Preparation of PDMS and PDMS-UiO-66 oxygen-rich membranes and modules for membrane-aerated biofilm reactors.

A membrane-aerated biofilm reactor (MABR) combines membrane technology with biofilm processes and has unique advantages in the treatment of organic wastewater and volatile wastewater. The common membranes for MABR systems usually have relatively uneven pore structures and low bubble point pressure, resulting in unsatisfactory O2 utilization and wastewater treatment efficiency. In this work, polydimethylsiloxane (PDMS) and UiO-66 (a Zr-based metal organic framework) were coated on the surface of a commercial polypropylene (PP) hollow fiber membrane to prepare oxygen-rich MABR membranes and modules, which showed an attractive O2 utilization rate and wastewater treatment efficiency. The bubble points of the PDMS and PDMS-UiO-66 membranes were significantly higher than those of the PP membranes, and the PDMS-UiO-66 membranes had better oxygen enrichment capacity and biological affinity. The optimal PDMS-UiO-66 membrane modules had an O2 permeance of 31.65 GPU (1 GPU = 3.35 × 10-10 mol m-2 s-1 Pa-1), with O2/N2 selectivity of 2.21. The membrane hanging effect and processing capacity for domestic sewage were greatly improved. This study may provide insights and guidelines to fabricate porous mixed matrix membranes and modules in the industry for MABR. The developed products are expected to be applied in the actual separation process.

Femtosecond Laser Combined with Hydrothermal Method to Construct Three-Dimensional Spatially Distributed Wurtzite ZnO Micro/Nanostructures to Enhance Photocatalytic Properties.

Conventional approaches employing nanopowder particles or deposition photocatalytic nanofilm materials encounter challenges such as performance instability, susceptibility to detachment, and recycling complications in practical photocatalytic scenarios. In this study, a novel fabrication strategy is proposed that uses femtosecond laser direct writing of self-sourced metal to prepare a self-supporting microstructure substrate and combines the hydrothermal method to construct a three-dimensional spatially distributed metal oxide micro/nanostructure. The obtained wurtzite ZnO micro/nanostructure has excellent wetting properties while obtaining a larger specific surface area and can achieve effective adsorption of methyl orange molecules. Moreover, the tight integration of ZnO with the surface interface of the self-sourced metal microstructure substrate will facilitate efficient charge transfer. Simultaneously, it improves the efficiency of light utilization (absorption) and the number of active sites in the photocatalytic process, ultimately leading to excellent photodegradation stability. This result provides an innovative technology solution for achieving efficient semiconductor surface-interface photocatalytic performance and stability.

Discovery and SAR of JTE-151: A Novel RORγ Inhibitor for Clinical Development.

A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.

Roles of the Siglec family in bone and bone homeostasis.

Tremendous progress has been seen in the study of the role of sialic acid binding im-munoglobulin type lectins (Siglecs) in osteoimmunology in the past two decades. Interest in Siglecs as immune checkpoints has grown from the recognition that Siglecs have relevance to human disease. Siglecs play important roles in inflammation and cancer, and play key roles in immune cell signaling. By recognizing common sialic acid containing glycans on glycoproteins and glycolipids as regulatory receptors for immune cell signals, Siglecs are expressed on most immune cells and play important roles in normal homeostasis and self-tolerance. In this review, we describe the role that the siglec family plays in bone and bone homeostasis, including the regulation of osteoclast differentiation as well as recent advances in inflammation, cancer and osteoporosis. Particular emphasis is placed on the relevant functions of Siglecs in self-tolerance and as pattern recognition receptors in immune responses, thereby potentially providing emerging strategies for the treatment of bone related diseases.

Directional Drop Rebound on Adhesive-Gradient Micro-Nanostructured Surfaces Formed by a Femtosecond Laser.

The dynamic behavior of droplets hitting a solid surface has received extensive attention due to its broad application prospects. Additionally, controlling the rebound behavior of impacting droplets is an important research topic. Current methods for investigating this behavior focus on the construction of a differentiated wettability surface, which is characterized by contact angle measurements, or a differentiated topography surface, which is represented by geometric height. This information allows one to obtain the nonuniform kinetic energy distribution of rebounding droplets and to realize control of rebounding droplet behavior. In this paper, femtosecond laser processing is proposed for the fabrication of an anisotropic surface with differences in adhesion, which allows for the control of impacting droplet rebound behavior. The experimental results show that the micro-nanostructure of the surface affects its adhesion. By changing the micro-nanostructure of the solid surface, the difference in surface adhesion can be controlled, thereby realizing precise control of impacting droplet rebound behavior. This study demonstrates that the micro-nanostructured surface formed by a femtosecond laser can be used to control a droplet rebound direction and landing site, which is of great significance to the development of liquid transport, microfluidic devices, and other fields.

Macamide B suppresses lung cancer progression potentially via the ATM signaling pathway.

Macamides are a class of bioactive natural products obtained from Lepidium meyenii (maca), which have been reported to exert inhibitory activity in cancer. However, their role in lung cancer is currently unknown. In the present study, macamide B was shown to inhibit the proliferation and invasion of lung cancer cells, as determined by Cell Counting Kit-8 and Transwell assays, respectively. By contrast, macamide B induced cell apoptosis, as determined by Annexin V-FITC assay. Moreover, combined treatment with macamide B and olaparib, an inhibitor of poly (ADP-ribose) polymerase, further suppressed the proliferation of lung cancer cells. At the molecular level, the expression of ataxia-telangiectasia mutated (ATM), RAD51, p53 and cleaved caspase-3 were significantly increased by macamide B, as determined by western blotting, whereas the expression levels of Bcl-2 were decreased. By contrast, when ATM expression was knocked down by small interfering RNA technology in A549 cells treated with macamide B, the expression levels of ATM, RAD51, p53 and cleaved caspase-3 were reduced, whereas those of Bcl-2 were increased. Consistently, cell proliferation and invasive ability were partially rescued by ATM knockdown. In conclusion, macamide B inhibits lung cancer progression by inhibiting cell proliferation and invasion, and inducing apoptosis. Furthermore, macamide B may participate in regulating the ATM signaling pathway. The present study provides a potential new natural drug for treating patients with lung cancer.

Evaluating Effects of Dynamic Interventions to Control COVID-19 Pandemic: A Case Study of Guangdong, China.

The emergence of different virus variants, the rapidly changing epidemic, and demands for economic recovery all require continual adjustment and optimization of COVID-19 intervention policies. For the purpose, it is both important and necessary to evaluate the effectiveness of different policies already in-place, which is the basis for optimization. Although some scholars have used epidemiological models, such as susceptible-exposed-infected-removed (SEIR), to perform evaluation, they might be inaccurate because those models often ignore the time-varying nature of transmission rate. This study proposes a new scheme to evaluate the efficiency of dynamic COVID-19 interventions using a new model named as iLSEIR-DRAM. First, we improved the traditional LSEIR model by adopting a five-parameter logistic function ß(t) to depict the key parameter of transmission rate. Then, we estimated the parameters by using an adaptive Markov Chain Monte Carlo (MCMC) algorithm, which combines delayed rejection and adaptive metropolis samplers (DRAM). Finally, we developed a new quantitative indicator to evaluate the efficiency of COVID-19 interventions, which is based on parameters in ß(t) and considers both the decreasing degree of the transmission rate and the emerging time of the epidemic inflection point. This scheme was applied to seven cities in Guangdong Province. We found that the iLSEIR-DRAM model can retrace the COVID-19 transmission quite well, with the simulation accuracy being over 95% in all cities. The proposed indicator succeeds in evaluating the historical intervention efficiency and makes the efficiency comparable among different cities. The comparison results showed that the intervention policies implemented in Guangzhou is the most efficient, which is consistent with public awareness. The proposed scheme for efficiency evaluation in this study is easy to implement and may promote precise prevention and control of the COVID-19 epidemic.

Anisotropic Ice Adhesion of Micro-Nano-Structured Metal Surface by a Femtosecond Laser.

The icephobic materials induced using micro-nano-structured surfaces have aroused great attention for promising applications. Previously, the characterization of ice adhesion of icephobic materials by shear force is usually performed without direction discrimination along the surface whatever the surface is anisotropic or not. In this work, we studied the direction-dependent ice adhesion strength on groove-shaped micro-nano-structured aluminum alloy surfaces formed using a femtosecond laser. It is found that the ice adhesion strength on the surfaces exhibits anisotropy, which corresponds to a smaller ice adhesion strength in the direction parallel to the groove than that orthogonal to the groove. Furthermore, it is found that the ice adhesion strength decreases with the increase in groove width in the orthogonal direction, while it does not change much in the parallel direction. The anisotropic ice adhesion strength is attributed to the change of wettability and morphology in the two directions. The findings in this work suggest that anisotropic ice adhesion should be fully considered when designing an icephobic micro-nano-structured metal structure, which is of great significance to the characterization and application of icephobic materials.

Effects of frost formation on the ice adhesion of micro-nano structure metal surface by femtosecond laser.

In this work, we study the effect and evolution of frost condensation on the ice adhered micro-nano structured Ni metal surface. By measuring the ice adhesion strength to the porous-structured surface under different frosting coverage, it is found that the ice adhesion on the surface changes not only with the morphology but also with the different evolution stages of the frosting coverage. Combining the changes in surface morphology and low-temperature wettability, the reasons for the changes in the ice adhesion strength are attributed to the change of wettability of the porous-structured surface under different frosting coverage, which affects the infiltration state of the surface and results in different mechanical interlocking, air-pockets and cracks states at the ice-solid interface. Moreover, it is found that the ice adhesion strength of the hydrophobic and hydrophilic porous-structured surface tends to be the same when the surface is heavily frosted. In addition, we demonstrate that both the hydrophobic and hydrophilic columnar-structured surfaces have smaller ice adhesion strength than the original surface without any micro-nano structures regardless of whether the surface is frosted or not, and the measured lowest ice adhesion strength of the hydrophobic columnar-structured surface can be down to 30 kPa in all frosted evolution stages, which is less than one tenth of the original surface. The findings in this work suggest that the influence of frosting should be fully considered when designing the icephobic micro-nano structured metal structure, and it can further serve as an important guidance for the design of passive icephobic surfaces expected to be free from the frosting effect.

ß-Substituted Alkenyl Heteroarenes as Dipolarophiles in the Cu(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides Empowered by a Dual Activation Strategy: Stereoselectivity and Mechanistic Insight.

The catalytic asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides with various electron-deficient alkenes provide the most straightforward protocol for the preparation of enantioenriched pyrrolidines in organic synthesis. However, the employment of conjugated alkenyl heteroarenes as dipolarophiles in such protocols to afford a class of particularly important molecules in medicinal chemistry is still a great challenge. Herein, we report that various ß-substituted alkenyl heteroarenes, challenging internal alkene substrates without a strong electron-withdrawing substituent, were successfully employed as dipolarophiles for the first time in the Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides. This reaction furnishes a large array of multistereogenic heterocycles incorporating both the biologically important pyrrolidine and heteroarene skeletons in good yields with exclusive diastereoselectivity and excellent enantioselectivity. Our extensive density functional theory (DFT) calculations proposed a working model to explain the origin of the stereochemical outcome and elucidated uncommon dual activation/coordination of both the dipole and dipolarophile substrates by the metal, in which a sterically bulky, rigid, and monodentate phosphoramidite ligand with triple-homoaxial chirality plays a pivotal role in providing an effective chiral pocket around the metal center, resulting in high enantioselectivity. The additional coordination of the heteroatom in the dipolarophile substrate to Cu is also critical for the exclusive diastereoselectivity and enhanced reactivity. Our calculations also predicted the reverse and high enantioinduction for the corresponding substrates with monocyclic heteroarenes as well as regiospecific cycloaddition to the less reactive internal C═C bond of one related dipolarophile diene substrate. Such unique steric effect-directed enantioswitching and coordination-directed regioselectivity were verified experimentally.

Clinical significance of LARGE1 in progression of liver cancer and the underlying mechanism.

Liver cancer is a malignant disease and causes thousands of death each year. The prognosis is dismal for patients with metastasis and recurrence. It is urgent to disclose the cause and mechanism underlying liver cancer. LARGE1 encodes a glycosyltransferase and was reported to promote progression in cancer. But its role in liver cancer is unknown. In this study, LARGE1 displayed upregulated expression in liver cancer cells. When LARGE1 was knocked down in SMMC-7721 and Huh-7 cells, the ability of cell proliferation and colony formation were decreased significantly. Cell migration and invasion were suppressed. The number of cells in G1 phase increased but decreased in S phase. Cell apoptosis was not affected. Tumor growth in vivo was also inhibited. Tumor volume was decreased from 1270 mm3 to 721 mm3 (p < 0.05) and tumor weight from 0.95 g to 0.63 g (p < 0.05). Furthermore, the expression of ß-catenin, TCF and Cyclin D1 was reduced when LARGE1 was knocked down but increased in LARGE1-overexpressed cells. LGK-974, a specific inhibitor in canonical Wnt signaling, inhibited cell proliferation even when LARGE1 was over-expressed. In tumor tissues, LARGE1 was increased by 4.8 folds compared to paratumoral tissues. And higher LARGE1 expression caused shorter survival. Clinicopathological analysis demonstrated that LARGE1 was associated with TNM stage (Ⅰ/Ⅱ vs III/IV, p = 0.005). Therefore, LARGE1 promotes progression and regulates Wnt/ß-catenin signaling pathway in liver cancer.

A new entry to highly functionalized pyrroles via a cascade reaction of α-amino esters and alkynals.

Here, we developed an expedient access route to highly functionalized pyrroles from readily available α-amino acid ester hydrochlorides and alkynals via a cascade condensation/intramolecular cyclization followed by a unique C-N ester migration process. A variety of 1,2,3-trisubstituted pyrroles, which were difficult to acquire with the common methodologies, were successfully prepared in good yields under mild conditions.

Asymmetric synthesis of quaternary α-trifluoromethyl α-amino acids by Ir-catalyzed allylation followed by kinetic resolution.

Facile access to quaternary α-trifluoromethyl α-amino acids has been developed. This sequential reaction involves an Ir-catalyzed asymmetric allylation of α-trifluoromethyl aldimine esters followed by an unprecedented kinetic resolution.

Catalytic asymmetric synthesis of quaternary trifluoromethyl α- to ε-amino acid derivatives via umpolung allylation/2-aza-Cope rearrangement.

In this study, we developed an efficient Ir-catalyzed cascade umpolung allylation/2-aza-Cope rearrangement of tertiary α-trifluoromethyl α-amino acid derivatives for the preparation of a variety of quaternary α-trifluoromethyl α-amino acids in high yields with excellent enantioselectivities. The umpolung reactivity empowered by the activation of the key isatin-ketoimine moiety obviates the intractable enantioselectivity control in Pd-catalyzed asymmetric linear α-allylation. In combination with quasi parallel kinetic resolution or kinetic resolution, the generality of this method is further demonstrated by the first preparation of enantioenriched quaternary trifluoromethyl ß-, γ-, δ- and ε-amino acid derivatives.

Stereodivergent assembly of tetrahydro-γ-carbolines via synergistic catalytic asymmetric cascade reaction.

Enantiomerically enriched indole-containing heterocycles play a vital role in bioscience, medicine, and chemistry. As one of the most attractive subtypes of indole alkaloids, highly substituted tetrahydro-γ-carbolines are the basic structural unit in many natural products and pharmaceuticals. However, the syntheses of tetrahydro-γ-carbolines with high functionalities from readily available reagents are significant challenging. In particular, the stereodivergent syntheses of tetrahydro-γ-carbolines containing multi-stereogenic centers remain quite difficult. Herein, we report an expedient and stereodivergent assembly of tetrahydro-γ-carbolines with remarkably high levels of stereoselective control in an efficient cascade process from aldimine esters and indolyl allylic carbonates via a synergistic Cu/Ir catalyst system. Control experiments-guided optimization of synergistic catalysts and mechanistic investigations reveal that a stereodivergent allylation reaction and a subsequent highly stereoselective iso-Pictet-Spengler cyclization are the key elements to success.

Catalytic Asymmetric Umpolung Allylation/2-Aza-Cope Rearrangement for the Construction of α-Tetrasubstituted α-Trifluoromethyl Homoallylic Amines.

A general protocol for the preparation of enantioenriched α-tetrasubstituted α-trifluoromethyl homoallylic amines is disclosed. Despite the significant challenge in stereoselectivity control, Ir-catalyzed asymmetric cascade umpolung allylation/2-aza-Cope rearrangement of trifluoromethylated fluorenone imines with allylic carbonates was realized with excellent efficiency and remarkable stereoselectivity. These were enabled by the suitable protective imino moiety and an unexpectedly exclusive E-geometrical imine of the allylation intermediate. This methodology is also applicable to facile access to chiral α-trisubstituted α-trifluoromethyl homoallylic amines in similarly high yield and stereoselectivity.

Catalytic Asymmetric Synthesis of α-Trifluoromethyl Homoallylic Amines via Umpolung Allylation/2-Aza-Cope Rearrangement: Stereoselectivity and Mechanistic Insight.

An unprecedented Ir-catalyzed asymmetric cascade umpolung allylation/2-aza-Cope rearrangement of trifluoroethylisatin ketimines has been realized. The current method provides a facile access to biologically important α-trifluoromethyl-containing homoallylic amines in high yields with excellent enantioselectivity. Notably, umpolung reactivity of trifluoroethylisatin ketimine was discovered for the first time. Mechanism studies revealed the key intermediates in the initial umpolung allylation and the stereospecific chirality transfer in the subsequent 2-aza-Cope rearrangement.

Enantioselective synthesis of multi-nitrogen-containing heterocycles using azoalkenes as key intermediates.

Chiral multi-nitrogen-containing heterocycles, such as pyrazole, imidazole and pyridazine, are widely found in naturally occurring organic compounds and pharmaceuticals, and hence, their stereoselective and efficient synthesis is an important issue in organic synthesis. Out of the variety of methods that have been developed over the past century, the catalytic asymmetric cyclization and cycloaddition reactions are recognized as the most synthetically useful strategies due to their step-, atom- and redox-economic nature. In particular, the recently developed annulation reactions using azoalkenes as key intermediates show their great ability to construct diverse types of multi-nitrogen-containing heterocycles. In this feature article, we critically analyse the strategic development and the efficient transformation of azoalkenes to chiral heterocycles and α-functionalized ketone derivatives since 2010. The plausible mechanism for each reaction model is also discussed.

Synergistic Cu/Pd-Catalyzed Asymmetric Allenylic Alkylation of Azomethine Ylides for the Construction of α-Allene-Substituted Nonproteinogenic α-Amino Acids.

An unprecedented asymmetric allenylic alkylation of readily available imine esters, which was enabled by a synergistic Cu/Pd catalysis, has been developed. This dual catalytic system possesses good substrate compatibility, delivering a diverse array of nonproteinogenic α-allenylic α-mono- or α,α-disubstituted α-amino acids (α-AAs) with high yields and generally excellent enantioselectivities. Furthermore, the scalability and practicability of the current synthetic protocol were proven by performing gram-scale reactions and by the first catalytic asymmetric synthesis of naturally occurring (S)-γ-allenic α-amino acid, respectively.

Synergistic catalysis for cascade allylation and 2-aza-cope rearrangement of azomethine ylides.

The efficient construction of enantiomerically enriched molecules from simple starting materials via catalytic asymmetric synthesis strategies is a key challenge in synthetic chemistry. Metallated azomethine ylides are commonly-used synthons for the preparation of N-heterocycles and α-amino acids. Remarkably, to date, the utilization of azomethine ylides for the facile access to chiral amines has proven elusive. Here, we report that a synergistic Cu/Ir-catalytic system combined with careful tuning of the steric congestion can be used to convert aldimine esters to a variety of chiral homoallylic amines via a cascade allylation/2-aza-Cope rearrangement. The elucidation of the distinct effects of each stereogenic center of the allylation intermediates on the stereochemical outcome and chirality transfer in the rearrangement further guided the selection of catalysts combination.