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1.
Mol Cell ; 81(7): 1370-1371, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33798414

RESUMO

Using a forward-genetic screening of macrophages from randomly mutagenized mice, Kayagaki et al. (2021) identify NINJ1 that mediates plasma membrane rupture following various types of programmed cell death, an event previously thought to be passive.


Assuntos
Moléculas de Adesão Celular Neuronais , Fatores de Crescimento Neural , Animais , Membrana Celular , Células Endoteliais , Macrófagos , Camundongos
2.
Endocrine ; 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33818715

RESUMO

PURPOSE: Obese individuals have an increased risk of hypothyroidism. This study investigated the sex-specific association between obesity phenotypes and the development of hypothyroidism. METHODS: The study population was derived from a health management cohort in Shandong Provincial Hospital from 2012 to 2016. In total, 9011 baseline euthyroid adults were included and classified into four groups according to obesity phenotype: metabolically healthy nonobese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy nonobese (MUNO), and metabolically unhealthy obese (MUO). The median follow-up time was 1.92 (1.00-2.17) years. Incidence density was evaluated and a generalized estimation equation method was used to investigate the associations between obesity phenotypes and the development of hypothyroidism. RESULTS: The incidence densities of hypothyroidism in males with a consistent obesity phenotype were 12.19 (8.62-16.76), 15.87 (11.39-21.56), 14.52 (6.74-27.57), and 19.88 (14.06-27.34) per 1000 person-years in the MHNO, MHO, MUNO, and MUO groups, respectively. After adjusting for confounding factors, compared with the MHNO phenotype, the MHO, MUNO, and MUO phenotypes were independent risk factors for developing hypothyroidism in males. In the subgroup analysis, the MHO and MUO phenotypes were independent risk factors for developing hypothyroidism in males under 55 years, while the MUNO phenotype was an independent risk factor in males over 55 years. The MHO, MUNO, and MUO phenotypes were not independent risk factors for hypothyroidism in females. CONCLUSION: Both obesity and metabolic abnormities are associated with a higher risk of hypothyroidism in males. The underlying mechanism of the sex and age differences in this association needs further investigation.

3.
Front Endocrinol (Lausanne) ; 12: 578909, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33737906

RESUMO

Purpose: Previous studies have suggested that cholesterol may influence thyroid function. Since statins are widely used for their cholesterol-lowering effect, we aimed to assess the association between statin use and thyroid function, and also to explore the role of the cholesterol-lowering effect in it. Methods: We performed a retrospective cohort study derived from REACTION study. Eligible subjects receiving statin therapy were included in the statin group, and sex-, age-, total cholesterol (TC)-, and thyroid function-matched participants without lipid-lowering therapy were included in the control group. The median follow-up time was three years. Outcomes of thyroid function were evaluated at the end of follow-up. We used multivariable regression models to assess the association between statin use and outcomes of thyroid function, and also performed mediation analyses to explore the role of cholesterol in it. Results: A total of 5,146 participants were screened, and 201 eligible subjects in the statin group and 201 well-matched subjects in the control group were analyzed. At the end of follow-up, TC and thyroid-stimulating hormone (TSH) levels in the statin group were lower than those in the control group (both p < 0.05), and the percentage of euthyroid subjects was higher in the statin group (88.06% vs. 76.12%, p = 0.002). The incidence rate of subclinical hypothyroidism (SCH) in euthyroid subjects was lower in the statin group (6.29% vs. 14.86%, p = 0.009), and the remission rate among subjects with SCH was higher in the statin group (50.00% vs. 15.38%, p = 0.008). In multivariable regression analyses, statin use was independently associated with lower TSH levels and higher odds to be euthyroid (OR 2.335, p = 0.004) at the end of follow-up. Mediation analyses showed the association between statin use and TSH levels were mediated by TC changes during follow-up. Conclusion: Statin use was associated with benefits of thyroid function, and TC changes serve as a mediator of the association between statin use and TSH levels. Further studies are needed to clarify the possible underlying mechanism.

4.
BMC Res Notes ; 14(1): 104, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741075

RESUMO

OBJECTIVE: To address the challenge of computational identification of cell type-specific regulatory elements on a genome-wide scale. RESULTS: We propose SeqEnhDL, a deep learning framework for classifying cell type-specific enhancers based on sequence features. DNA sequences of "strong enhancer" chromatin states in nine cell types from the ENCODE project were retrieved to build and test enhancer classifiers. For any DNA sequence, positional k-mer (k = 5, 7, 9 and 11) fold changes relative to randomly selected non-coding sequences across each nucleotide position were used as features for deep learning models. Three deep learning models were implemented, including multi-layer perceptron (MLP), Convolutional Neural Network (CNN) and Recurrent Neural Network (RNN). All models in SeqEnhDL outperform state-of-the-art enhancer classifiers (including gkm-SVM and DanQ) in distinguishing cell type-specific enhancers from randomly selected non-coding sequences. Moreover, SeqEnhDL can directly discriminate enhancers from different cell types, which has not been achieved by other enhancer classifiers. Our analysis suggests that both enhancers and their tissue-specificity can be accurately identified based on their sequence features. SeqEnhDL is publicly available at https://github.com/wyp1125/SeqEnhDL .

5.
Plant Sci ; 305: 110831, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33691965

RESUMO

Cereal crops accumulate large amounts of starch which is synthesized and stored in amyloplasts in the form of starch grains (SGs). Despite significant progress in deciphering starch biosynthesis, our understanding of amyloplast development in rice (Oryza sativa) endosperm remains largely unknown. Here, we report a novel rice floury mutant named enlarged starch grain1 (esg1). The mutant has decreased starch content, altered starch physicochemical properties, slower grain-filling rate and reduced 1000-grain weight. A distinctive feature in esg1 endosperm is that SGs are much larger, mainly due to an increased number of starch granules per SG. Spherical and loosely assembled granules, together with those weakly stained SGs may account for decreased starch content in esg1. Map-based cloning revealed that ESG1 encodes a putative permease subunit of a bacterial-type ABC (ATP-binding cassette) lipid transporter. ESG1 is constitutively expressed in various tissues. It encodes a protein localized to the chloroplast and amyloplast membranes. Mutation of ESG1 causes defective galactolipid synthesis. The overall study indicates that ESG1 is a newly identified protein affecting SG development and subsequent starch biosynthesis, which provides novel insights into amyloplast development in rice.

6.
FEBS Open Bio ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33728819

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. SAMM50 encodes Sam50, a mitochondrial outer membrane protein involved in the removal of reactive oxygen species, mitochondrial morphology, and regulation of mitophagy. Certain single nucleotide polymorphisms (SNPs) of SAMM50 have been reported to be correlated with NAFLD. However, the contribution of SAMM50 polymorphisms to the occurrence and severity of fatty liver in the Chinese Han cohort has rarely been reported. Here, we investigated the association between SAMM50 polymorphisms (rs738491 and rs2073082) and NAFLD in a Chinese Han cohort, as well as the mechanistic basis of this association. Clinical information and blood samples were collected from 380 NAFLD cases and 380 normal subjects for the detection of genotypes and biochemical parameters. Carriers of the rs738491 T-allele or rs2073082 G-allele of SAMM50 exhibit increased susceptibility to NAFLD (OR=1.39; 95% CI=1.14-1.71, P=0.001; OR=1.31; 95% CI=1.05-1.62, P=0.016, respectively) and are correlated with elevated serum TG, ALT, and AST levels. The presence of the T allele (TT+CT) of rs738491 (P<0.01) or G allele (AG+GG) of rs2073082 (P=0.03) is correlated with the severity of fatty liver in the NAFLD cohort. In vitro studies indicated that SAMM50 gene polymorphisms decrease its expression and SAMM50 deficiency results in increased lipid accumulation due to a decrease in fatty acid oxidation. Overexpression of SAMM50 enhances fatty acid oxidation and mitigates intracellular lipid accumulation. Our results confirm the association between the SAMM50 rs738491 and rs2073082 polymorphisms and the risk of fatty liver in a Chinese cohort. The underlying mechanism may be related to decreased fatty acid oxidation caused by SAMM50 deficiency.

7.
Mult Scler Relat Disord ; 50: 102843, 2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33609924

RESUMO

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) is an autoimmune astrocyte disease that mainly affects the optic nerve and spinal cord resulting in blindness or paralysis. Rituximab (RTX) is a chimeric monoclonal antibody directed against the surface antigen of CD20 on B lymphocytes and is an emerging treatment option in NMOSD. The present review aimed to conduct an update systematic review and meta-analysis for the efficacy of RTX in the treatment of NMOSD and analyze main factors affecting the efficacy of RTX. METHODS: The following Medical Subject Heading (MeSH) and related entry terms are used to search English literature in PubMed, MEDLINE and CENTRAL databases, respectively. MeSH include: Neuromyelitis optic and Rituximab; entry terms include: NMO Spectrum Disorder, NMO Spectrum Disorders, Neuromyelitis Optica (NMO) Spectrum Disorder, Neuromyelitis Optica Spectrum Disorders, Devic Neuromyelitis Optica, Neuromyelitis Optica, Devic, Devic's Disease, Devic Syndrome, Devic's Neuromyelitis Optica, Neuromyelitis Optica (NMO) Spectrum Disorders, CD20 Antibody, Rituximab CD20 Antibody, Mabthera, IDEC-C2B8 Antibody, GP2013, Rituxan; (note: literature retrieval operators "AND" "OR" "NOT" are used to link MeSH with Entry Terms.) 54 studies were included in this systematic review and 29 studies were included in meta-analysis. The main efficacy indicators were the difference of the expanded disability status scale (EDSS) and annualized relapse rate (ARR) between before and after rituximab treatments. RESULTS: In 29 studies involving 732 patients (643 women, 84 men, 5 with unknown gender), the EDSS and ARR were reduced by an average of -0.57 (95%CI, -0.69 to -0.44), -1.57 (95%CI, -1.78 to -1.35), respectively. CONCLUSION: Our systematic review and update meta-analysis provide new evidences that RTX can effectively improve disability and reduce ARR ratio.

8.
BMC Genomics ; 22(1): 53, 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33446101

RESUMO

BACKGROUND: Genome-wide change of polyadenylation (polyA) sites (also known as alternative polyadenylation, APA) is emerging as an important strategy of gene regulation in response to stress in plants. But little is known in woody perennials that are persistently dealing with multiple abiotic stresses. RESULTS: Here, we performed a genome-wide profiling of polyadenylation sites under heat and cold treatments in Populus trichocarpa. Through a comprehensive analysis of polyA tail sequences, we identified 25,919 polyA-site clusters (PACs), and revealed 3429 and 3139 genes shifted polyA sites under heat and cold stresses respectively. We found that a small proportion of genes possessed APA that affected the open reading frames; and some shifts were commonly identified. Functional analysis of genes displaying shifted polyA tails suggested that pathways related to RNA metabolism were linked to regulate the APA events under both heat and cold stresses. Interestingly, we found that the heat stress induced a significantly more antisense PACs comparing to cold and control conditions. Furthermore, we showed that a unique cis-element (AAAAAA) was predominately enriched downstream of PACs in P. trichocarpa genes; and this sequence signal was only absent in shifted PACs under the heat condition, indicating a distinct APA mechanism responsive to heat tolerance. CONCLUSIONS: This work provides a comprehensive picture of global polyadenylation patterns in response to temperatures stresses in trees. We show that the frequent change of polyA tail is a potential mechanism of gene regulation responsive to stress, which are associated with distinctive sequence signatures.

9.
Nat Immunol ; 22(2): 205-215, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33398183

RESUMO

Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8+ T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1α-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell-intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Metabolismo Energético , Ativação Linfocitária , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental/metabolismo , Mitocôndrias/metabolismo , Microambiente Tumoral , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Células HEK293 , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/imunologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Hipóxia Tumoral
10.
Cancer Med ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33232580

RESUMO

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with a high incidence and poor prognosis. Exploration of the underlying mechanisms and effective prognostic indicators is conducive to clinical management and optimization of treatment. The RNA-seq and clinical phenotype data of HCC were retrieved from The Cancer Genome Atlas (TCGA), and differential expression analysis was performed. Then, a differential lncRNA-miRNA-mRNA regulatory network was constructed, and the key genes were further identified and validated. By integrating this network with the online tool-based ceRNA network, an HCC-specific ceRNA network was obtained, and lncRNA-miRNA-mRNA regulatory axes were extracted. RNAs associated with prognosis were further obtained, and multivariate Cox regression models were established to identify the prognostic signature and nomogram. As a result, 198 DElncRNAs, 120 DEmiRNAs, and 2827 DEmRNAs were identified, and 30 key genes identified from the differential network were enriched in four cancer-related pathways. Four HCC-specific lncRNA-miRNA-mRNA regulatory axes were extracted, and SNHG11, CRNDE, MYLK-AS1, E2F3, and CHEK1 were found to be related with HCC prognosis. Multivariate Cox regression analysis identified a prognostic signature, comprised of CRNDE, MYLK-AS1, and CHEK1, for overall survival (OS) of HCC. A nomogram comprising the prognostic signature and pathological stage was established and showed some net clinical benefits. The AUC of the prognostic signature and nomogram for 1-year, 3-year, and 5-year survival was 0.777 (0.657-0.865), 0.722 (0.640-0.848), and 0.630 (0.528-0.823), and 0.751 (0.664-0.870), 0.773 (0.707-0.849), and 0.734 (0.638-0.845), respectively. These results provided clues for the study of potential biomarkers and therapeutic targets for HCC. In addition, the obtained 30 key genes and 4 regulatory axes might also help elucidate the underlying mechanism of HCC.

11.
J Mol Cell Cardiol ; 151: 3-14, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33130149

RESUMO

AIMS: The progression of myocardial infarction (MI) involves multiple metabolic disorders. Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate multiple cardiovascular functions. G protein-coupled bile acid receptor (TGR5) is one of the receptors sensing bile acids to mediate their biological functions. In this study, we aimed to elucidate the effects of bile acids-TGR5 signaling pathways in myocardial infarction (MI). METHODS AND RESULTS: Blood samples of AMI patients or control subjects were collected and plasma was used for bile acid metabolism analysis. We discovered that bile acid levels were altered and deoxycholic acid (DCA) was substantially reduced in the plasma of AMI patients. Mice underwent either the LAD ligation model of MI or sham operation. Both MI and sham mice were gavaged with 10 mg/kg/d DCA or vehicle control since 3-day before the operation. Cardiac function was assessed by ultrasound echocardiography, infarct area was evaluated by TTC staining and Masson trichrome staining. Administration of DCA improved cardiac function and reduced ischemic injury at the 7th-day post-MI. The effects of DCA were dependent on binding to its receptor TGR5. Tgr5-/- mice underwent the same MI model. Cardiac function deteriorated and infarct size was increased at the 7th-day post-MI, which were not savaged by DCA administration. Moreover, DCA inhibited interleukin (IL)-1ß expression in the infarcted hearts, and ameliorated IL-1ß activation at 1-day post-MI. DCA inhibited NF-κB signaling and further IL-1ß expression in cultured neonatal mouse cardiomyocytes under hypoxia as well as cardio-fibroblasts with the treatment of LPS. CONCLUSIONS: DCA-TGR5 signaling pathway activation decreases inflammation and ameliorates heart function post-infarction. Strategies that control bile acid metabolism and TGR5 signaling to ameliorate the inflammatory responses may provide beneficial effects in patients with myocardial infarction.

12.
Sensors (Basel) ; 20(19)2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33036470

RESUMO

Thanks to their high magnetoresistance and integration capability, magnetic tunnel junction-based magnetoresistive sensors are widely utilized to detect weak, low-frequency magnetic fields in a variety of applications. The low detectivity of MTJs is necessary to obtain a high signal-to-noise ratio when detecting small variations in magnetic fields. We fabricated serial MTJ-based sensors with various junction area and free-layer electrode aspect ratios. Our investigation showed that their sensitivity and noise power are affected by the MTJ geometry due to the variation in the magnetic shape anisotropy. Their MR curves demonstrated a decrease in sensitivity with an increase in the aspect ratio of the free-layer electrode, and their noise properties showed that MTJs with larger junction areas exhibit lower noise spectral density in the low-frequency region. All of the sensors were able detect a small AC magnetic field (Hrms = 0.3 Oe at 23 Hz). Among the MTJ sensors we examined, the sensor with a square-free layer and large junction area exhibited a high signal-to-noise ratio (4792 ± 646). These results suggest that MTJ geometrical characteristics play a critical role in enhancing the detectivity of MTJ-based sensors.

13.
Reproduction ; 160(6): 931-941, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33112771

RESUMO

Asthenozoospermia (AS), defined as low-motility spermatozoa in the ejaculate, is a frequent cause of human male infertility. DJ-1 (also known as PARK7), a protein highly associated with male sterility, binds to the mitochondrial complex I subunit to protect mitochondrial function. However, its involvement in spermatogenesis has not been fully elucidated. Previously, the levels of DJ-1 were shown to be significantly decreased in testicular tissues of rats with ornidazole (ORN)-induced AS. Here, we used a rat model to investigate the localization and expression levels of DJ-1 and its interacting NDUFS3 and NDUFA4 mitochondrial complex I subunits, as well as AS-induced metabolic alterations in testicular tissues. ORN significantly reduced the levels of DJ-1 in the nucleus of secondary spermatocytes, while increasing the expression of NDUFS3 in the cytoplasm of primary spermatocytes. Further, NDUFA4 showed higher expression after treatment with ORN. The principal ORN-induced changes in metabolic small molecules related to the accumulation of glucose, glutamine, and N-acetyl aspartate, enhancement of purine pathway, increase of the phosphatidic acid (PA) (18:0/18:1), phosphatidylethanolamine (PE) (16:0/18:1), and PA (18:0/20:4) lipid metabolites, and imbalance in the concentrations of Na+ and K+. However, we did not observe any abnormalities of certain small metabolic molecules and metal ions in semen samples from patients with AS. In conclusion, these results suggest that DJ-1 deficiency in testicular tissues might be closely related to the localization of NDUFS3 and content of NDUFA4, thus causing abnormalities in the mitochondrial energy metabolism and multiple other metabolic pathways.

14.
BMJ Open ; 10(9): e036786, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32967875

RESUMO

OBJECTIVES: This study aimed to set a data-driven achievable performance benchmark, explore the process-outcome association and speculate about the net gain in quality improvement with benchmarking. DESIGN: Observational study. SETTING: Patient survey conducted at 466 secondary and tertiary hospitals across 31 provinces, autonomous regions and municipalities in China. PARTICIPANTS: 183 334 patients diagnosed with chronic heart failure (CHF) who were treated at 466 Chinese hospitals from January 2011 through May 2017. PRIMARY INDEPENDENT VARIABLES: Hospital process composite performance (HPCP). SECONDARY INDEPENDENT VARIABLES: Patient-level and hospital-level characteristics. PRIMARY OUTCOME MEASURE: Patients getting better or recovered after treatment, in-hospital mortality, length of hospital stay (LOS) and medical cost. METHODS: HPCP was calculated using denominator-based weights. Mixed random-intercept models were used to evaluate the contributions of HPCP on patient outcomes and to speculate quality improvement after adjusting HPCP to benchmark level. RESULTS: When all hospitals were to operate at the benchmark level, the proportion of patients getting better or recovered after treatment would increase in most hospitals, particularly those with low baseline rates. However, there was no evidence for lowering in-hospital mortality, significant savings in cost or shortening LOS. CONCLUSIONS: Increasing the adherence rate of CHF care and closing the gap in HPCP between hospitals have important implications for improving patient condition.

15.
Small ; 16(42): e2004129, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32939987

RESUMO

Herein, it is demonstrated that N-rich carbonized silk fibroin materials (CSFs) can serve as efficient peroxidase, and oxidase mimics. Their enzyme-like activities are highly dependent on carbonization conditions. CSFs obtained at low temperatures do not exhibit significant catalytic reactivity, while their enzyme-like catalysis performance is greatly activated after high-temperature treatment. Such a phenomenon is mainly ascribed to the increase of graphitization degree and graphitic nitrogen and the emergence of disordered graphitic structures during the formation of turbostratic carbon. In addition, inspired by the excellent photothermal conversion efficiency, and temperature-dependent catalytic behavior of CSFs, near-infrared light can be used to remotely control their enzyme-like activities. More importantly, as-prepared robust silk-derived nanosheets can be applied to photothermal-catalytic cancer therapy and sensing. It is believed that such a smart artificial enzyme system will throw up exciting new opportunities for the chemical industry and biotechnology.

16.
Life Sci ; 258: 118217, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768575

RESUMO

AIMS: Astrocytes expressing the aquaporin-4 (AQP4) water channel are pathogenic, disease specific immunoglobulins (IgG) found in neuromyelitis optica spectrum disorder (NMOSD), referred to as NMO-IgG, which targets astrocytic AQP4. The interleukin-6 (IL-6) signaling when astrocytes were exposed to NMO-IgG present in the serum of NMOSD patients was evaluated. MAIN METHODS: Serum or human-IgG from NMOSD or healthy controls were exposed to astrocytes. The selectivity and immuno-pathological consequences of Ig binding to surface epitopes were measured by confocal microscopy. Astrocytes were exposed to medium, IL-6, soluble IL-6 receptor (sIL-6R), IL-6 + sIL-6R (IL-6/R), NMO-IgG or control-IgG, NMO-IgG + IL-6/R. The expression of key proteins in IL-6 signaling pathway, IL-6 cytokine and mRNA levels were evaluated by western blotting, enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. KEY FINDINGS: Serum or NMO-IgG from NMOSD patients both induced the rapid downregulation of AQP4 expression on the surface of astrocytes. Stimulation of astrocytes with NMO-IgG, IL-6/R, and NMO-IgG + IL-6/R resulted in the enhancement of IL-6 mRNA expression. Meanwhile, the exogenous addition of NMO-IgG elicited an inflammatory transcriptional response that involved signaling through the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway. Inhibition of the IL-6/JAK/STAT3 pathway with the JAK1/2 specific inhibitor, AZD1480, reversed the associated increase of IL-6. SIGNIFICANCE: Our findings suggest that NMO-IgG can stimulate the astrocytic JAK1/2/STAT3-dependent inflammatory response, which represents one of the important events in NMO pathogenesis. Inhibition of the JAK1/2 signaling pathway may be a novel promising therapy for NMOSD.


Assuntos
Astrócitos/metabolismo , Imunoglobulina G/sangue , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Neuromielite Óptica/sangue , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Animais , Astrócitos/efeitos dos fármacos , Autoanticorpos/sangue , Autoanticorpos/farmacologia , Células Cultivadas , Feminino , Humanos , Imunoglobulina G/farmacologia , Interleucina-6/agonistas , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Wistar , Fator de Transcrição STAT3/agonistas , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Adulto Jovem
17.
Genes (Basel) ; 11(9)2020 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-32842486

RESUMO

Accumulating evidence indicates that long non-coding RNAs (lncRNAs) have certain similarities with messenger RNAs (mRNAs) and are associated with numerous important biological processes, thereby demanding methods to distinguish them. Based on machine learning algorithms, a variety of methods are developed to identify lncRNAs, providing significant basic data support for subsequent studies. However, many tools lack certain scalability, versatility and balance, and some tools rely on genome sequence and annotation. In this paper, we propose a convenient and accurate tool "PreLnc", which uses high-confidence lncRNA and mRNA transcripts to build prediction models through feature selection and classifiers. The false discovery rate (FDR) adjusted P-value and Z-value were used for analyzing the tri-nucleotide composition of transcripts of different species. Conclusions can be drawn from the experiment that there were significant differences in RNA transcripts among plants, which may be related to evolutionary conservation and the fact that plants are under evolutionary pressure for a longer time than animals. Combining with the Pearson correlation coefficient, we use the incremental feature selection (IFS) method and the comparison of multiple classifiers to build the model. Finally, the balanced random forest was used to construct the classifier, and PreLnc obtained 91.09% accuracy for 349,186 transcripts of animals and plants. In addition, by comparing standard performance measurements, PreLnc performed better than other prediction tools.

18.
Ecotoxicol Environ Saf ; 206: 111179, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32861964

RESUMO

This study investigated the application of a specific soil washing method to remove Cu and Pb from contaminated agricultural soil. To develop an efficient leaching agent of heavy metal compounds for use in farmland soil, a mixed chelator (MC) was prepared using potassium fulvic acid (PFA, 3.2%) and citric acid (CIT, 0.16 M) in a volume ratio of 4:1 (PFA:CIT = 4:1); the optimal solid-liquid ratio (S/L = 1:20), initial pH value (4.51) and contact time (360 min) were also explored. Under optimal conditions, the removal efficiencies of MC for Cu and Pb were 42.92% and 50.46%, respectively, both of which performed better than PFA (27.86% of Cu and 17.91% of Pb) and CIT (42.04% of Cu and 41.46% of Pb). The effective states, bioavailability and relative mobilities of Cu and Pb in soil were also efficiently reduced by MC, which also increased the stability of these elements, thereby lowering the risk to soil health. More importantly, MC not only had little effect on the soil physicochemical properties (e.g., pH, organic matter (OM), cation exchange capacity (CEC), ammonium nitrogen (AN), available phosphorus (AP) and rapidly available potassium (AK)), but also improved the restored soil. Furthermore, soil structure, surface elements and the enzyme activity did not exhibit significantly loss. Therefore, MC has great potential for remediating agricultural soil.


Assuntos
Cobre/análise , Recuperação e Remediação Ambiental/métodos , Chumbo/análise , Poluentes do Solo/análise , Benzopiranos/química , Disponibilidade Biológica , Quelantes/química , Ácido Cítrico/química , Poluição Ambiental , Metais Pesados/análise , Fósforo , Potássio , Solo/química
20.
Biomed Res Int ; 2020: 2489175, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32685455

RESUMO

Background: Although Henoch-Schönlein purpura nephritis (HSPN) is characterized by glomerular deposition of aberrantly glycosylated immunoglobulin A1 (IgA1), the underlying mechanism of HSPN progression has not yet been completely elucidated. In this study, we integrated transcriptomic and proteomic analyses to explore the underlying mechanism of HSPN progression. Methods: RNA sequencing and tandem mass tag- (TMT-) based quantitative proteomics were used to gain serum transcriptomic and proteomic profiles of patients with different types of HSPN (3 × type 1, 3 × type 2, and 3 × type 3). Student's t-tests were performed to obtain the significance of the differential gene expression. The clusterProfiler package was used to conduct the functional annotation of the DEGs for both Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways. Results: A total of 2315 mRNAs and 30 proteins were differentially expressed between the different types of HSPN. 58 mRNAs and one protein changed continuously during HSPN development and are potential biomarkers for HSPN progression. The validation cohort (another 9 patients) confirmed the high-throughput results of the transcriptomic and proteomic analyses. A total of 385 significant pathways were related to HSPN progression, and four of them were closely related to clinical biochemical indicators and may play an important role in the progression of HSPN. Those pathways reveal that HSPN progression may be related to the inhibition of inflammation, promotion of apoptosis, and repair of renal injury. Conclusions: Four pathways were found to be closely related to HSPN progression, and it seems that HSPN progression is mainly due to the inhibition of inflammation, promotion of apoptosis, and repair of renal injury.

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