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1.
J Virol ; 97(7): e0061023, 2023 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-37367229

RESUMO

Members of the Sarbecovirus subgenus of Coronaviridae have twice caused deadly threats to humans. There is increasing concern about the rapid mutation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has evolved into multiple generations of epidemic variants in 3 years. Broad neutralizing antibodies are of great importance for pandemic preparedness against SARS-CoV-2 variants and divergent zoonotic sarbecoviruses. Here, we analyzed the structural conservation of the receptor-binding domain (RBD) from representative sarbecoviruses and chose S2H97, a previously reported RBD antibody with ideal breadth and resistance to escape, as a template for computational design to enhance the neutralization activity and spectrum. A total of 35 designs were purified for evaluation. The neutralizing activity of a large proportion of these designs against multiple variants was increased from several to hundreds of times. Molecular dynamics simulation suggested that extra interface contacts and enhanced intermolecular interactions between the RBD and the designed antibodies are established. After light and heavy chain reconstitution, AI-1028, with five complementarity determining regions optimized, showed the best neutralizing activity across all tested sarbecoviruses, including SARS-CoV, multiple SARS-CoV-2 variants, and bat-derived viruses. AI-1028 recognized the same cryptic RBD epitope as the parental prototype antibody. In addition to computational design, chemically synthesized nanobody libraries are also a precious resource for rapid antibody development. By applying distinct RBDs as baits for reciprocal screening, we identified two novel nanobodies with broad activities. These findings provide potential pan-sarbecovirus neutralizing drugs and highlight new pathways to rapidly optimize therapeutic candidates when novel SARS-CoV-2 escape variants or new zoonotic coronaviruses emerge. IMPORTANCE The subgenus Sarbecovirus includes human SARS-CoV, SARS-CoV-2, and hundreds of genetically related bat viruses. The continuous evolution of SARS-CoV-2 has led to the striking evasion of neutralizing antibody (NAb) drugs and convalescent plasma. Antibodies with broad activity across sarbecoviruses would be helpful to combat current SARS-CoV-2 mutations and longer term animal virus spillovers. The study of pan-sarbecovirus NAbs described here is significant for the following reasons. First, we established a structure-based computational pipeline to design and optimize NAbs to obtain more potent and broader neutralizing activity across multiple sarbecoviruses. Second, we screened and identified nanobodies from a highly diversified synthetic library with a broad neutralizing spectrum using an elaborate screening strategy. These methodologies provide guidance for the rapid development of antibody therapeutics against emerging pathogens with highly variable characteristics.


Assuntos
Anticorpos Antivirais , Anticorpos Amplamente Neutralizantes , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , Anticorpos de Domínio Único , Animais , Humanos , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/química , Anticorpos Antivirais/metabolismo , Anticorpos Amplamente Neutralizantes/biossíntese , Anticorpos Amplamente Neutralizantes/química , Anticorpos Amplamente Neutralizantes/metabolismo , Quirópteros , COVID-19/virologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/imunologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/metabolismo , Estrutura Terciária de Proteína , Modelos Moleculares , Ligação Proteica
2.
Am J Pathol ; 193(11): 1750-1761, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-36775060

RESUMO

Some human retinal diseases are characterized by pathology that is restricted to specific cell types and to specific regions of the eye. Several disease entities either selectively affect or spare the macula, the retina region at the center of the posterior pole. Photoreceptor cells in the macula are involved in high-acuity vision and require metabolic support from non-neuronal cell types. Some macular diseases involve the retinal pigment epithelium (RPE), an epithelial cell layer with several metabolic-support functions essential for the overlying photoreceptors. In the current study, the ways in which RPE confers region-specific disease susceptibility were determined by examining heterogeneity within RPE tissue from human donors. RPE nuclei from the macular and peripheral retina were profiled using joint single-nucleus RNA and ATAC sequencing. The expression of several genes differed between macular and peripheral RPE. Region-specific ATAC peaks were found, suggesting regulatory elements used exclusively by macular or peripheral RPE. Across anatomic regions, subpopulations of RPE were identified that appeared to have differential levels of expression of visual cycle genes. Finally, loci associated with age-related macular degeneration were examined for a better understanding of RPE-specific disease phenotypes. These findings showed variations in the regulation of gene expression in the human RPE by region and subpopulation, and provide a source for a better understanding of the molecular basis of macular disease.


Assuntos
Degeneração Macular , Doenças Retinianas , Humanos , Epitélio Pigmentado da Retina/metabolismo , Transcriptoma/genética , Cromatina/genética , Cromatina/metabolismo , Retina/patologia , Degeneração Macular/patologia , Doenças Retinianas/patologia
3.
Plant Cell ; 33(6): 1907-1926, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-33730150

RESUMO

Seed size is a major factor determining crop yields that is controlled through the coordinated development of maternal and zygotic tissues. Here, we identified Arabidopsis MATERNAL EFFECT EMBRYO ARREST45 (MEE45) as a B3 transcription factor that controls cell proliferation and maternally regulates seed size through its transcriptional activation of AINTEGUMENTA (ANT) and its downstream control of auxin biosynthesis in the ovule integument. After characterizing reduced seed and organ size phenotypes in mee45 mutants and finding that overexpression of MEE45 causes oversized seeds, we discovered that the MEE45 protein can bind to the promoter region of the ANT locus and positively regulate its transcription. ANT in-turn activates the expression of auxin biosynthetic genes (e.g. YUCCA4) in the ovule integument. Our results thus illustrate mechanisms underlying maternal tissue-mediated regulation of seed size and suggest that MEE45 and its downstream components can be harnessed to develop higher-yielding crop varieties.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/metabolismo , Ácidos Indolacéticos/metabolismo , Sementes/crescimento & desenvolvimento , Fatores de Transcrição/genética , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proliferação de Células/genética , Regulação da Expressão Gênica de Plantas , Herança Materna/genética , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Tamanho do Órgão , Óvulo Vegetal/citologia , Óvulo Vegetal/genética , Células Vegetais , Plantas Geneticamente Modificadas , Sementes/genética , Fatores de Transcrição/metabolismo
4.
Inj Prev ; 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39025671

RESUMO

OBJECTIVES: To identify risk factors associated with falls in older people in rural China. METHODS: A prospective cohort study was conducted across 27 villages in the rural areas of Ningxia, China. After excluding individuals younger than 60 years, a total of 758 out of the initial 822 participants were ultimately included for the collection of baseline information. Participants were followed up through telephone calls or face-to-face interviews at 3rd, 6th and 12th months following the baseline investigation. The Cox proportional hazards regression model was used to examine risk factors of falls. RESULTS: A total of 758 participants underwent baseline information surveys, and all samples were included in the Cox model analysis. The study found that being woman (RR=1.879, 95% CI: 1.313 to 2.668), smoking (RR=1.972, 95% CI: 1.238 to 3.143), use of painkillers (RR=1.700, 95% CI: 1.226 to 2.356) and higher systolic blood pressure (SBP) (RR=1.081, 95% CI: 1.013 to 1.154) were associated with higher risk of falls among the elderly in rural China. After excluding those who were lost to follow-up or deceased, 738 participants completed the follow-up. There were 341 men (46.2%) and 397 women (53.8%), with an average age of 66.8±5.0 years. The fall rate in study area was 23.8% during the follow-up period. CONCLUSIONS: The fall rate among the elderly in rural China was higher than other areas. Our findings revealed that being woman, smoking, medication usage, elevated SBP and people with a higher body mass index were risk factors for developing falls.

5.
Hum Mol Genet ; 30(16): 1543-1558, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34014299

RESUMO

The human neural retina is a light sensitive tissue with remarkable spatial and cellular organization. Compared with the periphery, the central retina contains more densely packed cone photoreceptor cells with unique morphologies and synaptic wiring. Some regions of the central retina exhibit selective degeneration or preservation in response to retinal disease and the basis for this variation is unknown. In this study, we used both bulk and single-cell RNA sequencing to compare gene expression within concentric regions of the central retina. We identified unique gene expression patterns of foveal cone photoreceptor cells, including many foveal-enriched transcription factors. In addition, we found that the genes RORB1, PPFIA1 and KCNAB2 are differentially spliced in the foveal, parafoveal and macular regions. These results provide a highly detailed spatial characterization of the retinal transcriptome and highlight unique molecular features of different retinal regions.


Assuntos
Células Fotorreceptoras Retinianas Cones , Doenças Retinianas , Fóvea Central , Humanos , Retina/metabolismo , Células Fotorreceptoras Retinianas Cones/metabolismo , Doenças Retinianas/genética , Transcriptoma/genética
6.
J Transl Med ; 21(1): 497, 2023 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-37488584

RESUMO

BACKGROUND: Celiac disease (CeD) is a primary malabsorption syndrome with no specific therapy, which greatly affects the quality of life. Since the pathogenesis of CeD remains riddled, based on multiple transcriptome profiles, this study aimed to establish an immune interaction network and elucidated new mechanisms involved in the pathogenesis of CeD, providing potentially new evidence for the diagnosis and treatment of CeD. METHODS: Three microarray and three RNA sequencing datasets of human duodenal tissue with or without CeD were included in Gene Expression Omnibus and respectively merged into derivation and validation cohorts. Differential expression gene and functional enrichment analysis were developed, then pyroptosis enrichment score (PES) model was established to quantify pyroptosis levels. Immune infiltration and co-expression network were constructed based on Xcell database. Protein-protein interaction and weighted gene co-expression network analysis were determined to identify pyroptosis relative hub genes, whose predictive efficiency were tested using a least absolute shrinkage and selection operator (LASSO) regression model. CeD animal and in vitro cell line models were established to verify the occurrence of pyroptosis and molecules expression employing immunofluorescence, western blotting, cell counting kit-8 assay and enzyme-linked immunosorbent assay. Analysis of single-cell RNAseq (scRNAseq) was performed using "Seurat" R package. RESULTS: Differentially expressed genes (DEGs) (137) were identified in derivation cohort whose function was mainly enriched in interferon response and suppression of metabolism. Since an enrichment of pyroptosis pathway in CeD was unexpectedly discovered, a PES model with high efficiency was constructed and verified with two external databases, which confirmed that pyroptosis was significantly upregulated in CeD epithelia. γδT cells exhibited high expression of IFN-γ were the most relevant cells associated with pyroptosis and occupied a greater weight in the LASSO predictive model of CeD. An accumulation of GSDMD expressed in epithelia was identified using scRNAseq, while animal model and in vitro experiments confirmed that epithelium cells were induced to become "pre-pyroptotic" status via IFN-γ/IRF1/GSDMD axis. Furthermore, gluten intake triggered pyroptosis via caspase-1/GSDMD/IL-1ß pathway. CONCLUSION: Our study demonstrated that pyroptosis was involved in the pathogenesis of CeD, and elucidated the novel role of γδT cells in mediating epithelial cell pyroptosis.


Assuntos
Doença Celíaca , Piroptose , Animais , Humanos , Transcriptoma , Qualidade de Vida , Células Epiteliais
7.
Molecules ; 28(22)2023 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-38005218

RESUMO

Quantum dot nanobeads (QBs) were used as signal source to develop competitive lateral flow immunoassay (LFIA) for the detection of chloramphenicol (CAP). The quantitative detection of CAP was achieved by calculating the total color difference (∆E) values of the test line (T line) using the images of test strips. QB-based LFIA (QBs-LFIA) allowed the effective dynamic linear detection of CAP in the range of 0.1-1.5 ng/mL. The limit of detection (LOD) was 3.0 ng/mL, which was 50 and 667 times lower than those achieved for two different brands of colloidal gold kits. The recoveries of CAP during real-sample detection were 82.82-104.91% at spiked levels of 0.1, 0.7, and 1.5 ng/mL. These results indicate that the developed QBs-LFIA facilitates the sensitive detection of CAP.


Assuntos
Cloranfenicol , Pontos Quânticos , Imunoensaio/métodos , Limite de Detecção , Coloide de Ouro
8.
Nature ; 534(7605): 69-74, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27251276

RESUMO

During photosynthesis, the plant photosystem II core complex receives excitation energy from the peripheral light-harvesting complex II (LHCII). The pathways along which excitation energy is transferred between them, and their assembly mechanisms, remain to be deciphered through high-resolution structural studies. Here we report the structure of a 1.1-megadalton spinach photosystem II-LHCII supercomplex solved at 3.2 Å resolution through single-particle cryo-electron microscopy. The structure reveals a homodimeric supramolecular system in which each monomer contains 25 protein subunits, 105 chlorophylls, 28 carotenoids and other cofactors. Three extrinsic subunits (PsbO, PsbP and PsbQ), which are essential for optimal oxygen-evolving activity of photosystem II, form a triangular crown that shields the Mn4CaO5-binding domains of CP43 and D1. One major trimeric and two minor monomeric LHCIIs associate with each core-complex monomer, and the antenna-core interactions are reinforced by three small intrinsic subunits (PsbW, PsbH and PsbZ). By analysing the closely connected interfacial chlorophylls, we have obtained detailed insights into the energy-transfer pathways between the antenna and core complexes.


Assuntos
Microscopia Crioeletrônica , Complexos de Proteínas Captadores de Luz/química , Complexos de Proteínas Captadores de Luz/ultraestrutura , Complexo de Proteína do Fotossistema II/química , Complexo de Proteína do Fotossistema II/ultraestrutura , Spinacia oleracea/química , Carotenoides/química , Clorofila/química , Transporte de Elétrons , Subunidades Proteicas/química
9.
Nutr J ; 21(1): 63, 2022 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-36242082

RESUMO

BACKGROUND: Diet is a modifiable risk factor for cardiovascular diseases (CVD), but there is still a lack of tools to assess dietary intakes of this high-risk population in Ningxia, China. OBJECTIVE: We aim to evaluate the validity and reliability of the semi-quantitative food frequency questionnaire (SFFQ) in the groups in Ningxia using a 24-hour dietary recall method. METHOD: Two hundred five participants were included in the analysis. The two FFQs were 6 months apart, and during this time two 24-hour dietary recalls (24HDRs) were completed. Statistical methods were compared using inter-class correlation coefficient, unadjusted, energy-adjusted, de-attenuated correlation coefficient, quartile classification, weighted K values, and 95% limits of agreement (LOA). RESULTS: The inter-class correlation coefficients between FFQ1 and FFQ2 ranged from 0.25 to 0.73. The number of subjects classified as identical or adjacent was 72.2 to 85.9%. The crude correlation coefficient between FFQs and 24HDRs was 0.30 ~ 0.81, the energy-adjusted correlation coefficient was 0.16 ~ 0.83, and the de-attenuated correlation coefficient was 0.19 ~ 0.98. Weighted k statistics and Bland-Altman plots showed acceptable agreement between FFQs and 24HDRs. CONCLUSION: The FFQ developed for the population at high risk of cardiovascular and cerebrovascular diseases in areas of Ningxia can be used to measure the dietary intake of nutrients and food groups reliably and validly.


Assuntos
Doenças Cardiovasculares , Ingestão de Energia , Doenças Cardiovasculares/epidemiologia , Dieta , Inquéritos sobre Dietas , Humanos , Reprodutibilidade dos Testes , Inquéritos e Questionários
10.
Mikrochim Acta ; 189(4): 144, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35292904

RESUMO

A simple smartphone-integrated ratiometric fluorescent sensing system for visual determination of copper ions (Cu2+) and fluoroquinolones (FQs) was developed based on carbon dots (CDs) which were synthesized through the high-temperature pyrolysis of citric acid. In this system, with the fluorescence resonance energy transfer effect between CDs and 2,3-diaminophenazine (oxOPD), the detection of Cu2+ and ciprofloxacin (CIP, an example for FQs) was realized. Cu2+ catalyzes the oxidation of OPD to form oxOPD with yellow fluorescence, resulting in the quenching of CDs. In addition, CIP can inhibit the catalytic activity of Cu2+ and induce the recovery of CDs fluorescence. Under the excitation of 400 nm, the changes of CDs fluorescence at 472 nm and oxOPD fluorescence at 556 nm were monitored. The detection results showed that the sensing system exhibited good selectivity and sensitivity to Cu2+ and CIP with the limit of detection of 2.32 × 10-8 mol L-1 and 0.2 ng mL-1, respectively. In addition, a smartphone was developed as a portable analyzer to capture the change of fluorescence color and quickly analyze the concentration of Cu2+ and CIP. The proposed smartphone-based sensing platform has satisfactory sensitivity, and it has application prospects for detecting Cu2+ and FQs in food safety monitoring.


Assuntos
Carbono , Pontos Quânticos , Cobre , Corantes Fluorescentes , Fluoroquinolonas , Limite de Detecção
11.
Molecules ; 27(23)2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36500416

RESUMO

A multicolor immunochromatographic assay platform based on quantum dot nanobeads (QBs) for the rapid and simultaneous detection of nitrofuran metabolites in different aquatic products is documented. These metabolites include 3-amino-2-oxazolidinone (AOZ), 1-aminohydantoin (AHD), semicarbazide (SEM), and 3-amino-5-morpholino-methyl-1,3-oxazolidinone (AMOZ). QBs with emission colors of red, yellow, green, and orange were employed and functionalized with the corresponding antibodies to each analyte to develop a multicolor channel. The visual detection limits (cutoff values) of our method for AOZ, AHD, SEM, and AMOZ reached up to 50 ng/mL, which were 2, 20, 20, and 20 times lower than those of traditional colloidal gold test strips, respectively. The test strip is capable of detection within 10 min in real samples while still achieving good stability and specificity. These results demonstrate that the developed multicolor immunochromatographic assay platform is a promising technique for multiplex, highly sensitive, and on-site detection of nitrofuran metabolites.


Assuntos
Nitrofuranos , Pontos Quânticos , Contaminação de Alimentos/análise , Nitrofuranos/química , Cromatografia de Afinidade/métodos , Semicarbazidas
12.
Microvasc Res ; 135: 104144, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33515567

RESUMO

Ischemic stroke is a leading cause of morbidity and mortality worldwide, with oxidative stress playing a key role in the injury mechanism of thrombolytic therapy. There is increasing evidence that oxidative stress damages endothelial cells (ECs), degrades tight junction proteins (TJs), and contributes to increased blood-brain barrier (BBB) permeability. It has been demonstrated that the breakdown of BBB could increase the risk of intracerebral hemorrhagic transformation in ischemic stroke. And an episode of cerebral ischemia/reperfusion (I/R) also initiates oxidative stress-mediated inflammatory processes in ECs, which further promotes BBB disruption and the progression of brain injury. Previous studies have revealed that antioxidants could inhibit ROS generation and attenuate BBB disruption after cerebral I/R. Peroxiredoxin 4 (Prx4) is a member of the antioxidant enzymes family (Prx1-6) and has been characterized to be an efficient H2O2 scavenger. It should be noted that Prx4 may be directly involved in the protection of ECs from the effects of ROS and function in ECs as a membrane-associated peroxidase. This paper reviewed the implication of Prx4 on vascular integrity and neuroinflammation following a cerebral I/R injury.


Assuntos
Barreira Hematoencefálica/enzimologia , Permeabilidade Capilar , Células Endoteliais/enzimologia , Mediadores da Inflamação/metabolismo , AVC Isquêmico/enzimologia , Neuroimunomodulação , Peroxirredoxinas/metabolismo , Traumatismo por Reperfusão/enzimologia , Animais , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/patologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Humanos , AVC Isquêmico/imunologia , AVC Isquêmico/patologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Junções Íntimas/enzimologia , Junções Íntimas/imunologia , Junções Íntimas/patologia
13.
PLoS Biol ; 16(6): e2004880, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29879109

RESUMO

N6-methyladenosine (m6A) RNA methylation is the most abundant modification on mRNAs and plays important roles in various biological processes. The formation of m6A is catalyzed by a methyltransferase complex including methyltransferase-like 3 (METTL3) as a key factor. However, the in vivo functions of METTL3 and m6A modification in mammalian development remain unclear. Here, we show that specific inactivation of Mettl3 in mouse nervous system causes severe developmental defects in the brain. Mettl3 conditional knockout (cKO) mice manifest cerebellar hypoplasia caused by drastically enhanced apoptosis of newborn cerebellar granule cells (CGCs) in the external granular layer (EGL). METTL3 depletion-induced loss of m6A modification causes extended RNA half-lives and aberrant splicing events, consequently leading to dysregulation of transcriptome-wide gene expression and premature CGC death. Our findings reveal a critical role of METTL3-mediated m6A in regulating the development of mammalian cerebellum.


Assuntos
Adenosina/análogos & derivados , Cerebelo/embriologia , Metiltransferases/metabolismo , RNA Mensageiro/genética , Adenosina/metabolismo , Processamento Alternativo/genética , Animais , Apoptose/genética , Células Cultivadas , Cerebelo/anormalidades , Cerebelo/patologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Regulação da Expressão Gênica/genética , Metilação , Metiltransferases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Estabilidade de RNA/genética , RNA Mensageiro/metabolismo
14.
Wei Sheng Yan Jiu ; 50(2): 256-260, 2021 Mar.
Artigo em Zh | MEDLINE | ID: mdl-33985633

RESUMO

OBJECTIVE: To analyze the relationship between children lipid accumulation product(CLAP) and body mass index(BMI) and cardiovascular risk factors in children and adolescents. METHODS: A current situation study design was adopted. A total of 936 children and adolescents aged 12 to 18 years old in Yinchuan City were selected from September 2017 to September 2019 by a convenient sampling method. Among them, 537(57. 40%) boys and an average age of(14. 82±2. 08) years old, the number of Han and other ethnic groups were 705(75. 30%) and 231(24. 70%) respectively. And conduct questionnaire surveys(using Yinchuan Children's Blood Pressure Survey-standard questionnaire, which mainly includes basic information, birth and infant feeding, physical activity and sleep, etc. ), physical examination(including height, weight, blood pressure and body components) and biochemical index detection(including fasting blood glucose and blood lipids), using binary classification Logistics regression to analyze the correlation between CLAP and BMI and cardiovascular risk factors, and ROC curve analysis of the accuracy of CLAP and BMI in the diagnosis of cardiovascular risk factors. RESULTS: The association between CLAP≥P75 and BMI normal weight and cardiovascular risk factor aggregation≥2 was 38. 13(95%CI 23. 83-61. 00) times(P<0. 05) of CLAP<P75 and BMI non-obese, which was higher than that of other different combinations and cardiovascular risk factors Correlation. The accuracy of CLAP≥P75 combined with BMI in the diagnosis of cardiovascular risk factor aggregation≥2 was 0. 87(95%CI 0. 85-0. 89), higher than other diagnoses. CONCLUSION: CLAP and BMI are associated with cardiovascular risk factors.


Assuntos
Doenças Cardiovasculares , Produto da Acumulação Lipídica , Adolescente , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Fatores de Risco Cardiometabólico , Doenças Cardiovasculares/epidemiologia , Criança , Humanos , Masculino , Obesidade , Fatores de Risco
15.
J Virol ; 93(18)2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31270223

RESUMO

The Zika virus (ZIKV) life cycle involves multiple steps and requires interactions with host factors. However, the inability to systematically identify host regulatory factors for ZIKV has hampered antiviral development and our understanding of pathogenicity. Here, using a bioactive compound library with 2,659 small molecules, we applied a high-throughput and imaging-based screen to identify host factors that modulate ZIKV infection. The screen yielded hundreds of hits that markedly inhibited or potentiated ZIKV infection in SNB-19 glioblastoma cells. Among the hits, URMC-099, a mixed-lineage kinase 3 (MLK3) inhibitor, significantly facilitated ZIKV replication in both SNB-19 cells and the neonatal mouse brain. Using gene silencing and overexpression, we further confirmed that MLK3 was a host restriction factor against ZIKV. Mechanistically, MLK3 negatively regulated ZIKV replication through induction of the inflammatory cytokines interleukin-6 (IL-6), IL-8, tumor necrosis factor alpha (TNF-α), and monocyte chemoattractant protein 1 (MCP-1) but did not modulate host interferon-related pathways. Importantly, ZIKV activated the MLK3/MKK7/Jun N-terminal protein kinase (JNK) pathway in both SNB-19 cells and neonatal mouse brain. Together, these findings reveal a critical role for MLK3 in regulating ZIKV infection and facilitate the development of anti-ZIKV therapeutics by providing a number of screening hits.IMPORTANCE Zika fever, an infectious disease caused by the Zika virus (ZIKV), normally results in mild symptoms. Severe infection can cause Guillain-Barré syndrome in adults and birth defects, including microcephaly, in newborns. Although ZIKV was first identified in Uganda in 1947 in rhesus monkeys, a widespread epidemic of ZIKV infection in South and Central America in 2015 and 2016 raised major concerns. To date, there is no vaccine or specific medicine for ZIKV. The significance of our research is the systematic discovery of small molecule candidates that modulate ZIKV infection, which will allow the development of antiviral therapeutics. In addition, we identified MLK3, a key mediator of host signaling pathways that can be activated during ZIKV infection and limits virus replication by inducing multiple inflammatory cytokines. These findings broaden our understanding of ZIKV pathogenesis.


Assuntos
MAP Quinase Quinase Quinases/metabolismo , Infecção por Zika virus/metabolismo , Zika virus/metabolismo , Animais , Antivirais/farmacologia , Linhagem Celular , Efeito Citopatogênico Viral/efeitos dos fármacos , Efeito Citopatogênico Viral/fisiologia , Ensaios de Triagem em Larga Escala/métodos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Interferons/farmacologia , MAP Quinase Quinase Quinases/genética , Camundongos , Camundongos Endogâmicos BALB C , Microcefalia , Vírus Sincicial Respiratório Humano , Vírus Sendai , Transdução de Sinais/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Infecção por Zika virus/virologia , MAP Quinase Quinase Quinase 11 Ativada por Mitógeno
16.
New Phytol ; 228(2): 570-585, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32473605

RESUMO

Plant organellar RNA editing is a distinct type of post-transcriptional RNA modification that is critical for plant development. We showed previously that the RNA editing factor SlORRM4 is required for mitochondrial function and fruit ripening in tomato (Solanum lycopersicum). However, a comprehensive atlas of the RNA editing mediated by SlORRM4 is lacking. We observed that SlORRM4 is targeted to both chloroplasts and mitochondria, and its knockout results in pale-green leaves and delayed fruit ripening. Using high-throughput sequencing, we identified 12 chloroplast editing sites and 336 mitochondrial editing sites controlled by SlORRM4, accounting for 23% of chloroplast sites in leaves and 61% of mitochondrial sites in fruits, respectively. Analysis of native RNA immunoprecipitation sequencing revealed that SlORRM4 binds to 31 RNA targets; 19 of these targets contain SlORRM4-dependent editing sites. Large-scale analysis of putative SlORRM4-interacting proteins identified SlRIP1b, a RIP/MORF protein. Moreover, functional characterization demonstrated that SlRIP1b is involved in tomato fruit ripening. Our results indicate that SlORRM4 binds to RNA targets and interacts with SlRIP1b to broadly affect RNA editing in tomato organelles. These results provide insights into the molecular and functional diversity of RNA editing factors in higher plants.


Assuntos
Edição de RNA , Solanum lycopersicum , Cloroplastos/genética , Cloroplastos/metabolismo , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Organelas/genética , Organelas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Edição de RNA/genética , Motivo de Reconhecimento de RNA , RNA de Plantas/metabolismo
17.
Public Health Nutr ; : 1-7, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32345383

RESUMO

OBJECTIVE: To develop an equation that can estimate the 24-h urinary Na excretion by using casual spot urine specimen for older hypertensive participants in rural Ningxia and further to compare with the INTERSALT method, Kawasaki method and Tanaka method. DESIGN: Older hypertensive participants in rural Ningxia provided their casual spot urine samples and 24-h urine samples between January 2015 and February 2017. Sex-specific equation was developed using linear forward stepwise regression analysis. Model fit was assessed using adjusted R2. Approximately half of all participants were randomly selected to validate the equation. Mean differences, intraclass correlation coefficients and Bland-Altman plots were used to evaluate the performance of all methods. SETTING: Pingluo County and Qingtongxia County in Ningxia Hui Autonomous Region, China. PARTICIPANTS: Older hypertensive participants in rural Ningxia. RESULTS: Totally, 807 of 1120 invited participants provided qualified 24-h urine samples and spot urine samples. There was no statistical difference comparing the laboratory-based method against the new method and the INTERSALT method, while Kawasaki method had the largest bias with a mean difference of 40·81 g/d (95 % CI 39·27, 42·35 g/d). Bland-Altman plots showed similar pattern of the results. CONCLUSION: The INTERSALT method and the new equation have the potential to estimate the 24-h urinary Na excretion in this study population. However, the extrapolation of the results to other population needs to be careful. Future research is required to establish a more reliable method to estimate 24-h urinary Na excretion.

18.
Lipids Health Dis ; 19(1): 11, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31952540

RESUMO

BACKGROUND: Previous evidence suggests that plasma phospholipid fatty acids (PPFAs) and HOMA insulin resistance (HOMA-IR) are independently related to leukocyte telomere length (LTL). However, there is limited evidence of regarding the effect of their interaction on relative LTL (RLTL). Therefore, here, we aimed to determine the effect of the interaction between PPFAs and HOMA-IR on RLTL. METHODS: We conducted a cross-sectional study, involving a total of 1246 subjects aged 25-74 years. PPFAs and RLTL were measured, and HOMA-IR was calculated. The effect of the interaction between PPFAs and HOMA-IR on RLTL was assessed by univariate analysis, adjusting for potential confounders. RESULTS: In age-adjusted analyses, multivariate linear regression revealed a significant association of the levels of elaidic acid, HOMA-IR, monounsaturated fatty acids (MUFA) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) with RLTL. After adjustment of age and gender, race, smoking, drinking, tea, and exercise, elaidic acid, and omega-3 (n-3) PUFA were negatively associated with RLTL, and HOMA-IR and n-6 PUFA were positively associated with RLTL. These associations were not significantly altered upon further adjustment for anthropometric and biochemical indicators. Meanwhile, the effect of the interaction of elaidic acid and HOMA-IR on RLTL was significant, and remained unchanged even after adjusting for the aforementioned potential confounders. Interestingly, individuals who had the lowest HOMA-IR and the highest elaidic acid levels presented the shortest RLTL. CONCLUSIONS: Our findings indicated that shorter RLTL was associated with lower HOMA-IR and higher elaidic acid level. These findings might open a new avenue for exploring the potential role of the interaction between elaidic acid and HOMA-IR in maintaining RLTL.


Assuntos
Resistência à Insulina/fisiologia , Leucócitos/metabolismo , Fosfolipídeos/sangue , Telômero/metabolismo , Adulto , Idoso , Estudos Transversais , Ácidos Graxos Monoinsaturados/sangue , Ácidos Graxos Ômega-6/sangue , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Telômero/genética , Homeostase do Telômero/genética , Homeostase do Telômero/fisiologia
19.
J Biol Chem ; 293(16): 5975-5986, 2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29496996

RESUMO

Induction of interferons (IFNs) is a central event of antiviral innate immunity. As crucial posttranscriptional regulators, microRNAs (miRNAs) are important for IFN-mediated host defense. Although screening has indicated a substantial number of miRNAs to be differentially expressed after IFN stimulation, the detailed mechanisms of these miRNAs in the antiviral response are underexplored and of great significance. Here, we show that hsa-miR-1225-3p is specifically down-regulated by type I IFN through the IFN/JAK/STAT signaling pathway. Silencing endogenous miR-1225-3p inhibited infection by multiple IFN-susceptible viruses, including hepatitis C virus, Sendai virus, and Newcastle disease virus. In contrast, overexpression of miR-1225-3p impaired the antiviral effect of IFNs and facilitated viral infection. Regarding the mechanism, we identified growth factor receptor-bound protein 2-associated binding protein 3 (GAB3) as a direct target of miR-1225-3p. GAB3 expression was up-regulated by IFN, and overexpression of GAB3 demonstrated potent antiviral effects through enhancing IFN response and virus-triggered innate immune activation. Taken together, our findings reveal the biological function of miR-1225-3p for the first time and propose a novel antiviral regulation pathway in which miRNA and GAB3 participate. This study contributes to the understanding of host miRNA participation in antiviral processes of IFN.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antivirais/farmacologia , Regulação para Baixo/efeitos dos fármacos , Interferons/farmacologia , MicroRNAs/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , MicroRNAs/imunologia , Transdução de Sinais/efeitos dos fármacos
20.
Phys Rev Lett ; 122(12): 123903, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30978034

RESUMO

We demonstrate valley-dependent vortex generation in photonic graphene. Without breaking inversion symmetry, the excitation of two valleys leads to the formation of an optical vortex upon Bragg reflection to the third equivalent valley, with its chirality determined by the valley degree of freedom. Vortex-antivortex pairs with valley-dependent topological charge flipping are also observed and corroborated by numerical simulations. Furthermore, we develop a three-band effective Hamiltonian model to describe the dynamics of the coupled valleys and find that the commonly used two-band model is not sufficient to explain the observed vortex degeneracy lifting. Such valley-polarized vortex states arise from high-band excitation without a synthetic-field-induced gap opening. Our results from a photonic setting may provide insight for the study of valley contrasting and Berry-phase-mediated topological phenomena in other systems.

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