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Severe COVID-19 has been associated with coinfections with bacterial and fungal pathogens. Notably, patients with COVID-19 who develop Staphylococcus aureus bacteremia exhibit higher rates of mortality than those infected with either pathogen alone. To understand this clinical scenario, we collected and examined S. aureus blood and respiratory isolates from a hospital in New York City during the early phase of the pandemic from both SARS-CoV-2+ and SARS-CoV-2- patients. Whole genome sequencing of these S. aureus isolates revealed broad phylogenetic diversity in both patient groups, suggesting that SARS-CoV-2 coinfection was not associated with a particular S. aureus lineage. Phenotypic characterization of the contemporary collection of S. aureus isolates from SARS-CoV-2+ and SARS-CoV-2- patients revealed no notable differences in several virulence traits examined. However, we noted a trend toward overrepresentation of S. aureus bloodstream strains with low cytotoxicity in the SARS-CoV-2+ group. We observed that patients coinfected with SARS-CoV-2 and S. aureus were more likely to die during the acute phase of infection when the coinfecting S. aureus strain exhibited high or low cytotoxicity. To further investigate the relationship between SARS-CoV-2 and S. aureus infections, we developed a murine coinfection model. These studies revealed that infection with SARS-CoV-2 renders mice susceptible to subsequent superinfection with low cytotoxicity S. aureus. Thus, SARS-CoV-2 infection sensitizes the host to coinfections, including S. aureus isolates with low intrinsic virulence. IMPORTANCE: The COVID-19 pandemic has had an enormous impact on healthcare across the globe. Patients who were severely infected with SARS-CoV-2, the virus causing COVID-19, sometimes became infected with other pathogens, which is termed coinfection. If the coinfecting pathogen is the bacterium Staphylococcus aureus, there is an increased risk of patient death. We collected S. aureus strains that coinfected patients with SARS-CoV-2 to study the disease outcome caused by the interaction of these two important pathogens. We found that both in patients and in mice, coinfection with an S. aureus strain lacking toxicity resulted in more severe disease during the early phase of infection, compared with infection with either pathogen alone. Thus, SARS-CoV-2 infection can directly increase the severity of S. aureus infection.
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COVID-19 , Coinfecção , SARS-CoV-2 , Infecções Estafilocócicas , Staphylococcus aureus , COVID-19/complicações , COVID-19/microbiologia , Coinfecção/microbiologia , Coinfecção/virologia , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidade , Infecções Estafilocócicas/microbiologia , Humanos , Animais , Camundongos , SARS-CoV-2/genética , Filogenia , Feminino , Cidade de Nova Iorque/epidemiologia , Masculino , Virulência , Pessoa de Meia-Idade , Sequenciamento Completo do Genoma , Bacteriemia/microbiologia , Modelos Animais de Doenças , IdosoRESUMO
The bacterial microbiota promotes the life cycle of the intestine-dwelling whipworm Trichuris by mediating hatching of parasite eggs ingested by the mammalian host. Despite the enormous disease burden associated with Trichuris colonization, the mechanisms underlying this transkingdom interaction have been obscure. Here, we used a multiscale microscopy approach to define the structural events associated with bacteria-mediated hatching of eggs for the murine model parasite Trichuris muris. Through the combination of scanning electron microscopy (SEM) and serial block face SEM (SBFSEM), we visualized the outer surface morphology of the shell and generated 3D structures of the egg and larva during the hatching process. These images revealed that exposure to hatching-inducing bacteria catalyzed asymmetric degradation of the polar plugs prior to exit by the larva. Unrelated bacteria induced similar loss of electron density and dissolution of the structural integrity of the plugs. Egg hatching was most efficient when high densities of bacteria were bound to the poles. Consistent with the ability of taxonomically distant bacteria to induce hatching, additional results suggest chitinase released from larva within the eggs degrade the plugs from the inside instead of enzymes produced by bacteria in the external environment. These findings define at ultrastructure resolution the evolutionary adaptation of a parasite for the microbe-rich environment of the mammalian gut.
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Microbiota , Trichuris , Camundongos , Animais , Microscopia Eletrônica de Varredura , Bactérias , Larva , Óvulo , MamíferosRESUMO
BACKGROUND: Alzheimer's disease (AD) represents the common neurodegenerative disease featured by the manifestations of cognitive impairment and memory loss. AD could be alleviated with medication and improving quality of life. Clinical treatment of AD is mainly aimed at improving the cognitive function of patients. Donepezil, memantine and galantamine are commonly used drug. But they could only relieve AD, not cure it. Therefore, new treatment strategies focusing on AD pathogenesis are of great significance and value. Myricetin (Myr) is a natural flavonoid extracted from Myrica rubra. And it shows different bioactivities, such as anti-inflammation, antioxidation as well as central nervous system (CNS) activities. Nonetheless, its associated mechanism in treating AD remains unknown. PURPOSE: Here we focused on investigating Myr's effect on treating AD and exploring if its protection on the nervous system activity was associated with specifically inhibiting P38 MAPK signaling pathway while regulating mitochondria-NLRP3 inflammasome-microglia. STUDY DESIGN AND METHODS: This work utilized triple transgenic mice (3 × Tg-AD) as AD models and Aß25-35 was used to induce BV2 cells to build an in vitro AD model. Behavioristics, pathology and related inflammatory factors were examined. Molecular mechanisms are investigated by western-blot, immunofluorescence staining, CETSA, molecular docking, network pharmacology. RESULTS: According to our findings, Myr could remarkably improve memory loss, spatial learning ability, Aß plaque deposition, neuronal and synaptic damage in 3 × Tg-AD mice through specifically inhibiting P38 MAPK pathway activation while restraining microglial hyperactivation. Furthermore, Myr promoted the transformation of microglial phenotype, restored the mitochondrial fission-fusion balance, facilitated mitochondrial biogenesis, and restrained NLRP3 inflammasome activation and neuroinflammation. For the in-vitro experiments, P38 agonist dehydrocorydaline (DHC) was utilized to confirm the key regulatory role of P38 MAPK signaling pathway on the mitochondria-NLRP3 inflammasome-microglia channel. CONCLUSIONS: Our results revealed the therapeutic efficacy of Myr in experimental AD, and implied that the associated mechanism is possibly associated with inhibiting tmitochondrial dysfunction, activating NLRP3 inflammasome, and neuroinflammation which was mediated by P38 MAPK pathway. Myr is the drug candidate in AD therapy via targeting P38 MAPK pathway.
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Doença de Alzheimer , Doenças Neurodegenerativas , Camundongos , Animais , Inflamassomos , Doença de Alzheimer/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Microglia , Doenças Neurodegenerativas/metabolismo , Doenças Neuroinflamatórias , Simulação de Acoplamento Molecular , Qualidade de Vida , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Camundongos Transgênicos , Sistema de Sinalização das MAP Quinases , Transtornos da Memória/metabolismo , Mitocôndrias , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Peptídeos beta-Amiloides/metabolismoRESUMO
The bacterial microbiota promotes the life cycle of the intestine-dwelling whipworm Trichuris by mediating hatching of parasite eggs ingested by the mammalian host. Despite the enormous disease burden associated with Trichuris colonization, the mechanisms underlying this transkingdom interaction have been obscure. Here, we used a multiscale microscopy approach to define the structural events associated with bacteria-mediated hatching of eggs for the murine model parasite Trichuris muris . Through the combination of scanning electron microscopy (SEM) and serial block face SEM (SBFSEM), we visualized the outer surface morphology of the shell and generated 3D structures of the egg and larva during the hatching process. These images revealed that exposure to hatching-inducing bacteria catalyzed asymmetric degradation of the polar plugs prior to exit by the larva. Although unrelated bacteria induced similar loss of electron density and dissolution of the structural integrity of the plugs, egg hatching was most efficient in the presence of bacteria that bound poles with high density such as Staphylococcus aureus . Consistent with the ability of taxonomically distant bacteria to induce hatching, additional results suggest chitinase released from larva within the eggs degrade the plugs from the inside instead of enzymes produced by bacteria in the external environment. These findings define at ultrastructure resolution the evolutionary adaptation of a parasite for the microbe-rich environment of the mammalian gut.
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Nosocomial infections caused by multidrug-resistant (MDR) Enterobacter cloacae complex (ECC) pathogens are on the rise. However, the virulence strategies employed by these pathogens remain elusive. Here, we study the interaction of ECC clinical isolates with human serum to define how this pathogen evades the antimicrobial action of complement, one of the first lines of host-mediated immune defense. We identified a small number of serum-sensitive strains, including Enterobacter hormaechei strain NR3055, which we exploited for the in vitro selection of serum-resistant clones. Comparative genomics between the serum-sensitive NR3055 strain and the isolated serum-resistant clones revealed a premature stop codon in the wzy gene of the capsular polysaccharide biosynthesis locus of NR3055. The complementation of wzy conferred serum resistance to NR3055, prevented the deposition of complement proteins on the bacterial surface, inhibited phagocytosis by human neutrophils, and rendered the bacteria virulent in a mouse model of peritonitis. Mice exposed to a nonlethal dose of encapsulated NR3055 were protected from subsequent lethal infections by encapsulated NR3055, whereas mice that were previously exposed to unencapsulated NR3055 succumbed to infection. Thus, capsule is a key immune evasion determinant for E. hormaechei, and it is a potential target for prophylactics and therapeutics to combat these increasingly MDR human pathogens. IMPORTANCE Infections caused by antimicrobial resistant bacteria are of increasing concern, especially those due to carbapenem-resistant Enterobacteriaceae pathogens. Included in this group are species of the Enterobacter cloacae complex, regarding which there is a paucity of knowledge on the infection biology of the pathogens, despite their clinical relevance. In this study, we combine techniques in comparative genomics, bacterial genetics, and diverse models of infection to establish capsule as an important mechanism of Enterobacter pathogens to resist the antibacterial activity of serum, a first line of host defense against bacterial infections. We also show that immune memory targeting the Enterobacter capsule protects against lethal infection. The further characterization of Enterobacter infection biology and the immune response to infection are needed for the development of therapies and preventative interventions targeting these highly antibiotic resistant pathogens.
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Enterobacter , Infecções por Enterobacteriaceae , Humanos , Camundongos , Animais , Virulência , Enterobacter/genética , Antibacterianos/farmacologia , Polissacarídeos , Testes de Sensibilidade Microbiana , Infecções por Enterobacteriaceae/microbiologiaRESUMO
Deep-learning techniques have significantly improved object detection performance, especially with binocular images in 3D scenarios. To supervise the depth information in stereo 3D object detection, reconstructing the 3D dense depth of LiDAR point clouds causes higher computational costs and lower inference speed. After exploring the intrinsic relationship between the implicit depth information and semantic texture features of the binocular images, we propose an efficient and accurate 3D object detection algorithm, FCNet, in stereo images. First, we construct a multi-scale cost-volume containing implicit depth information using the normalized dot-product by generating multi-scale feature maps from the input stereo images. Secondly, the variant attention model enhances its global and local description, and the sparse region monitors the depth loss deep regression. Thirdly, for balancing the channel information preservation of the re-fused left-right feature maps and computational burden, a reweighting strategy is employed to enhance the feature correlation in merging the last-layer features of binocular images. Extensive experiment results on the challenging KITTI benchmark demonstrate that the proposed algorithm achieves better performance, including a lower computational cost and higher inference speed in 3D object detection.
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Staphylococcus aureus is an opportunistic pathogen and chief among bloodstream-infecting bacteria. S. aureus produces an array of human-specific virulence factors that may contribute to immune suppression. Here, we defined the response of primary human phagocytes following infection with S. aureus using RNA-sequencing (RNA-Seq). We found that the overall transcriptional response to S. aureus was weak both in the number of genes and in the magnitude of response. Using an ex vivo bacteremia model with fresh human blood, we uncovered that infection with S. aureus resulted in the down-regulation of genes related to innate immune response and cytokine and chemokine signaling. This muted transcriptional response was conserved across diverse S. aureus clones but absent in blood exposed to heat-killed S. aureus or blood infected with the less virulent staphylococcal species Staphylococcus epidermidis. Notably, this signature was also present in patients with S. aureus bacteremia. We identified the master regulator S. aureus exoprotein expression (SaeRS) and the SaeRS-regulated pore-forming toxins as key mediators of the transcriptional suppression. The S. aureus-mediated suppression of chemokine and cytokine transcription was reflected by circulating protein levels in the plasma. Wild-type S. aureus elicited a soluble milieu that was restrictive in the recruitment of human neutrophils compared with strains lacking saeRS. Thus, S. aureus blunts the inflammatory response resulting in impaired neutrophil recruitment, which could promote the survival of the pathogen during invasive infection.
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Interações Hospedeiro-Patógeno , Neutrófilos , Infecções Estafilocócicas , Staphylococcus aureus , Bacteriemia/imunologia , Bacteriemia/microbiologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Citocinas/metabolismo , Regulação Bacteriana da Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Neutrófilos/imunologia , Neutrófilos/microbiologia , Proteínas Citotóxicas Formadoras de Poros/genética , Infecções Estafilocócicas/sangue , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidade , Staphylococcus epidermidis/patogenicidade , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Membrane protein efflux pumps confer antibiotic resistance by extruding structurally distinct compounds and lowering their intracellular concentration. Yet, there are no clinically approved drugs to inhibit efflux pumps, which would potentiate the efficacy of existing antibiotics rendered ineffective by drug efflux. Here we identified synthetic antigen-binding fragments (Fabs) that inhibit the quinolone transporter NorA from methicillin-resistant Staphylococcus aureus (MRSA). Structures of two NorA-Fab complexes determined using cryo-electron microscopy reveal a Fab loop deeply inserted in the substrate-binding pocket of NorA. An arginine residue on this loop interacts with two neighboring aspartate and glutamate residues essential for NorA-mediated antibiotic resistance in MRSA. Peptide mimics of the Fab loop inhibit NorA with submicromolar potency and ablate MRSA growth in combination with the antibiotic norfloxacin. These findings establish a class of peptide inhibitors that block antibiotic efflux in MRSA by targeting indispensable residues in NorA without the need for membrane permeability.
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Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Antibacterianos/química , Proteínas de Bactérias/metabolismo , Microscopia Crioeletrônica , Humanos , Testes de Sensibilidade Microbiana , Proteínas Associadas à Resistência a Múltiplos Medicamentos/química , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/farmacologia , Staphylococcus aureus/metabolismoRESUMO
BACKGROUND: To evaluate the levels of osteoglycin (OGN) in patients with cardiovascular disease. METHODS: A meta-analysis was conducted on retrospective studies that compared patients with and without cardiovascular disease. Data including the levels of OGN, low density lipoprotein (LDL), and high density lipoprotein (HDL) were analyzed and expressed as mean differences (MD) with a 95% confidence interval (CI). RESULTS: This meta-analysis included 6 studies with a total of 1,443 patients. The results showed that the concentration of OGN in the blood of patients with cardiovascular disease was significantly elevated compared to that observed in control patients. There were no significant differences in LDL and HDL expression between cardiovascular patients and control patients. Sensitivity analysis and funnel plots showed that this investigation was robust and had low publication bias. DISCUSSION: This report demonstrated that the blood concentration of OGN in patients with cardiovascular disease is significantly elevated compared to that in control patients. Furthermore, the elevated levels of OGN suggests that OGN may be a biomarker/or therapeutic target for patients with cardiovascular disease. Although the structure of OGN is simple, it is indispensable in many important life processes. It plays a protective role in the occurrence of cardiovascular and cerebrovascular diseases through antioxidant, anti-inflammatory, anti-apoptosis and increasing tolerance to hypoxia.
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Peptídeos e Proteínas de Sinalização Intercelular , Pulmão , Biomarcadores , Humanos , Estudos RetrospectivosRESUMO
Infections caused by the Gram-positive bacterium Staphylococcus aureus remain a significant health threat globally. The production of bicomponent pore-forming leukocidins plays an important role in S. aureus pathogenesis. Transcriptionally, these toxins are primarily regulated by the Sae and Agr regulatory systems. However, the posttranslational regulation of these toxins is largely unexplored. In particular, one of the leukocidins, LukAB, has been shown to be both secreted into the extracellular milieu and associated with the bacterial cell envelope. Here, we report that a major cell wall hydrolase, autolysin (Atl), controls the sorting of LukAB from the cell envelope to the extracellular milieu, an effect independent of transcriptional regulation. By influencing the sorting of LukAB, Atl modulates S. aureus cytotoxicity toward primary human neutrophils. Mechanistically, we found that the reduction in peptidoglycan cleavage and increased LukAB secretion in the atl mutant can be reversed through the supplementation of exogenous mutanolysin. Altogether, our study revealed that the cell wall hydrolase activity of Atl and the cleavage of peptidoglycan play an important role in controlling the sorting of S. aureus toxins during secretion.
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Infecções Estafilocócicas , Staphylococcus aureus , Proteínas de Bactérias/genética , Proteínas de Bactérias/toxicidade , Humanos , Leucocidinas , N-Acetil-Muramil-L-Alanina Amidase/genética , Peptidoglicano , Infecções Estafilocócicas/microbiologia , VirulênciaRESUMO
Channel estimation is a challenging task in a millimeter-wave (mm Wave) massive multiple-input multiple-output (MIMO) system. The existing deep learning scheme, which learns the mapping from the input to the target channel, has great difficulty in estimating the exact channel state information (CSI). In this paper, we consider the quantized received measurements as a low-resolution image, and we adopt the deep learning-based image super-resolution technique to reconstruct the mm Wave channel. Specifically, we exploit a state-of-the-art channel estimation framework based on residual learning and multi-path feature fusion (RL-MFF-Net). Firstly, residual learning makes the channel estimator focus on learning high-frequency residual information between the quantized received measurements and the mm Wave channel, while abundant low-frequency information is bypassed through skip connections. Moreover, to address the estimator's gradient dispersion problem, a dense connection is added to the residual blocks to ensure the maximum information flow between the layers. Furthermore, the underlying mm Wave channel local features extracted from different residual blocks are preserved by multi-path feature fusion. The simulation results demonstrate that the proposed scheme outperforms traditional methods as well as existing deep learning methods, especially in the low signal-to-noise-ration (SNR) region.
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Myocardial ischaemia-reperfusion injury (MI/RI) induces injury against cardiomyocytes and triggers myocardial infarction. Previously, we demonstrated that tetramethylprazine (TMP) was a promising therapeutic agent for attenuating MI/RI. However, poor absorption and low homing efficiency are two main obstacles to the further application of TMP. In this study, a platelet membrane-cloaking TMP-loaded microemulsion (P/TMP-MEs) capable of promoting in vivo absorption and decreasing non-targeted accumulation was fabricated for the improved MI/RI therapy. The average particle size and zeta potential of P/TMP-MEs were 35.9 ± 2.5 nm and -29.4 ± 3.1 mV, respectively. 35.4 ± 2.4 wt% TMP was released from P/TMP-MEs after 48 h of incubation with rat plasma. The coating of the platelet membrane significantly decreased the internalisation of P/TMP-MEs by THP-1 macrophage-like cells compared with the non-platelet modified TMP-loaded microemulsion (TMP-MEs). Besides, P/TMP-MEs did not activate the complement system. After treatment with P/TMP-MEs, the dehydrogenase (LDH) level of the cardiomyocytes was significantly lower than other controls. Rats single-administrated with P/TMP-MEs exhibited the area under the plasma concentration-time curve (AUC) at 463796.7 ± 53614.3 ng/mL/h, and â¼400 ng/mL TMP could still be detected from the plasma after 24 h of administration, exhibiting a prolonged blood circulation time as the platelet membrane coating. More importantly, in the MI/RI therapy in vivo, the creatine kinase (CK) and LDH of the rats treated with P/TMP-MEs were remarkably decreased compared with the free TMP and TMP-MEs groups. The combinational strategy of platelet membrane coating and microemulsion assembly endows TMP with a better prospect for MI/RI therapy.
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Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Animais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos , Tamanho da Partícula , Ratos , Ratos Sprague-DawleyRESUMO
Staphylococcus aureus bi-component pore-forming leukocidins are secreted toxins that directly target and lyse immune cells. Intriguingly, one of the leukocidins, Leukocidin AB (LukAB), is found associated with the bacterial cell envelope in addition to secreted into the extracellular milieu. Here, we report that retention of LukAB on the bacterial cells provides S. aureus with a pre-synthesized active toxin that kills immune cells. On the bacteria, LukAB is distributed as discrete foci in two distinct compartments: membrane-proximal and surface-exposed. Through genetic screens, we show that a membrane lipid, lysyl-phosphatidylglycerol (LPG), and lipoteichoic acid (LTA) contribute to LukAB deposition and release. Furthermore, by studying non-covalently surface-bound proteins we discovered that the sorting of additional exoproteins, such as IsaB, Hel, ScaH, and Geh, are also controlled by LPG and LTA. Collectively, our study reveals a multistep secretion system that controls exoprotein storage and protein translocation across the S. aureus cell wall.
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Membrana Celular/metabolismo , Parede Celular/metabolismo , Staphylococcus aureus/metabolismo , Fatores de Virulência/metabolismo , Animais , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/toxicidade , Citotoxinas/metabolismo , Citotoxinas/toxicidade , Humanos , Leucocidinas/metabolismo , Leucocidinas/toxicidade , Lipopolissacarídeos/genética , Lipopolissacarídeos/metabolismo , Lisina/genética , Lisina/metabolismo , Camundongos , Fagócitos/efeitos dos fármacos , Fosfatidilgliceróis/genética , Fosfatidilgliceróis/metabolismo , Transporte Proteico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Ácidos Teicoicos/genética , Ácidos Teicoicos/metabolismo , Fatores de Virulência/toxicidadeRESUMO
Acquiring desirable device performance with deep-blue color purity that fulfills practical application requirements is still a challenge. Bipolar fluorescent emitters with hybrid local and charge transfer (HLCT) state may serve to address this issue. Herein, by inserting anthracene core in the deep-blue building blocks, the authors successfully developed two highly twisted D-π-A fluorescent emitters, ICz-An-PPI and IP-An-PPI, featuring different acceptor groups. Both exhibited superb thermal stabilities, high photo luminescent quantum yields and excellent bipolar transport capabilities. The non-doped OLEDs using ICz-An-PPI and IP-An-PPI as the emitting layers showed efficient blue emission with an external quantum efficiency (EQEmax ) of 4.32 % and 5.41 %, and the CIE coordinates of (0.147, 0.180) and (0.149, 0.150), respectively. In addition, the deep blue doped device based on ICz-An-PPI was achieved with an excellent CEmax of 5.83 cd A-1 , EQEmax of 4.6 % and the CIE coordinate of (0.148, 0.078), which is extremely close to the National Television Standards Committee (NTSC) standard. Particularly, IP-An-PPI-based doped device had better performance, with an EQEmax of 7.51 % and the CIE coordinate of (0.150, 0.118), which was very impressive among the recently reported deep-blue OLEDs with the CIEy <0.12. Such high performance may be attributed to the hot exciton HLCT mechanism via T7 to S2 . Our work may provide a new approach for designing high-efficiency deep-blue materials.
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High-performance deep-blue emitters with external quantum efficiencies (EQEs) exceeding 5 % are still scarce in organic light-emitting diodes (OLEDs). In this work, by introducing a [1,2,4]triazolo[1,5-a] pyridine (TP) unit at the N1 position of phenanthroimidazole (PI), two luminescent materials, PTPTPA and PTPTPA, were obtained. Systematic photophysical analysis showed that the TP block is suitable for constructing hybridized local and charge-transfer (HLCT) emitters. Its moderate electron-withdrawing ability and rigid planar structure can enhance the CT component while ensuring color purity. In addition, compared with PTPTPA, the additional phenyl ring of PTPBPTA not only increased the oscillator strength, but also decreased the Stokes shift. TDDFT calculations pointed out facile reverse intersystem crossing processes in PTPTPA from high-lying triplet states to the singlet excited state. A nondoped device based on PTPTPA as emitter showed impressive performance with EQEmax of 7.11 % and CIE coordinates of (0.15, 0.09). At the same time, it was also an efficient host for yellow and red phosphorescent OLEDs. By doping yellow (PPYBA) and red (BTPG) phosphorescent dyes into PTPTPA, a white OLED with a high EQE of 23.85 % was achieved. The successful design of PTPTPA not only provided an optimization choice for OLED emitters, but also demonstrated the empirical rules for the design of multifunctional deep-blue emitters.
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Bacterial biofilms are linked with chronic infections and have properties distinct from those of planktonic, single-celled bacteria. The virulence mechanisms associated with Staphylococcus aureus biofilms are becoming better understood. Human neutrophils are critical for the innate immune response to S. aureus infection. Here, we describe two virulence strategies that converge to promote the ability of S. aureus biofilms to evade killing by neutrophils. Specifically, we show that while neutrophils exposed to S. aureus biofilms produce extracellular traps (NETs) and phagocytose bacteria, both mechanisms are inefficient in clearance of the biofilm biomass. This is attributed to the leukocidin LukAB, which promotes S. aureus survival during phagocytosis. We also show that the persistence of biofilm bacteria trapped in NETs is facilitated by S. aureus nuclease (Nuc)-mediated degradation of NET DNA. This study describes key aspects of the interaction between primary human neutrophils and S. aureus biofilms and provides insight into how S. aureus evades the neutrophil response to cause persistent infections.
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Proteínas de Bactérias/imunologia , Biofilmes , Evasão da Resposta Imune , Leucocidinas/imunologia , Nuclease do Micrococo/imunologia , Neutrófilos/imunologia , Staphylococcus aureus/patogenicidade , Proteínas de Bactérias/genética , Biofilmes/crescimento & desenvolvimento , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/microbiologia , Humanos , Leucocidinas/genética , Viabilidade Microbiana , Nuclease do Micrococo/genética , Neutrófilos/microbiologia , Neutrófilos/patologia , Fagocitose , Staphylococcus aureus/imunologia , VirulênciaRESUMO
Two novel bipolar deep-blue fluorescent emitters, IP-PPI and IP-DPPI, featuring different lengths of the phenyl bridge, were designed and synthesized, in which imidazo[1,2-a]pyridine (IP) and phenanthroimidazole (PI) were proposed as an electron acceptor and an electron donor, respectively. Both of them exhibit outstanding thermal stability and high emission quantum yields. All the devices based on these two materials showed negligible efficiency roll-off with increasing current density. Impressively, non-doped organic light-emitting diodes (OLEDs) based on IP-PPI and IP-DPPI exhibited external quantum efficiencies (EQEs) of 4.85 % and 4.74 % with CIE coordinates of (0.153, 0.097) and (0.154, 0.114) at 10000â cd m-2 , respectively. In addition, the 40â wt % IP-PPI doped device maintained a high EQE of 5.23 % with CIE coordinates of (0.154, 0.077) at 10000â cd m-2 . The doped device based on 20â wt % IP-DPPI exhibited a higher deep-blue electroluminescence (EL) performance with a maximum EQE of up to 6.13 % at CIE of (0.153, 0.078) and maintained an EQE of 5.07 % at 10000â cd m-2 . To the best of our knowledge, these performances are among the state-of-the art devices with CIEy ≤0.08 at a high brightness of 10000â cd m-2 . Furthermore, by doping a red phosphorescent dye Ir(MDQ)2 (MDQ=2-methyldibenzo[f,h]quinoxaline) into the IP-PPI and IP-DPPI hosts, high-performance red phosphorescent OLEDs with EQEs of 20.8 % and 19.1 % were achieved, respectively. This work may provide a new approach for designing highly efficient deep-blue emitters with negligible roll-off for OLED applications.
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Misfolding of translated proteins occurs in all domains of life. In most cells, misfolded proteins coalesce in discrete aggregates at distinct cellular locations. In many bacteria, including mycobacteria, protein aggregates are located at the cellular pole. Yet the mechanism by which aggregates are sorted to the mycobacterial pole is not known. Here, we show that in Mycobacterium smegmatis, the small heat shock protein HspX plays a critical role in the polar localization of aggregates of a model fluorescent misfolded protein, GLR103. HspX itself has a polar localization, which is dependent on its N-terminal domain. In a strain deleted for hspX, GLR103 is less liable to aggregation and no longer localizes to the pole, and redirecting HspX to the septum radically disrupts the normal polar localization of GLR103 aggregates. To further investigate the role of HspX in native protein aggregation, we performed semi-quantitative mass-spectrometry of mycobacterial protein aggregates in wild-type, hspX-deleted and hspX-overexpressing strains. We identified a subset of proteins that appeared to be HspX-dependent for aggregate formation. Furthermore, we demonstrate that for validated native protein aggregates, sorting to the cellular pole following proteotoxic stress required HspX. In summary, we have identified the cellular function of HspX in Mycobacterium smegmatis as both a pro-aggregase and polar sortase.
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Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Choque Térmico/metabolismo , Mycobacterium smegmatis/metabolismo , Processamento de Imagem Assistida por Computador , Espectrometria de Massas , Microscopia de Fluorescência , Plasmídeos/metabolismo , Agregados Proteicos , Desnaturação Proteica , Domínios Proteicos , Dobramento de ProteínaRESUMO
Staphylococcus aureus is a human pathogen responsible for high morbidity and mortality worldwide. Recurrent infections with this bacterium are common, suggesting that S. aureus thwarts the development of sterilizing immunity. S. aureus strains that cause disease in humans produce up to five different bicomponent toxins (leukocidins) that target and lyse neutrophils, innate immune cells that represent the first line of defense against S. aureus infections. However, little is known about the role of leukocidins in blunting adaptive immunity. Here, we explored the effects of leukocidins on human dendritic cells (DCs), antigen-presenting cells required for the development of adaptive immunity. Using an ex vivo infection model of primary human monocyte-derived dendritic cells, we found that S. aureus, including strains from different clonal complexes and drug resistance profiles, effectively kills DCs despite efficient phagocytosis. Although all purified leukocidins could kill DCs, infections with live bacteria revealed that S. aureus targets and kills DCs primarily via the activity of leukocidin LukAB. Moreover, using coculture experiments performed with DCs and autologous CD4+ T lymphocytes, we found that LukAB inhibits DC-mediated activation and proliferation of primary human T cells. Taken together, the data determined in the study reveal a novel immunosuppressive strategy of S. aureus whereby the bacterium blunts the development of adaptive immunity via LukAB-mediated injury of DCs.IMPORTANCE Antigen-presenting cells such as dendritic cells (DCs) fulfill an indispensable role in the development of adaptive immunity by producing proinflammatory cytokines and presenting microbial antigens to lymphocytes to trigger a faster, specific, and long-lasting immune response. Here, we studied the effect of Staphylococcus aureus toxins on human DCs. We discovered that the leukocidin LukAB hinders the development of adaptive immunity by targeting human DCs. The ability of S. aureus to blunt the function of DCs could help explain the high frequency of recurrent S. aureus infections. Taken together, the results from this study suggest that therapeutically targeting the S. aureus leukocidins may boost effective innate and adaptive immune responses by protecting innate leukocytes, enabling proper antigen presentation and T cell activation.
Assuntos
Proteínas de Bactérias/toxicidade , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/fisiologia , Evasão da Resposta Imune , Leucocidinas/toxicidade , Infecções Estafilocócicas/patologia , Staphylococcus aureus/patogenicidade , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/microbiologia , Humanos , Ativação Linfocitária , Modelos BiológicosRESUMO
Geological and hydrogeological conditions in karst areas are complicated from the viewpoint of engineering. The construction of underground structures in these areas is often disturbed by the gushing of karst water, which may delay the construction schedule, result in economic losses, and even cause heavy casualties. In this paper, an innovative method of multichannel transient Rayleigh wave detecting is proposed by introducing the concept of arrival time difference phase between channels (TDP). Overcoming the restriction of the space-sampling law, the proposed method can extract the phase velocities of different frequency components from only two channels of transient Rayleigh wave recorded on two adjacent detecting points. This feature greatly improves the work efficiency and lateral resolution of transient Rayleigh wave detecting. The improved multichannel transient Rayleigh wave detecting method is applied to the detection of karst caves and fractures in rock mass of the foundation pit of Yan'an Road Station of Guiyang Metro. The imaging of the detecting results clearly reveals the distribution of karst water inflow channels, which provided significant guidance for water plugging and enabled good control over karst water gushing in the foundation pit.