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1.
Stat Methods Med Res ; : 9622802211007522, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33881369

RESUMO

Risk-prediction models for health outcomes are used in practice as part of clinical decision-making, and it is essential that their performance be externally validated. An important aspect in the design of a validation study is choosing an adequate sample size. In this paper, we investigate the sample size requirements for validation studies with binary outcomes to estimate measures of predictive performance (C-statistic for discrimination and calibration slope and calibration in the large). We aim for sufficient precision in the estimated measures. In addition, we investigate the sample size to achieve sufficient power to detect a difference from a target value. Under normality assumptions on the distribution of the linear predictor, we obtain simple estimators for sample size calculations based on the measures above. Simulation studies show that the estimators perform well for common values of the C-statistic and outcome prevalence when the linear predictor is marginally Normal. Their performance deteriorates only slightly when the normality assumptions are violated. We also propose estimators which do not require normality assumptions but require specification of the marginal distribution of the linear predictor and require the use of numerical integration. These estimators were also seen to perform very well under marginal normality. Our sample size equations require a specified standard error (SE) and the anticipated C-statistic and outcome prevalence. The sample size requirement varies according to the prognostic strength of the model, outcome prevalence, choice of the performance measure and study objective. For example, to achieve an SE < 0.025 for the C-statistic, 60-170 events are required if the true C-statistic and outcome prevalence are between 0.64-0.85 and 0.05-0.3, respectively. For the calibration slope and calibration in the large, achieving SE < 0.15 would require 40-280 and 50-100 events, respectively. Our estimators may also be used for survival outcomes when the proportion of censored observations is high.

2.
J Chromatogr A ; 1646: 462100, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33892256

RESUMO

The Kováts retention index is a dimensionless quantity that characterizes the rate at which a compound is processed through a gas chromatography column. This quantity is independent of many experimental variables and, as such, is considered a near-universal descriptor of retention time on a chromatography column. The Kováts retention indices of a large number of molecules have been determined experimentally. The "NIST 20: GC Method/Retention Index Library" database has collected and, more importantly, curated retention indices of a subset of these compounds resulting in a highly valued reference database. The experimental data in the library form an ideal data set for training machine learning models for the prediction of retention indices of unknown compounds. In this article, we describe the training of a graph neural network model to predict the Kováts retention index for compounds in the NIST library and compare this approach with previous work [1]. We predict the Kováts retention index with a mean unsigned error of 28 index units as compared to 44, the putative best result using a convolutional neural network [1]. The NIST library also incorporates an estimation scheme based on a group contribution approach that achieves a mean unsigned error of 114 compared to the experimental data. Our method uses the same input data source as the group contribution approach, making its application straightforward and convenient to apply to existing libraries. Our results convincingly demonstrate the predictive powers of systematic, data-driven approaches leveraging deep learning methodologies applied to chemical data and for the data in the NIST 20 library outperform previous models.

3.
Neuropharmacology ; 190: 108561, 2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33852823

RESUMO

Arginine vasopressin (AVP), a neuropeptide with widespread receptors in brain regions important for socioemotional processing, is critical in regulating various mammalian social behavior and emotion. Although a growing body of task-based brain imaging studies have revealed the effects of AVP on brain activity associated with emotion processing, social cognition and behaviors, the potential modulations of AVP on resting-state brain activity remain largely unknown. Here, the current study addressed this issue by adopting a machine learning approach to distinguish administration of AVP and placebo, employing the amplitude of low-frequency fluctuation (ALFF) as a measure of resting-state brain activity. The brain regions contributing to the classification were then subjected to functional connectivity and decoding analyses, allowing for a data-driven quantitative inference on psychophysiological functions. Our results indicated that ALFF across multiple neural systems were sufficient to distinguish between AVP and placebo at individual level, with the contributing regions distributed across the social cognition network, sensorimotor regions and emotional processing network. These findings suggest that the role of AVP in socioemotional functioning recruits multiple brain networks distributed across the whole brain rather than specific localized neural pathways. Beyond these findings, the current data-driven approach also opens a novel avenue to delineate neural underpinnings of various neuropeptides or hormones.

4.
Eur J Prev Cardiol ; 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33772274

RESUMO

AIMS: The 12-lead electrocardiogram (ECG) is routinely performed in children with hypertrophic cardiomyopathy (HCM). An ECG risk score has been suggested as a useful tool for risk stratification, but this has not been independently validated. This aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events. METHODS AND RESULTS: Data from 356 childhood HCM patients with a mean age of 10.1 years (±4.5) were collected from a retrospective, multi-centre international cohort. Three hundred and forty-seven (97.5%) patients had ECG abnormalities at baseline, most commonly repolarization abnormalities (n = 277, 77.8%); left ventricular hypertrophy (n = 240, 67.7%); abnormal QRS axis (n = 126, 35.4%); or QT prolongation (n = 131, 36.8%). Over a median follow-up of 3.9 years (interquartile range 2.0-7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93-2.04). No ECG variables were associated with 5-year arrhythmic event on univariable or multivariable analysis. The ECG risk score threshold of >5 had modest discriminatory ability [C-index 0.60 (95% CI 0.484-0.715)], with corresponding negative and positive predictive values of 96.7% and 6.7. CONCLUSION: In a large, international, multi-centre cohort of childhood HCM, ECG abnormalities were common and varied. No ECG characteristic, either in isolation or combined in the previously described ECG risk score, was associated with 5-year sudden cardiac death risk. This suggests that the role of baseline ECG phenotype in improving risk stratification in childhood HCM is limited.

5.
PLoS One ; 16(3): e0248699, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33730033

RESUMO

Terror Management Theory (TMT) suggests that death-related thoughts activate proximal defense which allows people to suppress or rationalize death awareness. So far there is no direct evidence to support the emotional response in the proximal defense process. The current research aimed to address this issue by examining behavioral (e.g., accuracy and reaction time) and neural responses (e.g., P1 and N400 amplitude) related to emotional arousal following death-related thoughts during proximal defense. Before engaged in emotional words (e.g., anxiety, fear and neutral) judgment task, participants answered questions that referred to emotional and physical changes about death to induce mortality salience (MS). In the control condition, participants received similar instructions concerning the experience of watching TV. Behavioral results showed that longer reaction time of words was seen in control group than MS group. The ERPs results showed that after reminders of death-related thoughts, in condition of MS, fear words elicited larger P1 ERP amplitudes, while the control group did not have this effect, which might reflect that emotional words caused different early attention patterns between MS group and control group. Moreover, compared with control group, larger N400 ERP amplitudes were elicited in condition of MS, suggesting larger cognitive inhibition of words processing caused by emotional reaction. The above results indicate that the early stages after mortality salience will induce fear and anxiety, but soon these negative emotions are suppressed and are at a lower level of accessibility. This result provides electrophysiological evidence for the proximal defense hypothesis of terror management theory.

6.
Elife ; 102021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33759762

RESUMO

Corruption often involves bribery, when a briber suborns a power-holder to gain advantages usually at a cost of moral transgression. Despite its wide presence in human societies, the neurocomputational basis of bribery remains elusive. Here, using model-based fMRI, we investigated the neural substrates of how a power-holder decides to accept or reject a bribe. Power-holders considered two types of moral cost brought by taking bribes: the cost of conniving with a fraudulent briber, encoded in the anterior insula, and the harm brought to a third party, represented in the right temporoparietal junction. These moral costs were integrated into a value signal in the ventromedial prefrontal cortex. The dorsolateral prefrontal cortex was selectively engaged to guide anti-corrupt behaviors when a third party would be harmed. Multivariate and connectivity analyses further explored how these neural processes depend on individual differences. These findings advance our understanding of the neurocomputational mechanisms underlying corrupt behaviors.

7.
Neuroscience ; 459: 39-49, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33540051

RESUMO

Hierarchy is a pervasive feature of social organization. The ability to rapidly discriminate hierarchical information is critical for social interaction. Here, we took advantage of a special technique in electroencephalography (EEG) known as fast periodic visual stimulation (FPVS). We used this technique, which captures the automatic perception of faces, to explore the neural signature of social dominance discrimination. A stream of computer-generated faces was presented at 6 Hz, i.e. six faces/second. In the experimental condition, faces alternated from high to low social dominance within a sequence, bringing about a frequency of interest of 3 Hz (6 Hz/2), i.e. three high/low dominance faces appeared in one second. In two control conditions, we presented faces which came exclusively from one of two hierarchical ranks (either lower or higher). Participants were asked to respond to information unrelated to this hierarchical information, namely pressing the spacebar when the fixation changes color. Results revealed a significant 3 Hz response for the experimental condition only. This response was located bilaterally in the occipito-temporal region, indicating discrimination of differences in social dominance. Through the use of FPVS, we provide electrophysiological evidence to show that social hierarchical information can be detected automatically.

8.
J Chem Phys ; 154(5): 051102, 2021 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-33557535

RESUMO

"Δ-machine learning" refers to a machine learning approach to bring a property such as a potential energy surface (PES) based on low-level (LL) density functional theory (DFT) energies and gradients close to a coupled cluster (CC) level of accuracy. Here, we present such an approach that uses the permutationally invariant polynomial (PIP) method to fit high-dimensional PESs. The approach is represented by a simple equation, in obvious notation VLL→CC = VLL + ΔVCC-LL, and demonstrated for CH4, H3O+, and trans and cis-N-methyl acetamide (NMA), CH3CONHCH3. For these molecules, the LL PES, VLL, is a PIP fit to DFT/B3LYP/6-31+G(d) energies and gradients and ΔVCC-LL is a precise PIP fit obtained using a low-order PIP basis set and based on a relatively small number of CCSD(T) energies. For CH4, these are new calculations adopting an aug-cc-pVDZ basis, for H3O+, previous CCSD(T)-F12/aug-cc-pVQZ energies are used, while for NMA, new CCSD(T)-F12/aug-cc-pVDZ calculations are performed. With as few as 200 CCSD(T) energies, the new PESs are in excellent agreement with benchmark CCSD(T) results for the small molecules, and for 12-atom NMA, training is done with 4696 CCSD(T) energies.

9.
Hepatology ; 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33609283

RESUMO

Myofibroblasts play a pivotal role in the development and progression of hepatocellular carcinoma (HCC). Here, we aimed to explore the role and mechanism of myofibroblast Musashi RNA binding protein 2 (MSI2) in HCC progression. Myofibroblast infiltration and collagen deposition were detected and assessed in the tissues from 117 HCC patients. Transgenic mice (Msi2ΔCol1a1 ) with floxed Msi2 allele and Col1a1-CreER were constructed to generate a myofibroblast-specific Msi2 knockout model. Mouse HCC cells were orthotopically transplanted into the Msi2ΔCol1a1 or the control mice (Msi2F/F ). We found that the deposition of collagen fibers, the main product of myofibroblasts, predicted a poor prognosis for HCC; meanwhile, we detected high MSI2 expression in the peritumoral infiltrated myofibroblasts. Conditional deletion of Msi2 in myofibroblasts significantly inhibited the growth of orthotopically implanted HCC, reduced both intrahepatic and lung metastasis, and prolonged the overall survival of tumor-bearing mice (P = 0.002). In vitro analysis demonstrated that myofibroblasts promoted cell proliferation, invasion, and epithelial-mesenchymal transformation of HCC cells, whereas Msi2 deletion in myofibroblasts reversed these effects. Mechanically, Msi2 knockout decreased myofibroblast-derived IL6 and IL11 secretion by inhibiting the ERK1/2 pathway, and thus attenuated the cancer stem cell promoting effect of myofibroblasts. Interestingly, we found that the simultaneous knockout of Msi2 in myofibroblasts and knockdown of Msi2 in HCC cells could not further attenuate the implanted HCC progression. CONCLUSION: Myofibroblast-specific Msi2 knockout abrogated the tumor-promoting function of myofibroblasts and inhibited HCC progression in mouse models. Targeting myofibroblast MSI2 expression may thus prove to be a therapeutic strategy for HCC treatment in the future.

10.
J Cell Mol Med ; 25(3): 1568-1582, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33410581

RESUMO

The pro-inflammatory and pro-fibrotic liver microenvironment facilitates hepatocarcinogenesis. However, the effects and mechanisms by which the hepatic fibroinflammatory microenvironment modulates intrahepatic hepatocellular carcinoma (HCC) progression and its response to systematic therapy remain largely unexplored. We established a syngeneic orthotopic HCC mouse model with a series of persistent liver injury induced by CCl4 gavage, which mimic the dynamic effect of hepatic pathology microenvironment on intrahepatic HCC growth and metastasis. Non-invasive bioluminescence imaging was applied to follow tumour progression over time. The effect of the liver microenvironment modulated by hepatic injury on sorafenib resistance was investigated in vivo and in vitro. We found that the persistent liver injury facilitated HCC growth and metastasis, which was positively correlated with the degree of liver inflammation rather than the extent of liver fibrosis. The inflammatory cytokines in liver tissue were clearly increased after liver injury. The two indicated cytokines, tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), both promoted intrahepatic HCC progression via STAT3 activation. In addition, the hepatic inflammatory microenvironment contributed to sorafenib resistance through the anti-apoptotic protein mediated by STAT3, and STAT3 inhibitor S3I-201 significantly improved sorafenib efficacy impaired by liver inflammation. Clinically, the increased inflammation of liver tissues was accompanied with the up-regulated STAT3 activation in HCC. Above all, we concluded that the hepatic inflammatory microenvironment promotes intrahepatic HCC growth, metastasis and sorafenib resistance through activation of STAT3.

11.
Gerontology ; : 1-10, 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33271531

RESUMO

INTRODUCTION: Cardiac aging is the major risk factor for advanced heart disease, which is the leading cause of death in developed countries, accounting for >30% of deaths worldwide. OBJECTIVE: To discover the detailed mechanism of cardiac aging and develop an effective therapeutic candidate drug to treat or delay cardiac aging. METHODS: We used D-galactose to induce cardiac aging in Nrf2+/+ and Nrf2-/- mice, and then treated these mice with vehicle or the Nrf2 activator, CDDO-imidazolide (CDDO-Im). RESULTS AND CONCLUSIONS: D-galactose injection significantly induced cardiac aging, cell apoptosis, and oxidative stress in Nrf2+/+ mice, all of which were further exacerbated in Nrf2-/- mice. CDDO-Im treatment can effectively weaken oxidative stress and enhance the activities of antioxidant enzymes, but CDDO-Im lost its antioxidative effect in the Nrf2-/- mice. Nrf2 activator CDDO-Im could therefore effectively protect against D-galactose-induced cardiac aging by inhibiting oxidative stress, suggesting that CDDO-Im might be a potential and promising therapeutic candidate drug to treat cardiac aging.

12.
J Chem Phys ; 153(24): 244301, 2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33380113

RESUMO

A full-dimensional, permutationally invariant potential energy surface (PES) for the glycine amino acid is reported. A precise fit to energies and gradients calculated at the density functional theory (DFT)/B3LYP level of electronic-structure theory with Dunning's aug-cc-pVDZ basis set is performed involving 20 000 low-energy points and associated Cartesian gradients plus about 50 000 additional higher-energy points. The fact that newly calculated DFT/B3LYP energies for the main stationary points are close to the coupled-cluster single-double-triple [CCSD(T)] values, recently reported in the literature, provides reassurance about the accuracy of the constructed PES. Eight conformers and numerous saddle points are identified and characterized by describing geometries, relative stability, and harmonic frequencies. Stochastic and dynamical approaches are employed to study the vibrational ground state. Specifically, diffusion Monte Carlo simulations and approximate quantum dynamics, performed by means of the adiabatic switching semiclassical initial value representation technique, provide zero-point energies in excellent agreement with each other. The PES we report is sufficiently complete to permit spectroscopic and dynamical studies on glycine, which may be of interest to the biochemical and astrochemistry communities.

13.
Science ; 370(6520): 1072-1077, 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33243885

RESUMO

Since the discovery of roaming as an alternative molecular dissociation pathway in formaldehyde (H2CO), it has been indirectly observed in numerous molecules. The phenomenon describes a frustrated dissociation with fragments roaming at relatively large interatomic distances rather than following conventional transition-state dissociation; incipient radicals from the parent molecule self-react to form molecular products. Roaming has been identified spectroscopically through static product channel-resolved measurements, but not in real-time observations of the roaming fragment itself. Using time-resolved Coulomb explosion imaging (CEI), we directly imaged individual "roamers" on ultrafast time scales in the prototypical formaldehyde dissociation reaction. Using high-level first-principles simulations of all critical experimental steps, distinctive roaming signatures were identified. These were rendered observable by extracting rare stochastic events out of an overwhelming background using the highly sensitive CEI method.

14.
Cell Death Dis ; 11(10): 830, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024090

RESUMO

Elongation factor Tu GTP binding domain containing 2 (EFTUD2), a spliceosomal GTPase, plays a pivotal role in multiple organ development and innate immune. It has been reported that EFTUD2 is a new host factor with activity against HCV infection. However, the role of EFTUD2 in solid tumors, including hepatocellular carcinoma (HCC), remains unexplored. In this study, we investigated the molecular function of EFTUD2 in HCC. Data from The Cancer Genome Atlas (TCGA) indicated an upregulation of EFTUD2 in HCC tissues compared to that in nontumor liver tissues. Immunohistochemical analysis performed on two independent HCC cohorts confirmed the upregulation of EFTUD2 in HCC tissues and further suggested that a high level of EFTUD2 expression predicted shorter overall and recurrence-free survival in HCC patients. Functional studies suggested that siRNA interference with EFTUD2 expression significantly suppressed cell viability, blocked cell cycle progression, facilitated tumor cell apoptosis, and inhibited metastasis, while the enhancement of EFTUD2 expression promoted the proliferation and migration of HCC cells both in vitro and in vivo. Surprisingly, we also found that the stable knockdown of EFTUD2 expression via lentivirus infection was lethal for HCC cells. This finding suggested that EFTUD2 was essential for maintaining the survival of HCC cells. Mechanistically, RNA sequencing and gene set enrichment analysis (GSEA) suggested that the gene sets of epithelial-mesenchymal transition (EMT) and the JAK/STAT3 pathway were enriched in EFTUD2-overexpressing cells. Further verification indicated that EFTUD2-overexpressing cells exhibited an EMT-like phenotype and had enhanced STAT3 activation, while the STAT3 inhibitor S3I-201 partially blocked these pro-malignant effects of EFTUD2 overexpression. In summary, we report EFTUD2 as a novel oncogene that helps to maintain the survival of HCC cells and promotes HCC progression through the activation of STAT3. The high level of expression of EFTUD2 in HCC tissues indicates shorter overall and recurrence-free survival in HCC patients.

15.
Phys Chem Chem Phys ; 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32969434

RESUMO

We present a full-dimensional potential energy surface for acetylacetone (AcAc) using full and fragmented permutationally invariant polynomial approaches. Previously reported MP2/aVTZ energies and gradients are augmented by additional calculations at this level of theory for the fits. Numerous stationary points are reported as are the usual metrics to assess the precision of the fit. The electronic barrier height for the H-atom transfer is roughly 2.2 kcal mol-1. Diffusion Monte Carlo (DMC) calculations are used to calculate the ground state wavefunction and zero-point energy of acetylacetone. These together with fixed-node DMC calculations for the first excited-state provide the predicted tunneling splitting due to the barrier to H-transfer separating two equivalent wells. Simpler 1d calculations of this splitting are also reported for varying barrier heights including the CCSD(T) barrier height of 3.2 kcal mol-1. Based on those results the DMC splitting of 160 cm-1 with a statistical uncertainty of roughly 21 cm-1, calculated using the MP2-based PES, is estimated to decrease to 100 cm-1 for a barrier of 3.2 kcal mol-1. The fragmented surface is shown to be fast to evaluate.

16.
Pulm Pharmacol Ther ; 63: 101935, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32783991

RESUMO

BACKGROUD: Magnesium lithospermate B (MLB) is a major bioactive component of Slavia miltiorrhiza, which has been widely used in heart diseases on account of its anti-inflammatory, anti-oxidative, anti-proliferative and anti-fibrotic properties. Substance P(SP) is a small molecule neuropeptide, which was secreted much more during heart failure, and has an obvious function of immune enhancement and inflammation induction. This study aimed to investigate the protective effects of MLB on pulmonary artery banding (PAB) induced right ventricular (RV) dysfunction. METHODS: The mouse model of PAB was established. The mice were intraperitoneal (IP) injection treated with MLB (10 mg kg-1·d-1) for 4 weeks and p38 mitogen-activated protein kinase (MAPK) activator was given at the same time. Echocardiography were performed on day 28. Then the hearts were harvested, and substance P (SP), inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and cardiac fibrosis were detected. The macrophages and fibroblasts were stimulated by SP separately, and then treated with MLB as well as p38MAPK activator. The inflammatory cytokines from macrophage, the proliferation and fibrosis of cardiac fibroblasts were measured. The expression of p38MAPK proteins were confirmed by immunoblotting. FINDINGS: MLB preserved RV ejection fraction (EF), FS, RV/(LV + septum), HW/BW index and blunted RV inflammation as well as fibrosis. Phosphorylated-p38 (p-p38) MAPK was up-regulated, which was partially reversed by MLB treatment. However, p38MAPK activator abolished the effects of MLB on RV dysfunction, suggesting a key role of p38MPAK pathway in the effects of MLB reversing RV dysfunction. In external experiment, MLB reversed the increase of inflammatory cytokines from macrophage, the proliferation and fibrosis of cardiac fibroblasts which was simulated by SP. In accordance with in vivo study, p38MAPK activator abolished the effects of MLB on macrophage as well as fibroblasts. INTERPRETATION: MLB improves PAB induced right ventricular remodeling by alleviating inflammation via p38MAPK pathway. Thus, MLB may offer the therapeutic potential for the patients of RV dysfunction.

17.
Am J Pathol ; 190(11): 2267-2281, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32805235

RESUMO

Liver fibrosis is an increasing health problem worldwide, for which no effective antifibrosis drugs are available. Although the involvement of aerobic glycolysis in hepatic stellate cell (HSC) activation has been reported, the role of pyruvate kinase M2 (PKM2) in liver fibrogenesis still remains unknown. We examined PKM2 expression and location in liver tissues and primary hepatic cells. The in vitro and in vivo effects of a PKM2 antagonist (shikonin) and its allosteric agent (TEPP-46) on liver fibrosis were investigated in HSCs and liver fibrosis mouse model. Chromatin immunoprecipitation sequencing and immunoprecipitation were performed to identify the relevant molecular mechanisms. PKM2 expression was significantly up-regulated in both mouse and human fibrotic livers compared with normal livers, and mainly detected in activated, rather than quiescent, HSCs. PKM2 knockdown markedly inhibited the activation and proliferation of HSCs in vitro. Interestingly, the PKM2 dimer, rather than the tetramer, induced HSC activation. PKM2 tetramerization induced by TEPP-46 effectively inhibited HSC activation, reduced aerobic glycolysis, and decreased MYC and CCND1 expression via regulating histone H3K9 acetylation in activated HSCs. TEPP-46 and shikonin dramatically attenuated liver fibrosis in vivo. Our findings demonstrate a nonmetabolic role of PKM2 in liver fibrosis. PKM2 tetramerization or suppression could prevent HSC activation and protects against liver fibrosis.


Assuntos
Células Estreladas do Fígado/enzimologia , Cirrose Hepática/enzimologia , Multimerização Proteica , Piruvato Quinase/metabolismo , Acetilação , Animais , Ciclina D1/metabolismo , Feminino , Células Estreladas do Fígado/patologia , Histonas/metabolismo , Humanos , Cirrose Hepática/patologia , Masculino , Camundongos , Compostos Orgânicos/farmacologia , Proteínas Proto-Oncogênicas c-myc/metabolismo
18.
J Agric Food Chem ; 68(37): 9896-9905, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32809820

RESUMO

A 6.2 m high immature bamboo (Phyllostachys nigra) was divided into seven fractions. The bamboo cell walls and lignin samples from young to old were characterized by 1H-13C correlation heteronuclear single-quantum coherence (HSQC) nuclear magnetic resonance (NMR) spectroscopy both qualitatively and semiquantitatively. Mature bamboo and bamboo shoot samples were used as comparison references. HSQC-NMR analysis proved that cellulose and arabinoxylan have already deposited in bamboo shoot, and cellulose amount increased during growth. Lignin side chain linkage formation started from ß-ether (ß-O-4), then phenylcoumaran (ß-5), and finally resinol (ß-ß). Ferulic acid and p-coumaric acid (pCA) were formed at the earlier stages in the immature bamboo, and the pCA proportion decreased throughout the lignification process. We propose that the bamboo lignification process is distinct from both woody and other herbaceous plants, where syringyl units deposited at the early stage and polymerized with the ß-O-4 linkage. Then guaiacyl units formed gradually, and finally, p-hydroxyphenyl units formed.

19.
Neuroreport ; 31(14): 1015-1023, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-32858649

RESUMO

Neural stem cells (NSCs) are self-renewing, multipotent cells, and remain in our brains throughout life. They could be activated by brain damage and involved in the central nervous system (CNS) repair and motor functional recovery. Previous research demonstrated that miR-221 could regulate proliferation, differentiation, and survival. However, the effect of miR-221 on NSCs remains unknown. In this study, we showed that overexpression of miR-221 inhibited the expression of phosphatase and tensin homolog (PTEN) protein and increased the phosphorylation level of protein kinase B (AKT). More importantly, an AKT-specific inhibitor abolished the effect of miR-221 on the phosphorylation level of AKT. 5-Bromo-2-deoxyUridine (BrdU) incorporation assay and Cyclin D1 expression showed that miR-221 overexpression further promoted the NSCs proliferation. However, knocking down miR-221 inhibited cell proliferation. The AKT-specific inhibitor also blocked the proliferative efficiency of miR-221. These results demonstrated that miR-221 overexpression promoted the proliferation of cultured rat NSCs, for which the PTEN/AKT pathway activation was one possible mechanism. Our research may provide a novel investigating strategy to improve stem cell treatment for CNS diseases.

20.
Exp Mol Med ; 52(7): 1062-1074, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32632241

RESUMO

Dexmedetomidine (DEX) is an anesthetic that is widely used in the clinic, and it has been reported to exhibit paradoxical effects in the progression of multiple solid tumors. In this study, we sought to explore the mechanism by which DEX regulates hepatocellular carcinoma (HCC) progression underlying liver fibrosis. We determined the effects of DEX on tumor progression in an orthotopic HCC mouse model of fibrotic liver. A coculture system and a subcutaneous xenograft model involving coimplantation of mouse hepatoma cells (H22) and primary activated hepatic stellate cells (aHSCs) were used to study the effects of DEX on HCC progression. We found that in the preclinical mouse model of liver fibrosis, DEX treatment significantly shortened median survival time and promoted tumor growth, intrahepatic metastasis and pulmonary metastasis. The DEX receptor (ADRA2A) was mainly expressed in aHSCs but was barely detected in HCC cells. DEX dramatically reinforced HCC malignant behaviors in the presence of aHSCs in both the coculture system and the coimplantation mouse model, but DEX alone exerted no significant effects on the malignancy of HCC. Mechanistically, DEX induced IL-6 secretion from aHSCs and promoted HCC progression via STAT3 activation. Our findings provide evidence that the clinical application of DEX may cause undesirable side effects in HCC patients with liver fibrosis.

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