RESUMEN
Parkinson's disease (PD) represents the second most widespread neurodegenerative disease, and early monitoring and diagnosis are urgent at present. Tyrosine hydroxylase (TH) is a key enzyme for producing dopamine, the levels of which can serve as an indicator for assessing the severity and progression of PD. This renders the specific detection and visualization of TH a strategically vital way to meet the above demands. However, a fluorescent probe for TH monitoring is still missing. Herein, three rationally designed wash-free ratiometric fluorescent probes were proposed. Among them, TH-1 exhibited ideal photophysical properties and specific dual-channel bioimaging of TH activity in SH-SY5Y nerve cells. Moreover, the probe allowed for in vivo imaging of TH activity in zebrafish brain and living striatal slices of mice. Overall, the ratiometric fluorescent probe TH-1 could serve as a potential tool for real-time monitoring of PD in complex biosystems.
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Colorantes Fluorescentes , Tirosina 3-Monooxigenasa , Pez Cebra , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Tirosina 3-Monooxigenasa/metabolismo , Tirosina 3-Monooxigenasa/análisis , Animales , Ratones , Humanos , Imagen Óptica , Línea Celular Tumoral , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismoRESUMEN
Ultraviolet light emitting diodes (UV-LEDs) face the challenges including insufficient hole injection and severe electron leakage. Quantum dots (QDs) have been proven to provide three-dimensionally localized states for carriers, thereby enhancing carrier confinement. Therefore, UV-LEDs employing InGaN QDs are designed and studied in this paper. The APSYs software is used to simulate UV-LEDs. Simulation results indicate that the QDs effectively improve the electron and hole concentration in the active region. However, UV-LEDs with QDs experience efficiency droop due to serious electron leakage. What's more, the lattice mismatch between last quantum barrier (LQB) and electron blocking layer (EBL) leads to the polarization field, which induces the downward band bending at the LQB/EBL interface and reduces effective barrier height of EBL for electrons. The AlInGaN/AlInGaN lattice matched superlattice (LMSL) EBL is designed to suppress electron leakage while mitigating lattice mismatch between LQB and EBL. The results indicate that the utilization of QDs and LMSL EBL contributes to increasing the electron and hole concentration in the active region, reducing electron leakage, enhancing radiative recombination rate, and reducing turn-on voltage. The efficiency droop caused by electron leakage is mitigated. When the injection current is 120â mA, the external quantum efficiency is increased to 9.3% and the output power is increased to 38.3â mW. This paper provides a valuable reference for addressing the challenges of insufficient hole injection and severe electron leakage.
RESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with minimal treatment options and a global rise in prevalence. PDAC is characterized by frequent driver mutations including KRAS and TP53 (p53), and a dense, acidic tumor microenvironment (TME). The relation between genotype and TME in PDAC development is unknown. Strikingly, when wild type (WT) Panc02 PDAC cells were adapted to growth in an acidic TME and returned to normal pH to mimic invasive cells escaping acidic regions, they displayed a strong increase of aggressive traits such as increased growth in 3-dimensional (3D) culture, adhesion-independent colony formation and invasive outgrowth. This pattern of acidosis-induced aggressiveness was observed in 3D spheroid culture as well as upon organotypic growth in matrigel, collagen-I and combination thereof, mimicking early and later stages of PDAC development. Acid-adaptation-induced gain of cancerous traits was further increased by p53 knockout (KO), but only in specific extracellular matrix (ECM) compositions. Akt- and Transforming growth factor-ß (TGFß) signaling, as well as expression of the Na+ /H+ exchanger NHE1, were increased by acid adaptation. Whereas Akt inhibition decreased spheroid growth regardless of treatment and genotype, stimulation with TGFßI increased growth of WT control spheroids, and inhibition of TGFß signaling tended to limit growth under acidic conditions only. Our results indicate that a complex crosstalk between tumor acidosis, ECM composition and genotype contributes to PDAC development. The findings may guide future strategies for acidosis-targeted therapies.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Matriz Extracelular/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Microambiente Tumoral , Proteína p53 Supresora de Tumor/genética , Neoplasias PancreáticasRESUMEN
The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that adaptation to growth at an extracellular pH (pHe ) mimicking acidic tumor niches is associated with upregulated net acid extrusion capacity and elevated intracellular pH at physiological pHe , but not at acidic pHe . Using metabolic profiling, shotgun lipidomics, imaging and biochemical analyses, we show that the acid adaptation-induced phenotype is characterized by a shift toward oxidative metabolism, increased lipid droplet-, triacylglycerol-, peroxisome content and mitochondrial hyperfusion. Peroxisome proliferator-activated receptor-α (PPARA, PPARα) expression and activity are upregulated, at least in part by increased fatty acid uptake. PPARα upregulates genes driving increased mitochondrial and peroxisomal mass and ß-oxidation capacity, including mitochondrial lipid import proteins CPT1A, CPT2 and SLC25A20, electron transport chain components, peroxisomal proteins PEX11A and ACOX1, and thioredoxin-interacting protein (TXNIP), a negative regulator of glycolysis. This endows acid-adapted cancer cells with increased capacity for utilizing fatty acids for metabolic needs, while limiting glycolysis. As a consequence, the acid-adapted cells exhibit increased sensitivity to PPARα inhibition. We conclude that PPARα is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches.
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Acidosis , Neoplasias , Humanos , Factores de Transcripción/genética , Regulación de la Expresión Génica , PPAR alfa/genética , PPAR alfa/metabolismo , Ácidos Grasos/metabolismo , Neoplasias/metabolismo , Metabolismo de los Lípidos , Hígado/metabolismo , Microambiente TumoralRESUMEN
Our recent study suggests that FBXW7 loss of function plays a critical function in esophageal cancer. However, the mechanism of FBXW7 in promoting esophageal cancer is still unclear. Here, we explored the interaction protein of FBXW7 by screening of GST-pulldown and LC-MS/MS analysis in esophageal squamous cell carcinoma (ESCC) and identified ANXA2 as a potential target of FBXW7. FBXW7 loss of function could restore the expression of ANXA2 and promote the malignant biological characteristics of ESCC cells in vitro. Up-regulation of ANXA2 enhances the ERK pathway in ESCC. Furthermore, the 23rd tyrosine residue of ANXA2, phosphorylated by SRC, was regarded as playing important roles in the FBXW7-related degradation system. In clinical samples, we found that ANXA2 had high expression in ESCC tissues. High ANXA2 was associated with poor tumor staging. More importantly, we designed a combination regimen including SCH779284, a clinical ERK inhibitor against the phosphorylation of EKR and siRNA targeting ANXA2 by intratumor injection, and it produced potent inhibitory effects on the growth of xenograft tumors in vivo. In conclusion, this study provided evidence that FBXW7 loss of function could promote esophageal cancer through ANXA2 overexpression, and this novel regulation pathway may be used as an efficient target for ESCC treatment.
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Anexina A2 , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Neoplasias Esofágicas/patología , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Carcinoma de Células Escamosas/patología , Fosforilación , Cromatografía Liquida , Espectrometría de Masas en Tándem , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Anexina A2/metabolismoRESUMEN
Adipose-derived cells (ADCs) from white adipose tissue are promising stem cell candidates because of their large regenerative reserves and the potential for cardiac regeneration. However, given the heterogeneity of ADC and its unsolved mechanisms of cardiac acquisition, ADC-cardiac transition efficiency remains low. In this study, we explored the heterogeneity of ADCs and the cellular kinetics of 39,432 single-cell transcriptomes along the leukemia inhibitory factor (LIF)-induced ADC-cardiac transition. We identified distinct ADC subpopulations that reacted differentially to LIF when entering the cardiomyogenic program, further demonstrating that ADC-myogenesis is time-dependent and initiates from transient changes in nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. At later stages, pseudotime analysis of ADCs navigated a trajectory with 2 branches corresponding to activated myofibroblast or cardiomyocyte-like cells. Our findings offer a high-resolution dissection of ADC heterogeneity and cell fate during ADC-cardiac transition, thus providing new insights into potential cardiac stem cells.
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Miocitos Cardíacos , Factor 2 Relacionado con NF-E2 , Factor Inhibidor de Leucemia/genética , Factor Inhibidor de Leucemia/farmacología , RNA-Seq , Diferenciación Celular/genéticaRESUMEN
BACKGROUND: The lactate receptor GPR81 contributes to cancer development through unclear mechanisms. Here, we investigate the roles of GPR81 in three-dimensional (3D) and in vivo growth of breast cancer cells and study the molecular mechanisms involved. METHODS: GPR81 was stably knocked down (KD) in MCF-7 human breast cancer cells which were subjected to RNA-seq analysis, 3D growth, in situ- and immunofluorescence analyses, and cell viability- and motility assays, combined with KD of key GPR81-regulated genes. Key findings were additionally studied in other breast cancer cell lines and in mammary epithelial cells. RESULTS: GPR81 was upregulated in multiple human cancer types and further upregulated by extracellular lactate and 3D growth in breast cancer spheroids. GPR81 KD increased spheroid necrosis, reduced invasion and in vivo tumor growth, and altered expression of genes related to GO/KEGG terms extracellular matrix, cell adhesion, and Notch signaling. Single cell in situ analysis of MCF-7 cells revealed that several GPR81-regulated genes were upregulated in the same cell clusters. Notch signaling, particularly the Notch ligand Delta-like-4 (DLL4), was strikingly downregulated upon GPR81 KD, and DLL4 KD elicited spheroid necrosis and inhibited invasion in a manner similar to GPR81 KD. CONCLUSIONS: GPR81 supports breast cancer aggressiveness, and in MCF-7 cells, this occurs at least in part via DLL4. Our findings reveal a new GPR81-driven mechanism in breast cancer and substantiate GPR81 as a promising treatment target.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Ácido Láctico/metabolismo , Ligandos , Transducción de Señal , Necrosis , Receptor Notch1/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismoRESUMEN
RATIONALE: The BMPs (bone morphogenetic proteins) are essential morphogens in angiogenesis and vascular development. Disruption of BMP signaling can trigger cardiovascular diseases, such as arteriovenous malformations. OBJECTIVE: A computational model predicted that BMP4 and BMP9 and their inhibitors MGP (matrix gamma-carboxyglutamic acid [Gla] protein) and CV2 (crossveinless-2) would form a regulatory system consisting of negative feedback loops with time delays and that BMP9 would trigger oscillatory expression of the 2 inhibitors. The goal was to investigate this regulatory system in endothelial differentiation and vascular growth. METHODS AND RESULTS: Oscillations in the expression of MGP and CV2 were detected in endothelial cells in vitro, using quantitative real-time polymerase chain reaction and immunoblotting. These organized temporally downstream BMP-related activities, including expression of stalk-cell markers and cell proliferation, consistent with an integral role of BMP9 in vessel maturation. In vivo, the inhibitors were located in distinct zones in relation to the front of the expanding retinal network, as determined by immunofluorescence. Time-dependent changes of the CV2 location in the retina and the existence of an endothelial population with signs of oscillatory MGP expression in developing vasculature supported the in vitro findings. Loss of MGP or its BMP4-binding capacity disrupted the retinal vasculature, resulting in poorly formed networks, especially in the venous drainage areas, and arteriovenous malformations as determined by increased cell coverage and functional testing. CONCLUSIONS: Our results suggest a previously unknown mechanism of temporal orchestration of BMP4 and BMP9 activities that utilize the tandem actions of the extracellular antagonists MGP and CV2. Disruption of this mechanism may contribute to vascular malformations and disease.
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Proteínas Morfogenéticas Óseas/metabolismo , Proteínas de Unión al Calcio/metabolismo , Proteínas Portadoras/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Modelos Cardiovasculares , Neovascularización Fisiológica , Animales , Vasos Sanguíneos/crecimiento & desarrollo , Vasos Sanguíneos/metabolismo , Proteínas Morfogenéticas Óseas/genética , Humanos , Proteína Gla de la MatrizRESUMEN
Soil contamination by organic compounds has received worldwide concern for decades. Here, we found that dibutyl phthalate (DBP) could be degraded on moist quartz sand (QS, crystal, a typical soil constituent) during stirring, and the removal rate reached 57.2 ± 3.1% after 8 h of reaction. The introduction of peroxymonosulfate (PMS) and zerovalent iron (Fe0) substantially improved the decomposition of DBP to 94.2 ± 1.6% in 8 h, suggesting they have great contributions. DBP decomposition was caused by multiple reactive species, such as surface silicon-based radicals (like ≡SiOâ¢) and other reactive species like superoxide radical (O2â¢-), hydroxyl radical (â¢OH), and sulfate radical (SO4â¢-). In the QS/ultrapure water system, DBP was mainly attacked by O2â¢- or ≡SiOâ¢, with the formation of hydrolysis products. In the iron@QS/PMS system, due to the activation of PMS by Fe0, SO4â¢- and â¢OH were produced while the latter led to DBP degradation, and thus hydroxyl substitution products of DBP were ubiquitous. DBP was hardly removed on amorphous supporters like silica gel, alumina, and red soil even with the presence of PMS and Fe0, indicating the indispensable role of surface radicals on crystals like QS. This work presents a new remediation technology for polluted soil, especially aquifer.
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Dibutil Ftalato , Contaminantes Químicos del Agua , Peróxidos , Cuarzo , Arena , Contaminantes Químicos del Agua/análisisRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and irreversible lung disease. Studies have shown that epithelial-mesenchymal transition (EMT) plays an important role in the development of IPF. The NLRP3 inflammasome is reported to be activated and play an important role in many respiratory diseases. However, whether the NLRP3 inflammasome is activated in alveolar epithelial cells as well as the regulatory role of NLRP3 in EMT have not been reported. In this study, we transfected NLRP3 siRNA into A549 and RLE-6TN cells and treated them with bleomycin (BLM) for 24h. Then, we detected the expression of NLRP3 inflammasome-related proteins, EMT-related proteins and transforming growth factor-ß1 (TGF-ß1) via western blotting, immunofluorescence and real-time quantitative PCR. The mRNA and protein level of NLRP3, ASC and caspase-1 increased after treatment with BLM. The IL-1ß levels were significantly decreased after inhibition of NLRP3 and caspase-1. E-cadherin expression increased and α-SMA was reduced in the BLM group when inhibited by NLRP3. The level of TGF-ß1 was reduced after NLRP3 silencing. These results indicated that the NLRP3 inflammasome was activated in alveolar epithelial cells and that NLRP3 may regulate EMT through TGF-ß1. These results may extend our understanding of the mechanism of pulmonary fibrosis and provide a new therapeutic target for pulmonary fibrosis.
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Transición Epitelial-Mesenquimal , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Alveolos Pulmonares/metabolismo , Fibrosis Pulmonar/metabolismo , Bleomicina/farmacología , Cadherinas/efectos de los fármacos , Cadherinas/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Fosforilación , Alveolos Pulmonares/efectos de los fármacos , Fibrosis Pulmonar/inducido químicamente , Proteína smad3/metabolismoRESUMEN
RATIONALE: Endothelial cells have the ability to undergo endothelial-mesenchymal transitions (EndMTs), by which they acquire a mesenchymal phenotype and stem cell-like characteristics. We previously found that EndMTs occurred in the endothelium deficient in matrix γ-carboxyglutamic acid protein enabling endothelial cells to contribute cells to vascular calcification. However, the mechanism responsible for initiating EndMTs is not fully understood. OBJECTIVE: To determine the role of specific serine proteases and sex determining region Y-box 2 (Sox2) in the initiation of EndMTs. METHODS AND RESULTS: In this study, we used in vivo and in vitro models of vascular calcification to demonstrate that serine proteases and Sox2 are essential for the initiation of EndMTs in matrix γ-carboxyglutamic acid protein-deficient endothelium. We showed that expression of a group of specific serine proteases was highly induced in endothelial cells at sites of vascular calcification in Mgp null aortas. Treatment with serine protease inhibitors decreased both stem cell marker expression and vascular calcification. In human aortic endothelial cells, this group of serine proteases also induced EndMTs, and the activation of proteases was mediated by Sox2. Knockdown of the serine proteases or Sox2 diminished EndMTs and calcification. Endothelial-specific deletion of Sox2 decreased expression of stem cell markers and aortic calcification in matrix γ-carboxyglutamic acid protein-deficient mice. CONCLUSIONS: Our results suggest that Sox2-mediated activation of specific serine proteases is essential for initiating EndMTs, and thus, may provide new therapeutic targets for treating vascular calcification.
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Calcinosis , Endotelio Vascular/metabolismo , Mesodermo/metabolismo , Serina Endopeptidasas/metabolismo , Animales , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Células Cultivadas , Endotelio Vascular/patología , Endotelio Vascular/ultraestructura , Activación Enzimática , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Perfilación de la Expresión Génica/métodos , Humanos , Immunoblotting , Calicreínas/genética , Calicreínas/metabolismo , Mesodermo/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microscopía Electrónica de Rastreo , Microscopía Electrónica de Transmisión , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Elastasa Pancreática/genética , Elastasa Pancreática/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Serina Endopeptidasas/genética , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/metabolismo , Proteína Gla de la MatrizAsunto(s)
Antagonistas Adrenérgicos beta/farmacología , Enfermedades de la Aorta/prevención & control , Células Endoteliales/efectos de los fármacos , Etanolaminas/farmacología , Factores de Transcripción SOXB1/metabolismo , Calcificación Vascular/prevención & control , Animales , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/patología , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología , Modelos Animales de Enfermedad , Regulación hacia Abajo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Ratones Noqueados , Ratones Noqueados para ApoE , Osteopontina/genética , Osteopontina/metabolismo , Factores de Transcripción SOXB1/genética , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Calcificación Vascular/genética , Calcificación Vascular/metabolismo , Calcificación Vascular/patología , Proteína Gla de la MatrizRESUMEN
Matrix Gla protein (MGP) is an antagonist of bone morphogenetic proteins and expressed in vascular endothelial cells. Lack of MGP causes vascular abnormalities in multiple organs in mice. The objective of this study is to define the role of MGP in early endothelial differentiation. We find that expression of endothelial markers is highly induced in Mgp null organs, which, in wild type, contain high MGP expression. Furthermore, Mgp null embryonic stem cells express higher levels of endothelial markers than wild-type controls and an abnormal temporal pattern of expression. We also find that the Mgp-deficient endothelial cells adopt characteristics of mesenchymal stem cells. We conclude that loss of MGP causes dysregulation of early endothelial differentiation.
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Proteínas de Unión al Calcio/metabolismo , Diferenciación Celular , Células Endoteliales/citología , Células Endoteliales/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Células Madre Embrionarias de Ratones/citología , Animales , Biomarcadores/metabolismo , Proteínas de Unión al Calcio/deficiencia , Recuento de Células , Proteínas de la Matriz Extracelular/deficiencia , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteína Gla de la MatrizRESUMEN
MicroRNAs (miRNAs) have been shown to play essential roles in regulating the activity of human hepatocellular carcinoma (HCC) cells, thereby contributing to the suppression of invasion and metastasis. In this study, using gain and loss of function assays, we demonstrated that miR-302b was frequently down-regulated in clinical HCC specimens, as compared with 15 corresponding adjacent normal tissues. Overexpression of miR-302b suppressed HCC cell invasion and metastasis. Regulation of NF-κB and matrix metalloproteinase (MMP)-2 expression by miR-302b was mediated via AKT2 in SMMC-7721 cells. Silencing AKT2 produced effects similar to those of miR-302b overexpression, which included inhibiting SMMC-7721 cell invasion and metastasis and dereasing NF-κB and MMP-2 expression. Furthermore, overexpression of AKT2 attenuated the effects of miR-302b overexpression. Taken together, our findings indicate that miR-302b inhibits SMMC-7721 cell invasion and metastasis by targeting AKT2, suggesting that miR-302b might represent a potential therapeutic target for HCC intervention.
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Carcinoma Hepatocelular/embriología , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/metabolismo , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Regiones no Traducidas 3' , Línea Celular Tumoral , Perfilación de la Expresión Génica , Silenciador del Gen , Células HEK293 , Humanos , Inmunohistoquímica , Metaloproteinasa 2 de la Matriz/metabolismo , FN-kappa B/metabolismo , Subunidad p50 de NF-kappa B/metabolismo , Invasividad Neoplásica , Metástasis de la NeoplasiaRESUMEN
Cerebral arteriovenous malformations (AVMs) are common vascular malformations, which may result in hemorrhagic strokes and neurological deficits. Bone morphogenetic protein (BMP) and Notch signaling are both involved in the development of cerebral AVMs, but the cross-talk between the two signaling pathways is poorly understood. Here, we show that deficiency of matrix Gla protein (MGP), a BMP inhibitor, causes induction of Notch ligands, dysregulation of endothelial differentiation, and the development of cerebral AVMs in MGP null (Mgp(-/-)) mice. Increased BMP activity due to the lack of MGP induces expression of the activin receptor-like kinase 1, a BMP type I receptor, in cerebrovascular endothelium. Subsequent activation of activin receptor-like kinase 1 enhances expression of Notch ligands Jagged 1 and 2, which increases Notch activity and alters the expression of Ephrin B2 and Ephrin receptor B4, arterial and venous endothelial markers, respectively. Reducing the expression of Jagged 1 and 2 in the Mgp(-/-) mice by crossing them with Jagged 1 or 2 deficient mice reduces Notch activity, normalizes endothelial differentiation, and prevents cerebral AVMs, but not pulmonary or renal AVMs. Our results suggest that Notch signaling mediates and can modulate changes in BMP signaling that lead to cerebral AVMs.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Unión al Calcio/deficiencia , Proteínas de Unión al Calcio/metabolismo , Proteínas de la Matriz Extracelular/deficiencia , Guanilato-Quinasas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Malformaciones Arteriovenosas Intracraneales/etiología , Malformaciones Arteriovenosas Intracraneales/prevención & control , Proteínas de la Membrana/metabolismo , Receptores Notch/metabolismo , Análisis de Varianza , Animales , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Proteínas de Unión al Calcio/genética , Diferenciación Celular/fisiología , Células Endoteliales/fisiología , Efrina-B2/metabolismo , Proteínas de la Matriz Extracelular/genética , Eliminación de Gen , Immunoblotting , Proteína Jagged-1 , Proteína Jagged-2 , Ratones , Ratones Noqueados , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de la Familia Eph/metabolismo , Proteínas Serrate-Jagged , Microtomografía por Rayos X , Proteína Gla de la MatrizAsunto(s)
Antagonistas Adrenérgicos beta/farmacología , Encéfalo/irrigación sanguínea , Células Endoteliales/patología , Etanolaminas/farmacología , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/metabolismo , Malformaciones Arteriovenosas Intracraneales/tratamiento farmacológico , Factores de Transcripción SOXB1/metabolismo , Sitios de Unión , Células Cultivadas , Regulación hacia Abajo , Células Endoteliales/metabolismo , Humanos , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/genética , Malformaciones Arteriovenosas Intracraneales/genética , Malformaciones Arteriovenosas Intracraneales/metabolismo , Regiones Promotoras Genéticas , Factores de Transcripción SOXB1/genética , Transducción de SeñalRESUMEN
BACKGROUND: Ice and snow sports, which are inherently high risk due to their physically demanding nature, pose significant challenges in terms of participant safety. These activities increase the likelihood of injuries, largely due to reduced bodily agility and responsiveness in cold, often unpredictable winter environments. The critical need for effective injury prevention in these sports is emphasized by the considerable impact injuries have on the health of participants, alongside the economic and social costs associated with medical and rehabilitative care. In the context of ice and snow sports environments, applying the E principles of injury prevention to evaluate intervention measures can guide the implementation of future sports safety and other health promotion intervention measures in this field. When well executed, this approach can substantially reduce both the frequency and severity of injuries, thereby significantly enhancing the safety and long-term viability of these challenging sports. OBJECTIVE: The objective of this study was to rigorously assess and statistically substantiate the efficacy of diverse injury prevention strategies in ice and snow sports, aiming to bolster future safety measures with solid empirical evidence. DESIGN: Systematic review and meta-analysis. METHODS: The overarching aim of this research was to meticulously aggregate and scrutinize a broad spectrum of scholarly literature, focusing on the quantifiable efficacy of diverse, multicomponent intervention strategies in mitigating the incidence of injuries within the realm of ice and snow sports. This endeavour entailed an exhaustive extraction of data from esteemed academic databases, encompassing publications up to September 30, 2023. In pursuit of methodological excellence and analytical rigor, the study employed advanced bias assessment methodologies, notably the AMSTAR 2 and GRADE approaches, alongside sophisticated random-effects statistical modelling. This comprehensive approach was designed to ensure the utmost validity, reliability, and scholarly integrity of the study's findings. RESULTS: Fifteen papers, including 9 randomized controlled trials, 3 caseâcontrol studies, and 3 cohort studies with 26,123 participants and 4,382 injuries, were analysed. The findings showed a significant reduction in injury rates through various interventions: overall injury prevention (RR = 0.50, 95% CI 0.42-0.63), educational training (RR = 0.50, 95% CI 0.34-0.73), educational videos (RR = 0.53, 95% CI 0.34-0.81), protective equipment (RR = 0.64, 95% CI 0.46-0.87), and policy changes (RR = 0.28, 95% CI 0.16-0.49). Subgroup analysis revealed potential heterogeneity in compliance (p = 0.347). Compared to controls, multicomponent interventions effectively reduced injury rates. CONCLUSION: This systematic review and meta-analysis demonstrated that multicomponent interventions significantly prevent injuries in ice and snow sports. By applying the E principles of injury prevention and constructing a framework for practical injury prevention research in ice and snow sports, we can gradually shift towards a systemic paradigm for a better understanding of the development and prevention of sports injuries. Moreover, sports injury prevention is a complex and dynamic process. Therefore, high-quality experiments in different scenarios are needed in future research to provide more reliable evidence, offer valuable and relevant prevention information for practitioners and participants, and help formulate more effective preventive measures in practice.
RESUMEN
The magnetic skyrmions exhibit intriguing topological behaviors, holding promise for future applications in the realm of spintronic devices. Despite recent advancements, achieving spontaneous magnetic skyrmions and topological transitions in magnets featuring uniaxial magnetic anisotropy, particularly at elevated temperatures (>100 K), remains a challenging endeavor. Here, single-crystal Fe5Si3 nanorods with the central symmetry and uniaxial magnetic anisotropy were successfully synthesized on a mica substrate through chemical vapor deposition, which exhibit a high Curie temperature (TC) of about 372 K. The real-time observation, facilitated by Lorentz transmission electron microscopy, revealed the spontaneous formation of magnetic skyrmions and evolution of domains in focused ion beam-prepared Fe5Si3 thin foils. Moreover, Fe5Si3 device transport measurements expose notable magnetoresistance (MR) effects, enabling the interchange between positive and negative MR across specific temperature settings. These results offer various potential avenues for exploring diverse topological spin textures and their formation mechanisms, indicating inventive applications for iron-silicon alloy in the realm of spintronics.
RESUMEN
Harsh environments in poorly perfused tumor regions may select for traits driving cancer aggressiveness. Here, we investigated whether tumor acidosis interacts with driver mutations to exacerbate cancer hallmarks. We adapted mouse organoids from normal pancreatic duct (mN10) and early pancreatic cancer (mP4, KRAS-G12D mutation, ± p53 knockout) from extracellular pH 7.4 to 6.7, representing acidic niches. Viability was increased by acid adaptation, a pattern most apparent in wild-type (WT) p53 organoids, and exacerbated upon return to pH 7.4. This led to increased survival of acid-adapted organoids treated with gemcitabine and/or erlotinib, and, in WT p53 organoids, acid-induced attenuation of drug effects. New genetic variants became dominant during adaptation, yet they were unlikely to be its main drivers. Transcriptional changes induced by acid and drug adaptation differed overall, but acid adaptation increased the expression of gemcitabine resistance genes. Thus, adaptation to acidosis increases cancer cell viability after chemotherapy.
Asunto(s)
Desoxicitidina , Resistencia a Antineoplásicos , Gemcitabina , Organoides , Neoplasias Pancreáticas , Microambiente Tumoral , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Animales , Organoides/efectos de los fármacos , Organoides/metabolismo , Organoides/patología , Resistencia a Antineoplásicos/genética , Ratones , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Humanos , Concentración de Iones de Hidrógeno , Acidosis/patología , Acidosis/metabolismo , Adaptación Fisiológica/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Supervivencia Celular/efectos de los fármacosRESUMEN
Recently, water resources have become scarce due to the growing global population and human impact on the environment, coupled with the effects of climate change. For solving the problem of global freshwater shortage and increasing the value of discarded polyphenylene sulfide (PPS) filter bags, in this study, balsa wood was used as the base of a photothermal solar evaporator, chitosan solution was used as the binder, and the main photothermal conversion materials used were polyphenylene sulfide (CP) carbide and copper sulfide. In order to create synergistic photothermal conversion materials, freeze-drying and in situ precipitation were used to deposit the photothermal conversion materials on top of the balsa wood. The prepared CP/CuS-wood evaporator has excellent water evaporation performance and light conversion capability, with a water evaporation rate of 2.68 kg m-2 h-1 and a photothermal conversion efficiency of 93.2% under simulated one solar intensity irradiation. In addition, the evaporator can effectively remove organic dyes such as methylene blue and methyl orange. The evaporator's durability and seawater desalination capability have also been confirmed through seawater desalination experiments and outdoor tests. Studies have shown that solar interface photothermal evaporators are a viable solution for desalination and wastewater treatment. This eco-friendly, economically viable and stable photothermal evaporator mentioned in this paper has pioneering features and will be a new paradigm for desalination and wastewater treatment.