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AIDS is a pandemic disease caused by HIV that affects 37 million people worldwide. Current antiretroviral therapy slows disease progression but does not eliminate latently infected cells, which resupply active virus, thus necessitating lifelong treatment with associated compliance, cost, and chemoexposure issues. Latency-reversing agents (LRAs) activate these cells, allowing for their potential clearance, thus presenting a strategy to eradicate the infection. Protein kinase C (PKC) modulators-including prostratin, ingenol esters, bryostatin, and their analogs-are potent LRAs in various stages of development for several clinical indications. While LRAs are promising, a major challenge associated with their clinical use is sustaining therapeutically meaningful levels of the active agent while minimizing side effects. Here we describe a strategy to address this problem based on LRA prodrugs, designed for controllable release of the active LRA after a single injection. As intended, these prodrugs exhibit comparable or superior in vitro activity relative to the parent compounds. Selected compounds induced higher in vivo expression of CD69, an activation biomarker, and, by releasing free agent over time, significantly improved tolerability when compared to the parent LRAs. More generally, selected prodrugs of PKC modulators avoid the bolus toxicities of the parent drug and exhibit greater efficacy and expanded tolerability, thereby addressing a longstanding objective for many clinical applications.

Fly ash–slag-based alkali-activated materials have excellent mechanical performance and a low carbon footprint, and they have emerged as a promising alternative to Portland cement. Therefore, replacing traditional Portland cement with slag–desulfurization gypsum-based alkali-activated materials will help to make better use of the waste, protect the environment, and improve the materials' performance. In order to better understand it and thus better use it in engineering, it needs to be characterized for performance and compositional design. This study developed a novel framework for performance characterization and composition design by combining Categorical Gradient Boosting (CatBoost), simplicial homology global optimization (SHGO), and laboratory tests. The CatBoost characterization model was evaluated and discussed based on SHapley Additive exPlanations (SHAPs) and a partial dependence plot (PDP). Through the proposed framework, the optimal composition of the slag–desulfurization gypsum-based alkali-activated materials with the maximum flexural strength and compressive strength at 1, 3, and 7 days is Ca(OH)2: 3.1%, fly ash: 2.6%, DG: 0.53%, alkali: 4.3%, modulus: 1.18, and W/G: 0.49. Compared with the material composition obtained from the traditional experiment, the actual flexural strength and compressive strength at 1, 3, and 7 days increased by 26.67%, 6.45%, 9.64%, 41.89%, 9.77%, and 7.18%, respectively. In addition, the results of the optimal composition obtained by laboratory tests are very close to the predictions of the developed framework, which shows that CatBoost characterizes the performance well based on test data. The developed framework provides a reasonable, scientific, and helpful way to characterize the performance and determine the optimal composition for civil materials. [ABSTRACT FROM AUTHOR]

Vault nanoparticles represent promising vehicles for drug and probe delivery. Innately found within human cells, vaults are stable, biocompatible nanocapsules possessing an internal volume that can encapsulate hundreds to thousands of molecules. They can also be targeted. Unlike most nanoparticles, vaults are nonimmunogenic and monodispersed and can be rapidly produced in insect cells. Efforts to create vaults with modified properties have been, to date, almost entirely limited to recombinant bioengineering approaches. Here we report a systematic chemical study of covalent vault modifications, directed at tuning vault properties for research and clinical applications, such as imaging, targeted delivery, and enhanced cellular uptake. As supra-macromolecular structures, vaults contain thousands of derivatizable amino acid side chains. This study is focused on establishing the comparative selectivity and efficiency of chemically modifying vault lysine and cysteine residues, using Michael additions, nucleophilic substitutions, and disulfide exchange reactions. We also report a strategy that converts the more abundant vault lysine residues to readily functionalizable thiol terminated side chains through treatment with 2-iminothiolane (Traut's reagent). These studies provide a method to doubly modify vaults with cell penetrating peptides and imaging agents, allowing for in vitro studies on their enhanced uptake into cells.

The leakage channel in complex fractured formation has multi-scale characteristics and uncertainty, which is difficult for the traditional bridge loss circulation materials achieving effective adaptive bridging plugging. Based on the characteristics of the shape memory materials, the temperature sensitive shape memory lost circulation materials activated by the leakage layer temperature are prepared. According to the requirements of drilling plugging technology, the preparation process and conditions are optimized, and the temperature resistance, expansion performance and drilling fluid compatibility are tested. The fracture plugging effects under different conditions are compared and evaluated, and a set of formula of plugging fluid for 2-4 mm coexisting fractures is optimized. After reaching the activation temperature, the system can play the role of self adaptive bridging plugging, and improve the pressure bearing capacity and adaptability. [ABSTRACT FROM AUTHOR]