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1.
Nat Commun ; 12(1): 897, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33563974

RESUMO

The dynamics, duration, and nature of immunity produced during SARS-CoV-2 infection are still unclear. Here, we longitudinally measured virus-neutralising antibody, specific antibodies against the spike (S) protein, receptor-binding domain (RBD), and the nucleoprotein (N) of SARS-CoV-2, as well as T cell responses, in 25 SARS-CoV-2-infected patients up to 121 days post-symptom onset (PSO). All patients seroconvert for IgG against N, S, or RBD, as well as IgM against RBD, and produce neutralising antibodies (NAb) by 14 days PSO, with the peak levels attained by 15-30 days PSO. Anti-SARS-CoV-2 IgG and NAb remain detectable and relatively stable 3-4 months PSO, whereas IgM antibody rapidly decay. Approximately 65% of patients have detectable SARS-CoV-2-specific CD4+ or CD8+ T cell responses 3-4 months PSO. Our results thus provide critical evidence that IgG, NAb, and T cell responses persist in the majority of patients for at least 3-4 months after infection.


Assuntos
Anticorpos Antivirais/imunologia , /virologia , Linfócitos T/imunologia , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Memória Imunológica , Interferon gama/metabolismo , Cinética , Antígenos Comuns de Leucócito/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptores CCR7/metabolismo
2.
J Med Virol ; 93(4): 1923-1925, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33386773

RESUMO

SARS-CoV-2 nucleocapsid (N) protein has been proposed as a good vaccine target. N-specific T cells were observed in SARS-CoV-2 N immunized mice and COVID-19 convalescents. It is of importance to identify the T cell responses triggered by SARS-CoV-2 N protein. Intradermal immunization with SARS-CoV N protein was demonstrated to elicit non-protective T cell responses which may be avoided by intranasal vaccination. Therefore, we conducted intranasal vaccination of BALB/c mice with recombinant adenovirus type-5 expressing SARS-CoV-2 N protein. Such procedure induced CD8 T cell responses in the lung. Meanwhile CD4 T cell responses were observed in the spleen, which was associated with robust antibody production. Our study further supports the notion that SARS-CoV-2 N protein can work as a target for vaccine development.

3.
FEBS J ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33025631

RESUMO

Neddylation is one type of protein post-translational modification by conjugating a ubiquitin-like protein neural precursor cell-expressed developmentally downregulated protein 8 to substrate proteins via a cascade involving E1, E2, and E3 enzymes. The best-characterized substrates of neddylation are cullins, essential components of cullin-RING E3 ubiquitin-ligase complexes. The discovery of noncullin neddylation targets indicates that neddylation may have diverse biological functions. Indeed, neddylation has been implicated in various cellular processes including cell cycle progression, metabolism, immunity, and tumorigenesis. Here, we summarized the reported neddylation substrates and also discuss the functions of neddylation in the immune system and metabolism.

4.
Exp Lung Res ; 46(9): 321-331, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32820688

RESUMO

BACKGROUND: Asthma is one of the most frequent and serious diseases worldwide. Inflammation has been reported to correlate with airway remodeling, which is critical for the progression of asthma. Better understanding of novel molecules modulating asthma and the underlying mechanism will benefit explorations of new treatments. Method: To explore the role of miR-200a and miR-200b in asthma, miR-200a mimics/inhibitor and miR-200b mimics/inhibitor were employed in A549 cells, respectively. Expression levels of inflammatory cytokines, including TNF-α, IL-4, IL-5, IL-13 and IL-1ß, were measured by quantitative real time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). A dual luciferase reporter assay was performed to identify whether miR-200a/200b directly bound to Orosomucoid 1-like 3 (ORMDL3). ERK, p-ERK and MMP-9, involved in downstream pathways of ORMDL3, were detected using qRT-PCR and western blotting. Results: MiR-200a/200b silencing significantly increased the expression of inflammatory cytokines, including TNF-α, IL-4, IL-5, IL-13 and IL-1ß, in A549 cells. ORMDL3 was the target gene of miR-200a/200b, with high expression levels in miR-200a inhibitor and miR-200b inhibitor groups. MiR-200a and miR-200b played synergistic roles in the regulation of the inflammatory effect in A549 cells. Expression levels of p-ERK and MMP-9 were significantly increased in miR-200a inhibitor and miR-200b inhibitor groups and were rescued by ERK inhibitor and MMP-9 inhibitor, respectively. Conclusion: These findings suggest that miR-200a and miR-200b are required to regulate asthma inflammation. Reduction in miR-200a/200b promotes the development of asthma inflammation by targeting ORMDL3 to activate the ERK/MMP-9 pathway. Therefore, elevating miR-200a and miR-200b and decreasing ORMDL3 might be potential strategies for inhibition of the asthma process.

5.
Nanotechnology ; 31(37): 375401, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32480392

RESUMO

Rechargeable aqueous zinc-ion batteries (ZIBs) have attracted significant attention due to the distinguishing characteristics of zinc metal, including its low price, abundance in earth, safety and high theoretical specific capacity of 820 mAh g-1. Manganese dioxide (MnO2) is a promising cathode for ZIBs due to high theoretical specific capacity, high discharge voltage plateau, cost-effectiveness and nontoxicity. However, the low electronic conductivity and volumetric changes during electrochemical cycling hinder its practical utilization. Herein, we demonstrate a polyacrylic acid (PAA)-assisted assembling strategy to fabricate freestanding and flexible MnO2/carbon nanotube/PAA (MnO2/CNT/PAA) cathodes for ZIBs. PAA plays an important role in providing excellent mechanical properties to the free-standing electrode. Moreover, the presence of CNT forms an electron conductive network, and the porous structure of MnO2/CNT/PAA electrode accommodates the volumetric variations of MnO2 during charge/discharge cycling. The as-fabricated quasi-solid-state Zn-MnO2/CNT/PAA battery delivers a high charge storage capacity of 302 mAh g-1 at 0.3 A g-1 and retains 82% of the initial capacity after 1000 charge/discharge cycles at 1.5 A g-1. The calculated volumetric energy density of Zn-MnO2/CNT/PAA battery is 8.5 mW h cm-3 (with a thickness of 0.08 cm), which is significantly higher than the reported alkali-ion batteries (1.3 mW h cm-3) and comparable to supercapacitors (6.8 mW h cm-3) and Ni-Zn batteries (7.76 mW h cm-3). The current work demonstrates that free-standing MnO2/CNT/PAA composite is a promising cathode for ZIBs.

6.
Appl Spectrosc ; 74(10): 1230-1237, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32597684

RESUMO

The confocal Raman microscope (CRM) is a powerful tool in analytical science. Image quality is the most important performance indicator of CRM systems. The point spread function (PSF) is one of the most useful tools to evaluate the image quality of microscopic systems. A method based on a point-like object is proposed to measure the PSF of CRM, and the size effect of spherical objects is discussed. A series of phantoms are fabricated by embedding different sizes of polystyrene microspheres into polydimethylsiloxane matrix. The diameters of microspheres are from 0.2 µm to 5 µm. The phantoms are tested by measuring the PSF of a commercial CRM whose nominal lateral resolution is about 1 µm. Results of the PSF are obtained and the accuracy of resolution is used to evaluate the size effect of the microspheres. Experimental results are well consistent with theoretical analysis. The error of the PSF can be decreased by reducing the diameter of the microsphere but meanwhile the signal-to-noise ratio (S/N) will be lowered as well. The proper diameter of microspheres is proposed in consideration of the trade-off between the S/N and the measurement error of the PSF. Results indicate that the method provides a useful approach to measurement of the PSF and the resolution of the CRM.

7.
Sheng Li Xue Bao ; 72(2): 167-174, 2020 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-32328610

RESUMO

Humans with chronic psychological stress are prone to develop multiple disorders of body function including impairment of immune system. Chronic psychological stress has been reported to have negative effects on body immune system. However, the underlying mechanisms have not been clearly demonstrated. All immune cells are derived from hematopoietic stem cells (HSC) in the bone marrow, including myeloid cells which comprise the innate immunity as a pivotal component. In this study, to explore the effects of chronic psychological stress on HSC and myeloid cells, different repeated restraint sessions were applied, including long-term mild restraint in which mice were individually subjected to a 2 h restraint session twice daily (morning and afternoon/between 9:00 and 17:00) for 4 weeks, and short-term vigorous restraint in which mice were individually subjected to a 16 h restraint session (from 17:00 to 9:00 next day) for 5 days. At the end of restraint, mice were sacrificed and the total cell numbers in the bone marrow and peripheral blood were measured by cell counting. The proportions and absolute numbers of HSC (Lin-CD117+Sca1+CD150+CD48-) and myeloid cells (CD11b+Ly6C+) were detected by fluorescence activated cell sorting (FACS) analysis. Proliferation of HSC was measured by BrdU incorporation assay. The results indicated that the absolute number of HSC was increased upon long-term mild restraint, but was decreased upon short-term vigorous restraint with impaired proliferation. Both long-term mild restraint and short-term vigorous restraint led to the accumulation of CD11b+Ly6C+ cells in the bone marrow as well as in the peripheral blood, as indicated by the absolute cell numbers. Taken together, long-term chronic stress led to increased ratio and absolute number of HSC in mice, while short-term stress had opposite effects, which suggests that stress-induced accumulation of CD11b+Ly6C+ myeloid cells might not result from increased number of HSC.


Assuntos
Proliferação de Células , Células-Tronco Hematopoéticas/citologia , Restrição Física , Estresse Psicológico , Animais , Antígenos Ly/metabolismo , Células da Medula Óssea/citologia , Antígeno CD11b/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
8.
Nanoscale ; 12(6): 4150-4158, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32022061

RESUMO

Rechargeable aqueous zinc-ion batteries (ZIBs) have attracted significant attention in the energy storage field. Manganese-based materials are the most promising cathode materials for ZIBs but they suffer from low electronic conductivity. Herein, a high-performance cathode for ZIBs based on nanocomposites consisting of mixed-valence manganese dioxide (Mn III and IV) and polypyrrole (MnOx/PPy) is prepared through an efficient one-step organic/inorganic interface redox reaction. The role of polypyrrole (PPy) in the MnOx/PPy cathode is elaborated. It not only provides an effective conductive network for MnOx but also contributes to the capacity of the composite. By optimizing the amount of PPy, the MnOx/PPy composite with 12 wt% PPy exhibits the highest capacity. As a result, the corresponding Zn-MnOx/PPy battery delivers a high capacity (302.0 mA h g-1 at 0.15 A g-1), excellent rate performance (159.9 mA h g-1 at 3 A g-1) and superior cycling stability. Furthermore, the results of ex situ characterization analysis reveal that H+ and Zn2+ insertion/extraction both occur in MnOx/PPy particles during the discharging/charging process, while only Zn2+ insertion/extraction occurs in the PPy electrode. This work develops an efficient one-step synthesis method for large scale production of manganese-based materials/conducting polymers as the cathode for ZIB application, and provides an insight into its energy storage mechanism.

9.
Proc Natl Acad Sci U S A ; 117(5): 2473-2483, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31941714

RESUMO

Neddylation is a ubiquitination-like pathway that controls cell survival and proliferation by covalently conjugating NEDD8 to lysines in specific substrate proteins. However, the physiological role of neddylation in mammalian metabolism remains elusive, and no mitochondrial targets have been identified. Here, we report that mouse models with liver-specific deficiency of NEDD8 or ubiquitin-like modifier activating enzyme 3 (UBA3), the catalytic subunit of the NEDD8-activating enzyme, exhibit neonatal death with spontaneous fatty liver as well as hepatic cellular senescence. In particular, liver-specific UBA3 deficiency leads to systemic abnormalities similar to glutaric aciduria type II (GA-II), a rare autosomal recessive inherited fatty acid oxidation disorder resulting from defects in mitochondrial electron transfer flavoproteins (ETFs: ETFA and ETFB) or the corresponding ubiquinone oxidoreductase. Neddylation inhibition by various strategies results in decreased protein levels of ETFs in neonatal livers and embryonic hepatocytes. Hepatic neddylation also enhances ETF expression in adult mice and prevents fasting-induced steatosis and mortality. Interestingly, neddylation is active in hepatic mitochondria. ETFs are neddylation substrates, and neddylation stabilizes ETFs by inhibiting their ubiquitination and degradation. Moreover, certain mutations of ETFs found in GA-II patients hinder the neddylation of these substrates. Taken together, our results reveal substrates for neddylation and add insight into GA-II.


Assuntos
Flavoproteínas Transferidoras de Elétrons/metabolismo , Ácidos Graxos/metabolismo , Fígado/metabolismo , Deficiência Múltipla de Acil Coenzima A Desidrogenase/metabolismo , Animais , Flavoproteínas Transferidoras de Elétrons/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genética , Proteína NEDD8/genética , Proteína NEDD8/metabolismo , Oxirredução , Ubiquitinação , Ubiquitinas/genética , Ubiquitinas/metabolismo
10.
Brain Res Bull ; 154: 102-105, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31733348

RESUMO

Unconjugated bilirubin, the end product of heme catabolism and antioxidant, induced brain damage in human neonates is a well-recognized clinical syndrome. However, the cellular and molecular mechanisms underlying bilirubin neurotoxicity remain unclear. To characterize the sequence of events leading to bilirubin-induced neurotoxicity, we investigated whether bilirubin-induced glial activation was involved in bilirubin neurotoxicity by exposing co-cultured rat glial cells and cerebellar granule neurons (CGN) to bilirubin. We found that bilirubin could markedly induce the expression of TNF-α and iNOS in glial cells, and even at low concentrations, the co-culture of glial cells with neurons significantly enhances neurotoxicity of bilirubin. Pretreatment of the co-cultured cells with minocycline protected CGN from glia-mediated bilirubin neurotoxicity and inhibited overexpression of TNF-α and iNOS in glia. Furthermore, we found that high doses of bilirubin were able to induce glial injury, and minocycline attenuated bilirubin-induced glial cell death. Our data suggest that glial cells play an important role in brain damage caused by bilirubin, and minocycline blocks bilirubin-induced encephalopathy possibly by directly and indirectly inhibiting neuronal death pathways.

11.
Cancer Cell Int ; 19: 255, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31592239

RESUMO

Background: Hepatocellular carcinoma (HCC), the most common primary cancer of the liver, is one of the most common malignancies and the leading cause of cancer-related death worldwide. Leucine-rich repeat and sterile alpha motif containing 1 (LRSAM1) is an E3 ubiquitin ligase involved in diverse cellular activities, including the regulation of cargo sorting, cell adhesion and antibacterial autophagy. The role of LRSAM1 in HCC remains unknown. Methods: In this study, we reviewed the TCGA database and then performed gain-of-function and loss-of-function analyses of LRSAM1 in HCC cell lines. Results: We found that the mRNA expression level of LRSAM1 was significantly increased in clinical HCC tissues in the TCGA database. Transient LRSAM1 knockdown in several human HCC cell lines led to reduced growth in conventional culture conditions. Stable LRSAM1 knockdown in HepG2 cells led to impaired anchorage-independent growth whereas its stable ectopic overexpression yielded the opposite effects. LRSAM1 overexpression in HepG2 cells enhanced in vivo tumorigenicity, whereas LRSAM1 knockdown in this cell line significantly impaired tumor growth. Conclusions: Our data suggest that LRSAM1 promotes the oncogenic growth of human HCC cells, although the underlying mechanisms remain to be explored.

12.
Theranostics ; 9(3): 811-828, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809310

RESUMO

Targeting cancer stem cells (CSCs) has been proposed as a new strategy to eradicate malignancies, including hepatocellular carcinoma (HCC). However, the mechanisms by which CSCs sustain their self-renewal and chemoresistance remain elusive. Nanog is a master transcriptional regulator of stemness, especially in CSCs. Its expression is tightly regulated by the ubiquitin-proteasome system in embryonic stem cells (ESCs). Whether the suppression of Nanog ubiquitination contributes to its over-expression in CSCs has not been explored. In addition, the role of receptor for activated C kinase 1 (RACK1), an adaptor protein implicated in HCC growth, in liver CSC-like traits remains to be determined. Methods: In vitro and in vivo assays were performed to investigate the role of RACK1 in liver CSC-like phenotype and murine ESC function. How RACK1 regulates Nanog expression was explored by immunoblotting and immunohistochemistry. The interaction of RACK1 with Nanog and the consequent effects on Nanog ubiquitination and stemness were then analyzed. Results: RACK1 promotes self-renewal and chemoresistance of human liver CSCs and maintains murine ESC function. Consistently, RACK1 enhances the expression of Nanog in human HCC cells and murine ESCs. The protein levels of RACK1 in clinical HCC tissues positively correlate with those of Nanog. Further exploration indicates that RACK1 directly binds to Nanog, which prevents its recruitment of E3 ubiquitin ligase FBXW8 and ubiquitin-dependent degradation. The interaction with Nanog is essential for RACK1 to promote stemness. Conclusions: Our data provide novel insights into the regulation of Nanog protein levels, as well the key role of RACK1 to enhance self-renewal and chemoresistance of CSCs in human HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/metabolismo , Proteína Homeobox Nanog/metabolismo , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Receptores de Quinase C Ativada/metabolismo , Animais , Ligação Competitiva , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Células-Tronco Embrionárias , Proteínas F-Box/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos NOD , Proteína Homeobox Nanog/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Ligação Proteica , Ubiquitinação
13.
Proc Natl Acad Sci U S A ; 116(10): 4661-4670, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30765517

RESUMO

The development of the cerebellum depends on intricate processes of neurogenesis, migration, and differentiation of neural stem cells (NSCs) and progenitor cells. Defective cerebellar development often results in motor dysfunctions and psychiatric disorders. Understanding the molecular mechanisms that underlie the complex development of the cerebellum will facilitate the development of novel treatment options. Here, we report that the receptor for activated C kinase (Rack1), a multifaceted signaling adaptor protein, regulates mammalian cerebellar development in a cell type-specific manner. Selective deletion of Rack1 in mouse NSCs or granule neuron progenitors (GNPs), but not Bergmann glial cells (BGs), causes severe defects in cerebellar morphogenesis, including impaired folia and fissure formation. NSCs and GNPs lacking Rack1 exhibit enhanced Wnt/ß-catenin signaling but reduced Sonic hedgehog (Shh) signaling. Simultaneous deletion of ß-catenin in NSCs, but not GNPs, significantly rescues the Rack1 mutant phenotype. Interestingly, Rack1 controls the activation of Shh signaling by regulating the ubiquitylation and stability of histone deacetylase 1 (HDAC1)/HDAC2. Suppression of HDAC1/HDAC2 activity in the developing cerebellum phenocopies the Rack1 mutant. Together, these results reveal a previously unknown role of Rack1 in controlling mammalian cerebellar development by opposite regulation of Wnt/ß-catenin and Shh signaling pathways.


Assuntos
Cerebelo/crescimento & desenvolvimento , Cerebelo/metabolismo , Proteínas Hedgehog/metabolismo , Receptores de Quinase C Ativada/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Camundongos , Camundongos Knockout , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Receptores de Quinase C Ativada/genética , Transdução de Sinais , Proteínas Wnt/genética , beta Catenina/genética
14.
Front Cell Neurosci ; 13: 539, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31920545

RESUMO

Purkinje cells (PCs) in the cerebellum receive two excitatory afferents including granule cells-derived parallel fiber (PF) and the climbing fiber. Scaffolding protein Rack1 is highly expressed in the cerebellar PCs. Here, we found delayed formation of specific cerebellar vermis lobule and impaired motor coordination in PC-specific Rack1 conditional knockout mice. Our studies further revealed that Rack1 is essential for PF-PC synapse formation. In addition, Rack1 plays a critical role in regulating synaptic plasticity and long-term depression (LTD) induction of PF-PC synapses without changing the expression of postsynaptic proteins. Together, we have discovered Rack1 as the crucial molecule that controls PF-PC synaptogenesis and synaptic plasticity. Our studies provide a novel molecular insight into the mechanisms underlying the neural development and neuroplasticity in the cerebellum.

15.
Mol Cell Biochem ; 451(1-2): 155-163, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30019299

RESUMO

As a classic differentiation agent, all-trans retinoic acid (ATRA) has been widely used in the treatment of acute promyelocytic leukemia (APL). However, the clinical application of ATRA has strict limitations, for its severe side effects due to the accumulation of peripheral blood leukocytes. The scaffold protein RACK1 (Receptor for activated C kinase 1), which regulates multiple signaling pathways, has been proposed to contribute to the survival of leukemic progenitors. But it remains unclear whether it is also involved in the oncogenic growth of APL. In the present study, we demonstrate that silencing of endogenous RACK1 expression synergized with ATRA to promote the death of NB4 and HL-60 APL cells without effect on cell differentiation induced by ATRA. Interestingly, RACK1 knockdown combined with ATRA treatment mainly induces apoptosis. It is distinct to the necrotic cell death induced by idarubicin in combination with ATRA, a regimen extensively used in the clinic to prevent neutrophil accumulation. Further exploration revealed that the lysosome-autophagy pathway is likely to be responsible for the anti-apoptotic role of RACK1. Taken together, our findings indicate that RACK1 is essential in maintaining the malignant features of APL, and targeting RACK1 may have promising therapeutic implications in the treatment of APL.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia , Leucemia Promielocítica Aguda/patologia , Proteínas de Neoplasias/deficiência , Receptores de Quinase C Ativada/deficiência , Tretinoína/farmacologia , Diferenciação Celular , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas
16.
PLoS Pathog ; 14(11): e1007440, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30462731

RESUMO

CD4+ T cells play predominant roles in protective immunity against blood-stage Plasmodium infection, both for IFN-γ-dependent effector mechanisms and providing B cell helper signals. Neddylation, an ubiquitination-like process triggered by covalent conjugation of NEDD8 to specific targets, has emerged as a potential regulator of T cell activities to TCR engagement. However, its contribution to T cell-mediated immunity to blood-stage malaria remains unclear. Here using an experimental model induced by Plasmodium yoelii 17XNL, and conditional knockout mice with T cell-specific deficiency of crucial components of neddylation pathway, we demonstrate activation of neddylation in T cells during blood-stage Plasmodium infection is essential for parasite control and host survival. Mechanistically, we show that apart from promoting CD4+ T cell activation, proliferation, and development of protective T helper 1 (Th1) cell response as suggested previously, neddylation is also required for supporting CD4+ T cell survival, mainly through B-cell lymphoma-2 (Bcl-2) mediated suppression of the mitochondria-dependent apoptosis. Furthermore, we provide evidence that neddylation contributes to follicular helper T (Tfh) cell differentiation, probably via augmenting the ubiquitin ligase Itch activity and proteasomal degradation of FoxO1, thereby facilitating germinal center (GC) formation and parasite-specific antibody production. This study identifies neddylation as a positive regulator of anti-Plasmodium immunity and provides insight into an involvement of such pathway in host resistance to infectious diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Malária/imunologia , Proteína NEDD8/fisiologia , Imunidade Adaptativa/imunologia , Animais , Linfócitos B/imunologia , Imunidade Celular , Interferon gama/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL/fisiologia , Camundongos Knockout , Proteína NEDD8/metabolismo , Plasmodium yoelii/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Células Th1/imunologia
17.
Rev Sci Instrum ; 89(9): 096108, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30278700

RESUMO

High-space-resolving information of hotspot electron temperature is a foundation for further research on physical processes of implosion in inertial confinement fusion. This work proposed a novel high-space-resolving electron temperature detector, which is based on the bremsstrahlung radiation mechanism of the implosion hotspot and uses two-channel Kirkpatrick-Baez microscopes. In this novel detector, an optical quasi-coaxis method was used to eliminate the strong impact of the view field difference on the high space resolution and correctness of the electron temperature diagnosis, and a compound KB microscope method was proposed to reduce the number of spherical reflectors and save space.

18.
J Pain Res ; 11: 2247-2256, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349351

RESUMO

Purpose: Ventral tegmental area (VTA) dopamine system plays an important role in depression and is also involved in pain experience. In this study, we investigated the VTA dopaminergic (DA) neuron firing and local field potential (LFP) in pain-related depression, and we try to explore the underlying relationship between pain and depression. Materials and methods: We used neuropathic pain model [spare nerve injury (SNI)] to induce pain-related depression. The Dixon up-down method was used to test mechanical hypersensitivity. Behavioral changes like open field test, sucrose preference test, and forced swim test were used to test depression-like behaviors. Gabapentin (GBP) was used to explore the chronic analgesic treatment that could reverse pain-related depression. To investigate the in vivo variations of VTA DA neuron firing and LFP, multichannel acquisition processor system was used. Results: We used SNI to induce depression-like behaviors. Repeated GBP treatment reversed these behaviors after 14 days of injection. An in vivo electrophysiological analysis of the firing characteristics of VTA DA neurons and LFP revealed that SNI increased the firing rate of DA neurons, but not the burst firing activity. Surprisingly, chronic GBP reversed the firing rate of DA neurons and reduced the burst firing activity. Moreover, SNI increased the LFP power in delta and theta oscillation and decreased it in beta oscillation. Repeated administration of GBP significantly suppressed theta oscillation. Above all, chronic GBP altered these characteristics to reverse depression-like behaviors. Conclusion: The present study confirmed that the tonic firing activity of VTA DA neurons, but not the burst firing activity, was the key factor in peripheral neuropathy-induced depression. Chronic GBP regulated the firing pattern of DA neurons and decreased theta oscillation in VTA to treat pain-related depression. This variation tendency of electrophysiological characteristics of VTA DA neurons and theta oscillation in VTA might represent an attempt to cope with pain-related negative mood disorder.

19.
Rev Sci Instrum ; 89(8): 083108, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30184675

RESUMO

An eight-channel x-ray flat crystal spectrometer was developed for high energy density physics research at the Shenguang-III (SG-III) laser facility. The spectrometer uses trihydroxymethylaminomethane crystals (2d = 8.78 Å) to record Ti K-shell emission in the photon energy range of 4.65-5.05 keV. The spectrometer couples to an x-ray framing camera to achieve time-resolution. This has four microstrips, and each strip records two snapshots of the emission image. Based on the intersection positioning system with a dual-charge coupled device, the alignment system is easily operated and efficient. The instrument was tested and used for Au hohlraum plasma diagnosis experiments on SG-III. The He-α line and its Li-like satellites and the Ly-α line of a Ti tracer were detected, from which the spectral resolution of the instrument was analyzed. The spectral resolution E/ΔE at the Ti He-α line ranges from about 500 to 880 and mainly limited by the x-ray source size.

20.
Oncol Lett ; 15(5): 8039-8045, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29849806

RESUMO

Neddylation is a ubiquitination-like pathway. It has been reported that neddylation inhibition with the pharmacological agent MLN4924 potently uppresses lipopolysaccharide (LPS)-induced proinflammatory cytokine production, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, by preventing the degradation of phosphorylated inhibitor of κB (p-IκB) in macrophages. However, whether neddylation serves a similar role in neutrophils remains unknown. In the present study MLN4924 treatment led to the accumulation of P-IκBα in neutrophils as well as the decreased production of TNF-α, IL-6 and IL-1ß in response to LPS, in a dose-dependent manner. The viability of neutrophils was only marginally affected in the same conditions, without statistical significance. Furthermore, the nuclear factor (NF)-κB inhibitor JSH-23 mimicked the effects of MLN4924 in neutrophils, and the inhibitory effects of MLN4924 on LPS-induced proinflammatory cytokine production diminished in the presence of JSH-23. Thus, the results of the present study suggest that neddylation inhibition suppresses neutrophil function by suppressing the NF-κB signaling pathway.

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