A combined strategy of building blocks recognition and molecular network construction, termed the building blocks‐based molecular network (BBMN), was first presented to facilitate the efficient ...discovery of novel natural products. By mapping the BBMN of the total alkaloid fraction of Flueggea suffruticosa, three Securinega alkaloids (SEAs) with unusual chemical architectures, suffranidines A–C (1–3), were discovered and isolated. Compound 1 characterizes an unprecedented 8/5/6/5/6/6/6/6‐fused octacyclic scaffold with a unique cage‐shaped 3‐azatricyclo6.4.0.03,11dodecane core. Compounds 2 and 3 are highly modified SEA dimers that incorporate additional C6 motifs. A hypothetical biosynthetic pathway for 1–3 was proposed. In addition, 1 significantly induced neuronal differentiation and neurite extension by upregulating eukaryotic elongation factor 2 (eEF2)‐mediated protein synthesis.
A building blocks‐based molecular network (BBMN) strategy was first presented and resulted in the discovery of three novel Securinega alkaloids. Compound 1 features an unprecedented 8/5/6/5/6/6/6/6‐fused octacyclic scaffold with a unique cage‐shaped 3‐azatricyclo6.4.0.03,11dodecane core, which also exhibited remarkable effects on neuronal differentiation and neurite extension.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The re-emergence of Zika virus (ZIKV) in the Western Hemisphere has resulted in global public health crisis since 2015. ZIKV preferentially infects and targets human neural progenitor cells (hNPCs) ...and causes fetal microcephaly upon maternal infection. hNPCs not only play critical roles during fetal brain development, but also persist in adult brain throughout life. Yet the mechanism of innate antiviral immunity in hNPCs remains largely unknown. Here, we show that ZIKV infection triggers the abundant production of virus-derived small interfering RNAs in hNPCs, but not in the more differentiated progenies or somatic cells. Ablation of key RNAi machinery components significantly enhances ZIKV replication in hNPCs. Furthermore, enoxacin, a broad-spectrum antibiotic that is known as an RNAi enhancer, exerts potent anti-ZIKV activity in hNPCs and other RNAi-competent cells. Strikingly, enoxacin treatment completely prevents ZIKV infection and circumvents ZIKV-induced microcephalic phenotypes in brain organoid models that recapitulate human fetal brain development. Our findings highlight the physiological importance of RNAi-mediated antiviral immunity during the early stage of human brain development, uncovering a novel strategy to combat human congenital viral infections through enhancing RNAi.
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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
Excessive reactive oxygen species (ROS) accumulation is involved in the pathogenesis of liver fibrosis and damage, specifically in the developing embryo that is extremely sensitive to oxidative ...stress. Herein, a liver injury model in chick embryo was established by using 2,2-azobis (2-amidinopropane) dihydrochloride (AAPH), which was used to investigate the effect of cyclo(-Phe-Phe) (CPP), a natural dipeptide found in foods and beverages. The results showed that CPP significantly alleviated AAPH-induced liver pathological damage, hepatic dysfunction and inhibited the excessive production of ROS in both chick embryo liver and HepG2 cells. Additionally, CPP increased the antioxidative activity of glutathione peroxidase (GPx) and superoxide dismutase (SOD), as well as elevated the level of glutathione (GSH), suggesting that CPP combating liver injury probably depends on its antioxidant capability. Mechanistically, CPP upregulated the mRNA and protein expression of heme oxyense-1 (HO-1) and NADPH quinone oxidoreductase 1 (NQO1)
and
, along with promoting the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) while inhibiting its degradation through binding with Kelch-like ECH-associated protein 1 (Keap1). In conclusion, this study proposes a potential peptide drug for the treatment of hepatic damage induced by oxidative stress and also unravels its mechanism of action.
Chemical neurotransmission occurs at chemical synapses and endocrine glands, but up to now there was no means for direct monitoring of neurotransmitter exocytosis fluxes and their precise kinetics ...from inside an individual synapse. The fabrication of a novel finite conical nanoelectrode is reported perfectly suited in size and electrochemical properties for probing amperometrically inside what appears to be single synapses and monitoring individual vesicular exocytotic events in real time. This allowed obtaining direct and important physiological evidences which may yield important and new insights into the nature of synaptic communications.
Chemical neurotransmission occurs at chemical synapse, but up to now there was no means for direct monitoring of neurotransmitter exocytosis and its precise kinetics from inside individual infinitesimal synapse. A novel finite conical nanoelectrode is fabricated and used in a newly developed amperometric method (see picture) for probing inside what appears to be single synapses.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Drug‐induced liver injury (DILI) is a leading cause of therapy failure in the clinic and also contributes much to acute liver failure cases. Investigations of predictive sensitivity in animal models ...have limitations due to interspecies differences. Previously reported in vitro models of liver injury based on primary human hepatocytes (PHHs) cannot meet the requirements of high physiological fidelity, low cost, simple operation, and high throughput with improved sensitivity. Herein, we developed an integrated biomimetic array chip (iBAC) for establishing extracellular matrix (ECM)‐based models. A collagen‐based 3D PHH model was constructed on the iBAC as a case for the prediction of clinical DILI at throughput. The iBAC has a three‐layer structure with a core component of 3D implanting holes. At an initial cell seeding numbers of 5000–10,000, the collagen‐based 3D PHH model was optimized with improved and stabilized liver functionality, including cell viability, albumin, and urea production. Moreover, basal activities of most metabolic enzymes on the iBAC were maintained for at least 12 days. Next, a small‐scale hepatotoxicity screening indicated that the 3D PHH model on the iBAC was more sensitive for predicting hepatotoxicity than the 2D PHH model on the plate. Finally, a large‐scale screening of liver toxicity using 122 clinical drugs further demonstrated that the collagen‐based 3D PHH model on the iBAC had superior predictive sensitivity compared to all previously reported in vitro models. These results indicated the importance of 3D collagen for liver physiological functionality and hepatotoxicity prediction. We anticipant it being a promising tool for risk assessment of drug‐induced hepatotoxicity with a widespread acceptance in drug industry.
A collagen‐based 3D primary human hepatocyte model on an integrated biomimetic array chip for the prediction of clinical drug‐induced liver injury was developed. Industrialized validation of liver toxicity using 122 clinical drugs demonstrated that this model had superior predictive sensitivity compared to all previously reported in vitro models. The improved sensitivity indicated the importance of the 3D collagen for liver physiological functionality and hepatotoxicity prediction.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
The recent advanced LIGO/Virgo detections of gravitational waves (GWs) from stellar binary black hole (BBH) mergers, in particular GW190521, which is potentially associated with a quasar, ...have stimulated renewed interest in active galactic nuclei as factories of merging BBHs. Compact objects evolving from massive stars are unavoidably enshrouded by a massive envelope to form accretion-modified stars (AMSs) in the dense gaseous environment of a supermassive black hole (SMBH) accretion disk. We show that most AMSs form binaries due to gravitational interaction with each other during radial migration in the SMBH disk, forming BBHs inside the AMS. When a BBH is born, its orbit is initially governed by the tidal torque of the SMBH. Bondi accretion onto a BBH at a hyper-Eddington rate naturally develops and then controls the evolution of its orbits. We find that Bondi accretion leads to efficient removal of the orbital angular momentum of the binary, whose final merger produces a GW burst. Meanwhile, the Blandford–Znajek mechanism pumps the spin energy of the merged BH to produce an electromagnetic counterpart (EMC). Moreover, hyper-Eddington accretion onto the BBH develops powerful outflows and triggers a Bondi explosion, which manifests itself as an EMC of the GW burst, depending on the viscosity of the accretion flow. Thermal emission from the Bondi sphere appears as one of the EMCs. The BBHs radiate GWs with frequencies of ∼10
2
Hz, which are accessible to LIGO.
Objective
To determine whether serum prealbumin levels are associated with long‐term survival after hepatectomy in patients with primary hepatocellular carcinoma(HCC).
Methods
A consecutive sample of ...526 patients with HCC who underwent potentially curative hepatectomy from August 2007 to August 2010 was retrospectively analyzed. Patients were classified as having normal or reduced serum prealbumin based on cut‐off values of 200 or 182 mg/L.
Results
Multivariate analysis identified the preoperative level of serum prealbumin as an independent prognostic factor of long‐term survival (P < 0.05): Survival was significantly better for those with normal levels than for those with reduced levels, based on either cut‐off value. Similar results were observed in subgroup analyses based on the degree of cirrhosis, level of ɑ‐fetoprotein and Barcelona Clinic Liver Cancer stage.
Conclusions
Preoperative level of serum prealbumin may be useful for predicting long‐term survival in patients with HCC after hepatectomy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Robust ceramic color converters withstanding strong laser irradiations have recently drawn great attention for laser‐driven white lighting. However, the local emission within the incident laser spot ...usually expands to the whole surface area of the ceramics, which definitely makes it hard to achieve white light with high luminance and high directionality. Herein, a new strategy is proposed to solve the problem by elaborately introducing uniform spherical pores (diameter of ≈2 µm) into the phosphor ceramics with controlled contents from 8 to 24.6 vol%. The well‐distributed pores, acting as light scattering centers, enable reduction of the luminescent spot size greatly but without any losses in conversion efficiency. By using the high‐scattering ceramic color converters with 15% porosity, the light spot diameter is decreased by 46% and the central illuminance is increased by 156%. Moreover, laser‐driven white light with an enhanced beam directionality and uniformity is also achieved. A superhigh luminous flux of 7199 lm is realized by using this promising color converter in a rotary mode. The designed high‐scattering ceramics with controllable microstructures show great potential for use in extra‐high luminance laser‐driven lighting and projection.
Phosphor ceramics stand out in laser‐driven white lighting. A quite different design strategy is proposed to construct high‐light‐scattering ceramics. The beam expansion ratio is decreased from 3.14 to 1.68 and the center beam illuminance is increased by 156% in the highly scattering sample. Eventually, truly quasi‐point laser‐driven white light with high luminance and high directionality is achieved.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In this work, by combining the superiority of polyoxometalates (POMs) and catalytic single‐metal site Co of metalloporphyrin, a series of mixed‐valence POM‐based metal‐organic frameworks (MOFs) ...composites is synthesized by a post‐modification method. The electron‐transfer property of POM@PCN‐222(Co) composite is significantly enhanced owing to the directional electron‐transfer from POM to single‐metal site Co in PCN‐222(Co). In particular, H‐POM@PCN‐222(Co) gives a high Faradaic efficiency of 96.2% for electroreduction of CO2 into CO and good stability over 10 h. DFT calculations confirm that the directional electron transfer, which accelerates the multi‐electron transfer from the electrode to active single‐metal site Co, enriches the electron density of the Co center, and ultimately reduces the energy of the rate‐determining step, thus increasing the catalytic activity of CO2 reduction reaction (CO2RR). This work therefore suggests some new insight for the design of efficient electrocatalysts for CO2RR.
By combining the superiority of polyoxometalates (POM) and single‐metal site Co in porphyrin, a series of POM‐based metal–organic frameworks composites have been synthesized. Directional electron transfer from POM to single‐metal site Co in PCN‐222(Co) accelerates the electron‐transfer efficiency, enriches the electron density of the active center, and ultimately gives rise to high electrocatalytic CO2 reduction reaction activity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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