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Two-dimensional transition metal dichalcogenide (TMDC) thin films have been extensively employed in microelectronics research. Molybdenum disulfide (MoS2), as one of prominent candidates of this class, has been applied in photodetectors, integrated electronic devices, gas sensing, and electrochemical catalysis, owing to its extraordinary optoelectronic, chemical, and mechanical properties. Synthesis of MoS2crystal film is the key to its application. However, the reported technology revealed several drawbacks, containing limited surface area, prolonged high-temperature environment, and unsatisfying crystallinity. In order to enhance the convenience of MoS2applications, there is a pressing need for optimized fabrication technology, which could be quicker, with a large area, with adequate crystallinity and heat-saving. In this work, we presented an ultraviolet laser-assisted synthesis technology, accomplishing rapid growth (with the growth rate of about 40µm s-1) of centimeter-scale MoS2films at room temperature. To achieve this, we self-assembled a displaceable reaction chamber system, coupled with krypton fluoride ultraviolet pulse laser. The laser motion speed and trajectory could be customized in the software, allowing the maskless patterning of crystal films. As application, we exhibited a photodetector with the integration of synthesized MoS2and lead sulfide colloidal quantum dots (PbS CQDs), displaying broadband photodetection from ultraviolet, visible to near-infrared spectrum (365-1550 nm), with the detectivity of 109-1010Jones, and the rising time of 0.2-0.3 s. This work not only demonstrated a high-process-efficiency synthesis of TMDC materials, but also has opened up new opportunities for ultraviolet laser used in optoelectronics.
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Infrared solar cells are regarded as candidates for expanding the solar spectrum of c-Si cells, and the window electrodes are usually transparent conductive oxide (TCO) such as widely used indium tin oxide material. However, due to the low transmittance of the TCO in the near-infrared region, most near-infrared light cannot penetrate the electrode and be absorbed by the active layer. Here, the propose a simple procedure to fabricate the window materials with high near-infrared transmittance and high electrical conductivity, namely the hydrogen-doped indium oxide (IHO) films prepared by room temperature magnetron sputtering. The low-temperature annealed IHO conductive electrodes exhibit high mobility of 98 cm2 V-1 s-1 and high infrared transmittance of 85.2% at 1300 nm, which endows the lead quantum dot infrared solar cell with an improved short-circuit current density of 37.2 mA cm-2 and external quantum efficiency of 70.22% at 1280 nm. The proposed preparation process is simple and compatible with existing production lines, which gifts the IHO transparent conductive film great potential in broad applications that simultaneously require high infrared transmittance and high conductivity.
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Monolayer MoS2 possesses good electron mobility, structural flexibility and a direct band gap, enabling it to be a promising candidate for flexible and wearable optoelectronic devices. In this article, the lateral monolayer MoS2 homojunctions were prepared by a nitrogen plasma selective doping technique. The monolayer MoS2 thin films were synthesized by chemical vapor deposition and characterized by photoluminescence, atom force microscope and Raman spectroscopy. The electronic and photoelectric properties of the lateral pn and npn homojunctions were discussed. The results showed that the rectifying ratio of the pn homojunction diode is â¼103. As a photodetector of pn homojunction, the optical responsivity is up to 48.5 A W-1, the external quantum efficiency is 11 301%, the detectivity is â¼109 Jones and the response time is 20 ms with the laser of 532 nm and the reverse bias voltage of 10 V. As a bipolar junction transistor of npn homojunction, the amplification coefficient reached â¼102. A controllable plasma doping technique, compatible with traditional CMOS process, is utilized to realize the monolayer MoS2 based pn and npn homojunctions, and it propels the potential applications of 2D materials in the electronic, optoelectronic devices and circuits.
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Breast cancer (BC) and prostate cancer (PC) are the second most common malignant tumors in women and men in western countries, respectively. The risks of death are 14% for BC and 9% for PC. Abnormal estrogen and androgen levels are related to carcinogenesis of the breast and prostate. Estradiol stimulates cancer development in BC. The effect of estrogen on PC is concentration-dependent, and estrogen can regulate androgen production, further affecting PC. Estrogen can also increase the risk of androgen-induced PC. Androgen has dual effects on BC via different metabolic pathways, and the role of the androgen receptor (AR) in BC also depends on cell subtype and downstream target genes. Androgen and AR can stimulate both primary PC and castration-resistant PC. Understanding the mechanisms of the effects of estrogen and androgen on BC and PC may help us to improve curative BC and PC treatment strategies.
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Androgênios/metabolismo , Neoplasias da Mama/metabolismo , Estrogênios/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Estradiol , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Fosforilação , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/metabolismo , Risco , Transdução de SinaisRESUMO
Low damaged doping of two-dimensional (2D) materials proves to be a significant obstacle in realizing fundamental devices such as p-n junction diodes and transistors due to its atom layer thickness. In this work, the defect formation energy and p-type conduction behavior of nitrogen plasma doping are investigated by first principle calculation. Low damaged substitutional p-type doping in MoS2 using low energy nitrogen plasma composed of N+ and N2 + is achieved by a novel toroidal magnetic field (TMF). The TMF helps to raise the concentration of N2 + ions at low RF power condition. The electrical characteristics of double-layer MoS2 field-effect transistors (FETs) clearly show an efficient p-type doping behavior. Atomic force microscope is applied to verify the slight damage in MoS2. X-ray photoelectron spectroscopy, photoluminescence and Raman spectroscopy confirm the effective p-type doping characteristic with weak damage. These findings provide a low damage technology for efficient carrier modulation of MoS2 and other homogeneous TMDC materials, which overcomes barriers in developing 2D electronic and optoelectronic devices.
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UNLABELLED: Clinical evidence suggests that many cases of serious idiosyncratic drug-induced liver injury are mediated by the adaptive immune system in response to hepatic drug-protein adducts, also referred to as "drug-induced allergic hepatitis"; but detailed mechanistic proof has remained elusive due to the lack of animal models. We have hypothesized that drug-induced allergic hepatitis is as rare in animals as it is in humans due at least in part to the tolerogenic nature of the liver. We provide evidence that immune tolerance can be overcome in a murine model of halothane-induced liver injury initiated by trifluoroacetylated protein adducts of halothane formed in the liver. Twenty-four hours after female Balb/cJ mice were initially treated with halothane, perivenous necrosis and an infiltration of CD11b(+) Gr-1(high) cells were observed in the liver. Further study revealed a subpopulation of myeloid-derived suppressor cells within the CD11b(+) Gr-1(high) cell fraction that inhibited the proliferation of both CD4(+) and CD8(+) T cells. When CD11b(+) Gr-1(high) cells were depleted from the liver with Gr-1 antibody treatment, enhanced liver injury was observed at 9 days after halothane rechallenge. Toxicity was associated with increased serum levels of interleukin-4 and immunoglobulins G1 and E directed against hepatic trifluoroacetylated protein adducts, as well as increased hepatic infiltration of eosinophils and CD4(+) T cells, all features of an allergic reaction. When hepatic CD4(+) T cells were depleted 5 days after halothane rechallenge, trifluoroacetylated protein adduct-specific serum immunoglobulin and hepatotoxicity were reduced. CONCLUSION: Our data provide a rational approach for developing animal models of drug-induced allergic hepatitis mediated by the adaptive immune system and suggest that impaired liver tolerance may predispose patients to this disease.
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Antígeno CD11b/imunologia , Linfócitos T CD8-Positivos/imunologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Halotano/toxicidade , Hepatite/imunologia , Células Mieloides/metabolismo , Alanina Transaminase/metabolismo , Análise de Variância , Animais , Antígeno CD11b/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Hepatite/patologia , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Células Mieloides/efeitos dos fármacos , Óxido Nítrico/metabolismo , Distribuição AleatóriaRESUMO
Electrode materials optimization is one of the keys to improving the energy storage characteristics of secondary batteries. Herein, a VO2@carbon@SnS2 composite is developed by coating SnS2 quantum dots (QDs) on lamellar VO2@carbon nanorods, yielding a high-performance aluminum-ion battery cathode. SnS2 QDs embedded in VO2@carbon accelerate electron transport, while the in situ coating of carbon improves cycling stability. When cycling at 0.5 A g-1, capacity is maintained at 157.6 mA h g-1 after 200 cycles. Even at 1.0 A g-1, the cathode can be stably cycled 1000 times. Capacity remains at 176.3 mA h g-1 and coulombic efficiency is 99.1% at temperatures below -10 °C after 100 cycles. These findings provide new ideas for the development of QD-modified composites for application in secondary batteries.
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Metastasis is the main culprit of cancer-related death and account for the poor prognosis of hepatocellular carcinoma. Although platelets have been shown to accelerate tumor cell metastasis, the exact mechanism remained to be fully understood. Here, we found that high blood platelet counts and increased tumor tissue ADAM10 expression indicated the poor prognosis of HCC patients. Meanwhile, blood platelet count has positive correlation with tumor tissue ADAM10 expression. In vitro, we revealed that platelet increased ADAM10 expression in tumor cell through TLR4/NF-κB signaling pathway. ADAM10 catalyzed the shedding of CX3CL1 which bound to CX3CR1 receptor, followed by inducing epithelial to mesenchymal transition and activating RhoA signaling in cancer cells. Moreover, knockdown HCC cell TLR4 (Tlr4) or inhibition of ADAM10 prevented platelet-increased tumor cell migration, invasion and endothelial permeability. In vivo, we further verified in mice lung metastatic model that platelet accelerated tumor metastasis via cancer cell TLR4/ADAM10/CX3CL1 axis. Overall, our study provides new insights into the underlying mechanism of platelet-induced HCC metastasis. Therefore, targeting the TLR4/ADAM10/CX3CL1 axis in cancer cells hold promise for the inhibition of platelet-promoted lung metastasis of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Humanos , Carcinoma Hepatocelular/patologia , Receptor 4 Toll-Like/metabolismo , Neoplasias Hepáticas/patologia , Transição Epitelial-Mesenquimal , Transdução de Sinais , Proteína ADAM10/metabolismo , Movimento Celular , Linhagem Celular Tumoral , Metástase Neoplásica , Proteínas de Membrana/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Quimiocina CX3CL1RESUMO
Previous research has revealed that platelets promote tumor metastasis by binding to circulating tumor cells (CTCs). However, the role of platelets in epithelial-mesenchymal transition (EMT) of cancer cells at the primary tumor site, the crucial initial step of tumor metastasis, remains to be elucidated. Here, we found that platelet releasate enhanced EMT and motility of hepatocellular carcinoma (HCC) cells via AMPK/mTOR-induced autophagy. RNA-seq indicated that platelet releasate altered TGF-ß signaling pathway of cancer cells. Inhibiting TGFBR or deleting platelet TGF-ß1 suppressed AMPK/mTOR pathway activation and autophagy induced by platelet releasate. Compared with Pf4cre-; Tgfb1fl/fl mice, HCC orthotopic models established on Pf4cre+; Tgfb1fl/fl mice showed reduced TGF-ß1 in primary tumors, which corresponded with decreased cancer cell EMT, autophagy, migration ability and tumor metastasis. Inhibition of autophagy via Atg5 knockdown in cancer cells negated EMT and metastasis induced by platelet-released TGF-ß1. Clinically, higher platelet count correlated with increased TGF-ß1, LC3 and N-cad expression in primary tumors of HCC patients, suggesting a link between platelets and HCC progression. Our study indicates that platelets promote cancer cell EMT in the primary tumor and HCC metastasis through TGF-ß1-induced HCC cell autophagy via the AMPK/mTOR pathway. These findings offer novel insights into the role of platelets in HCC metastasis and the potential therapeutic targets for HCC metastasis.
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Autofagia , Plaquetas , Carcinoma Hepatocelular , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas , Transdução de Sinais , Fator de Crescimento Transformador beta1 , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Animais , Plaquetas/metabolismo , Plaquetas/patologia , Humanos , Camundongos , Movimento Celular , Linhagem Celular Tumoral , Serina-Treonina Quinases TOR/metabolismo , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Metástase Neoplásica , Masculino , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismoRESUMO
AIMS: Breast cancer is the most prevalent cancer in females, and approximately 70 % of all patients have evidence of metastatic bone disease, which substantially affects the quality of life and survival rate of breast cancer patients. Osteoporosis has become a global public health problem, and the abnormal activation of osteoclasts is the key to the progression of osteoporosis and the key to both diseases lies in the osteoclasts. Effective drug treatments are lacking and there is an urgent need to explore new drugs. MATERIALS AND METHODS: We observed the effects of pogostone (PO) on osteoclast differentiation, bone resorption function and other indicators, and F-actin ring formation by using Trap staining, SEM and immunofluorescence, and further explored the targets of pogostone in regulating osteoclast differentiation and function using qPCR and Western Blot. In addition, we used CCK 8, Transwell, and flow cytometry to study the effects of pogostone on proliferation, invasion, migration, and apoptosis of MDA-MB-231 cells. Animal models were also constructed for in vivo validation. KEY FINDINGS: Pogostone inhibits osteoclast differentiation, bone resorption, formation of F-actin ring, and the expression of specific genes by attenuated NF-kB degradation and phosphorylation of JNK. In vitro, pogostone suppresses invasion of breast cancer cells, migration, and promotes their apoptosis. In mouse models, pogostone attenuated osteoclast formation and bone resorption, blocked breast cancer cells migration, and supprsed breast cancer-induced osteolysis and ovariectomized (OVX)-mediated osteoporosis. SIGNIFICANCE: These biological functions of pogostone make it a potential drug for treatment of breast cancer-associated bone metastasis in the future.
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Reabsorção Óssea , Neoplasias da Mama , Osteólise , Osteoporose , Animais , Camundongos , Feminino , Humanos , Osteoclastos/metabolismo , Osteólise/tratamento farmacológico , Osteólise/metabolismo , Osteólise/patologia , NF-kappa B/metabolismo , Sistema de Sinalização das MAP Quinases , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Actinas/metabolismo , Qualidade de Vida , Diferenciação Celular , Reabsorção Óssea/metabolismo , Osteoporose/metabolismo , Ligante RANK/metabolismo , OsteogêneseRESUMO
Short-wave infrared detectors are increasingly important in the fields of autonomous driving, food safety, disease diagnosis, and scientific research. However, mature short-wave infrared cameras such as InGaAs have the disadvantage of complex heterogeneous integration with complementary metal-oxide-semiconductor (CMOS) readout circuits, leading to high cost and low imaging resolution. Herein, a low-cost, high-performance, and high-stability Tex Se1- x short-wave infrared photodiode detector is reported. The Tex Se1- x thin film is fabricated through CMOS-compatible low-temperature evaporation and post-annealing process, showcasing the potential of direct integration on the readout circuit. The device demonstrates a broad-spectrum response of 300-1600 nm, a room-temperature specific detectivity of 1.0 × 1010 Jones, a -3 dB bandwidth up to 116 kHz, and a linear dynamic range of over 55 dB, achieving the fastest response among Te-based photodiode devices and a dark current density 7 orders of magnitude smaller than Te-based photoconductive and field-effect transistor devices. With a simple Si3 N4 packaging, the detector shows high electric stability and thermal stability, meeting the requirements for vehicular applications. Based on the optimized Tex Se1- x photodiode detector, the applications in material identification and masking imaging is demonstrated. This work paves a new way for CMOS-compatible infrared imaging chips.
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Antigen-specific tolerance is a key goal of experimental immunotherapies for autoimmune disease and allograft rejection. This outcome could selectively inhibit detrimental inflammatory immune responses without compromising functional protective immunity. A major challenge facing antigen-specific immunotherapies is ineffective control over immune signal targeting and integration, limiting efficacy and causing systemic non-specific suppression. Here we use intra-lymph node injection of diffusion-limited degradable microparticles that encapsulate self-antigens with the immunomodulatory small molecule, rapamycin. We show this strategy potently inhibits disease during pre-clinical type 1 diabetes and allogenic islet transplantation. Antigen and rapamycin are required for maximal efficacy, and tolerance is accompanied by expansion of antigen-specific regulatory T cells in treated and untreated lymph nodes. The antigen-specific tolerance in type 1 diabetes is systemic but avoids non-specific immune suppression. Further, microparticle treatment results in the development of tolerogenic structural microdomains in lymph nodes. Finally, these local structural and functional changes in lymph nodes promote memory markers among antigen-specific regulatory T cells, and tolerance that is durable. This work supports intra-lymph node injection of tolerogenic microparticles as a powerful platform to promote antigen-dependent efficacy in type 1 diabetes and allogenic islet transplantation.
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Diabetes Mellitus Tipo 1 , Transplante das Ilhotas Pancreáticas , Humanos , Tolerância Imunológica , Autoantígenos , Linfonodos/patologia , SirolimoRESUMO
3D bioprinting has been developed as an effective and powerful technique for the fabrication of living tissue constructs in a well-controlled manner. However, most existing 3D bioprinting strategies face substantial challenges in replicating delicate and intricate tissue-specific structural organizations using mechanically weak biomaterials such as hydrogels. Embedded bioprinting is an emerging bioprinting strategy that can directly fabricate complex structures derived from soft biomaterials within a supporting matrix, which shows great promise in printing large vascularized tissues and organs. Here, we provide a state-of-the-art review on the development of embedded bioprinting including extrusion-based and light-based processes to manufacture complex tissue constructs with biomimetic architectures. The working principles, bioinks, and supporting matrices of embedded printing processes are introduced. The effect of key processing parameters on the printing resolution, shape fidelity, and biological functions of the printed tissue constructs are discussed. Recent innovations in the processes and applications of embedded bioprinting are highlighted, such as light-based volumetric bioprinting and printing of functional vascularized organ constructs. Challenges and future perspectives with regard to translating embedded bioprinting into an effective strategy for the fabrication of functional biological constructs with biomimetic structural organizations are finally discussed. STATEMENT OF SIGNIFICANCE: It is still challenging to replicate delicate and intricate tissue-specific structural organizations using mechanically-weak hydrogels for the fabrication of functional living tissue constructs. Embedded bioprinting is an emerging 3D printing strategy that enables to produce complex tissue structures directly inside a reservoir filled with supporting matrix, which largely widens the choice of bioprinting inks to ECM-like hydrogels. Here we aim to provide a comprehensive review on various embedded bioprinting techniques mainly including extrusion-based and light-based processes. Various bioinks, supporting matrices, key processing parameters as well as their effects on the structures and biological functions of resultant living tissue constructs are discussed. We expect that it can provide an important reference and generate new insights for the bioprinting of large vascularized tissues and organs with biological functions.
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Bioimpressão , Materiais Biocompatíveis , Bioimpressão/métodos , Hidrogéis , Impressão Tridimensional , Engenharia Tecidual/métodos , Alicerces Teciduais/químicaRESUMO
Indium tin oxide (ITO) is widely used in a variety of optoelectronic devices, occupying a huge market share of $1.7 billion. However, traditional preparation methods such as magnetron sputtering limit the further development of ITO in terms of high preparation temperature (>350 °C) and low mobility (â¼30 cm2 V-1 s-1). Herein, we develop an adjustable process to obtain high-mobility ITO with both appropriate conductivity and infrared transparency at room temperature by a reactive plasma deposition (RPD) system, which has many significant advantages including low-ion damage, low deposition temperature, large-area deposition, and high throughput. By optimizing the oxygen flow during the RPD process, ITO films with a high mobility of 62.1 cm2 V-1 s-1 and a high average transparency of 89.7% at 800-2500 nm are achieved. Furthermore, the deposited ITO films present a smooth surface with a small roughness of 0.3 nm. The stability of ITO films to heat, humidity, radiation, and alkali environments is also investigated with carrier mobility average changes of 19.3, 4.4, and 4.7%, showcasing strong environmental adaptability. We believe that stable ITO films with high mobility prepared by a low-damage deposition method will be widely used in full spectral optoelectronic applications, such as tandem solar cells, infrared photodetectors, light-emitting diodes, etc.
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Recent clinical studies show activating multiple innate immune pathways drives robust responses in infection and cancer. Biomaterials offer useful features to deliver multiple cargos, but add translational complexity and intrinsic immune signatures that complicate rational design. Here a modular adjuvant platform is created using self-assembly to build nanostructured capsules comprised entirely of antigens and multiple classes of toll-like receptor agonists (TLRas). These assemblies sequester TLR to endolysosomes, allowing programmable control over the relative signaling levels transduced through these receptors. Strikingly, this combinatorial control of innate signaling can generate divergent antigen-specific responses against a particular antigen. These assemblies drive reorganization of lymph node stroma to a pro-immune microenvironment, expanding antigen-specific T cells. Excitingly, assemblies built from antigen and multiple TLRas enhance T cell function and antitumor efficacy compared to ad-mixed formulations or capsules with a single TLRa. Finally, capsules built from a clinically relevant human melanoma antigen and up to three TLRa classes enable simultaneous control of signal transduction across each pathway. This creates a facile adjuvant design platform to tailor signaling for vaccines and immunotherapies without using carrier components. The modular nature supports precision juxtaposition of antigen with agonists relevant for several innate receptor families, such as toll, STING, NOD, and RIG.
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Recently approved cancer immunotherapies - including CAR-T cells and cancer vaccination, - show great promise. However, these technologies are hindered by the complexity and cost of isolating and engineering patient cells ex vivo. Lymph nodes (LNs) are key tissues that integrate immune signals to coordinate adaptive immunity. Directly controlling the signals and local environment in LNs could enable potent and safe immunotherapies without cell isolation, engineering, and reinfusion. Here we employ intra-LN (i.LN.) injection of immune signal-loaded biomaterial depots to directly control cancer vaccine deposition, revealing how the combination and geographic distribution of signals in and between LNs impact anti-tumor response. We show in healthy and diseased mice that relative proximity of antigen and adjuvant in LNs - and to tumors - defines unique local and systemic characteristics of innate and adaptive response. These factors ultimately control survival in mouse models of lymphoma and melanoma. Of note, with appropriate geographic signal distributions, a single i.LN. vaccine treatment confers near-complete survival to tumor challenge and re-challenge 100 days later, without additional treatments. These data inform design criteria for immunotherapies that leverage biomaterials for loco-regional LN therapy to generate responses that are systemic and specific, without systemically exposing patients to potent or immunotoxic drugs.
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Vacinas Anticâncer , Melanoma , Animais , Sinais (Psicologia) , Linfonodos , Melanoma/terapia , Camundongos , Resultado do Tratamento , VacinaçãoRESUMO
BACKGROUND: Metabolic reprogramming is a hallmark of pulmonary arterial hypertension. Platelet activation has been implicated in pulmonary arterial hypertension (PAH), whereas the role of platelet in the pathogenesis of PAH remains unclear. METHODS: First, we explored the platelet function of semaxanib' a inhibitor of VEGF receptor (SU5416)/hypoxia mice and monocrotaline-injected rats PAH model. Then we investigated pulmonary arterial smooth muscle cell aerobic glycolysis after being treated with platelet supernatant. TGF (transforming growth factor)-ßRI, pyruvate kinase muscle 2, and other antagonists were applied to identify the underlying mechanism. In addition, platelet-specific deletion TGF-ß1 mice were exposed to chronic hypoxia and SU5416. Cardiopulmonary hemodynamics, vascular remodeling, and aerobic glycolysis of pulmonary arterial smooth muscle cell were determined. RESULTS: Here, we demonstrate that platelet-released TGF-ß1 enhances the aerobic glycolysis of pulmonary arterial smooth muscle cells after platelet activation via increasing pyruvate kinase muscle 2 expression. Mechanistically, platelet-derived TGF-ß1 regulate spyruvate kinase muscle 2 expression through mTOR (mammalian target of rapamycin)/c-Myc/PTBP-1(polypyrimidine tract binding protein 1)/hnRNPA-1(heterogeneous nuclear ribonucleoprotein A1) pathway. Platelet TGF-ß1 deficiency mice are significantly protected from SU5416 plus chronic hypoxia-induced PAH, including attenuated increases in right ventricular systolic pressure and less pulmonary vascular remodeling. Also, in Pf4cre+ Tgfb1fl/fl mice, pulmonary arterial smooth muscle cells showed lower glycolysis capacity and their pyruvate kinase muscle 2 expression decreased. CONCLUSIONS: Our data demonstrate that TGF-ß1 released by platelet contributes to the pathogenesis of PAH and further highlights the role of platelet in PAH.
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Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Animais , Proliferação de Células , Glicólise , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Mamíferos/metabolismo , Camundongos , Músculos , Miócitos de Músculo Liso/metabolismo , Isoformas de Proteínas/metabolismo , Artéria Pulmonar/metabolismo , Piruvato Quinase/genética , Piruvato Quinase/metabolismo , Ratos , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima , Remodelação Vascular/fisiologiaRESUMO
Autoimmune diseases like multiple sclerosis (MS), type 1 diabetes, and lupus occur when the immune system attacks host tissue. Immunotherapies that promote selective tolerance without suppressing normal immune function are of tremendous interest. Here, nanotechnology was used for rational assembly of peptides and modulatory immune cues into immune complexes. Complexes containing self-peptides and regulatory nucleic acids reverse established paralysis in a preclinical MS model. Importantly, mice responding to immunotherapy maintain healthy, antigen-specific B and T cell responses during a foreign antigen challenge. A therapeutic library isolating specific components reveals that regulatory nucleic acids suppress inflammatory genes in innate immune cells, while disease-matched peptide sequences control specificity of tolerance. Distinct gene expression profiles in cells and animals are associated with the immune signals administered in particulate and soluble forms, highlighting the impact of biophysical presentation of signals. This work provides insight into the rational manipulation of immune signaling to drive tolerance.
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Doenças Autoimunes , Diabetes Mellitus Tipo 1 , Animais , Doenças Autoimunes/tratamento farmacológico , Sinais (Psicologia) , Tolerância Imunológica , Camundongos , Linfócitos T , Linfócitos T ReguladoresRESUMO
Sanguinarine, a benzophenanthridine alkaloid, has been described to have an antiplatelet activity. However, its antithrombotic effect and the mechanism of platelet inhibition have not thoroughly been explored. The current study found that sanguinarine had an inhibitory effect on thrombus formation. This inhibitory effect was quite evident both in the flow-chamber assays as well as in a murine model of FeCl3-induced carotid artery thrombosis. Further investigations also revealed that sanguinarine inhibited the collagen-induced human platelet aggregation and granule release. At the same time, it also prevented platelet spreading and adhesion to immobilized fibrinogen. The molecular mechanisms of its antiplatelet activity were found to be as follows: 1. Reduced phosphorylation of the downstream signaling pathways in collagen specific receptor GPVI (Syk-PLCγ2 and PI3K-Akt-GSK3ß); 2. Inhibition of collagen-induced increase in the intracellular Ca2+ concentration ([Ca2+]i); 3. Inhibition of integrin αIIbß3 outside-in signaling via reducing ß3 and Src (Tyr-416) phosphorylation. It can be concluded that sanguinarine inhibits collagen-induced platelet activation and reduces thrombus formation. This effect is mediated via inhibiting the phosphorylation of multiple components in the GPVI signaling pathway. Current data also indicate that sanguinarine can be of some clinical value to treat cardiovascular diseases involving an excess of platelet activation.
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Monolayer 2H-phase MoS2-based photodetectors exhibit high photon absorption but suffer from low photoresponse, which severely limits their applications in optoelectronic fields. The metallic 1T phase of MoS2, while transporting carriers faster, shows negligible response to visible light, which limits its usage in photodetectors. Herein, we propose an ultrafast-response MoS2-based photodetector having a channel that consists of a 2H-MoS2 sensitizing monolayer on top of 1T@2H-MoS2. The 1T@2H-MoS2 layer has a thickness of several nanometers and is a mixture of metallic 1T-MoS2 and semiconducting 2H-MoS2, imparting metal-like properties to the photodetector. Compared with the monolayer 2H-MoS2 photodetector, we observed a drastic increase in the photoresponse of the 2H-MoS2/1T@2H-MoS2 vertically stacked photodetector to a value of 1917 A W-1. Owing to the presence of metallic 1T-MoS2 within the metal-like 1T@2H-MoS2, the performance of the 2H-MoS2/1T@2H-MoS2 vertically stacked photodetector is voltage bias-modulated with an external quantum efficiency (EQE) of up to 448,384% and a specific detectivity of up to â¼1011 Jones. The higher carrier density and higher mobility of the 1T@2H-MoS2 layer explain the better bias-modulated performance. In addition, the interface between 2H-MoS2 and 1T@2H-MoS2 ensures fewer dangling bonds and reduced lattice mismatching. Thus, this study presents an exclusive vertically stacked MoS2-based photodetector that lays the foundation for the development of photodetectors exhibiting higher photoresponse.