumonia, accounting for 20-40% of children's CAP[5]. As we know the Impact of Mycoplasma pneumoniae coinfection in children with adenovirus pneumonia, which has drawn the attention of the society and the Paediatrician now has not been reported before. This study aimed to investigate the impacts of MP coinfection on hospitalized AP patients, to identify the risk factors for those patients. Methods Nasopharyngeal swabs (NPSs) or sputum specimens for Culturing were collected from patients once they were admitted to our hospital. ADV-Ag, MP-IgM and MP nucleic acid was tested at the same time, then we classify under two groups(single AP groups and AP groups coinfected with MP) . The clinical manifestations, laboratory and imaging findings and clinical medication of the two groups were compared and analyzed.Results A total of 171 patients diagnosed with single AP and 125 patients diagnosed with AP coinfected with MP. Coinfection group lead to a significantly longer duration of fever than single AP group(p=0.03). Shortness of breath was more commonly found in the coinfection group(P = 0.023).there was no statistical difference in pulmonary signs and blood tests between the two groups (P > 0.05). pulmonary imaging, such as pulmonary consolidation, atelectasis, pleural effusion and multi lobe lesions were more common in the coinfection group (P < 0.05). The patients with coinfection had a more severe symptom, leading to a significantly longer hospitalization time, and increasing the proportion of patients using glucocorticoids and / or gamma globulin, needing oxygen inhalation(P < 0.05). Conclusions The occurrence of adenovirus pneumonia coinfected MP is high. prediction factors of prolonged fever duration and pulmonary imaging can be used to predict MP coinfection in children with adenovirus pneumonia. AP patients coinfected MP may easily turn into severe illness, and a reasonable change in treatment is necessary.

Background: To understand the prevalence of HIV-1 drug resistance and the mutation patterns in ART-failure individuals in Liaoning Province, China, we conducted a cross-sectional survey.Patients and methods: Plasma samples were collected from HIV-1-positive individuals who experienced ART failure in Liaoning Province between April 2018 and September 2019.Genotype resistance test was performed using an in-house assay on these collected samples. Factors associated with drug resistance were identified by logistic regression analysis.Results: A total of 256 HIV-1-positive individuals experiencing ART failure were tested for drug resistance from April 2018 to September 2019. Of these, the most predominant genotype was CRF01_AE, accounting for 77.73%. The resistance rate to any of the three classes of antiretroviral drugs (NNRTIs, NRTIs, and PIs) was 64.84%. Among 256 ART-failure patients, 62.89% showed drug resistance to NNRTIs, 50.39% to NRTIs, and 3.13% to PIs. G190S (31.25%) and Y181C (25.78%) mutations were the most common NNRTIs resistance mutations, and K65R (29.69%), M184V (28.52%) were the most common NRTIs resistance mutations. Factors associated with drug resistance included current ART regimen, viral load.Conclusion: The high drug resistance rate among ART-failure individuals in Liaoning Province needs more attention. Corresponding strategies for the risk factors associated with HIV drug resistance can better control and prevent the prevalence of resistance.

Summary This study aims to develop the expert consensus on nurse’s human caring for Corona Virus Disease 2019 (COVID-19) patients in different sites, and thus provide a guideline on providing whole process and systematic caring for COVID-19 patients. Based on the frontline experiences of human caring for COVID-19 patients and the review of literature, the initial draft of consensus was made and finalized after online meeting and revisions. The experts reached consensus on the following parts: terms and definitions, principles of human caring for COVID-19 patients, and human caring measures for COVID-19 patients in different sites. The expert consensus is practical, concise, and reasonable for guiding the nurses providing human caring for COVID-19 patients, as well as other similar infectious diseases.

Exercise preconditioning (EP) can alleviate myocardial ischemic/hypoxic injury by inducing endogenous cardioprotection. Hematoxylin–eosin (HE), hematoxylin-basic fuchsin-picric acid (HBFP), and chromotrope-2R brilliant green (C-2R BG) staining have been used to visualize myocardial ischemic/hypoxic changes in previous EP studies, but comprehensive evaluation and comparisons of these methods are lacking. This study evaluated ischemic/hypoxic changes in adjacent myocardial sections by HE, HBFP, and C-2R BG and compared the characteristics of sections stained by these three methods to show changes associated with exercise-induced myocardial ischemic/hypoxic injury. Rats were randomly divided into four groups: control (C), exercise preconditioning (EP), exhaustive exercise (EE), and exercise preconditioning + exhaustive exercise (EP + EE). Adjacent myocardial sections were stained as described above and compared to evaluate the effects of exercise-induced myocardial ischemic/hypoxic injury. The three staining methods revealed consistent localization patterns of myocardial ischemic/hypoxic injury in all groups. Results suggest that EP can alleviate exhaustive exercise-induced myocardial ischemic/hypoxic injury, and the three staining methods are suitable for the histological study of exercise-induced myocardial ischemic/hypoxic injury and protection. HE staining is a simple procedure but is not specific for myocardial ischemic/hypoxic injury. HBFP and C-2R BG staining can be used to specifically visualize myocardial ischemic/hypoxic injury.

ICEHpa1 was identified in the genome of a serovar 8 Haemophilus parasuis ST288 isolate YHP170504 from a case of swine lower respiratory tract infection. The aim of the present study was to characterize the integrative conjugative element ICEHpa1 and its multiresistance region. Susceptibility testing was determined by broth microdilution and the complete ICEHpa1 was identified by WGS analysis. The full sequence of ICEHpa1 was analyzed with bioinformatic tools. The presence of ICEHpa1, its circular intermediate and integration site were confirmed by PCR and sequence analysis. Transfer of ICEHpa1 was confirmed by conjugation. ICEHpa1 has a size of 68,922 bp with 37.42% GC content and harbors 81 genes responsible for replication and stabilization, transfer, integration, and accessory functions, as well as seven different resistance genes [bla Rob- 3, tet(B), aphA1, strA, strB, aac(6)'-Ie-aph(2')-Ia, and sul2]. Conjugation experiments showed that ICEHpa1 could be transferred to H. parasuis V43 with frequencies of 6.1 × 10-6. This is the first time a multidrug-resistance ICE has been reported in H. parasuis. Seven different resistance genes were located on a novel integrative conjugative element ICEHpa1, which suggests that the ICEHpa1 is capable of acquiring foreign genes and serving as a carrier for various resistance genes.

To analyze characteristics and underlying evolutionary processes of IncC and IncI1 plasmids in a multidrug-resistant avian E. coli strain, antibiotic susceptibility testing, PCR, conjugation assays, and next-generation sequencing were performed. The type 1 IncC plasmid pEC009.1 harbored three antimicrobial resistance regions including ISEcp1-bla