12 research outputs found
Controlling Defect Formation of Nanoscale AlN: Toward Efficient Current Conduction of UltrawideâBandgap Semiconductors
Ultrawideâbandgap semiconductors such as AlN, BN, and diamond hold tremendous promise for highâefficiency deepâultraviolet optoelectronics and highâpower/frequency electronics, but their practical application has been limited by poor current conduction. Through a combined theoretical and experimental study, it is shown that a critical challenge can be addressed for AlN nanostructures by using Nârich epitaxy. Under Nârich conditions, the pâtype Alâsubstitutional Mgâdopant formation energy is significantly reduced by 2Â eV, whereas the formation energy for Nâvacancy related compensating defects is increased by â3Â eV, both of which are essential to achieve high hole concentrations of AlN. Detailed analysis of the currentâvoltage characteristics of AlN pâiân diodes suggests that current conduction is dominated by holeâcarrier tunneling at room temperature, which is directly related to the activation energy of Mg dopants. At high Mg concentrations, the dispersion of Mg acceptor energy levels leads to drastically reduced activation energy for a portion of Mg dopants, evidenced by the small tunneling energy of 67 meV, which explains the efficient current conduction and the very small turnâon voltage (â5Â V) for the diodes made of nanoscale AlN. This work shows that nanostructures can overcome the dopability challenges of ultrawideâbandgap semiconductors and significantly increase the efficiency of devices.Controlled defects formation and efficient current conduction of nanoscale AlN are realized. Under Nârich epitaxy conditions, the formation energy for Nâvacancy related compensating defects is increased by nearly 3Â eV, eliminating donorâlike compensating defects. Meanwhile, the pâtype Alâsubstitutional Mgâdopant formation energy is reduced by 2Â eV, significantly enhancing Mgâdopant incorporation and reducing hole carrier tunneling barrier.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162750/3/aelm202000337-sup-0001-SuppMat.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162750/2/aelm202000337_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162750/1/aelm202000337.pd
Chalcone attenuates Staphylococcus aureus virulence by targeting sortase A and alpha-hemolysin
Staphylococcus aureus (S.aureus) resistance, considered a dilemma for the clinical treatment of this bacterial infection, is becoming increasingly intractable. Novel anti-virulence strategies will undoubtedly provide a path forward in combating these resistant bacterial infections. Sortase A (SrtA), an enzyme responsible for anchoring virulence-related surface proteins, and alpha-hemolysin (Hla), a pore-forming cytotoxin, have aroused great scientific interest, as they have been regarded as targets for promising agents against S. aureus infection. In this study, we discovered that chalcone, a natural small compound with little anti-S. aureus activity, could significantly inhibit SrtA activity with an IC50 of 53.15 uM and Hla hemolysis activity with an IC50 of 17.63 uM using a fluorescence resonance energy transfer (FRET) assay and a hemolysis assay, respectively. In addition, chalcone was proven to reduce protein A (SpA) display in intact bacteria, binding to fibronectin, formation of biofilm and S. aureus invasion. Chalcone could down-regulate the transcriptional levels of the hla gene and the agrA gene, thus leading to a reduction in the expression of Hla and significant protection against Hla-mediated A549 cell injury; more importantly, chalcone could also reduce mortality in infected mice. Additionally, molecular dynamics simulations and mutagenesis assays were used to identify the mechanism of chalcone against SrtA, which implied that the inhibitory activity lies in the bond between chalcone and SrtA residues Val168, Ile182, and Arg197. Taken together, the in vivo and in vitro experiments suggest that chalcone is a potential novel therapeutic compound for S. aureus infection via targeting SrtA and Hla
Chalcone Attenuates Staphylococcus aureus Virulence by Targeting Sortase A and Alpha-Hemolysin
Staphylococcus aureus (S.aureus) resistance, considered a dilemma for the clinical treatment of this bacterial infection, is becoming increasingly intractable. Novel anti-virulence strategies will undoubtedly provide a path forward in combating these resistant bacterial infections. Sortase A (SrtA), an enzyme responsible for anchoring virulence-related surface proteins, and alpha-hemolysin (Hla), a pore-forming cytotoxin, have aroused great scientific interest, as they have been regarded as targets for promising agents against S. aureus infection. In this study, we discovered that chalcone, a natural small compound with little anti-S. aureus activity, could significantly inhibit SrtA activity with an IC50 of 53.15 ÎŒM and Hla hemolysis activity with an IC50 of 17.63 ÎŒM using a fluorescence resonance energy transfer (FRET) assay and a hemolysis assay, respectively. In addition, chalcone was proven to reduce protein A (SpA) display in intact bacteria, binding to fibronectin, formation of biofilm and S. aureus invasion. Chalcone could down-regulate the transcriptional levels of the hla gene and the agrA gene, thus leading to a reduction in the expression of Hla and significant protection against Hla-mediated A549 cell injury; more importantly, chalcone could also reduce mortality in infected mice. Additionally, molecular dynamics simulations and mutagenesis assays were used to identify the mechanism of chalcone against SrtA, which implied that the inhibitory activity lies in the bond between chalcone and SrtA residues Val168, Ile182, and Arg197. Taken together, the in vivo and in vitro experiments suggest that chalcone is a potential novel therapeutic compound for S. aureus infection via targeting SrtA and Hla
Downregulation of RIG-I mediated by ITGB3/c-SRC/STAT3 signaling confers resistance to interferon-α-induced apoptosis in tumor-repopulating cells of melanoma
BackgroundInterferon-α (IFN-α) plays a pivotal role in host antitumor immunity, and the evasion of IFN-α signaling pathway can lead to IFN-α resistance during the treatment of cancer. Although the interplay between IFN-α and tumor cells has been extensively investigated in differentiated tumor cells, much less attention has been directed to tumor-repopulating cells (TRCs).MethodsThree-dimentional soft fibrin matrix was used to select and grow highly malignant and tumorigenic melanoma TRCs. The regulation of integrin ÎČ3 (ITGB3)-c-SRC-STAT signaling pathway in melanoma TRCs was investigated both in vitro and in vivo. The relevant mRNA and protein expression levels were analyzed by qRT-PCR and western blot analysis. Immunoprecipitation and chromatin immunoprecipitation (ChIP) followed by qPCR (ChIP-qPCR) assays were performed to detect protein-protein and protein-DNA interactions. The clinical impacts of retinoic acid inducible gene-I (RIG-I) were assessed in melanoma datasets obtained from The Cancer Genome Atlas and Gene Expression Omnibus profiles.ResultsIFN-α-induced apoptosis was decreased in melanoma TRCs. Compared with conventional flask-cultured cells, IFN-α-mediated STAT1 activation was diminished in melanoma TRCs. Decreased expression of RIG-I in melanoma TRCs led to diminished activation of STAT1 via enhancing the interaction between Src homology region 2 domain-containing phosphatase-1 and STAT1. In addition, low expression levels of RIG-I correlated with poor prognosis in patients with melanoma. STAT3 was highly phosphorylated in TRCs and knockdown of STAT3 reversed the downregulation of RIG-I in TRCs. Knockdown of STAT3 resulted in STAT1 activation and increased expression of the pro-apoptosis genes in IFN-α-treated TRCs. Combined treatment of STAT3 inhibitor and IFN-α increased the apoptosis rate of TRCs. Disruption of ITGB3/c-SRC/STAT3 signaling pathway significantly elevated the efficiency of IFN-α-induced apoptosis of TRCs.ConclusionsIn melanoma TRCs, ITGB3-c-SRC-STAT3 pathway caused RIG-I repression and then affect STAT1 activation to cause resistance to IFN-α-induced apoptosis. RIG-I is a prognostic marker in patients with melanoma. Combination of STAT3 inhibitor and IFN-α could enhance the efficacy of melanoma treatment. Our findings may provide a new concept of combinatorial treatment for future immunotherapy
Controlling Defect Formation of Nanoscale AlN: Toward Efficient Current Conduction of UltrawideâBandgap Semiconductors
Ultrawideâbandgap semiconductors such as AlN, BN, and diamond hold tremendous promise for highâefficiency deepâultraviolet optoelectronics and highâpower/frequency electronics, but their practical application has been limited by poor current conduction. Through a combined theoretical and experimental study, it is shown that a critical challenge can be addressed for AlN nanostructures by using Nârich epitaxy. Under Nârich conditions, the pâtype Alâsubstitutional Mgâdopant formation energy is significantly reduced by 2Â eV, whereas the formation energy for Nâvacancy related compensating defects is increased by â3Â eV, both of which are essential to achieve high hole concentrations of AlN. Detailed analysis of the currentâvoltage characteristics of AlN pâiân diodes suggests that current conduction is dominated by holeâcarrier tunneling at room temperature, which is directly related to the activation energy of Mg dopants. At high Mg concentrations, the dispersion of Mg acceptor energy levels leads to drastically reduced activation energy for a portion of Mg dopants, evidenced by the small tunneling energy of 67 meV, which explains the efficient current conduction and the very small turnâon voltage (â5Â V) for the diodes made of nanoscale AlN. This work shows that nanostructures can overcome the dopability challenges of ultrawideâbandgap semiconductors and significantly increase the efficiency of devices.Controlled defects formation and efficient current conduction of nanoscale AlN are realized. Under Nârich epitaxy conditions, the formation energy for Nâvacancy related compensating defects is increased by nearly 3Â eV, eliminating donorâlike compensating defects. Meanwhile, the pâtype Alâsubstitutional Mgâdopant formation energy is reduced by 2Â eV, significantly enhancing Mgâdopant incorporation and reducing hole carrier tunneling barrier.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162750/3/aelm202000337-sup-0001-SuppMat.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162750/2/aelm202000337_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162750/1/aelm202000337.pd