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Until now, polymyxin resistance has involved chromosomal mutations but has never been reported via horizontal gene transfer. During a routine surveillance project on antimicrobial resistance in commensal Escherichia coli from food animals in China, a major increase of colistin resistance was observed. When an E coli strain, SHP45, possessing colistin resistance that could be transferred to another strain, was isolated from a pig, we conducted further analysis of possible plasmid-mediated polymyxin resistance. Herein, we report the emergence of the first plasmid-mediated polymyxin resistance mechanism, MCR-1, in Enterobacteriaceae. The mcr-1 gene in E coli strain SHP45 was identified by whole plasmid sequencing and subcloning. MCR-1 mechanistic studies were done with sequence comparisons, homology modelling, and electrospray ionisation mass spectrometry. The prevalence of mcr-1 was investigated in E coli and Klebsiella pneumoniae strains collected from five provinces between April, 2011, and November, 2014. The ability of MCR-1 to confer polymyxin resistance in vivo was examined in a murine thigh model. Polymyxin resistance was shown to be singularly due to the plasmid-mediated mcr-1 gene. The plasmid carrying mcr-1 was mobilised to an E coli recipient at a frequency of 10−1 to 10−3 cells per recipient cell by conjugation, and maintained in K pneumoniae and Pseudomonas aeruginosa. In an in-vivo model, production of MCR-1 negated the efficacy of colistin. MCR-1 is a member of the phosphoethanolamine transferase enzyme family, with expression in E coli resulting in the addition of phosphoethanolamine to lipid A. We observed mcr-1 carriage in E coli isolates collected from 78 (15%) of 523 samples of raw meat and 166 (21%) of 804 animals during 2011–14, and 16 (1%) of 1322 samples from inpatients with infection. The emergence of MCR-1 heralds the breach of the last group of antibiotics, polymyxins, by plasmid-mediated resistance. Although currently confined to China, MCR-1 is likely to emulate other global resistance mechanisms such as NDM-1. Our findings emphasise the urgent need for coordinated global action in the fight against pan-drug-resistant Gram-negative bacteria. Ministry of Science and Technology of China, National Natural Science Foundation of China.

This study proposes a compact, low-profile, four-port dual-band monopole multiple-input-multiple-output (MIMO) antenna array for unmanned aerial vehicle (UAV) communication systems. Each monopole antenna of the array features a modified T-shaped radiator configuration and is printed on a Rogers RT5880 substrate with compact dimensions of 134.96 mm × 134.96 mm × 0.8 mm. A four-element square MIMO configuration with sequential 0°, 90°, 180°, and 270° rotations was integrated smoothly into the UAV body. A prototype of the MIMO array was fabricated and experimentally evaluated, with measured results showing a close correlation to simulated results. The proposed dual-band monopole antenna demonstrated one of the widest impedance bandwidths of 46.15% at 2.4 GHz (2.04 to 3.25 GHz) IEEE 802.11b and 31.85% at 5.8 GHz (5.37 to 7.38 GHz) IEEE 802.11a on a thin 0.0064 λo substrate while achieving high transmission efficiency. The isolation of the proposed four-port MIMO design was measured at 23 dB at 2.4 GHz and 19 dB at 5.8 GHz. The MIMO array’s total efficiency of each monopole antenna was measured at 96% at 2.4 GHz and 89% at 5.8 GHz. The design has measured diversity parameters such as an ECC below 0.01 and a DG of approximately 10. Based on these results, the proposed design suits the UAV communication system.

Objective. To investigate the value of coagulation indicators D-dimer (DD), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (Fg) in predicting the severity and prognosis of COVID-19. Methods. A total of 115 patients with confirmed COVID-19, who were admitted to Tianyou Hospital of Wuhan University of Science and Technology between January 18, 2020, and March 5, 2020, were included. The dynamic changes of DD, PT, APTT, and Fg were tested, and the correlation with CT imaging, clinical classifications, and prognosis was studied. Results. Coagulation disorder occurred at the early stage of COVID-19 infection, with 50 (43.5%) patients having DD increased and 74 (64.3%) patients having Fg increased. The levels of DD and Fg were correlated with clinical classification. Among 23 patients who deceased, 18 had DD increased at the first lab test, 22 had DD increased at the second and third lab tests, and 18 had prolonged PT at the third test. The results from ROC analyses for mortality risk showed that the AUCs of DD were 0.742, 0.818, and 0.851 in three times of test, respectively; PT was 0.643, 0.824, and 0.937. In addition, with the progression of the disease, the change of CT imaging was closely related to the increase of the DD value (P<0.01). Conclusions. Coagulation dysfunction is more likely to occur in severe and critically ill patients. DD and PT could be used as the significant indicators in predicting the mortality of COVID-19.

The mcr-1 gene confers transferable colistin resistance. mcr-1-positive Enterobacteriaceae (MCRPE) have attracted substantial medical, media, and political attention; however, so far studies have not addressed their clinical impact. Herein, we report the prevalence of MCRPE in human infections and carriage, clinical associations of mcr-1-positive Escherichia coli (MCRPEC) infection, and risk factors for MCRPEC carriage. We undertook this study at two hospitals in Zhejiang and Guangdong, China. We did a retrospective cross-sectional assessment of prevalence of MCRPE infection from isolates of Gram-negative bacteria collected at the hospitals from 2007 to 2015 (prevalence study). We did a retrospective case-control study of risk factors for infection and mortality after infection, using all MCRPEC from infection isolates and a random sample of mcr-1-negative E coli infections from the retrospective collection between 2012 and 2015 (infection study). We also did a prospective case-control study to assess risk factors for carriage of MCRPEC in rectal swabs from inpatients with MCRPEC and mcr-1 negative at the hospitals and collected between May and December, 2015, compared with mcr-1-negative isolates from rectal swabs of inpatients (colonisation study). Strains were analysed for antibiotic resistance, plasmid typing, and transfer analysis, and strain relatedness. We identified 21 621 non-duplicate isolates of Enterobacteriaceae, Acinetobacter spp, and Pseudomonas aeruginosa from 18 698 inpatients and 2923 healthy volunteers. Of 17 498 isolates associated with infection, mcr-1 was detected in 76 (1%) of 5332 E coli isolates, 13 (<1%) of 348 Klebsiella pneumoniae, one (<1%) of 890 Enterobacter cloacae, and one (1%) of 162 Enterobacter aerogenes. For the infection study, we included 76 mcr-1-positive clinical E coli isolates and 508 mcr-1-negative isolates. Overall, MCRPEC infection was associated with male sex (209 [41%] vs 47 [63%], adjusted p=0·011), immunosuppression (30 [6%] vs 11 [15%], adjusted p=0·011), and antibiotic use, particularly carbapenems (45 [9%] vs 18 [24%], adjusted p=0·002) and fluoroquinolones (95 [19%] vs 23 [30%], adjusted p=0·017), before hospital admission. For the colonisation study, we screened 2923 rectal swabs from healthy volunteers, of which 19 were MCRPEC, and 1200 rectal swabs from patients, of which 35 were MCRPEC. Antibiotic use before hospital admission (p<0·0001) was associated with MCRPEC carriage in 35 patients compared with 378 patients with mcr-1-negative E coli colonisation, whereas living next to a farm was associated with mcr-1-negative E coli colonisation (p=0·03, univariate test). mcr-1 could be transferred between bacteria at high frequencies (10−1 to 10−3), and plasmid types and MCRPEC multi-locus sequence types (MLSTs) were more variable in Guangdong than in Zhejiang and included the human pathogen ST131. MCRPEC also included 17 unreported ST clades. In 2017, colistin will be formally banned from animal feeds in China and switched to human therapy. Infection with MRCPEC is associated with sex, immunosuppression, and previous antibiotic exposure, while colonisation is also associated with antibiotic exposure. MLST and plasmid analysis shows that MCRPEC are diversely spread throughout China and pervasive in Chinese communities. National Key Basic Research Program of China, National Natural Science Foundation of China/Zhejiang, National Key Research and Development Program, and MRC, UK.

Innate immunity is the first immunological defence against pathogens. During virus infection detection of nucleic acids is crucial for the inflammatory response. Here we identify DNA-dependent protein kinase (DNA-PK) as a DNA sensor that activates innate immunity. We show that DNA-PK acts as a pattern recognition receptor, binding cytoplasmic DNA and triggering the transcription of type I interferon (IFN), cytokine and chemokine genes in a manner dependent on IFN regulatory factor 3 (IRF-3), TANK-binding kinase 1 (TBK1) and stimulator of interferon genes (STING). Both cells and mice lacking DNA-PKcs show attenuated cytokine responses to both DNA and DNA viruses but not to RNA or RNA virus infection. DNA-PK has well-established functions in the DNA repair and V(D)J recombination, hence loss of DNA-PK leads to severe combined immunodeficiency (SCID). However, we now define a novel anti-microbial function for DNA-PK, a finding with implications for host defence, vaccine development and autoimmunity. For multicellular organisms, the innate immune system is the first immunological defence against infection, rapidly recognizing and responding to the presence of any pathogen. Many different cell types contribute to the innate immunity, including fibroblasts, epithelial cells, dendritic cells and macrophages. Once alerted to injury or infection, these cells release proteins called cytokines, interferons and chemokines into the blood or directly into tissue. These proteins act as messengers and interact with receptors on the surfaces of other cells in the immune system, stimulating them to join the battle against the infection. Detecting nucleic acids such as DNA is an important part of recognizing pathogens and infectious agents, particularly viruses, and activating the innate immune system. However, while the presence of DNA in the cytoplasm is known to initiate an innate immune response, we do not fully understand how this foreign DNA is sensed, or how the innate immune system is activated once foreign DNA has been detected. Here Ferguson et al. report that a well-known complex of three proteins, collectively called DNA-dependent protein kinase, is able to activate an innate immune response when it detects foreign DNA. This enzyme, called DNA-PK for short, is best known for its ability to repair broken DNA inside the nucleus. Now Ferguson et al. have found that it is also present at high levels within fibroblasts, cells that are often primary targets of viral infection, and they go on to explain how the detection of DNA by DNA-PK triggers a sequence of events that leads to the innate immune response being activated. These events include the transcription of type I interferon, chemokines and cytokines in a manner that depends on the presence IRF-3, a transcription factor that has a central role in the response of the immune system to viral infection. By identifying a role for DNA-PK in the cytoplasm as a DNA sensor, the work of Ferguson et al. increases our understanding of innate immunity. It may also, in the future, lead to an improved understanding of autoimmunity, and might also assist in the development of more immunogenic vaccines based on DNA or microbes that contain DNA.

HighlightsA ginsenoside Rh2-based multifunctional liposome system (Rh2-lipo) was innovatively developed.Rh2-lipo not only innovatively challenges the position of cholesterol as a liposome component, but also provides another innovative potential system with multiple functions for anti-cancer drug delivery.Liposomes hold great potential in anti-cancer drug delivery and the targeting treatment of tumors. However, the clinical therapeutic efficacy of liposomes is still limited by the complexity of tumor microenvironment (TME) and the insufficient accumulation in tumor sites. Meanwhile, the application of cholesterol and polyethylene glycol (PEG), which are usually used to prolong the blood circulation and stabilize the structure of liposomes respectively, has been questioned due to various disadvantages. Herein, we developed a ginsenoside Rh2-based multifunctional liposome system (Rh2-lipo) to effectively address these challenges once for all. Different with the conventional ‘wooden’ liposomes, Rh2-lipo is a much more brilliant carrier with multiple functions. In Rh2-lipo, both cholesterol and PEG were substituted by Rh2, which works as membrane stabilizer, long-circulating stealther, active targeting ligand, and chemotherapy adjuvant at the same time. Firstly, Rh2 could keep the stability of liposomes and avoid the shortcomings caused by cholesterol. Secondly, Rh2-lipo showed a specifically prolonged circulation behavior in the blood. Thirdly, the accumulation of the liposomes in the tumor was significantly enhanced by the interaction of glucose transporter of tumor cells with Rh2. Fourth, Rh2-lipo could remodel the structure and reverse the immunosuppressive environment in TME. When tested in a 4T1 breast carcinoma xenograft model, the paclitaxel-loaded Rh2-lipo realized high efficient tumor growth suppression. Therefore, Rh2-lipo not only innovatively challenges the position of cholesterol as a liposome component, but also provides another innovative potential system with multiple functions for anti-cancer drug delivery.

Ginseng has been used worldwide as traditional medicine for thousands of years, and ginsenosides have been proved to be the main active components for their various pharmacological activities. Based on their structures, ginsenosides can be divided into ginseng diol-type A and ginseng triol-type B with different pharmacological effects. In this study, six ginsenosides, namely ginsenoside Rb1, Rh2, Rg3, Rg5 as diol-type ginseng saponins, and Rg1 and Re as triol-type ginseng saponins, which were reported to be effective for ischemia-reperfusion (I/R) treatment, were chosen to compare their protective effects on cerebral I/R injury, and their mechanisms were studied by in vitro and in vivo experiments. It was found that all ginsenosides could reduce reactive oxygen species (ROS), inhibit apoptosis and increase mitochondrial membrane potential in cobalt chloride-induced (CoCl2-induced) PC12 cells injury model, and they could reduce cerebral infarction volume, brain neurological dysfunction of I/R rats in vivo. The results of immunohistochemistry and western blot showed that the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), silencing information regulator (SIRT1) and nuclear transcription factor P65 (NF-κB) in hippocampal CA1 region of some ginsenoside groups were also reduced. In general, the effect on cerebral ischemia of Rb1 and Rg3 was significantly improved compared with the control group, and was the strongest among all the ginsenosides. The effect on SIRT1 activation of ginsenoside Rb1 and the inhibition effect of TLR4/MyD88 protein expression of ginsenoside Rb1 and Rg3 were significantly stronger than that of other groups. The results indicated that ginsenoside Rg1, Rb1, Rh2, Rg3, Rg5 and Re were effective in protecting the brain against ischemic injury, and ginsenoside Rb1 and Rg3 have the strongest therapeutic activities in all the tested ginsenosides. Their neuroprotective mechanism is associated with TLR4/MyD88 and SIRT1 activation signaling pathways, and they can reduce cerebral ischemic injury by inhibiting NF-κB transcriptional activity and the expression of proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).

This paper presents the design and analysis of a metamaterial-based compact dual-band antenna for WBAN applications. The antenna is designed and fabricated on a 0.254 mm thick semi-flexible substrate, RT/Duroid® 5880, with a relative permittivity of 2.2 and a loss tangent of 0.0009. The total dimensions of the antenna are 0.26λ o ×0.19λ o ×0.002λ o , where λ o corresponds to the free space wavelength at 2.45 GHz. To enhance overall performance and isolate the antenna from adverse effects of the human body, it is backed by a 2×2 artificial magnetic conductor (AMC) plane. The total volume of the AMC integrated design is 0.55λ o ×0.55λ o ×0.002λ o . The paper investigates the antenna’s performance both with and without AMC integration, considering on- and off-body states, as well as various bending conditions in both E and H -planes. Results indicate that the AMC-integrated antenna gives improved measured gains of 6.61 dBi and 8.02 dBi, with bandwidths of 10.12% and 7.43% at 2.45 GHz and 5.80 GHz, respectively. Furthermore, the AMC integrated antenna reduces the specific absorption rate (SAR) to (>96%) and (>93%) at 2.45 GHz and 5.80 GHz, meeting FCC requirements for low SAR at both frequencies when placed in proximity to the human body. CST Microwave Studio (MWS) and Ansys High-Frequency Structure Simulation (HFSS), both full-wave simulation tools, are utilized to evaluate the antenna’s performance and to characterize the AMC unit cell. The simulated and tested results are in mutual agreement. Due to its low profile, high gain, adequate bandwidth, low SAR values, and compact size, the AMC integrated antenna is considered suitable for WBAN applications.

Marseilleviruses are a group of double-stranded DNA viruses infecting Acanthamoeba within the phylum Nucleocytoviricota and are ubiquitous in water and soil globally. Here, we report six strains of marseilleviruses isolated from environmental samples in the Yangtze River Delta and the Pearl River Delta, China. Viral particles exhibited icosahedral shaped capsids measuring about 220 ~ 240 nm in diameter. Based on stability assays, viral particles were halotolerant and acid-tolerant, but sensitive to chloroform and high temperature. Genomics and phylogenetic analyses showed that these strains were highly conserved compared with other reported marseilleviruses. Diverse members of the small multidrug resistance (SMR) family of transporter, which is a type of antibiotics resistance gene (ARG) and contribute to the feature of antibiotic resistance in bacteria, to our best knowledge, are firstly described in Marseilleviridae . The alignments of primary structures and in-silico tertiary structures reveal structural and potential functional similarity between giant viral and bacterial SMR, suggesting a possible role in viruses’ interaction with antibiotics. The biological properties of marseillevirus and the discovery of viral SMR provide insight in the external and intracellular environment fitness of these large amoeba-infecting viruses.

Background Annual breast magnetic resonance imaging (MRI) is highly recommended to assist mammography for women at high risk of breast cancer (BC). This study explored the knowledge, attitude, and willingness toward breast MRI screening among women at high risk of BC. Methods This cross-sectional study enrolled women at high risk of BC between August 2022 and January 2023 in Beijing, China. A structural equation model (SEM) was used to analyze the relationships among knowledge, attitude, and willingness. Results A total of 596 questionnaires were collected, and 412 questionnaires (69.13%) were valid. The women’s knowledge and attitude scores were 7.75 ± 2.79 (possible range: 0–12) and 48.53 ± 6.31 (possible range: 13–65). Among the women, 297 (72.09%) were willing to undergo regular breast MRI screening. The SEM showed that knowledge had direct effect on attitude [β = 0.77, 95% CI: (0.57, 0.98), P  < 0.001], the attitude had direct effect on willingness [β = 0.02, 95% CI: (0.01, 0.02), P  < 0.001], knowledge had an indirect effect on willingness through attitude [β = 0.01, 95% CI: (0.01,0.02), P  < 0.001], and the direct effect of knowledge on practice was not significant. Conclusions The women at high risk of BC had insufficient knowledge and a relatively positive attitude toward breast MRI screening. Most of them were willing to undergo regular breast MRI screening. Advertising and public health education programs should be designed to improve their knowledge and attitude, therefore improving their willingness and practice.