Since the global outbreak of SARS-CoV-2 (COVID-19), infections of diverse human organs along with multiple symptoms continue to be reported. However, the susceptibility of the brain to SARS-CoV-2, ...and the mechanisms underlying neurological infection are still elusive. Here, we utilized human embryonic stem cell-derived brain organoids and monolayer cortical neurons to investigate infection of brain with pseudotyped SARS-CoV-2 viral particles. Spike-containing SARS-CoV-2 pseudovirus infected neural layers within brain organoids. The expression of ACE2, a host cell receptor for SARS-CoV-2, was sustained during the development of brain organoids, especially in the somas of mature neurons, while remaining rare in neural stem cells. However, pseudotyped SARS-CoV-2 was observed in the axon of neurons, which lack ACE2. Neural infectivity of SARS-CoV-2 pseudovirus did not increase in proportion to viral load, but only 10% of neurons were infected. Our findings demonstrate that brain organoids provide a useful model for investigating SARS-CoV-2 entry into the human brain and elucidating the susceptibility of the brain to SARS-CoV-2.
Summary Background Currently, metastatic renal cell carcinoma is treated with sequential single agents targeting VEGF or mTOR. Here, we aimed to assess lenvatinib, everolimus, or their combination as ...second-line treatment in patients with metastatic renal cell carcinoma. Methods We did a randomised, phase 2, open-label, multicentre trial at 37 centres in five countries and enrolled patients with advanced or metastatic, clear-cell, renal cell carcinoma. We included patients who had received treatment with a VEGF-targeted therapy and progressed on or within 9 months of stopping that agent. Patients were randomised via an interactive voice response system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The randomisation procedure dynamically minimised imbalances between treatment groups for the stratification factors haemoglobin and corrected serum calcium. The primary objective was progression-free survival in the intention-to-treat population. This study is closed to enrolment but patients' treatment and follow-up is ongoing. This study is registered with ClinicalTrials.gov , number NCT01136733. Findings Between March 16, 2012, and June 19, 2013, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged progression-free survival compared with everolimus alone (median 14·6 months 95% CI 5·9–20·1 vs 5·5 months 3·5–7·1; hazard ratio HR 0·40, 95% CI 0·24–0·68; p=0·0005), but not compared with lenvatinib alone (7·4 months 95% CI 5·6–10·2; HR 0·66, 95% CI 0·30–1·10; p=0·12). Single-agent lenvatinib significantly prolonged progression-free survival compared with everolimus alone (HR 0·61, 95% CI 0·38–0·98; p=0·048). Grade 3 and 4 events occurred in fewer patients allocated single-agent everolimus (25 50%) compared with those assigned lenvatinib alone (41 79%) or lenvatinib plus everolimus (36 71%). The most common grade 3 or 4 treatment-emergent adverse event in patients allocated lenvatinib plus everolimus was diarrhoea (ten 20%), in those assigned single-agent lenvatinib it was proteinuria (ten 19%), and in those assigned single-agent everolimus it was anaemia (six 12%). Two deaths were deemed related to study drug, one cerebral haemorrhage in the lenvatinib plus everolimus group and one myocardial infarction with single-agent lenvatinib. Interpretation Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. Further study of lenvatinib is warranted in patients with metastatic renal cell carcinoma. Funding Eisai Inc.
Ternary blend approaches are demonstrated as a universal means to improve overall performance of organic photovoltaics (OPVs) in both indoor and outdoor conditions. A comparative study on two ...donors:one acceptor (2D:1A) and one donor:two acceptors (1D:2A) ternary blends shows that both approaches are universally effective for indoor and outdoor operation; the 1D:2A devices incorporating a nonfullerene acceptor (NFA) benefit from less charge recombination and higher power conversion efficiencies (PCEs) for various irradiation conditions, while the performance of the 2D:1A blends depends on the emission spectrum of the incident light source. The synergistic merits of NFAs and ternary structure in the 1D:2A ternary OPVs secure better performance and generality regardless of the incident lighting. A combination of experimental and theoretical analyses unveils that NFAs optimize packing and arrangement of molecules to build efficient cascade ternary junctions in the 1D:2A blends, which can be important design guidelines for the third component in ternary OPVs. The optimized 1D:2A ternary OPV exhibits a new record PCE of 25.6% under a 200 lux light‐emitting diode (LED) and 26.4% under a 1000 lux LED, and superior durability under industrial relevant thermal stress, suggesting new opportunities in diverse practical applications challenging the currently dominant PV technologies.
This study provides important guidelines for the third component in ternary organic photovoltaics (OPVs), involving high molecular compatibility with main components and favorable ternary junction formation with cascade band alignment. With a high efficiency in any irradiation conditions (≈26.4% under light‐emitting diodes) and superior thermal durability, ternary OPVs incorporating nonfullerene acceptors open new opportunities in broad practical applications.
Astrocytes and microglia are brain‐resident glia that can establish harmful inflammatory environments in disease contexts and thereby contribute to the progression of neuronal loss in ...neurodegenerative disorders. Correcting the diseased properties of glia is therefore an appealing strategy for treating brain diseases. Previous studies have shown that serum/ glucocorticoid related kinase 1 (SGK1) is upregulated in the brains of patients with various neurodegenerative disorders, suggesting its involvement in the pathogenesis of those diseases. In this study, we show that inhibiting glial SGK1 corrects the pro‐inflammatory properties of glia by suppressing the intracellular NFκB‐, NLRP3‐inflammasome‐, and CGAS‐STING‐mediated inflammatory pathways. Furthermore, SGK1 inhibition potentiated glial activity to scavenge glutamate toxicity and prevented glial cell senescence and mitochondrial damage, which have recently been reported as critical pathologic features of and therapeutic targets in Parkinson disease (PD) and Alzheimer disease (AD). Along with those anti‐inflammatory/neurotrophic functions, silencing and pharmacological inhibition of SGK1 protected midbrain dopamine neurons from degeneration and cured pathologic synuclein alpha (SNCA) aggregation and PD‐associated behavioral deficits in multiple in vitro and in vivo PD models. Collectively, these findings suggest that SGK1 inhibition could be a useful strategy for treating PD and other neurodegenerative disorders that share the common pathology of glia‐mediated neuroinflammation.
Synopsis
Pathogenic involvement of SGK1 has been implicated in various neurodegenerative disorders. In this study, we show that inhibition of SGK1 in glia treats Parkinson disease (PD) via suppressing glial inflammation and potentiating glial neurotrophic functions.
SGK inhibition reduces neuroinflammation and protects dopamine neurons from degeneration.
PD – associated behavioral deficits are improved in PD mice after SGK inhibition.
Inhibition of SGK1 could be a useful strategy for treating PD and other neurodegenerative disorders.
Pathogenic involvement of SGK1 has been implicated in various neurodegenerative disorders. In this study, we show that inhibition of SGK1 in glia treats Parkinson disease (PD) via suppressing glial inflammation and potentiating glial neurotrophic functions.
To improve the interfacial properties of super fabrics, the effect of surface treatment on the dopamine monomer concentration was investigated. Carbon and aramid composites were manufactured with the ...same lamination structures using VARTM. The mechanical strength and stiffness of the fiber composite materials with polydopamine surface treatment were investigated. The surface treatment improved the mechanical properties of carbon and aramid fabric composites. The composites showed the highest tensile strength and stiffness at the dopamine and tris(hydroxymethyl) aminomethane (TRIS) concentrations of 1.5 g/L and 40 mM, respectively. For surface treatment with 1 g/L polydopamine and 40 mM TRIS, the bending strength was the best and improved by more than 11%.
Scope
Garcinia cambogia (G. cambogia) is known to have antiobesity effects. In this study, the therapeutic effects of G. cambogia on glucose homeostasis in obesity‐induced diabetes are explored and ...the underlying mechanisms are investigated.
Methods and results
C2C12 myotubes are treated with G. cambogia; glucose uptake, intracellular Ca2+ levels, and related alterations in signaling pathways are examined. High‐fat diet (HFD)‐fed mice are administered G. cambogia for 8 weeks; oral glucose tolerance is evaluated, and the regulation of identified targets of signaling pathways in quadriceps skeletal muscle are examined in vivo. G. cambogia increases glucose uptake in C2C12 myotubes and induces the upregulation of AMPK, ACC, and p38 MAPK phosphorylation. Notably, G. cambogia markedly elevates both intracellular Ca2+ levels, activating CaMKII, a Ca2+‐sensing protein, and TBC1D4‐mediated GLUT4 translocation, to facilitate glucose uptake. Furthermore, high‐glucose‐induced inhibition of glucose uptake and signal transduction is reverted by G. cambogia. In an HFD‐induced diabetes mouse model, G. cambogia administration results in significant blood glucose‐lowering effects, which are attributed to the regulation of targets that have been identified in vitro, in quadricep skeletal muscle.
Conclusion
These findings provide new insights into the mechanism by which G. cambogia regulates glucose homeostasis in obesity‐induced diabetes.
Proposed mechanism of the therapeutic effect of Garcinia cambogia against obesity‐induced diabetes. G. cambogia inhibits HFD‐induced hyperglycemia by activating the Ca2+/CaMKII/AMPK/p38/TBC1D4 signaling pathway and GLUT4 translocation in skeletal muscle cells, leading to glucose uptake and homeostasis.
Zinc oxide (ZnO) nano flowers uniformly attached to the surface of Molybdenum disulfide (MoS2) sheet were successfully prepared via a simple facile one pot hydrothermal method. The morphology and ...microstructure of the prepared samples was characterized using field – emission scanning electron microscopy (FE-SEM), Transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and photoluminescence (PL) spectroscopy. The Brunauer-Emmett-Teller (BET) surface area was determined using physical and chemical analyzer. The characterization results showed that the flowers like ZnO micro-structures were uniformly attached to the surface of MoS2. The as-prepared MoS2/ZnO composite showed enhanced photocatalytic activity and considerable stability for the photo degradation of phenol red as compared with pure MoS2 and ZnO under both UV and visible light irradiation. Such an enhancement of photo degradation capability was ascribed to the synergistic effect between the flowers-shaped ZnO particles and sheet-like structure of MoS2, which boost the migration efficiency of photo-induced electrons and hinder electron-hole recombination rate. It was also found that the amount of MoS2 in the composite has a significant effect on the degradation activity. Moreover, the antibacterial activity test towards the gram negative Escherichia-coli showed that the MoS2/ZnO composite has better antibacterial properties compared to pure ZnO and MoS2.
•MoS2/ZnO composite was prepared from facile one pot hydrothermal method.•Phenol red was used to test the photocatalytic degradation activity of the prepared composite.•Uniform distribution of ZnO particles on the large surface of MoS2 sheet enhanced the electron-hole separation ability.•Improved antibacterial property was obtained with the introducing of MoS2 sheet.
•Large eddy simulation was conducted forflow inside a volute-type centrifugal pump.•Flow losses were caused by the impeller-volute interaction.•Leakage to/fromtop and bottom cavities produced flow ...loss.•Leakage to the gap between the volute tongue and impeller produced flow loss.
The flow characteristics in a volute-type centrifugal pump operating at design (Qd = 35 m3/h) and off-design (Qoff = 20 m3/h) conditions are investigated using large eddy simulation. Numerical results indicate that separation bubbles are generated on both the pressure and suction sides of impeller blades. At the off-design condition, the blade pressure side contains a larger recirculation zone with highly unsteady characteristics due to impeller-volute interactions. The vortices shed from a blade trailing edge due to its rotation strongly interact with those from the following blade and leakage through radial gaps at the off-design condition, generating stronger vortices in a wider region inside the volute, whereas this mutual interaction is weak at the design condition. Flow separation also occurs around the volute tongue at both operating conditions. At the off-design condition, a part of high-pressure fluid discharged from the volute does not follow the main stream to the outlet duct but re-enters into the volute area near the volute tongue. This pressurized fluid forms a high adverse pressure gradient on the blade pressure side, resulting in strong unsteady separation there. Also, a high pressure gradient in the axial direction at the radial gaps is formed especially near the volute tongue, creating the leakage into the cavities. Inside the volute, azimuthal vortices exist and grow along the volute passage. A secondary motion induced by these vortices also significantly affects the leakage to the cavities. All of these flow losses contain unsteady features that are strongly influenced by impeller-volute interactions, especially at the off-design condition.
Short-chain alkanes (SCA; C2-C4) emitted from geological sources contribute to photochemical pollution and ozone production in the atmosphere. Microorganisms that oxidize SCA and thereby mitigate ...their release from geothermal environments have rarely been studied. In this study, propane-oxidizing cultures could not be grown from acidic geothermal samples by enrichment on propane alone, but instead required methane addition, indicating that propane was co-oxidized by methanotrophs. "Methylacidiphilum" isolates from these enrichments did not grow on propane as a sole energy source but unexpectedly did grow on C3 compounds such as 2-propanol, acetone, and acetol. A gene cluster encoding the pathway of 2-propanol oxidation to pyruvate via acetol was upregulated during growth on 2-propanol. Surprisingly, this cluster included one of three genomic operons (pmoCAB3) encoding particulate methane monooxygenase (PMO), and several physiological tests indicated that the encoded PMO3 enzyme mediates the oxidation of acetone to acetol. Acetone-grown resting cells oxidized acetone and butanone but not methane or propane, implicating a strict substrate specificity of PMO3 to ketones instead of alkanes. Another PMO-encoding operon, pmoCAB2, was induced only in methane-grown cells, and the encoded PMO2 could be responsible for co-metabolic oxidation of propane to 2-propanol. In nature, propane probably serves primarily as a supplemental growth substrate for these bacteria when growing on methane.
Consistent with the observation that ammonia-oxidizing bacteria (AOB) outnumber ammonia-oxidizing archaea (AOA) in many eutrophic ecosystems globally, AOB typically dominate activated sludge aeration ...basins from municipal wastewater treatment plants (WWTPs). In this study, we demonstrate that the growth of AOA strains inoculated into sterile-filtered wastewater was inhibited significantly, in contrast to uninhibited growth of a reference AOB strain. In order to identify possible mechanisms underlying AOA-specific inhibition, we show that complex mixtures of organic compounds, such as yeast extract, were highly inhibitory to all AOA strains but not to the AOB strain. By testing individual organic compounds, we reveal strong inhibitory effects of organic compounds with high metal complexation potentials implying that the inhibitory mechanism for AOA can be explained by the reduced bioavailability of an essential metal. Our results further demonstrate that the inhibitory effect on AOA can be alleviated by copper supplementation, which we observed for pure AOA cultures in a defined medium and for AOA inoculated into nitrifying sludge. Our study offers a novel mechanistic explanation for the relatively low abundance of AOA in most WWTPs and provides a basis for modulating the composition of nitrifying communities in both engineered systems and naturally occurring environments.
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