Ferroptosis, a recently identified form of non-apoptotic cell death, is involved in several physiological and pathological processes. Although lipid peroxidation plays a central role in triggering ...ferroptosis, the essential regulator of lipid metabolism in ferroptosis remains poorly defined. Here, we show that acyl-CoA synthetase long-chain family member 4 (ACSL4) is required for ferroptotic cancer cell death. Compared with ferroptosis-sensitive cells (e.g., HepG2 and HL60), the expression of ACSL4 was remarkably downregulated in ferroptosis-resistant cells (e.g., LNCaP and K562). In contrast, the expression of other ACSLs, including ACSL1, ACSL3, ACSL5, and ACSL6, did not correlate with ferroptosis sensitivity. Moreover, knockdown of ACSL4 by specific shRNA inhibited erastin-induced ferroptosis in HepG2 and HL60 cells, whereas overexpression of ACSL4 by gene transfection restored sensitivity of LNCaP and K562 cells to erastin. Mechanically, ACSL4-mediated production of 5-hydroxyeicosatetraenoic acid (5-HETE) contributed to ferroptosis. Pharmacological inhibition of 5-HETE production by zileuton limited ACSL4 overexpression-induced ferroptosis. Collectively, these results indicate that ACSL4 is not only a sensitive monitor of ferroptosis, but also an important contributor of ferroptosis.
Ferroptosis is a form of non-apoptotic cell death originally identified in cancer cells. However, the key regulator of ferroptosis in mitochondria remains unknown. Here, we show that CDGSH iron ...sulfur domain 1 (CISD1, also termed mitoNEET), an iron-containing outer mitochondrial membrane protein, negatively regulates ferroptotic cancer cell death. The classical ferroptosis inducer erastin promotes CISD1 expression in an iron-dependent manner in human hepatocellular carcinoma cells (e.g., HepG2 and Hep3B). Genetic inhibition of CISD1 increased iron-mediated intramitochondrial lipid peroxidation, which contributes to erastin-induced ferroptosis. In contrast, stabilization of the iron sulfur cluster of CISD1 by pioglitazone inhibits mitochondrial iron uptake, lipid peroxidation, and subsequent ferroptosis. These findings indicate a novel role of CISD1 in protecting against mitochondrial injury in ferroptosis.
Boron nitride (BN) structures are featured by their excellent thermal and chemical stability and unique electronic and optical properties. However, the lack of controlled synthesis of quality samples ...and the electrically insulating property largely prevent realizing the full potential of BN nanostructures. A comprehensive overview of the current status of the synthesis of two‐dimensional hexagonal BN sheets, three dimensional porous hexagonal BN materials and BN‐involved heterostructures is provided, highlighting the advantages of different synthetic methods. In addition, structural characterization, functionalizations and prospective applications of hexagonal BN sheets are intensively discussed. One‐dimensional BN nanoribbons and nanotubes are then discussed in terms of structure, fabrication and functionality. In particular, the existing routes in pursuit of tunable electronic and magnetic properties in various BN structures are surveyed, calling upon synergetic experimental and theoretical efforts to address the challenges for pioneering the applications of BN into functional devices. Finally, the progress in BN superstructures and novel B/N nanostructures is also briefly introduced.
Boron nitride nanostructures have attracted intense attention for their excellent properties. Controlled synthesis of quality samples and the electrically insulating property largely prevents the realization of the full potential of BN nanostructures. The current status of the synthesis and applications of two dimensional h‐BN are reviewed, as well as versatile strategies in pursuit of tunable electronic and magnetic properties in BN nanostructures.
Since the early nineteenth century, it has been known that an electric potential can be generated by driving an ionic liquid through fine channels or holes under a pressure gradient. More recently, ...it has been reported that carbon nanotubes can generate a voltage when immersed in flowing liquids, but the exact origin of these observations is unclear, and generating electricity without a pressure gradient remains a challenge. Here, we show that a voltage of a few millivolts can be produced by moving a droplet of sea water or ionic solution over a strip of monolayer graphene under ambient conditions. Through experiments and density functional theory calculations, we find that a pseudocapacitor is formed at the droplet/graphene interface, which is driven forward by the moving droplet, charging and discharging at the front and rear of the droplet. This gives rise to an electric potential that is proportional to the velocity and number of droplets. The potential is also found to be dependent on the concentration and ionic species of the droplet, and decreases sharply with an increasing number of graphene layers. We illustrate the potential of this electrokinetic phenomenon by using it to create a handwriting sensor and an energy-harvesting device.
Summary Background Nivolumab has shown improved survival in the treatment of advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. We assessed the safety and activity of ...combination nivolumab plus ipilimumab as first-line therapy for NSCLC. Methods The open-label, phase 1, multicohort study (CheckMate 012) cohorts reported here were enrolled at eight US academic centres. Eligible patients were aged 18 years or older with histologically or cytologically confirmed recurrent stage IIIb or stage IV, chemotherapy-naive NSCLC. Patients were randomly assigned (1:1:1) by an interactive voice response system to receive nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks, or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicities, or withdrawal of consent. Data from the latter two cohorts, which were considered potentially suitable for further clinical development, are presented in this report; data from the other cohort (as well as several earlier cohorts) are described in the appendix . The primary outcome was safety and tolerability, assessed in all treated patients. This ongoing study is registered with ClinicalTrials.gov , number NCT01454102. Findings Between May 15, 2014, and March 25, 2015, 78 patients were randomly assigned to receive nivolumab every 2 weeks plus ipilimumab every 12 weeks (n=38) or nivolumab every 2 weeks plus ipilimumab every 6 weeks (n=40). One patient in the ipilimumab every-6-weeks cohort was excluded before treatment; therefore 77 patients actually received treatment (38 in the ipilimumab every-12-weeks cohort; 39 in the ipilimumab every-6-weeks cohort). At data cut-off on Jan 7, 2016, 29 (76%) patients in the ipilimumab every-12-weeks cohort and 32 (82%) in the ipilimumab every-6-weeks cohort had discontinued treatment. Grade 3–4 treatment-related adverse events occurred in 14 (37%) patients in the ipilimumab every-12-weeks cohort and 13 (33%) patients in the every-6-weeks cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (three 8% and no patients), pneumonitis (two 5% and one 3% patients), adrenal insufficiency (one 3% and two 5% patients), and colitis (one 3% and two 5% patients). Treatment-related serious adverse events were reported in 12 (32%) patients in the ipilimumab every-12-weeks cohort and 11 (28%) patients in the every-6-weeks cohort. Treatment-related adverse events (any grade) prompted treatment discontinuation in four (11%) patients in the every-12-weeks cohort and five (13%) patients in the every-6-weeks cohort. No treatment-related deaths occurred. Confirmed objective responses were achieved in 18 (47% 95% CI 31–64) patients in the ipilimumab every-12-weeks cohort and 15 (38% 95% CI 23–55) patients in the ipilimumab every-6-weeks cohort; median duration of response was not reached in either cohort, with median follow-up times of 12·8 months (IQR 9·3–15·5) in the ipilimumab every-12-weeks cohort and 11·8 months (6·7–15·9) in the ipilimumab every-6-weeks cohort. In patients with PD-L1 of 1% or greater, confirmed objective responses were achieved in 12 (57%) of 21 patients in the ipilimumab every-12-weeks cohort and 13 (57%) of 23 patients in the ipilimumab every-6-weeks cohort. Interpretation In NSCLC, first-line nivolumab plus ipilimumab had a tolerable safety profile and showed encouraging clinical activity characterised by a high response rate and durable response. To our knowledge, the results of this study are the first suggestion of improved benefit compared with anti-PD-1 monotherapy in patients with NSCLC, supporting further assessment of this combination in a phase 3 study. Funding Bristol-Myers Squibb.
Competitive adsorption and selectivity of benzene and water vapor on the microporous metal organic frameworks (HKUST-1). Display omitted
•HKUST-1 has much higher capacity for benzene than MIL-101 ...below 12mbar.•The isosteric heat of benzene is much higher than water on the HKUST-1.•Adsorption selectivity of HKUST-1 for C6H6/H2O is up to 8.3 at 318K and 1.0mbar.•Diffusion rate of benzene is ∼17times faster than that of water vapor in HKUST-1.
Competitive adsorption and selectivity of benzene and water vapor were studied on the microporous metal organic frameworks (HKUST-1). The adsorption equilibrium and kinetics of pure component as well as binary mixtures of benzene and water vapor were systematically investigated on the HKUST-1. Their binary adsorption selectivity and permeation selectivity are predicted via the IAST method. Results showed that the equilibrium data of benzene and water vapor depicted the Langmuir–Freundlich and Dual Site Langmuir–Freundlich (DSLF) type adsorption isotherms, respectively. Benzene exhibited much higher isosteric heat and desorption activation energy than water vapor, indicating a stronger interaction with the HKUST-1. The adsorption selectivity of benzene/water on the HKUST-1 was of about ∼8.32 at 318K and 1.0mbar, and its diffusivity selectivity was about 17.6 at 298K and 1.5mbar, respectively. Breakthrough curves of benzene showed a remaining capacity of about 94.7% and 72.9% in the presence of 13 and 34RH%. Thus, the HKUST-1 is more selective or preferential adsorption for benzene molecules in comparison to water molecules at high temperature and low pressure. Also, it shows the advantage of kinetic separation for VOCs and water vapor.
As one of the most popular image oversegmentations, superpixel has been commonly used as supporting regions for primitives to reduce computations in various computer vision tasks. In this paper, we ...propose a novel superpixel segmentation approach based on a distance function that is designed to balance among boundary adherence, intensity homogeneity, and compactness (COM) characteristics of the resulting superpixels. Given an expected number of superpixels, our method begins with initializing the superpixel seed positions to obtain the initial labels of pixels. Then, we optimize the superpixels iteratively based on the defined distance measurement. We update the positions and intensities of superpixel seeds based on the three-sigma rule. The experimental results demonstrate that our algorithm is more effective and accurate than previous superpixel methods and achieves a comparable tradeoff between superpixel COM and adherence to object boundaries.
Carbon nanotubes have many material properties that make them attractive for applications. In the context of nanoelectronics, interest has focused on single-walled carbon nanotubes (SWNTs) because ...slight changes in tube diameter and wrapping angle, defined by the chirality indices (n, m), will shift their electrical conductivity from one characteristic of a metallic state to one characteristic of a semiconducting state, and will also change the bandgap. However, this structure-function relationship can be fully exploited only with structurally pure SWNTs. Solution-based separation methods yield tubes within a narrow structure range, but the ultimate goal of producing just one type of SWNT by controlling its structure during growth has proved to be a considerable challenge over the last two decades. Such efforts aim to optimize the composition or shape of the catalyst particles that are used in the chemical vapour deposition synthesis process to decompose the carbon feedstock and influence SWNT nucleation and growth. This approach resulted in the highest reported proportion, 55 per cent, of single-chirality SWNTs in an as-grown sample. Here we show that SWNTs of a single chirality, (12, 6), can be produced directly with an abundance higher than 92 per cent when using tungsten-based bimetallic alloy nanocrystals as catalysts. These, unlike other catalysts used so far, have such high melting points that they maintain their crystalline structure during the chemical vapour deposition process. This feature seems crucial because experiment and simulation both suggest that the highly selective growth of (12, 6) SWNTs is the result of a good structural match between the carbon atom arrangement around the nanotube circumference and the arrangement of the catalytically active atoms in one of the planes of the nanocrystal catalyst. We anticipate that using high-melting-point alloy nanocrystals with optimized structures as catalysts paves the way for total chirality control in SWNT growth and will thus promote the development of SWNT applications.
The proteasome is an ATP-dependent, 2.5-megadalton molecular machine that is responsible for selective protein degradation in eukaryotic cells. Here we present cryo-electron microscopy structures of ...the substrate-engaged human proteasome in seven conformational states at 2.8-3.6 Å resolution, captured during breakdown of a polyubiquitylated protein. These structures illuminate a spatiotemporal continuum of dynamic substrate-proteasome interactions from ubiquitin recognition to substrate translocation, during which ATP hydrolysis sequentially navigates through all six ATPases. There are three principal modes of coordinated hydrolysis, featuring hydrolytic events in two oppositely positioned ATPases, in two adjacent ATPases and in one ATPase at a time. These hydrolytic modes regulate deubiquitylation, initiation of translocation and processive unfolding of substrates, respectively. Hydrolysis of ATP powers a hinge-like motion in each ATPase that regulates its substrate interaction. Synchronization of ATP binding, ADP release and ATP hydrolysis in three adjacent ATPases drives rigid-body rotations of substrate-bound ATPases that are propagated unidirectionally in the ATPase ring and unfold the substrate.
Dielectrics with ultralow permittivity within 2 times that of air, excellent mechanical performance, and high thermal stability are highly attractive to many applications. However, since the finding ...of silica aerogels in the 1930s, no alternative ultralight porous dielectric with density below 10 mg/cm3 has been developed. Here we present three-dimensional hierarchical boron nitride foam with permittivity of 1.03 times that of air, density of 1.6 mg/cm3, and thermal stability up to 1200 °C obtained by chemical vapor deposition on a nickel foam template. This BN foam exhibits complete recovery after cyclic compression exceeding 70% with permittivity within 1.12 times that of air. Gathering all these exceptional characters, the BN foam should create a breakthrough development of flexible ultralow-permittivity dielectrics and ultralight materials.
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