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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).)

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.

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.)

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.

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.

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.)

Background: To investigate the optimal dose of pretreated-dexmedetomidine in fentanyl-induced cough (FIC) suppression., Methods: Patients of 180 undergoing elective surgery with general anesthesia, aged 18-65 years, BMI 18.5-30 kg/m 2 , ASA I or II, were equally randomized into four groups (n = 45) to receive intravenous pretreatment of dexmedetomidine with 0 (group 1), 0.3 (group 2), 0.6 (group 3) and 0.9 (group 4) mcg/kg over 10 mins, respectively. After the pretreatment, all patients were given a 5-s intravenous injection of fentanyl 4 mcg/kg. The symptoms of irritating cough including the severity and onset time were recorded for 1 min after fentanyl injection. General anesthesia induction was completed with midazolam, propofol and cisatracurium, then endotracheal tube or laryngeal mask was inserted and connected to an anesthesia machine. MAP, HR and SpO 2 at the beginning of pretreatment (T0), 3 min (T1), 6 min (T2), 9 min (T3) and 12 min (T4) after the beginning of pretreatment were recorded. Side effects of dexmedetomidine, such as bradycardia, hypertension, hypotension, and respiratory depression were also recorded during the course., Results: Totally 168 patients completed the study. The incidences of cough were 52.4, 42.9, 11.9, and 14.3% in groups 1, 2, 3, and 4, respectively, with no significant differences between groups 1 and 2 (P > 0.05) and between groups 3 and 4 (P > 0.05). The incidence and severity of cough in groups 3 and 4 were significantly lower than those in groups 1 and 2 (P < 0.05). Compared to T0, HR at T2 (P < 0.05), T3 (P < 0.01), and T4 (P < 0.01) decreased significantly and MAP at T4 decreased significantly (P < 0.05) in group 4. Bradycardia occurred in 1 case and respiratory depression occurred in 1 case in group 4. Compared to group 1, the onset time of cough in the other 3 groups were delayed significantly (P < 0.05)., Conclusion: Pretreated dexmedetomidine 0.6 mcg/kg blous intravenous infusion over 10 mins could reduce FIC effectively without side effects., Trial Registration: This study was registered in ClinicalTrials.gov (NCT03126422), April 13, 2017.

Ru III incorporated with magnetic nanosized CMC/Fe 3 O 4 hybrid (Ru III @CMC/Fe 3 O 4 ) has readily developed by a very simple self-organized procedure of RuCl 3 and Na-CMC/Fe 3 O 4 organic/inorganic hybrid. The self-organized fresh and recovered catalyst was well characterized by ICP-AES, FTIR, XRD, TGA-DSC-DTG, SEM-EDS-mapping, TEM, and XPS techniques. The elemental maps confirmed that the Ru III species are well dispersed in a homogeneous manner on the surface of CMC/Fe 3 O 4 magnetic hybrid nanoparticles. After full characterization, its catalytic activity was investigated in the synthesis of pyranopyrazole and polyhydroquinoline derivatives. Under optimal conditions, all reactions proceeded well and afforded the desired products in excellent yields. There was no significant effect of electron withdrawing or donating nature of substituent on aryl aldehydes in the formation of these target compounds. The salient features of the present new protocol are broad substrate scope, mild reaction conditions, good-to-excellent yields, operational simplicity, energy-efficiency, high atom-economy, easy isolation of products and no column chromatographic separation. Moreover, Ru III @CMC/Fe 3 O 4 can be easily recovered by using a magnetic field and directly reused for several cycles without significant loss of its activity. The recovered catalyst was confirmed by TEM, XPS, XRD, and SEM-EDS analyses. One-pot multicomponent reactions for green synthesis of pyranopyrazole and polyhydroquinoline derivatives have been performed using a self-organized Ru III @CMC/Fe 3 O 4 nanocatalyst.

The pericyclases are a growing superfamily of enzymes that catalyze pericyclic reactions. We report a pericyclase IccD catalyzing an inverse-electron demand Diels-Alder (IEDDA) reaction with a rate acceleration of 3 × 10 5 -fold in the biosynthesis of fungal natural product ilicicolin H. We demonstrate IccD is highly periselective toward the IEDDA cycloaddition over a competing normal electron demand Diels-Alder (NEDDA) reaction from an ambimodal transition state. A predicted flavoenzyme IccE was identified to epimerize the IEDDA product 8- epi-ilicicolin H to ilicicolin H, a step that is critical for the observed antifungal activity of ilicicolin H. Our results reveal the ilicicolin H biosynthetic pathway and add to the collection of pericyclic reactions that are catalyzed by pericyclases.

Ranking among the most effective anticancer drugs, anthracyclines represent an important family of aromatic polyketides generated by type II polyketide synthases (PKSs). After formation of polyketide cores, the post-PKS tailoring modifications endow the scaffold with various structural diversities and biological activities. Here we demonstrate an unprecedented four-enzyme-participated hydroxyl regioisomerization process involved in the biosynthesis of kosinostatin. First, KstA15 and KstA16 function together to catalyze a cryptic hydroxylation of the 4-hydroxyl-anthraquinone core, yielding a 1,4-dihydroxyl product, which undergoes a chemically challenging asymmetric reduction-dearomatization subsequently acted by KstA11; then, KstA10 catalyzes a region-specific reduction concomitant with dehydration to afford the 1-hydroxyl anthraquinone. Remarkably, the shunt product identifications of both hydroxylation and reduction-dehydration reactions, the crystal structure of KstA11 with bound substrate and cofactor, and isotope incorporation experiments reveal mechanistic insights into the redox dearomatization and rearomatization steps. These findings provide a distinguished tailoring paradigm for type II PKS engineering.

The first Trypsin from porcine pancreas catalyzed a novel one-pot three-component reaction of α-bromoketone, primary alkylamines, and phenylisothiocyanate for the synthesis of thiazole-imine derivatives with high yields (up to 98%) in a short time under mild conditions. The results revealed that Trypsin exhibited excellent catalytic activity and great tolerance for broad substrates. This Trypsin-catalyzed three component convergent method provides a novel strategy for the synthesis of thiazole-2-imine derivatives and expands the promiscuous functions of enzymes in organic synthesis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Postpartum estrogen withdrawal is known to be a particularly vulnerable time for depressive symptoms. Ovariectomized adult mice (OVX-mice) treated with hormone-simulated pregnancy (HSP mice) followed by a subsequent estradiol benzoate (EB) withdrawal (EW mice) exhibited depression- and anxiety-like behaviors, as assessed by forced swim, tail suspension and elevated plus-maze, while HSP mice, OVX mice or EB-treated OVX mice (OVX/EB mice) did not. The survival and neurite growth of newborn neurons in hippocampal dentate gyrus were examined on day 5 after EW. Compared with controls, the numbers of 28-day-old BrdU(+) and BrdU(+)/NeuN(+) cells were increased in HSP mice but significantly decreased in EW mice; the numbers of 10-day-old BrdU(+) cells were increased in HSP mice and OVX/EB mice; and the density of DCX(+) fibers was reduced in EW mice and OVX mice. The phosphorylation of hippocampal NMDA receptor (NMDAr) NR2B subunit or Src was increased in HSP mice but decreased in EW mice. NMDAr agonist NMDA prevented the loss of 28-day-old BrdU(+) cells and the depression- and anxiety-like behaviors in EW mice. NR2B inhibitor Ro25-6981 or Src inhibitor dasatinib caused depression- and anxiety-like behaviors in HSP mice with the reduction of 28-day-old BrdU(+) cells. The hippocampal BDNF levels were reduced in EW mice and OVX mice. TrkB receptor inhibitor K252a reduced the density of DCX(+) fibers in HSP mice without the reduction of 28-day-old BrdU(+) cells, or the production of affective disorder. Collectively, these results indicate that postpartum estrogen withdrawal impairs hippocampal neurogenesis in mice that show depression- and anxiety-like behaviors., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: The volatile components of the Hui formula "Ha Hei Lili" were extracted by steam distillation extraction (SD) and supercritical CO2 fluid extraction, and the structures were analyzed and identified by GC-MS., Methods: The GC-MS conditions were set as follows: Rxi-5Sil MS quartz capillary column (30 m x 0.25 mm, 0.25 μm), the initial temperature of 50 degrees C to keep 1 min, to 10 degrees C/min heating to 120 degrees C, maintained 3 min, then to 3 degrees C/min heating to 200 degrees C, maintained 3 min, and then to 5 degreesC/min heating to 290 degrees C, maintained until completion of analysis; helium as the carrier gas, column flow rate 1.0 ml/min, split ratio 25: 1, inlet temperature 250 degrees C, EI ionization source 70 eV, ion source temperature 230 degrees C, scan range of m/z 35 - 500., Results: Yield of volatile oil were 0.21% and 5.44% extracted by SD and SFE methods, respectively; and for SD method, 36 kinds of compounds were identified, accounted for 87.02% of total mass of volatile oil; for SFE method, 38 kinds of constituents were identified, accounted for 97.47% of total mass of volatile oil., Conclusion: The type of constituents contained in the volatile oil extracted by SD and SFE methods are totally different; and GC-MS can be used to identify the structures and relative content of volatile components, the results of this study can provide an experimental basis for development and utilization of Hui formula "Ha Hei Lili".

Objective: To investigate the prevalence of depressive symptom and its influencing factors among primary and middle school students in urban-rural-integrated area of Chongqing., Methods: A total of 3 013 primary and middle school students from an urban-rural-integrated area of Chongqing were selected by using multistage stratified cluster sampling method in this study. The general information, physical activities and physical examination conditions were investigated. Meanwhile, the depress symptoms were assessed by using children's depression inventory (CDI) and the incidence of adolescence related events were evaluated by using pubertal development scale (PDS). Chi-square test was used to analyze the detection rate of depression symptoms among different population and Logistic regression was used to analyse the influencing factors of depressive symptoms among primary and middle school students., Results: The detection rate of depressive symptoms was 20.1% (607/3013) totally, and it was gradually higher among the students with bad to good economic status (28.3%/18.4%/18.3%, chi2 = 28.415, P < 0.05). The students' detection rate of depression symptoms in different development level compared to companion by self image were 43.1%, 26.5%, 22.0% and 15.8% (chi2 = 79.621, P < 0.01). Among the senior school students, worse economic status, higher development level in self-evaluation, and no physical activities in a recent month (including physical training, aerobic exercise) were considered as the influencing factors of depressive symptoms., Conclusion: Focusing on the physical and mental health of growing children, establishing a good school environment and family environment, and strengthening physical activities will contribute to reducing the incidence of depressive symptoms.

Objective: Six1 and Six4 are expressed in several tumors, and associated with tumor progress and poor prognosis. The aim of this study was to investigate the expression of Six1 and Six4 in esophageal squamous cell carcinoma (ESCC), and to evaluate their correlation with the clinicopathological factors and prognosis., Methods: Tissue microarray technology and immunohistochemical method (EnVision) were used to detect the expression of Six1 and Six4 in the tumor tissues and corresponding adjacent normal epithelium of esophagus from 292 ESCC patients., Results: Among the 292 ESCC patients, the positive rates of Six1 and Six4 protein expression in tumor tissues were 72.9% (213/292) and 56.2% (164/292), respectively, significantly higher than the expression rate of 33.2% (97/292) and 32.5% (95/292) in adjacent normal epithelium of esophagus (P < 0.05). Chi square test showed that the expression of Six1 protein was related to tumor size, depth of tumor invasion and patient survival status; higher Six4 protein expression level was related to poor differentiation and increased depth of invasion. Single factor Log-rank analysis revealed that gender, TNM stage, Six1 protein expression level were related to the overall survival of ESCC patients (P < 0.05), while the five-year survival rate was significantly higher in the Six1-negative group than the Six1-positive group [51.9% (41/79) vs. 43.7% (93/213)]. Multi-factor Cox proportional risk model analysis showed that TNM stage and positive expression of Six1 were independent prognostic factors for ESCC patients (P < 0.05)., Conclusions: Six1 and Six4 are highly expressed in ESCC. Their expression levels are closely related to the progress and prognosis of ESCC. Over-expression of Six1 is related to poor prognosis in ESCC patients. Thus, Six1 could be used as an important prognostic indicator for ESCC patients.

Kosinostatin (KST), an antitumor antibiotic, features a pyrrolopyrrole moiety spirally jointed to a five-membered ring of an anthraquinone framework glycosylated with a γ-branched octose. By a combination of in silico analysis, genetic characterization, biochemical assay, and precursor feeding experiments, a biosynthetic pathway for KST was proposed, which revealed (1) the pyrrolopyrrole moiety originates from nicotinic acid and ribose, (2) the bicyclic amidine is constructed by a process similar to the tryptophan biosynthetic pathway, and (3) a discrete adenylation enzyme and a peptidyl carrier protein (PCP) are responsible for producing a PCP-tethered building block parallel to type II polyketide synthase (PKS) rather than for the PKS priming step by providing the starter unit. These findings provide an opportunity to further explore the inexplicable enzymatic logic that governs the formation of pyrrolopyrrole moiety and the spirocyclic skeleton., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background & Objective: P27 protein and cyclin E were negative cell cycle regulators. Until the present, the influence of P27 protein and cyclin E on progression of colon cancer was unclear. The aim of this study was to observe the expression features of P27 protein and cyclin E in the tissues of colon neoplasms, and to investigate the relationship between colon neoplasms and tumor special growth factor (TSGF)., Methods: Sixty-nine cases of samples included 23 normal tissues, 28 colon polyps (13 inflammatory polyps and 15 adenomatous polyps), and 18 colon carcinomas. The location and expression of P27 protein and cyclin E were determined using immunohistochemical method in all samples. These samples were diagnosed using formal pathological techniques simultaneously; the relationship between colon neoplasms and TSGF was also investigated., Results: The positive signal of P27 and cyclin E was found mainly in the cytoplasm and extracellular matrix of normal colon tissues, inflammatory polyps, and adenomatous polyps. Less amount of positive expression product of P27 protein and cyclin E was observed in colon carcinoma cells; and the positive signal was only located in the cytoplasm of gland-like cells. The content of TSGF in colon carcinoma tissues was significantly higher than that in normal tissues (117.3+/-57.02 versus 64.16+/-27.5,P< 0.01), but there was no significant difference between colon carcinoma tissues and inflammatory polyp tissues (117.3+/-57.02 versus 92.5+/-47.9,P >0.05)., Conclusion: P27 protein and cyclin E participate in the adjustment process of colon neoplasm occurrence and progression. The reduced expression of P27 protein and cyclin E may indicate the possibility of colon carcinoma.