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1.
Small ; : e2311435, 2024 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-38461533

RESUMEN

All weather, high-efficiency, energy-saving anti-icing/de-icing materials are of great importance for solving the problem of ice accumulation on outdoor equipment surfaces. In this study, a composite material with energy storage, active electro-/photo-thermal de-icing and passive super-hydrophobic anti-icing properties is proposed. Fluorinated epoxy resin and MWCNTs/PTFE particles are used to prepare the top multifunctional anti-icing/de-icing layer, which exhibited super-hydrophobicity with water contact angle greater than 155° and conductivity higher than 69 S m-1 . The super-hydrophobic durability of the top layer is verified through tape peeling and sandpaper abrasion tests. The surface can be heated by applying on voltage or light illumination, showing efficient electro-/photo-thermal and all-day anti-icing/de-icing performance. The oleogel material at the bottom layer is capable to absorb energy during heating process and release it during cooling process by phase transition, which greatly delayed the freezing time and saved energy. The icing test of single ice droplet, electro-/photo-thermal de-icing and defrosting tests also proved the high efficiency and energy saving of the anti-icing/de-icing strategy. This study provided a new way to manufacture multi-functional materials for practical anti-icing/de-icing applications.

2.
Chemistry ; 30(32): e202400536, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38527310

RESUMEN

In this study, we conduct extensive high-pressure experiments to investigate phase stability in the cobalt-nitrogen system. Through a combination of synthesis in a laser-heated diamond anvil cell, first-principles calculations, Raman spectroscopy, and single-crystal X-ray diffraction, we establish the stability fields of known high-pressure phases, hexagonal NiAs-type CoN, and marcasite-type CoN2 within the pressure range of 50-90 GPa. We synthesize and characterize previously unknown nitrides, Co3N2, Pnma-CoN and two polynitrides, CoN3 and CoN5, within the pressure range of 90-120 GPa. Both polynitrides exhibit novel types of polymeric nitrogen chains and networks. CoN3 feature branched-type nitrogen trimers (N3) and CoN5 show π-bonded nitrogen chain. As the nitrogen content in the cobalt nitride increases, the CoN6 polyhedral frameworks transit from face-sharing (in CoN) to edge-sharing (in CoN2 and CoN3), and finally to isolated (in CoN5). Our study provides insights into the intricate interplay between structure evolution, bonding arrangements, and high-pressure synthesis in polynitrides, expanding the knowledge for the development of advanced energy materials.

3.
J Infect Dis ; 228(2): 149-159, 2023 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-36861215

RESUMEN

Omicron and its subvariants have steadily gained greater capability of immune escape compared to other variants of concern, resulting in an increased incidence of reinfections even among vaccinated individuals. We evaluated the antibody response to Omicron BA.1, BA.2, and BA.4/5 in US military members vaccinated with the primary 2-dose series of Moderna mRNA-1273 in a cross-sectional study. While nearly all vaccinated participants had sustained spike (S) IgG and neutralizing antibodies (ND50) to the ancestral strain, only 7.7% participants had detectable ND50 to Omicron BA.1 at 8 months postvaccination. The neutralizing antibody response to BA.2 and BA.5 was similarly reduced. The reduced antibody neutralization of Omicron correlated with the decreased antibody binding to the receptor-binding domain. The participants' seropositivity to the nuclear protein positively correlated with ND50. Our data emphasizes the need for continuous vigilance in monitoring for emerging variants and the need to identify potential alternative targets for vaccine design.


Asunto(s)
COVID-19 , Personal Militar , Humanos , Vacuna nCoV-2019 mRNA-1273 , Formación de Anticuerpos , Estudios Transversales , SARS-CoV-2/genética , Anticuerpos Neutralizantes , Anticuerpos Antivirales
4.
Opt Express ; 31(6): 10805-10819, 2023 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-37157619

RESUMEN

In this paper, an all-dielectric metasurface consisting of a unit cell containing a nanocube array and organized periodically on a silicon dioxide substrate is designed and analyzed. By introducing asymmetric parameters that can excite the quasi-bound states in the continuum, three Fano resonances with high Q-factor and high modulation depth may be produced in the near-infrared range. Three Fano resonance peaks are excited by magnetic dipole and toroidal dipole, respectively, in conjunction with the distributive features of electromagnetism. The simulation results indicate that the discussed structure can be utilized as a refractive index sensor with a sensitivity of around 434 nm/RIU, a maximum Q factor of 3327, and a modulation depth equal to 100%. The proposed structure has been designed and experimentally investigated, and its maximum sensitivity is 227 nm/RIU. At the same time, the modulation depth of the resonance peak at λ = 1185.81 nm is nearly 100% when the polarization angle of the incident light is 0 °. Therefore, the suggested metasurface has applications in optical switches, nonlinear optics, and biological sensors.

5.
Proc Natl Acad Sci U S A ; 117(18): 9747-9754, 2020 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-32312811

RESUMEN

Sub-Neptunes are common among the discovered exoplanets. However, lack of knowledge on the state of matter in [Formula: see text]O-rich setting at high pressures and temperatures ([Formula: see text]) places important limitations on our understanding of this planet type. We have conducted experiments for reactions between [Formula: see text] and [Formula: see text]O as archetypal materials for rock and ice, respectively, at high [Formula: see text] We found anomalously expanded volumes of dense silica (up to 4%) recovered from hydrothermal synthesis above ∼24 GPa where the [Formula: see text]-type (Ct) structure appears at lower pressures than in the anhydrous system. Infrared spectroscopy identified strong OH modes from the dense silica samples. Both previous experiments and our density functional theory calculations support up to 0.48 hydrogen atoms per formula unit of ([Formula: see text])[Formula: see text] At pressures above 60 GPa, [Formula: see text]O further changes the structural behavior of silica, stabilizing a niccolite-type structure, which is unquenchable. From unit-cell volume and phase equilibrium considerations, we infer that the niccolite-type phase may contain H with an amount at least comparable with or higher than that of the Ct phase. Our results suggest that the phases containing both hydrogen and lithophile elements could be the dominant materials in the interiors of water-rich planets. Even for fully layered cases, the large mutual solubility could make the boundary between rock and ice layers fuzzy. Therefore, the physical properties of the new phases that we report here would be important for understanding dynamics, geochemical cycle, and dynamo generation in water-rich planets.

6.
Chin J Physiol ; 66(5): 313-325, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37929342

RESUMEN

The flowers of daylily (Hemerocallis fulva Linn.) have been used as vegetable and medicinal herb for thousands of years in Taiwan and eastern Asia. Daylily flowers have been demonstrated to exert several biomedical properties. In this study, we provided the evidences show that daylily flowers exert anti-inflammatory activity in vitro and improved the sleep quality in vivo. We demonstrated that adult volunteers received water extract of daylily flowers improved sleep quality, sleep efficiency and daytime functioning, while sleep latency was reduced, compared to the adult volunteers received water. In addition, we demonstrated that aqueous and ethanol extracts of daylily flowers inhibited nitric oxide and interleukin-6 production in lipopolysaccharide-activated macrophages. Furthermore, the quantitative high performance liquid chromatography-based analysis showed the rutin content of the aqueous extract, ethanolic extract, ethyl acetate fractions of ethanolic extract, and water fractions of ethanolic extract were 7.27, 23.30, 14.71, and 57.43 ppm, respectively. These results indicate that daylily flowers have the potential to be a nutraceutical for improving inflammatory-related diseases and sleep quality in the future.


Asunto(s)
Hemerocallis , Extractos Vegetales , Calidad del Sueño , Humanos , Flores/química , Hemerocallis/química , Interleucina-6 , Macrófagos , Óxido Nítrico , Extractos Vegetales/farmacología
7.
Small ; 18(15): e2105414, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35233944

RESUMEN

Border-nearing microrobots with self-propelling and navigating capabilities have promising applications in micromanipulation and bioengineering, because they can stimulate the surrounding fluid flow for object transportation. However, ensuring the biosafety of microrobots is a concurrent challenge in bioengineering applications. Here, macrophage template-based microrobots (cell robots) that can be controlled individually or in chain-like swarms are proposed, which can transport various objects. The cell robots are constructed using the phagocytic ability of macrophages to load nanomagnetic particles while maintaining their viability. The robots exhibit high position control accuracy and generate a flow field that can be used to transport microspheres and sperm when exposed to an external magnetic field near a wall. The cell robots can also form chain-like swarms to transport a large object (more than 100 times the volume). This new insight into the manipulation of macrophage-based cell robots provides a new concept by converting other biological cells into microrobots for micromanipulation in biomedical applications.


Asunto(s)
Robótica , Campos Magnéticos , Micromanipulación , Microesferas
8.
Nature ; 532(7597): 85-9, 2016 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-27078568

RESUMEN

Numerous natural systems contain surfaces or threads that enable directional water transport. This behaviour is usually ascribed to hierarchical structural features at the microscale and nanoscale, with gradients in surface energy and gradients in Laplace pressure thought to be the main driving forces. Here we study the prey-trapping pitcher organs of the carnivorous plant Nepenthes alata. We find that continuous, directional water transport occurs on the surface of the 'peristome'--the rim of the pitcher--because of its multiscale structure, which optimizes and enhances capillary rise in the transport direction, and prevents backflow by pinning in place any water front that is moving in the reverse direction. This results not only in unidirectional flow despite the absence of any surface-energy gradient, but also in a transport speed that is much higher than previously thought. We anticipate that the basic 'design' principles underlying this behaviour could be used to develop artificial fluid-transport systems with practical applications.


Asunto(s)
Magnoliopsida/anatomía & histología , Magnoliopsida/metabolismo , Agua/metabolismo , Animales , Transporte Biológico , Biomimética , Insectos , Epidermis de la Planta/anatomía & histología , Epidermis de la Planta/metabolismo , Propiedades de Superficie , Movimientos del Agua
9.
J Sci Food Agric ; 102(13): 6100-6111, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35474458

RESUMEN

BACKGROUND: Vitis vinifera L. cv. Syrah grapevines in most Chinese viticulture regions generally have compact clusters that increase the susceptibility to diseases and inhibit coloration of the inner berries. Gibberellic acid (GA3 ) is a plant growth regulator that is widely used during grape cultivation to elongate the rachis, control fruit set, and decrease cluster compactness. In this study, Syrah grapevines were treated with GA3 before flowering in 2019 and 2020 to determine the optimal GA3 treatment concentrations and times for decreasing bunch compactness, while minimizing the negative effects on the wine grape cluster weight. RESULTS: Pre-flowering GA3 applications at 3, 5, and 7 mg L-1 , especially treatment at 20 days before flowering, decreased Syrah grape bunch compactness by decreasing the fruit set rate and promoting bunch elongation, with minimal adverse effects on the healthy grape cluster weight in both years. The 7 mg L-1 GA3 treatment at 20 days before flowering significantly increased reducing sugar, total phenolic, tannin, and total anthocyanin contents of Syrah grape berries in 2019 and 2020. Moreover, high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry, hierarchical cluster, and principal component analysis results indicated GA3 applications before flowering (3, 5, and 7 mg L-1 ) significantly affected the accumulation of different anthocyanins in Syrah grape berries. Notably, the application of 7 mg L-1 GA3 at 20 days before flowering resulted in the highest anthocyanin content. CONCLUSION: Pre-flowering gibberellin application can decrease bunch compactness and improve the quality of Syrah grape berries. These findings reflect the potential utility of gibberellin treatments for decreasing cluster compactness and increasing the quality of wine grapes. © 2022 Society of Chemical Industry.


Asunto(s)
Vitis , Vino , Antocianinas/análisis , Flavonoides/análisis , Frutas/química , Giberelinas/farmacología , Fenotipo , Vitis/química , Vino/análisis
10.
Small ; 17(42): e2103423, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34554641

RESUMEN

Wet adhesion is greatly demanded in fields of wearable devices, wound dressings, and smart robotics. However, reusable, noninvasive and convenient adhesive pads in the liquid environment have remained a challenge. Here, a novel concept of underwater adhesion inspired by the diving beetle, which utilizes the air bubbles as an adhesive to realize nondestructive and repeatable adhesion working across a wide range of scales is shown. The mechanism of underwater bubble adhesion is revealed by the capillarity of air-bubble bridge, of which the property depends on the dynamic bubble contact angles and the gap distance. The design principle of the air bubble-based underwater adhesion is proposed and validated to tune the interfacial acting force by theoretical and experimental results. Finally, a strong, reusable surface adhesive based on air bubble bridges is demonstrated from macro- to microscales in applications of particle manipulation and particle self-assembly. This unique view of underwater bubble adhesion provides new ideas for broader applications.


Asunto(s)
Aire , Escarabajos , Adhesivos , Animales , Fenómenos Físicos , Tensión Superficial
11.
Small ; 17(41): e2103986, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34510759

RESUMEN

Injecting micro/nanorobots into the body to kill tumors is one of the ultimate ambitions for medical nanotechnology. However, injecting current micro/nanorobots based on 3D-printed biocompatible materials directly into blood vessels for targeted therapy is often difficult, and mistakes in targeting can cause serious side effects, such as blood clots, oxidative stress, or inflammation. The natural affinity of macrophages to tumors, and their natural phagocytosis and ability to invade tumors, make them outstanding drug delivery vehicles for targeted tumor therapy. Hence, a magnetically controlled cell robot (MCR) based on a macrophage drug carrier is proposed. Here, living macrophages are converted into MCRs through endocytosis of specially-designed magnetic nanoparticles loaded with doxorubicin and indocyanine green. Following this, the MCRs can be transported to tumors through the blood vessels using external magnetic fields, and penetrate the blood vessels into the interior of the tumor due to their deformability. With the MCR's cascaded drug release, targeted killing of tumors in mice is demonstrated, with minimal effects on the normal surrounding tissue. The ability to impart precise drug doses onto natural cells, such as macrophages, and load various functional components into the MCRs, offers an efficient method for precise targeted therapy.


Asunto(s)
Nanopartículas , Neoplasias , Robótica , Animales , Doxorrubicina , Sistemas de Liberación de Medicamentos , Macrófagos , Ratones , Neoplasias/tratamiento farmacológico
12.
J Acoust Soc Am ; 149(2): 1069, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33639792

RESUMEN

Sound source localization in noisy and reverberant rooms using microphone arrays remains a challenging task, especially for small-sized arrays. Recent years have seen promising advances on deep learning assisted approaches by reformulating the sound localization problem as a classification one. A key to the deep learning-based approaches lies in extracting sound location features effectively in noisy and reverberant conditions. The popularly adopted features are based on the well-established generalized cross correlation phase transform (GCC-PHAT), which is known to be helpful in combating room reverberation. However, the GCC-PHAT features may not be applicable to small-sized arrays. This paper proposes a deep learning assisted sound localization method using a small-sized microphone array constructed by two orthogonal first-order differential microphone arrays. An improved feature extraction scheme based on sound intensity estimation is also proposed by decoupling the correlation between sound pressure and particle velocity components in the whitening weighting construction to enhance the robustness of the time-frequency bin-wise sound intensity features. Simulation and real-world experimental results show that the proposed deep learning assisted approach can achieve higher spatial resolution and is superior to its state-of-the-art counterparts using the GCC-PHAT or sound intensity features for small-sized arrays in noisy and reverberant environments.

13.
Langmuir ; 36(32): 9443-9448, 2020 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-32693594

RESUMEN

The popularity of humidity sensing for respiratory analysis of patients is gradually increasing because of its portability and cost-effectiveness. However, current flexible humidity sensors are mainly made of polymer films, whose poor hygroscopicity and breathability reduce their sensitivity and comfort. In this study, a highly sensitive humidity sensor was developed using non-woven fabric (NWF) coated with graphene oxide (GO). Bovine serum albumin was used to improve the adsorption of GO onto the NWF, and its effect on sensitivity was investigated by adjusting its concentration. High-humidity sensitivity was experimentally validated by testing different relative humidity levels, and its fast response and excellent feasibility under diverse breathing conditions were verified by successful monitoring of fast and deep breathing, differentiating nose and mouth breathing, and even identifying simple spoken words. This study developed a breathable and skin-friendly humidity sensor based on GO/NWF, which is a promising device for human healthcare.

14.
J Acoust Soc Am ; 148(3): 1732, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33003857

RESUMEN

The first-order steerable differential arrays (FOSDAs), which have found a variety of applications in speech and audio processing, are usually designed by construction of two orthogonal dipoles using four microphones. Actually, however, three microphones are enough to construct a FOSDA by forming two dipoles with a shared microphone, which is the scheme with the minimum number of microphones and, hence, the most cost-effective. This paper studies the design and analysis of such three-element FOSDAs by using a least-squares method. In particular, the effect of the array configuration on the three-element FOSDA is studied, and optimum array configurations under different steering angle ranges are derived in terms of both beampattern fitting quality and white noise gain. It also reveals that care should be taken to avoid a conservative setting of the steering angle range in order to achieve superior design of the three-element FOSDA.

15.
J Cell Biochem ; 120(7): 11454-11461, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30854698

RESUMEN

As a cancer-related long noncoding RNA, functionality of GASL1 has only been characterized in liver cancer. Our study aimed to investigate the possible involvement of GASL1 in postoperative recurrence of gastric adenocarcinoma. A total of 112 gastric adenocarcinoma patients with a tumor located in the distal third who received gastrectomy distal resection in The Second Hospital of Dalian Medical University from January 2012 to January 2015 were included in this study. Patients were followed up for 3 years. Another 56 healthy people were also included to serve as a control group. Blood was extracted from each subject on the day of discharge, on the day of diagnosis of recurrence or at the end of follow-up. The GASL1 expression vector was transfected into gastric adenocarcinoma cell lines. It was observed that plasma levels of GASL1 were significantly lower, while plasma levels of transforming growth factor-ß1 (TGF-ß1) were significantly higher in patients than in healthy controls on the day of discharge. Patients with distant recurrence showed significantly lower plasma levels of GASL1 and significantly higher plasma levels of TGF-ß1 compared with patients with local recurrence and patients without recurrence. During follow-up, plasma levels of GASL1 and TGF-ß1 were negatively correlated in patients with distant recurrence but not in other groups of patients. GASL1 overexpression inhibited, while TGF-ß1 treatment promoted cell migration and invasion. Overexpression of GASL1 led to downregulated and GASL1 knockdown led to upregulated TGF-ß1. However, TGF-ß1 showed no significant effects on GASL1 expression. We conclude that GASL1 may participate in the distant recurrence of gastric adenocarcinoma through the interactions with TGF-ß1.

16.
Anal Chem ; 91(15): 9424-9429, 2019 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-31313917

RESUMEN

Single-domain antibodies (sdAb), recombinantly produced variable heavy domains derived from the unconventional heavy chain antibodies found in camelids, provide stable, well-expressed binding elements with excellent affinity that can be tailored for specific applications through protein engineering. Complex matrices, such as plasma and serum, can dramatically reduce assay sensitivity. Thus, to achieve highly sensitive detection in complex matrices a highly efficient assay is essential. We produced sdAb as genetically linked dimers, and trimers, each including SpyTag at their C-terminus. The constructs were immobilized onto dyed magnetic microspheres to which SpyCatcher had been coupled and characterized in terms of their performance as capture reagents in sandwich assays. Initial tests on the ability of oriented monomer, dimer, and trimer captures to improve detection versus unoriented constructs in an assay for staphylococcal enterotoxin B spiked into buffer showed the oriented dimer format provided the best sensitivity while offering robust protein production. Thus, this format was utilized to improve a sdAb-based assay for the detection of dengue virus (DENV) nonstructural protein 1 (NS1) in serum. Detection of NS1 from each of the four DENV serotypes spiked into 50% normal human serum was increased by at least a factor of 5 when using the oriented dimer capture. We then demonstrated the potential of using the oriented dimer capture to improve detection of NS1 in clinical samples. This general method should enhance the utility of sdAb incorporated into any diagnostic assay, including those for high consequence pathogens.


Asunto(s)
Anticuerpos Inmovilizados/inmunología , Inmunoensayo/métodos , Orientación Espacial , Péptidos/química , Anticuerpos de Dominio Único/inmunología , Inmunoensayo/normas , Límite de Detección , Microesferas , Multimerización de Proteína , Proteínas no Estructurales Virales/sangre
17.
Nat Mater ; 17(10): 935-942, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30250072

RESUMEN

Various natural materials have hierarchical microscale and nanoscale structures that allow for directional water transport. Here we report an ultrafast water transport process in the surface of a Sarracenia trichome, whose transport velocity is about three orders of magnitude faster than those measured in cactus spine and spider silk. The high velocity of water transport is attributed to the unique hierarchical microchannel organization of the trichome. Two types of ribs with different height regularly distribute around the trichome cone, where two neighbouring high ribs form a large channel that contains 1-5 low ribs that define smaller base channels. This results in two successive but distinct modes of water transport. Initially, a rapid thin film of water is formed inside the base channels (Mode I), which is followed by ultrafast water sliding on top of that thin film (Mode II). This two-step ultrafast water transport mechanism is modelled and experimentally tested in bio-inspired microchannels, which demonstrates the potential of this hierarchal design for microfluidic applications.

18.
Inorg Chem ; 58(13): 8300-8307, 2019 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-31194523

RESUMEN

We have synthesized pyrite-type PtO2 (py-PtO2) at 50-60 GPa and successfully recovered it at 1 bar. The observed O-O stretching vibration in Raman spectra provides direct evidence for inter-oxygen bonding in the structure. We also identified the O-H vibrations in py-PtO2 synthesized from the low-temperature areas, indicating hydrogenation, py-PtO2H x ( x ≤ 1). Diffraction patterns are consistent with a range of degrees of hydrogenation controlled by temperature. We found that py-PtO2 has a high bulk modulus, 314 ± 4 GPa. The chemical behaviors found in py-PtO2 have implications for the hydrogen storage in materials with anion-anion bonding, and the geochemistry of oxygen, hydrogen, and transition metals in the deep planetary interiors.

19.
J Acoust Soc Am ; 146(6): 4883, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31893720

RESUMEN

Direction of arrival (DOA) estimation of sound sources using a spherical microphone array is usually performed in the spherical harmonic (SH) domain. In a non-noisy environment, it suffices to use only the zeroth- and first-order spherical harmonic beams (SHBs) in the SH domain for DOA estimation. One such method is based on the pseudo-intensity vector (PIV), which is attractive due to its low computational complexity. To improve the performance of the PIV method in reverberant environments, some methods have been proposed recently to further exploit high-order SHBs. However, these methods ignore the effect of noise on high-order SHBs, which may lead to poor performance in low signal-to-noise ratio (SNR) environments. To address the problem, this paper proposes an order-aware scheme that is able to select the high-order SHBs reliable for robust DOA estimation of multiple speech sources. Simulation and real-world experimental results demonstrate that the order-aware scheme based methods outperform their existing counterparts with less computational complexity in terms of both accuracy and robustness of DOA estimation. Moreover, the performance improvement is more significant in low SNR environment and in a scenario with small angular separation of sources.

20.
Nat Chem Biol ; 12(12): 1097-1104, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27775716

RESUMEN

Proteins of the bromodomain and extraterminal (BET) family, in particular bromodomain-containing protein 4 (BRD4), are of great interest as biological targets. BET proteins contain two separate bromodomains, and existing inhibitors bind to them monovalently. Here we describe the discovery and characterization of probe compound biBET, capable of engaging both bromodomains simultaneously in a bivalent, in cis binding mode. The evidence provided here was obtained in a variety of biophysical and cellular experiments. The bivalent binding results in very high cellular potency for BRD4 binding and pharmacological responses such as disruption of BRD4-mediator complex subunit 1 foci with an EC50 of 100 pM. These compounds will be of considerable utility as BET/BRD4 chemical probes. This work illustrates a novel concept in ligand design-simultaneous targeting of two separate domains with a drug-like small molecule-providing precedent for a potentially more effective paradigm for developing ligands for other multi-domain proteins.


Asunto(s)
Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/química , Dominios Proteicos/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/química , Apoptosis/efectos de los fármacos , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Proteínas Nucleares/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Especificidad por Sustrato , Factores de Transcripción/metabolismo
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