Radical substitution on tetrasulfides is demonstrated to be a highly effective means to prepare unsymmetric disulfides. Alkyl and aryl radicals generated thermally or photochemically underwent ...substitution on readily prepared dialkyl, diaryl, and diacyl tetrasulfides to yield the corresponding disulfides in good to excellent yields. Classic and contemporary thermal and photochemical radical sources could be employed; while photoredox catalysis approaches led to either oxidation or reduction of the tetrasulfide, energy transfer photocatalysis was particularly useful. The success of the approach is driven by the thermodynamic stability of the perthiyl radicals formed upon substitution on the tetrasulfide; they simply combine under the reaction conditions to provide the starting tetrasulfide. Competition kinetic experiments reveal that alkyl radical substitution on tetrasulfides is a rapid reaction (6 × 10
M
s
) that is enhanced at least 6-fold upon moving from dialkyl tetrasulfide to diacyl tetrasulfide due to favorable polar effects. This unique and versatile reaction enables introduction of disulfide moieties from a variety of radical precursors and straightforward access to hydropersulfides.
A highly enantioselective intramolecular annulation reaction of 1,3-diols catalyzed by a triazolium N-heterocyclic carbene (NHC) precatalyst is disclosed, affording the corresponding medium-sized ...lactones in moderate to good yields with high enantioselectivities. It is worth noting that this compatible catalytic system has been successfully applied to assemble a broad range of chiral medium-sized lactones, including ones with eight-, nine-, ten-, eleven-, and twelve-membered rings.
The ubiquitous structure of δ‐lactones makes the development of new methods for their enantioselective and stereoselective synthesis an important ongoing challenge. The intermolecular dynamic kinetic ...resolution (DKR) of β‐halo‐α‐ketoesters cooperatively catalyzed by an N‐heterocyclic carbene and a Lewis acid generates two contiguous stereocenters with remarkable diastereoselectivity through an oxidation/lactonization sequence.
Enantioenriched δ‐lactones were accessed by an intermolecular dynamic kinetic resolution of β‐halo‐α‐ketoesters in an oxidation/lactonization sequence. The process generates two contiguous stereocenters with remarkable diastereoselectivity through the cooperative catalysis of an N‐heterocyclic carbene and a Lewis acid. DQ=3,3′,5,5′‐tetra‐tert‐butyldiphenoquinone (oxidant).
Abstract
Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation
1
, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant ...cancers
2
. Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic and cell-intrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we show that the fully reduced forms of vitamin K—a group of naphthoquinones that includes menaquinone and phylloquinone
3
—confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for γ-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-4
4,5
, was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle
6
. The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis.
Abstract This study aimed to apply pathomics to predict Matrix metalloproteinase 9 (MMP9) expression in glioblastoma (GBM) and investigate the underlying molecular mechanisms associated with ...pathomics. Here, we included 127 GBM patients, 78 of whom were randomly allocated to the training and test cohorts for pathomics modeling. The prognostic significance of MMP9 was assessed using Kaplan–Meier and Cox regression analyses. PyRadiomics was used to extract the features of H&E-stained whole slide images. Feature selection was performed using the maximum relevance and minimum redundancy (mRMR) and recursive feature elimination (RFE) algorithms. Prediction models were created using support vector machines (SVM) and logistic regression (LR). The performance was assessed using ROC analysis, calibration curve assessment, and decision curve analysis. MMP9 expression was elevated in patients with GBM. This was an independent prognostic factor for GBM. Six features were selected for the pathomics model. The area under the curves (AUCs) of the training and test subsets were 0.828 and 0.808, respectively, for the SVM model and 0.778 and 0.754, respectively, for the LR model. The C-index and calibration plots exhibited effective estimation abilities. The pathomics score calculated using the SVM model was highly correlated with overall survival time. These findings indicate that MMP9 plays a crucial role in GBM development and prognosis. Our pathomics model demonstrated high efficacy for predicting MMP9 expression levels and prognosis of patients with GBM.
Celastrol and triptolide, as the two main bio-activity ingredients in
have wide anticancer pharmacological potency, as well as anti-inflammatory and immunosuppression effects. However, they have ...potential hepatotoxicity and underlying mechanisms of them-induced toxicity mediated by hepatic CYP450s have not been well delineated. In the present study, we accessed the toxic effects and possible mechanism of celastrol and triptolide on primary rat hepatocytes. Models of subdued/enhanced activity of CYP450 enzymes in primary rat hepatocytes were also constructed to evaluate the relationship between the two ingredients and CYP450s. LC-MS/MS was used to establish a detection method of the amount of triptolide in rat hepatocytes. As the results, cell viability, biochemical index, and mitochondrial membrane potential indicated that celastrol and triptolide had toxic potencies on hepatocytes. Moreover, the toxic effects were enhanced when the compounds combined with 1-aminobenzotriazole (enzyme inhibitor) while they were mitigated when combined with phenobarbital (an enzyme inducer). Meanwhile, celastrol could affect the amount of triptolide in the cell. We therefore put forward that increase of triptolide in the cell might be one of the main causes of hepatotoxicity caused by
.
The discrete cross-entropy optimization algorithm iteratively samples solutions according to a probability density on the solution space. The density is adapted to the good solutions observed in the ...present sample before producing the next sample. The adaptation is controlled by a so-called smoothing parameter. We generalize this model by introducing a flexible concept of feasibility and desirability into the sampling process. In this way, our model covers several other optimization procedures, in particular the ant-based algorithms. The focus of this paper is on some theoretical properties of these algorithms. We examine the first hitting time τ of an optimal solution and give conditions on the smoothing parameter for τ to be finite with probability one. For a simple test case we show that runtime can be polynomially bounded in the problem size with a probability converging to 1. We then investigate the convergence of the underlying density and of the sampling process. We show, in particular, that a constant smoothing parameter, as it is often used, makes the sample process converge in finite time, freezing the optimization at a single solution that need not be optimal. Moreover, we define a smoothing sequence that makes the density converge without freezing the sample process and that still guarantees the reachability of optimal solutions in finite time. This settles an open question from the literature.
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•WGAN-GP characterizes high-dimensional aquifer properties into low-dimensional vectors through the utilization of an image processing strategy.•The Densely-connected convolutional ...neural network (OANW) to construct surrogate for groundwater contaminant transport model.•The WGAN-GP and OANW are integrated into the ILUES inversion framework to achieve an effective inversion of the groundwater model parameters.•The two ILUES frameworks are analyzed in terms of accuracy and computational efficiency, respectively.
In the inverse estimation of groundwater model parameters (e.g., contaminant source parameters and hydraulic conductivity fields), data assimilation is the most commonly used method for solving the inverse problem. However, data assimilation requires iterative calculation, which tends to increase the computational costs. This is particularly problematic when dealing with high-dimensional problems. In this study, we propose a hybrid inversion framework, which combines a generative adversarial network (GAN) and a convolutional neural network (CNN) for groundwater model parameter estimation. The GAN is equipped with gradient penalties (WGAN-GP) to achieve fast characterization of high-dimensional aquifer structures with low-dimensional vectors (200 dimensions). Meanwhile, this study proposes an enhanced convolutional neural network (OANW), which introduces two-layer weights near the contamination source to achieve an effective surrogate of the process-based groundwater model. Moreover, an iterative local update ensemble smoother (ILUES) is applied for simultaneous identification of the contaminant source parameters and hydraulic conductivity fields in the inversion stage. The results demonstrate that by integrating WGAN-GP and OANW, the ILUES framework accurately characterizes the aquifer parameters and significantly improves the efficiency of the computational process.
Rapid growth of genome data provides opportunities for updating microbial evolutionary relationships, but this is challenged by the discordant evolution of individual genes. Here we build a reference ...phylogeny of 10,575 evenly-sampled bacterial and archaeal genomes, based on a comprehensive set of 381 markers, using multiple strategies. Our trees indicate remarkably closer evolutionary proximity between Archaea and Bacteria than previous estimates that were limited to fewer "core" genes, such as the ribosomal proteins. The robustness of the results was tested with respect to several variables, including taxon and site sampling, amino acid substitution heterogeneity and saturation, non-vertical evolution, and the impact of exclusion of candidate phyla radiation (CPR) taxa. Our results provide an updated view of domain-level relationships.
This paper analyzes the stochastic runtime of the cross-entropy (CE) algorithm for the well-studied standard problems ONEMAX and LEADINGONES. We prove that the total number of solutions the algorithm ...needs to evaluate before reaching the optimal solution (i.e., its runtime) is bounded by a polynomial Q(n) in the problem size n with a probability growing exponentially to 1 with n if the parameters of the algorithm are adapted to n in a reasonable way. Our polynomial bound Q(n) for ONEMAX outperforms the well-known runtime bound of the 1-ANT algorithm, a particular ant colony optimization algorithm. Our adaptation of the parameters of the CE algorithm balances the number of iterations needed and the size of the samples drawn in each iteration, resulting in an increased efficiency. For the LEADINGONES problem, we improve the runtime of the algorithm by bounding the sampling probabilities away from 0 and 1. The resulting runtime outperforms the known stochastic runtime for a univariate marginal distribution algorithm, and is very close to the known expected runtime of variants of max-min ant systems. Bounding the sampling probabilities allows the CE algorithm to explore the search space even for test functions with a very rugged landscape as the LEADINGONES function.
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