Since China is facing a complicated international situation and sustainable development requirement at the same time, this paper examines the effects of external uncertainty, international sanctions, ...on green innovations by adopting the system generalized method of moments (GMM) estimation for 30 provinces (autonomous region and municipalities) from 1997 to 2019. We employ green inventions as the dependent variable and 5 indicators of sanctions (including unilateral, plurilateral, multilateral, economic, and intensity) as the main explanatory variables alternately. For further robustness tests, we use substitution variable green utility models, adopt sub-samples in different regions, change the empirical methodology, and add omitted variables. We also examine the mechanism effects of three possible channels. The conclusion is that plurilateral and economic sanctions both present significant negative impacts on green innovations, whereas China was not affected by unilateral or multilateral sanctions during the sample period. GDP, interpersonal globalization, and environment are proved to be the possible channels through which sanctions affect green innovations. Our research findings should assist Chinese-listed companies suffering from sanctions to make better responses on their way to green innovations.
ABCA1, an ATP-binding cassette (ABC) subfamily A exporter, mediates the cellular efflux of phospholipids and cholesterol to the extracellular acceptor apolipoprotein A-I (apoA-I) for generation of ...nascent high-density lipoprotein (HDL). Mutations of human ABCA1 are associated with Tangier disease and familial HDL deficiency. Here, we report the cryo-EM structure of human ABCA1 with nominal resolutions of 4.1 Å for the overall structure and 3.9 Å for the massive extracellular domain. The nucleotide-binding domains (NBDs) display a nucleotide-free state, while the two transmembrane domains (TMDs) contact each other through a narrow interface in the intracellular leaflet of the membrane. In addition to TMDs and NBDs, two extracellular domains of ABCA1 enclose an elongated hydrophobic tunnel. Structural mapping of dozens of disease-related mutations allows potential interpretation of their diverse pathogenic mechanisms. Structural-based analysis suggests a plausible “lateral access” mechanism for ABCA1-mediated lipid export that may be distinct from the conventional alternating-access paradigm.
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•Cryo-EM structure of human ABCA1 at 4.1 Å resolution•An “outward-facing” conformation of TMD in the nucleotide-free state•An elongated hydrophobic tunnel within the massive extracellular domains•Structural mapping allows mechanistic interpretation of disease mutations
The human ABCA1 transporter moves lipids from within the membrane through a narrow gate to support HDL biosynthesis.
Osteosarcoma (OS) is the most common primary bone malignancy that affects children and young adults. OS is characterized by a high degree of malignancy, strong invasiveness, rapid disease ...progression, and extremely high mortality rate; it is considered as a serious threat to the human health globally. The incidence of OS is common in the metaphysis of long tubular bones, but rare in the spine, pelvis, and sacrum areas; moreover, majority of the OS patients present with only a single lesion. OS has a bimodal distribution pattern, that is, its incidence peaks in the second decade of life and in late adulthood. We examine historical and current literature to present a succinct review of OS. In this review, we have discussed the types, clinical diagnosis, and modern and future treatment methods of OS. The purpose of this article is to inspire new ideas to develop more effective therapeutic options.
The Hedgehog (Hh) pathway involved in development and regeneration is activated by the extracellular binding of Hh to the membrane receptor Patched (Ptch). We report the cryo-EM structures of human ...Ptch1 alone and in complex with the N-terminal domain of human Sonic hedgehog (ShhN) at resolutions of 3.9 Å and 3.6 Å, respectively. Ptch1 comprises two interacting extracellular domains ECD1 and ECD2 and twelve transmembrane segments (TMs), with TMs 2-6 constituting the sterol-sensing domain (SSD). Two steroid-shaped densities are resolved in both structures, one enclosed by ECD1/2, and the other on the membrane-facing cavity of SSD. Structure-guided mutational analysis shows that interaction between ShhN and Ptch1 is steroid-dependent. The structure of a steroid binding-deficient Ptch1 mutant displays pronounced conformational rearrangements.
We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were ...more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Putative therapeutic targets or biomarkers were identified among each subtype. Importantly, the LAR subtype showed more ERBB2 somatic mutations, infrequent mutational signature 3 and frequent CDKN2A loss. The comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC.
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•We build the genomic and transcriptomic landscape of 465 primary TNBCs•Chinese TNBC cases demonstrate more PIK3CA mutations and LAR subtype•Transcriptomic data classify TNBCs into four subtypes•Multi-omics profiling identifies potential targets within specific TNBC subtypes
Jiang et al. characterize primary Chinese triple-negative breast cancer (TNBC) and classify it into four subtypes. They find that these TNBCs have more frequent PIK3CA mutations and chromosome 22q11 copy-number gains than non-Asian TNBCs and that the LAR subtype has more ERBB2 somatic mutations and CDKN2A loss.
Abstract
Clear cell carcinoma (CCC), endometrioid carcinoma (EC), and serous carcinoma (SC) are the major histological subtypes of epithelial ovarian cancer (EOC), whose differences in carcinogenesis ...are still unclear. Here, we undertake comprehensive proteomic profiling of 80 CCC, 79 EC, 80 SC, and 30 control samples. Our analysis reveals the prognostic or diagnostic value of dysregulated proteins and phosphorylation sites in important pathways. Moreover, protein co-expression network not only provides comprehensive view of biological features of each histological subtype, but also indicates potential prognostic biomarkers and progression landmarks. Notably, EOC have strong inter-tumor heterogeneity, with significantly different clinical characteristics, proteomic patterns and signaling pathway disorders in CCC, EC, and SC. Finally, we infer MPP7 protein as potential therapeutic target for SC, whose biological functions are confirmed in SC cells. Our proteomic cohort provides valuable resources for understanding molecular mechanisms and developing treatment strategies of distinct histological subtypes.
ABSTRACT
Lignin is a major component of plant cell walls and is essential for plant growth and development. Lignin biosynthesis is controlled by a hierarchical regulatory network involving multiple ...transcription factors. In this study, we showed that the gene encoding an APETALA 2/ethylene‐responsive element binding factor (AP2/ERF) transcription factor, PagERF81, from poplar 84 K (Populus alba × P. glandulosa) is highly expressed in expanding secondary xylem cells. Two independent homozygous Pagerf81 mutant lines created by gene editing, produced significantly more but smaller vessel cells and longer fiber cells with more lignin in cell walls, while PagERF81 overexpression lines had less lignin, compared to non‐transgenic controls. Transcriptome and reverse transcription quantitative PCR data revealed that multiple lignin biosynthesis genes including Cinnamoyl CoA reductase 1 (PagCCR1), Cinnamyl alcohol dehydrogenase 6 (PagCAD6), and 4‐Coumarate‐CoA ligase‐like 9 (Pag4CLL9) were up‐regulated in Pagerf81 mutants, but down‐regulated in PagERF81 overexpression lines. In addition, a transient transactivation assay revealed that PagERF81 repressed the transcription of these three genes. Furthermore, yeast one hybrid and electrophoretic mobility shift assays showed that PagERF81 directly bound to a GCC sequence in the PagCCR1 promoter. No known vessel or fiber cell differentiation related genes were differentially expressed, so the smaller vessel cells and longer fiber cells observed in the Pagerf81 lines might be caused by abnormal lignin deposition in the secondary cell walls. This study provides insight into the regulation of lignin biosynthesis, and a molecular tool to engineer wood with high lignin content, which would contribute to the lignin‐related chemical industry and carbon sequestration.
The APETALA 2/ethylene‐responsive element binding factor (AP2/ERF) transcription factor PagERF81 plays an important role in lignin biosynthesis and xylem cell differentiation in poplar and the monolignol biosynthesis gene PagCCR1 is a direct target of PagERF81.
Recent studies have implied that circHIPK3, an abundant circular RNA (circRNA), participates in tumorigenesis and cancer progression. Its expression and potential functions in human gallbladder ...cancer were examined in this study. We show that circHIPK3 is upregulated in human gallbladder cancer cells. But its level is low in gallbladder epithelial cells. circHIPK3 silencing by targeted siRNA potently inhibited survival and proliferation of established and primary human gallbladder cancer cells, while inducing cell apoptosis. Conversely, ectopic over-expression of circHIPK3 can further promote cancer cell proliferation. In gallbladder cancer cells, circHIPK3 sponged the tumor-suppressive microRNA-124 (miR-124) to sequester and inhibit its activity, thereby leading to increased expression of miR-124 targets, including ROCK1 (rho-associated protein kinase 1) and CDK6 (rho-associated protein kinase). Ectopic over-expression of miR-124 b y a lentiviral vector mimicked and abolished actions by circHIPK3 siRNA in gallbladder cancer cells. At last, we show that circHIPK3 is upregulated in human gallbladder cancer tissues, which is correlated with miR-124 downregulation and ROCK1-CDK6 upregulation. Together, we conclude that circHIPK3 promotes gallbladder cancer cell growth possibly by sponging miR-124. The over-expressed circHIPK3 could be a novel therapeutic target and diagnosis marker of human gallbladder cancer.
•circHIPK3 is upregulated in established and primary human gallbladder cancer cells.•circHIPK3 siRNA inhibits human gallbladder cancer cell survival and proliferation.•Ectopic circHIPK3 over-expression promotes gallbladder cancer cell proliferation.•circHIPK3 targets miR-124 in gallbladder cancer cells.•circHIPK3 upregulation correlates with miR-124 downregulation in gallbladder cancer tissues.
Atomic Fe in N‐doped carbon (FeNC) electrocatalysts for oxygen (O2) reduction at the cathode of proton exchange membrane fuel cells are the most promising alternative to platinum‐group‐metal ...catalysts. Despite recent progress on atomic FeNC O2 reduction, their controlled synthesis and stability for practical applications remain challenging. A two‐step synthesis approach has recently led to significant advances in terms of Fe‐loading and mass activity; however, the Fe utilization remains low owing to the difficulty of building scaffolds with sufficient porosity that electrochemically exposes the active sites. Herein, this issue is addressed by coordinating Fe in a highly porous nitrogen‐doped carbon support (≈3295 m2 g−1), prepared by pyrolysis of inexpensive 2,4,6‐triaminopyrimidine and a Mg2+ salt active site template and porogen. Upon Fe coordination, a high electrochemical active site density of 2.54 × 1019 sites gFeNC−1 and a record 52% FeNx electrochemical utilization based on in situ nitrite stripping are achieved. The Fe single atoms are characterized pre‐ and post‐electrochemical accelerated stress testing by aberration‐corrected high‐angle annular dark field scanning transmission electron microscopy, showing no Fe clustering. Moreover, ex situ X‐ray absorption spectroscopy and low‐temperature Mössbauer spectroscopy suggest the presence of penta‐coordinated Fe sites, which are further studied by density functional theory calculations.
An iron–nitrogen–carbon oxygen reduction electrocatalyst with penta‐coordinated sites and high electrochemical active sites utilization is prepared by low‐temperature Fe coordination in a porous nitrogen‐doped carbon synthetized through the ionothermal pyrolysis of 2,4,6‐triaminopyrimidine. The structure of the active site is studied by means of X‐ray absorption and Mössbauer spectroscopy and the effect of axial ligands through density functional theory calculations.
We propose a multi-phase, multi-resolution SPH method for fluid/solid interaction with multi-GPU implementation and dynamic load balancing following the movement of the refinement regions. The ...primary design goal of this framework is to maintain the efficiency of the single-resolution SPH model running on a single GPU. To this end, a multi-background mesh is introduced, and the domain is regarded as a nested multi-domain with different resolutions. Validation using both a δ-SPH and Riemann SPH model is shown, and applications to the simulation of the water entry of a projectile with a high Froude number are considered, with comparisons to experimental data from three challenging test cases, showing the proposed model's ability to correctly reproduce the free surface evolution on water entry, the motion of the projectile, and the formation and evolution of multiple cavities depending on entry angle and velocity. An analysis of the computational performance and resolutions achieved (up to 120 million particles) is also provided across several test cases.
•A multi-GPU, multi-node implementation is developed using CUDA for the GPU execution.•The efficiencies of the multi-GPU and multi-resolution model are presented and validated.•The two-phase flow of three water entry cases of slender body is simulated using the model.•The SPH model can provide a sharp interface between the air and water for water entry problems.
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