Antibody–drug conjugates (ADCs) are gradually revolutionizing clinical cancer therapy. The antibody–drug conjugate linker molecule determines both the efficacy and the adverse effects, and so has a major influence on the fate of ADCs. An ideal linker should be stable in the circulatory system and release the cytotoxic payload specifically in the tumor. However, existing linkers often release payloads nonspecifically and inevitably lead to off-target toxicity. This defect is becoming an increasingly important factor that restricts the development of ADCs. The pursuit of ADCs with optimal therapeutic windows has resulted in remarkable progress in the discovery and development of novel linkers. The present review summarizes the advance of the chemical trigger, linker‒antibody attachment and linker‒payload attachment over the last 5 years, and describes the ADMET properties of ADCs. This work also helps clarify future developmental directions for the linkers.
We constructed complex models of SARS-CoV-2 spike protein binding to pangolin or human ACE2, the receptor for virus transmission, and estimated the binding free energy changes using molecular dynamics simulation. SARS-CoV-2 can bind to both pangolin and human ACE2, but has a significantly lower binding affinity for pangolin ACE2 due to the increased binding free energy (9.5 kcal mol −1). Human ACE2 is among the most polymorphous genes, for which we identified 317 missense single-nucleotide variations (SNVs) from the dbSNP database. Three SNVs, E329G (rs143936283), M82I (rs267606406) and K26R (rs4646116), had a significant reduction in binding free energy, which indicated higher binding affinity than wild-type ACE2 and greater susceptibility to SARS-CoV-2 infection for people with them. Three other SNVs, D355N (rs961360700), E37K (rs146676783) and I21T (rs1244687367), had a significant increase in binding free energy, which indicated lower binding affinity and reduced susceptibility to SARS-CoV-2 infection.
The heterogeneous internal structure of quasi-brittle materials governs several aspects of their behavior, especially in the nonlinear range. Size and spacing of weak spots (e.g., aggregate-matrix interfaces, flaws, and slip planes) where failure is likely to occur are two of the most important material characteristic lengths that can be used to characterize the micro-and meso-structure of these materials. Discrete (lattice and particle) models can be conveniently used to directly model these geometrical features, but they tend to be computationally expensive, and consequently, the derivation of macroscopic continuum-based approximations is often highly beneficial. The current study demonstrates that the continuum macroscale approximation of discrete fine-scale models leads naturally to a high-order microplane theory characterized by multiple characteristic lengths. The average weak spot spacing is shown to be associated with strain gradient effects; whereas the average weak spot size is shown to be associated with the Cosserat characteristics of the theory. The formulated microplane theory is compared with and contrasted to classical continuum theories available in the literature. Finally, for strain softening, known in the case of first-order local formulations to cause strain localization in an unrealistic vanishing size volume, a localization limiter capable of enforcing the minimum localization size to be of a finite value is formulated, exploiting the spectral wave propagation analysis approach.
Summary Shale, like many other sedimentary rocks, is typically heterogeneous and anisotropic and is characterized by partial alignment of anisotropic clay minerals and naturally formed bedding planes. In this study, a micromechanical framework based on the lattice discrete particle model is formulated to capture these features. Material anisotropy is introduced through an approximated geometric description of shale internal structure, which includes representation of material property variation with orientation and explicit modeling of parallel lamination. The model is calibrated by carrying out numerical simulations to match various experimental data, including the ones relevant to elastic properties, Brazilian tensile strength, and unconfined compressive strength. Furthermore, parametric study is performed to investigate the relationship between the mesoscale parameters and the macroscopic properties. It is shown that the dependence of the elastic stiffness, strength, and failure mode on loading orientation can be captured successfully. Finally, a homogenization approach based on the asymptotic expansion of field variables is applied to upscale the proposed micromechanical model, and the properties of the homogenized model are analyzed. Copyright © 2017 John Wiley & Sons, Ltd.
The bulk supply of the antiviral C -nucleoside analogue remdesivir is largely hampered by a low-yielding C -glycosylation step in which the base is coupled to the pentose unit. Here, we disclose a significantly improved methodology for this critical transformation. By utilizing diisopropylamine as a cost-effective additive, the addition reaction furnishes an optimal yield of 75% of the desired ribofuranoside adduct, representing the highest yield obtained thus far for this key step. The method proved suitable for hectogram scale synthesis without column chromatographic operations.
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