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71.
Minh V. Huynh Derek Parsonage Tom E. Forshaw Venkat R. Chirasani G. Aaron Hobbs Hanzhi Wu Jingyun Lee Cristina M. Furdui Leslie B. Poole Sharon L. Campbell 《The Journal of biological chemistry》2022,298(8)
The recent development of mutant-selective inhibitors for the oncogenic KRASG12C allele has generated considerable excitement. These inhibitors covalently engage the mutant C12 thiol located within the phosphoryl binding loop of RAS, locking the KRASG12C protein in an inactive state. While clinical trials of these inhibitors have been promising, mechanistic questions regarding the reactivity of this thiol remain. Here, we show by NMR and an independent biochemical assay that the pKa of the C12 thiol is depressed (pKa ∼7.6), consistent with susceptibility to chemical ligation. Using a validated fluorescent KRASY137W variant amenable to stopped-flow spectroscopy, we characterized the kinetics of KRASG12C fluorescence changes upon addition of ARS-853 or AMG 510, noting that at low temperatures, ARS-853 addition elicited both a rapid first phase of fluorescence change (attributed to binding, Kd = 36.0 ± 0.7 μM) and a second, slower pH-dependent phase, taken to represent covalent ligation. Consistent with the lower pKa of the C12 thiol, we found that reversible and irreversible oxidation of KRASG12C occurred readily both in vitro and in the cellular environment, preventing the covalent binding of ARS-853. Moreover, we found that oxidation of the KRASG12C Cys12 to a sulfinate altered RAS conformation and dynamics to be more similar to KRASG12D in comparison to the unmodified protein, as assessed by molecular dynamics simulations. Taken together, these findings provide insight for future KRASG12C drug discovery efforts, and identify the occurrence of G12C oxidation with currently unknown biological ramifications. 相似文献
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O. Modesto Olanya Joseph E. Sites Aaron K. Hoshide 《Biocontrol Science and Technology》2016,26(5):651-664
Published research on process-based models for biocontrol of foodborne pathogens on produce is limited. The aim of this research was to develop cost model estimates for competitive exclusion (CE) process using Pseudomonas fluorescens and Pseudomonas chlororaphis (non-plant pathogenic and non-human pathogen) as biocontrol against Salmonella enterica on tomatoes. Cost estimates were based on material inputs, equipment, facilities, and projected processing conditions of post-harvest packaging of tomatoes. The microbiological data for inactivation of S. enterica was based on published papers. The small-scale processing facility was assumed to have a processing capacity of 2000 kg of tomatoes/hour for 16 h per day, operational 6 days a week, and for 3-months /year. The large-scale facility was assumed to have a processing capacity of 100,000 kg of tomatoes/hour. Estimated initial capital investment costs for small and large-scale models (production facility) were US$391,000 and US$2.1 million. Application of CE for biocontrol of S. enterica on tomatoes was estimated at US$0.0058–0.073/kg of tomatoes during commercial processing operations. This exceeds chlorine wash technology estimated at US$0.00046/kg and is competitive with gaseous chlorine dioxide at US$0.02–0.21/kg. For high-value produce, CE may complement existing technologies increase food safety, reduce storage loses, and extend shelf life of produce. 相似文献
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The output of individual neurons is dependent on both synaptic and intrinsic membrane properties. While it is clear that the response of an individual neuron can be facilitated or inhibited based on the summation of its constituent synaptic inputs, it is not clear whether subthreshold activity, (e.g. synaptic “noise”- fluctuations that do not change the mean membrane potential) also serve a function in the control of neuronal output. Here we studied this by making whole-cell patch-clamp recordings from 29 mouse thalamocortical relay (TC) neurons. For each neuron we measured neuronal gain in response to either injection of current noise, or activation of the metabotropic glutamate receptor-mediated cortical feedback network (synaptic noise). As expected, injection of current noise via the recording pipette induces shifts in neuronal gain that are dependent on the amplitude of current noise, such that larger shifts in gain are observed in response to larger amplitude noise injections. Importantly we show that shifts in neuronal gain are also dependent on the intrinsic sensitivity of the neuron tested, such that the gain of intrinsically sensitive neurons is attenuated divisively in response to current noise, while the gain of insensitive neurons is facilitated multiplicatively by injection of current noise- effectively normalizing the output of the dLGN as a whole. In contrast, when the cortical feedback network was activated, only multiplicative gain changes were observed. These network activation-dependent changes were associated with reductions in the slow afterhyperpolarization (sAHP), and were mediated at least in part, by T-type calcium channels. Together, this suggests that TC neurons have the machinery necessary to compute multiple output solutions to a given set of stimuli depending on the current level of network stimulation. 相似文献
80.
Jin Goo Lee Jae‐Ha Myung Aaron B. Naden Ok Sung Jeon Yong Gun Shul John T. S. Irvine 《Liver Transplantation》2020,10(10)
For efficient catalysis and electrocatalysis well‐designed, high‐surface‐area support architectures covered with highly dispersed metal nanoparticles with good catalyst‐support interactions are required. In situ grown Ni nanoparticles on perovskites have been recently reported to enhance catalytic activities in high‐temperature systems such as solid oxide cells (SOCs). However, the micrometer‐scale primary particles prepared by conventional solid‐state reactions have limited surface area and tend to retain much of the active catalytic element within the bulk, limiting efficacy of such exsolution processes in low‐temperature systems. Here, a new, highly efficient, solvothermal route is demonstrated to exsolution from smaller scale primary particles. Furthermore, unlike previous reports of B‐site exsolution, it seems that the metal nanoparticles are exsolved from the A‐site of these perovskites. The catalysts show large active site areas and strong metal‐support interaction (SMSI), leading to ≈26% higher geometric activity (25 times higher mass activity with 1.4 V of Eon‐set) and stability for oxygen‐evolution reaction (OER) with only 0.72 µg base metal contents compared to typical 20 wt% Ni/C and even commercial 20 wt% Ir/C. The findings obtained here demonstrate the potential design and development of heterogeneous catalysts in various low‐temperature electrochemical systems including alkaline fuel cells and metal–air batteries. 相似文献