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Nod-like receptor family pyrin-containing protein 3 (NLRP3) inflammasome plays a pathologic role in metabolic dysfunction-associated steatohepatitis (MASH), but the molecular mechanism regulating the NLRP3 inflammasome activation in hepatocellular lipotoxicity remains largely unknown. Bromodomain-containing protein 4 (BRD4) has emerged as a key epigenetic reader of acetylated lysine residues in enhancer regions that control the transcription of key genes. The aim of this study is to investigate if and how BRD4 regulated the NLRP3 inflammasome activation and pyroptosis in MASH. Using the AML12 and primary mouse hepatocytes stimulated by palmitic acid (PA) as an in vitro model of hepatocellular lipotoxicity, we found that targeting BRD4 by genetic knockdown or a selective BRD4 inhibitor MS417 protected against hepatosteatosis; and this protective effect was attributed to inhibiting the activation of NLRP3 inflammasome and reducing the expression of Caspase-1, gasdermin D (GSDMD), interleukin (IL)-1ß and IL-6. Moreover, BRD4 inhibition limited the voltage-dependent anion channel-1 (VDAC1) expression and oligomerization in PA-treated AML12 hepatocytes, thereby suppressing the NLRP3 inflammasome activation. Additionally, the expression of BRD4 enhanced in MASH livers of humans. Mechanistically, BRD4 was upregulated during hepatocellular lipotoxicity that in turn modulated the active epigenetic mark H3K27ac at the promoter regions of the Vdac and Gsdmd genes, thereby enhancing the expression of VDAC and GSDMD. Altogether, our data provide novel insights into epigenetic mechanisms underlying BRD4 activating the NLRP3 inflammasome and promoting GSDMD-mediated pyroptosis in hepatocellular lipotoxicity. Thus, BRD4 might serve as a novel therapeutic target for the treatment of MASH.
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Hepatocitos , Inflamasomas , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas de Unión a Fosfato , Piroptosis , Factores de Transcripción , Animales , Humanos , Masculino , Ratones , Proteínas que Contienen Bromodominio , Proteínas de Ciclo Celular , Hígado Graso/metabolismo , Hígado Graso/patología , Furanos , Gasderminas , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Indenos/farmacología , Inflamasomas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas Nucleares , Ácido Palmítico/farmacología , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Fosfato/genética , Piroptosis/efectos de los fármacos , Sulfonamidas/farmacología , Factores de Transcripción/metabolismo , Factores de Transcripción/genéticaRESUMEN
The continuous deepening of aging has posed new challenges for global sustainable development. Measuring the impact of population aging on carbon emissions is crucial for the next stage of climate governance. However, the structural changes in social production and consumption make it difficult to evaluate the impact effects. Therefore, this study constructed a bidirectional fixed Space Durbin Model to explore the mediating pathway of aging's impact on carbon emissions. Furthermore, we have established high-precision prediction models to simulate the evolution trajectory of carbon emissions under multi-factor driving scenarios. The main findings are as follows: (1) The process of carbon emission reduction due to population aging has significant energy hindrance effect and industrial structure effect, while the process of carbon growth is constrained by the consumption enhancement effect, technology progress effect and labor participation effect. (2) The moderating effects of energy consumption and technological innovation on carbon emissions under the aging process are 10.74% and 10.24%, respectively, while the moderating effects of industrial structure and labor force participation are relatively weak. (3) The goodness of fit of the MNGM-ARIMA and MNGM-BPNN models is over 97%. Carbon emissions in the high aging regions show a decreasing trend in all scenarios except the energy consumption-driven scenario, while in the medium and low aging regions decrease slowly only in the R&D- and labor supply-driven scenarios. This study advocates developing heterogeneous emission reduction measures based on the degree of aging, accelerating supply side upgrading, and increasing the proportion of green consumption.
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Carbono , Humanos , Modelos TeóricosRESUMEN
OBJECTIVE: As a prodromal stage to major depressive disorder (MDD), subthreshold depression (StD) has a higher prevalence in the population, resulting in a greater healthcare burden. StD individuals' current negative emotion could be moderated by attentional deployment. However, it remains unclear whether attentional deployment training can mitigate subsequent negative emotion in StD individuals. METHODS: Based on 160 participants, we combined decision task (Experiment 1, N = 69), eye-tracking (Experiment 2, N = 40), and EEG (Experiment 3, N = 51) techniques to investigate how one-week attentional deployment (gain-focus, GF) training modulated the emotional processing of negative stimulus and its underlying neural correlates in StD individuals. RESULTS: After one-week GF training, StD individuals significantly reduced the first fixation time and total fixation time on the negative part (missed opportunities) of decision outcome and showed a decrease in emotional sensitivity to missed opportunities. An increase in N1 and decrease in P3 and LPP (late positive potentials) amplitudes, as well as a decrease in alpha oscillation, were observed when StD individuals faced missed opportunities after training. Additionally, the extent of reduction in StD individuals' emotional sensitivity to missed opportunities could be significantly predicted by the degree of decrease in alpha oscillation. CONCLUSION: One-week attentional deployment training could modulate negative emotion in StD individuals and the degree of change in alpha oscillation might act as an objective indicator for the effectiveness of training. SIGNIFICANCE: Our study provides a convenient and effective approach to alleviate the negative emotion of StD individuals.
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Atención , Depresión , Electroencefalografía , Emociones , Humanos , Masculino , Femenino , Atención/fisiología , Adulto Joven , Depresión/fisiopatología , Depresión/psicología , Emociones/fisiología , AdultoRESUMEN
Signal Transducer and Activator of Transcription (STAT) proteins represent a critical transcription factor family with multifaceted roles in diverse fundamental eukaryotic processes. In Drosophila, STAT exerts a pivotal regulatory influence on oogenesis, governing the early differentiation of follicular cells and ensuring proper encapsulation of germ-line cells. However, the role of STAT in egg development in silkworms remains unknown. In the present study, using CRISPR/Cas9 technology, we successfully generated a strain of silkworms with targeted deletion of the STAT-L gene, which resulted in significant reproductive abnormalities observed in female moths, including shortened fallopian tubes and reduced egg production. The ovaries dissected from STAT-L knockout silkworms during the pupal stage of silkworm exhibited varying degrees of fusion among egg chambers. Additionally, paraffin sections of prepupal ovaries also revealed evidence of egg chambers fusion. To elucidate the molecular mechanism underlying the role of the STAT-L gene regulation on egg development in silkworm, we performed ovarian transcriptomic analysis following STAT-L knockout. Our findings indicated that STAT-L gene can modulate Notch signaling pathway by down-regulating APH-1 gene expression. These results suggest that STAT-L gene plays a crucial role in normal egg chamber formation in silkworms, potentially through its influence on Notch signaling pathway expression.
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Globally, breast cancer (BC) is the predominant malignancy with a significant death rate due to metastasis. The epithelial-mesenchymal transition (EMT) is a fundamental initiator for metastatic progression. Through advanced computational strategies, TCF19 was identified as a critical EMT-associated gene with diagnostic and prognostic significance in BC, based on a novel EMT score. Molecular details and the pro-EMT impact of the TCF19/miR-199a-5p/SP1/LOXL2 axis were explored in BC cell lines through in vitro validations, and the oncogenic and metastatic potential of TCF19 and LOXL2 were investigated using subcutaneous and tail-vein models. Additionally, BC-specific enrichment of TCF19 and LOXL2 was measured using a distribution landscape driven by diverse genomic analysis techniques. Molecular pathways revealed that TCF19-induced LOXL2 amplification facilitated migratory, invasive, and EMT activities of BC cells in vitro, and promoted the growth and metastatic establishment of xenografts in vivo. TCF19 decreases the expression of miR-199a-5p and alters the nuclear dynamics of SP1, modulating SP1's affinity for the LOXL2 promoter, leading to increased LOXL2 expression and more malignant characteristics in BC cells. These findings unveil a novel EMT-inducing pathway, the TCF19/miR-199a-5P/SP1/LOXL2 axis, highlighting the pivotal role of TCF19 and suggesting potential for novel therapeutic approaches for more focused BC interventions.
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Aminoácido Oxidorreductasas , Neoplasias de la Mama , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , MicroARNs , Factor de Transcripción Sp1 , Humanos , Transición Epitelial-Mesenquimal/genética , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Factor de Transcripción Sp1/metabolismo , Factor de Transcripción Sp1/genética , Animales , Aminoácido Oxidorreductasas/genética , Aminoácido Oxidorreductasas/metabolismo , Ratones , Línea Celular Tumoral , Movimiento Celular , Metástasis de la Neoplasia , Transducción de Señal , Ratones DesnudosRESUMEN
The first 1,000 days of human life lay the foundation for brain development and later cognitive growth. However, the developmental rules of the functional connectome during this critical period remain unclear. Using high-resolution, longitudinal, task-free functional magnetic resonance imaging data from 930 scans of 665 infants aged 28 postmenstrual weeks to 3 years, we report the early maturational process of connectome segregation and integration. We show the dominant development of local connections alongside a few global connections, the shift of brain hubs from primary regions to high-order association cortices, the developmental divergence of network segregation and integration along the anterior-posterior axis, the prediction of neurocognitive outcomes, and their associations with gene expression signatures of microstructural development and neuronal metabolic pathways. These findings advance our understanding of the principles of connectome remodeling during early life and its neurobiological underpinnings and have implications for studying typical and atypical development.
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Encéfalo , Conectoma , Imagen por Resonancia Magnética , Humanos , Lactante , Masculino , Femenino , Encéfalo/metabolismo , Encéfalo/crecimiento & desarrollo , Encéfalo/fisiología , Preescolar , Red Nerviosa/fisiología , Recién NacidoRESUMEN
The present study investigated the impact of social exclusion on prosocial behavior, examining the roles of relational need threat and regulatory focus. Utilizing a questionnaire study with 483 participants (Study 1) and an experimental study with 100 participants (Study 2), we found that (1) social exclusion negatively predicted prosocial behavior; (2) relational need threat fully mediated the relationship between social exclusion and prosocial behavior; and (3) regulatory focus, categorized as either promotion or prevention, moderated this relationship in opposite directions. In conclusion, our findings reveal that social exclusion does indeed trigger prosocial behavior. Meanwhile, relational need threat and regulatory focus have a co-action impact on this process. These findings have been carefully discussed within the frameworks of the temporal need-threat model and the cognitive-affective personality system theory.
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Diamond-like carbon (DLC) coatings are effective in protecting the key components of marine equipment and can greatly improve their short-term performance (1.5~4.5 h). However, the lack of investigation into their long-term (more than 200 h) performance cannot meet the service life requirements of marine equipment. Here, three multilayered DLC coatings, namely Ti/DLC, TiCx/DLC, and Ti-TiCx/DLC, were prepared, and their long-term corrosion resistance was investigated. Results showed that the corrosion current density of all DLC coatings was reduced by 1-2 orders of magnitude compared with bare 316L stainless steel (316Lss). Moreover, under long-term (63 days) immersion in a 3.5 wt.% NaCl solution, all DLC coatings could provide excellent long-term corrosion protection for 316Lss, and Ti-TiCx/DLC depicted the best corrosion resistance; the polarization resistances remained at ~3.0 × 107 Ω·cm2 after immersion for 63 days, with more interfaces to hinder the penetration of the corrosive media. Meanwhile, during neutral salt spray (3000 h), the corrosion resistance of Ti/DLC and TiCx/DLC coatings showed a certain degree of improvement because the insoluble corrosion products at the defects blocked the subsequent corrosion. This study can provide a route to designing amorphous carbon protective coatings for long-term marine applications in different environments.
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A type of circular Airyprime function of complex-variable Gaussian vortex (AFCGV) wave packets in a strongly nonlocal nonlinear medium is introduced numerically, combining the properties of helicity states and abrupt autofocusing. We investigate the effects of the chirp factor, distribution parameter, and decay factor on the AFCGV wave packets in the strongly nonlocal nonlinear medium. Interestingly, by adjusting the distribution parameter, the AFCGV wave packets can exhibit stable rotational motions in various shapes, such as symmetric lobes and doughnuts. In addition, the Poynting vector and the gradient force of the AFCGV wave packets are also discussed. Our research not only explains the theoretical model for controlling AFCGV wave packets but also advances fundamental research on self-bending and autofocusing structured light fields.
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The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, essential for cellular communication, orchestrates a myriad of physiological and pathological processes. Recently, the intricate association between the pathway's dysregulation and the progression of malignant tumors has garnered increasing attention. Nevertheless, there is no systematic summary detailing the anticancer effects of molecules targeting the JAK/STAT pathway in the context of tumor progression. This review offers a comprehensive overview of pharmaceutical agents targeting the JAK/STAT pathway, encompassing phytochemicals, synthetic drugs, and biomolecules. These agents can manifest their anticancer effects through various mechanisms, including inhibiting proliferation, inducing apoptosis, suppressing tumor metastasis, and angiogenesis. Notably, we emphasize the clinical challenges of drug resistance while spotlighting the potential of integrating JAK/STAT inhibitors with other therapies as a transformative approach in cancer treatment. Moreover, this review delves into the avant-garde strategy of employing nanocarriers to enhance the solubility and bioavailability of anticancer drugs, significantly amplifying their therapeutic prowess. Through this academic exploration of the multifaceted roles of the JAK/STAT pathway in the cancer milieu, we aim to sketch a visionary trajectory for future oncological interventions.
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Neoplasias , Transducción de Señal , Humanos , Transducción de Señal/fisiología , Quinasas Janus/metabolismo , Factores de Transcripción STAT/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , CarcinogénesisRESUMEN
Differentiation of human embryonic stem cells (hESCs) into human embryonic stem cells-derived parathyroid-like cells (hESC-PT) has clinical significance in providing new therapies for congenital and acquired parathyroid insufficiency conditions. However, a highly reproducible, well-documented method for parathyroid differentiation remains unavailable. By imitating the natural process of parathyroid embryonic development, we proposed a new hypothesis about the in vitro differentiation of parathyroid-like cells. Transcriptome, differentiation marker protein detection and parathyroid hormone (PTH) secretion assays were performed after the completion of differentiation. To optimize the differentiation protocol and further improve the differentiation rate, we designed glial cells missing transcription factor 2 (GCM2) overexpression lentivirus transfection assays and constructed hESCs-derived parathyroid organoids. The new protocol enabled hESCs to differentiate into hESC-PT. HESC-PT cells expressed PTH, GCM2 and CaSR proteins, low extracellular calcium culture could stimulate hESC-PT cells to secrete PTH. hESC-PT cells overexpressing GCM2 protein secreted PTH earlier than their counterpart hESC-PT cells. Compared with the two-dimensional cell culture environment, hESCs-derived parathyroid organoids secreted more PTH. Both GCM2 lentiviral transfection and three-dimensional cultures could make hESC-PT cells functionally close to human parathyroid cells. Our study demonstrated that hESCs could differentiate into hESC-PT in vitro, which paves the road for applying the technology to treat hypoparathyroidism and introduces new approaches in the field of regenerative medicine.
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Diferenciación Celular , Células Madre Embrionarias Humanas , Organoides , Glándulas Paratiroides , Hormona Paratiroidea , Factores de Transcripción , Humanos , Organoides/citología , Organoides/metabolismo , Células Madre Embrionarias Humanas/citología , Células Madre Embrionarias Humanas/metabolismo , Glándulas Paratiroides/citología , Glándulas Paratiroides/metabolismo , Hormona Paratiroidea/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Células Cultivadas , Técnicas de Cultivo de Célula/métodos , Proteínas NuclearesRESUMEN
RATIONALE: Previous studies have found that the main treatment of sinus arrest is pacemaker treatment. It is rare to have 12 s of sinus arrest after radiofrequency ablation, and whether a permanent pacemaker is implanted immediately in this case is not described in the guidelines. PATIENT CONCERNS: A 76-year-old male patient with persistent atrial fibrillation (AF) developed sinus arrest lasting 12 s in the early morning of the fourth day after using radiofrequency ablation for pulmonary vein isolation. DIAGNOSIS: The patient was diagnosed with AF and sinus arrest. INTERVENTIONS: The patient received cardiopulmonary resuscitation, intravenous injection of atropine 1 mg, and intravenous infusion of isoproterenol 1mg and immediately recovered consciousness thereafter. Approximately, 1.5 h later, the patient underwent surgery to install a temporary pacemaker in the right femoral vein. OUTCOMES: The patient had repeated episodes of sinus arrest after the implantation of a temporary pacemaker. After 3 weeks, the patient stabilized and was discharged. The patient was followed up for 1 year and did not experience any recurrence of sinus arrest or AF. LESSONS: We consider the potential for postoperative myocardial edema, injury to the sinoatrial node during the procedure, propafenone poisoning, and autonomic dysfunction as contributors to the occurrence of sinus arrest after radiofrequency ablation. When sinus arrest occurs after radiofrequency ablation, we can choose the appropriate treatment according to the patient's condition.
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Fibrilación Atrial , Cardiomiopatías , Ablación por Catéter , Enfermedades Genéticas Congénitas , Paro Cardíaco , Atrios Cardíacos/anomalías , Bloqueo Cardíaco , Ablación por Radiofrecuencia , Masculino , Humanos , Anciano , Resultado del Tratamiento , Ablación por Catéter/efectos adversos , Ablación por Catéter/métodos , Fibrilación Atrial/diagnóstico , Paro Cardíaco/cirugíaRESUMEN
Accurate chromosome segregation in mitosis relies on sister kinetochores forming stable attachments to microtubules (MTs) extending from opposite spindle poles and establishing biorientation. To achieve this, erroneous kinetochore-MT interactions must be resolved through a process called error correction, which dissolves improper kinetochore-MT attachment and allows new interactions until biorientation is achieved. The Aurora B kinase plays key roles in driving error correction by phosphorylating Dam1 and Ndc80 complexes, while Mps1 kinase, Stu2 MT polymerase and phosphatases also regulate this process. Once biorientation is formed, tension is applied to kinetochore-MT interaction, stabilizing it. In this review article, we discuss the mechanisms of kinetochore-MT interaction, error correction and biorientation. We focus mainly on recent insights from budding yeast, where the attachment of a single MT to a single kinetochore during biorientation simplifies the analysis of error correction mechanisms.
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Proteínas de Saccharomyces cerevisiae , Saccharomycetales , Saccharomyces cerevisiae/genética , Cinetocoros , Microtúbulos/genética , Mitosis , Segregación Cromosómica , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
Functional signals emerge from the structural network, supporting multiple cognitive processes through underlying molecular mechanism. The link between human brain structure and function is region-specific and hierarchical across the neocortex. However, the relationship between hierarchical structure-function decoupling and the manifestation of individual behavior and cognition, along with the significance of the functional systems involved, and the specific molecular mechanism underlying structure-function decoupling remain incompletely characterized. Here, we used the structural-decoupling index (SDI) to quantify the dependency of functional signals on the structural connectome using a significantly larger cohort of healthy subjects. Canonical correlation analysis (CCA) was utilized to assess the general multivariate correlation pattern between region-specific SDIs across the whole brain and multiple cognitive traits. Then, we predicted five composite cognitive scores resulting from multivariate analysis using SDIs in primary networks, association networks, and all networks, respectively. Finally, we explored the molecular mechanism related to SDI by investigating its genetic factors and relationship with neurotransmitter receptors/transporters. We demonstrated that structure-function decoupling is hierarchical across the neocortex, spanning from primary networks to association networks. We revealed better performance in cognition prediction is achieved by using high-level hierarchical SDIs, with varying significance of different brain regions in predicting cognitive processes. We found that the SDIs were associated with the gene expression level of several receptor-related terms, and we also found the spatial distributions of four receptors/transporters significantly correlated with SDIs, namely D2, NET, MOR, and mGluR5, which play an important role in the flexibility of neuronal function. Collectively, our findings corroborate the association between hierarchical macroscale structure-function decoupling and individual cognition and provide implications for comprehending the molecular mechanism of structure-function decoupling. PRACTITIONER POINTS: Structure-function decoupling is hierarchical across the neocortex, spanning from primary networks to association networks. High-level hierarchical structure-function decoupling contributes much more than low-level decoupling to individual cognition. Structure-function decoupling could be regulated by genes associated with pivotal receptors that are crucial for neuronal function flexibility.
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Conectoma , Neocórtex , Fenómenos Fisiológicos del Sistema Nervioso , Humanos , Imagen por Resonancia Magnética/métodos , Cognición/fisiología , Encéfalo/fisiología , Conectoma/métodos , Neocórtex/diagnóstico por imagenRESUMEN
Intrauterine adhesion (IUA) is characterized by endometrial fibrosis. S100A8/A9 plays an important role in inflammation and fibroblast activation. However, the role of S100A8/A9 in IUA remains unclear. In this study, we collect normal and IUA endometrium to verify the expression of S100A8/A9. Human endometrial stromal cells (hEnSCs) are isolated to evaluate fibrosis progression after S100A8/A9 treatment. A porcine IUA model is established by electrocautery injury to confirm the therapeutic effect of menstrual blood-derived stromal cells (MenSCs) on IUA. Our study reveals increased S100A8/A9 expression in IUA endometrium. S100A8/A9 significantly enhances hEnSCs proliferation and upregulates fibrosis-related and inflammation-associated markers. Furthermore, S100A8/A9 induces hEnSCs fibrosis through the RAGE-JAK2-STAT3 pathway. Transplantation of MenSCs in a porcine IUA model notably enhances angiogenesis, mitigates endometrial fibrosis and downregulates S100A8/A9 expression. In summary, S100A8/A9 induces hEnSCs fibrosis via the RAGE-JAK2-STAT3 pathway, and MenSCs exhibit marked effects on endometrial restoration in the porcine IUA model.
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Enfermedades Uterinas , Femenino , Humanos , Animales , Porcinos , Endometrio , Calgranulina A/genética , Células Epiteliales , Inflamación , Janus Quinasa 2/genética , Factor de Transcripción STAT3RESUMEN
AIMS: This study aimed to improve the production of mutantioxidin, an antioxidant encoded by a biosynthetic gene cluster (mao) in Streptococcus mutans UA140, through a series of optimization methods. METHOD AND RESULTS: Through the construction of mao knockout strain S. mutans UA140∆mao, we identified mutantioxidin as the antioxidant encoded by mao and verified its antioxidant activity through a reactive oxygen species (ROS) tolerance assay. By optimizing the culture medium and fermentation time, 72 h of fermentation in chemically defined medium (CDM) medium was determined as the optimal fermentation conditions. Based on two promoters commonly used in Streptococcus (ldhp and xylS1p), eight promoter refactoring strains were constructed, nevertheless all showed impaired antioxidant production. In-frame deletion and complementation experiments demonstrated the positive regulatory role of mao1 and mao2, on mao. Afterward, the mao1 and mao2, overexpression strain S. mutans UA140/pDL278:: mao1mao2, were constructed, in which the production of mutantioxidin was improved significantly. CONCLUSIONS: In this study, through a combination of varied strategies such as optimization of fermentation conditions and overexpression of regulatory genes, production of mutantioxidin was increased by 10.5 times ultimately.
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Caries Dental , Streptococcus mutans , Humanos , Streptococcus mutans/genética , Antioxidantes , Streptococcus , Regiones Promotoras Genéticas , Monoaminooxidasa/genética , Biopelículas , Caries Dental/prevención & controlRESUMEN
Background: Tertiary lymphoid structure (TLS) is a unique organ that carries out tumor cell elimination at tumor sites. It is continuously stimulated by inflammatory tumor signals and has been found to augment immunotherapy response. However, the detailed mechanisms behind it still need to be defined. Methods: To explore and grasp the whole picture of TLS from a pan-cancer view, we collected nine TLS-related genes from previous studies. We performed a comprehensive analysis of 9637 samples across 33 tumor types accessed from The Cancer Genome Atlas (TCGA) database. EdU, Transwell, and flow cytometry were performed on the feature gene PTGDS in U251 cells. The regulatory role of PTGDS on PD-L1 expression and macrophage polarization was verified. Results: Alteration analysis showed that mutations of TLS-related genes were widespread and relatively high. Clustering analysis based on the expression of these nine genes obtained two distinct clusters, with high EIF1AY and PTGDS in cluster 2 and better overall survival in cluster 1. To distinguish the two clusters, we utilized six machine learning algorithms and filtrated EIF1AY, PTGDS, SKAP1, and RBP5 as the characteristic genes, among which the former two genes were proved to be hazardous. PTGDS was found to regulate PD-L1 expression and also promoted the proliferation and migration of U251 cells. The knockdown of PTGDS could reduce the migration of macrophages and inhibit the polarization of macrophages into M2-phenotype. In addition, we established a TLS score to demonstrate patients' TLS activity. The low TLS-score group overlapped with cluster 1 and displayed a better prognosis. Besides, the low TLS-score group was related to better immunotherapy responses. The HE staining of histopathological sections confirmed that the low TLS-score group exhibited higher infiltration of immune cells. Conclusion: This study reveals broad molecular, tumorigenic, and immunogenic signatures for further functional and therapeutic studies of tertiary lymphoid structure. The TLS score we established effectively predicted immunotherapy response and patients' survival. Its future application and combination await more research.
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Morphology of the absorber plays a decisive role in photoelectric conversion efficiency (PCE) of kersterite solar cells. Cu2ZnSn(S,Se)4 (CZTSSe) grain prepared from dimethyl sulfoxide (DMSO)-based solution easily grows into large grains, which can lead to the formation of some holes at the back of the absorber. These holes cause the recombination of photocarriers and greatly weaken the performance of CZTSSe devices. Here, trace amounts of thioglycolic acid (TGA) are introduced to the DMSO-based solution, and a combination of TGA and metal is formed in the absorber, leading to the formation of fine grains in the CZTSSe absorber. Next, post-annealing (PA) in a N2 atmosphere is performed to promote Na diffusion, helping the transition from a fine-grain layer to a low-resistivity carbon layer at the interface between CZTSSe and Mo and avoiding the drawbacks of the DMSO-based system. Finally, the champion PCE of the CZTSSe device can be improved to 10.05% from 8.06%. The conclusions demonstrate that the construction of a carbon layer can boost the performance of CZTSSe devices.
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Atherosclerotic cardiovascular disease and its complications are a high-incidence disease worldwide. Numerous studies have shown that blood flow shear has a huge impact on the function of vascular endothelial cells, and it plays an important role in gene regulation of pro-inflammatory, pro-thrombotic, pro-oxidative stress, and cell permeability. Many important endothelial cell mechanosensitive genes have been discovered, including KLK10, CCN gene family, NRP2, YAP, TAZ, HIF-1α, NF-κB, FOS, JUN, TFEB, KLF2/KLF4, NRF2, and ID1. Some of them have been intensively studied, whereas the relevant regulatory mechanism of other genes remains unclear. Focusing on these mechanosensitive genes will provide new strategies for therapeutic intervention in atherosclerotic vascular disease. Thus, this article reviews the mechanosensitive genes affecting vascular endothelial cells, including classical pathways and some newly screened genes, and summarizes the latest research progress on their roles in the pathogenesis of atherosclerosis to reveal effective therapeutic targets of drugs and provide new insights for anti-atherosclerosis.