4,848 research outputs found

    DataSheet_1_LysM protein BdLM1 of Botryosphaeria dothidea plays an important role in full virulence and inhibits plant immunity by binding chitin and protecting hyphae from hydrolysis.docx

    No full text
    Botryosphaeria dothidea infects hundreds of woody plants and causes a severe economic loss to apple production. In this study, we characterized BdLM1, a protein from B. dothidea that contains one LysM domain. BdLM1 expression was dramatically induced at 6 h post-inoculation in wounded apple fruit, strongly increased at 7 d post-inoculation (dpi), and peaked at 20 dpi in intact shoots. The knockout mutants of BdLM1 had significantly reduced virulence on intact apple shoots (20%), wounded apple shoots (40%), and wounded apple fruit (40%). BdLM1 suppressed programmed cell death caused by the mouse protein BAX through Agrobacterium-mediated transient expression in Nicotiana benthamiana, reduced H2O2 accumulation and callose deposition, downregulated resistance gene expression, and promoted Phytophthora nicotianae infection in N. benthamiana. Moreover, BdLM1 inhibited the active oxygen burst induced by chitin and flg22, bound chitin, and protected fungal hyphae against degradation by hydrolytic enzymes. Taken together, our results indicate that BdLM1 is an essential LysM effector required for the full virulence of B. dothidea and that it inhibits plant immunity. Moreover, BdLM1 could inhibit chitin-triggered plant immunity through a dual role, i.e., binding chitin and protecting fungal hyphae against chitinase hydrolysis.</p

    Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS<sup>G12D</sup>

    No full text
    KRASG12D, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRASG12D PROTACs. Mechanism studies with the representative compound 8o demonstrated that the potent, rapid, and selective degradation of KRASG12D induced by 8o was via a VHL- and proteasome-dependent manner. This compound selectively and potently suppressed the growth of multiple KRASG12D mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRASG12D-driven cancers as the complementary therapeutic strategy to KRAS inhibition

    Bioactive Ceria Nanoenzymes Target Mitochondria in Reperfusion Injury to Treat Ischemic Stroke

    No full text
    Overproduction of reactive oxygen species by damaged mitochondria after ischemia is a key factor in the subsequent cascade of damage. Delivery of therapeutic agents to the mitochondria of damaged neurons in the brain is a potentially promising targeted therapeutic strategy for the treatment of ischemic stroke. In this study, we developed a ceria nanoenzymes synergistic drug-carrying nanosystem targeting mitochondria to address multiple factors of ischemic stroke. Each component of this nanosystem works individually as well as synergistically, resulting in a comprehensive therapy. Alleviation of oxidative stress and modulation of the mitochondrial microenvironment into a favorable state for ischemic tolerance are combined to restore the ischemic microenvironment by bridging mitochondrial and multiple injuries. This work also revealed the detailed mechanisms by which the proposed nanodelivery system protects the brain, which represents a paradigm shift in ischemic stroke treatment

    Cu–Zn Cation Disorder in Kesterite Cu2ZnSn(SxSe1–x)4 Solar Cells

    Get PDF
    Cu–Zn cation disorder plays a vital and controversial role in kesterite CuZnSn(S1–xSex)4 solar cells. We demonstrate using density functional theory and nonadiabatic molecular dynamics simulations that the Cu–Zn disorder across different planes (i.e., Cu–Sn and Cu–Zn planes) is significantly more detrimental to device performance than the case when disorder is confined only to the Cu–Zn planes. The main reason is that different plane disorder induces a significant elongation of Sn–S/Se bond lengths, leading to a downshift of the conduction band minimum, decreasing the band gap, and reducing the optical absorption. Moreover, Cu–Zn disorder across different planes accelerates nonradiative electron–hole recombination and decreases charge carrier lifetime due to the reduction of the band gap and enhanced electron-vibrational interaction. Our results provide a theoretical explanation for the influence of Cu–Zn disorder on material performance and offer valuable insight into the design of more efficient solar cells

    Cu–Zn Cation Disorder in Kesterite Cu<sub>2</sub>ZnSn(S<sub><i>x</i></sub>Se<sub>1–<i>x</i></sub>)<sub>4</sub> Solar Cells

    No full text
    Cu–Zn cation disorder plays a vital and controversial role in kesterite CuZnSn(S1–xSex)4 solar cells. We demonstrate using density functional theory and nonadiabatic molecular dynamics simulations that the Cu–Zn disorder across different planes (i.e., Cu–Sn and Cu–Zn planes) is significantly more detrimental to device performance than the case when disorder is confined only to the Cu–Zn planes. The main reason is that different plane disorder induces a significant elongation of Sn–S/Se bond lengths, leading to a downshift of the conduction band minimum, decreasing the band gap, and reducing the optical absorption. Moreover, Cu–Zn disorder across different planes accelerates nonradiative electron–hole recombination and decreases charge carrier lifetime due to the reduction of the band gap and enhanced electron-vibrational interaction. Our results provide a theoretical explanation for the influence of Cu–Zn disorder on material performance and offer valuable insight into the design of more efficient solar cells

    Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS<sup>G12D</sup>

    No full text
    KRASG12D, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRASG12D PROTACs. Mechanism studies with the representative compound 8o demonstrated that the potent, rapid, and selective degradation of KRASG12D induced by 8o was via a VHL- and proteasome-dependent manner. This compound selectively and potently suppressed the growth of multiple KRASG12D mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRASG12D-driven cancers as the complementary therapeutic strategy to KRAS inhibition

    State space model detection of driving fatigue considering individual differences and time cumulative effect

    No full text
    Fatigue is an important cause of traffic crashes, and effective fatigue detection models can reduce these crashes. Research has found large differences in fatigued driving performance from driver to driver, as well as a significant cumulative effect of fatigue on a given driver over time. Both sources of variation can decrease the accuracy of detection systems, but previous studies have not done enough to evaluate these differences. The purpose of this study is therefore to develop a fatigue detection model that considers individual differences and the time cumulative effect of fatigue. Data on the lateral position of the car in its lane, steering wheel movement, speed, and eye movement were collected from 22 drivers using a driving simulator with an eye-tracking system. Drivers’ subjective fatigue scores were collected using the Karolinska Sleepiness Scale. State space models (SSMs) were built to detect fatigue in each driver, considering his or her individual features. As a time series model, the SSM can also address the time cumulative effect of fatigue, and it does not require a large dataset to achieve high levels of accuracy. The differences in SSM results confirm that diversity does exist among drivers’ fatigued driving performance, so the ability of the SSM to take into account driver-specific information from each individual driver suggests that it is more suitable for fatigue detection than models that use aggregated driver data. Results show that the fatigue detection accuracy of the SSM (77.73%) is higher than that of artificial neural network models (61.37%). The advantages of accuracy, high interpretability, and flexibility make the SSM a comprehensive and valuable individualized fatigue detection model for commercial use

    Discovery of 1H-pyrazolo[3,4-<i>b</i>]pyrazine derivatives as selective allosteric inhibitor of protein tyrosine phosphatase SHP2 for the treatment of KRAS<sup>G12C</sup>-mutant non-small cell lung cancer

    No full text
    The high expression or mutation of SHP2 can induce cancer, so targeting SHP2 has become a new strategy for cancer treatment. In this study, we used the previously reported SHP2 allosteric inhibitor IACS-13909 as a lead drug for structural derivation and modification, and synthesized three SHP2 inhibitors. Among them, 1H-pyrazolo[3,4-b]pyrazine derivative 4b was a highly selective SHP2 allosteric inhibitor, with an IC50 value of 3.2 nM, and its inhibitory activity was 17.75 times than that of the positive control IACS-13909. The cell proliferation experiment detected that compound 4b would markedly inhibit the proliferation of various cancer cells. Interestingly, compound 4b was highly sensitive to KRASG12C-mutant non-small cell lung cancer NCI-H358 cells, with an IC50 value of 0.58 μM and its antiproliferative activity was 4.79 times than that of IACS-13909. Furthermore, the combination therapy of compound 4b and KRASG12C inhibitor sotorasib would play a strong synergistic effect against NCI-H358 cells. The western blot experiment detected that compound 4b markedly downregulated the phosphorylation levels of ERK and AKT in NCI-H358 cells. Molecular docking study predicted that compound 4b bound to the allosteric site of SHP2 and formed H-bond interactions with key residues Thr108, Glu110, Arg111, and Phe113. In summary, this study aims to provide new ideas for the development of SHP2 allosteric inhibitors for the treatment of KRASG12C mutant non-small cell lung cancer. Communicated by Ramaswamy H. Sarma</p
    corecore