Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC)
. BCAA transaminase 2 (BCAT2) was essential for the collateral lethality ...conferred by deletion of malic enzymes in PDAC and the BCAA-BCAT metabolic pathway contributed to non-small-cell lung carcinomas (NSCLCs) other than PDAC
. However, the underlying mechanism remains undefined. Here we reveal that BCAT2 is elevated in mouse models and in human PDAC. Furthermore, pancreatic tissue-specific knockout of Bcat2 impedes progression of pancreatic intraepithelial neoplasia (PanIN) in LSL-Kras
; Pdx1-Cre (KC) mice. Functionally, BCAT2 enhances BCAA uptake to sustain BCAA catabolism and mitochondrial respiration. Notably, BCAA enhances growth of pancreatic ductal organoids from KC mice in a dose-dependent manner, whereas addition of branched-chain α-keto acid (BCKA) and nucleobases rescues growth of KC organoids that is suppressed by BCAT2 inhibitor. Moreover, KRAS stabilizes BCAT2, which is mediated by spleen tyrosine kinase (SYK) and E3 ligase tripartite-motif-containing protein 21 (TRIM21). In addition, BCAT2 inhibitor ameliorates PanIN formation in KC mice. Of note, a lower-BCAA diet also impedes PDAC development in mouse models of PDAC. Thus, BCAT2-mediated BCAA catabolism is critical for development of PDAC harbouring KRAS mutations. Targeting BCAT2 or lowering dietary BCAA may have translational significance.
The regio‐ and enantioselective (3+3) cycloaddition of nitrones with 2‐indolylmethanols was accomplished by the cooperative catalysis of hexafluoroisopropanol (HFIP) and chiral phosphoric acid (CPA). ...Using this approach, a series of indole‐fused six‐membered heterocycles were synthesized in high yields (up to 98 %), with excellent enantioselectivities (up to 96 % ee) and exclusive regiospecificity. This approach enabled not only the first organocatalytic asymmetric (3+3) cycloaddition of nitrones but also the first C3‐nucleophilic asymmetric (3+3) cycloaddition of 2‐indolylmethanols. More importantly, theoretical calculations elucidated the role of the cocatalyst HFIP in helping CPA control the reactivity and enantioselectivity of the reaction, demonstrating a new mode of cooperative catalysis.
The regio‐ and enantioselective (3+3) cycloaddition of nitrones with 2‐indolylmethanols has been established under the cooperative catalysis of hexafluoroisopropanol (HFIP) and chiral phosphoric acid (CPA). This approach not only realized the first organocatalytic asymmetric (3+3) cycloaddition of nitrones and the first C3‐nucleophilic asymmetric (3+3) cycloaddition of 2‐indolylmethanols but also revealed a new mode of cooperative catalysis.
Breast cancer is now the most frequently diagnosed malignancy, and metastasis remains the leading cause of death in breast cancer. However, little is known about the dynamic changes during the ...evolvement of dissemination. In this study, 65 968 cells from four patients with breast cancer and paired metastatic axillary lymph nodes are profiled using single‐cell RNA sequencing (scRNA‐seq) and spatial transcriptomics. A disseminated cancer cell cluster with high levels of oxidative phosphorylation (OXPHOS), including the upregulation of cytochrome C oxidase subunit 6C and dehydrogenase/reductase 2, is identified. The transition between glycolysis and OXPHOS when dissemination initiates is noticed. Furthermore, this distinct cell cluster is distributed along the tumor's leading edge. The findings here are verified in three different cohorts of breast cancer patients and an external scRNA‐seq dataset, which includes eight patients with breast cancer and paired metastatic axillary lymph nodes. This work describes the dynamic metabolic evolvement of early disseminated breast cancer and reveals a switch between glycolysis and OXPHOS in breast cancer cells as the early event during lymph node metastasis.
By single‐cell RNA sequencing and spatial transcriptomics, the early early‐disseminated breast cancer cells are found to travel from the border of primary tumor to axillary lymph nodes. During this metastasis, a switch between glycolysis and oxidative phosphorylation occurs in early disseminated breast cancer cells, indicating an interesting dynamic metabolic evolvement.
In this paper, we introduce a new skeleton pruning method based on contour partitioning. Any contour partition can be used, but the partitions obtained by discrete curve evolution (DCE) yield ...excellent results. The theoretical properties and the experiments presented demonstrate that obtained skeletons are in accord with human visual perception and stable, even in the presence of significant noise and shape variations, and have the same topology as the original skeletons. In particular, we have proven that the proposed approach never produces spurious branches, which are common when using the known skeleton pruning methods. Moreover, the proposed pruning method does not displace the skeleton points. Consequently, all skeleton points are centers of maximal disks. Again, many existing methods displace skeleton points in order to produces pruned skeletons
Abstract
Rationally constructing and manipulating the in situ formed catalytically active surface of catalysts remains a tremendous challenge for a highly efficient water electrolysis. Herein, an ...anion and cation co‐induced strategy is presented to modulate in situ catalyst dissolution‐redeposition and to achieve the directional reconstruction of Zn and S co‐doped Fe
2
O
3
and Fe
3
O
4
on iron foams (Zn,S‐Fe
2
O
3
‐Fe
3
O
4
/IF), for oxygen evolution reaction (OER). Benefiting from Zn, S co‐doping and the presence of Fe
3
O
4
, a directionally reconstructed surface is obtained. The Fe
2
O
3
in the Zn,S‐Fe
2
O
3
‐Fe
3
O
4
/IF is directionally reconstructed into FeOOH (Zn,S‐Fe
3
O
4
‐FeOOH/IF), in which the S leaching promotes the Fe dissolution and the Zn co‐deposition regulates the activity of the obtained FeOOH. Moreover, the presence of Fe
3
O
4
provides a stable site for FeOOH deposition, and thus causes more FeOOH active components to be formed. Directionally reconstructed Zn,S‐Fe
3
O
4
‐FeOOH/IF outperformes many state‐of‐the‐art OER catalysts and demonstrates a remarkable stability. The experimental and density functional theory (DFT) calculation results show that the introduction of Zn‐doped FeOOH with abundant oxygen vacancies through directional reconstruction has activated lattice O atoms, facilitating the OER process on the heterojunction surface following the lattice oxygen mechanism (LOM) pathway. This work makes a stride in co‐induced strategy modulating directional reconstruction.
Catalytic kinetic resolution (KR) and dynamic kinetic asymmetric transformation (DyKAT) are alternative and complementary avenues to access chiral stereoisomers of both starting materials and ...reaction products. The development of highly efficient chiral catalytic systems for kinetically controlled processes has therefore been one of the linchpins in asymmetric synthesis. N‐heterocyclic carbene (NHC)/copper cooperative catalysis has enabled highly efficient KR and DyKAT of racemic N‐tosylaziridines by 3+3 annulation with isatin‐derived enals, leading to highly enantioenriched N‐tosylaziridine derivatives (up to >99 % ee) and a large library of spirooxindole derivatives with high structural diversity and stereoselectivity (up to >95:5 d.r., >99 % ee). Mechanistic studies suggest that the NHC can bind reversibly to the copper catalyst without compromising its catalytic activity and regulate the catalytic activity of the copper complex to switch the chemoselection between KR and DyKAT.
Highly efficient kinetic resolution and dynamic kinetic asymmetric transformation of racemic N‐tosylaziridines with isatin‐derived enals have been achieved by the cooperative catalysis of chiral N‐heterocyclic carbene (NHC) and copper complexes, leading to highly enantioenriched N‐tosylaziridines and spirooxindole derivatives with high structural diversity.
Proton pump inhibitors, including omeprazole, rabeprazole, lansoprazole, and pantoprazole, achieved simultaneous enantioselective determination in the human plasma by chiral liquid ...chromatography–tandem mass spectrometry. The four corresponding stable isotope‐labeled proton pump inhibitors were adopted as the internal standards. Each enantiomer and the internal standards were extracted with acetonitrile containing 0.1% ammonia, then separated with a Chiralpak IC column (5 µm, 4.6 mm × 150 mm) within 10 min. The mobile phase was composed of acetonitrile–ammonium acetate (10 mM) containing 0.2% acetic acid (50:50, v/v). To quantify all enantiomers, an API 4000 tandem mass spectrometer was used, and multiple reaction monitoring transitions were performed on m/z 360.1→242.1, 384.1→200.1, 370.1→252.1, and 346.1→198.1, respectively. No significant matrix effect was observed for all analytes. The calibration curve for all enantiomers were linear from 1.25 to 2500 ng/mL. The precisions for intra‐ and inter‐run were < 14.2%, and the accuracy fell in the interval of –5.3 to 8.1%. Stability of samples was confirmed under the storage and processing conditions. The developed method was also suitable for separation and determination of ilaprazole enantiomers. The validated method combining the equilibrium dialysis method was applied to the protein binding ratio studies of four pairs proton pump inhibitor enantiomers in human plasma.
For high-temperature catalytic reaction, it is of significant importance and challenge to construct stable active sites in catalysts. Herein, we report the construction of sufficient and stable ...copper clusters in the copper‒ceria catalyst with high Cu loading (15 wt.%) for the high-temperature reverse water gas shift (RWGS) reaction. Under very harsh working conditions, the ceria nanorods suffered a partial sintering, on which the 2D and 3D copper clusters were formed. This partially sintered catalyst exhibits unmatched activity and excellent durability at high temperature. The interaction between the copper and ceria ensures the copper clusters stably anchored on the surface of ceria. Abundant in situ generated and consumed surface oxygen vacancies form synergistic effect with adjacent copper clusters to promote the reaction process. This work investigates the structure-function relation of the catalyst with sintered and inhomogeneous structure and explores the potential application of the sintered catalyst in C1 chemistry.
Abstract
Background
In gut microbiome studies, the cultured gut microbial resource plays essential roles, such as helping to unravel gut microbial functions and host-microbe interactions. Although ...several major studies have been performed to elucidate the cultured human gut microbiota, up to 70% of the Unified Human Gastrointestinal Genome species have not been cultured to date. Large-scale gut microbial isolation and identification as well as availability to the public are imperative for gut microbial studies and further characterizing human gut microbial functions.
Results
In this study, we constructed a human Gut Microbial Biobank (hGMB; homepage:
hgmb.nmdc.cn
) through the cultivation of 10,558 isolates from 31 sample mixtures of 239 fresh fecal samples from healthy Chinese volunteers, and deposited 1170 strains representing 400 different species in culture collections of the International Depository Authority for long-term preservation and public access worldwide. Following the rules of the International Code of Nomenclature of Prokaryotes, 102 new species were characterized and denominated, while 28 new genera and 3 new families were proposed. hGMB represented over 80% of the common and dominant human gut microbial genera and species characterized from global human gut 16S rRNA gene amplicon data (
n
= 11,647) and cultured 24 “most-wanted” and “medium priority” taxa proposed by the Human Microbiome Project. We in total sequenced 115 genomes representing 102 novel taxa and 13 previously known species. Further in silico analysis revealed that the newly sequenced hGMB genomes represented 22 previously uncultured species in the Unified Human Gastrointestinal Genome (UHGG) and contributed 24 representatives of potentially “dark taxa” that had not been discovered by UHGG. The nonredundant gene catalogs generated from the hGMB genomes covered over 50% of the functionally known genes (KEGG orthologs) in the largest global human gut gene catalogs and approximately 10% of the “most wanted” functionally unknown proteins in the FUnkFams database.
Conclusions
A publicly accessible human Gut Microbial Biobank (hGMB) was established that contained 1170 strains and represents 400 human gut microbial species. hGMB expands the gut microbial resources and genomic repository by adding 102 novel species, 28 new genera, 3 new families, and 115 new genomes of human gut microbes.
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