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1.
Sci Rep ; 11(1): 7508, 2021 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-33820957

RESUMEN

The aim is to investigate that 17ß-estradiol (E2)/estrogen receptors (ERs) activation normalizes splenic CD4 + T lymphocytes proliferation and cytokine production through inhibition of endoplasmic reticulum stress (ERS) following hemorrhage. The results showed that hemorrhagic shock (hemorrhage through femoral artery, 38-42 mmHg for 90 min followed by resuscitation of 30 min and subsequent observation period of 180 min) decreased the CD4+ T lymphocytes proliferation and cytokine production after isolation and incubation with Concanavalin A (5 µg/mL) for 48 h, induced the splenic injury with evidences of missed contours of the white pulp, irregular cellular structure, and typical inflammatory cell infiltration, upregulated the expressions of ERS biomarkers 78 kDa glucose-regulated protein (GRP78) and activating transcription factor 6 (ATF6). Either E2, ER-α agonist propyl pyrazole triol (PPT) or ERS inhibitor 4-Phenylbutyric acid administration normalized these parameters, while ER-ß agonist diarylpropionitrile administration had no effect. In contrast, administrations of either ERs antagonist ICI 182,780 or G15 abolished the salutary effects of E2. Likewise, ERS inducer tunicamycin induced an adverse effect similarly to that of hemorrhagic shock in sham rats, and aggravated shock-induced effects, also abolished the beneficial effects of E2 and PPT, respectively. Together, the data suggest that E2 produces salutary effects on CD4+ T lymphocytes function, and these effects are mediated by ER-α and GPR30, but not ER-ß, and associated with the attenuation of hemorrhagic shock-induced ERS.

2.
Artículo en Inglés | MEDLINE | ID: mdl-33831864

RESUMEN

INTRODUCTION: Laryngeal squamous cell carcinoma (LSCC) is diverse in its natural history and responsiveness to treatments. There is an urgent need to generate candidate biomarkers for the stratification and individualization of treatment to avoid overtreatment or inadequate treatment. Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been identified as an oncogenic gene in multiple human tumors entitles, and dysregulation of NEAT1 was tightly linked to carcinogenesis and cancer progression. METHODS: One hundred two paraffin samples of LSCC patients were collected. Furthermore, in situ hybridization (ISH), Kaplan-Meier, and MTT were used to analyze the relationship between NEAT1 and the progress of LSCC. RESULTS: In this study, ISH revealed that NEAT1 was strongly expressed in the nucleus. The increased expression of NEAT1 was correlated with T grade, neck nodal metastasis, clinical stage, drinking history, or smoking history of LSCC. The Kaplan-Meier analysis indicated that patients with higher NEAT1 expression had a worse overall survival in LSCC patients. In addition, NEAT1 knockdown significantly inhibited the growth of LSCC cells. CONCLUSION: Together, these results suggested that NEAT1 involved in the progress of LSCC and might act as a tumor oncogenic gene. This study provides a potential new marker and target for gene therapy in the treatment of LSCC.

3.
Artículo en Inglés | MEDLINE | ID: mdl-33835225

RESUMEN

PURPOSE: To describe a non-anatomic arthroscopic all-inside repair technique for middle-aged and older patients with medial meniscus posterior root tears (MMPRTs) and to evaluate the short- to mid-term clinical and radiologic results. The hypothesis was that this procedure would yield good clinical outcome results and structural healing in middle- and older-aged patients. METHODS: This was a retrospective study evaluating patients who had undergone MMPRT repair by suturing the meniscal root directly to the capsule, rather than by the transtibial technique, between 2013 and 2016. This all-inside repair technique was performed for patients with type II MMPRTs who were over 40 years old. Exclusion criteria included tibial osteotomy due to malalignment, concomitant multiple-ligament injuries and follow-up time less than 2 years. The Lysholm score, Tegner activity score and International Knee Documentation Committee (IKDC) score were evaluated preoperatively and at the final follow-up. Medial meniscal extrusion, the International Cartilage Repair Society (ICRS) grades of the medial compartment, and the healing status of the medial meniscus root were assessed on magnetic resonance imaging preoperatively and at the final follow-up. RESULTS: Twenty-nine patients (mean age 61.7 ± 7.9) were included; the mean follow-up duration was 46.2 ± 7.9 months. The mean Lysholm score significantly improved from 33.7 ± 20.9 preoperatively to 81.7 ± 19.9 at the final follow-up (p < 0.001), the median Tegner activity score improved from 1.0 (range 1-4) to 3.0 (range 2-4, p < 0.001), and the mean IKDC score improved from 20.1 ± 16.4 to 69.6 ± 16.2 (p < 0.001). On MRI, 9 (31%) cases had complete healing; 17 (59%) had partial healing; and 3 (10%) had failed healing (ICCs ≥ 0.92). Mean meniscal extrusion significantly increased from 2.3 ± 1.7 mm preoperatively to 3.5 ± 1.5 mm postoperatively (p < 0.001, ICCs ≥ 0.92). CONCLUSION: Non-anatomic arthroscopic all-inside repair of MMPRTs to the posterior capsule yielded good to excellent clinical results and a high rate of healing in the medial meniscus root on MRI in middle-aged and older patients at short- to mid-term follow-up, despite increased meniscal extrusion. This method is an alternative to the transtibial pullout repair technique for treating MMPRTs in middle- and older-aged patients. LEVEL OF EVIDENCE: Level IV.

4.
Hu Li Za Zhi ; 68(2): 53-64, 2021 Apr.
Artículo en Chino | MEDLINE | ID: mdl-33792019

RESUMEN

BACKGROUND: Patients with coronary heart disease (CHD) who quit smoking exhibit lower rates of heart attack recurrence and mortality than their peers who continue smoking. However, most male patients with CHD resume smoking after hospital discharge. PURPOSE: To explore the effectiveness of motivational interventions and mobile social network support on smoking cessation and other predictors of smoking cessation in male patients with CHD. METHODS: An experimental design was used, and a convenience sample was recruited from a cardiology ward of a hospital in northern Taiwan. The participants were randomly assigned to the experimental group (n = 57) and control group (n = 64). During hospitalization, each participant completed a questionnaire after undergoing cardiac catheterization. The questionnaire included a demographic datasheet, the Fagerström Test for Nicotine Dependence, and the contemplation ladder. Afterward, the experimental group received motivational interventions, filled out a self-efficacy scale and the contemplation ladder, and joined an online mobile social group (LINE) for three months. The control group received regular care and a smoking cessation booklet, and then filled out the self-efficacy scale and contemplation ladder. An intention-to-treat analysis was adopted to evaluate smoke cessation status. Information on post-discharge smoking status was collected from the participants via the Line communications app or phone calls at three-months after hospital discharge and was further confirmed using urinary cotinine levels. RESULTS: The results revealed that both groups registered improvements in motivation to quit smoking. This motivation was relatively higher in the experimental group after the intervention than in the control group. The smoking cessation rate in the experimental group (35.09%) was higher than that in the control group (17.19%). However, the intergroup difference in the cessation rate only approached statistical significance (OR: 2.34; p = .055) after controlling for the baseline difference between the two groups. Controlling for the effects of the intervention, age of smoking initiation, first diagnosis of CHD, and self-efficacy were identified as predictors of smoking cessation. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Healthcare providers are encouraged to provide motivational interviews to enhance the motivation of their patients to quit smoking as well as to incorporate self-efficacy into related interventions to increase the smoking cessation rate.


Asunto(s)
Enfermedad Coronaria , Entrevista Motivacional , Cese del Hábito de Fumar , Red Social , Telemedicina , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/terapia , Humanos , Masculino , Alta del Paciente , Cese del Hábito de Fumar/métodos , Cese del Hábito de Fumar/psicología , Cese del Hábito de Fumar/estadística & datos numéricos , Taiwán/epidemiología , Resultado del Tratamiento
5.
Medicine (Baltimore) ; 100(14): e25315, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33832105

RESUMEN

BACKGROUND: Programmed cell death ligand 1 (PD-L1), which is highly expressed in a variety of malignant tumors, is closely related to clinicopathological features and prognosis. However, there are few studies on the potential effects of PD-L1 on thyroid carcinoma, the incidence of which has shown an upward trend worldwide. This study aimed to explore the association between PD-L1 expression and clinicopathological features and prognosis of thyroid cancer. METHODS: An elaborate retrieval was performed using Medline, PubMed, Cochrane Library, EMBASE, Web of Science, WanFang databases, and China National Knowledge Infrastructure to determine the association between PD-L1 expression and disease-free survival (DFS), overall survival (OS), and clinicopathological features in patients with thyroid cancer. Study selection, data extraction, risk assessment, and data synthesis were performed independently by 2 reviewers. In this meta-analysis, RevMan 5.3 and Stata 15.1 were used for bias risk assessment and data synthesis. RESULTS: After a detailed search, 2546 cases reported in 13 articles were included in this meta-analysis. The outcomes revealed that high expression of PD-L1 in patients with thyroid cancer was associated with poor DFS (hazard ratio [HR] = 3.37, 95% confidence interval [CI] 2.54-4.48, P < .00001) and OS (HR = 2.52, 95% CI: 1.20-5.32, P = .01). High PD-L1 expression was associated with tumor size ≥2 cm, tumor recurrence, extrathyroidal extension, concurrent thyroiditis, unifocal tumor, and absence of psammoma body (P < .05). Subgroup analysis showed that positive expression of PD-L1 was related to poor prognosis for DFS of non-medullary thyroid carcinoma, and the overexpression of PD-L1 in differentiated thyroid carcinoma (DTC) was related to tumor recurrence, concurrent thyroiditis, extrathyroidal extension, unifocal DTC, late stage DTC, and BRAFV600E mutation in DTC. CONCLUSION: PD-L1 is a significant predictor of prognosis and malignancy of thyroid cancer (especially DTC), and PD-L1 inhibitors may be a promising therapeutic option for refractory thyroid cancer in the future.

6.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(3): 299-304, 2021 Mar.
Artículo en Chino | MEDLINE | ID: mdl-33834970

RESUMEN

OBJECTIVE: To explore the risk factors of acute respiratory distress syndrome (ARDS) secondary to severe multiple trauma and the role of clinical guidance. METHODS: The clinical data of 115 patients with severe multiple trauma admitted to the trauma center of Zhenjiang First People's Hospital from December 2017 to September 2020 were retrospectively analyzed. According to whether ARDS occurred within 1 week of the disease course, the patients were divided into ARDS group and non-ARDS group. The basic post-traumatic data, initial treatment measures (within 24 hours), pathophysiology, stress metabolism, and post-traumatic complications of the two groups of patients were selected for univariate analysis, the statistically different indicators of univariate analysis were incorporated into the multivariate Logistic regression analysis to screen out independent high-risk factors that affect the occurrence of ARDS in patients with severe multiple trauma, and a receiver operating characteristic curve (ROC curve) was drawn to analyze the effects of each risk factor on the occurrence of ARDS. RESULTS: Among 115 patients, there were 45 cases in the ARDS group and 70 cases in the non-ARDS group. Compared with the non-ARDS group, the patients in the ARDS group were older (years: 57.45±15.37 vs. 45.68±12.70), and the proportion of patients combined with moderate-severe chest trauma, traumatic brain injury (TBI), shock, and massive blood transfusion were higher (71.11% vs. 31.43%, 44.44% vs. 28.57%, 80.00% vs. 67.14%, 46.67% vs. 27.14%). In the ARDS group, procalcitonin [PCT (µg/L): 29.73±6.08 vs. 12.45±2.12], thrombomodulin [TM (ng/L): 83.43±16.34 vs. 37.66±14.64], blood glucose (mmol/L: 17.2±5.0 vs. 10.3±2.4), triacylglycerol [TG (mmol/L): 3.77±0.57 vs. 2.22±0.63], interleukin-6 [IL-6 (ng/L): 38.97±10.79 vs. 25.98±5.40], tumor necrosis factor-α [TNF-α (ng/L): 48.78±13.99 vs. 35.30±13.03], intra-abdominal pressure [mmHg (1 mmHg = 0.133 kPa): 25.21±3.59 vs. 11.98±4.91], serum creatinine [SCr (µmol/L): 180.45±42.35 vs. 132.17±49.36] and blood urea nitrogen [BUN (mmol/L): 13.83±4.97 vs. 8.80±4.32] were significantly higher than those in the non-ARDS group; the proportion of patients with crystal infusion volume ≥ 3 000 mL (26.67% vs. 34.29%) and platelet count [PLT (×109/L): 72.67±7.96 vs. 127.99±17.65] and the levels of plasma glutathione peroxidase [GSH-Px (kU/L): 87.15±27.81 vs. 161.15±17.94], plasma superoxide dismutase [SOD (kU/L): 92.65±32.67 vs. 125.58±38.96] were significantly lower than those in the non-ARDS group, the differences were statistically significant (all P < 0.05). Multivariate Logistic regression analysis showed that 11 indicators such as age, combined moderate-severe chest trauma, combined TBI, massive blood transfusion, PCT, TM, blood glucose, TNF-α, plasma GSH-Px, intra-abdominal pressure and SCr were independent risk factors that could predict ARDS secondary to severe multiple trauma, the odds ratio (OR) and 95% confidence interval (95%CI) were 1.201 (1.035-1.165), 3.414 (1.217-8.876), 2.889 (1.124-8.109), 3.134 (1.322-9.261), 1.467 (1.096-2.307), 2.428 (0.024-0.973), 5.787 (1.246-9.642), 1.106 (0.949-5.108), 7.450 (1.587-10.261), 3.144 (1.217-8.876), 1.051 (1.002-1.542) respectively, the P values were 0.008, 0.024, 0.044, 0.017, 0.018, 0.045, 0.026, 0.037, 0.005, 0.029, 0.033 respectively. ROC curve analysis showed that plasma GSH-Px had a higher predictive value for ARDS secondary to severe multiple trauma, the area under ROC curve (AUC) = 0.873, 95%CI was 0.798-0.928, P = 0.000, when the best cut-off value at 72.22 kU/L, its sensitivity was 86.7%, specificity was 75.7%, positive predictive value was 69.6%, and negative predictive value was 89.8%. The Logistic regression model established by 11 independent high-risk factors had an accuracy rate of 81.74% in predicting ARDS secondary to severe multiple trauma, which had a good guiding significance for predicting ARDS. CONCLUSIONS: Our study showed that there are many risk factors for ARDS secondary to severe multiple trauma, involving basic post-traumatic data, initial treatment measures, pathophysiology, stress metabolism, post-traumatic complications, etc. Early identification and intervention may be beneficial to improve the success rate of treatment for such patients.


Asunto(s)
Traumatismo Múltiple , Humanos , Traumatismo Múltiple/complicaciones , Pronóstico , Curva ROC , /etiología , Estudios Retrospectivos , Factores de Riesgo
7.
Front Immunol ; 12: 649551, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33815409

RESUMEN

Pancreatic cancer is a lethal malignancy with a poor prognosis. This study aims to identify pancreatic cancer-related genes and develop a robust diagnostic model to detect this disease. Weighted gene co-expression network analysis (WGCNA) was used to determine potential hub genes for pancreatic cancer. Their mRNA and protein expression levels were validated through reverse transcription PCR (RT-PCR) and immunohistochemical (IHC). Diagnostic models were developed by eight machine learning algorithms and ten-fold cross-validation. Four hub genes (TSPAN1, TMPRSS4, SDR16C5, and CTSE) were identified based on bioinformatics. RT-PCR showed that the four hub genes were expressed at medium to high levels, IHC revealed that their protein expression levels were higher in pancreatic cancer tissues. For the panel of these four genes, eight models performed with 0.87-0.92 area under the curve value (AUC), 0.91-0.94 sensitivity, and 0.84-0.86 specificity in the validation cohort. In the external validation set, these models also showed good performance (0.86-0.98 AUC, 0.84-1.00 sensitivity, and 0.86-1.00 specificity). In conclusion, this study has identified four hub genes that might be closely related to pancreatic cancer: TSPAN1, TMPRSS4, SDR16C5, and CTSE. Four-gene panels might provide a theoretical basis for the diagnosis of pancreatic cancer.

8.
Artículo en Inglés | MEDLINE | ID: mdl-33797136

RESUMEN

Layered oxides as the cathode materials of sodium-ion batteries are receiving extensive attention due to their high capacity and flexible composition. However, the layered cathode tends to be thermodynamically and electrochemically unstable during sodiation and de-sodiation. Herein, we for the first time propose the "pinning effect" and controllable "pinning point" in sodium storage layered cathodes to enhance the structural stability and achieve the optimal electrochemical performance. 0%, 2.5% and 7.3% transition-metal (TM) occupancies in Na-site as pinning points are obtained through adjusting the feeding ratio of iron in Na 0.67 Mn 0.5 Co 0.5- x Fe x O 2 system. Results show that 2.5% TM pinning is beneficial to restrain the potential slab sliding and enhance the structural stability, resulting in an ultra-low volume variation of 0.6% and maintaining the smooth two-dimensional channel for Na-ion transfer. Finally, the Na 0.67 Mn 0.5 Co 0.4 Fe 0.1 O 2 cathode with the optimal TM pinning delivers outstanding cycling performance of over 1000 cycles and superior rate capability up to 10C.

9.
Dalton Trans ; 50(14): 4914-4922, 2021 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-33877188

RESUMEN

The Eu-doped K0.5Na0.5NbO3 pellucid ceramics were first prepared via a conventional solid-state reaction, and they exhibited light illumination-induced high-contrast photochromism of both optical transmittance and photoluminescence behaviors. Through thermal treatment, the optical performances could return to their initial states and displayed excellent reversibility. Eu3+ ions were selected as the luminescent activator for detecting the local environment of the K0.5Na0.5NbO3 host. Meanwhile, the effects of the amount of Eu3+ present on phase structures, microstructures, optical transmittance and photoluminescence intensities were systematically investigated. The results suggest that Eu-doped K0.5Na0.5NbO3 transparent ceramics possess multifunctionality including photochromism, photoluminescence and optical switching properties, and that they exhibit promising potential for non-destructive optical data storage application.

10.
Nat Commun ; 12(1): 2029, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33795689

RESUMEN

Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear. Here, we report that IL-2/IL-15 receptor ß chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1ß induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1ß to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1ßR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation.


Asunto(s)
Citocinas/inmunología , Proteína Coestimuladora de Linfocitos T Inducibles/inmunología , Activación de Linfocitos/inmunología , Diana Mecanicista del Complejo 1 de la Rapamicina/inmunología , Diana Mecanicista del Complejo 2 de la Rapamicina/inmunología , Células T Invariantes Asociadas a Mucosa/inmunología , Animales , Diferenciación Celular/inmunología , Células Cultivadas , Citocinas/metabolismo , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Interleucina-15/inmunología , Interleucina-15/metabolismo , Interleucina-2/inmunología , Interleucina-2/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Células T Invariantes Asociadas a Mucosa/citología , Células T Invariantes Asociadas a Mucosa/metabolismo , Transducción de Señal/inmunología , Serina-Treonina Quinasas TOR/inmunología , Serina-Treonina Quinasas TOR/metabolismo
11.
Bioresour Technol ; 331: 125058, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33812136

RESUMEN

How to achieve stable mainstream deammonification is still a huge challenge. In this work, satisfactory nitrogen removal were achieved in a deammonification granular sludge reactor (R1, 0.42 ± 0.03 kg N / (m3·d)) and a mixed flocculent with granular sludge reactor (R2, 0.39 ± 0.04 kg N / (m3·d)) at ambient temperature (21-28 ℃) . The good adaptability of anammox bacteria (Candidatus Jettenia) to ambient temperature ensured its efficient activity (0.84-1.54 mg N/(g VSS·h)). The overexpression ammonia monooxygenase gene abundances in ammonia oxidizing bacteria (Nitrosomonas) was also predicted. The inhibition of hydrazine and the competition of denitrifying bacteria (Denitratisoma) to nitrite nitrogen, leading to a low Nitrospira relative abundances (0.2%-2.1%) . It was also found that R1 was more resistant to the unfavorable condition. For R2, higher Denitratisoma abundances (9.2%-18.5%) and predicted metabolic pathway abundances related to carbon metabolism were observed.

12.
J Headache Pain ; 22(1): 25, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33858323

RESUMEN

BACKGROUND: Granger causality analysis (GCA) has been used to investigate the pathophysiology of migraine. Amygdala plays a key role in pain modulation of migraine attack. However, the detailed neuromechanism remained to be elucidated. We applied GCA to explore the amygdala-based directional effective connectivity in migraine without aura (MwoA) and to determine the relation with clinical characteristics. METHODS: Forty-five MwoA patients and forty age-, sex-, and years of education-matched healthy controls(HCs) underwent resting-state functional magnetic resonance imaging (fMRI). Bilateral amygdala were used as seed regions in GCA to investigate directional effective connectivity and relation with migraine duration or attack frequency. RESULTS: MwoA patients showed significantly decreased effective connectivity from right amygdala to right superior temporal gyrus, left superior temporal gyrus and right precentral gyrus compared with HCs. Furthermore, MwoA patients demonstrated significantly decreased effective connectivity from the left amygdala to the ipsilateral superior temporal gyrus. Also, MwoA patients showed enhanced effective connectivity from left inferior frontal gyrus to left amygdala. Effective connectivity outflow from right amygdala to right precentral gyrus was negatively correlated to disease duration. CONCLUSIONS: Altered directional effective connectivity of amygdala demonstrated that neurolimbic pain networks contribute to multisensory integration abnormalities and deficits in pain modulation of MwoA patients.


Asunto(s)
Migraña sin Aura , Amígdala del Cerebelo/diagnóstico por imagen , Encéfalo , Mapeo Encefálico , Humanos , Imagen por Resonancia Magnética , Migraña sin Aura/diagnóstico por imagen , Corteza Prefrontal
13.
Acta Pharmacol Sin ; 2021 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-33875797

RESUMEN

The excess deposition of underlying extracellular matrix (ECM) in adipose tissue is defined as adipose tissue fibrosis that is a major contributor to metabolic disorder such as obesity and type 2 diabetes. Anti-fibrosis therapy has received much attention in the treatment of metabolic disorders. Orosomucoid (ORM) is an acute-phase protein mainly produced by liver, which is also an adipokine. In this study, we investigated the effects of ORM on adipose tissue fibrosis and the potential mechanisms. We showed that ORM1-deficient mice exhibited an obese phenotype, manifested by excessive collagen deposition in adipose tissues and elevated expression of ECM regulators such as metalloproteinases (MMP-2, MMP-13, MMP-14) and tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3). Administration of exogenous ORM (50 mg· kg-1· d-1, ip) for 7 consecutive days in high-fat diet (HFD)-fed mice and leptin receptor (LepR)-deficient db/db mice attenuated these abnormal expressions. Meanwhile, ORM administration stimulated AMP-activated protein kinase (AMPK) phosphorylation and decreased transforming growth factor-ß1 (TGF-ß1) level in adipose tissues of the mice. In TGF-ß1-treated 3T3-L1 fibroblasts, ORM (10 µg/mL) improved the impaired expression profiles of fibrosis-related genes, whereas a selective AMPK inhibitor dorsomorphin (1 µmol/mL) abolished these effects. Together, our results suggest that ORM exerts a direct anti-fibrosis effect in adipose tissue via AMPK activation. ORM is expected to become a novel target for the treatment of adipose tissue fibrosis.

14.
Proc Natl Acad Sci U S A ; 118(15)2021 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-33876772

RESUMEN

The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals to regulate critical cellular processes such as mRNA translation, lipid biogenesis, and autophagy. Germline and somatic mutations in mTOR and genes upstream of mTORC1, such as PTEN, TSC1/2, AKT3, PIK3CA, and components of GATOR1 and KICSTOR complexes, are associated with various epileptic disorders. Increased mTORC1 activity is linked to the pathophysiology of epilepsy in both humans and animal models, and mTORC1 inhibition suppresses epileptogenesis in humans with tuberous sclerosis and animal models with elevated mTORC1 activity. However, the role of mTORC1-dependent translation and the neuronal cell types mediating the effect of enhanced mTORC1 activity in seizures remain unknown. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2) are translational repressors downstream of mTORC1. Here we show that the ablation of 4E-BP2, but not 4E-BP1, in mice increases the sensitivity to pentylenetetrazole (PTZ)- and kainic acid (KA)-induced seizures. We demonstrate that the deletion of 4E-BP2 in inhibitory, but not excitatory neurons, causes an increase in the susceptibility to PTZ-induced seizures. Moreover, mice lacking 4E-BP2 in parvalbumin, but not somatostatin or VIP inhibitory neurons exhibit a lowered threshold for seizure induction and reduced number of parvalbumin neurons. A mouse model harboring a human PIK3CA mutation that enhances the activity of the PI3K-AKT pathway (Pik3ca H1047R-Pvalb ) selectively in parvalbumin neurons shows susceptibility to PTZ-induced seizures. Our data identify 4E-BP2 as a regulator of epileptogenesis and highlight the central role of increased mTORC1-dependent translation in parvalbumin neurons in the pathophysiology of epilepsy.

15.
Stem Cell Reports ; 16(4): 926-939, 2021 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-33798448

RESUMEN

Mucosal-associated invariant T (MAIT) cells are innate-like unconventional T cells that are abundant in humans and have attracted increasing attention in recent years. Mesenchymal stem cells (MSCs) are crucial regulators of immune cells. However, whether MAIT cells are regulated by MSCs is unclear. Here, we explored the effect of MSCs on MAIT cells and revealed the underlying mechanism. We found that MSCs did not influence the proliferation of MAIT cells but strikingly induced an activated phenotype with an increased expression of CD69, TNF-α, IFN-γ, and granzyme B. Moreover, MSCs activated MAIT cells in a TCR-MR1-independent mechanism through MSC-secreted IL-15. We revealed that MSC-derived IL-15 activated MAIT cells by enhancing autophagy activity, which was abolished by the autophagy inhibitor 3-methyladenine. Based on our findings, MAIT cells are activated by MSCs through IL-15-induced autophagy, which may help elucidate the mechanisms underlying some immune responses and diseases and provide guidance for future research.

16.
Sci Adv ; 7(16)2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33863732

RESUMEN

Blackbody-sensitive room-temperature infrared detection is a notable development direction for future low-dimensional infrared photodetectors. However, because of the limitations of responsivity and spectral response range for low-dimensional narrow bandgap semiconductors, few low-dimensional infrared photodetectors exhibit blackbody sensitivity. Here, highly crystalline tellurium (Te) nanowires and two-dimensional nanosheets were synthesized by using chemical vapor deposition. The low-dimensional Te shows high hole mobility and broadband detection. The blackbody-sensitive infrared detection of Te devices was demonstrated. A high responsivity of 6650 A W-1 (at 1550-nm laser) and the blackbody responsivity of 5.19 A W-1 were achieved. High-resolution imaging based on Te photodetectors was successfully obtained. All the results suggest that the chemical vapor deposition-grown low-dimensional Te is one of the competitive candidates for sensitive focal-plane-array infrared photodetectors at room temperature.

18.
Artículo en Inglés | MEDLINE | ID: mdl-33861071

RESUMEN

Hybrid surfaces with tunable topography, chemistry, and stiffness have potential to rebuild native extracellular matrix (ECM) and manipulate cell behavior in vitro. However, the fabrication of controllable hybrid surfaces is still challenging. In this study, colloidal self-assembly technology was used to program particles into highly ordered structures with hybrid chemistry and stiffness at biointerfaces. These colloidal self-assembled patterns (cSAPs), including unary, binary, and ternary cSAPs, composed of silicon (Si), polystyrene (PS), and/or poly(N-isopropylacrylamide) (pNIPAM) nanogels (PNGs), were fabricated using either coassembly or layer-by-layer (LBL) methods. The selected binary cSAPs (i.e., PS/PNG and PNG/PS) have a tunable surface topography and wettability between 25 and 37 °C; thus, they can be used as dynamic cell culture substrates. Human adipose-derived mesenchymal stem cells (hASCs), bone marrow-derived mesenchymal stem cells (hBMSCs), and macrophages (THP-1) were investigated on these hybrid cSAPs under a static or dynamic system. The results showed that hybrid cSAPs significantly influenced the focal adhesions, cell morphology, cell migration, and gene expressions of stem cells. In general, stem cells had more vinculin puncta, smaller spreading size, and faster migration speed than the TCPS control. Hybrid cSAPs up-regulated gene expressions of focal adhesion kinase (FAK) and chondrocytes (AGG and SOX9) under static culture, while they also up-regulated osteocytes (COL1 and RUNX2) under dynamic culture. THP-1 macrophages were at M0 state on all cSAPs under static culture. However, cells became sensitive under dynamic culture. For example, some M1 genes (i.e., IL6, CD68, and TNFα) and M2 genes (i.e., IL10 and CD206) were down-regulated, while other M1 genes (i.e., IL1ß) and M2 genes (i.e., TGF-ß and IL1ra) were up-regulated, depending on the particle combinations. In conclusion, new hybrid cSAPs with thermoresponsive surface properties are versatile materials for stem cells and macrophages manipulation.

19.
J Cell Biol ; 220(6)2021 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-33836042

RESUMEN

Mitotic entry involves inhibition of protein phosphatase 2A bound to its B55/Tws regulatory subunit (PP2A-B55/Tws), which dephosphorylates substrates of mitotic kinases. This inhibition is induced when Greatwall phosphorylates Endos, turning it into an inhibitor of PP2A-Tws. How this mechanism operates spatiotemporally in the cell is incompletely understood. We previously reported that the nuclear export of Greatwall in prophase promotes mitotic progression. Here, we examine the importance of the localized activities of PP2A-Tws and Endos for mitotic regulation. We find that Tws shuttles through the nucleus via a conserved nuclear localization signal (NLS), but expression of Tws in the cytoplasm and not in the nucleus rescues the development of tws mutants. Moreover, we show that Endos must be in the cytoplasm before nuclear envelope breakdown (NEBD) to be efficiently phosphorylated by Greatwall and to bind and inhibit PP2A-Tws. Disrupting the cytoplasmic function of Endos before NEBD results in subsequent mitotic defects. Evidence suggests that this spatiotemporal regulation is conserved in humans.

20.
Inorg Chem ; 2021 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-33840189

RESUMEN

Incorporating radical ligands into metal complexes is one of the emerging trends in the design of single-molecule magnets (SMMs). While significant effort has been expended to generate multinuclear transition metal-based SMMs with bridging radical ligands, less attention has been paid to mononuclear transition metal-radical SMMs. Herein, we describe the first α-diiminato radical-containing mononuclear transition metal SMM, namely, [κ2-PhTttBu]Fe(AdNCHCHNAd) (1), and its analogue [κ2-PhTttBu]Fe(CyNCHCHNCy) (2) (PhTttBu = phenyltris(tert-butylthiomethyl)borate, Ad = adamantyl, and Cy = cyclohexyl). 1 and 2 feature nearly identical geometric and electronic structures, as shown by X-ray crystallography and electronic absorption spectroscopy. A more detailed description of the electronic structure of 1 was obtained through EPR and Mössbauer spectroscopies, SQUID magnetometry, and DFT, TD-DFT, and CAS calculations. 1 and 2 are best described as high-spin iron(II) complexes with antiferromagnetically coupled α-diiminato radical ligands. A strong magnetic exchange coupling between the iron(II) ion and the ligand radical was confirmed in 1, with an estimated coupling constant J < -250 cm-1 (J = -657 cm-1, DFT). Calibrated CAS calculations revealed that the ground-state Fe(II)-α-diiminato radical configuration has significant ionic contributions, which are weighted specifically toward the Fe(I)-neutral α-diimine species. Experimental data and theoretical calculations also suggest that 1 possesses an easy-axis anisotropy, with an axial zero-field splitting parameter D in the range from -4 to-1 cm-1. Finally, dynamic magnetic studies show that 1 exhibits slow magnetic relaxation behavior with an energy barrier close to the theoretical maximum, 2|D|. These results demonstrate that incorporating strongly coupled α-diiminato radicals into mononuclear transition metal complexes can be an effective strategy to prepare SMMs.

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