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Magnetic nanomaterials are gaining interest for their many applications in technological areas from information science and computing to next-generation quantum energy materials. While magnetic materials have historically been nanostructured through techniques such as lithography and molecular beam epitaxy, there has recently been growing interest in using soft matter self-assembly. In this work, a triblock terpolymer, poly(isoprene-block-styrene-block-ethylene oxide) (ISO), is used as a structure directing agent for aluminosilicate sol nanoparticles and magnetic material precursors to generate organic-inorganic bulk hybrid films with co-continuous morphology. After thermal processing into mesoporous materials, results from a combination of small angle X-ray scattering (SAXS) and scanning electron microscopy (SEM) are consistent with the double gyroid morphology. Nitrogen sorption measurements reveal a type IV isotherm with H1 hysteresis, and yield a specific surface area of around 200 m2 g-1 and an average pore size of 23 nm. The magnetization of the mesostructured material as a function of applied field shows magnetic hysteresis and coercivity at 300 K and 10 K. Comparison of magnetic measurements between the mesoporous gyroid and an unstructured bulk magnetic material, derived from the identical inorganic precursors, reveals the structured material exhibits a coercivity of 250 Oe, opposed to 148 Oe for the unstructured at 10 K, and presence of remnant magnetic moment not conventionally found in bulk hematite; both of these properties are attributed to the mesostructure. This scalable route to mesoporous magnetic materials with co-continuous morphologies from block copolymer self-assembly may provide a pathway to advanced magnetic nanomaterials with a range of potential applications.
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Oral delivery, while a highly desirable form of nanoparticle-drug administration, is limited by challenges associated with overcoming several biological barriers. Here, the authors study how fluorescent and poly(ethylene glycol)-coated (PEGylated) core-shell silica nanoparticles sized 5 to 50 nm interact with major barriers including intestinal mucus, intestinal epithelium, and stomach acid. From imaging fluorescence correlation spectroscopy studies using quasi-total internal reflection fluorescence microscopy, diffusion of nanoparticles through highly scattering mucus is progressively hindered above a critical hydrodynamic size around 20 nm. By studying Caco-2 cell monolayers mimicking the intestinal epithelia, it is observed that ultrasmall nanoparticles below 10 nm diameter (Cornell prime dots, [C' dots]) show permeabilities correlated with high absorption in humans from primarily enhanced passive passage through tight junctions. Particles above 20 nm diameter exclusively show active transport through cells. After establishing C' dot stability in artificial gastric juice, in vivo oral gavage experiments in mice demonstrate successful passage through the body followed by renal clearance without protein corona formation. Results suggest C' dots as viable candidates for oral administration to patients with a proven pathway towards clinical translation and may generate renewed interest in examining silica as a food additive and its effects on nutrition and health.
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Portadores de Fármacos , Nanopartículas , Humanos , Ratos , Camundongos , Animais , Portadores de Fármacos/química , Células CACO-2 , Ratos Sprague-Dawley , Dióxido de Silício/química , Nanopartículas/químicaRESUMO
Block copolymers (BCPs) are particularly effective in creating soft nanostructured templates for transferring complex 3D network structures into inorganic materials that are difficult to fabricate by other methods. However, achieving control of the local ordering within these 3D networks over large areas remains a significant obstacle to advancing material properties. Here, we address this challenge by directing the self-assembly of a 3D alternating diamond morphology by solvent vapor annealing of a triblock terpolymer film on a chemically patterned substrate. The hexagonal substrate patterns were designed to match a (111) plane of the diamond lattice. Commensurability between the sparse substrate pattern and the BCP lattice produced a uniformly ordered diamond network within the polymer film, as confirmed by a combination of atomic force microscopy and cross-sectional imaging using focused ion beam scanning electron microscopy. The successful replication of the complex and well-ordered 3D network structure in gold promises to advance optical metamaterials and has potential applications in nanophotonics.
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Osteocytes are the resident mechanosensory cells in bone. They are responsible for skeletal homeostasis and adaptation to mechanical cues. Integrin proteins play a prominent role in osteocyte mechanotransduction, but the details are not well stratified. Intravital imaging with multiphoton microscopy presents an opportunity to study molecular level mechanobiological events in vivo and presents an opportunity to study integrin dynamics in osteocytes. However, fluorescent imaging limitations with respect to excessive optical scattering and low signal to noise ratio caused by mineralized bone matrix make such investigations non-trivial. Here, we demonstrate that ultra-small and bright fluorescent core-shell silica nanoparticles (<7 nm diameter), known as Cornell Prime Dots (C'Dots), are well-suited for the in vivo bone microenvironment and can improve intravital imaging capabilities. We report validation studies for C'Dots as a novel, locally injectable in vivo osteocyte imaging tool for both non-specific cellular uptake and for targeting integrins. The pharmacokinetics of C'Dots reveal distinct sex differences in nanoparticle intracellular dynamics and clearance in osteocytes, which represents a novel topic of study in bone biology. Integrin-targeted C'Dots were used to study osteocyte integrin dynamics. To the best of our knowledge, we report here the first evidence of osteocyte integrin endocytosis and recycling in vivo. Our results provide novel insights in osteocyte biology and will open up new lines of investigation that were previously unavailable in vivo.
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Integrinas , Osteócitos , Feminino , Masculino , Humanos , Osteócitos/metabolismo , Integrinas/metabolismo , Mecanotransdução Celular/fisiologia , Osso e Ossos/diagnóstico por imagem , Matriz ÓsseaRESUMO
Porous polymer-derived membranes are useful for applications ranging from filtration and separation technologies to energy storage and conversion. Combining block copolymer (BCP) self-assembly with the industrially scalable, non-equilibrium phase inversion technique (SNIPS) yields membranes comprising periodically ordered top surface structures supported by asymmetric, hierarchical substructures that together overcome performance tradeoffs typically faced by materials derived from equilibrium approaches. This review first reports on recent advances in understanding the top surface structural evolution of a model SNIPS-derived system during standard membrane formation. Subsequently, the application of SNIPS to multicomponent systems is described, enabling pore size modulation, chemical modification, and transformation to non-polymeric materials classes without compromising the structural features that define SNIPS membranes. Perspectives on future directions of both single-component and multicomponent membrane materials are provided. This points to a rich and fertile ground for the study of fundamental as well as applied problems using non-equilibrium-derived asymmetric porous materials with tunable chemistry, composition, and structure.
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Despite advances by recently approved antibody-drug conjugates in treating advanced gastric cancer patients, substantial limitations remain. Here, several key obstacles are overcome by developing a first-in-class ultrasmall (sub-8-nanometer (nm)) anti-human epidermal growth factor receptor 2 (HER2)-targeting drug-immune conjugate nanoparticle therapy. This multivalent fluorescent core-shell silica nanoparticle bears multiple anti-HER2 single-chain variable fragments (scFv), topoisomerase inhibitors, and deferoxamine moieties. Most surprisingly, drawing upon its favorable physicochemical, pharmacokinetic, clearance, and target-specific dual-modality imaging properties in a "hit and run" approach, this conjugate eradicated HER2-expressing gastric tumors without any evidence of tumor regrowth, while exhibiting a wide therapeutic index. Therapeutic response mechanisms are accompanied by the activation of functional markers, as well as pathway-specific inhibition. Results highlight the potential clinical utility of this molecularly engineered particle drug-immune conjugate and underscore the versatility of the base platform as a carrier for conjugating an array of other immune products and payloads.
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The field of quantum materials has experienced rapid growth over the past decade, driven by exciting new discoveries with immense transformative potential. Traditional synthetic methods to quantum materials have, however, limited the exploration of architectural control beyond the atomic scale. By contrast, soft matter self-assembly can be used to tailor material structure over a large range of length scales, with a vast array of possible form factors, promising emerging quantum material properties at the mesoscale. This review explores opportunities for soft matter science to impact the synthesis of quantum materials with advanced properties. Existing work at the interface of these two fields is highlighted, and perspectives are provided on possible future directions by discussing the potential benefits and challenges which can arise from their bridging.
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To address the key challenges in the development of next-generation drug delivery systems (DDS) with desired physicochemical properties to overcome limitations regarding safety, in vivo efficacy, and solid tumor penetration, an ultrasmall folate receptor alpha (FRα) targeted silica nanoparticle (C'Dot) drug conjugate (CDC; or folic acid CDC) was developed. A broad array of methods was employed to screen a panel of CDCs and identify a lead folic acid CDC for clinical development. These included comparing the performance against antibody-drug conjugates (ADCs) in three-dimensional tumor spheroid penetration ability, assessing in vitro/ex vivo cytotoxic efficacy, as well as in vivo therapeutic outcome in multiple cell-line-derived and patient-derived xenograft models. An ultrasmall folic acid CDC, EC112002, was identified as the lead candidate out of >500 folic acid CDC formulations evaluated. Systematic studies demonstrated that the lead formulation, EC112002, exhibited highly specific FRα targeting, multivalent binding properties that would mediate the ability to outcompete endogenous folate in vivo, enzymatic responsive payload cleavage, stability in human plasma, rapid in vivo clearance, and minimal normal organ retention organ distribution in non-tumor-bearing mice. When compared with an anti-FRα-DM4 ADC, EC112002 demonstrated deeper penetration into 3D cell-line-derived tumor spheroids and superior specific cytotoxicity in a panel of 3D patient-derived tumor spheroids, as well as enhanced efficacy in cell-line-derived and patient-derived in vivo tumor xenograft models expressing a range of low to high levels of FRα. With the growing interest in developing clinically translatable, safe, and efficacious DDSs, EC112002 has the potential to address some of the critical limitations of the current systemic drug delivery for cancer management.
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Receptor 1 de Folato , Sistemas de Liberação de Fármacos por Nanopartículas , Neoplasias , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Receptor 1 de Folato/metabolismo , Receptor 1 de Folato/uso terapêutico , Ácido Fólico/química , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Dióxido de Silício/uso terapêuticoRESUMO
PURPOSE: Despite dramatic growth in the number of small-molecule drugs developed to treat solid tumors, durable therapeutic options to control primary central nervous system malignancies are relatively scarce. Chemotherapeutic agents that appear biologically potent in model systems have often been found to be marginally effective at best when given systemically in clinical trials. This work presents for the first time an ultrasmall (<8 nm) multimodal core-shell silica nanoparticle, Cornell prime dots (or C' dots), for the efficacious treatment of high-grade gliomas. EXPERIMENTAL DESIGN: This work presents first-in-kind renally clearable ultrasmall (<8 nm) multimodal C' dots with surface-conjugated doxorubicin (DOX) via pH-sensitive linkers for the efficacious treatment in two different clinically relevant high-grade glioma models. RESULTS: Optimal drug-per-particle ratios of as-developed nanoparticle-drug conjugates were established and used to obtain favorable pharmacokinetic profiles. The in vivo efficacy results showed significantly improved biological, therapeutic, and toxicological properties over the native drug after intravenous administration in platelet-derived growth factor-driven genetically engineered mouse model, and an EGF-expressing patient-derived xenograft (EGFR PDX) model. CONCLUSIONS: Ultrasmall C' dot-drug conjugates showed great translational potential over DOX for improving the therapeutic outcome of patients with high-grade gliomas, even without a cancer-targeting moiety.
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Glioma , Nanopartículas , Animais , Linhagem Celular Tumoral , Doxorrubicina , Sistemas de Liberação de Medicamentos/métodos , Glioma/tratamento farmacológico , Humanos , Camundongos , Dióxido de Silício , Índice TerapêuticoRESUMO
The interrogation of metabolic parameters like pH in live-cell experiments using optical super-resolution microscopy (SRM) remains challenging. This is due to a paucity of appropriate metabolic probes enabling live-cell SRM-based sensing. Here we introduce ultrasmall fluorescent core-shell aluminosilicate nanoparticle sensors (FAM-ATTO647N aC' dots) that covalently encapsulate a reference dye (ATTO647N) in the core and a pH-sensing moiety (FAM) in the shell. Only the reference dye exhibits optical blinking enabling live-cell stochastic optical reconstruction microscopy (STORM). Using data from cells incubated for 60 minutes with FAM-ATTO647N aC' dots, pixelated information from total internal reflection fluorescence (TIRF) microscopy-based ratiometric sensing can be combined with that from STORM-based localizations via the blinking reference dye in order to enhance the resolution of ratiometric pH sensor maps beyond the optical diffraction limit. A nearest-neighbor interpolation methodology is developed to quantitatively address particle compositional heterogeneity as determined by separate single-particle fluorescence imaging methods. When combined with STORM-based estimates of the number of particles per vesicle, vesicle size, and vesicular motion as a whole, this analysis provides detailed live-cell spatial and functional information, paving the way to a comprehensive mapping and understanding of the spatiotemporal evolution of nanoparticle processing by cells important, e.g. for applications in nanomedicine.
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Recent developments in quantum materials hold promise for revolutionizing energy and information technologies. The use of soft matter self-assembly, for example, by employing block copolymers (BCPs) as structure directing or templating agents, offers facile pathways toward quantum metamaterials with highly tunable mesostructures via scalable solution processing. Here, we report the preparation of patternable mesoporous niobium carbonitride-type thin film superconductors through spin-coating of a hybrid solution containing an amphiphilic BCP swollen by niobia sol precursors and subsequent thermal processing in combination with photolithography. Spin-coated as-made BCP-niobia hybrid thin films on silicon substrates after optional photolithographic definition are heated in air to produce a porous oxide, and subsequently converted in a multistep process to carbonitrides via treatment with high temperatures in reactive gases including ammonia. Grazing incidence small-angle X-ray scattering suggests the presence of ordered mesostructures in as-made BCP-niobia films without further annealing, consistent with a distorted alternating gyroid morphology that is retained upon thermal treatments. Wide-angle X-ray scattering confirms the synthesis of phase-pure niobium carbonitride nanocrystals with rock-salt lattices within the mesoscale networks. Electrical transport measurements of unpatterned thin films show initial exponential rise in resistivity characteristic of thermal activation in granular systems down to 12.8 K, at which point resistivity drops to zero into a superconducting state. Magnetoresistance measurements determine the superconducting upper critical field to be over 16 T, demonstrating material quality on par with niobium carbonitrides obtained from traditional solid-state synthesis methods. We discuss how such cost-effective and scalable solution-based quantum materials fabrication approaches may be integrated into existing microelectronics processing, promising the emergence of a technology with tremendous academic and industrial potential by combining the capabilities of soft matter self-assembly with quantum materials.
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Superconducting quantum metamaterials are expected to exhibit a variety of novel properties, but have been a major challenge to prepare as a result of the lack of appropriate synthetic routes to high-quality materials. Here, the discovery of synthesis routes to block copolymer (BCP) self-assembly-directed niobium nitrides and carbonitrides is described. The resulting materials exhibit unusual structure retention even at temperatures as high as 1000 °C and resulting critical temperature, Tc , values comparable to their bulk analogues. Applying the concepts of soft matter self-assembly, it is demonstrated that a series of four different BCP-directed mesostructured superconductors are accessible from a single triblock terpolymer. Resulting materials display a mesostructure-dependent Tc without substantial variation of the XRD-measured lattice parameters. Finally, field-dependent magnetization measurements of a sample with double-gyroid morphology show abrupt jumps comparable in overall behavior to flux avalanches. Results suggest a fruitful convergence of soft and hard condensed matter science.
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Importance: Sentinel lymph node (SLN) mapping agents approved for current surgical practice lack sufficient brightness and target specificity for high-contrast, sensitive nodal visualization. Objective: To evaluate whether an ultrasmall, molecularly targeted core-shell silica nanoparticle (Cornell prime dots) can safely and reliably identify optically avid SLNs in head and neck melanoma during fluorescence-guided biopsy. Design, Setting, and Participants: This nonrandomized clinical trial enrolled patients aged 18 years or older with histologically confirmed melanoma in whom SLN mapping was indicated. Exclusion criteria included known pregnancy, breast-feeding, or medical illness unrelated to the tumor. The trial was conducted between February 2015 and March 2018 at Memorial Sloan Kettering Cancer Center, with postoperative follow-up of 2 years. Data analysis was conducted from February 2015 to March 2018. Interventions: Patients received standard-of-care technetium Tc 99m sulfur colloid followed by a microdose administration of integrin-targeting, dye-encapsulated nanoparticles, surface modified with polyethylene glycol chains and cyclic arginine-glycine-aspartic acid-tyrosine peptides (cRGDY-PEG-Cy5.5-nanoparticles) intradermally. Main Outcomes and Measures: The primary end points were safety, procedural feasibility, lowest particle dose and volume for maximizing nodal fluorescence signal, and proportion of nodes identified by technetium Tc 99m sulfur colloid that were optically visualized by cRGDY-PEG-Cy5.5-nanoparticles. Secondary end points included proportion of patients in whom the surgical approach or extent of dissection was altered because of nodal visualization. Results: Of 24 consecutive patients enrolled (median [interquartile range] age, 64 [51-71] years), 18 (75%) were men. In 24 surgical procedures, 40 SLNs were excised. Preoperative localization of SLNs with technetium Tc 99m sulfur colloid was followed by particle dose-escalation studies, yielding optimized doses and volumes of 2 nmol and 0.4 mL, respectively, and maximum SLN signal-to-background ratios of 40. No adverse events were observed. The concordance rate of evaluable SLNs by technetium Tc 99m sulfur colloid and cRGDY-PEG-Cy5.5-nanoparticles was 90% (95% CI, 74%-98%), 5 of which were metastatic. Ultrabright nanoparticle fluorescence enabled high-sensitivity SLN visualization (including difficult-to-access anatomic sites), deep tissue imaging, and, in some instances, detection through intact skin, thereby facilitating intraoperative identification without extensive dissection of adjacent normal tissue or nerves. Conclusions and Relevance: This study found that nanoparticle-based fluorescence-guided SLN biopsy in head and neck melanoma was feasible and safe. This technology holds promise for improving lymphatic mapping and SLN biopsy procedures, while potentially mitigating procedural risks. This study serves as a first step toward developing new multimodal approaches for perioperative care. Trial Registration: ClinicalTrials.gov Identifier: NCT02106598.
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Neoplasias de Cabeça e Pescoço/diagnóstico , Biópsia Guiada por Imagem/métodos , Melanoma/diagnóstico , Nanopartículas , Biópsia de Linfonodo Sentinela/métodos , Linfonodo Sentinela/patologia , Dióxido de Silício/farmacologia , Idoso , Feminino , Humanos , Metástase Linfática , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Cintilografia , Estudos RetrospectivosRESUMO
Polymeric microcapsules with shells containing homogeneous pores with uniform diameter on the nanometer scale are reported. The mesoporous microcapsules are obtained from confined self-assembly of amphiphilic block copolymers with a selective porogen in the shell of water-in-oil-in-water double emulsion drops. The use of double emulsion drops as a liquid template enables the formation of homogeneous capsules of 100s of microns in diameter, with aqueous cores encapsulated in a shell membrane with a tunable thickness of 100s of nanometers to 10s of microns. Microcapsules with shells that exhibit an ordered gyroidal morphology and three-dimensionally connected mesopores are obtained from the triblock terpolymer poly(isoprene)-block-poly(styrene)-block-poly(4-vinylpyridine) coassembled with pentadecylphenol as a porogen. The bicontinuous shell morphology yields nanoporous paths connecting the inside to the outside of the microcapsule after porogen removal; by contrast, one-dimensional hexagonally packed cylindrical pores, obtained from a traditional diblock copolymer system with parallel alignment to the surface, would block transport through the shell. To enable the mesoporous microcapsules to withstand harsh conditions, such as exposure to organic solvents, without rupture of the shell, we develop a cross-linking method of the nanostructured triblock terpolymer shell after its self-assembly. The microcapsules exhibit pH-responsive permeability to polymeric solutes, demonstrating their potential as a filtration medium for actively tunable macromolecular separation and purification. Furthermore, we report a tunable dual-phase separation method to fabricate microcapsules with hierarchically porous shells that exhibit ordered mesoporous membrane walls within sponge-like micron-sized macropores to further control shell permeability.
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Stochastic optical reconstruction microscopy (STORM) is an optical super-resolution microscopy (SRM) technique that traditionally requires toxic and non-physiological imaging buffers and setups that are not conducive to live-cell studies. It is observed that ultrasmall (<10 nm) fluorescent core-shell aluminosilicate nanoparticles (aC' dots) covalently encapsulating organic fluorophores enable STORM with a single excitation source and in a regular (non-toxic) imaging buffer. It is shown that fourfold coordinated aluminum is responsible for dye blinking, likely via photoinduced redox processes. It is demonstrated that this phenomenon is observed across different dye families leading to probes brighter and more photostable than the parent free dyes. Functionalization of aC' dots with antibodies allows targeted fixed cell STORM imaging. Finally, aC' dots enable live-cell STORM imaging providing quantitative measures of the size of intracellular vesicles and the number of particles per vesicle. The results suggest the emergence of a powerful ultrasmall, bright, and photostable optical SRM particle platform with characteristics relevant to clinical translation for the quantitative assessment of cellular structures and processes from live-cell imaging.
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Silicatos de Alumínio/química , Microscopia de Fluorescência/métodos , Nanopartículas , Tamanho da Partícula , Linhagem Celular , Sobrevivência Celular , Humanos , Processamento de Imagem Assistida por ComputadorRESUMO
During breast cancer bone metastasis, tumor cells interact with bone microenvironment components including inorganic minerals. Bone mineralization is a dynamic process and varies spatiotemporally as a function of cancer-promoting conditions such as age and diet. The functional relationship between skeletal dissemination of tumor cells and bone mineralization, however, is unclear. Standard histological analysis of bone metastasis frequently relies on prior demineralization of bone, while methods that maintain mineral are often harsh and damage fluorophores commonly used to label tumor cells. Here, fluorescent silica nanoparticles (SNPs) are introduced as a robust and versatile labeling strategy to analyze tumor cells within mineralized bone. SNP uptake and labeling efficiency of MDA-MB-231 breast cancer cells is characterized with cryo-scanning electron microscopy and different tissue processing methods. Using a 3D in vitro model of marrow-containing, mineralized bone as well as an in vivo model of bone metastasis, SNPs are demonstrated to allow visualization of labeled tumor cells in mineralized bone using various imaging modalities including widefield, confocal, and light sheet microscopy. This work suggests that SNPs are valuable tools to analyze tumor cells within mineralized bone using a broad range of bone processing and imaging techniques with the potential to increase the understanding of bone metastasis.
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Neoplasias Ósseas , Neoplasias da Mama , Nanopartículas , Neoplasias Ósseas/diagnóstico por imagem , Osso e Ossos , Linhagem Celular Tumoral , Feminino , Humanos , Dióxido de Silício , Microambiente TumoralRESUMO
Porous materials design often faces a trade-off between the requirements of high internal surface area and high reagent flux. Inorganic materials with asymmetric/hierarchical pore structures or well-defined mesopores have been tested to overcome this trade-off, but success has remained limited when the strategies are employed individually. Here, the attributes of both strategies are combined and a scalable path to porous titanium nitride (TiN) and carbon membranes that are conducting (TiN, carbon) or superconducting (TiN) is demonstrated. These materials exhibit a combination of asymmetric, hierarchical pore structures and well-defined mesoporosity throughout the material. Fast transport through such TiN materials as an electrochemical double-layer capacitor provides a substantial improvement in capacity retention at high scan rates, resulting in state-of-the-art power density (28.2 kW kg-1) at competitive energy density (7.3 W-h kg-1). In the case of carbon membranes, a record-setting power density (287.9 kW kg-1) at 14.5 W-h kg-1 is reported. Results suggest distinct advantages of such pore architectures for energy storage and conversion applications and provide an advanced avenue for addressing the trade-off between high-surface-area and high-flux requirements.
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The convergence of 3D printing techniques and nanomaterials is generating a compelling opportunity space to create advanced materials with multiscale structural control and hierarchical functionalities. While most nanoparticles consist of a dense material, less attention has been payed to 3D printing of nanoparticles with intrinsic porosity. Here, we combine ultrasmall (about 10 nm) silica nanocages with digital light processing technique for the direct 3D printing of hierarchically porous parts with arbitrary shapes, as well as tunable internal structures and high surface area. Thanks to the versatile and orthogonal cage surface modifications, we show how this approach can be applied for the implementation and positioning of functionalities throughout 3D printed objects. Furthermore, taking advantage of the internal porosity of the printed parts, an internal printing approach is proposed for the localized deposition of a guest material within a host matrix, enabling complex 3D material designs.
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Ferroptosis is a regulated form of necrotic cell death that is caused by the accumulation of oxidized phospholipids, leading to membrane damage and cell lysis1,2. Although other types of necrotic death such as pyroptosis and necroptosis are mediated by active mechanisms of execution3-6, ferroptosis is thought to result from the accumulation of unrepaired cell damage1. Previous studies have suggested that ferroptosis has the ability to spread through cell populations in a wave-like manner, resulting in a distinct spatiotemporal pattern of cell death7,8. Here we investigate the mechanism of ferroptosis execution and discover that ferroptotic cell rupture is mediated by plasma membrane pores, similarly to cell lysis in pyroptosis and necroptosis3,4. We further find that intercellular propagation of death occurs following treatment with some ferroptosis-inducing agents, including erastin2,9 and C' dot nanoparticles8, but not upon direct inhibition of the ferroptosis-inhibiting enzyme glutathione peroxidase 4 (GPX4)10. Propagation of a ferroptosis-inducing signal occurs upstream of cell rupture and involves the spreading of a cell swelling effect through cell populations in a lipid peroxide- and iron-dependent manner.
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Ferroptose/fisiologia , Osmose/fisiologia , Morte Celular/fisiologia , Linhagem Celular Tumoral , Células HeLa , Humanos , Ferro/metabolismo , Células MCF-7 , Necrose/metabolismo , Necrose/patologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Células U937RESUMO
Three-dimensional (3D) periodic ordering of silicon (Si), an inorganic semiconductor, on the mesoscale was achieved by combining block copolymer (BCP) self-assembly (SA) based mesoporous alternating gyroidal network formation with nonequilibrium transient laser heating. 3D continuous and periodically ordered alternating gyroidal mesoporous carbon thin-film networks were prepared from spin coating, SA under solvent vapor annealing (SVA), and thermal processing of mixtures of a triblock terpolymer with resorcinol resols. The resulting mesoporous thin films, acting as structure-directing templates, were backfilled with amorphous silicon (a-Si). Nanosecond excimer laser heating led to transient Si melts conformally filling the template pores and subsequent Si crystallization. The ordered mesostructure of the organic polymer-derived templates was kept intact, despite being thermally unstable at the high temperatures around the Si melting point (MP), leading to high pattern transfer fidelity. As evidenced by a combination of grazing incidence small-angle X-ray scattering (GISAXS) and scanning electron microscopy (SEM), after template removal, the crystalline Si (c-Si) inherited the inverse network topology of the 3D mesoporous thin-film templates, but with reduced F222 space group symmetry (D2 point group symmetry) from compression of the cubic alternating gyroid lattice. Structures with this reduced symmetry have been proposed as photonic and phononic materials exhibiting topologically protected Weyl points, adding to the emerging field of BCP SA-directed quantum materials promising advanced physics and materials properties.