Bitter taste receptor activation by cholesterol and an intracellular tastant.

Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors1. Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants2-6, although the molecular mechanisms for recognizing diverse chemicals and initiating cellular signalling are still poorly understood. Here we report two cryo-electron microscopy structures for TAS2R14 complexed with Ggust (also known as gustducin) and Gi1. Both structures have an orthosteric binding pocket occupied by endogenous cholesterol as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1, including a direct interaction with the α5 helix of Ggust and Gi1. Computational and biochemical studies validate both ligand interactions. Our functional analysis identified cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator with direct agonist activity at TAS2R14. Moreover, the orthosteric pocket is connected to the allosteric site via an elongated cavity, which has a hydrophobic core rich in aromatic residues. Our findings provide insights into the ligand recognition of bitter taste receptors and suggest activities of TAS2R14 beyond bitter taste perception via intracellular allosteric tastants.

Silver-Enabled Dearomative Trifluoromethoxylation of Indoles.

The only known method for the dearomative trifluoromethoxylation of indoles is preliminary, with only one substrate successfully undergoing the reaction. In this study, we not only developed a broadly applicable method for indole dearomative trifluoromethoxylation but also achieved divergent trifluoromethoxylation by fine-tuning the reaction conditions. Under optimized conditions, with a silver salt and an easily handled OCF3 reagent, various indoles smoothly underwent dearomatization to afford a diverse array of ditrifluoromethoxylated indolines in 50-84% isolated yields with up to 37:1 diastereoselectivity, and fluorinated trifluoromethoxylated indolines were obtained with exclusive trans selectivity. In addition, the reaction conditions were compatible with other heteroaromatic rings as well as styrene moieties.

The effects of video double-lumen tubes on intubation complications in patients undergoing thoracic surgery: A randomised controlled study.

BACKGROUND: Tracheal injuries, vocal cord injuries, sore throat and hoarseness are common complications of double-lumen tube (DLT) intubation. OBJECTIVE: This study aimed to evaluate the effects of 'video double-lumen tubes' (VDLTs) on intubation complications in patients undergoing thoracic surgery. DESIGN: A randomised controlled study. SETTINGT: Xuzhou Cancer Hospital, Xuzhou, China, from January 2023 to June 2023. PATIENTS: One hundred eighty-two patients undergoing elective thoracic surgery with one-lung ventilation were randomised into two groups: 90 in the DLT group and 92 in the VDLT group. INTERVENTION: VDLT was selected for intubation in the VDLT group, and DLT was selected for intubation in the DLT group. A fibreoptic bronchoscope (FOB) was used to record tracheal and vocal cord injuries. MAIN OUTCOME MEASURES: The primary outcomes were the incidence of moderate-to-severe tracheal injury and the incidence of vocal cord injury. The secondary outcomes included the incidence and severity of postoperative 24 and 48 h sore throat and hoarseness. RESULTS: The incidence of moderate-to-severe tracheal injury was 32/90 (35.6%) in the DLT group, and 45/92 (48.9%) in the VDLT group ( P  = 0.077; relative risk 1.38, 95% CI, 0.97 to 1.95). The incidence of vocal cord injury was 31/90 (34.4%) and 34/92 (37%) in the DLT and VDLT groups, respectively ( P  = 0.449). The incidence of postoperative 24 h sore throat and hoarseness was significantly higher in the VDLT group than in the DLT group (for sore throat: P  = 0.032, relative risk 1.63, 95% CI, 1.03 to 2.57; for hoarseness: P  = 0.018, relative risk 1.48, 95% CI, 1.06 to 2.06). CONCLUSION: There was no statistically significant difference in the incidence of moderate-to-severe tracheal injury and vocal cord injury between DLTs and VDLTs. While improving the first-attempt success rate, intubation with VDLT increased the incidence of postoperative 24 h sore throat and hoarseness. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier: ChiCTR2300067348.

Direct Dehydroxytrifluoromethoxylation of Alcohols.

The first example of a direct dehydroxytrifluoromethoxylation of alcohols has been developed. This method generated an alkyl fluoroformate in situ from alcohols, followed by nucleophilic trifluoromethoxylation with trifluoromethyl arylsulfonate (TFMS) as the trifluoromethoxylation reagent. The reaction is operationally simple and scalable, and it proceeds under mild reaction conditions to provide access to a wide range of trifluoromethyl ethers from alcohols. In addition, this method is suitable for the late-stage trifluoromethoxylation of complex small molecules.

Transition metal-free direct trifluoromethylthiolation of indoles using trifluoromethanesulfonyl chloride in the presence of triphenylphosphine.

A novel triphenylphosphine-mediated direct trifluoromethylthiolation of indole derivatives using trifluoromethanesulfonyl chloride as the SCF3 source was developed. Sodium iodide facilitated this transformation by generating iodine in situ which was found to accelerate this transformation. The use of a transition metal-free protocol, readily available reagents, and mild reaction conditions allowed this protocol to be easily scaled up.

Iodine-catalysed regioselective thiolation of flavonoids using sulfonyl hydrazides as sulfenylation reagents.

Iodine-catalysed regioselective sulfenylation of flavonoid derivatives with sulfonyl hydrazides was developed. Various flavonoid thioethers were obtained in moderate to good yield. The thiolation could be conveniently directed to C-8 for flavone, flavonol, dihydroflavone, and isoflavone derivatives or to C-7 for aurone derivatives by employing the isopropyl ethers of flavonoids bearing free OH groups at the C-5 or C-4 positions.

Discovery of the First-in-class G9a/GLP PROTAC Degrader.

Aberrantly expressed lysine methyltransferases G9a and GLP, which catalyze mono- and di-methylation of histone H3 lysine 9 (H3K9), have been implicated in numerous cancers. Recent studies have uncovered both catalytic and non-catalytic oncogenic functions of G9a/GLP. As such, G9a/GLP catalytic inhibitors have displayed limited anticancer activity. Here, we report the discovery of the first-in-class G9a/GLP proteolysis targeting chimera (PROTAC) degrader, 10 (MS8709), as a potential anticancer therapeutic. 10 induces G9a/GLP degradation in a concentration-, time, and ubiquitin-proteasome system (UPS)-dependent manner, does not alter the mRNA expression of G9a/GLP and is selective for G9a/GLP over other methyltransferases. Moreover, 10 displays superior cell growth inhibition to the parent G9a/GLP inhibitor UNC0642 in prostate, leukemia, and lung cancer cells and has suitable mouse pharmacokinetic properties for in vivo efficacy studies. Overall, 10 is a valuable chemical biology tool to further investigate the functions of G9a/GLP and a potential therapeutic for treating G9a/GLP-dependent cancers.

Discovery of the First-in-Class G9a/GLP PROTAC Degrader.

Aberrantly expressed lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), have been implicated in numerous cancers. Recent studies have uncovered both catalytic and noncatalytic oncogenic functions of G9a/GLP. As such, G9a/GLP catalytic inhibitors have displayed limited anticancer activity. Here, we report the discovery of the first-in-class G9a/GLP proteolysis targeting chimera (PROTAC) degrader 10 (MS8709), as a potential anticancer therapeutic. 10 induces G9a/GLP degradation in a concentration-, time-, and ubiquitin-proteasome system (UPS)-dependent manner. Futhermore, 10 does not alter the mRNA expression of G9a/GLP and is selective for G9a/GLP over other methyltransferases. Moreover, 10 displays superior cell growth inhibition to the parent G9a/GLP inhibitor UNC0642 in prostate, leukemia, and lung cancer cells and has suitable mouse pharmacokinetic properties for in vivo efficacy studies. Overall, 10 is a valuable chemical biology tool to further investigate the functions of G9a/GLP and a potential therapeutic for treating G9a/GLP-dependent cancers.

A validated UHPLC-MS/MS assay for rapid and sensitive determination of crisaborale in human plasma and its clinico-pharmacokinetic application.

Crisaborole ointment, 2%, is a non-steroidal, topical anti-inflammatory phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. To date, a specific analytic method of crisaborole in plasma has not been reported. The aim of this study was to develop a rapid, sensitive and robust UHPLC-MS/MS method for the quantitative detection of crisaborole in human plasma by using deuterated crisaborole-d4 as the internal standard (IS). The analyte was well extracted from human plasma with acetonitrile and subsequently eluted with gradient acetonitrile and water in short run time of 3.3 min. Negative electrospray ionization in multiple reaction monitoring mode was employed to acquire the quantification ion pairs of m/z 250.0→118.0 for crisaborole and m/z 254.0→121.9 for IS. The assay met the regulations of the US Food and Drug Administration and the European Medicines Agency for assay validation with a good linearity in the calibration range of 0.20-80 ng/mL. Intra-day and inter-day precision was less than 9.17% and the accuracy was - 2.29%-6.33% across all the quality control samples. The average extraction recovery of analyte and IS was 84.61% and 91.43%, respectively, and consistent over different quality control samples. The fully validated method was successfully used for the drug level measurement in ten healthy Chinese subjects receiving crisaborole ointment. Our novel UPLC-MS/MS assay for the quantification of plasma crisaborole concentrations in human samples may be easily used in clinical practice and help to reveal the pharmacokinetic profiles of crisaborole in Chinese population.

Clinical, economic and humanistic outcomes of medication therapy management services: A systematic review and meta-analysis.

Background: Medication therapy management (MTM) services is a method that can effectively improve patients' conditions, but the efficacy of economic and humanistic outcomes remain unclear. This systematic review and meta-analysis aim to use economic, clinical and humanistic outcomes to evaluate the multi-benefits of MTM services. Method: A systematic review and meta-analysis was conducted by retrieving PubMed, EMBASE, the Cochrane Library and ClinicalTrial.gov from the inception to April 2022. There were two reviewers screening the records, extracting the data, and assessing the quality of studies independently. Results: A total of 81 studies with 60,753 participants were included. MTM services were more effective in clinical outcomes with decreasing the rate of readmission (OR: 0.78; 95% CI: 0.73 to 0.83; I2 = 56%), emergency department visit (OR: 0.88; 95% CI: 0.81 to 0.96; I2 = 32%), adverse drug events (All-cause: OR: 0.68; 95% CI: 0.56 to 0.84; I2 = 61%; SAE: OR: 0.51; 95% CI: 0.33 to 0.79; I2 = 35%) and drug-related problems (MD: -1.37; 95% CI: -2.24 to -0.5; I2 = 95%), reducing the length of stay in hospital (MD: -0.74; 95% CI: -1.37 to -0.13; I2 = 70%), while the economic and humanistic outcomes were less effective. Conclusion: Our systematic review and meta-analysis demonstrated that MTM services had great ability to improve patients' clinical conditions while the efficacy of economic and humanistic outcomes, with some of the outcomes showing high degree of heterogeneity and possible publication bias, required more future studies to provide stronger evidence. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=349050], identifier [CRD42022349050].

Visible-light-driven reversible shuttle vicinal dihalogenation using lead halide perovskite quantum dot catalysts.

Dihalogenation of alkenes to the high-added value vicinal dihalides is a prominent process in modern synthetic chemistry. However, their effective conversion still requires the use of expensive and hazardous agents, sacrificial half-reaction coupling or primary energy input. Here, we show a photocatalytically assisted shuttle (p-shuttle) strategy for redox-neutral and reversible vicinal dihalogenation using low-cost and stable 1,2-dihaloethane under visible light illumination. Energetic hot electrons from metal-halide perovskite QDs enable the challenging photocatalytic reactions. Ultrafast laser transient absorption spectroscopy have unveiled the energy matching of the hot electrons with the high reduction potential of 1,2-dihaloethane, via two consecutive photoexcitation process. Powered by the sustainable energy as the only energy input, our new catalytic system using metal-halide perovskite QDs for dibromination, dichlorination and even unexplored hetero-dihalogenation, shows good tolerance with a wide range of alkenes at room temperature. In contrast to homogeneous photocatalysts, chalcogenide QDs and other semiconductor catalysts, perovskite QDs deliver previously unattainable performance in photoredox shuttle vicinal dihalogenation with the turnover number over 120,000. This work provides new opportunities in visible-light-driven heterogeneous catalysis for unlocking novel chemical transformations.

Structure-Based Discovery of Inhibitors of the SARS-CoV-2 Nsp14 N7-Methyltransferase.

An under-explored target for SARS-CoV-2 is the S-adenosyl methionine (SAM)-dependent methyltransferase Nsp14, which methylates the N7-guanosine of viral RNA at the 5'-end, allowing the virus to evade host immune response. We sought new Nsp14 inhibitors with three large library docking strategies. First, up to 1.1 billion lead-like molecules were docked against the enzyme's SAM site, leading to three inhibitors with IC50 values from 6 to 50 µM. Second, docking a library of 16 million fragments revealed 9 new inhibitors with IC50 values from 12 to 341 µM. Third, docking a library of 25 million electrophiles to covalently modify Cys387 revealed 7 inhibitors with IC50 values from 3.5 to 39 µM. Overall, 32 inhibitors encompassing 11 chemotypes had IC50 values < 50 µM and 5 inhibitors in 4 chemotypes had IC50 values < 10 µM. These molecules are among the first non-SAM-like inhibitors of Nsp14, providing starting points for future optimization.

Dual-network self-healing hydrogels composed of graphene oxide@nanocellulose and poly(AAm-co-AAc).

A nature-inspired strategy is developed to build dual-network hydrogels made up of rigid graphene oxide-functionalized nanocellulose (GO@NC) network and flexible poly[acrylamide-co-(acrylic acid)] (poly(AAm-co-AAc)) network. A pre-stretching method is used to form a muscle-shape anisotropic architecture. The penetration of poly(AAm-co-AAc) flexible network relieves the stiffness of NC network, thus improving the average elongation at break from 86.2 % to 748.0 %. Compared with the poly(AAm-co-AAc), the average rupture tensile strength rises remarkably by 228.6 %. The dual-crosslinked strategy endows the GO@NC-poly(AAm-co-AAc) hydrogels with a fast, stable and repeatable self-healing ability, which can achieve 85.0 % of healing efficiency after only 600 s of self-healing and maintain 76.2 % of initial strength after 10 cycles of breaking-self-healing. The superb self-healing ability is similar to the muscle function. For potential applications, the hydrogels can achieve real-time, stable, and long-term sensing as smart wearable strain sensors (high gauge factor: 5.13), and can effectively purify Sudan IV wastewater as green recyclable adsorbents.

Multiple beneficial outcomes of medication therapy management interventions in randomized control trials and non-randomized control trials: A protocol for systematic review and meta-analysis.

BACKGROUND: Medication therapy management (MTM) service is an effective method to reduce medication-related problems and improve patients' multiple kinds of outcomes. However, the lack of comprehensive review for MTM services has hindered its development. As a result, we are aiming to evaluate the current benefits of MTM services with multiple outcomes. METHOD: An electronic search will be performed for randomized controlled trials (RCTs) or non-randomized control trials (NRCTs) that reported MTM services or pharmaceutical services as interventions from PubMed, The Cochrane Library, Embase, and ClinicalTrial. gov. The odds ratios, mean differences, and standard mean differences and their 95% confidence intervals (95% confidence intervals) will be calculated with fixed or random effect models. RESULTS: This study will evaluate the multiple benefits of MTM services in clinical endpoints, quality of life, economy, and drug-related problems. CONCLUSION: The results will review eligible studies released in the past twenty years and provide more comprehensive evidence of the efficacy of MTM services. ETHICS AND DISSEMINATION: Ethical approval is not applicable for this study.

Selective C-H trifluoromethoxylation of (hetero)arenes as limiting reagent.

Methods for direct C-H trifluoromethoxylation of arenes and heteroarenes are rare, despite the importance of trifluoromethoxylated compounds for pharmaceuticals, agrochemicals, and material sciences. Especially selective C-H trifluoromethoxylation of pyridines remains a formidable challenge. Here we show a general late-stage C-H trifluoromethoxylation of arenes and heteroarenes as limiting reagent with trifluoromethoxide anion. The reaction is mediated by silver salts under mild reaction conditions, exhibiting broad substrate scope and wide functional-group compatibility. In addition, ortho-position selective C-H trifluoromethoxylation of pyridines is observed. The method is not only applicable to the gram-scale synthesis of trifluoromethoxylated products but also allows efficient late-stage C-H trifluoromethoxylation of marketed small-molecule drugs, common pharmacophores and natural products.

Synthesis and antioxidant evaluation of desmethylxanthohumol analogs and their dimers.

Four ring-closed analogs of natural prenylated chalcone desmethylxanthohumol (1) and their dimers were synthesized from the commercially available 1-(2,4,6-trihydroxyphenyl)ethan-1-one in five and six linear steps, respectively. The structures of the eight new derivatives were confirmed using1H NMR, 13C NMR and HRMS. The antioxidant activity of the new chalcone derivatives were evaluated in a PC12 cell model of H2O2-induced oxidative damage. The SAR studies suggested that the catechol motif was essential for the antioxidant activity. Moreover, the dimers showed better antioxidant activity than their corresponding monomers did. Among them, compound 14d was the most potent and increased PC12 cell viability from 25% to 85%. Flow cytometric analysis showed that compound 14d, the most potent compound, decreased the apoptotic PC12 cell percentage and significantly reduced the LDH release and 8-OHdG generation but increased the GSH levels in H2O2-treated PC12 cells. Furthermore, compound 14d had a higher FRAP value than that of gallic acid. It also reduced the stable ABTS+ free radical with a lower EC50 than that of gallic acid.

Time-bandwidth problem in room temperature slow light.

For many applications of slow or stopped light, the delay-time-bandwidth product is a fundamental issue. So far, however, slow-light demonstrations do not show a large delay-time-bandwidth product, especially in room temperature solids. Here we demonstrate that the use of artificial inhomogeneous broadening has the potential to solve this problem. A proof-of-principle experiment is done using slow light produced by two-beam coupling in a photorefractive crystal Ce:BaTiO3 where Bragg selection is used to provide the artificial inhomogeneity. Examples of how to generalize this concept for use with other room temperature slow-light solids are also given.

Implementation of optical associative memory by a computer-generated hologram with a novel thresholding scheme.

An associative memory based on a model by Rizvi and Zubairy [Appl. Opt. 33, 3642 (1994)] is experimentally demonstrated. The parallel optical interconnection is realized compactly by computer-generated holograms. A novel scheme of real-time thresholding is proposed and is proved to be effective and simple to implement. Stored images are successfully retrieved with both complete and partial inputs.