Atroposelective Synthesis of Axial Biaryls by Dynamic Kinetic Resolution Using Engineered Imine Reductases.

Axially chiral biaryls are ubiquitous scaffolds in natural products, bioactive molecules, chiral ligands and catalysts, but biocatalytic methods for their asymmetric synthesis are limited. Here, we report a highly efficient biocatalytic route for the atroposelective synthesis of biaryls via dynamic kinetic resolution (DKR). This DKR approach features a transient six-membered aza-acetal bridge-promoted racemization followed by an imine-reductase (IRED)-catalyzed stereoselective reduction to construct the axial chirality at ambient conditions. Directed evolution of an IRED from Streptomyces sp. GF3546 provided a variant (S-IRED-Ss-M11) capable of catalyzing the DKR process to access a variety of biaryl aminoalcohols in high yields and excellent enantioselectivities (up to 98% yield and >99:1 enantiomeric ratio). Molecular dynamics simulation studies on the S-IRED-Ss-M11 variant revealed the origin of its improved activity and atroposelectivity. By exploiting the substrate promiscuity of IREDs and the power of directed evolution, our work further extends the biocatalysts' toolbox to construct challenging axially chiral molecules.

Synthesis and Biological Evaluation of ß-Lactam Derivatives Targeting Speckle-Type POZ Protein (SPOP).

Speckle-type POZ protein (SPOP) acts as a cullin3-RING ubiquitin ligase adaptor, which facilitates the recognition and ubiquitination of substrate proteins. Previous research suggests that targeting SPOP holds promise in the treatment of clear cell renal cell carcinoma (ccRCC). On the basis of the reported SPOP inhibitor 230D7, a series of ß-lactam derivatives were synthesized in this study. The biological activity assessment of these compounds revealed E1 as the most potent inhibitor, which can disrupt the SPOP-substrate interactions in vitro and suppress the colony formation of ccRCC cells. Taken together, this study provided compound E1 as a potent inhibitor against ccRCC and offered insight into the development of the ß-lactam SPOP inhibitor.

Sequence-based drug design as a concept in computational drug design.

Drug development based on target proteins has been a successful approach in recent decades. However, the conventional structure-based drug design (SBDD) pipeline is a complex, human-engineered process with multiple independently optimized steps. Here, we propose a sequence-to-drug concept for computational drug design based on protein sequence information by end-to-end differentiable learning. We validate this concept in three stages. First, we design TransformerCPI2.0 as a core tool for the concept, which demonstrates generalization ability across proteins and compounds. Second, we interpret the binding knowledge that TransformerCPI2.0 learned. Finally, we use TransformerCPI2.0 to discover new hits for challenging drug targets, and identify new target for an existing drug based on an inverse application of the concept. Overall, this proof-of-concept study shows that the sequence-to-drug concept adds a perspective on drug design. It can serve as an alternative method to SBDD, particularly for proteins that do not yet have high-quality 3D structures available.

Reactive Janus Particle Compatibilizer with Adjustable Structure and Optimal Interface Location for Compatibilization of Highly Immiscible Polymer Blends.

Highly immiscible blend materials with distinctive and excellent properties play a key role in meeting the application needs, especially in extreme environments, and reactive nanoparticles are used to increase the interface adhesion and optimize the morphology of highly immiscible blending. However, these reactive nanoparticles tend to aggregate and even agglomerate during reactive blending, which significantly deteriorates their compatibilization efficiency. Herein, reactive Janus particles with the epoxy group and various siloxane molecular long chain grafting ratios (E-JP-PDMS) were synthesized using SiO2@PDVB Janus particles (JP) and used as compatibilizers for polyamide and methyl vinyl silicone elastomer (PA/MVQ) blends, which were highly immiscible. The effects of the structure of E-JP-PDMS Janus nanoparticles on their location at the interfaces between the PA and MVQ as well as their compatibilization efficiency for the PA/MVQ blends were investigated. The location and dispersion of E-JP-PDMS at the interfaces were improved by increasing the PDMS content in E-JP-PDMS. The average diameter of the MVQ domains of the PA/MVQ (70/30, w/w) was 79.5 µm and was reduced to 5.3 µm in the presence of 3.0 wt % of the E-JP-PDMS with 65 wt % PDMS. As a comparison, it was 45.1 µm in the presence of 3.0 wt % of a commercial compatibilizer (ethylene-butylacylate-maleic anhydride copolymer, denoted as EBAMAH), which provides a guideline for the design and preparation of efficient compatibilizers for highly immiscible polymer blends.

Design, Synthesis, and biological evaluation of HDAC6 inhibitors based on Cap modification strategy.

The abnormal biological functions of HDAC6 were closely related to the occurrence and development of various tumors, making HDAC6 gradually become promising therapeutic target for cancer treatment and inspiring researchers to explore and develop selective HDAC inhibitors. In this study, based on the classical pharmacophore model of HDAC inhibitors, 20 compounds were designed and synthesized by modifying the Cap group, and the biological activities of the target compounds were assessed through anti-proliferation and enzyme inhibition experiments. The title compounds exhibited varying degrees of inhibitory activities against the selected tumor cell lines, especially the compounds 9m, 9q, and 12c, which were further evaluated at the enzymatic level. The enzyme inhibition assay showed that compound 12c exerted broad-spectrum enzyme inhibitory activities and compounds 9m and 9q were more inclined to inhibit HDAC6, exhibiting certain selective inhibitory activities among the representative subtypes. Moreover, the binding modes of compounds 9q and 12c in HDAC1&6 were further explored via computational approaches to elucidate the molecular mechanisms underlying selective inhibitory activities, providing valuable hints for the discovery of novel HDAC6 inhibitors.

Effect on the health of newborns caused by extreme temperature in Guangzhou.

By using 64,270 daily observations from a large hospital in Guangzhou between 2017 and 2019, we analyzed the impact of extreme temperature on the health of newborns via OLS regression with time fixed effect. Given that the short-term temperature change can be regarded as exogenous and random, solving the potential endogenous problem is critical. We find that extreme temperature negatively affects the health of newborns. The Apgar score, an index for evaluating neonatal health, decreases by 0.008 (0.029%) when the duration of extreme temperature events increases by a day. A series of robustness checks verify the reliability of this negative effect. Extreme temperature also has a particularly serious effect on the health of newborns whose mothers have poor education. By gradually extending the observation period, we find that the effect of extreme temperature on neonatal health is mainly concentrated 1-6 weeks before delivery, whereas the effect of extreme temperature on hospitalization cost is mainly concentrated 4-8 weeks before delivery. This paper provides a valuable reference for evaluating the health and social costs of extreme weather, and our findings are conducive to the construction of climate-resilient health systems, especially in Guangzhou.

Does institutional quality affect air pollution?

As environmental pollution brings a series of problems to society and residential lives, how to effectively reduce air pollution and control climate change have become urgent problems. Since institutional quality is an important factor affecting air quality, we evaluated the causal relationship between them based on cross-country panel data from 2000 to 2016. We find that the improvement of institutional quality significantly reduces [Formula: see text], and this pollution reduction effect is obvious in high-income countries and in countries with common laws. Furthermore, under the components of institutional quality, the quality of government regulation, the degree of rule of law, corruption control, and government effectiveness have significant emission reduction effects. To explore how institutional quality affects air pollution, we perform mechanism analysis from the perspective of economic development, foreign trade, and technology progress. We further verify three environmental propositions including the Environmental Kuznets Curve, the Pollution Paradise Hypothesis, and Porter Hypothesis. Results show that the pollution reduction effect of institutional quality can be mediated by economic development rate, foreign direct investment, and technological progress. The Environmental Kuznets Curve exists, the Pollution Paradise Hypothesis is validated in countries with lower institutional quality level, and the improvement of the institutional quality can achieve the Porter Effect through technological progress.

Comparative Lipidomics Analysis of Human Milk and Infant Formulas Using UHPLC-Q-TOF-MS.

The lipidome and fatty acid composition of human milk and different infant formulas with animal- and/or plant-based fat sources are analyzed and compared in this study. The results obtained using positive and negative ionization modes indicate that there are 48 and 71 lipid species, respectively, that are common between the human milk and infant formulas. Moreover, the fatty acid composition in infant formulas varies significantly, depending on the fat source. Human milk is rich in triacylglycerols that contain linoleic acid, α-linolenic acid, arachidonic acid, and docosahexaenoic acid. Meanwhile, the triacylglycerols in IFB comprise long-chain fatty acids at the sn-1,3 position. Compared to human milk, IFC has the same level of sphingomyelin species. Based on univariate and multivariate analyses, there are 37, 34, 31, and 36 lipid species that can be used to distinguish between human milk and infant formulas. Overall, the results reported herein are useful in designing new milk formulas that better mimic human milk.

Have traffic restrictions improved air quality? A shock from COVID-19.

With the outbreak of COVID-19 (Corona Virus Disease, 2019), China adopted traffic restrictions to reduce the spread of COVID-19. Using daily data before and after the outbreak of COVID-19, an exogenous shock, this paper analyzes the effects of private vehicle restriction policies on air pollution. We find that the private vehicle restriction policies reduce the degree of air pollution to a certain extent. However, their effect varies with other policies implemented in the same period and the economic development of the city itself. Through the analysis of different categories of restrictions, we find that restriction policy for local fuel vehicles and the restriction policy based on the last digit of license plate numbers have the best effect in reducing air pollution. Under the background of COVID-19 epidemic and the implementation of private vehicle restriction policies and other traffic control policies during this period, we have also obtained other enlightenment on air pollution control.