A rhodium(
iii
)-catalyzed redox-neutral spiroannulation approach to access the spirobenzo
b
1,4oxazine-benzo
c
chromene skeleton is described in this contribution. A variety of spiro5.5-heterocyclic ...scaffolds were obtained in moderate to excellent yields under mild conditions. Key features of this protocol are good substrate scope, silver-free conditions, low catalyst loadings, easy handling under air and 100% atom economy. Furthermore, scale-up reactions and late-stage derivatizations highlight the potential synthetic utility of this methodology.
A rhodium(
iii
)-catalyzed redox-neutral 3+3 spiroannulation approach to access the spirobenzo
b
1,4oxazine-benzo
c
chromene skeleton is reported herein.
The spillover effect of the energy markets and the CET plays an important role in guiding the realization of two-carbon target; using the network spillover methodology of Diebold, Yilmaz, Jozef ...Barunı´k, and Toma´sKrehlı´k, we examine both the static and dynamic connectedness of CO2 emissions trading (CET) market, steam coal market, new energy, and traditional energy market in China from early Dec 2013 to the end of July 2021. At last, we verified the stability of the model and obtained the following findings: (1) the total spillover effect index is 13.91% between those markets, and it is mainly focused on short term. Moreover, the dynamic spillover effect is time-varying, and it is greatly influenced by the domestic and international environment; (2) the connectedness of the CET market with other energy markets is neutral, the development of new energy market is strong, it is the main transmitter to other markets, especially to the traditional energy market except for the steam coal market, and the coal market is an effect transmitter. These results provide a theoretical reference for investors and policy makers who are concerned with the return connectedness among the CET market, new energy market, and steam coal market in China.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Drug resistance is one of the most intractable issues for successful treatment in current clinical practice. Although many mutations contributing to drug resistance have been identified, the ...relationship between the mutations and the related pharmacological profile of drug candidates has yet to be fully elucidated, which is valuable both for the molecular dissection of drug resistance mechanisms and for suggestion of promising treatment strategies to counter resistant. Hence, effective prediction approach for estimating the sensitivity of mutations to agents is a new opportunity that counters drug resistance and creates a high interest in pharmaceutical research. However, this task is always hampered by limited known resistance training samples and accurately estimation of binding affinity. Upon this challenge, we successfully developed Auto In Silico Macromolecular Mutation Scanning (AIMMS), a web server for computer-aided de novo drug resistance prediction for any ligand–protein systems. AIMMS can qualitatively estimate the free energy consequences of any mutations through a fast mutagenesis scanning calculation based on a single molecular dynamics trajectory, which is differentiated with other web services by a statistical learning system. AIMMS suite is available at http://chemyang.ccnu.edu.cn/ccb/server/AIMMS/.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Among six extant tiger subspecies, the South China tiger (Panthera tigris amoyensis) once was widely distributed but is now the rarest one and extinct in the wild. All living South China tigers are ...descendants of only two male and four female wild-caught tigers and they survive solely in zoos after 60 years of effective conservation efforts. Inbreeding depression and hybridization with other tiger subspecies were believed to have occurred within the small, captive South China tiger population. It is therefore urgently needed to examine the genomic landscape of existing genetic variation among the South China tigers.
In this study, we assembled a high-quality chromosome-level genome using long-read sequences and re-sequenced 29 high-depth genomes of the South China tigers. By combining and comparing our data with the other 40 genomes of six tiger subspecies, we identified two significantly differentiated genomic lineages among the South China tigers, which harbored some rare genetic variants introgressed from other tiger subspecies and thus maintained a moderate genetic diversity. We noticed that the South China tiger had higher F
values for longer runs of homozygosity (ROH > 1 Mb), an indication of recent inbreeding/founder events. We also observed that the South China tiger had the least frequent homozygous genotypes of both high- and moderate-impact deleterious mutations, and lower mutation loads than both Amur and Sumatran tigers. Altogether, our analyses indicated an effective genetic purging of deleterious mutations in homozygous states from the South China tiger, following its population contraction with a controlled increase in inbreeding based on its pedigree records.
The identification of two unique founder/genomic lineages coupled with active genetic purging of deleterious mutations in homozygous states and the genomic resources generated in our study pave the way for a genomics-informed conservation, following the real-time monitoring and rational exchange of reproductive South China tigers among zoos.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
T-cell acute lymphoblastic leukemia (T-ALL) is caused by the accumulation of multiple genetic alterations. To determine the frequency of common genetic mutations and possible prognostic markers in ...childhood T-ALL, we performed targeted sequencing of 67 genes across 64 cases treated according to Taiwan Pediatric Oncology Group protocols between January 2002 and December 2015. Together, 302 variants were identified in 60 genes including 233 single nucleotide variants and 69 indels. Sixty-four samples had a median number of six genetic lesions each (range 1-17). Thirteen genes had mutation frequencies > 10%, and 5 were > 20%, with the highest being NOTCH1 (70.31%). Protocadherins FAT1 (32.81%) and FAT3 (17.19%), and the ubiquitin ligase component FBXW7 (28.13%) had higher mutation frequencies than previously reported. Other mutation frequencies (PHF6, DNM2, DNMT3A, CNOT3, and WT1) were within previously reported ranges. Three epigenetic-related genes (KMT2D, DNMT3A, and EZH2) were mutated in our cohort. JAK-STAT signaling pathway genes had mutation frequencies of 3-13% and were observed in 23 cases (35.94%). Changes to genes in the ErbB signaling pathway were detected in 20 cases (31.25%). Patients with NOTCH1/FBXW7 mutations and RAS/PTEN germline exhibited better 5-year overall survival rates.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The pathological identification of lymph node (LN) metastasis is demanding and tedious. Although convolutional neural networks (CNNs) possess considerable potential in improving the process, the ...ultrahigh-resolution of whole slide images hinders the development of a clinically applicable solution. We design an artificial-intelligence-assisted LN assessment workflow to facilitate the routine counting of metastatic LNs. Unlike previous patch-based approaches, our proposed method trains CNNs by using 5-gigapixel images, obviating the need for lesion-level annotations. Trained on 5907 LN images, our algorithm identifies metastatic LNs in gastric cancer with a slide-level area under the receiver operating characteristic curve (AUC) of 0.9936. Clinical experiments reveal that the workflow significantly improves the sensitivity of micrometastasis identification (81.94% to 95.83%, P < .001) and isolated tumor cells (67.95% to 96.15%, P < .001) in a significantly shorter review time (-31.5%, P < .001). Cross-site evaluation indicates that the algorithm is highly robust (AUC = 0.9829).
The potato dry rot disease caused by
spp. seriously reduces potato yield and threatens human health. However, potential biocontrol agents cannot guarantee the stability and activity of biocontrol. ...Here, 18 synthetic microbial communities of different scales were constructed, and the synthetic microbial communities with the best biocontrol effect on potato dry rot disease were screened through in vitro and in vivo experiments. The results show that the synthetic community composed of
,
,
,
,
and
has the best biocontrol activity. Metabolomics results show that
interacts with other member strains to produce caproic acid and reduce the disease index to 38.01%. Furthermore, the mycelial growth inhibition after treatment with caproic acid was 77.54%, and flow cytometry analysis showed that the living conidia rate after treatment with caproic acid was 11.2%. This study provides potential value for the application of synthetic microbial communities in potatoes, as well as the interaction mechanisms between member strains of synthetic microbial communities.
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Objective
Increasing evidence indicates that the cyclic GMP‐AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway has a critical pathogenic role in systemic lupus erythematosus ...(SLE). Expression levels of the interferon (IFN)–inducible gene IFIT3 are elevated in SLE patients. However, it is still not clear how IFIT3 contributes to the pathogenesis of SLE. This study was undertaken to investigate the activation of the cGAS/STING signaling pathway in human SLE monocytes, and to determine how elevated expression of IFIT3 could contribute to overactive cGAS/STING signaling in patients with SLE.
Methods
Monocytes from SLE patients or healthy controls were examined for activity of the cGAS/STING signaling pathway and expression levels of IFIT3. Correlations between cGAS/STING signaling activity and SLE clinical features were analyzed. Gain‐ or loss‐of‐function experiments were used to determine the role of IFIT3 in cGAS/STING signaling. Coimmunoprecipitation assays were used to identify the interaction between IFIT3 and other proteins.
Results
The cGAS/STING signaling pathway was found to have enhanced activity in monocytes from SLE patients compared to healthy controls, as indicated by the higher expression of IFNβ downstream. Levels of IFIT3 were significantly elevated in human SLE monocytes, and this was positively correlated with the activity of the cGAS/STING signaling pathway. In vitro, the expression of VACV70‐induced IFNβ was reduced by knockdown of IFIT3, whereas overexpression of IFIT3 produced an opposite effect. Finally, IFIT3 was found to interact with both STING and TANK‐binding kinase 1.
Conclusion
These findings suggest that IFIT3 is one of the genes that contributes to the overactive cGAS/STING signaling pathway in human SLE monocytes. IFIT3 may therefore serve as a novel therapeutic target for blocking the production of type I IFN and other proinflammatory cytokines by the cGAS/STING signaling pathway in patients with SLE.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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•Porous nitrogen-doped reduced graphene oxides (PNrGOs) as an excellent metal-free catalyst for 4-nitrophenol (4-NP) reduction.•PNrGOs showing superior catalytic activity compared ...with those of other catalysts.•Insight into the mechanism of catalytic reduction of 4-NP to 4-aminophenol by PNrGO.•Pore creation and nitrogen-doping jointly enhancing the catalytic activity of PNrGO.
Herein, a series of metal-free porous nitrogen-doped reduced graphene oxides (PNrGOs) are obtained and employed as metal-free catalysts for the reduction of aromatic nitrophenols. Owing to the developed holey structure, unique two-dimensional structure, higher nitrogen content and excellent electron transfer ability, the PNrGOs show outstanding catalytic activity for nitrophenol reduction. Among the PNrGOs, 2-PNrGO has the largest specific surface area (778 m2·g−1) and suitable nitrogen content (5.67 at.%), displaying the highest reaction rate of 1.563 min−1 and maximal turnover frequency for 4-nitrophenol of 8.75 × 10−5 mol·mg−1·min−1, which is comparable even superior to the reported noble metal-based catalyst. The catalytic reaction kinetic model, surface active sites, electron transfer pathway and the role of pore and nitrogen dopant were investigated by experimental and theoretical calculations thoroughly. The results demonstrated that the strongly active sites can merely be created by the synergistic effect between the nitrogen-doping and holey structure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Despite new developments in cancer therapy, chemotherapy and radiotherapy remain the cornerstone of breast cancer treatment. Therefore, finding ways to reduce the toxicity and increase sensitivity is ...particularly important. Tumor necrosis factor alpha (TNF-α) exerts multiple functions in cell proliferation, differentiation and apoptosis. In the present study, we investigated whether TNF-α could enhance the effect of chemotherapy and radiotherapy against breast cancer cells.
Cell growth was determined by MTT assay in vitro, and by using nude mouse tumor xenograft model in vivo. Cell cycle and apoptosis/necrosis were evaluated by flow cytometry. DNA damage was visualized by phospho-Histone H2A.X staining. mRNA expression was assessed by using real-time PCR. Protein expression was tested by Western blot assay.
TNF-α strengthened the cytotoxicity of docetaxel, 5-FU and cisplatin against breast cancer cells both in vitro and in vivo. TNF-α activated NF-κB pathway and dependently up-regulated expressions of CyclinD1, CyclinD2, CyclinE, CDK2, CDK4 and CDK6, the key regulators participating in G1→S phase transition. As a result, TNF-α drove cells out of quiescent G0/G1 phase, entering vulnerable proliferating phases. Treatment of TNF-α brought more DNA damage after Cs
-irradiation and strengthened G2/M and S phase cell cycle arrest induced by docetaxel and cisplatin respectively. Moreover, the up-regulation of RIP3 (a necroptosis marker) by 5-FU, and the activation of RIP3 by TNF-α, synergistically triggered necroptosis (programmed necrosis). Knockdown of RIP3 attenuated the synergetic effect of TNF-α and 5-FU.
TNF-α presented radiotherapy- and chemotherapy-sensitizing effects against breast cancer cells.
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