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Pathological angiogenesis of liver sinusoidal endothelial cells (LSEC) plays a crucial role in the progression of metabolic dysfunction-associated steatohepatitis (MASH)-induced liver fibrosis. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have shown promising therapeutic potential against MASH. This study aimed to investigate the impact of MSC-sEV on LSEC angiogenesis and elucidate the underlying molecular mechanisms. The effects of MSC-sEV on LSEC angiogenesis were evaluated in Tumor Necrosis Factor- alpha (TNF-α)-treated LSECs in vitro and in Methionine and Choline Deficient Diet (MCD)-induced MASH mice in vivo. Herein, we found that MSC-sEV effectively suppressed LSEC angiogenesis by targeting the angiogenesis marker Angiogenin 2 (Ang-2) in both TNF-α-treated LSECs and MASH mice. Gene manipulation experiments revealed that the primary mechanism by which MSC-sEV inhibited LSEC angiogenesis was through the modulation of nuclear factor kappa B inhibitor alpha (IκBα) / nuclear factor kappa B (NF-κB) / Ang-2 pathway. Additionally, mass spectrometry and co-immunoprecipitation (Co-IP) data suggested that MSC-sEV delivered the ubiquitin specific peptidase 9 X-linked (USP9X) protein to LSECs, leading to enhanced IκBα deubiquitination and NF-κB in activation, ultimately resulting in the inhibition of Ang-2-mediated LSEC angiogenesis. Knockdown of USP9X attenuated the regulatory effects of MSC-sEV on Ang-2 expression, LSEC angiogenesis, and the progression of MASH. In conclusion, our findings indicate that USP9X delivered via MSC-sEV can suppress LSEC angiogenesis and alleviate MASH-induced liver fibrosis through the IκBα/NF-κB/Ang-2 signaling pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Extracellular vesicles (EVs) are vesicle-like bodies with a double membrane structure that are released from the cell membrane or secreted by cells into the extracellular environment. These include exosomes, microvesicles, and apoptotic bodies. There is growing evidence indicating that the composition of liver cell contents changes following injury. The quantity of EVs and the biologically active substances they carry vary depending on the condition of the liver cells. Hepatocytes utilize EVs to modulate the functions of different liver cells and transfer them to distant organs via the systemic circulation, thereby playing a crucial role in intercellular communication. This review provides a concise overview of the research on the effects and potential mechanisms of hepatocyte-derived EVs (Hep-EVs) on liver diseases and extrahepatic diseases under different physiological and pathological conditions. Common liver diseases discussed include non-alcoholic fatty liver disease (NAFLD), viral hepatitis, alcoholic liver disease, drug-induced liver damage, and liver cancer. Given that NAFLD is the most prevalent chronic liver disease globally, this review particularly highlights the use of hepatocyte-derived EVs in NAFLD for disease progression, diagnosis, and treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: To discuss whether decreasing the pressure of endotracheal tube cuff slowly with a constant speed can decrease the incidence of coughing during extubation., Methods: Ninety patients undergoing elective noncardiac surgery under general anesthesia with endotracheal intubation were randomly divided into two groups: group P, the pilot balloon was connected to a syringe and an aneroid manometer through a three-way stopcock, respectively, and the decrease of cuff pressure was controlled at 3 cmH 2 O/s during deflating before extubation; group C, the pressure in endotracheal tube cuff was decreased suddenly with a syringe extracting the air from the cuff rapidly at once exactly before extubation. The incidence of coughing during extubation period was recorded. Mean arterial pressure (MAP) and heart rate (HR) were recorded before general anesthesia induction (T0), just before cuff deflation (T1), immediately after deflation (T2), at 1 min (T3), 3 min (T4), and 5 min after extubation (T5). The occurrence of adverse reactions was also recorded., Results: The initiation of coughing during extubation period occurs at immediately the time of balloon deflation. Compared with group C, the incidence of coughing was significantly decreased (P = 0.001), MAP and HR were significantly decreased at T2-T4 and T2-T5, respectively (P < 0.05 for all), and the incidence of pharyngolaryngeal discomfort after extubation was significantly reduced (P = 0.021) in group P., Conclusions: Decreasing the pressure of endotracheal tube cuff slowly with a constant speed can significantly reduce the incidence of coughing during extubating period, stabilize hemodynamics, and reduce the incidence of adverse reactions., (© 2024. The Author(s).)

Efficient cytosolic delivery is a significant hurdle when using short interfering RNA (siRNA) in therapeutic applications. Here we show that cholesterol-rich exosomes are prone to entering cancer cells through membrane fusion, achieving direct cytosolic delivery of siRNA. Molecular dynamics simulations suggest that deformation and increased contact with the target cell membrane facilitate membrane fusion. In vitro we show that cholesterol-enriched milk-derived exosomes (MEs) achieve a significantly higher gene silencing effect of siRNA, inducing superior cancer cell apoptosis compared with the native and cholesterol-depleted MEs, as well as conventional transfection agents. When administered orally or intravenously to mice bearing orthotopic or subcutaneous tumours, the cholesterol-enriched MEs/siRNA exhibit antitumour activity superior to that of lipid nanoparticles. Collectively, by modulating the cholesterol content of exosome membranes to facilitate cell entry via membrane fusion, we provide a promising approach for siRNA-based gene therapy, paving the way for effective, safe and simple gene therapy strategies., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

A one-pot strategy for iron-catalyzed C2,3-H arylphosphorylation of electron-deficient quinoxalines with phosphines and aryl compounds is reported. The proposed method features the use of non-noble metal catalysts, the capacity of utilizing multiple aryl compounds as substrates, the simultaneous formation of C-P and C-C bonds in one pot, the simplicity of its operation, the mildness of the reaction conditions, and its compatibility with a wide range of substrates. Moreover, it offers a practical route for direct access to 2-aryl-3-phosphino N -heteroarenes, a class of potential cyclometalated C^N and N^P bidentate ligands that are difficult to prepare with existing C(sp 2 )-H functionalization methods.

We have disclosed silver(I)-induced switching of regioselectivity in rhodium-catalyzed C-H alkynylation of indole derivatives with the help of a pivaloyl directing group by tuning C-H metalation modes. The judicious choice of AgOAc, Ag 2 O, and Ag 2 CO 3 affords an array of C2-alkynylated indoles, C4-alkynylated indoles, and C2,C4-dialkynylated indoles, respectively. The synthetic utility of the alkyne fragment is demonstrated by derivatization into valuable indole-based compounds.

Surgical resection, the mainstay for melanoma treatment, faces challenges due to high tumor recurrence rates and complex postoperative wound healing. Chronic inflammation from residual disease and the risk of secondary infections impede healing. We introduce an innovative, injectable hydrogel system that integrates a multifaceted therapeutic approach. The hydrogel, crosslinked by calcium ions with sodium alginate, encapsulates a blood clot rich in dendritic cells (DCs) chemoattractants and melanoma cell-derived nanovesicles (NVs), functioning as a potent immunostimulant. This in situ recruitment strategy overcomes the limitations of subcutaneous tumor vaccine injections and more effectively achieves antitumor immunity. Additionally, the hydrogel incorporates Chlorella extracts, enhancing its antimicrobial properties to prevent wound infections and promote healing. One of the key findings of our research is the dual functionality of Chlorella extracts; they not only expedite the healing process of infected wounds but also increase the hydrogel's ability to stimulate an antitumor immune response. Given the patient-specific nature of the blood clot and NVs, our hydrogel system offers customizable solutions for individual postoperative requirements. This personalized approach is highlighted by our study, which demonstrates the synergistic impact of the composite hydrogel on preventing melanoma recurrence and hastening wound healing, potentially transforming postsurgical melanoma management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Regiodivergent transition-metal-catalyzed oxidative C5- and ortho -alkynylation of 2-arylthiazoles have been demonstrated. Namely, Pd(II)-catalysis selectively generated C5-alkynylated products from the reaction of 2-arylthiazoles and terminal alkynes. In contrast, Ru(II)-catalysis exclusively provided ortho -alkynylated products from the same substrates. This protocol features a wide substrate scope, good functional group tolerance, high atom-economy, and exclusive regioselectivity. The alkynylated products can be readily converted into highly valuable synthons, which hold potential for applications in the fields of medicinal chemistry and materials science.

The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum (ER) presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy. In this study, we initially validated celastrol (CEL) as an inducer of immunogenic cell death (ICD) by promoting ER stress and autophagy in colorectal cancer (CRC) cells. Subsequently, an ER-targeted strategy was posited, involving the codelivery of CEL with PD-L1 small interfering RNAs (siRNA) using KDEL peptide-modified exosomes derived from milk (KME), to enhance chemoimmunotherapy outcomes. Our findings demonstrate the efficient transportation of KME to the ER via the Golgi-to-ER pathway. Compared to their non-targeting counterparts, KME exhibited a significant augmentation of the CEL-induced ICD effect. Additionally, it facilitated the release of danger signaling molecules (DAMPs), thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the tumor. Concurrently, the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression, consequently fostering the proliferation and activity of CD8 + T cells. Ultimately, the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors in vivo . Collectively, a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Authors.)

The exploration of remote functionalization of indoles is impeded by the inherently dominant reactivity intrinsic to the pyrrole moiety. Herein, we delineate a novel strategy facilitated by Lewis acid mediation, enabling the remote C-H functionalization, which culminates in the synthesis of an array of selectively functionalized indole derivatives, encompassing 3-trifluoroacetyl and 5-benzoyl motifs, utilizing trifluoroacetic anhydride and various acyl chlorides. Notably, the protocol exhibits versatility, as epitomized by the extension of C5-acylation to alkylation and sulfonation reactions. This methodology is distinguished by its exemplary regio- and chemo-selectivity, extensive substrate scope, commendable tolerance to a diverse array of functional groups, and the employment of comparatively mild reaction conditions.

Two complementary regiodivergent C-H alkynylations of 2-arylthiazoles are reported. When Ru II catalysis is employed, an aryl ortho -alkynylation process is favored. The alkynylated products are gained in good yields. With the use of Pd II catalysis, a thiazole C5-alkynylation process is developed, allowing for the construction of C5-alkynylated products. This strategy not only expands the methods for the functionalization of 2-arylthiazoles, but also provides new opportunities for the rapid assembly of complex molecular structures, which may have great potential in organic synthesis, medicinal chemistry, and materials science.

Foam flooding is an important tool for reservoir development. This study aims to further investigate the interaction between stimulus-responsive wormlike micelle (WLM)-CO 2 foams and crude oil. We performed micromorphology experiments as our major studies and used molecular dynamics simulations as an auxiliary tool for interfacial analysis. We utilized foam generation, liquid separation, and defoaming as the entry points of experimental research and energy as the quantitative assessment index to investigate the dynamic process of the action of different oil contents and oil phase types in a DOAPA@NaSal-H + foam system. We also examined the role of NaSal in the generation and development of the foam system. Results indicated that the law of crude oil's effect on foam could be summarized as "low contents are beneficial and high contents are harmful." In addition, although the DOAPA@NaSal-H + foam system has high compatibility for saturated and aromatic hydrocarbons, it is highly suitable for application in reservoir environments with relatively high asphaltene and resin contents. Through combined experimental and simulation approaches, we clarified the law governing the stability of the DOAPA@NaSal-H + foam system in different oil-containing environments, identified the key role of NaSal, and provided a reference for the targeted application of the DOAPA@NaSal-H + foam system in different oil reservoirs.

Elevated interstitial fluid pressure (IFP) within pathological tissues (e.g., tumors, obstructed kidneys, and cirrhotic livers) creates a significant hindrance to the transport of nanomedicine, ultimately impairing the therapeutic efficiency. Among these tissues, solid tumors present the most challenging scenario. While several strategies through reducing tumor IFP have been devised to enhance nanoparticle delivery, few approaches focus on modulating the intrinsic properties of nanoparticles to effectively counteract IFP during extravasation and penetration, which are precisely the stages obstructed by elevated IFP. Herein, we propose an innovative solution by engineering nanoparticles with a fusiform shape of high curvature, enabling efficient surmounting of IFP barriers during extravasation and penetration within tumor tissues. Through experimental and theoretical analyses, we demonstrate that the elongated nanoparticles with the highest mean curvature outperform spherical and rod-shaped counterparts against elevated IFP, leading to superior intratumoral accumulation and antitumor efficacy. Super-resolution microscopy and molecular dynamics simulations uncover the underlying mechanisms in which the high curvature contributes to diminished drag force in surmounting high-pressure differentials during extravasation. Simultaneously, the facilitated rotational movement augments the hopping frequency during penetration. This study effectively addresses the limitations posed by high-pressure impediments, uncovers the mutual interactions between the physical properties of NPs and their environment, and presents a promising avenue for advancing cancer treatment through nanomedicine., Competing Interests: Competing interests statement:The authors declare no competing interest.

An organoselenium-catalyzed C2,3-diarylation of unprotected N-H indoles with electron-rich aromatics has been developed. This one-pot multicomponent tandem cross-dehydrogenation coupling reaction allows for the incorporation of two different aromatic groups to indoles. More importantly, this approach offers significant advantages, including a high atom and step economy, eliminating the need for prepreparation of the reaction substrates, streamlining the synthetic process and enhancing its practicality. Overall, this organoselenium-catalyzed C2,3-diarylation reaction presents an efficient and versatile strategy for the functionalization of indole derivatives.

We report an innovative synthetic strategy for the generation of polysubstituted indoles from indolines, aryldiazonium salts, and azoles. The methodology encompasses an electrophilic substitution reaction affording C5-indoline intermediates which undergo an iodine-mediated oxidative transformation coupled with C-H functionalization to yield the indole derivatives.

A directing-group-free strategy for oxidative regioselective aminochalcogenation of indolines with amines and dichalconides is presented. This strategy combines tandem coupling sequences and oxidative dehydrogenation methods in a multi-component reaction, enabling the fast construction of a series of C2,3- or C2,5-aminochalcogenated indole derivatives. Moreover, the application of this synthetic approach is demonstrated through the late-stage modification of pharmaceuticals and the derivatization of the products, highlighting its potential and significance.

Lung cancer is the leading cause of cancer death, and its effective treatment is a difficult medical problem. Lung cancer belongs to the traditional Chinese medicine(TCM) disease categories of lung accumulation, lung amassment, and overstrain cough. Rich theoretical basis and practical experience have been accumulated in the TCM treatment of lung cancer. Astragali Radix is one of the representatives of Qi-tonifying drugs. It mainly treat the lung cancer with the syndrome of Qi deficiency and pathogen stagnation, following the principle of reinforcing healthy Qi and eliminating patgogenic Qi. Astragali Radix exerts a variety of pharmacological activities in the treatment of lung cancer, including inhibiting tumor cell proliferation and promoting tumor cell apoptosis, inhibiting tumor invasion and migration, regulating the tumor microenvironment, suppressing tumor angiogenesis, modulating autophagy, inducing macrophage polarization, enhancing immunity, inhibiting immune escape, and reversing cisplatin resistance. The active ingredients of Astragali Radix in treating lung cancer include polysaccharides, saponins, and flavonoids. This study reviewed the pharmacological activities and active ingredients of Astragali Radix in the treatment of lung cancer, providing a basis for the development and utilization of Astragali Radix resources and active ingredients and the research and development of anti-tumor drugs.

A metal-free one-pot oxidative cross-dehydrogenation coupling reaction for the formation of C-N/C-C bonds at the C2,3-positions of indoles with azoles and quinoxalinones has been developed. The proposed method has several notable features, including metal-free catalysis, the use of N-H free indoles as substrates, ease of operation, mild reaction conditions, and compatibility with a wide range of substrates.

Background: The aim of this paper was to explore pupillary monitoring for determining remifentanil consumption during general anesthesia and evaluating postoperative recovery quality., Methods: Eighty patients undergoing elective laparoscopic uterine surgery were randomly divided into pupillary monitoring group (Group P) and control group (Group C). In Group P, remifentanil dosage during general anesthesia was determined according to pupil dilation reflex; in Group C, it was adjusted according to hemodynamic changes. Intraoperative remifentanil consumption and endotracheal tube extraction time were recorded. The Numerical Rating Scale (NRS) Score, hemodynamic changes, and opioid-related adverse reactions in the post-anesthesia care unit were also recorded. The parameters of pupil light reflex from extubation to 30 min after extubation were analyzed in Group P, and the responsiveness of these parameters and hemodynamic changes to NRS was determined by ROC curve analyses., Results: Compared with Group C, in Group P, intraoperative remifentanil consumption, the NRS Score at 20 minutes after extubation, extubation time, and the incidence of nausea, vomiting, and respiratory amnesia were all significantly decreased (all, P<0.05). In Group P, ∆HR and ∆MAP had no value in judging the change of NRS. The ROC values and diagnostic cutoff values of ΔInit, ΔACV, and ΔMCV responding to NRS variation were 0.775 (95% CI: 0.582-0.968), 0.734(95% CI: 0.537-0.930), and 0.822 (95% CI: 0.648-0.997) and 0.21 (sensitivity, 92.3%; specificity, 23.1%), -1.3 (sensitivity, 92.3%; specificity, 18.3%), and -1.0 (sensitivity, 84.6%; specificity, 17.7%), respectively., Conclusions: Intraoperative pupil dilation reflex monitoring can reduce remifentanil consumption and improve postoperative recovery quality. Furthermore, postoperative pupil light reflex monitoring can help evaluate pain degree with high sensitivity.

The clinical utility of gemcitabine, an antimetabolite antineoplastic agent applied in various chemotherapy treatments, is limited due to the required intravenous injection. Although chemical structure modifications of gemcitabine result in enhanced oral bioavailability, these modifications compromise complex synthetic routes and cause unexpected side effects. In this study, gemcitabine-loaded glycocholic acid-modified micelles (Gem-PPG) were prepared for enhanced oral chemotherapy. The in vitro transport pathway experiments revealed that intact Gem-PPG were transported across the intestinal epithelial monolayer via an apical sodium-dependent bile acid transporter (ASBT)-mediated pathway. In mice, the pharmacokinetic analyses demonstrated that the oral bioavailability of Gem-PPG approached 81%, compared to less than 20% for unmodified micelles. In addition, the antitumor activity of oral Gem-PPG (30 mg/kg, BIW) was superior to that of free drug injection (60 mg/kg, BIW) in the xenograft model. Moreover, the assessments of hematology, blood chemistry, and histology all indicated the hypotoxicity profile of the drug-loaded micelles.

Study Objectives: We explored the effects of stellate ganglion block on postoperative sleep disturbance in patients scheduled to undergo radical surgery for gastrointestinal malignancies., Methods: Forty such patients were randomly assigned to the control group (Group C) or the preoperative stellate ganglion block treatment group (Group S). Using actigraphy, sleep quality was evaluated on the first night before the operation and first, second, and third postoperative nights. The Pittsburgh Sleep Quality Index scale was used for sleep state assessment on 1 day preoperatively and the first, second, third, fifth, and seventh days postoperatively. Plasma interleukin (IL)-1, IL-6, and IL-10 and melatonin levels were checked at 1 day preoperatively and the first and third days postoperatively. Mean arterial pressure, heart rate, and pulse oxygen saturation (SpO 2 ) were recorded before general anesthesia induction, immediately after tracheal intubation, at the beginning of the operation, 1 and 2 hours after the beginning of the operation, at the end of the operation, immediately after extubation, and 30 minutes after transfer to the postanesthesia care unit., Results: Compared with Group C, in Group S sleep efficiency, total sleep time, and sleep maintenance were increased and sleep period change index, number of awakenings, wake after sleep onset, and body movements were reduced on the first and second postoperative nights; Pittsburgh Sleep Quality Index scores and occurrence of postoperative sleep disturbance were lower on the first and second nights postoperatively; IL-6 was reduced on the first night postoperatively; IL-1 and IL-10 were reduced on the third night postoperatively; melatonin was increased on the first night postoperatively; and mean arterial pressure and heart rate were decreased before general anesthesia induction, immediately after tracheal intubation, and at the end of the operation (all P < .05). Conclusions: Stellate ganglion block alleviates postoperative sleep disturbance by reducing postoperative inflammatory response, increasing melatonin levels, and stabilizing perioperative hemodynamics in patients undergoing radical surgery for gastrointestinal malignancies., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: The Effect of Stellate Ganglion Block on Postoperative Sleep Disturbance and Cognitive Function in Elderly Surgical Patients; URL: https://clinicaltrials.gov/ct2/show/NCT04800653; Identifier: NCT04800653., Citation: Yan S, Wang Y, Yu L, et al. Stellate ganglion block alleviates postoperative sleep disturbance in patients undergoing radical surgery for gastrointestinal malignancies. J Clin Sleep Med . 2023;19(9):1633-1642., (© 2023 American Academy of Sleep Medicine.)

Herein, a ruthenium-mediated remote C-H mono- and disulfonylation of 2-pyridones with arylsulfonyl chlorides is developed. The catalytic system consisting of a [Ru( p -cymene)Cl 2 ] 2 catalyst and KOAc additive allows 2-pyridones to undergo C3,C5-disulfonylation in 1,4-dioxane, and C5-sulfonylation when the C3-position of 2-pyridones is blocked. The successful transformation of the products and late-stage modification of estrone further highlighted the potential utility and significance of this synthetic protocol. Preliminary mechanistic studies indicated that the remote regioselectivity might be dictated via chelation-assisted ruthenation.

A novel and effective Rh III - and Pd II -controlled switchable C-H alkenylation of 2-pyridylthiophenes with alkenes is realized. The alkenylation reactions proceeded smoothly in a highly regio- and stereo-selective manner to afford a broad range of C3- and C5-alkenylated products. Depending on the catalyst employed, the reactions involve two typical approaches: C3-alkenylation via chelation-assisted rhodation and C5-alkenylation via electrophilic palladation. This regiodivergent synthetic protocol was successfully applied for the straightforward building of π-conjugated difunctionalized 2-pyridylthiophenes, which may show great potential in organic electronic materials.

Introduction: Rocuronium intravenous pain is common in induction of general anesthesia. The aim of our study was to determine the median effective dose (ED 50 ) of prophylactic intravenous remifentanil for the prevention of rocuronium injection pain and to explore the effect of age on the ED 50 ., Methods: Eighty-nine adult patients undergoing elective general anesthesia, ASA I or II, regardless of gender or weight, were stratified according to age: group R1 18-44 years, group R2 45-59 years, and group R3 60-80 years. The initial dose of prophylactic remifentanil before rocuronium injection was set at 1 μg/kg lean body weight (LBW). The remifentanil doses were adjusted according to the degree of injection pain using the Dixon sequential method, with a ratio of 1.1 between adjacent doses. Injection pain was graded, and the occurrence of injection pain and adverse reactions were recorded. The ED 50 and 95% confidence intervals (CIs) of remifentanil were calculated using the Dixon-Massey formula. Patients were asked whether they recalled feeling any injection pain in the post-anesthesia care unit (PACU)., Results: The ED 50 (95% CIs) of prophylactic remifentanil for the prevention of rocuronium injection pain were 1.266 μg/kg (1.186-1.351 μg/kg), 1.188 μg/kg (1.065-1.324 μg/kg), and 1.070 μg/kg (1.014-1.129 μg/kg) LBW in group R1, group R2, and group R3, respectively. No adverse reactions to remifentanil occurred in any group. In PACU, 84.6, 86.7, and 85.7% of patients who experienced injection pain had memories of the pain in group R1, group R2, and group R3, respectively., Conclusions: Prophylactic intravenous remifentanil can prevent rocuronium injection pain, and its ED 50 decreases with age, with 1.266 μg/kg (18-44 years), 1.188 μg/kg (45-59 years), and 1.070 μg/kg LBW (60-80 years), respectively., Trial Registration: ClinicalTrials.gov: NCT05217238 (registration date 18 Dec 2021)., (© 2023. The Author(s).)

With over 300 million severe cases and 1.5 million deaths annually, invasive fungal diseases (IFDs) are a major medical burden and source of global morbidity and mortality. The World Health Organization (WHO) recently released the first-ever fungal priority pathogens list including 19 fungal pathogens, considering the perceived public health importance. Most of the pathogenic fungi are opportunistic and cause diseases in patients under immunocompromised conditions such as HIV infection, cancer, chemotherapy, transplantation, and immune suppressive drug therapy. Worryingly, the morbidity and mortality caused by IFDs are continuously on the rise due to the limited available antifungal therapies, the emergence of drug resistance, and the increase of population that is vulnerable to IFDs. Moreover, the COVID-19 pandemic worsened IFDs as a globe health threat as it predisposes the patients to secondary life-threatening fungi. In this mini-review, we provide a perspective on the advances and strategies for combating IFDs with antifungal therapies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Xanthoceras sorbifolium Bunge leaves (XLs) are valuable resources rich in phytochemicals, especially in flavonoids, but they are rarely exploited and utilized., Objective: The purpose of this paper is to reduce the waste of XLs resources (usually used as agricultural waste) and extract the high added value of active ingredients from XLs., Methods: The extraction of flavonoids from XLs using ultrasonic-assisted extraction (UAE) was reported. Response surface methodology (RSM) was used to adopt different ultrasonic conditions such as ethanol concentration, liquid:solid ratio, and ultrasonic power. In addition, the chemical structures were identified using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and HPLC., Results: Response surface analysis indicated the optimal level of ethanol concentration, liquid:solid ratio, and ultrasonic power as 71.49%, 13.87 mL/g, and 157.49 W respectively for the maximum response of total flavonoids (5.52 ± 0.23%), which fitted well with the predicted value (5.68 ± 0.17%). In addition, the extracts from XLs exhibited potent antioxidant activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) ammonium salt (ABTS)., Conclusion: The potent antioxidant activity of flavonoids from XLs is beneficial for their application in the food and drug industry, which will facilitate the rise of the added value of the flavonoids from XLs., Highlights: Myricetin, rutin, and epicatechin, which may be responsible for the antioxidant activity of the extracts from XLs, were confirmed by UPLC-MS/MS and HPLC analysis. The extracted flavonoids can be used as a natural antioxidant additive to food products., (© The Author(s) 2022. Published by Oxford University Press on behalf of AOAC INTERNATIONAL. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

An efficient Pd II - and Rh III -controlled site-selective C-H bond alkynylation of imidazopyridines using (bromoethynyl)triisopropylsilane is disclosed. The divergent methodology allows straightforward access to a wide range of products alkynylated at the C3 and ortho positions. This strategy is suggestive of a practical platform that can be suitable for late-stage diversification and may assist in the design of more selective and complementary catalytic systems.

Objective: The aim of this study was to test the hypothesis whether serum level of calpains could become a meaningful biomarker for diagnosis of acute lung injury (ALI) in clinical after cardiac surgery using cardiopulmonary bypass (CPB) technology., Methods and Results: Seventy consecutive adults underwent cardiac surgery with CPB were included in this prospective study. Based on the American-European Consensus Criteria (AECC), these patients were divided into ALI ( n = 20, 28.57%) and non-ALI ( n = 50, 71.43%) groups. Serum level of calpains in terms of calpains' activity which was expressed as relative fluorescence unit (RFU) per microliter and measured at beginning of CPB (baseline), 1 h during CPB, end of CPB as well as 1, 12, and 24 h after CPB. Difference of serum level of calpains between two groups first appeared at the end of CPB and remained different at subsequent test points. Univariate and multivariate logistic regression analysis indicated that serum level of calpains 1 h after CPB was an independent predictor for postoperative ALI (OR 1.011, 95% CI 1.001, 1.021, p = 0.033) and correlated with a lower PaO 2 /FiO 2 ratio in the first 2 days (The first day: r = -0.389, p < 0.001 and the second day: r = -0.320, p = 0.007) as well as longer mechanical ventilation time (r = 0.440, p < 0.001), intensive care unit (ICU) length of stay (LOS) (r = 0.419, p < 0.001) and hospital LOS (r = 0.297, p = 0.013)., Conclusion: Elevated serum level of calpains correlate with impaired lung function and poor clinical outcomes, indicating serum level of calpains could act as a potential biomarker for postoperative ALI following CPB in adults., Clinical Trial Registration: [https://clinicaltrials.gov/show/NCT05610475], identifier [NCT05610475]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yi, Chen, Ma, Fu, Song, Zhang, Chen, Tang, Lu, Li, Zhang, Song, Zhu, Wang, Wang and Wang.)

The Fine-Gray proportional sub-distribution hazards (PSH) model is among the most popular regression model for competing risks time-to-event data. This article develops a fast safe feature elimination method, named PSH-SAFE, for fitting the penalized Fine-Gray PSH model with a Lasso (or adaptive Lasso) penalty. Our PSH-SAFE procedure is straightforward to implement, fast, and scales well to ultrahigh dimensional data. We also show that as a feature screening procedure, PSH-SAFE is safe in a sense that the eliminated features are guaranteed to be inactive features in the original Lasso (or adaptive Lasso) estimator for the penalized PSH model. We evaluate the performance of the PSH-SAFE procedure in terms of computational efficiency, screening efficiency and safety, run-time, and prediction accuracy on multiple simulated datasets and a real bladder cancer data. Our empirical results show that the PSH-SAFE procedure possesses desirable screening efficiency and safety properties and can offer substantially improved computational efficiency as well as similar or better prediction performance in comparison to their baseline competitors., (© 2022 John Wiley & Sons Ltd.)

We report an Rh(I)-catalyzed C-H bond alkylation of PhenCarPhos [ N -(2-(diphenylphosphaneyl)phenyl)carbazole] and some congener phosphine ligands with alkenes. The C-H bond functionalization occurred exclusively at the C1 position of the carbazolyl unit because the trivalent phosphine acts as a directing group. This protocol provides straightforward access to a large library of C1-alkyl substituted PhenCarPhos, which outperformed common commercial or unfunctionalized phosphines and their precursors in the Pd-catalyzed carbon dioxide-fixation reactions with propargylic amines.

An efficient copper-iodine cocatalyzed intermolecular C-H aminocyanation of indoles with a broad substrate scope has been developed for the first time. This method enables highly step-economic access to 2-amino-3-cyanoindoles in moderate to good yields and provides a complementary strategy for the regioselective difunctionalization of carbon═carbon double bonds of interest in organic synthesis and related areas. Mechanistic studies suggest that these transformations are initiated by iodine-mediated C2-H amination with azoles, followed by copper-catalyzed C3-H cyanation with ethyl cyanoformate.

Adjuvants can regulate the immune response triggered by vaccines. Traditional aluminum adjuvants can induce humoral immunity, but they lack the ability to effectively induce Th1 cellular immunity, which is not conducive to the development of vaccines with improved protective effects. Aluminum adjuvants from different sources may have different physicochemical properties, and therefore, completely different immune responses can be triggered. This suggests that adjuvant recognition by the immune system and its responses are closely associated with the physicochemical properties of the adjuvant itself. To test this hypothesis, in this study, we developed a new method for preparing an aluminum adjuvant. This aluminum adjuvant has a pseudoboehmite structure, strong protein adsorption capacity, and excellent suspension stability. The adjuvant was tested using the hepatitis B virus surface antigen (HBsAg) as a model antigen for immunization; the results showed that this aluminum adjuvant effectively induced not only humoral immunity but also an outstanding cellular immune response. These results provide a reference for improving the efficacy of adjuvants., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Background: Dexmedetomidine has controversial influence on cardiac electrophysiology. The aim of this study was to explore the effects of dexmedetomidine on perioperative cardiac electrophysiology in patients undergoing general anesthesia., Methods: Eighty-one patients were randomly divided into four groups: groups D 1 , D 2 , D 3 receiving dexmedetomidine 1, 1, 0.5 μg/kg over 10 min and 1, 0.5, 0.5 μg/kg/h continuous infusion respectively, and control group (group C) receiving normal saline. Twelve-lead electrocardiograms were recorded at the time before dexmedetomidine/normal saline infusion (T 1 ), loading dose finish (T 2 ), surgery ending (T 6 ), 1 h (T 7 ) after entering PACU, 24 h (T 8 ), 48 h (T 9 ), 72 h (T 10 ) and 1 month (T 11 ) postoperatively. Cardiac circulation efficiency (CCE) were also recorded., Results: Compared with group C, QTc were significantly increased at T 2 in groups D 1 and D 2 while decreased at T 7 and T 8 in group D 3 (P < 0.05), iCEB were decreased at T 8 (P < 0.05). Compared with group D 1 , QTc at T 2 , T 6 , T 7 , T 9 and T 10 and iCEB at T 8 were decreased, and CCE at T 2 -T 4 were increased in group D 3 significantly (P < 0.05). Compared with group D 2 , QTc at T 2 and iCEB at T 8 were decreased and CCE at T 2 and T 3 were increased in group D 3 significantly (P < 0.05)., Conclusions: Dexmedetomidine at a loading dose of 0.5 μg/kg and a maintenance dose of 0.5 μg/kg/h can maintain stability of cardiac electrophysiology during perioperative period and has no significant adverse effects on CCE., Trial Registration: ClinicalTrials.gov NCT04577430 (Date of registration: 06/10/2020)., (© 2022. The Author(s).)

Recombinant protein vaccines, with highly pure ingredients and good safety, are gradually replacing some attenuated and inactivated vaccines in clinical practice. However, since their low immunogenicity of the recombinant proteins, adjuvants are often needed to enhance immune response after vaccination. Aluminum adjuvant has been widely used in some vaccines for decades, it can induce strong humoral immunity, but the deficiency of cellular immunity limits its application for some vaccines. Therefore, it is urgently needed to develop novel adjuvant to increase not only humoral but also cellular immune response. To address this, we designed and prepared a new nano adjuvant (PF3) through microfluidization by the combination of saponin (Ginsenoside Rg1) and oil-in-water nano emulsion (NE) in the present study. As compared to aluminum adjuvant, PF3 had stronger humoral and cellular immune induction effect because of high cellular uptake and activization of immune response pathways. Furthermore, PF3 showed better immune enhancement and acceptable biosafety equivalent to that of aluminum adjuvant. In addition, no obvious changes of PF3 were observed in size and zeta potential after 12 weeks storage at 4 and 37°C, demonstrating its high stability in vitro . This study provided an adjuvant platform to replace traditional aluminum adjuvant in design of recombinant vaccines., Competing Interests: Author YW was employed by Beijing Institute of Biological Products Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shan, Wang, Li, Wei, Zhang, Hao, Hou, Wang, Li, Wang and Xu.)

Background: The aim of this study was to explore the effects of dexmedetomidine on glucose-related hormones and lactate levels in non-diabetic patients undergoing malignant gastrointestinal tumor radical resection., Methods: Groups D1 and D2 received dexmedetomidine loading dose 1 µg/kg and maintenance dose 0.25 and 0.5 µg/kg/h, respectively. Group C received saline solution. Glucose, lactate, insulin, glucagon, cortisol, epinephrine, norepinephrine and dopamine levels were measured before dexmedetomidine infusion (T1), 1 h after surgery beginning (T2), at surgery ending (T3), and 1 h after transfer to the postanesthesia care unit (T4)., Results: Compared with group C, glucose levels increased in group D2 at T2 and reduced in groups D1 and D2 at T4. Lactate levels reduced in groups D1 and D2 at T4. A positive correlation between glucose and lactate levels was found in all groups. Compared with group C, insulin level reduced in group D2 at T2; glucagon levels reduced in groups D1 and D2 at T4; cortisol levels reduced in group D1 at T4 and in group D2 at T3 and T4; epinephrine and norepinephrine levels reduced in group D1 at T4 and in group D2 at T2 and T4; and dopamine level reduced in group D2 at T4., Conclusions: Dexmedetomidine loading dose 1 µg/kg and maintenance dose 0.25 µg/kg/h produces a stable insulin level and significant postoperative decreases in glucagon, cortisol, epinephrine and norepinephrine secretion with stable maintenance of intraoperative and postoperative blood glucose levels and decreased postoperative lactate levels in non-diabetic patients under general anesthesia.

A copper-mediated 2,3-difunctionalization of indoles to afford 3-halogenated 2,3'-biindoles is described herein. The protocol uses readily available feedstocks and a naturally abundant copper catalyst system, which allows the regioselective formation of C-C and C-X (X = Cl & Br) bonds in one single operation. Here the copper metal salt serves not only as a catalyst but also as a reactant to provide the source of halogen. This operationally simple procedure avoids the utilization of environmentally unfriendly reagents and displays good functional group compatibility. Noteworthily, the introduction of halogen into molecules would offer great potential for further chemical transformations.

Purpose: To determine the effects of peak inspiratory pressure (PIP)-guided intracuff pressure (ICP) modulation of laryngeal mask airway (LMA) Supreme™ during laparoscopic cholecystectomy., Methods: Totally 120 patients were randomly divided using computer-generated numbers into a control group (n = 60; ICP, 60 cmH 2 O) and a PIP group (n = 60), in which ICP was increased with 5 cmH 2 O each time from PIP level until no air leaks from the oropharynx. PIP, ICP, cuff volume (CV), oropharyngeal leak pressure (OLP) and leak fraction (LF) were recorded before and after pneumoperitoneum establishment. Postoperative pharyngolaryngeal complications (sore throat, dysphagia, pharyngeal hematoma, and dysphonia) were also recorded., Results: Demographic data were similar in the two groups. The CV and ICP before and after pneumoperitoneum were significantly lower in the PIP group (CV: 15.6 ± 2.3 mL and 21.0 ± 2.6 mL; ICP: 14.3 ± 2.9 cmH 2 O and 20.5 ± 3.4 cmH 2 O) than in the control group (CV: 33.0 ± 2.8 mL and 32.8 ± 1.9 mL; ICP: 60.0 ± 0.1 cmH 2 O and 60.0 ± 0.1 cmH 2 O) ( P  < 0.05). Although OLP was lower in the PIP group ( P  < 0.05), the LF was similar in the two groups ( P  > 0.05). There were fewer postoperative pharyngolaryngeal complications in the PIP group ( P  < 0.05)., Conclusions: Compared with a fixed ICP of 60 cmH 2 O, PIP-guided ICP modulation during LMA Supreme™ use provided effective airway sealing at a lower CV and ICP, and produced fewer postoperative pharyngolaryngeal complications in patients undergoing laparoscopic cholecystectomy.

More than 60% of pharmaceuticals are related to natural products (NPs), chemicals produced by living organisms. Despite this, the rate of NP discovery has slowed over the past few decades. In many cases the rate-limiting step in NP discovery is structural characterization. Here we report the use of microcrystal electron diffraction (MicroED), an emerging cryogenic electron microscopy (CryoEM) method, in combination with genome mining to accelerate NP discovery and structural elucidation. As proof of principle we rapidly determine the structure of a new 2-pyridone NP, Py-469, and revise the structure of fischerin, an NP isolated more than 25 years ago, with potent cytotoxicity but hitherto ambiguous structural assignment. This study serves as a powerful demonstration of the synergy of MicroED and synthetic biology in NP discovery, technologies that when taken together will ultimately accelerate the rate at which new drugs are discovered., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: To evaluate the optimal dose of dexmedetomidine for perioperative blood glucose regulation in non-diabetic patients with gastrointestinal malignant tumor., Methods: One hundred patients were randomly divided into four groups: control group (group C), dexmedetomidine 1 μg/kg + 0.25 mcg/kg/h (group D 1 ); + 0.5 mcg/kg/h (group D 2 ); and + 1 mcg/kg/h (group D 3 ). Blood glucose concentrations were measured before dexmedetomidine infusion (T 1 ), 1 h after surgery beginning (T 2 ), at the end of surgery (T 3 ), and 1 h in PACU (T 4 ). Duration of surgery, extubation time, anesthetics doses, adverse reactions, postoperative pulmonary infection, total peritoneal drainage 2 days after surgery and hospital stay were recorded., Results: Compared with T 1 , blood glucose concentrations were higher at T 4 in group C and at T 2-4 in groups D 1 , D 2 , and D 3 ( p  < 0.01). Compared with group C, blood glucose concentrations were higher at T 2 and T 3 in groups D 2 and D 3 ( p  < 0.05), but significantly lower at T 4 in groups D 1 , D 2 , and D 3 ( p  < 0.01). Propofol and remifentanil consumption in groups D 1 , D 2 , and D 3 decreased significantly compared with group C ( p  < 0.01). In group D 3 , doses of ephedrine ( p  < 0.05) and atropine ( p  < 0.01) were higher, and extubation time was prolonged ( p  < 0.01) compared with the other groups. The incidence of bradycardia was higher in group D 3 than that in group C ( p  < 0.05)., Conclusions: Dexmedetomidine loading dose of 1 mcg/kg followed by maintenance with 0.25 mcg/kg/h can regulate perioperative blood glucose well in non-diabetic patients undergoing gastrointestinal malignant tumor resection and reduce doses of anesthetics without extending extubation time.

Acetohydroxyacid synthase (AHAS) is the first enzyme in the branched-chain amino acid biosynthetic pathway and is a validated target for herbicide and fungicide development. Here we report harzianic acid (HA, 1 ) produced by the biocontrol fungus Trichoderma afroharzianum t-22 (Tht22) as a natural product inhibitor of AHAS. The biosynthetic pathway of HA was elucidated with heterologous reconstitution. Guided by a putative self-resistance enzyme in the genome, HA was biochemically demonstrated to be a selective inhibitor of fungal AHAS, including those from phytopathogenic fungi. In addition, HA can inhibit a common resistant variant of AHAS in which the active site proline is mutated. Structural analysis of AHAS complexed with HA revealed the molecular basis of competitive inhibition, which differs from all known commercial AHAS inhibitors. The alternative binding mode also rationalizes the selectivity of HA, as well as effectiveness toward resistant mutants. A proposed role of HA biosynthesis by Tht22 in the rhizosphere is discussed based on the data.

Objective: To determine the median effective dose (ED50) of prophylactic intravenous lidocaine for the prevention of propofol medium-chain triglyceride/long-chain triglyceride (MCT/LCT) emulsion injection pain., Design: Prospective trial, Dixon up-and-down sequential method., Setting: Operating room of a single hospital., Patients: Thirty patients aged 18-65 years with American Society of Anesthesiologists (ASA) status I or II who were scheduled for elective surgery under general anesthesia (GA) were included., Interventions: The initial dose of prophylactic lidocaine before propofol MCT/LCT emulsion injection was set at 0.5 mg/kg lean body weight (LBW). The lidocaine dose was adjusted according to the degree of patients' injection pain using the Dixon up-and-down sequential method., Measurements: The ED50 and 95% confidence intervals (CIs) of lidocaine were calculated using the Dixon-Massey formula. Vital signs and adverse effects were recorded. In the postanesthesia care unit (PACU), patients were asked if they recalled feeling any injection pain with visual analog scale (VAS) evaluation., Results: The ED50 of lidocaine for the prevention of propofol MCT/LCT emulsion injection pain was 0.306 mg/kg LBW (95% CI, 0.262-0.357 mg/kg LBW). No adverse reactions to lidocaine occurred. In the PACU, 90.9% of patients who experienced injection pain recalled this pain (VAS score, 2.8±1.8)., Conclusions: Prophylactic intravenous lidocaine (0.306 mg/kg LBW) effectively prevented propofol MCT/LCT emulsion injection pain in 50% of patients scheduled for elective surgery under GA with no adverse reaction occurring., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sterile filtration is an effective method to remove any microorganisms present during nanoemulsion preparation. However, it lacks effective control parameters. Here, we established a simple and rapid approach for the process control of nanoemulsion sterile filtration by utilizing optical density detection as a process control parameter. During sterile filtration, the optical density or optical density ratio of the filtrate were continuously monitored to explore the correlation between optical density and the emulsion content and the change in the optical density ratio before and after sterile filtration. In the emulsion stability test, the optical density ratio was determined. A good correlation was obtained between the optical density and the nanoemulsion content during sterile filtration, thereby reducing sterile filtration loss. The optical density ratio changed significantly after sterile filtration, indicating that it could be used as a process control parameter to monitor leakage during emulsion sterile filtration. The optical density ratio can be a characterization index for stability monitoring as it is more sensitive than particle size detection and more convenient than large particle detection. These parameters may be used for sterile filtration process control and as an index for nanoemulsion characterization. This approach overcomes the limitations of existing nanoemulsion characterization methods., (Copyright © 2021. Published by Elsevier Inc.)

We report characterization of the biosynthetic pathway of the potent immunosuppressant (-)-FR901483 ( 1 ) through heterologous expression and enzymatic assays. The biosynthetic logic to form the azatricyclic alkaloid is consistent with those proposed in biomimetic syntheses and involves aza-spiro annulation of dityrosyl-piperazine to form a ketoaldehyde intermediate, followed by regioselective aldol condensation, stereoselective ketoreduction, and phosphorylation. A possible target of 1 is proposed based on the biosynthetic studies.

Phenylfuropyridone natural products from fungi exhibit a range of antibacterial and cytotoxicity activities, and can potentiate azole antifungal compounds. We elucidated the biosynthetic pathway of compounds in the citridone family through heterologous reconstitution of the pfp pathway. We demonstrate that multiple members of this family can be accessed from a reactive ortho-quinone methide (o-QM) intermediate through electrocyclization, cycloisomerization, or conjugate addition. Formation of the quaternary carbon center in citridone B is catalyzed by an epoxide-forming P450 enzyme, followed by carbon skeletal rearrangement. Our results showcase how nature harvests the reactivities of an o-QM intermediate to biosynthesize complex natural products., (© 2020 Wiley-VCH GmbH.)

We report herein P(III)-directed C-H bond alkenylation of (dialkyl)- and (diaryl)biarylphosphines using internal alkynes. Chloride-free [Rh(OAc)(COD)] 2 acts as a better catalyst than commercially available [RhCl(COD)] 2 . Conditions were developed to control the mono- and difunctionalization depending on the alkyne stoichiometry. One of these novel bisalkenylated (dialkyl)biarylphosphines was employed for the preparation of a palladium(II) complex, and some of these functionalized ligands outperformed their corresponding unfunctionalized phosphines in Pd-catalyzed amidation with sterically hindered aryl chlorides.

From February 2018 to January 2019, a field experiment of simulated nitrogen (N) depo-sition was conducted in Pinus armandii and Pinus yunnanensis plantations in the subalpine region of central Yunnan, China. The litterbag method was used for in situ litter (leaf and twig) decomposition experiment in both plantations. Four levels of N addition were applied, i.e ., control (CK, 0 g N·m -2 ·a -1 ), low nitrogen (LN, 5 g N·m -2 ·a -1 ), medium nitrogen (MN, 15 g N·m -2 ·a -1 ), and high nitrogen (HN, 30 g N·m -2 ·a -1 ). The results showed that the annual decomposition rates of leaf and twig in P. armandii were 34.8% and 18.0%, which were higher than the 32.2% (leaf) and 16.1% (twig) in P. yunnanensis. Under N deposition, the LN treatment reduced the time of 95% mass loss of leaf and twig litter in P. armandii by 0.202 and 1.624 years, the MN treatment reduced by 0.045 and 1.437 years, and the HN treatment increased by 0.840 and 2.112 years, respectively. In the P. yunnanensis plantation, the LN treatment reduced the time of 95% mass loss of leaf and twig litter by 0.766 and 4.053 years, while the MN treatment increased by 0.366 and 0.455 years, and the HN treatment increased by 0.826 and 0.906 years, respectively. Litter (leaf and twig) decomposition of both P. armandii and P. yunnanensis were promoted by low N treatment and inhibited by high N treatment. The effects of N deposition on litter decomposition of two plantations were significantly correlated with the contents of cellulose and lignin in litter. In conclusion, the responses of litter decomposition to N deposition mainly depended on the litter substrate, especially cellulose and lignin contents.

Biosynthetic pathways containing multiple core enzymes have potential to produce structurally complex natural products. Here we mined a fungal gene cluster that contains two predicted terpene cyclases (TCs) and a nonribosomal peptide synthetase (NRPS). We showed the flv pathway produces flavunoidine 1 , an alkaloidal terpenoid. The core of 1 is a tetracyclic, cage-like, and oxygenated sesquiterpene that is connected to dimethylcadaverine via a C-N bond and is acylated with 5,5-dimethyl-l-pipecolate. The roles of all flv enzymes are established on the basis of metabolite analysis from heterologous expression.

A four-enzyme catalyzed hydroxy regioisomerization of anthracycline was integrated into the biosynthetic pathway of aclacinomycin A (ALM-A), to generate a series of iso-ALMs via directed combinatorial biosynthesis combined with precursor-directed mutasynthesis. Most of the newly acquired iso-ALMs exhibit obviously (1-5-fold) improved antitumor activity. Therefore, we not only developed iso-ALMs with potential as clinical drugs but also demonstrated the utility of this tailoring tool for modification of anthracycline antibiotics in drug discovery and development.

We report the C-H alkylation of biarylphosphines at the ortho' position(s) with alkenes by using rhodium(I) catalysis, which provides straightforward access to a large library of multifunctionalized phosphines. Some of these modified ligands outperformed commercially available phosphines in the Pd-catalyzed carboxylation of aryl bromides with carbon dioxide in the presence of a photoredox catalyst., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)