Enantioselective [2+2]-cycloadditions with triplet photoenzymes.

Naturally evolved enzymes, despite their astonishingly large variety and functional diversity, operate predominantly through thermochemical activation. Integrating prominent photocatalysis modes into proteins, such as triplet energy transfer, could create artificial photoenzymes that expand the scope of natural biocatalysis1-3. Here, we exploit genetically reprogrammed, chemically evolved photoenzymes embedded with a synthetic triplet photosensitizer that are capable of excited-state enantio-induction4-6. Structural optimization through four rounds of directed evolution afforded proficient variants for the enantioselective intramolecular [2+2]-photocycloaddition of indole derivatives with good substrate generality and excellent enantioselectivities (up to 99% enantiomeric excess). A crystal structure of the photoenzyme-substrate complex elucidated the non-covalent interactions that mediate the reaction stereochemistry. This study expands the energy transfer reactivity7-10 of artificial triplet photoenzymes in a supramolecular protein cavity and unlocks an integrated approach to valuable enantioselective photochemical synthesis that is not accessible with either the synthetic or the biological world alone.

Chemogenetic Evolution of Diversified Photoenzymes for Enantioselective [2 + 2] Cycloadditions in Whole Cells.

Artificial photoenzymes with novel catalytic modes not found in nature are in high demand; yet, they also present significant challenges in the field of biocatalysis. In this study, a chemogenetic modification strategy is developed to facilitate the rapid diversification of photoenzymes. This strategy integrates site-specific chemical conjugation of various artificial photosensitizers into natural protein cavities and the iterative mutagenesis in cell lysates. Through rounds of directed evolution, prominent visible-light-activatable photoenzyme variants were developed, featuring a thioxanthone chromophore. They successfully enabled the enantioselective [2 + 2] photocycloaddition of 2-carboxamide indoles, a class of UV-sensitive substrates that are traditionally challenging for known photoenzymes. Furthermore, the versatility of this photoenzyme is demonstrated in enantioselective whole-cell photobiocatalysis, enabling the efficient synthesis of enantioenriched cyclobutane-fused indoline tetracycles. These findings significantly expand the photophysical properties of artificial photoenzymes, a critical factor in enhancing their potential for harnessing excited-state reactivity in stereoselective transformations.

A Three-in-One Integrated Cs3Bi2Br9@Co3O4 Heterostructure with Photoinduced Self-Heating Effect for Synergistically Enhancing the Photothermal CO2 Reduction.

Photothermal catalysis, which applies solar energy to produce photogenerated e-/h+ pairs as well as provide heat input, is recognized as a promising technology for high conversion efficiency of CO2 to value-added solar fuels. In this work, a "shooting three birds with one stone" approach is demonstrated to significantly enhance the photothermal CO2 reduction over the Cs3Bi2Br9@Co3O4 (CBB@Co3O4) heterostructure. Initially, Co3O4 with photoinduced self-heating effect serves as a photothermal material to elevate the temperature of the photocatalyst, which kinetically accelerates the catalytic reaction. Meanwhile, a p-n heterojunction is constructed between the p-type Co3O4 and n-type Cs3Bi2Br9 semiconductors, which has an intrinsic built-in electric field (BEF) to facilitate the separation of photogenerated e-/h+ pairs. Furthermore, the mesoporous Co3O4 matrix can afford abundant active sites for promoting adsorption/activation of CO2 molecules. Benefiting from these synergistic effects, the as-developed CBB@Co3O4 heterostructure achieves an impressive CO2-to-CO conversion rate of 168.56 µmol g-1 h-1 with no extra heat input. This work provides an insightful guidance for the construction of effective photothermal catalysts for CO2 reduction with high solar-to-fuel conversion efficiency.

HbA1c combined with glycated albumin or 1,5-anhydroglucitol improves the efficiency of diabetes screening in a Chinese population.

AIMS: This study aimed to evaluate the ability of HbA1c combined with glycated albumin (GA) or 1,5-anhydroglucitol (1,5-AG) to detect diabetes in residents of Jiangsu, China. METHODS: The oral glucose tolerance test (OGTT) was performed on 2184 people in Jiangsu. HbA1c , GA, 1,5-AG and other serum biochemical parameters were measured. Receiver operating characteristic curves were plotted to determine the optimal thresholds of HbA1c , GA and 1,5-AG according to the Youden index. RESULTS: (1) The optimal thresholds of HbA1c , GA and 1,5-AG for the screening of diabetes were ≥45 mmol/mol (6.3%), ≥13.0% and ≤23.0 µg/ml, respectively. (2) The sensitivities of HbA1c combined with GA and 1,5-AG were both 85%, higher than that of HbA1c (70%, p < 0.001). CONCLUSIONS: This study is suitable for cases where plasma glucose is unavailable. Among the residents of Jiangsu, HbA1c combined with GA or 1,5-AG can improve the sensitivity of diabetes screening, reduce the miss rate and save the use of OGTT. GA and 1,5-AG are superior in individuals with mild glucose metabolism disorder. GA enhances the detection of diabetes in the nonobese, and 1,5-AG enhances the detection in those with hyperuricaemia.

A step-scheme-based Cs3Bi2Br9 perovskite quantum dots@mesoporous Nb2O5 photocatalyst with boosted charge separation and CO2 reduction.

Solar-energy-powered CO2 reduction into valuable chemical fuels represents a highly promising strategy to address the currently energy and environmental issues. Owing to the nontoxicity and robust reduction capability, lead-free Cs3Bi2Br9 perovskite quantum dots (PQDs) are regarded as an attractive material for CO2 photoreduction. Nevertheless, the potential of their applications in this field has been restricted by the severe charge recombination, resulting in unsatisfactory photocatalytic performance. Herein, a step-scheme-based Cs3Bi2Br9@Nb2O5 (CBB@Nb2O5) nanocomposite was fabricated by embedding the CBB PQDs into mesoporous Nb2O5. Experimental studies, along with theoretical calculations, revealed that the charge migration route in the CBB@Nb2O5 nanocomposite conformed to the step-scheme (S-scheme) mode, enabling effective charge separation and strong redox ability preservation. Profiting from the promoted charge separation, as well as the improved CO2 adsorption contributed by mesoporous Nb2O5, the CBB@Nb2O5 nanocomposite unveiled superior CO2 photoreduction performance, with CO evolution rate reaching 143.63 µmol g-1h-1. The present study provides a potential strategy to manufacture highly-efficient perovskite-based photocatalysts for achieving carbon neutrality.

A retrospective review of rheumatology referral wait times within a health centre in Quebec, Canada.

It is important that inflammatory arthropathies such as rheumatoid arthritis be diagnosed promptly so that treatment can be administered in a timely fashion. However, there is considerable evidence that this process of care is delayed in many people. The aim of the study is to assess wait times between primary care referral and rheumatology assessment for new-onset inflammatory arthropathies. We performed a retrospective review related to new rheumatology consultations (N = 202) between September and November 2008 within the McGill University Health Centre, Montreal, Canada. At this centre, no formal triaging of rheumatology referrals exists. Of the 202 charts reviewed, wait times could be calculated in 164 cases. Only consultations for new-onset conditions were analyzed (N = 161). The results showed that patients with inflammatory arthritis were seen approximately 34.6 days (median 26) post-referral. Wait times for individuals who were ultimately diagnosed with non-urgent conditions (osteoarthritis, fibromyalgia and soft-tissue rheumatism) averaged 41.0 days (median 29). In conclusions, compared to non-urgent cases, individuals with inflammatory arthritis were seen about 1 week sooner. Nevertheless, provisional diagnosis provided on referrals did not appear to expedite wait times for persons with suspected inflammatory arthritis. This suggested that other factors, such as the concern of the patient, may have an influence on referral wait times. Implementation of a rapid access program or triage system may be helpful to further decrease wait times for inflammatory arthropathies.

Low density lipoprotein mimic nanoparticles composed of amphipathic hybrid peptides and lipids for tumor-targeted delivery of paclitaxel.

BACKGROUND: Low density lipoprotein (LDL) has been regarded as a promising antitumor drug vehicle. However some problems, such as rare source, difficulty of large-scale production, and potential safety concerns, hinder its clinical application. PURPOSE: The objective of this study is to develop a biomimetic LDL nanocarrier by replacing the native apolipoprotein B-100 (apoB-100) with an artificial amphipathic peptide and demonstrate its antitumor efficacy. METHODS: The amphipathic hybrid peptide (termed as FPL) consisting of a lipid binding motif of apoB-100 (LBMapoB)-polyethylene glycol (PEG)-folic acid (FA) was synthesized and characterized by 1H NMR and circular dichroism. FPL decorated lipoprotein-mimic nanoparticles (termed as FPLM NPs) were prepared by a modified solvent emulsification method. Paclitaxel (PTX) was incorporated into NPs and its content was quantified by HPLC analysis. The morphology of NPs was observed by transmission electron microscopy (TEM), and the particle size and zeta potential of NPs were determined by dynamic light scattering (DLS). The colloidal stability of FPLM NPs was evaluated in PBS containing bovine serum albumin (BSA). In vitro release of PTX loaded FPLM NPs was evaluated using the dialysis method. Cellular uptake and cytotoxity assayswere evaluated on human cervical cancer cells (HeLa) and lung cancer cells (A549). Tumor inhibition in vivo was investigated in M109 tumor-bearing mice via tail vein injection of Taxol formulation and PTX loaded NPs. RESULTS: The composition of FPLM NPs, including cholesteryl oleate, glyceryl trioleate, cholesterol, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and FPL peptides, was optimized to be 5:1:1:3:10 (w/w). FPLM NPs had a spherical shape with a mean diameter of 83 nm and a negative charge (-12 mV). FPLM NPs with optimum formulation had good colloidal stability in BSA solution.The release of PTX from FPLM NPs was slow and sustained. The uptake of FPLM NPs was higher in folate receptor (FR) overexpressing tumor cells (HeLa cells) than in FR deficient tumor cells (A549 cells). The intracellular distribution indicated that FPLM NPs had the lysosome escape capacity. The internalization mechanism of FPLM NPs was involved with clathrin- and caveolae-mediated endocytosis and FR played a positive role in the internalization of FPLM NPs. The CCK-8 assay demonstrated that FPLM NPs exhibited notably better anti-tumor effect than Taxol formulation in vitro. Moreover, PTX loaded FPLM NPs produced very marked anti-tumor efficiency in M109 tumor-bearing mice in vivo. CONCLUSION: FPLM NPs is a promising nanocarrier which can improve the therapeutic effect and reduce the side effects of antitumor drugs.

In vitro effect of mPEG2k-PCLx micelles on rat liver cytochrome P450 enzymes.

The present study was aimed to evaluate the effects of amphiphilic copolymer micelles on six major hepatic cytochrome P450 (CYP) isoforms. A series of mPEG2k-PCLx polymeric micelles (mPEG2k-PCL2k, mPEG2k-PCL3.5k, mPEG2k-PCL5k and mPEG2k-PCL10k) ranging from 20 to 100 nm were prepared to investigate the inhibitory or inductive activities by in vitro incubations of rat liver microsomes and primary rat hepatocytes. Inhibition of these polymeric micelles on CYP1A2, CYP2B1, CYP2C6, CYP2C11, CYP2D2 and CYP3A1/2 isoenzymes were observed above their critical micelle concentrations (>10 µg·mL-1) and in a concentration-dependent manner. The mPEG2k-PCL2k micelles showed the strongest inhibition of CYP1A2, followed by CYP2C11. The micelles with lower molecular weight PCL segment exhibited more potent inhibitory potential. Induction on CYP1A2, CYP2B1 and CYP3A1/2 activity (2.1-7.2-fold, 1.5-2.4-fold and 1.3-3.0-fold, respectively) were detected at all tested concentrations (0.1-1000 µg·mL-1 or 0.1-100 µg·mL-1). Accordingly, most of the mRNA levels were upregulated. As demonstrated in ex vivo fluorescence imaging results, the mPEG2k-PCLx micelles mainly accumulated in the liver after intravenous administration. In conclusion, mPEG2k-PCLx micelles can interfere with the normal metabolic function of CYP450s in vitro, indicating polymeric micelles as promising drug nano-carriers might cause micelle-drug interaction and the in vivo interaction deserves further investigation.