Cancer is a heterogeneous disease with many genetic variations. Lines of evidence have shown copy number variations (CNVs) of certain genes are involved in development and progression of many cancers ...through the alterations of their gene expression levels on individual or several cancer types. However, it is not quite clear whether the correlation will be a general phenomenon across multiple cancer types.
In this study we applied a bioinformatics approach integrating CNV and differential gene expression mathematically across 1025 cell lines and 9159 patient samples to detect their potential relationship.
Our results showed there is a close correlation between CNV and differential gene expression and the copy number displayed a positive linear influence on gene expression for the majority of genes, indicating that genetic variation generated a direct effect on gene transcriptional level. Another independent dataset is utilized to revalidate the relationship between copy number and expression level. Further analysis show genes with general positive linear influence on gene expression are clustered in certain disease-related pathways, which suggests the involvement of CNV in pathophysiology of diseases.
This study shows the close correlation between CNV and differential gene expression revealing the qualitative relationship between genetic variation and its downstream effect, especially for oncogenes and tumor suppressor genes. It is of a critical importance to elucidate the relationship between copy number variation and gene expression for prevention, diagnosis and treatment of cancer.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hepatocellular carcinoma (HCC) is one of the most lethal human cancers. Hepatitis B virus (HBV) infection accounts for nearly 50% of HCC cases. Recent studies indicate that HBV infection induces ...resistance to sorafenib, the first-line systemic treatment for advanced HCC for more than a decade, from 2007 to 2020. Our previous research shows that variant 1 (tv1) of proliferating cell nuclear antigen clamp-associated factor (PCLAF), overexpressed in HCC, protects against doxorubicin-induced apoptosis. However, there are no reports on the relevance of PCLAF in sorafenib resistance in HBV-related HCC. In this article, we found that PCLAF levels were higher in HBV-related HCC than in non-virus-related HCC using bioinformatics analysis. Immunohistochemistry (IHC) staining of clinical samples and the splicing reporter minigene assay using HCC cells revealed that PCLAF tv1 was elevated by HBV. Furthermore, HBV promoted the splicing of PCLAF tv1 by downregulating serine/arginine-rich splicing factor 2 (SRSF2), which hindered the inclusion of PCLAF exon 3 through a putative
-element (116-123), "
". The CCK-8 assay showed that HBV decreased cell susceptibility to sorafenib through SRSF2/PCLAF tv1. HBV reduced ferroptosis by decreasing intracellular Fe
levels and activating GPX4 expression via the SRSF2/PCLAF tv1 axis, according to a mechanism study. Suppressed ferroptosis, on the other hand, contributed to HBV-mediated sorafenib resistance through SRSF2/PCLAF tv1. These data suggested that HBV regulated PCLAF abnormal alternative splicing by suppressing SRSF2. HBV caused sorafenib resistance by reducing ferroptosis via the SRSF2/PCLAF tv1 axis. As a result, the SRSF2/PCLAF tv1 axis may be a prospective molecular therapeutic target in HBV-related HCC, as well as a predictor of sorafenib resistance. The inhibition of the SRSF2/PCLAF tv1 axis may be crucial in the emergence of systemic chemotherapy resistance in HBV-associated HCC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Multiresonance thermal activated delayed fluorescence (MR-TADF) materials with an efficient spin–flip transition between singlet and triplet excited states remain demanding. Herein, we report an ...MR-TADF compound (BN–Se) simultaneously possessing efficient (reverse) intersystem crossing (ISC/RISC), fast radiative decay, close-to-unity quantum yield, and narrowband emission by embedding a single selenium atom into a common 4,4′-diazaborin framework. Benefitting from the high RISC efficiency accelerated by the heavy-atom effect, organic light-emitting diodes (OLEDs) based on BN–Se manifest excellent performance with an external quantum efficiency of up to 32.6% and an ultralow efficiency roll-off of 1.3% at 1000 cd m–2. Furthermore, the high ISC efficiency and small inherent energy loss also render BN–Se a superior photosensitizer to realize the first example of visible (λex > 450 nm)-to-UV (λem < 350 nm) triplet–triplet annihilation upconversion, with a high efficiency (21.4%) and an extremely low threshold intensity (1.3 mW cm–2). This work not only aids in designing advanced pure organic molecules with fast exciton dynamics but also highlights the value of MR-TADF compounds beyond OLED applications.
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IJS, KILJ, NUK, PNG, UL, UM
Chronic kidney disease (CKD) is a major public health issue. At the histological level, renal fibrosis is the final common pathway of progressive kidney disease irrespective of the initial injury. ...Considerable evidence now indicates that renal inflammation plays a central role in the initiation and progression of CKD. Some of the inflammatory signaling molecules involved in CKD include: monocyte chemoattractant protein-1 (MCP-1), bradykinin B1 receptor (B1R), nuclear factor κB (NF-κB), tumor necrosis factor-α (TNFα), transforming growth factor β (TGF-β), and platelet-derived growth factor (PDGF). Multiple antifibrotic factors, such as interleukin-10 (IL-10), interferon-γ (IFN-γ), bone morphogenetic protein-7 (BMP-7), hepatocyte growth factor (HGF) are also downregulated in CKD. Therefore, restoration of the proper balance between pro- and antifibrotic signaling pathways could serve as a guiding principle for the design of new antifibrotic strategies that simultaneously target many pathways. The purpose of this review is to summarize the existing body of knowledge regarding activation of cytokine pathways and infiltration of inflammatory cells as a starting point for developing novel antifibrotic therapies to prevent progression of CKD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•A three-dimensional numerical model was established for the high-current free burning arc keyhole welding.•A novel suitable combined heat source model was proposed based on the arcing principle.•The ...evolution behavior of arc source, temperature field and flow field is visualized to exhibit how the high-current free burning arc creates a stable keyhole.
A three-dimensional numerical model was established to investigate the thermal coupling mechanism in the K-TIG (Keyhole Tungsten Inert Gas) keyhole and weld pool. Especially, to reflect the energy distribution in the new-developed high-current free burning arc, a novel, suitable combined heat source model was proposed. The dynamic process of heat source and the corresponding temperature field were studied to reflect the effect of arc on the workpiece. Keyhole evolution with temperature distribution and fluid flow in the weld pool was investigated to further explore the keyhole influence on the heat transfer and mechanical energy of the weld pool. Some new features of K-TIG were discovered. The higher temperature molten metal is distributed mainly in the upper part instead of the bottom of the weld pool, and the weld pool volume of K-TIG is large, up to 50 mm3. Finally, the first emerging time of a fully penetrated keyhole, keyhole size, and fusion line size were measured in stationary welding experiments. The simulation results agreed well with the measured data. The results lay a foundation for understanding the coupling behavior in energy source-keyhole-weld pool system, and they could promote the engineering application of K-TIG process.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chronic kidney disease (CKD) is a significant worldwide healthcare problem. Regardless of the initial injury, renal fibrosis is the common final pathway leading to end stage renal disease. Although ...the underlying mechanisms are not fully defined, evidence indicates that besides inflammation, oxidative stress plays a crucial role in the etiology of renal fibrosis. Oxidative stress results from an imbalance between the production of free radicals that are often increased by inflammation and mitochondrial dysfunction, and reduced anti-oxidant defenses. Several studies have demonstrated that oxidative stress may occur secondary to activation of transforming growth factor β1 (TGF-β1) activity, consistent with its role to increase nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) activity. A number of other oxidative stress-related signal pathways have also been identified, such as nuclear factor erythroid-2 related factor 2 (Nrf2), the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-cGMP-dependent protein kinase 1-phosphodiesterase (cGMP-cGK1-PDE) signaling pathway, and the peroxisome proliferator-activated receptor gamma (PPARγ) pathway. Several antioxidant and renoprotective agents, including cysteamine bitartrate, epoxyeicosatrienoic acids (EETs), and cytoglobin (Cygb) have demonstrated ameliorative effects on renal fibrosis in preclinical or clinical studies. The mechanism of action of many traditional Chinese medicines used to treat renal disorders is based on their antioxidant properties, which could form the basis for new therapeutic approaches. This review focuses on the signaling pathways triggered by oxidative stress that lead to renal fibrosis and provides an update on the development of novel anti-oxidant therapies for CKD.
Electrochemical reduction of CO 2 is considered to be an efficient strategy for converting CO 2 emissions into valued-added carbon compounds. However, it often suffers from high overpotential, low ...product faradaic efficiency and poor selectivity for the desired products. Herein, a cost-effective method was designed to anchor Ag nanoparticles onto 3D graphene-wrapped nitrogen-doped carbon foam (Ag-G-NCF) by direct carbonization of melamine foam loaded with graphene oxide and silver salt. Directly acting as a high-efficiency electrode for CO 2 electrochemical reduction, the Ag-G-NCF can efficiently and preferentially convert CO 2 to ethanol with faradaic efficiencies (FEs) of 82.1–85.2% at −0.6 to −0.7 V ( vs. RHE), overcoming the usual limitation of low FE and selectivity for C2 products. Density functional theory calculations confirmed that the pyridinic N species of the Ag-G-NCF catalyst exhibited a higher bonding ability toward CO* intermediates than other N species, and that then the Ag particles gradually converted the CO* to the OC–COH intermediate of ethanol. Its excellent performance in CO 2 electroreduction can be attributed to a combination of the synergistic catalysis occurring between the pyridinic N present at high content and the Ag nanoparticles, the hierarchical macroporous structure, and the good conductivity.
The catalytic performance of metal–organic framework (MOF)-based catalysts can be enhanced by increasing their catalytic sites, which prompts us to explore the multicore cluster-based skeletons by ...using designed functional ligands. Herein, the exquisite combination of Tb4(μ2–OH)2(CO2)8 cluster and 2,6-bis(2,4-dicarboxylphenyl)-4-(4-carboxylphenyl)pyridine (H5BDCP) ligand generated a highly robust nanoporous framework of {Tb4(BDCP)2(μ2–OH)2·3DMF·5H2O} n (NUC-58), in which each four {Tb4} clusters are woven together to generate an elliptical nanocage (aperature ca. 12.4 Å). As far as we know, NUC-58 is an excellent nanocage-cluster-based {Tb4}-organic framework with the outstanding confined pore environments of a large specific surface area, high porosity, and plentiful coexisting Lewis acid–base sites of Tb3+, μ2–OH and Npyridine atoms. Performed experiments exhibited that NUC-58 owns a better catalytic performance for the cycloaddition reactions under mild conditions with a high turnover number and turnover frequency. Furthermore, NUC-58, as an eminent heterogeneous catalyst, can enormously boost the Knoevenagel condensation reactions. Thus, this work opens a path for the precise design of polynuclear metal cluster-based MOFs with excellent catalysis, stability, and regenerative behavior.
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IJS, KILJ, NUK, PNG, UL, UM
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an unprecedented public health crisis. There are no approved ...vaccines or therapeutics for treating COVID-19. Here we report a humanized monoclonal antibody, H014, that efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nanomolar concentrations by engaging the spike (S) receptor binding domain (RBD). H014 administration reduced SARS-CoV-2 titers in infected lungs and prevented pulmonary pathology in a human angiotensin-converting enzyme 2 mouse model. Cryo-electron microscopy characterization of the SARS-CoV-2 S trimer in complex with the H014 Fab fragment unveiled a previously uncharacterized conformational epitope, which was only accessible when the RBD was in an open conformation. Biochemical, cellular, virological, and structural studies demonstrated that H014 prevents attachment of SARS-CoV-2 to its host cell receptors. Epitope analysis of available neutralizing antibodies against SARS-CoV and SARS-CoV-2 uncovered broad cross-protective epitopes. Our results highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19.
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