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1.
PLoS Pathog ; 19(12): e1011856, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38048356

RESUMEN

The rapid emergence of SARS-CoV-2 variants of concern (VOCs) calls for efforts to study broadly neutralizing antibodies elicited by infection or vaccination so as to inform the development of vaccines and antibody therapeutics with broad protection. Here, we identified two convalescents of breakthrough infection with relatively high neutralizing titers against all tested viruses. Among 50 spike-specific monoclonal antibodies (mAbs) cloned from their B cells, the top 6 neutralizing mAbs (KXD01-06) belong to previously defined IGHV3-53/3-66 public antibodies. Although most antibodies in this class are dramatically escaped by VOCs, KXD01-06 all exhibit broad neutralizing capacity, particularly KXD01-03, which neutralize SARS-CoV-2 from prototype to the emerging EG.5.1 and FL.1.5.1. Deep mutational scanning reveals that KXD01-06 can be escaped by current and prospective variants with mutations on D420, Y421, L455, F456, N460, A475 and N487. Genetic and functional analysis further indicates that the extent of somatic hypermutation is critical for the breadth of KXD01-06 and other IGHV3-53/3-66 public antibodies. Overall, the prevalence of broadly neutralizing IGHV3-53/3-66 public antibodies in these two convalescents provides rationale for novel vaccines based on this class of antibodies. Meanwhile, KXD01-06 can be developed as candidates of therapeutics against SARS-CoV-2 through further affinity maturation.


Asunto(s)
COVID-19 , Vacunas , Humanos , SARS-CoV-2/genética , Infección Irruptiva , Estudios Prospectivos , Anticuerpos Monoclonales , Anticuerpos Monoclonales Humanizados , Anticuerpos Antivirales , Anticuerpos Neutralizantes , Glicoproteína de la Espiga del Coronavirus/genética
2.
Theor Appl Genet ; 137(7): 158, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38864891

RESUMEN

Examining the connection between P and starch-related signals can help elucidate the balance between nutrients and yield. This study utilized 307 diverse maize inbred lines to conduct multi-year and multi-plot trials, aiming to explore the relationship among P content, starch content, and 100-kernel weight (HKW) of mature grains. A significant negative correlation was found between P content and both starch content and HKW, while starch content showed a positive correlation with HKW. The starch granules in grains with high-P and low-starch content (HPLS) were significantly smaller compared to grains with low-P high-starch content (LPHS). Additionally, mian04185-4 (HPLS) exhibited irregular and loosely packed starch granules. A significant decrease in ZmPHOs genes expression was detected in the HPLS line ZNC442 as compared to the LPHS line SCML0849, while no expression difference was observed in AGPase encoding genes between these two lines. The down-regulated genes in ZNC442 grains were enriched in nucleotide sugar and fatty acid anabolic pathways, while up-regulated genes were enriched in the ABC transporters pathway. An accelerated breakdown of fat as the P content increased was also observed. This implied that HPLS was resulted from elevated lipid decomposition and inadequate carbon sources. The GWAS analysis identified 514 significantly associated genes, out of which 248 were differentially expressed. Zm00001d052392 was found to be significantly associated with P content/HKW, exhibiting high expression in SCML0849 but almost no expression in ZNC442. Overall, these findings suggested new approaches for achieving a P-yield balance through the manipulation of lipid metabolic pathways in grains.


Asunto(s)
Fósforo , Almidón , Transcriptoma , Zea mays , Zea mays/genética , Zea mays/metabolismo , Almidón/metabolismo , Fósforo/metabolismo , Grano Comestible/genética , Grano Comestible/metabolismo , Regulación de la Expresión Génica de las Plantas , Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo , Fenotipo
3.
Opt Express ; 31(7): 11624-11632, 2023 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-37155793

RESUMEN

The optimization of trichromatic white light emitting diodes (LEDs) spectrum for application scenes related to the age of lighting users is proposed and demonstrated. Based on the spectral transmissivity of human eyes at different ages, the visual and non-visual responses of human eyes to different wavelengths of light, we have built the blue light hazards (BLH) and circadian action factor (CAF) related to the age of the lighting user. The BLH and CAF are used to evaluate the spectral combinations of high color rendering index (CRI) white LEDs obtained from different radiation flux ratios of red, green, and blue monochrome spectrum. The best spectra of white LEDs for lighting users at different ages in work and leisure scenes are achieved due to the optimization criterion of BLH proposed by us. This research provides a solution for intelligent health lighting design applicable to light users of different ages and application scenes.

4.
Cell Biol Toxicol ; 39(6): 2821-2839, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37002446

RESUMEN

Targeting BCL2 family proteins to induce cancer cell death has been successful in the treatment of cancer. BH3 mimetics such as ABT-737 not only induce cell death, but also activate autophagy. The molecular mechanism by which the BH3 mimetics induce autophagy is still controversial. In this study, we show that the BCL2/BCLXL/BCLw inhibitor navitoclax and the MCL1 inhibitor S63845 induce both apoptosis and autophagy in mouse embryonic fibroblasts (MEFs) and leukemia cell lines, while autophagy induced by navticlax and S63845 in leukemia cell lines requires the inhibition of caspase activities. Further experiments demonstrate that the autophagy induced by navitoclax or S63845 does not depend on Beclin 1, but downstream of Bax/Bak. Moreover, both navitoclax and S63845 treatment induce mtDNA release in MEFs, which activates STING and thereby induces autophagy, while STING KO inhibits both navitoclax- and S63845-induced autophagy. Furthermore, STING KO diminishes navitoclax- or S63845-induced apoptosis, suggesting that STING activation enhances rather than inhibits apoptosis. Thus, our findings provide new insights into the regulations of navitoclax- or S63845-induced autophagy and cell death.


Asunto(s)
Antineoplásicos , Leucemia , Animales , Ratones , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , ADN Mitocondrial , Línea Celular Tumoral , Fibroblastos/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Muerte Celular , Apoptosis , Antineoplásicos/farmacología , Autofagia
5.
Pharmacol Res ; 176: 106080, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35032663

RESUMEN

Combination therapy system has become a promising strategy for achieving favorable antitumor efficacy. Herein, a novel oral drug delivery system with colon localization and tumor targeting functions was designed for orthotopic colon cancer chemotherapy and photothermal combinational therapy. The polydopamine coated nanodiamond (PND) was used as the photothermal carrier, through the coupling of sulfhydryl-polyethylene glycol-folate (SH-PEG-FA) on the surface of PND to achieve systematic colon tumor targeting, curcumin (CUR) was loaded as the model drug, and then coated with chitosan (CS) to achieve the long gastrointestinal tract retention and colon localization functions to obtain PND-PEG-FA/CUR@CS nanoparticles. It has high photothermal conversion efficiency and good photothermal stability and exhibited near-infrared (NIR) laser-responsive drug release behavior. Folate (FA) modification effectively promotes the intracellular uptake of nanoparticles by CT26 cells, and the combination of chemotherapy and photothermal therapy (CT/PTT) can enhance cytotoxicity. Compared with free CUR group, nanoparticles prolonged the gastrointestinal tract retention time, accumulated more in colon tumor tissues, and exhibited good photothermal effect in vivo. More importantly, the CT/PTT group exhibited satisfactory tumor growth inhibition effects with good biocompatibility in vivo. In summary, this oral drug delivery system is an efficient platform for chemotherapy and photothermal combinational therapy of orthotopic colon cancer.


Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias del Colon/terapia , Curcumina/administración & dosificación , Ácido Fólico/administración & dosificación , Indoles/administración & dosificación , Nanodiamantes/administración & dosificación , Polietilenglicoles/administración & dosificación , Polímeros/administración & dosificación , Administración Oral , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacocinética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Terapia Combinada , Curcumina/química , Curcumina/farmacocinética , Liberación de Fármacos , Ácido Fólico/química , Ácido Fólico/farmacocinética , Indoles/química , Indoles/farmacocinética , Ratones Endogámicos BALB C , Nanodiamantes/química , Terapia Fototérmica , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Polímeros/química , Polímeros/farmacocinética
6.
J Cell Mol Med ; 23(12): 8328-8342, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31612566

RESUMEN

Thus far, the cellular and molecular mechanisms related to early (especially within 24 hours after acute myocardial infarct (MI)) exercise-mediated beneficial effects on MI have not yet been thoroughly established. In the present study, we demonstrated that acute MI rats that underwent early moderate exercise training beginning one day after MI showed no increase in mortality and displayed significant improvements in MI healing and ventricular remodelling, including an improvement in cardiac function, a decrease in infarct size, cardiomyocyte apoptosis, cardiac fibrosis and cardiomyocyte hypertrophy, and an increase in myocardial angiogenesis, left ventricular wall thickness and the number of cardiac telocytes in the border zone. Integrated miRNA-mRNA profiling analysis performed by the ingenuity pathway analysis system revealed that the inhibition of the TGFB1 regulatory network, activation of leucocytes and migration of leucocytes into the infarct zone comprise the molecular mechanism underlying early moderate exercise-mediated improvements in cardiac fibrosis and the pathological inflammatory response. The findings of the present study demonstrate that early moderate exercise training beginning one day after MI is safe and leads to significantly enhanced MI healing and ventricular remodelling. Understanding the mechanism behind the positive effects of this early training protocol will help us to further tailor suitable cardiac rehabilitation programmes for humans.


Asunto(s)
Inflamación/fisiopatología , Infarto del Miocardio/fisiopatología , Condicionamiento Físico Animal/fisiología , Remodelación Ventricular/fisiología , Animales , Apoptosis/genética , Modelos Animales de Enfermedad , Ecocardiografía , Femenino , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Corazón/fisiopatología , Humanos , Inflamación/genética , Inflamación/patología , MicroARNs/genética , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , ARN Mensajero/genética , Ratas Sprague-Dawley , Remodelación Ventricular/genética
7.
Cancer Immunol Immunother ; 68(3): 353-363, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30506460

RESUMEN

BACKGROUND: Blocking the programmed death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in hepatocellular carcinoma (HCC) is a very promising approach in immunotherapy. However, the correlation and prognostic values of serum soluble PD-1 and PD-L1 (sPD-1/sPD-L1) have not been explored conjointly in HCC patients. METHODS: This study retrospectively included 120 HCC patients receiving radical resection. The serum levels of sPD-1/sPD-L1 and inflammatory cytokines were measured by antibody array assay. Immunohistochemistry was applied to assess both the expression of membrane-bound PD-L1, and the number of CD4+ tumor-infiltrating lymphocytes (TILs) and CD8+ TILs. RESULTS: The best cut-off values of sPD-1 and sPD-L1 for predicting disease-free survival (DFS) were 33.0 µg/ml and 11.2 µg/ml, respectively. Multivariable analysis showed that sPD-L1 was a negative independent prognostic factor [DFS, Hazard Ratio (HR) 2.58, 95% CI 1.14-5.84, P = 0.023; overall survival (OS), HR 1.77, 95% CI 1.01-3.12, P = 0.048], while sPD-1 was a favorable independent prognostic factor (DFS, HR 0.32, 95% CI 0.14-0.74, P = 0.007; OS, HR 0.54, 95% CI 0.30-0.98, P = 0.044) in HCC patients. We also observed some similar associations between inflammatory cytokines (IL-10, IL-17, TNF-α) and sPD-1 or sPD-L1, as well as a close positive association between sPD-1 and sPD-L1. No significant associations of sPD-1/sPD-L1 with either intra-tumoral PD-L1 expression, or the numbers of CD4+ TILs and CD8+ TILs were determined. CONCLUSIONS: Our findings indicate that sPD-1 and sPD-L1 are independent prognostic factors with opposite prognostic roles in predicting both DFS and OS in HCC patients.


Asunto(s)
Antígeno B7-H1/sangre , Carcinoma Hepatocelular/mortalidad , Neoplasias Hepáticas/mortalidad , Receptor de Muerte Celular Programada 1/sangre , Adulto , Anciano , Proteína C-Reactiva/análisis , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/patología , Femenino , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/patología , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos
8.
AAPS PharmSciTech ; 21(1): 5, 2019 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-31749020

RESUMEN

As a synthetic clay material, laponite RDS (LR) was investigated as an effective drug carrier as a result of the special nanodisk structure together with the negative-charged surface to achieve enhanced cellular uptake and targeted delivery. In this research work, the synthesized oligomeric hyaluronic acid-aminophenylboronic acid (oHA-APBA) was entangled onto LR nanodisks to fabricate a valid targeted platform for breast cancer therapy. Briefly, through the formation of amide bonds, 3-APBA was connected to the chain of oHA with a substituted ratio of 4.0 ± 0.2% to synthesize oHA-APBA copolymer. Thereafter, doxorubicin (DOX) was inserted into the interlayer space of LR by the way of the ion exchange process, followed by an assembly with oHA-APBA as a targeted protection layer. The satisfactory drug encapsulation efficiency (> 80%) and narrow size distribution were achieved. The in vitro drug release study demonstrated the release of DOX from DOX@LR/oHA-APBA was sustained and acid dependent. In addition, after fitting the drug cumulative release of DOX@LR/oHA-APBA under different pH conditions with several kinetic models, it was identified that drug release from DOX@LR/oHA-APBA nanohybrids at pH 5.0 was mainly dependent on both diffusion and ion exchange effects. However, under the condition of pH 7.4, the drug was most efficiently released by diffusion effect. Importantly, DOX@LR/oHA-APBA showed remarkable cellular uptake and intracellular drug distribution in MCF-7 cells, which were consistent with inhibitory ability against MCF-7 cells. Hence, the high DOX loading capacity and enhanced cellular tracking can enlighten LR/oHA-APBA as an effective drug delivery carrier for breast cancer therapy.


Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Antibióticos Antineoplásicos/química , Ácidos Borónicos , Supervivencia Celular , Doxorrubicina/química , Portadores de Fármacos/química , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Ácido Hialurónico , Concentración de Iones de Hidrógeno , Cinética , Células MCF-7 , Nanoestructuras , Silicatos
9.
Inorg Chem ; 56(4): 2159-2164, 2017 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-28135078

RESUMEN

The highly odd-numbered 15-connected nonanuclear [Ln9(µ3-O)2(µ3-OH)12(O2C-)12(HCO2)3] and 9-connected trinuclear [Ln3(µ3-O)(O2C-)6(HCO2)3] lanthanide-carboxylate clusters with triangular and linear carboxylate bridging ligands were synergistically combined into Ln-MOFs, [(CH3)2NH2]3{[Ln9(µ3-O)2(µ3-OH)12(H2O)6][Ln3(µ3-O)(H2O)3](HCO2)3(BTB)6}·(solvent)x (abbreviated as JXNU-3, Ln = Gd, Tb, Er; BTB3- = benzene-1,3,5-tris(4-benzoate)), displaying a (3,9,15)-connected topological net. The JXNU-3(Tb) exhibits highly selective CO2 adsorption capacity over CH4 that resulted from the high localized charge density induced by the presence of the nonanuclear and trinuclear cluster units. In addition, JXNU-3(Tb) with high chemical stability and characteristic bright green color exhibits fluorescent pH sensing, which is pertinent to the different protonation levels of the carboxylate groups of the benzene-1,3,5-tris(4-benzoate) ligand with varying pH.

10.
Heliyon ; 10(1): e23885, 2024 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-38226282

RESUMEN

The quantified measurement and comprehensive analysis of artificial intelligence development (AIDEV) are vital for countries to form AI industrial ecology and promote the long-term development of regional AI technology. Based on the innovation ecosystems (IE) theory, this paper constructs an evaluation system to measure and analyze the spatiotemporal distribution and dynamic evolution of the AIDEV in China from 2011 to 2020. The results show that the AIDEV of China presents an overall upward trend and an obvious unbalance in the spatial distribution which is "eastern > central > western". Meanwhile, the provinces of low-level AIDEV are catching up with the high-level provinces, which leads to the regional difference of AIDEV narrowing. Moreover, the concentration and polarization phenomenon of AIDEV in China has been weakening and the AIDEV will continue to increase in the next three years. Further, there is a significantly positive spatial autocorrelation of AIDEV. Finally, high AIDEV provinces will increase the probability of surrounding provinces' AIDEV to develop. This paper expands the research stream in the field of AI research, extends the application scenarios of IE theory, and puts forward some relevant policy recommendations.

11.
Nat Commun ; 15(1): 2929, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38575602

RESUMEN

Portland cement (PC) is ubiquitously used in construction for centuries, yet the elucidation of its early-age hydration remains a challenge. Understanding the initial hydration progress of tricalcium aluminate (C3A) at molecular scale is thus crucial for tackling this challenge as it exhibits a proclivity for early-stage hydration and plays a pivotal role in structural build-up of cement colloids. Herein, we implement a series of ab-initio calculations to probe the intricate molecular interactions of C3A during its initial hydration process. The C3A surface exhibits remarkable chemical activity in promoting water dissociation, which in turn facilitates the gradual desorption of Ca ions through a metal-proton exchange reaction. The dissolution pathways and free energies of these Ca ions follow the ligand-exchange mechanism with multiple sequential reactions to form the ultimate products where Ca ions adopt fivefold or sixfold coordination. Finally, these Ca complexes reprecipitate on the remaining Al-rich layer through the interface-coupled dissolution-reprecipitation mechanism, demonstrating dynamically stable inner-sphere adsorption states. The above results are helpful in unmasking the early-age hydration of PC and advancing the rational design of cement-based materials through the bottom-up approach.

12.
Sci Total Environ ; 917: 170445, 2024 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-38296086

RESUMEN

Concrete is the main ingredient in construction, but it inevitably fractures during its service life, requiring a large amount of cement and aggregate for maintenance. Concrete healing through biomineralization can repair cracks and improve the durability of concrete, which is conducive to saving raw materials and reducing carbon emissions. This paper reviews the biodiversity of microorganisms capable of precipitating mineralization to repair the concrete and their mineralization ability under different conditions. To better understand the mass transfer process of precipitates, two biomineralization mechanisms, microbially-controlled mineralization and microbially-induced mineralization, have been briefly described. The application of microorganisms in the field of healing concrete, comprising passive healing and intrinsic healing, is discussed. The key insight on the interaction between cementitious materials and microorganisms is the main approach for developing novel self-healing concrete in the future to improve the corrosion resistance of concrete. At the same time, the limitations and challenges are also pointed out.


Asunto(s)
Biomineralización , Carbonato de Calcio , Materiales de Construcción , Carbono , Biodiversidad
13.
Exp Mol Pathol ; 95(2): 242-7, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23948278

RESUMEN

FoxO3a, a member of the forkhead transcription factors, has been demonstrated to be involved in myocardial ischemia/reperfusion (I/R) injury. Cardiac microvascular endothelial cells (CMECs) are some of the predominant cells damaged immediately after myocardial I/R injury. Despite the importance of injured CMECs in an ischemic heart, little is known about the involvement of FoxO3a in regulating CMECs injury. Thus, we used rat CMECs following simulated I/R to examine FoxO3a activation and signaling in relation to survival, the cell cycle and apoptosis in CMECs. We found that Akt negatively regulates activation of the FoxO3a pathway by phosphorylating FoxO3a in CMECs as demonstrated with an Akt inhibitor and activator. Upon I/R injury, the FoxO3a pathway was significantly activated in CMECs, which was accompanied by Akt deactivation. In parallel, the I/R of CMECs induced G1-phase arrest through p27(Kip1) up-regulation and significant activation of caspase-3. Accordingly, inhibition of the FoxO3a pathway by IGF-1, an Akt activator, could significantly block the I/R-enhanced activation of p27(Kip1) and caspase-3 in CMECs. Collectively, our results indicate that the FoxO3a pathway is involved in the I/R injury of CMECs at least in part through the regulation of cell cycle arrest and apoptosis, suggesting that the FoxO3a pathway may be a novel therapeutic target that protects against microvascular endothelial damage in ischemic hearts.


Asunto(s)
Células Endoteliales/metabolismo , Factores de Transcripción Forkhead/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Transducción de Señal , Animales , Apoptosis/fisiología , Western Blotting , Células Cultivadas , Modelos Animales de Enfermedad , Citometría de Flujo , Proteína Forkhead Box O3 , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
14.
Accid Anal Prev ; 185: 107019, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36907031

RESUMEN

Traffic crash datasets are often marred by the presence of anomalous data points, commonly referred to as outliers. These outliers can have a profound impact on the results obtained through the application of traditional methods such as logit and probit models, commonly used in the domain of traffic safety analysis, resulting in biased and unreliable estimates. To mitigate this issue, this study introduces a robust Bayesian regression approach, the robit model, which utilizes a heavy-tailed Student's t distribution to replace the link function of these thin-tailed distributions, effectively reducing the influence of outliers on the analysis. Furthermore, a sandwich algorithm based on data augmentation is proposed to enhance the estimation efficiency of posteriors. The proposed model is rigorously tested using a dataset of tunnel crashes, and the results demonstrate its efficiency, robustness, and superior performance compared to traditional methods. The study also reveals that several factors such as night and speeding have a significant impact on the injury severity of tunnel crashes. This research provides a comprehensive understanding of the outliers treatment methods in traffic safety studies and offers valuable recommendations for the development of appropriate countermeasures to effectively prevent severe injuries in tunnel crashes.


Asunto(s)
Accidentes de Tránsito , Heridas y Lesiones , Humanos , Accidentes de Tránsito/prevención & control , Teorema de Bayes , Modelos Logísticos
15.
Hematology ; 28(1): 2214465, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37222135

RESUMEN

The MCL1 inhibitors are undergoing clinical testing for multiple leukemia. However, because that MCL1 inhibition has on-target hematopoietic, hepatic and cardiac toxicities, there is substantial interest in finding agents can sensitize leukemia cells to the MCL1 inhibitors. Here we describe that the AKT inhibitors MK-2206 and Gsk690693 sensitize multiple leukemia cells to the MCL1 inhibitor S63845. Further experiments demonstrate that MK-2206 and Gsk690693 sensitize S63845 through the mitochondrial apoptosis pathway. Moreover, MK-2206 downregulates the anti-apoptotic protein BCLXL and induces the BH3-only pro-apoptotic protein BAD dephosphorylation and mitochondrial translocation. Knockdown of BAD significantly inhibits MK-2206-induced sensitization to S63845. Thus, our results suggest that MK-2206 sensitizes multiple leukemia cells to S63845-induced apoptosis, with the mechanisms involving BAD dephosphorylation and BCLXL downregulation.


Asunto(s)
Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas c-akt , Humanos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Apoptosis
16.
Cell Death Dis ; 14(7): 394, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-37393297

RESUMEN

Small molecule direct BAK activators can potentially be used for the development of anti-cancer drugs or as tools to study BAK activation. The thrombopoietin receptor agonist eltrombopag (Eltro) inhibits BAX activation and BAX-mediated apoptosis. Here we report that, in contrast to its function as a BAX inhibitor, Eltro directly binds BAK but induces its activation in vitro. Moreover, Eltro induces or sensitizes BAK-dependent cell death in mouse embryonic fibroblasts (MEFs) and Jurkat cells. Chemical shift perturbation analysis by NMR indicates that Eltro binds to the BAK α4/α6/α7 groove to initiate BAK activation. Further molecular docking by HADDOCK suggests that several BAK residues, including R156, F157, and H164, play an important role in the interaction with Eltro. The introduction of an R156E mutation in the BAK α4/α6/α7 groove not only decreases Eltro binding and Eltro-induced BAK activation in vitro but also diminishes Eltro-induced apoptosis. Thus, our data suggest that Eltro directly induces BAK activation and BAK-dependent apoptosis, providing a starting point for the future development of more potent and selective direct BAK activators.


Asunto(s)
Apoptosis , Fibroblastos , Animales , Ratones , Simulación del Acoplamiento Molecular , Proteína X Asociada a bcl-2/genética
17.
Front Psychol ; 13: 1044011, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36337536

RESUMEN

The entrepreneurial firms may be more vulnerable to the COVID-19 pandemic, and the entrepreneurs of entrepreneurial firms are also threatened by the revenues decline and business failure, which vehemently affect their well-being. The mental health of the entrepreneur decides whether the entrepreneurial firms can make the right decision, which is related to the healthy development of the entrepreneurial firms. Based on the event system theory and the cognitive appraisal theory, this paper aims to explore the effect of COVID-19 pandemic on the entrepreneur anxiety, and the threat perception and performance pressure are introduced to investigate the mediating mechanism and boundary of this effect. Using the simple random sampling to obtain questionnaire survey data, 168 entrepreneurs of entrepreneurial firms have participated in the empirical study, and the research results are as follows. First, the COVID-19 pandemic significantly positively affects entrepreneur anxiety. Second, the entrepreneur threat perception plays a mediating role between the COVID-19 pandemic and the entrepreneur anxiety, which means the COVID-19 pandemic can enhance the external threat perception of entrepreneurs, and then affect the entrepreneur anxiety. Third, the positive effect of the COVID-19 pandemic on the entrepreneur anxiety is strengthened by the entrepreneur performance pressure, while the positive effect of entrepreneur threat perception on entrepreneur anxiety is weakened by the entrepreneur performance pressure. The above findings are helpful to explore the mechanism of the COVID-19 pandemic and other critical crisis events on entrepreneurs' mental health from the new perspective of cognitive appraisal theory and event system theory, filling the research gaps between the COVID-19 pandemic and entrepreneur anxiety. Besides, this study broadens the applied range of the cognitive appraisal theory and the event system theory in the fields of crisis situations and entrepreneur research, and enriches the research outputs. Furthermore, this study will help provide a new theoretical analysis insight for the related research on how the COVID-19 pandemic affects entrepreneurs' psychology, and further deepen researchers to understand the mechanism of entrepreneur anxiety under the COVID-19 pandemic, providing theoretical inspirations for reducing entrepreneur anxiety. What's more, this study finds that individual pressure can affect their cognitive appraisal, which means that future research should take the pressure influential mechanism into consideration in the process of exploring "external stimulus--cognitive appraisal--emotional response," further expanding the theoretical model of cognitive appraisal proposed from the perspective of pressure.

18.
Front Public Health ; 10: 944742, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35903388

RESUMEN

It is a major practical problem to find out a pathway for firms to quickly recover from the performance decline in the context of the COVID-19 pandemic and other sudden major crisis in the current academic circles. Based on event system theory and structural adjustment to regain fit model, this paper empirically explores the impact of the COVID-19 pandemic on SMEs performance decline and discusses the management innovation response and organizational resilience mechanism of firms by virtue of the questionnaire survey data of SMEs in Guangdong Science and Technology Park in China. The research results elucidate that the criticality and disruption of the COVID-19 pandemic will not only lead to the SMEs performance decline, but also enable SMEs to carry out management innovation. Moreover, management innovation does not directly curb the SMEs performance decline caused by the COVID-19 pandemic, but indirectly inhibit it by promoting organizational resilience. In other words, the COVID-19 pandemic will indirectly promote organizational resilience through firm management innovation, thereby curbing the SMEs performance decline. A path of management innovation response and organizational resilience to reverse the performance decline can be obtained in the study when SMEs confronting sudden major crisis. Furthermore, the study also expands the application scope of structural adjustment to regain fit model, which provides a useful reference for firm crisis response and sustainable development.


Asunto(s)
COVID-19 , COVID-19/epidemiología , China/epidemiología , Atención a la Salud , Humanos , Pandemias
19.
Nat Commun ; 13(1): 1253, 2022 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-35273192

RESUMEN

Dissolution of minerals in water is ubiquitous in nature and industry, especially for the calcium silicate species. However, the behavior of such a complex chemical reaction is still unclear at atomic level. Here, we show that the ab initio molecular dynamics and metadynamics simulations enable quantitative analyses of reaction pathways, thermodynamics and kinetics of the calcium ion dissolution from the tricalcium silicate (Ca3SiO5) surface. The calcium sites with different coordination environments lead to different reaction pathways and free energy barriers. The low free energy barriers result in that the detachment of the calcium ion is a ligand exchange and auto-catalytic process. Moreover, the water adsorption, proton exchange and diffusion of water into the surface layer accelerate the leaching of the calcium ion from the surface step by step. The discovery in this work thus would be a landmark for revealing the mechanism of tricalcium silicate hydration.

20.
Ann Transl Med ; 10(13): 749, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35957717

RESUMEN

Background: Imageology uses high-throughput and automatic computing methods to transform medical image data into quantitative data with feature space, and then makes accurate quantitative analysis, extracts features and builds models, which can intuitively observe the overall features of lesions and the surrounding tissues, and provide rich invisible information. At present, the research on the imaging features of dynamic contrast-enhanced (DCE) and diffusion-weighted imaging (DWI) to predict the molecular typing value has achieved results, but the imaging model based on DWI and DCE-magnetic resonance imaging (MRI) is not enough to predict the molecular subtypes, and the prediction value of the prediction model based on the three-dimensional volume of interest of the lesion to the four molecular subtypes of breast cancer has not been fully studied. Methods: The clinical data of 202 breast cancer patients at our hospital from October 2020 to November 2021 were collected. All patients were examined with multimodal MRI before surgery. Base on immunohistochemical recombinant Ki-67 protein (Ki-67), estrogen receptor (ER), human epidermal growth factor receptor-2 (HER-2) and progesterone receptor (PR) results, the tumors were divided into four types According to the results of the sentinel lymph node (SLN) biopsies, the patients were divided into SLN (+) and SLN (-) groups. 3-dimensional (3D) Slicer software was used to outline the region of interest (ROI), and AMni-Kinetics software was used for feature extraction. The imaging characteristics were screened using least absolute shrinkage and selection operator (LASSO)-Logistic regression model using R statistical software, and the receiver operating characteristic (ROC) curve was drawn using "pROC" software package to evaluate the prediction efficiency of the model. Results: The most efficacious model at predicting SLN (+) in breast cancer patients with different molecular subtypes and SLN metastasis was the model based on the imageological characteristics of fat inhibition, and T2-weighted imaging (T2WI), T1-weighted imaging + C (T1WI-C), and DWI combined sequences at the tumor + 2 mm periphery. AUC (sensitivity, specificity) of the validation group were 0.831 (0.856, 0.891), 0.832 (0.660, 0.877), 0.801 (0.772, 0.765), 0.904 (0.769, 0.873), and 0.819 (0.810, 0.500) respectively when the tumor was 2 mm around the tumor. Conclusions: The imaging features extracted from multi-parameter DWI, T1WI+C, and T2WI in breast cancer have certain value at predicting different molecular types and SLNs of breast cancer.

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