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Polar metals have recently garnered increasing interest because of their promising functionalities. Here we report the experimental realization of an intrinsic coexisting ferromagnetism, polar distortion and metallicity in quasi-two-dimensional Ca3Co3O8. This material crystallizes with alternating stacking of oxygen tetrahedral CoO4 monolayers and octahedral CoO6 bilayers. The ferromagnetic metallic state is confined within the quasi-two-dimensional CoO6 layers, and the broken inversion symmetry arises simultaneously from the Co displacements. The breaking of both spatial-inversion and time-reversal symmetries, along with their strong coupling, gives rise to an intrinsic magnetochiral anisotropy with exotic magnetic field-free non-reciprocal electrical resistivity. An extraordinarily robust topological Hall effect persists over a broad temperature-magnetic field phase space, arising from dipole-induced Rashba spin-orbit coupling. Our work not only provides a rich platform to explore the coupling between polarity and magnetism in a metallic system, with extensive potential applications, but also defines a novel design strategy to access exotic correlated electronic states.
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Thanks to their tunable infrared absorption, solution processability, and low fabrication costs, HgTe colloidal quantum dots (CQDs) are promising for optoelectronic devices. Despite advancements in device design, their potential for imaging applications remains underexplored. For integration with Si-based readout integrated circuits (ROICs), top illumination is necessary for simultaneous light absorption and signal acquisition. However, most high-performing traditional HgTe CQD photodiodes are p-on-n stack and bottom-illuminated. Herein, we report top-illuminated inverted n-on-p HgTe CQD photodiodes using a robust p-type CQD layer and a thermally evaporated Bi2S3 electron transport layer. The p-type CQD solid is achieved by exploring the synergism in binary HgTe and Ag2Te CQDs. These photodetectors show a room-temperature detectivity of 3.4 × 1011 jones and an EQE of â¼44% at â¼1.7 µm wavelength, comparable to the p-on-n HgTe CQD photodiodes. A top-illuminated HgTe CQD short-wave infrared imager (640 × 512 pixels) was fabricated, demonstrating successful infrared imaging.
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Solution-processed colloidal quantum dot (CQD) photodiodes are compatible for monolithic integration with silicon-based readout circuitry, enabling ultrahigh resolution and ultralow cost infrared imagers. However, top-illuminated CQD photodiodes for longer infrared imaging suffer from mismatched energy band alignment between narrow-bandgap CQDs and the electron transport layer. In this work, we designed a new top-illuminated structure by replacing the sputtered ZnO layer with a SnO2 layer by atomic layer deposition. Benefiting from matched energy band alignment and improved heterogeneous interface, our top-illuminated CQD photodiodes achieve a broad-band response up to 1650 nm. At 220 K, these SnO2-based devices exhibit an ultralow dark current density of 3.5 nA cm-2 at -10 mV, reaching the noise limit for passive night vision. The detectivity is 4.1 × 1012 Jones at 1530 nm. These SnO2-based devices also demonstrate exceptional operation stability. By integrating with silicon-based readout circuitry, our CQD imager realizes water/oil discrimination and see-through smoke imaging.
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HgTe colloidal quantum dots (CQDs) are promising absorber systems for infrared detection due to their widely tunable photoresponse in all infrared regions. Up to now, the best-performing HgTe CQD photodetectors have relied on using aggregated CQDs, limiting the device design, uniformity and performance. Herein, we report a ligand-engineered approach that produces well-separated HgTe CQDs. The present strategy first employs strong-binding alkyl thioalcohol ligands to enable the synthesis of well-dispersed HgTe cores, followed by a second growth process and a final postligand modification step enhancing their colloidal stability. We demonstrate highly monodisperse HgTe CQDs in a wide size range, from 4.2 to 15.0 nm with sharp excitonic absorption fully covering short- and midwave infrared regions, together with a record electron mobility of up to 18.4 cm2 V-1 s-1. The photodetectors show a room-temperature detectivity of 3.9 × 1011 jones at a 1.7 µm cutoff absorption edge.
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Infrared solar cells (IRSCs) can supplement silicon or perovskite SCs to broaden the utilization of the solar spectrum. As an ideal infrared photovoltaic material, PbS colloidal quantum dots (CQDs) with tunable bandgaps can make good use of solar energy, especially the infrared region. However, as the QD size increases, the energy level shrinking and surface facet evolution makes us reconsider the matching charge extraction contacts and the QD passivation strategy. Herein, different to the traditional sol-gel ZnO layer, energy-level aligned ZnO thin film from a magnetron sputtering method is adopted for electron extraction. In addition, a modified hybrid ligand recipe is developed for the facet passivation of large size QDs. As a result, the champion IRSC delivers an open circuit voltage of 0.49 V and a power conversion efficiency (PCE) of 10.47% under AM1.5 full-spectrum illumination, and the certified PCE is over 10%. Especially the 1100 nm filtered efficiency achieves 1.23%. The obtained devices also show high storage stability. The present matched electron extraction and QD passivation strategies are expected to highly booster the IR conversion yield and promote the fast development of new conception QD optoelectronics.
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Electron transport layers (ETLs) are important components of high-performance all-inorganic perovskite nanocrystals light-emitting diodes (PNCs-LED). Herein, atomic layer deposition (ALD) of inorganic ZnO layer is combined to the organic 1,3,5-Tris(1-phenyl-1H-benzimidazol-2-yl)benzene (TPBi) to form dual ETLs to enhance both the efficiency and stability of PNCs-LED simultaneously. Optimization of ZnO thickness suggested that 10 cycles ALD yields the best performance of the devices. The external quantum efficiency of the device reaches to 7.21% with a low turn-on voltage (2.4 V). Impressively, the dual ETL PNCs-LED realizes maximumT50lifetime of 761 h at the initial luminance of 100 nit, which is one of the top lifetimes among PNCs-LEDs up to now. The improved performance of dual ETL PNCs-LED is mainly due to the improved charge transport balance with favorable energy level matching. These findings present a promising strategy to modify the function layer via ALD to achieve both highly efficient and stable PNCs-LED.
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Terahertz spectroscopy provides a powerful and informative link between infrared spectroscopy and microwave spectroscopy, and is now beginning to make its transition from initial development to broader use by chemists, materials scientists and biologists. In this study, utilizing terahertz spectroscopy we monitored the crystallization and isomerization of azobenzene. In flash-frozen trans-azobenzene solutions, the processes of crystallization and phase transition were observed. A new phase has been experimentally confirmed to exist stably at low temperatures. The results on gradual-frozen experiment indicate that the formation of the observed new phase is determined by the cooling rate. Besides, based on the distinctive spectral features of the isomers, the thermal- and photo-induced isomerization processes of azobenzene were investigated. This work presents that the terahertz spectroscopy has a great potential to study the phase transitions and crystallization of liquid samples under different freezing conditions.
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In this study, semi-starvation fluctuation driving PD granules cultivation in situ by microorganism exudate metabolites feedbacks was firstly investigated. The PD granules of high nitrite production were cultivated with an excellent mean nitrate-to-nitrite transformation rate (NTR) of 56.39% in just 30 days. The granules size was improved from the initial size of 0.09 ± 0.01 mm in diameter to a size above 2 mm when the extracellular polymeric substance (EPS) content increased from 80.21 ± 10.20 mg/g MLVSS to 777.00 ± 22.13 mg/g MLVSS. Acyl-homoserine lactone signals (AHLs) ultimately increased ten-fold more than the initially through 30 days of cultivation. Meanwhile, Thauera had been identified as the main function bacteria of PD, which enriched from 0.47% to 10.67%. Results demonstrated that AHLs, EPS, PD bacteria and the PD granules cultivation were closely associated. Semi-starvation fluctuation produced oligotrophic stress on bacterial community, a part of bacteria would be eliminated on starvation for oligotrophic stress and AHLs of bacteria regarded as distress signals resulted in the rapid formation of PD granules. A mechanism for PD granular cultivation with semi-starvation fluctuation was proposed from the aspect of oligotrophic stress. A better strategy for rapid PD granules cultivation was obtained and it could be useful for the mainstream granule-based PD combined with the anammox process application in the future.
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Desnitrificación , Aguas del Alcantarillado , Reactores Biológicos , Matriz Extracelular de Sustancias Poliméricas , Exudados y Transudados , Retroalimentación , NitrógenoRESUMEN
Heme-iron recycling from senescent red blood cells (erythrophagocytosis) accounts for the majority of total body iron in humans. Studies in cultured cells have ascribed a role for HRG1/SLC48A1 in heme-iron transport but the in vivo function of this heme transporter is unclear. Here we present genetic evidence in a zebrafish model that Hrg1 is essential for macrophage-mediated heme-iron recycling during erythrophagocytosis in the kidney. Furthermore, we show that zebrafish Hrg1a and its paralog Hrg1b are functional heme transporters, and genetic ablation of both transporters in double knockout (DKO) animals shows lower iron accumulation concomitant with higher amounts of heme sequestered in kidney macrophages. RNA-seq analyses of DKO kidney revealed large-scale perturbation in genes related to heme, iron metabolism and immune functions. Taken together, our results establish the kidney as the major organ for erythrophagocytosis and identify Hrg1 as an important regulator of heme-iron recycling by macrophages in the adult zebrafish.
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Citofagocitosis/fisiología , Eritrocitos/fisiología , Riñón Cefálico/metabolismo , Hemoproteínas/metabolismo , Proteínas Transportadoras de Solutos/fisiología , Proteínas de Pez Cebra/fisiología , Pez Cebra/fisiología , Animales , Animales Modificados Genéticamente , Femenino , Técnicas de Inactivación de Genes , Hematopoyesis/fisiología , Hemo/metabolismo , Hemoproteínas/genética , Hierro/metabolismo , Macrófagos/metabolismo , Masculino , Modelos Animales , Proteínas Transportadoras de Solutos/genética , Proteínas de Pez Cebra/genéticaRESUMEN
Dopamine (DA) is an essential neurotransmitter and hormone of the nervous system, its structural and conformational properties play critical roles in biological functions and signal transmission processes. Although this neuroactive molecule has been studied extensively, the low-frequency vibration features that are closely related to the conformation and molecular interactions in the terahertz (THz) band still remain unclear. In this study, a broadband THz time-domain spectroscopy (THz-TDS) system in the frequency band of 0.5-18 THz was used to characterize the unique THz fingerprint of DA. In addition, density functional theory (DFT) calculations were performed to analyze the vibrational properties of DA. The results suggest that each THz resonant absorption peak of DA corresponds to specific vibrational modes, and the collective vibration also exists in the broadband THz range. Moreover, the interactions between the DA ligand and the D2 and D3 receptors were investigated by docking, and the simulated THz spectra were obtained. The results indicate the dominant role of hydrogen bonding interactions and the specificity of molecular conformation. This work may help to understand the resonance coupling between THz electromagnetic waves and neurotransmitters.
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Espectroscopía de Terahertz , Vibración , Dopamina , Enlace de Hidrógeno , Conformación MolecularRESUMEN
The cooling-induced formation of a hydrate in aqueous NaCl solutions was probed using terahertz time-domain spectroscopy (THz-TDS). It was found that the NaCl hydrate formation is accompanied by the emergence of four new absorption peaks at 1.60, 2.43, 3.34 and 3.78 THz. Combining X-ray diffraction measurements with solid-state based density functional theory (DFT) calculations, we assign the observed terahertz absorption peaks to the vibrational modes of the formed NaCl·2H2O hydrate during cooling. This work shows that THz-TDS based analysis has great potential in studying ionic hydrates and the newly revealed collective vibrational modes could be sensitive indicators to achieve quantitative analysis in phase transitions and lattice dynamics.
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Human IgG1 and IgG3 antibodies (Abs) can mediate Ab-dependent cellular cytotoxicity (ADCC), and engineering of the Ab Fc (point mutation; defucosylation) has been shown to affect ADCC by modulating affinity for FcRγIIIa. In the absence of a CH 1 domain, many camelid heavy-chain Abs (HCAbs) naturally bear very long and flexible hinge regions connecting their VH H and CH 2 domains. To better understand the influence of hinge length and structure on HCAb ADCC, we produced a series of hinge-engineered epidermal growth factor receptor (EGFR)-specific chimeric camelid VH H-human Fc Abs and characterized their affinities for recombinant EGFR and FcRγIIIa, their binding to EGFR-positive tumor cells, and their ability to elicit ADCC. In the case of one chimeric HCAb (EG2-hFc), we found that variants bearing longer hinges (IgG3 or camelid hinge regions) showed dramatically improved ADCC in comparison with a variant bearing the human IgG1 hinge, in similar fashion to a variant with reduced CH 2 fucosylation. Conversely, an EG2-hFc variant bearing a truncated human IgG1 upper hinge region failed to elicit ADCC. However, there was no consistent association between hinge length and ADCC for four similarly engineered chimeric HCAbs directed against distinct EGFR epitopes. These findings demonstrate that the ADCC of some HCAbs can be modulated simply by varying the length of the Ab hinge. Although this effect appears to be heavily epitope-dependent, this strategy may be useful to consider during the design of VH H-based therapeutic Abs for cancer.
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Adenocarcinoma/terapia , Anticuerpos Monoclonales/metabolismo , Neoplasias de la Mama/terapia , Inmunoterapia/métodos , Proteínas Recombinantes de Fusión/genética , Adenocarcinoma/inmunología , Animales , Anticuerpos Monoclonales/genética , Afinidad de Anticuerpos , Citotoxicidad Celular Dependiente de Anticuerpos , Neoplasias de la Mama/inmunología , Camelidae , Línea Celular Tumoral , Receptores ErbB/inmunología , Receptores ErbB/metabolismo , Femenino , Humanos , Fragmentos Fc de Inmunoglobulinas/genética , Inmunoglobulina G/genética , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Mutación/genética , Unión Proteica , Ingeniería de ProteínasRESUMEN
Strong near-surface electromagnetic field formed by collective oscillation of electrons on Cu nanostructure a shows a strong dependence on geometry, offering a promising approach to boost the light absorption of ZnO photoactive layers with enhanced plasmon scattering. Here, a facile way to fabricate UV photodetectors with tunable configuration of the self-assembled Cu nanostructures on ZnO thin films is reported. The incident lights are effectively confined in ZnO photoactive layers with the existence of the uplayer Cu nanostructures, and the interdiffusion of Cu atoms during fabrication of the Cu nanostructures can improve the carrier transfer in ZnO thin films. The optical properties of the hybrid architectures are successfully tailored over a control of the geometric evolution of the Cu nanostructures, resulting in significantly enhanced photocurrent and responsivity of 2.26 mA and 234 A W-1 under a UV light illumination of 0.62 mW cm-2 at 10 V, respectively. The photodetectors also exhibit excellent reproducibility, stability, and UV-visible rejection ratio (R370 nm /R500 nm ) of ≈370, offering an approach of high-performance UV photodetectors for practical applications.
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Coordination of iron acquisition and heme synthesis is required for effective erythropoiesis. The small teleost zebrafish (Danio rerio) is an ideal vertebrate animal model to replicate various aspects of human physiology and provides an efficient and cost-effective way to model human pathophysiology. Importantly, zebrafish erythropoiesis largely resembles mammalian erythropoiesis. Gene discovery by large-scale forward mutagenesis screening has identified key components in heme and iron metabolism. Reverse genetic screens, using morpholino-knockdown and CRISPR/Cas9, coupled with the genetic tractability of the developing embryo have further accelerated functional studies. Ultimately, the ex utero development of zebrafish embryos combined with their transparency and developmental plasticity could provide a deeper understanding of the role of iron and heme metabolism during early vertebrate embryonic development.
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Modelos Animales de Enfermedad , Eritropoyesis , Hemo/metabolismo , Hierro/metabolismo , Pez Cebra/embriología , Animales , Desarrollo Embrionario , Humanos , RatonesRESUMEN
Herein, we demonstrate one of the highest terahertz group delay of 42.4 ps achieved experimentally at 0.23 THz, on a flexible planar metamaterial. The unit cell of metasurface is made up of a textured closed cavity and another experimentally concentric metallic arc. By tuning the central angle of the metallic arc, its intrinsic dipolar mode is in destructive interference with the spoof localized surface plasmon (SLSP) on textured closed cavity, which results in a plasmon-induced transparency phenomenon. The measured transmittances of as-fabricated samples using terahertz-time domain spectroscopy validate numerical results using extended coupled Lorentz oscillator model. It is found that the coupling coefficient and damping ratio of SLSP relies on the radius of the ring structure of textured closed cavity. As a consequence, the slow light maximum values become manoeuverable in strength at certain frequencies of induced transparency windows. To the best of our knowledge, our experimental result is currently the highest value demonstrated so far within metasurface at terahertz band.
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The neurotransmitter norepinephrine (NE) was investigated by broadband terahertz time-domain spectroscopy (THz-TDS) in the air-plasma system range from 0.5 to 18.2 THz. NE has a unique absorption spectrum in the THz band, which can be used as a characteristic fingerprint for molecular detection and identification. The temperature-dependent THz spectra of NE were recorded in the range from 83 to 293 K, and a blue-shift of the absorption peaks was observed as the temperature decreased. A solid-state density functional theory (DFT) calculation was implemented to better understand the low-frequency vibrational property of NE, and the calculated results agree well with the THz experimental observations. This result suggests that the broadband THz system can obtain more abundant spectral signals of NE and each THz resonance peak has its own specific vibrational mode, which corresponds to a specific structure and interaction. Even with the adjacent absorption peaks, the vibrational behaviors are different. The deformation of the aromatic ring and the flexibility of the side chain directly affect the NE molecular conformation, which may be closely associated with the receptor binding preference for the neurotransmitter. The conformational diversity of NE may help to understand the biological function of the neurotransmitter in the nervous system.
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Neurotransmisores/química , Norepinefrina/química , Modelos Químicos , Conformación Molecular , Neurotransmisores/efectos de la radiación , Norepinefrina/efectos de la radiación , Teoría Cuántica , Temperatura , Radiación Terahertz , Espectroscopía de Terahertz/métodos , VibraciónRESUMEN
Arterial spin labeling (ASL) magnetic resonance imaging has been widely applied to identify cerebral blood flow (CBF) abnormalities in a number of brain disorders. To evaluate its significance in detecting methamphetamine (MA) dependence, this study used a multivariate pattern classification algorithm, ie, a support vector machine (SVM), to construct classifiers for discriminating MA-dependent subjects from normal controls. Forty-five MA-dependent subjects, 45 normal controls, and 36 heroin-dependent subjects were enrolled. Classifiers trained with ASL-CBF data from the left or right cerebrum showed significant hemispheric asymmetry in their cross-validated prediction performance (P < 0.001 for accuracy, sensitivity, specificity, kappa, and area under the curve [AUC] of the receiver operating characteristics [ROC] curve). A classifier trained with ASL-CBF data from all cerebral regions (bilateral hemispheres and corpus callosum) was able to differentiate MA-dependent subjects from normal controls with a cross-validated prediction accuracy, sensitivity, specificity, kappa, and AUC of 89%, 94%, 84%, 0.78, and 0.95, respectively. The discrimination map extracted from this classifier covered multiple brain circuits that either constitute a network related to drug abuse and addiction or could be impaired in MA-dependence. The cerebral regions contribute most to classification include occipital lobe, insular cortex, postcentral gyrus, corpus callosum, and inferior frontal cortex. This classifier was also specific to MA-dependence rather than substance use disorders in general (ie, 55.56% accuracy for heroin dependence). These results support the future utilization of ASL with an SVM-based classifier for the diagnosis of MA-dependence and could help improve the understanding of MA-related neuropathology.
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Trastornos Relacionados con Anfetaminas/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética , Metanfetamina , Imagen de Perfusión , Máquina de Vectores de Soporte , Adulto , Área Bajo la Curva , Encéfalo/irrigación sanguínea , Estudios de Casos y Controles , Circulación Cerebrovascular , Humanos , Imagenología Tridimensional , Masculino , Curva ROC , Marcadores de Spin , Adulto JovenRESUMEN
Metal halide perovskite quantum dots (QDs) recently have attracted great research attentions. However, blue-emitting perovskite QDs generally suffer from low photoluminescence quantum yield (PLQY) because of easily formed defects and insufficient surface passivation. Replacement of lead with low toxicity elements is also preferred toward potential commercial applications. Here, we apply Cl-passivation to boost the PLQY of MA3Bi2Br9 QDs to 54.1% at the wavelength of 422 nm, a new PLQY record for blue emissive, lead-free perovskite QDs. Because of the incompatible crystal structures between MA3Bi2Br9 and MA3Bi2Cl9 and the careful kinetic control during the synthesis, Cl- anions are engineered to mainly locate on the surface of QDs acting as passivating ligands, which effectively suppress surface defects and enhance the PLQY. Our results highlight the potential of MA3Bi2Br9 QDs for applications of phosphors, scintillators, and light-emitting diodes.
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BACKGROUND: Gastrin is an important gastrointestinal hormone produced primarily by G-cells in the antrum of the stomach. It normally regulates gastric acid secretion and is implicated in a number of human disease states, but how its function affects breast cancer (BC) development is not documented. The current study investigated the suppressive effects of gastrin on BC and its underlying mechanisms. METHODS: Serum levels of gastrin were measured by enzyme-linked immunosorbent assay (ELISA) and correlation between gastrin level and development of BC was analyzed by chi-square test. Inhibitory effects of gastrin on BC were investigated by CCK-8 assay and nude mice models. Expressions of CCKBR/ERK/P65 in BC patients were determined through immunohistochemistry (IHC) and Western blot. Survival analysis was performed using the log-rank test. RESULTS: The results indicated that the serum level of gastrin in BC patients was lower compared with normal control. Cellular and molecular experiments indicated that reduction of gastrin is associated with inactivation of cholecystokinin B receptor (CCKBR)/ERK/P65 signaling in BC cells which is corresponding to molecular type of estrogen receptor (ER) positive BC. Furthermore, we found that low expression of gastrin/CCKBR/ERK /P65 was correlated to worse prognosis in BC patients. Gastrin or ERK/P65 activators inhibited ER+ BC through CCKBR-mediated activation of ERK/P65. Moreover, combination treatment with gastrin and tamoxifen more efficiently inhibited ER+ BC than tamoxifen alone. CONCLUSIONS: We concluded that low serum gastrin is related to increased risk of ER+ BC development. The results also established that CCKBR/ERK/P65 signaling function is generally tumor suppressive in ER+ BC, indicating therapies should focus on restoring, not inhibiting, CCKBR/ERK/P65 pathway activity.
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Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Gastrinas/sangre , Receptor de Colecistoquinina B/genética , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proteínas Portadoras/genética , Línea Celular Tumoral , Supervivencia sin Enfermedad , Receptor alfa de Estrógeno/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intracelular , Sistema de Señalización de MAP Quinasas/genética , Ratones , Proteínas de Neoplasias/genética , Pronóstico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Single domain antibodies (sdAbs) correspond to the antigen-binding domains of camelid antibodies. They have the same antigen-binding properties and specificity as monoclonal antibodies (mAbs) but are easier and cheaper to produce. We report here the development of sdAbs targeting human PCSK9 (proprotein convertase subtilisin/kexin type 9) as an alternative to anti-PCSK9 mAbs. After immunizing a llama with human PCSK9, we selected four sdAbs that bind PCSK9 with a high affinity and produced them as fusion proteins with a mouse Fc. All four sdAb-Fcs recognize the C-terminal Cys-His-rich domain of PCSK9. We performed multiple cellular assays and demonstrated that the selected sdAbs efficiently blocked PCSK9-mediated low density lipoprotein receptor (LDLR) degradation in cell lines, in human hepatocytes, and in mouse primary hepatocytes. We further showed that the sdAb-Fcs do not affect binding of PCSK9 to the LDLR but rather block its induced cellular LDLR degradation. Pcsk9 knock-out mice expressing a human bacterial artificial chromosome (BAC) transgene were generated, resulting in plasma levels of â¼300 ng/ml human PCSK9. Mice were singly or doubly injected with the best sdAb-Fc and analyzed at day 4 or 11, respectively. After 4 days, mice exhibited a 32 and 44% decrease in the levels of total cholesterol and apolipoprotein B and â¼1.8-fold higher liver LDLR protein levels. At 11 days, the equivalent values were 24 and 46% and â¼2.3-fold higher LDLR proteins. These data constitute a proof-of-principle for the future usage of sdAbs as PCSK9-targeting drugs that can efficiently reduce LDL-cholesterol, and as tools to study the Cys-His-rich domain-dependent sorting the PCSK9-LDLR complex to lysosomes.