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1.
Adv Mater ; : e2008194, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33645858

RESUMO

Oxygen-redox of layer-structured metal-oxide cathodes has drawn great attention as an effective approach to break through the bottleneck of their capacity limit. However, reversible oxygen-redox can only be obtained in the high-voltage region (usually over 3.5 V) in current metal-oxide cathodes. Here, we realize reversible oxygen-redox in a wide voltage range of 1.5-4.5 V in a P2-layered Na0.7 Mg0.2 [Fe0.2 Mn0.6 □0.2 ]O2 cathode material, where intrinsic vacancies are located in transition-metal (TM) sites and Mg-ions are located in Na sites. Mg-ions in the Na layer serve as "pillars" to stabilize the layered structure during electrochemical cycling, especially in the high-voltage region. Intrinsic vacancies in the TM layer create the local configurations of "□-O-□", "Na-O-□" and "Mg-O-□" to trigger oxygen-redox in the whole voltage range of charge-discharge. Time-resolved techniques demonstrate that the P2 phase is well maintained in a wide potential window range of 1.5-4.5 V even at 10 C. It is revealed that charge compensation from Mn- and O-ions contributes to the whole voltage range of 1.5-4.5 V, while the redox of Fe-ions only contributes to the high-voltage region of 3.0-4.5 V. The orphaned electrons in the nonbonding 2p orbitals of O that point toward TM-vacancy sites are responsible for reversible oxygen-redox, and Mg-ions in Na sites suppress oxygen release effectively.

2.
Environ Pollut ; 276: 116737, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33618119

RESUMO

The presence of antibiotics such as erythromycin, even in trace amounts, has long been acknowledged for negatively impacting ecosystems in freshwater environments. Although many studies have focused on the impact of antibiotic pollution at a macroecological level, the impact of erythromycin on microecosystems, such as freshwater biofilms, is still not fully understood. This knowledge gap may be attributed to the lack of robust multispecies biofilm models for fundamental investigations. Here, we used a lab-cultured multispecies biofilm model to elucidate the holistic response of a microbial community to erythromycin exposure using metagenomic and metabolomic approaches. Metagenomic analyses revealed that biofilm microbial diversity did not alter following erythromycin exposure. Notably, certain predicted metabolic pathways such as cell-cell communication pathways, amino acid metabolism, and peptidoglycan biosynthesis, mainly by the phyla Actinobacteria, Alpha/Beta-proteobacteria, Bacteroidetes, and Verrucomicrobia, were found to be involved in the maintenance of homeostasis-like balance in the freshwater biofilm. Further untargeted metabolomics data highlighted changes in lipid metabolism and linoleic acid metabolism and their related molecules as a direct consequence of erythromycin exposure. Overall, the study presented a unique picture of how multispecies biofilms respond to single environmental stress exposures. Moreover, the study demonstrated the feasibility of using lab simulated multispecies biofilms for investigating their interaction and reactivity of specific bioactive compounds or pollutants at a fundamental level.

3.
J Med Chem ; 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33596380

RESUMO

Flaviviruses, including Zika, dengue, and West Nile viruses, are important human pathogens. The highly conserved NS2B-NS3 protease of Flavivirus is essential for viral replication and therefore a promising drug target. Through compound screening, followed by medicinal chemistry studies, a novel series of 2,5,6-trisubstituted pyrazine compounds are found to be potent, allosteric inhibitors of Zika virus protease (ZVpro) with IC50 values as low as 130 nM. Their structure-activity relationships are discussed. The ZVpro inhibitors also inhibit homologous proteases of dengue and West Nile viruses, and their inhibitory activities are correlated. The most potent compounds 47 and 103 potently inhibited Zika virus replication in cells with EC68 values of 300-600 nM and in a mouse model of Zika infection. These compounds represent novel pharmacological leads for drug development against Flavivirus infections.

4.
Plant Dis ; 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33616429

RESUMO

Northern corn leaf blight (NCLB), caused by Setosphaeria turcica, is an important foliar disease in corn. Since 2005, the damage from NCLB has increased in Northeast China, probably due to the emergence of new physiological races. In this study, 883 single conidial isolates of S. turcica were obtained from 12 sites across three provinces of Northeast China between 2007 and 2017. The virulence of the isolates was evaluated in five corn lines (B37, B37Ht1, B37Ht2, B37Ht3, B37HtN). Sixteen physiological races (0, 1, 2, 3, N, 12, 13, 1N, 23, 2N, 3N, 123, 12N, 13N, 23N, and 123N) were obtained, depending on their resistance or susceptibility. Three races (0, 1, and 2) were most prevalent, with frequencies of 40.5%, 19.6%, and 11.3% in all isolates, respectively. Races varied across provinces and years. Virulence to more than one Ht resistance genes occurred in 21.5% of isolates, with 8.5% virulent to three or more genes. Overall, 41% of isolates were avirulent to all Ht genes, 36% were virulent to Ht1, 28% to Ht2, 11% to Ht3, and 16% to HtN. Isolates from Heilongjiang had a greater frequency of virulence to Ht2 and Ht3, whereas isolates from Jilin and Liaoning were more frequently virulent to Ht1 and HtN, respectively. The frequency of isolate virulence to Ht2 ranged from 8% in 2009 to a maximum of 29% in 2015, and in 2015, isolates were more virulent to Ht2 than Ht1. This study will help growers to purposefully select commercial hybrids with multiple effective Ht resistance genes, and reduce the utilization of Ht1 and Ht2 genes in the process of corn production to strengthen NCLB control.

5.
Macromol Rapid Commun ; : e2100010, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33634531

RESUMO

Water-resistant and high-strength adhesion on different surfaces has attracted considerable attention for decades. However, the adhesion performances of conventional adhesives suffer from deterioration in adhesion performances under water or wet conditions. This work proposes a dipole-dipole interaction strategy for fabricating a solvent-free adhesive that is synthesized via simple one-step copolymerization of dipole monomer acrylonitrile (AN), crosslinker poly(ethylene glycol) diacrylate (PEGDA) with variable length, and a monomer-soluble initiator that initiates room-temperature polymerization. The dipole-dipole interactions from cyan groups in AN concurrently contribute to strong cohesion and adhesion strength in bonding to a wide range of substrates including aluminum, ceramic, glass fiber, epoxy resin, polyethylene terephthalate, wood, and fractured large segmental bone. The adhesion strengths are dependent upon the length of PEGDA, and the shorter PEGDA-crosslinked PAN adhesive demonstrates outstanding water-resistant adhesion spanning pH 2 to pH 10 for 30 days with adhesion strength ranging from 3.31 to 3.97 MPa due to strong dipole-dipole pairing shielding. This dipole-dipole interaction and co-dissolution strategy open a new avenue for creating high-strength water-resistant adhesives for promising applications in engineering and hard-tissue repair.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33492493

RESUMO

PURPOSE: To evaluate the safety and feasibility of a newly designed 125I brachytherapy ureteral stent (BUS) in normal dogs. METHODS: A BUS loaded with 10 125I seeds (Group A: 0.8 mCi, Group B: 0.4 mCi, Group C: 0 mCi) was designed and tested in 27 normal beagle dogs. Routine blood tests, gross observations, cumulative radiation doses, tissue reaction assessed by hematoxylin-eosin/Masson staining, mRNA analysis by RT-qPCR and protein expression of Caspase-3, Collagen I, PCNA, and α-SMA were performed at 2, 4 and 8 weeks. RESULTS: The BUS was implanted successfully in all dogs (27/27) without surgery-related death. The ureter diameter and radiation injury score increased along with radiation accumulation (p < 0.05). Histopathologic analysis showed necrotic tissue and lateral fibrosis to different extents in the ureteral walls that gradually increased in all groups (p < 0.05); however, epithelial cell proliferation in groups A and B was lighter than that in the control group (p < 0.05). CONCLUSION: Placement of the newly designed 125I BUS was safe and feasible in dogs, and clinical studies are required to test its use in humans.

7.
Macromol Biosci ; : e2000303, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33393184

RESUMO

Glue protein as secretion from fruit fly larva plays a significant role in metamorphosis as cementing material for pupation sites. However, the biochemical composition of this macromolecule remains obscure. This study takes the advantage of high-resolution proteomic analysis to unveil the protein compositions. A glue protein group is identified as chitin-binding motifs by bioinformatic analysis. Computational modeling analysis of representative proteins illustrates the binding site between protein and chitin. A biosynthetic approach is used to fabricate a glue protein by a modified Escherichia coli recombinant system. The as-biosynthesized biomimetic glue protein is applied as an extracellular matrix to investigate its biocompatibility and functionality. It is found that the purified recombinant protein shows enhanced performance to cellular viability. This finding provides a potential biomacromolecule candidate as an extracellular matrix for cell culture.

8.
Neurosci Bull ; 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33421025

RESUMO

Ferroptosis is a form of iron-dependent regulated cell death. Evidence of its existence and the effects of its inhibitors on subarachnoid hemorrhage (SAH) is still lacking. In the present study, we found that liproxstatin-1 protected HT22 cells against hemin-induced injury by protecting mitochondrial functions and ameliorating lipid peroxidation. In in vivo experiments, we demonstrated the presence of characteristic shrunken mitochondria in ipsilateral cortical neurons after SAH. Moreover, liproxstatin-1 attenuated the neurological deficits and brain edema, reduced neuronal cell death, and restored the redox equilibrium after SAH. The inhibition of ferroptosis by liproxstatin-1 was associated with the preservation of glutathione peroxidase 4 and the downregulation of acyl-CoA synthetase long-chain family member 4 as well as cyclooxygenase 2. In addition, liproxstatin-1 decreased the activation of microglia and the release of IL-6, IL-1ß, and TNF-α. These data enhance our understanding of cell death after SAH and shed light on future preclinical studies.

9.
J Atheroscler Thromb ; 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33455996

RESUMO

AIMS: Recent studies suggested plaque erosion with noncritical stenosis could be treated distinctly from that with critical stenosis, but their morphological features remained largely unknown. The present study aimed to investigate morphological features of eroded plaques with different lumen stenosis using optical coherence tomography (OCT). METHODS: A total of 348 ST-segment elevated myocardial infarction patients with culprit OCT-defined plaque erosion (OCT-erosion) were analyzed. Based on the severity of lumen area stenosis, all patients with OCT-erosions were divided into the following three groups: Group A (area stenosis <50%, n=50); Group B (50% ≤area stenosis <75%, n=146); Group C (area stenosis ≥ 75%, n=152). RESULTS: Compared with patients in Groups A and B, patients in Group C were older (p=0.008) and had higher prevalence of hypertension (p=0.029). Angiographic analysis showed that 72.0% of the eroded plaques in Group A were located in the left anterior descending artery, followed by 67.8% in Group B, and 53.9% in Group C (p=0.039). OCT analysis showed that Group A had the highest prevalence of fibrous plaques (p<0.001) and nearby bifurcation (p=0.036), but the lowest prevalence of lipid-rich plaques (p<0.001), macrophage accumulation (p<0.001), microvessels (p=0.009), cholesterol crystals (p<0.001), and calcification (p=0.023). Multivariable regression analysis showed fibrous plaque (odds ratio [OR]: 3.014, 95% confidence interval [CI]: 1.932-4.702, p<0.001) and nearby bifurcation (OR: 1.750, 95% CI: 1.109-2.761, p=0.016) were independently associated with OCT-erosion with an area stenosis of <75%. CONCLUSIONS: More than half of OCT-erosions presented with <75% area stenosis, having distinct morphological features from those of OCT-erosions with critical stenosis. Fibrous plaque and nearby bifurcation were independently associated with noncritically stenotic OCT-erosion, suggesting that eroded plaques might need individualized treatment.

10.
Acc Chem Res ; 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33434011

RESUMO

ConspectusChemically induced transformations are postsynthetic processing reactions applied to first generation (as-synthesized) nanomaterials to modify property-defining factors such as atomic structure, chemical composition, surface chemistry, and/or morphology. Compared with conditions for direct synthesis of colloidal nanocrystals, postsynthetic chemical transformations can be conducted in relatively mild conditions with a more controllable process, which makes them suitable for the precise manipulation of nanomaterials and for trapping metastable phases that are typically inaccessible from the conventional synthetic routes. Each of the chemically induced transformations methods can result in substantial restructuring of the atomic structure, but their transformation pathways can be very different. And the converse is also true: the atomic structure of the parent material plays a large role in the pathway toward and the resulting chemically transformed product. Additionally, the characteristic length of the parent material greatly affects the structure, which affects the outcome of the reaction.In this Account, we show how the atomic structure and nanoscale size directs the product formation into materials that are inaccessible from analogous chemically transformations in bulk materials. Through examples from the three chemical transformation processes (cation/anion exchange, redox reactions, and ligand exchange and ligand etching), the effect of the atomic structure on chemical transformations is made apparent, and vice versa. For cation exchange, an anisotropic atomic lattice results in a unidirectional exchange boundary. And because the interface can extend through the full crystal, a substantial strain field can form, influencing the phase of the material. In the redox reaction that leads to the nanoscale Kirkendall effect, the atomic structure is the key to inverting the diffusion rates in a diffusion couple to form the hollow cores. And for ligand etching, if one of the materials in a heterostructure has a defected and\or defect-tolerant atomic structure, it can be preferentially etched and its atomic structure can undergo phase transformations while the other composition remains intact. For length scales, we show how the chemically induced transformations greatly differ between bulk, nanocrystal, and nanocluster characteristic sizes. For instance, the structural transformation on relatively large nanocrystals (2-100 nm) can be a continuous process when the activation volume is smaller than the nanocrystal, while for smaller nanoclusters (<2 nm) the transformation kinetics could be swift resulting in only discrete thermodynamic states. Comparing the two nanosystems (nanocrystals to small nanoclusters), we address how their atomic structural differences can direct the divergent transformation phenomena and the corresponding mechanisms. Understanding the nanoscale mechanisms of chemically induced transformations and how they differ from bulk processes is key to unlocking new science and for implementing this processing for functional materials.

11.
Nat Commun ; 12(1): 19, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397992

RESUMO

Amines are a class of compounds of essential importance in organic synthesis, pharmaceuticals and agrochemicals. Due to the importance of chirality in many practical applications of amines, enantioselective syntheses of amines are of high current interest. Here, we wish to report the development of (R,Ra)-N-Nap-Pyrinap and (R,Sa)-N-Nap-Pyrinap ligands working with CuBr to catalyze the enantioselective A3-coupling of terminal alkynes, aldehydes, and amines affording optically active propargylic amines, which are platform molecules for the effective derivatization to different chiral amines. With a catalyst loading as low as 0.1 mol% even in gram scale reactions, this protocol is applied to the late stage modification of some drug molecules with highly sensitive functionalities and the asymmetric synthesis of the tubulin polymerization inhibitor (S)-(-)-N-acetylcolchinol in four steps. Mechanistic studies reveal that, unlike reported catalysts, a monomeric copper(I) complex bearing a single chiral ligand is involved in the enantioselectivity-determining step.


Assuntos
Aminas/química , Aminas/síntese química , Teoria da Densidade Funcional , Ligantes , Rotação , Estereoisomerismo
12.
Immun Inflamm Dis ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33470559

RESUMO

INTRODUCTION: Previous studies of anti-dsDNA, nucleosome (Nucl), histone (His), and C1q antibodies have revealed their clinical value in systemic lupus erythematosus (SLE). However, the correlation between four autoantibodies and SLE activity, lupus nephritis (LN) remains controversial, and data are insufficient on longitudinal monitoring. This study aimed at evaluating the value of these autoantibodies in active LN, and their performance on cross-sectional evaluating and longitudinal monitoring of SLE disease activity. METHODS: Serum levels of four autoantibodies in 114 SLE patients, 219 other autoimmune disease patients (OAD), and 59 healthy controls were assayed by a quantitative immunoassay. Sera of 38 inpatients were obtained again after treatment. RESULTS: We found that serum levels of four autoantibodies were significantly higher in SLE than OAD patients (p < 001), active LN than non-renal SLE patients (p < .05), and higher in SLE patients with moderate and severe disease activity than mild disease activity (p < .01). Horizontally, serum level of each autoantibody was correlated with SLE disease activity index (SLEDAI) (p < .05), and correlation coefficient of anti-dsDNA was the highest (r = .585). For longitudinal monitoring, the decreased levels of four autoantibodies were found following treatment (p < .001). Serum level variations of these antibodies were positively correlated with variations of SLEDAI (p < .05). The correlation coefficient of anti-Nucl was the highest (r = .629). Although the levels of C3 and C4 increased after treatment, the change was not related to the change of SLEDAI (p > .05). CONCLUSIONS: Anti-C1q, anti-dsDNA, anti-Nucl, and anti-His perform well in diagnosing active LN and monitoring SLE disease activity. They could be indicators of active LN and SLE disease activity.

13.
Oral Dis ; 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33503275

RESUMO

BACKGROUND: Cyclin-dependent kinase 7 (CDK7) has been critically linked to human cancer. However, the roles of CDK7 in head and neck squamous cell carcinoma (HNSCC) remain incompletely known. Here, we sought to dissect the functions of CDK7 underlying HNSCC tumorigenesis and explore whether pharmacological inhibition of CDK7 could induce anti-cancer effects. METHODS: CDK7 expression was measured in a panel of HNSCC cell lines with p53 mutation and 20 pairs of HNSCC samples and adjacent non-tumor tissues. Genetic targeting and pharmacological inhibition of CDK7 were conducted to dissect the biological roles of CDK7 in p53-mutated HNSCC cells. An HNSCC xenograft model was developed to determine the therapeutic effects of THZ1 in vivo. Potential genes and pathways responsible for therapeutic effects of THZ1 were identified by genome-wide RNA-sequencing and bioinformatics interrogations. RESULTS: CDK7 expression was significantly elevated in cancerous cells and samples as compared with their adjacent non-tumor counterparts. Impaired cell proliferation, migration, and invasion as well increased apoptosis were observed in cells upon CDK7 knockdown or THZ1 exposure. THZ1 administration potently inhibited tumor overgrowth in vivo. Mechanistically, hundreds of genes enriched in cell proliferation, apoptosis, and cancer-related categories were identified to be potentially mediated the therapeutic effects of THZ1 in HNSCC. CONCLUSION: Our findings reveal that CDK7 might serve as a novel putative pro-oncogenic gene underlying HNSCC tumorigenesis and therapeutic targeting of CDK7 might be a promising strategy for p53-mutated HNSCC.

14.
J Agric Food Chem ; 69(7): 2138-2148, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33470120

RESUMO

Litchi chinensis seed is a valuable byproduct of the subtropical fruit litchi (L. chinensis Sonn.), whose extract (LSE) has been confirmed to ameliorate dyslipidemia, hyperglycemia, and oxidative stress caused by type 2 diabetes. However, if LSE exerts an effect on anti-hypertension and hypertensive renal damage remains unknown. In this study, 13 polyphenols and one fatty acid were identified by UPLC-Q/TOF-MS. Network pharmacological analysis revealed that the therapeutic effects of LSE may be involved in multitargets and multipathways, such as the TNF signaling pathway, interleukin (IL)-6-mediated signaling pathway, NF-kappa B signaling pathway, removal of superoxide radicals, negative regulation of blood pressure, and so forth. Moreover, spontaneously hypertensive rats (SHRs) were daily gavaged with LSE (60 mg/kg) for 10 weeks. LSE remarkably reduced systolic blood pressure (SBP). The hypertension-induced renal damage was improved by suppressing inflammation and oxidative stress, which was consistent with the prediction of network pharmacology. In addition, LSE treatment remarkably increased the relative abundances of Lactobacillus and the production of short-chain fatty acids in the intestine. Our study indicated that a byproduct of litchi, namely, litchi seed, may be effective in reducing SBP and alleviating hypertensive renal damage.

15.
Biomed Res Int ; 2021: 8743409, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33511212

RESUMO

Exosomes are vesicles with a diameter of 30-150 nm produced by living cells and secreted into the extracellular matrix. Exosomes mediate cellular communication by carrying active molecules, such as nucleic acids, proteins, and liposomes. Although exosomes are found in various body fluids, little is known about bile-derived exosomes. This review is the first to summarize the methods of bile storage and isolation of biliary exosomes, highlighting the roles of bile-derived exosomes, especially exosomal noncoding RNAs, in physiological and disease states and discussing their potential clinical applications.

16.
Funct Plant Biol ; 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33516276

RESUMO

In this study we analysed the influence of drought stress on the leaf morphological characteristics, osmotic adjustment substances, antioxidant enzymes, and resistance-related photosynthetic physiological indices of Harumi tangor plants grafted onto Poncirus trifoliata (Pt), Citrus junos (Cj), and Citrus tangerine (Ct). The leaf relative water content and leaf area of the three rootstocks decreased with increasing drought stress, with the smallest decrease in Cj. The relative conductivity and malondialdehyde content increased with increasing drought stress. Proline, total soluble sugar, soluble protein, and activities of superoxide dismutase, ascorbate peroxidase, and catalase increased with drought stress but decreased under severe drought stress, with Cj exhibiting the greatest increase in enzyme activity. The net photosynthetic rate, stomatal conductance, transpiration rate, and chlorophyll a and b content were all lower than those of the control, whereas intercellular CO2 concentration increased with increasing drought stress. The initial fluorescence and maximal quantum yield of PSII were approximately equal for all rootstocks but increased with increasing drought stress severity. The combined analysis of physiological indicators, membership function, and principal components indicated that the drought resistance of grafted H. tangor decreased in the order Cj > Ct > Pt.

17.
Carbohydr Polym ; 252: 117155, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33183606

RESUMO

Inulin-type fructans (ITFs) as functional fructans and soluble dietary fiber are a mixture of inulin, oligofructose and fructooligosaccharide with ß configuration. They are modified by gut microbiota at the end of ileum, subsequently, improve digestive system, metabolic syndrome, immune system and inflammatory diseases, and prevent against infection and cancer. However, it has been reported that inadequate consumption of ITFs aggravates the development of non-alcoholic fatty liver disease, results in gastrointestinal symptoms, liver cancer and intestinal inflammation. Therefore, this review summarizes the health benefits, pharmaceutical applications and safety evaluation of ITFs, which would direct their rational applications.

18.
Diagn Interv Radiol ; 27(1): 79-84, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33331281

RESUMO

PURPOSE: We aimed to assess the effectiveness of percutaneous radiofrequency ablation (PRFA) combined with iodine-125 (125I) seed strand brachytherapy (125I-BT) for treatment of occluded biliary stents. METHODS: From November 2015 to September 2017, 13 consecutive patients with occluded biliary metal stents, implanted for malignant obstruction, underwent PRFA combined with 125I-BT to reopen the bile duct. Data included clinical and technical success, stent patency, complications, and overall survival. RESULTS: The clinical and technical success rates were both 100%. One month after treatment, the total serum bilirubin level had decreased significantly (P < 0.001). Early complications of cholangitis or hemobilia were experienced by one patient each. Three patients (23.1%) had late complications, including two cases of cholangitis and one case of cholecystitis. During the mean follow-up of 233±82.9 days (range, 88-365 days), the stent patency time was 239±26.5 days (95% CI, 187-291 days), and the 6-month stent patency rate was 68.4%. Five patents died; the mean survival time was 298±30.1 days (95% CI, 239-358 days). The 6-month survival rate was 83%. CONCLUSION: PRFA therapy combined with 125I-BT is feasible and safe for patients with occluded metal stents placed for malignant biliary obstruction. Nevertheless, randomized controlled trails are needed to confirm the effectiveness of this new approach.

19.
J Immunol ; 206(4): 700-711, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33380496

RESUMO

Intradermal (ID) immunization is an attractive route of vaccination because it targets tissue rich in dendritic cells, has dose-sparing potential, and allows needle-free delivery. However, few adjuvants are effective, nonreactogenic, and compatible with needle-free delivery devices. In this study, we demonstrate that a combination adjuvant composed of cyclic-di-AMP (cdAMP) and the plant-derived nanoparticle adjuvant Nano-11 significantly enhanced the immune response to ID-injected vaccines in mice and pigs with minimal local reaction at the injection site. The cdAMP/Nano-11 combination adjuvant increased Ag uptake by lymph node-resident and migratory skin dendritic cell subpopulations, including Langerhans cells. ID immunization with cdAMP/Nano-11 expanded the population of germinal center B cells and follicular helper T cells in the draining lymph node and Ag-specific Th1 and Th17 cells in the spleen. It elicited an enhanced immune response with a significant increase of IgG1 and IgG2a responses in mice at a reduced dose compared with i.m. immunization. An increased IgG response was observed following needle-free ID immunization of pigs. Nano-11 and cdAMP demonstrated a strong synergistic interaction, as shown in the activation of mouse, human, and porcine APC, with increased expression of costimulatory molecules and secretion of TNF and IL-1ß. The combination adjuvant induced robust activation of both NF-κB and IFN regulatory factor signaling pathways and the NLRP3 inflammasome. We conclude that the combination of Nano-11 and cdAMP is a promising adjuvant for ID delivery of vaccines that supports a balanced immune response.

20.
Gene ; 773: 145374, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33359126

RESUMO

The Escherichia coli QseB/QseC signaling regulates expressions of more than 50 genes encoding flagellar proteins and proteins associated with virulence. Here we found that absence of the QseB/QseC signaling led to an early initiation of chromosomal replication and higher concentration of DnaA which is initiator for replication. The upstream region of dnaA promoter contains three potential QseB binding sites and absence of these binding sites increased transcription of the dnaA gene in wild-type cells but not in the cells lacking the qseB/qseC genes, showing that the QseB/QseC signaling regulates dnaA expression through the QseB binding sites. Also increased cell motility but neither cell size nor growth rate in ΔqseBC and ΔqseB cells was observed and these effects were reversed by ectopic expression of QseBC. Further, it was found that QseB interacted with the DnaK chaperone and FtsZ cell division protein in vivo, and absence of DnaK or partial inactivation of FtsZ decreased cell motility. Thus, we conclude that the QseB/QseC signaling modulates timing of replication initiation by regulating expression of DnaA, coordinates cell motility with cell division through interacting with the DnaK and FtsZ protein.


Assuntos
Movimento Celular/genética , Proteínas de Escherichia coli/genética , Escherichia coli/genética , Replicação do DNA/genética , Escherichia coli/patogenicidade , Regulação Bacteriana da Expressão Gênica/genética , Regiões Promotoras Genéticas , Transdução de Sinais/genética , Virulência/genética
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