Abstract
By resorting to the principle of remote activation, we herein demonstrate the first photoredox catalyzed (3+3) dipolar cycloaddition of nitrones with aryl cyclopropanes. Key to the fidelity ...of the reaction resides in a facile manner of substrate activation by single‐electron transfer (SET) oxidation with photoredox catalysis, and the reaction takes place through a stepwise cascade encompassing a three‐electron‐type nucleophilic substitution triggered cyclopropane ring‐opening and a diastereoselective 6‐endo‐
trig
radical cyclization manifold. The reaction proceeds under mild conditions with excellent regio‐ and stereoselectivity, nicely complementing the well‐developed Lewis acid catalyzed cycloaddition of donor‐acceptor cyclopropanes. Other merits of the protocol include wide scope of aryl cyclopropanes with diversified substitution patterns and good functional‐group compatibility. A mechanism involving an aryl radical cation promoted remote activation mode was also proposed and supported by mechanistic experiments.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The Three Gorges reservoir area in the Yangtze River economic belt has frequent geological disasters. To assist decision-makers make effective emergency decisions based on their experience, this ...paper proposes a dynamic geological disaster emergency plan selection scheme based on case-based reasoning and prospect theory. Geological information and data of disaster sites in the Three Gorges reservoir area are collected from the China Geological Environment Monitoring Institute and China Geological Survey of the Ministry of Natural Resources. First, historical geological disasters are analyzed to extract the gene structure characteristics and develop a gene library, from which geological and economic disaster indicators are selected. The indicator values are then divided into several intervals according to their corresponding distributions, which are then processed with a pruning method. Prospect theory is applied to compensate for the differences in decision-making, for which comprehensive foreground values and rank schemes are calculated. A comparison is made between the proposed method and other methods, besides, the Zigui County landslide in Hubei Province is taken as an example to verify the feasibility and effectiveness of the proposed method.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We studied the value of circulating tumor DNA (ctDNA) in predicting early postoperative tumor recurrence and monitoring tumor burden in patients with hepatocellular carcinoma (HCC). Plasma‐free DNA, ...germline DNA, and tissue DNA were isolated from 41 patients with HCC. Serial ctDNAs were analyzed by next‐generation sequencing before and after operation. Whole‐exome sequencing was used to detect the DNA of HCC and adjacent tissues. In total, 47 gene mutations were identified in the ctDNA of the 41 patients analyzed before surgery. ctDNA was detected in 63.4% and 46% of the patient plasma pre‐ and postoperation, respectively. The preoperative ctDNA positivity rate was significantly lower in the nonrecurrence group than in the recurrence group. With a median follow‐up of 17.7 months, nine patients (22%) experienced tumor recurrence. ctDNA positivity at two time‐points was associated with significantly shorter recurrence‐free survival (RFS). Tumors with NRAS, NEF2L2, and MET mutations had significantly shorter times to recurrence than those without mutations and showed high recurrence prediction performance by machine learning. Multivariate analyses showed that the median variant allele frequency (VAF) of mutations in preoperative ctDNA was a strong independent predictor of RFS. ctDNA is a real‐time monitoring indicator that can accurately reflect tumor burden. The median VAF of baseline ctDNA is a strong independent predictor of RFS in individuals with HCC.
Here, we studied the value of circulating tumor DNA (ctDNA), in combination with germline and tissue DNA by whole‐exome sequencing in patients withhepatocellular carcinoma (HCC). Our analysis demonstrated that ctDNA may serve as a real‐time monitoring indicator by accurately reflecting tumor burden, and as a strong independent predictor of recurrence‐free survival in HCC.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Problem
During endometriosis, there is an increase in the number of dysfunctional macrophages; however, the mechanisms underlying macrophage recruitment are not well understood. The aim of the ...present study was to determine the role of natural killer (NK) cell‐mediated secretion of chemokine (C‐C motif) ligand 2 (CCL2) from endometrial stromal cells (ESCs) in the recruitment of macrophages.
Method of study
Normal ESCs (nESC) and ectopic ESCs (eESCs) were separately co‐cultured with NK cells for a macrophage chemotaxis assay, and the number of chemotactic macrophages was counted. The expression of interleukin‐22 (IL‐22) and IL‐22 receptors was detected by ELISA and flow cytometry, respectively. eESCs were treated with 0.01, 0.1, and 1 ng/mL recombinant human IL‐22 (rhIL‐22) to determine the most effective concentration for stimulating CCL2 production. Following treatment with 1 ng/mL rhIL‐22, secretion of CCL2 was detected from both the eESC monoculture and the eESC/NK co‐culture.
Results
Compared with the eESC monoculture, the eESC/NK co‐culture recruited a significantly higher number of chemotactic macrophages. There was also an increase in the levels of IL‐22 and CCL2 secreted when eESCs were co‐cultured compared with the monoculture. Treatment with rhIL‐22 resulted in an increase in the levels of CCL2 secreted by eESCs, and the IL‐22‐induced CCL2 secretion was reversed by the IL‐22 antagonist, αIL‐22. Increased expression of IL‐22 resulted in an increase in the number of chemotactic macrophages, but was reversed by αIL‐22 and CCL2 antagonist (αCCL2).
Conclusion
Interleukin‐22 and CCL2 secretion by eESCs stimulated by NK cells contributes to the induction of macrophage recruitment and is thus implicated in the development of endometriosis.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
•A parameter called α is used for quantitative detection of lining voids.•This method can reduce the influence of negative factors to a certain extent.•Study results show that the α changes linearly ...with void height.
In this paper, a quantitative void detection method based on acoustic spectrum analysis is proposed to estimate the inner state of tunnel linings. Comparativeanalysesof time- and frequency-domain signals for different sizes of void are studied via numerical simulation and experimental testing. In order to realize quantitative evaluation of void size, a parameter based on frequency-domain analysis, called the spectrum density ratio (α), is extracted to estimate lining quality. Parameter α is calculated by analysing the spectrum density in different frequency bands. The results show that α increases linearly with void size and can be used to detect voids in linings. The method effectively characterises voids in tunnel linings, thereby allowing the engineering of stronger structures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hepatocellular carcinoma (HCC) is an immunotherapy-resistant malignancy characterized by high cellular heterogeneity. The diversity of cell types and the interplay between tumor and non-tumor cells ...remain to be clarified. Single cell RNA sequencing of human and mouse HCC tumors revealed heterogeneity of cancer-associated fibroblast (CAF). Cross-species analysis determined the prominent CD36
CAFs exhibited high-level lipid metabolism and expression of macrophage migration inhibitory factor (MIF). Lineage-tracing assays showed CD36
CAFs were derived from hepatic stellate cells. Furthermore, CD36 mediated oxidized LDL uptake-dependent MIF expression via lipid peroxidation/p38/CEBPs axis in CD36
CAFs, which recruited CD33
myeloid-derived suppressor cells (MDSCs) in MIF- and CD74-dependent manner. Co-implantation of CD36
CAFs with HCC cells promotes HCC progression in vivo. Finally, CD36 inhibitor synergizes with anti-PD-1 immunotherapy by restoring antitumor T-cell responses in HCC. Our work underscores the importance of elucidating the function of specific CAF subset in understanding the interplay between the tumor microenvironment and immune system.
Meloyunnanines A–C, three alkaloids with an unprecedented skeleton, were isolated from fruits of Melodinus yunnanensis. The structures featuring a caged-6/6/5/6/5/5 ring system were elucidated by the ...analysis of comprehensive spectroscopic and X-ray data. Biosynthetically, meloyunnanines A–C were assigned to monoterpenoid quinoline alkaloids (MQAs), derived from monoterpenoid indole alkaloids through oxidation and rearrangement. These compounds together with three known Melodinus MQAs were evaluated for their neurotrophic activity and scandine N 4-oxide exhibited significant effect.
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IJS, KILJ, NUK, PNG, UL, UM
Hypoxia inducible factors (HIFs) are activated in many tumors and show either promoter or suppressor activity, depending on tumor cell biology and background. However, the role of HIF member HIF‐2α ...remains unclear in hepatocellular carcinoma (HCC). Here, HIF‐2α expression was measured in HCC and paired peritumoral tissues by quantitative real‐time polymerase chain reaction, western blotting, and immunofluorescence assays, and the clinical significance was explored in 246 HCC patients. In cell culture, HIF‐2α levels were up‐regulated or down‐regulated by use of expression or short hairpin RNA recombinant plasmid, respectively. Cells were analyzed by immunoblotting, chromatin immunoprecipitation coupled with microarray, coimmunoprecipitation, and immunohistochemical staining. In vivo tumor growth was analyzed in nude mice. We found that the average expression of HIF‐2α was relatively low in HCC tissues, and the decreased level was associated with lower overall survival (P = 0.006). High HIF‐2α expression in HCC cells induced higher levels of apoptosis and expression of proapoptotic proteins and inhibited cell and tumor growth. Furthermore, HIF‐2α inhibited expression of the novel target gene, transcription factor dimerization partner 3 (TFDP3). TFDP3 protein was found to bind with E2F transcription factor 1 (E2F1) and inhibit its transcriptional activity through both p53‐dependent and ‐independent pathways. Reintroduction of TFDP3 expression reversed HIF‐2α‐induced apoptosis. Conclusions: Data gathered from cell lines, tumorigenicity studies, and primary HCC samples demonstrate a negative role of HIF‐2α in tumors, which is mediated by the TFDP3/E2F1 pathway. Our study provides evidence supporting a possible tumor‐suppressor role for HIF‐2α and has uncovered a mechanism that links HIF‐2α to a fundamental biological regulator, E2F1. (HEPATOLOGY 2013)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Continued interest in bioactive alkaloids led to the isolation of four undescribed alkaloids along with 74 known ones from the aerial parts of Tabernaemontana bufalina Lour. The structures of the yet ...undescribed alkaloids were elucidated based on NMR, IR, UV, MS and CD spectroscopic data and X-ray crystal diffraction and, according to the plant source, named as taberhaines A–D (1–4). The known compounds comprised of 66 monoterpenoid indole, three carboline and five isoquinoline alkaloids. Among them, the known apparicine inhibited significantly the activity of xanthine oxidase, which plays an important role for gout, with an IC50 value of 0.65 μM, compared to the standard drug allopurinol (IC50 = 0.60 μM).
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•Four undescribed alkaloids together with 74 known ones were isolated from Tabernaemontana bufalina.•The structures were determined by NMR spectra, CD data and X-ray diffraction.•Apparicine exhibited a significant inhibitory activity of xanthine oxidase compared to allopurinol.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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