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The Inconel 718 superalloy demonstrates the potential to fabricate high-temperature components using additive manufacturing. However, additively manufactured Inconel 718 typically exhibits low strength, necessitating post-heat treatments for precipitate strengthening. This study investigated the microstructures and mechanical properties of the Inconel 718 superalloy fabricated via laser powder bed fusion. The room-temperature and high-temperature tensile properties of the Inconel 718 alloy samples following various post-heat treatments were evaluated. The results indicate that the as-built samples exhibited columnar grains with fine cell structures. Solution treatment resulted in δ phase formation and grain recrystallization. Subsequent double aging led to finely distributed nanoscale γ' and γⳠparticles. These nanoscale particles provided high strength at both room and high temperatures, resulting in a balanced strength and ductility comparable to the wrought counterpart. High-temperature nanoindentation analyses revealed that the double-aging samples exhibited very high hardness and low creep rates at 650 °C.
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Abdominal aortic aneurysm (AAA) is a life-threatening disease characterized by extensive membrane destruction in the vascular wall that is closely associated with vascular smooth muscle cell (VSMC) phenotypic switching. A thorough understanding of the changes in regulatory factors during VSMC phenotypic switching is essential for managing AAA therapy. In this study, we revealed the impact of NRF2 on the modulation of VSMC phenotype and the development of AAA based on single-cell RNA sequencing analysis. By utilizing a murine model of VSMC-specific knockout of nuclear factor E2-related factor 2 (NRF2), we observed that the absence of NRF2 in VSMCs exacerbated AAA formation in an angiotensin II-induced AAA model. The downregulation of NRF2 promoted VSMC phenotypic switching, leading to an enhanced inflammatory response. Through genome-wide transcriptome analysis and loss- or gain-of-function experiments, we discovered that NRF2 upregulated the expression of VSMC contractile phenotype-specific genes by facilitating microRNA-145 (miR-145) expression. Our data identified NRF2 as a novel regulator involved in maintaining the VSMC contractile phenotype while also influencing AAA formation through an miR-145-dependent regulatory mechanism.
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Aneurisma de la Aorta Abdominal , MicroARNs , Músculo Liso Vascular , Miocitos del Músculo Liso , Factor 2 Relacionado con NF-E2 , Fenotipo , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/inducido químicamente , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Masculino , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Ratones Noqueados , Análisis de la Célula Individual , Ratones Endogámicos C57BL , Angiotensina II/farmacología , Análisis de Secuencia de ARN , Modelos Animales de EnfermedadRESUMEN
Titanium parts fabricated by additive manufacturing, i.e., laser or electron beam-powder bed fusion (L- or EB-PBF), usually exhibit columnar grain structures along the build direction, resulting in both microstructural and mechanical anisotropy. Post-heat treatments are usually used to reduce or eliminate such anisotropy. In this work, Ti-6Al-2Zr-1Mo-1V (TA15) alloy samples were fabricated by L-PBF to investigate the effect of post-heat treatment and load direction on the dynamic response of the samples. Post-heat treatments included single-step annealing at 800 °C (HT) and a hot isotropic press (HIP). The as-built and heat-treated samples were dynamically compressed using a split Hopkinson pressure bar at a strain rate of 3000 s-1 along the horizontal and vertical directions paralleled to the load direction. The microstructural observation revealed that the as-built TA15 sample exhibited columnar grains with fine martensite inside. The HT sample exhibited a fine lamellar structure, whereas the HIP sample exhibited a coarse lamellar structure. The dynamic compression results showed that post-heat treatment at 800 °C led to reduced flow stress but enhanced uniform plastic strain and damage absorption work. However, the HIP samples exhibited both higher stress, uniform plastic strain, and damage absorption work owing to the microstructure coarsening. Additionally, the load direction had a subtle influence on the flow stress, indicating the negligible anisotropy of flow stress in the samples. However, there was more significant anisotropy of the uniform plastic strain and damage absorption. The samples had a higher load-bearing capacity when dynamically compressed perpendicular to the build direction.
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Type I photodynamic therapy is considered to be a more promising cancer treatment than type II photodynamic therapy due to its non-oxygen-dependent characteristics. In this work, three D-A structure N,N'-dihydrophenazine (DHP)-based photosensitizers DP-CNPY, SMP-CNPY and DMP-CNPY were designed and synthesized by introducing different numbers of methyl groups in the backbone neighbor of DHP as the donor and combined with the typical strong electron acceptor 2-(pyridin-4-yl)acetonitrile. Among the three photosensitizers, SMP-CNPY with one methyl modification showed the best type I ROS (O2-Ë, ËOH) generation capacity and AIE performance. By encapsulation, SMP-CNPY was fabricated into nanoparticles, and SMP-CNPY NPs exhibited lipid droplet targeting ability with near-infrared (NIR) emission. Cell experiments have proved that SMP-CNPY NPs can effectively kill different kinds of cancer cells under normal oxygen conditions. Even under hypoxic and extreme hypoxic conditions, SMP-CNPY NPs can still produce ROS and kill cancer cells. This work holds significant potential in the field of type I AIE-active photosensitizers and provides a new strategy for overcoming the hypoxic dilemma in the malignant tumor microenvironment.
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Gotas Lipídicas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/síntesis química , Humanos , Gotas Lipídicas/química , Gotas Lipídicas/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Especies Reactivas de Oxígeno/metabolismo , Nanopartículas/química , Tamaño de la Partícula , Imagen Óptica , Supervivencia Celular/efectos de los fármacos , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular TumoralRESUMEN
BACKGROUND: The technology of capturing circulating tumor cells (CTCs) plays a crucial role in the diagnosis, evaluation of therapeutic efficacy, and prediction of prognosis in lung cancer. However, the presence of complex blood environment often results in severe nonspecific protein adsorption and interferences from blood cells, which negatively impacts the specificity of CTCs capture. There is a great need for development of novel nanomaterials for CTCs capture with prominent anti-nonspecific adsorptions from proteins or blood cells. RESULTS: We present a novel immune magnetic probe Fe3O4@(PEI/AA)4@Apt. The surface of Fe3O4 particles was modified with four layers of PEI/AA composite by layer-by-layer assembly. Furthermore, aptamers targeting epithelial marker EpCAM (SYL3C) and mesenchymal marker CSV (ZY5C) were simultaneously connected on Fe3O4@(PEI/AA)4 to improve the detection of different phenotypic CTCs and reduce false negatives. The results demonstrated that the (PEI/AA)4 coatings not only minimized non-specific protein adsorptions, but also significantly reduced the adsorption rate of red blood cells to a mere 1 %, as a result of which, the Fe3O4@(PEI/AA)4@Apt probe achieved a remarkably high capture efficiency toward CTCs (95.9 %). In the subsequent validation of clinical samples, the probe was also effective in capturing rare CTCs from lung cancer patients. SIGNIFICANCE AND NOVELTY: A (PEI/AA) polymerized composite with controllable layers was fabricated by layer-by-layer self-assembly technique, which displayed remarkable anti-nonspecific adsorption capabilities toward proteins and cells. Importantly, Fe3O4@(PEI/AA)4@Apt probe significantly improved CTCs capture purity in lung cancer patients to 89.36 %. For the first time, this study combined controllable (PEI/AA) layers with magnetic separation to innovatively build a resistant interface that significantly improves the specific capture performances of CTCs, broadening the application of this polymerized composite.
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Alginatos , Células Neoplásicas Circulantes , Polietileneimina , Humanos , Células Neoplásicas Circulantes/patología , Polietileneimina/química , Alginatos/química , Nanopartículas de Magnetita/química , Neoplasias Pulmonares/patología , Aptámeros de Nucleótidos/química , Adsorción , Propiedades de Superficie , Molécula de Adhesión Celular Epitelial/inmunologíaRESUMEN
Circulating tumor cells (CTCs) are widely considered as a reliable and promising class of markers in the field of liquid biopsy. As CTCs undergo epithelial-mesenchymal transition (EMT), phenotype detection of heterogeneous CTCs based on EMT markers is of great significance. In this report, an integrated analytical strategy that can simultaneously capture and differentially detect epithelial- and mesenchymal-expressed CTCs in bloods of non-small cell lung cancer (NSCLS) patients is proposed. First, a commercial biomimetic polycarbonate (PCTE) microfiltration membrane is employed as the capture interface for heterogenous CTCs. Meanwhile, differential detection of the captured CTCs is realized by preparing two distinct CdTe quantum dots (QDs) with red and green emissions, attached with EpCAM and Vimentin aptamers, respectively. For combined analysis, a polydimethylsiloxane (PDMS) chip with simple structure is designed, which integrates the membrane capture and QDs-based phenotype detection of CTCs. This chip not only implements the analysis of the number of CTCs down to 2 cells mL-1, but enables EMT process tracking according to the specific signals of the two QDs. Finally, this method is successfully applied to inspect the correlations of numbers or proportions of heterogenous CTCs in 94 NSCLS patients with disease stage and whether there is distant metastasis.
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The brain calibrates itself based on the past stimulus diet, which makes frequently observed stimuli appear as typical (as opposed to uncommon stimuli, which appear as distinctive). Based on predictive processing theory, the brain should be more "prepared" for typical exemplars, because these contain information that has been encountered frequently, allowing it to economically represent items of that category. Thus, one could ask whether predictability and typicality of visual stimuli interact, or rather act in an additive manner. We adapted the design by Egner and colleagues (2010), who used cues to induce expectations about stimulus category (face vs. chair) occurrence during an orthogonal inversion detection task. We measured BOLD responses with fMRI in 35 participants. First, distinctive stimuli always elicited stronger responses than typical ones in all ROIs, and our whole-brain directional contrasts for the effects of typicality and distinctiveness converge with previous findings. Second and importantly, we could not replicate the interaction between category and predictability reported by Egner et al. (2010), which casts doubt on whether cueing designs are ideal to elicit reliable predictability effects. Third, likely as a consequence of the lack of predictability effects, we found no interaction between predictability and typicality in any of the four tested regions (bilateral fusiform face areas, lateral occipital complexes) when considering both categories, nor in the whole brain. We discuss the issue of replicability in neuroscience and sketch an agenda for how future studies might address the same question.
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Encéfalo , Imagen por Resonancia Magnética , Estimulación Luminosa , Humanos , Masculino , Femenino , Imagen por Resonancia Magnética/métodos , Adulto , Adulto Joven , Encéfalo/fisiología , Encéfalo/diagnóstico por imagen , Mapeo Encefálico/métodos , Señales (Psicología) , Reconocimiento Visual de Modelos/fisiología , CaraRESUMEN
Background: Pediatric cerebral palsy (CP) is a non-progressive brain injury syndrome characterized by central motor dysfunction and insufficient brain coordination ability. The etiology of CP is complex and often accompanied by diverse complications such as intellectual disability and language disorders, making clinical treatment difficult. Despite the availability of pharmacological interventions, rehabilitation programs, and spasticity relief surgery as treatment options for CP, their effectiveness is still constrained. Electroacupuncture (EA) stimulation has demonstrated great improvements in motor function, but its comprehensive, objective therapeutic effects on pediatric CP remain to be clarified. Methods: We present a case of a 5-year-old Chinese female child who was diagnosed with CP at the age of 4. The patient exhibited severe impairments in motor, language, social, and cognitive functions. We performed a 3-month period of EA rehabilitation, obtaining resting state functional magnetic resonance imaging (rs-fMRI) of the patient at 0 month, 3 months and 5 months since treatment started, then characterized brain functional connectivity patterns in each phase for comparison. Results: After a 12-month follow-up, notable advancements were observed in the patient's language and social symptoms. Changes of functional connectivity patterns confirmed this therapeutic effect and showed specific benefits for different recovery phase: starting from language functions then modulating social participation and other developmental behaviors. Conclusion: This is a pioneering report demonstrating the longitudinal effect of EA stimulation on functional brain connectivity in CP patients, suggesting EA an effective intervention for developmental disabilities (especially language and social dysfunctions) associated with pediatric CP.
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BACKGROUND: The incidence of anastomotic leakage (AL) following esophagectomy is regarded as a noteworthy complication. There is a need for biomarkers to facilitate early diagnosis of AL in high-risk esophageal cancer (EC) patients, thereby minimizing its morbidity and mortality. We assessed the predictive abilities of inflammatory biomarkers for AL in patients after esophagectomy. METHODS: In order to ascertain the predictive efficacy of biomarkers for AL, Receiver Operating Characteristic (ROC) curves were generated. Furthermore, univariate, LASSO, and multivariate logistic regression analyses were conducted to discern the risk factors associated with AL. Based on these identified risk factors, a diagnostic nomogram model was formulated and subsequently assessed for its predictive performance. RESULTS: Among the 438 patients diagnosed with EC, a total of 25 patients encountered AL. Notably, elevated levels of interleukin-6 (IL-6), IL-10, C-reactive protein (CRP), and procalcitonin (PCT) were observed in the AL group as compared to the non-AL group, demonstrating statistical significance. Particularly, IL-6 exhibited the highest predictive capacity for early postoperative AL, exhibiting a sensitivity of 92.00% and specificity of 61.02% at a cut-off value of 132.13 pg/ml. Univariate, LASSO, and multivariate logistic regression analyses revealed that fasting blood glucose ≥7.0mmol/L and heightened levels of IL-10, IL-6, CRP, and PCT were associated with an augmented risk of AL. Consequently, a nomogram model was formulated based on the results of multivariate logistic analyses. The diagnostic nomogram model displayed a robust discriminatory ability in predicting AL, as indicated by a C-Index value of 0.940. Moreover, the decision curve analysis provided further evidence supporting the clinical utility of this diagnostic nomogram model. CONCLUSIONS: This predictive instrument can serve as a valuable resource for clinicians, empowering them to make informed clinical judgments aimed at averting the onset of AL.
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Fuga Anastomótica , Neoplasias Esofágicas , Esofagectomía , Nomogramas , Humanos , Fuga Anastomótica/diagnóstico , Fuga Anastomótica/etiología , Fuga Anastomótica/epidemiología , Fuga Anastomótica/sangre , Esofagectomía/efectos adversos , Neoplasias Esofágicas/cirugía , Masculino , Femenino , Persona de Mediana Edad , Anciano , Factores de Riesgo , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisis , Interleucina-6/sangre , Biomarcadores/sangre , Interleucina-10/sangre , Curva ROC , Polipéptido alfa Relacionado con Calcitonina/sangre , Valor Predictivo de las PruebasRESUMEN
The gel microsphere culture system (GMCS) showed various advantages for mesenchymal stem cell (MSC) expansion and delivery, such as high specific surface area, small and regular shape, extensive adjustability, and biomimetic properties. Although various technologies and materials have been developed to promote the development of gel microspheres, the differences in the biological status of MSCs between the GMCS and the traditional Petri dish culture system (PDCS) are still unknown, hindering gel microspheres from becoming a culture system as widely used as petri dishes. In the previous study, an excellent "all-in-one" GMCS has been established for the expansion of human adipose-derived MSCs (hADSCs), which showed convenient cell culture operation. Here, we performed transcriptome and proteome sequencing on hADSCs cultured on the "all-in-one" GMCS and the PDCS. We found that hADSCs cultured in the GMCS kept in an undifferentiation status with a high stemness index, whose transcriptome profile is closer to the adipose progenitor cells (APCs) in vivo than those cultured in the PDCS. Further, the high stemness status of hADSCs in the GMCS was maintained through regulating cell-ECM interaction. For application, bilayer scaffolds were constructed by osteo- and chondro-differentiation of hADSCs cultured in the GMCS and the PDCS. The effect of osteochondral regeneration of the bilayer scaffolds in the GMCS group was better than that in the PDCS group. This study revealed the high stemness and excellent functionality of MSCs cultured in the GMCS, which promoted the application of gel microspheres in cell culture and tissue regeneration.
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Tejido Adiposo , Diferenciación Celular , Células Madre Mesenquimatosas , Microesferas , Humanos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Tejido Adiposo/citología , Animales , Matriz Extracelular/metabolismo , Células Cultivadas , Andamios del Tejido/química , Geles/química , Condrogénesis , Osteogénesis , Técnicas de Cultivo de Célula/métodosRESUMEN
Background: COVID-19 has caused severe morbidity and mortality worldwide. After the end of the dynamic zero-COVID policy in China in December, 2022, concerns regarding reinfection were raised while little was known due to the lack of surveillance data in this country. Aims: This study reviews the probability, risk factors, and severity of severe acute respiratory syndrome coronavirus 2 Omicron variant reinfection, as well as the interval between infections, risk of onward transmission by reinfected cases, and the role of booster vaccination against reinfection. Sources: References for this review were identified through searches of PubMed and Web of Science up to September 24, 2023. Results: The rate of reinfection ranges from 3.1% to 13.0%. Factors associated with a higher risk of reinfection include being female, having comorbidities, and being unvaccinated. Reinfection with the BA.4 or BA.5 variant occurs approximately 180 days after the initial infection. Reinfections are less clinically severe than primary infections, and there is evidence of lower transmissibility. The debate surrounding the effectiveness and feasibility of booster vaccinations in preventing reinfection continues. Conclusions: The reinfection rate during the Omicron epidemic is significantly higher than in previous epidemic periods. However, the symptoms and infectivity of reinfection were weaker than those of the prior infection. Medical staff and individuals at high risk of reinfection should be vigilant. The efficacy of booster vaccinations in reducing reinfection is currently under debate.
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Epstein-Barr virus (EBV) can infect both B cells and epithelial cells (ECs), causing diseases such as mononucleosis and cancer. It enters ECs via Ephrin receptor A2 (EphA2). The function of interferon-induced transmembrane protein-1 (IFITM1) in EBV infection of ECs remains elusive. Here we report that IFITM1 inhibits EphA2-mediated EBV entry into ECs. RNA-sequencing and clinical sample analysis show reduced IFITM1 in EBV-positive ECs and a negative correlation between IFITM1 level and EBV copy number. IFITM1 depletion increases EBV infection and vice versa. Exogenous soluble IFITM1 effectively prevents EBV infection in vitro and in vivo. Furthermore, three-dimensional structure prediction and site-directed mutagenesis demonstrate that IFITM1 interacts with EphA2 via its two specific residues, competitively blocking EphA2 binding to EBV glycoproteins. Finally, YTHDF3, an m6A reader, suppresses IFITM1 via degradation-related DEAD-box protein 5 (DDX5). Thus, this study underscores IFITM1's crucial role in blocking EphA2-mediated EBV entry into ECs, indicating its potential in preventing EBV infection.
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Antígenos de Diferenciación , Efrina-A2 , Células Epiteliales , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Receptor EphA2 , Internalización del Virus , Humanos , Herpesvirus Humano 4/fisiología , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Células Epiteliales/virología , Células Epiteliales/metabolismo , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/metabolismo , Receptor EphA2/metabolismo , Efrina-A2/metabolismo , Efrina-A2/genética , Antígenos de Diferenciación/metabolismo , Antígenos de Diferenciación/genética , Animales , Células HEK293 , Unión Proteica , Ratones , Línea CelularRESUMEN
BACKGROUND: The effect of human 8-Oxoguanine DNA Glycosylase (hOGG1) on exogenous chemicals in esophageal squamous cell carcinoma (ESCC) remain unclear. The study plans to determine hOGG1 expression levels in ESCC and possible interactions with known environmental risk factors in ESCC. MATERIAL AND METHODS: We analyzed levels of exposure to urinary nitrosamines in volunteers from high and low prevalence areas by GC-MS. And we performed the interaction between hOGG1 gene and nitrosamine disinfection by-products by analyzing hOGG1 gene expression in esophageal tissues. RESULTS: In ESCC, nitrosamine levels were significantly increased and hOGG1 mRNA expression levels were significantly decreased. There was a statistically significant interaction between reduced hOGG1 mRNA levels and non-tap drinking water sources in ESCC. The apparent indirect association between ESCC and NMEA indicated that 33.4% of the association between ESCC and NMEA was mediated by hOGG1. CONCLUSION: In populations which exposed to high levels of environmental pollutants NDMA, low expression of hOGG1 may promote the high incidence of esophageal cancer in Huai'an. hOGG1 may be a novel mediator in nitrosamine-induced esophageal tumorigenesis.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Nitrosaminas , Humanos , Neoplasias Esofágicas/inducido químicamente , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/inducido químicamente , Carcinoma de Células Escamosas de Esófago/complicaciones , Nitrosaminas/toxicidad , Transformación Celular Neoplásica , ARN MensajeroRESUMEN
BACKGROUND: The experimental autoimmune myocarditis (EAM) model is valuable for investigating myocarditis pathogenesis. M1-type macrophages and CD4+T cells exert key pathogenic effects on EAM initiation and progression. Baicalein (5,6,7-trihydroxyflavone, C15H10O5, BAI), which is derived from the Scutellaria baicalensis root, is a primary bioactive compound with potent anti-inflammatory and antioxidant properties. BAI exerts good therapeutic effects against various autoimmune diseases; however, its effect in EAM has not been thoroughly researched. PURPOSE: This study aimed to explore the possible inhibitory effect of BAI on M1 macrophage polarisation and CD4+T cell differentiation into Th1 cells via modulation of the JAK-STAT1/4 signalling pathway, which reduces the secretion of pro-inflammatory factors, namely, TNF-α and IFN-γ, and consequently inhibits TNF-α- and IFN-γ-triggered apoptosis in cardiomyocytes of the EAM model mice. STUDY DESIGN AND METHODS: Flow cytometry, immunofluorescence, real-time quantitative polymerase chain reaction (q-PCR), and western blotting were performed to determine whether BAI alleviated M1/Th1-secreted TNF-α- and IFN-γ-induced myocyte death in the EAM model mice through the inhibition of the JAK-STAT1/4 signalling pathway. RESULTS: These results indicate that BAI intervention in mice resulted in mild inflammatory infiltrates. BAI inhibited JAK-STAT1 signalling in macrophages both in vivo and in vitro, which attenuated macrophage polarisation to the M1 type and reduced TNF-α secretion. Additionally, BAI significantly inhibited the differentiation of CD4+T cells to Th1 cells and IFN-γ secretion both in vivo and in vitro by modulating the JAK-STAT1/4 signalling pathway. This ultimately led to decreased TNF-α and IFN-γ levels in cardiac tissues and reduced myocardial cell apoptosis. CONCLUSION: This study demonstrates that BAI alleviates M1/Th1-secreted TNF-α- and IFN-γ-induced cardiomyocyte death in EAM mice by inhibiting the JAK-STAT1/4 signalling pathway.
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Apoptosis , Modelos Animales de Enfermedad , Flavanonas , Interferón gamma , Quinasas Janus , Miocarditis , Miocitos Cardíacos , Factor de Transcripción STAT1 , Transducción de Señal , Factor de Necrosis Tumoral alfa , Animales , Factor de Transcripción STAT1/metabolismo , Transducción de Señal/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Quinasas Janus/metabolismo , Ratones , Flavanonas/farmacología , Masculino , Interferón gamma/metabolismo , Apoptosis/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Miocarditis/tratamiento farmacológico , Factor de Transcripción STAT4/metabolismo , Enfermedades Autoinmunes/tratamiento farmacológico , Ratones Endogámicos BALB C , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Scutellaria baicalensis/química , Células TH1/efectos de los fármacos , Diferenciación Celular/efectos de los fármacosRESUMEN
The synchronized development of mineralized bone and blood vessels is a fundamental requirement for successful bone tissue regeneration. Adequate energy production forms the cornerstone supporting new bone formation. ETS variant 2 (ETV2) has been identified as a transcription factor that promotes energy metabolism reprogramming and facilitates the coordination between osteogenesis and angiogenesis. In vitro molecular experiments have demonstrated that ETV2 enhances osteogenic differentiation of dental pulp stem cells (DPSCs) by regulating the ETV2- prolyl hydroxylase 2 (PHD2)- hypoxia-inducible factor-1α (HIF-1α)- vascular endothelial growth factor A (VEGFA) axis. Notably, ETV2 achieves the rapid reprogramming of energy metabolism by simultaneously accelerating mitochondrial aerobic respiration and glycolysis, thus fulfilling the energy requirements essential to expedite osteogenic differentiation. Furthermore, decreased α-ketoglutarate release from ETV2-modified DPSCs contributes to microcirculation reconstruction. Additionally, we engineered hydroxyapatite/chitosan microspheres (HA/CS MS) with biomimetic nanostructures to facilitate multiple ETV2-DPSC functions and further enhanced the osteogenic differentiation. Animal experiments have validated the synergistic effect of ETV2-modified DPSCs and HA/CS MS in promoting the critical-size bone defect regeneration. In summary, this study offers a novel treatment approach for vascularized bone tissue regeneration that relies on energy metabolism activation and the maintenance of a stable local hypoxia signaling state.
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In situ monitoring of bone regeneration enables timely diagnosis and intervention by acquiring vital biological parameters. However, an existing gap exists in the availability of effective methodologies for continuous and dynamic monitoring of the bone tissue regeneration process, encompassing the concurrent visualization of bone formation and implant degradation. Here, we present an integrated scaffold designed to facilitate real-time monitoring of both bone formation and implant degradation during the repair of bone defects. Laponite (Lap), CyP-loaded mesoporous silica (CyP@MSNs) and ultrasmall superparamagnetic iron oxide nanoparticles (USPIO@SiO2) were incorporated into a bioink containing bone marrow mesenchymal stem cells (BMSCs) to fabricate functional scaffolds denoted as C@M/GLU using 3D bioprinting technology. In both in vivo and in vitro experiments, the composite scaffold has demonstrated a significant enhancement of bone regeneration through the controlled release of silicon (Si) and magnesium (Mg) ions. Employing near-infrared fluorescence (NIR-FL) imaging, the composite scaffold facilitates the monitoring of alkaline phosphate (ALP) expression, providing an accurate reflection of the scaffold's initial osteogenic activity. Meanwhile, the degradation of scaffolds was monitored by tracking the changes in the magnetic resonance (MR) signals at various time points. These findings indicate that the designed scaffold holds potential as an in situ bone implant for combined visualization of osteogenesis and implant degradation throughout the bone repair process.
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Vanadium-based materials, due to their diverse valence states and open-framework lattice, are promising cathodes for aqueous zinc ion batteries (AZIBs), but encounters the major challenges of in situ electrochemical activation process, potent polarity of the aqueous electrolyte and periodic expansion/contraction for efficient Zn2+ storage. Herein, architecting vanadium nitride (VN) nanosheets over titanium-based hollow nanoarrays skeletal host (denoted VNTONC) can simultaneously modulate address those challenges by creating multiple interfaces and maintaining the (1 1 1) phase of VN, which optimizes the Zn2+ storage and the stability of VN. Benefiting from the modulated crystalline thermodynamics during the electrochemical activation of VN, two outcomes are achieved; I) the cathode transforms into a nanocrystalline structure with increased active sites and higher conductivity and; II) a significant portion of the (1 1 1) crystal facets is retained in the process leading to the additional Zn2+ storage capacity. As a result, the as-prepared VNTONC electrode demonstrates remarkable discharge capacities of 802.5 and 331.8 mAh g-1 @ 0.5 and 6.0 A g-1, respectively, due to the enhanced kinetics as validated by theoretical calculations. The assembled VNTONC||Zn flexible ZIB demonstrates excellent Zn storage properties up to 405.6 mAh g-1, and remarkable robustness against extreme operating conditions.
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This study intends to explore the effects of Cucurbitacin B (CuB) and KIF20A on esophageal carcinoma (ESCA). Data were downloaded from the Cancer Genome Atlas (TCGA) database. The expression properties of KIF20A have been confirmed by GEPIA and ualcan from TCGA. The expression of KIF20A was determined using western blotting in ECA109 and KYSE150 cells after transfection with KIF20A, KIF20A siRNA, or numerical control siRNA (si-NC). Then, different concentrations of CuB were used to treat ECA109 and KYSE150 cells. CCK-8 and colony formation assays were used to measure cell viability, and a Transwell assay was utilized to assess cell migration and invasion ability. N-cadherin, E-cadherin, snail, p-Janus kinase 2 (JAK2), JAK2, p-signal transducer and activator of transcription 3 (STAT3), and STAT3 expression levels were evaluated using western blot. KIF20A was higher expressed in ESCA than in normal cells, and its overexpression was associated with squamous cell carcinoma, TNM stage, and lymph nodal metastasis of ESCA patients. In ECA109 and KYSE150 cells, increased KIF20A facilitated cell proliferation, migration, and invasion, whereas the knockdown of KIF20A can reverse these effects with N-cadherin. Snail expression diminished and E-cadherin increased. Similarly, CuB treatment could inhibit cell proliferation, migration, and invasion concentration dependently. Furthermore, KIF20A accelerated the expression of p-JAK2 and p-STAT3, while the application of CuB inhibited KIF20A expression and attenuated the activation of the JAK/STAT3 pathway. These findings revealed that CuB could inhibit the growth, migration, and invasion of ESCA through downregulating the KIF20A/JAK/STAT3 signaling pathway, and CuB could serve as an essential medicine for therapeutic intervention.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Triterpenos , Humanos , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Línea Celular Tumoral , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Transducción de Señal/genética , Carcinoma de Células Escamosas/genética , Proliferación Celular/genética , Movimiento Celular/genética , ARN Interferente Pequeño/farmacología , ARN Interferente Pequeño/uso terapéutico , Cadherinas/genética , Cadherinas/metabolismo , Regulación Neoplásica de la Expresión Génica , Cinesinas/genética , Cinesinas/metabolismo , Cinesinas/farmacologíaRESUMEN
3-D point clouds facilitate 3-D visual applications with detailed information of objects and scenes but bring about enormous challenges to design efficient compression technologies. The irregular signal statistics and high-order geometric structures of 3-D point clouds cannot be fully exploited by existing sparse representation and deep learning based point cloud attribute compression schemes and graph dictionary learning paradigms. In this paper, we propose a novel p-Laplacian embedding graph dictionary learning framework that jointly exploits the varying signal statistics and high-order geometric structures for 3-D point cloud attribute compression. The proposed framework formulates a nonconvex minimization constrained by p-Laplacian embedding regularization to learn a graph dictionary varying smoothly along the high-order geometric structures. An efficient alternating optimization paradigm is developed by harnessing ADMM to solve the nonconvex minimization. To our best knowledge, this paper proposes the first graph dictionary learning framework for point cloud compression. Furthermore, we devise an efficient layered compression scheme that integrates the proposed framework to exploit the correlations of 3-D point clouds in a structured fashion. Experimental results demonstrate that the proposed framework is superior to state-of-the-art transform-based methods in M-term approximation and point cloud attribute compression and outperforms recent MPEG G-PCC reference software.
RESUMEN
By introducing randomness on the environments, domain randomization (DR) imposes diversity to the policy training of deep reinforcement learning, and thus improves its capability of generalization. The randomization of environments, however, introduces another source of variability for the estimate of policy gradients, in addition to the already high variance incurred by trajectory sampling. Therefore, with standard state-dependent baselines, the policy gradient methods may still suffer high variance, causing a low sample efficiency during the training of DR. In this paper, we theoretically derive a bias-free and state/environment-dependent optimal baseline for DR, and analytically show its ability to achieve further variance reduction over the standard constant and state-dependent baselines for DR. Based on our theory, we further propose a variance reduced domain randomization (VRDR) approach for policy gradient methods, to strike a tradeoff between the variance reduction and computational complexity for the practical implementation. By dividing the entire space of environments into some subspaces and then estimating the state/subspace-dependent baseline, VRDR enjoys a theoretical guarantee of variance reduction and faster convergence than the state-dependent baselines. Empirical evaluations on six robot control tasks with randomized dynamics demonstrate that VRDR not only accelerates the convergence of policy training, but can consistently achieve a better eventual policy with improved training stability.