RESUMO
The nature of the anti-tumor immune response changes as primary tumors progress and metastasize. We investigated the role of resident memory (Trm) and circulating memory (Tcirm) cells in anti-tumor responses at metastatic locations using a mouse model of melanoma-associated vitiligo. We found that the transcriptional characteristics of tumor-specific CD8+ T cells were defined by the tissue of occupancy. Parabiosis revealed that tumor-specific Trm and Tcirm compartments persisted throughout visceral organs, but Trm cells dominated lymph nodes (LNs). Single-cell RNA-sequencing profiles of Trm cells in LN and skin were distinct, and T cell clonotypes that occupied both tissues were overwhelmingly maintained as Trm in LNs. Whereas Tcirm cells prevented melanoma growth in the lungs, Trm afforded long-lived protection against melanoma seeding in LNs. Expanded Trm populations were also present in melanoma-involved LNs from patients, and their transcriptional signature predicted better survival. Thus, tumor-specific Trm cells persist in LNs, restricting metastatic cancer.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Linfonodos/imunologia , Melanoma Experimental/imunologia , Melanoma/imunologia , Neoplasias Cutâneas/imunologia , Animais , Humanos , Camundongos , Vitiligo , Melanoma Maligno CutâneoRESUMO
Di Pilato et al. demonstrate that CXCR6 positions TCF-1- transitory CD8+ cytotoxic lymphocytes (CTLs) with perivascular CCR7+ dendritic cells (DCs) within the tumor stroma to receive IL-15 survival signals. The requirement for CXCR6 and its strong prediction of overall patient survival highlight the importance of continued CTL-DC interactions in sustaining tumor immunity.
Assuntos
Neoplasias , Linfócitos T Citotóxicos , Linfócitos T CD8-Positivos , Células Dendríticas , Humanos , Neoplasias/terapia , Transdução de SinaisRESUMO
Interleukin 6 (IL-6) is known to regulate the CD4 T cell function by inducing gene expression of a number of cytokines through activation of Stat3 transcription factor. Here, we reveal that IL-6 strengthens the mechanics of CD4 T cells. The presence of IL-6 during activation of mouse and human CD4 T cells enhances their motility (random walk and exploratory spread), resulting in an increase in travel distance and higher velocity. This is an intrinsic effect of IL-6 on CD4 T-cell fitness that involves an increase in mitochondrial Ca2+ Although Stat3 transcriptional activity is dispensable for this process, IL-6 uses mitochondrial Stat3 to enhance mitochondrial Ca2+-mediated motility of CD4 T cells. Thus, through a noncanonical pathway, IL-6 can improve competitive fitness of CD4 T cells by facilitating cell motility. These results could lead to alternative therapeutic strategies for inflammatory diseases in which IL-6 plays a pathogenic role.
Assuntos
Movimento Celular/fisiologia , Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Linfócitos T CD4-Positivos/metabolismo , Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Foxo1 is an essential transcription factor required for the survival and differentiation of memory CD8 T cells, yet it is unclear whether these Foxo1-dependent functions are inherently coupled. To address this question, we examined the effects of different Foxo1 posttranslational modifications. Phosphorylation of Foxo1 by Akt kinases at three distinct residues is well characterized to inhibit Foxo1 transcriptional activity. However, the effect of Foxo1 phosphorylation within its DNA-binding domain at serine 209 by Mst1 kinase is not fully understood. In this study, we show that an S209A phospho-null Foxo1 exhibited Akt-dependent nuclear trafficking in mouse CD8 T cells and augmented the expression of canonical Foxo1 target genes such as Il7r and Sell In contrast, an S209D phosphomimetic Foxo1 (SD-Foxo1) was largely excluded from the nucleus of CD8 T cells and failed to transactivate these genes. RNA sequencing analysis revealed that SD-Foxo1 was associated with a distinct Foxo1-dependent transcriptional profile, including genes mediating CD8 effector function and cell survival. Despite defective transactivation of canonical target genes, SD-Foxo1 promoted IL-15-mediated CD8 T cell survival in vitro and survival of short-lived effector cells in vivo in response to Listeria monocytogenes infection. However, SD-Foxo1 actively repressed CD127 expression and failed to generate memory precursors and long-lived memory T cells. Together, these data indicate that S209 is a critical residue for the regulation of Foxo1 subcellular localization and for balancing CD8 T cell differentiation and survival.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Proteína Forkhead Box O1/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Sítios de Ligação/genética , Biomimética , Diferenciação Celular , Sobrevivência Celular , Proteína Forkhead Box O1/genética , Redes Reguladoras de Genes , Células HEK293 , Humanos , Memória Imunológica , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Transgênicos , Mutação/genética , Fosforilação , Ligação Proteica , Serina/genéticaRESUMO
AIMS: This study aimed to evaluate the effects of storage and different temperatures on the antibacterial activity and physicochemical characteristics of several types of honey. METHODS AND RESULTS: Honeys stored for 16 weeks at 37 and 45°C showed significant declines in antibacterial activity determined by minimum inhibitory concentrations, the loss of hydrogen peroxide, decreases in honey pH, and increases in honey colour, with changes most pronounced at 45°C. In contrast, honeys stored for 16 weeks at ambient (â¼22°C) and cold (4, -20, and -80°C) temperatures showed only minor changes. In a second set of 12 honeys stored for 16-32 months at ambient temperature and then 4°C, honeys showed minor changes in antibacterial activity, increases in colour, and decreases in pH. For a third set of 17 honeys stored for five years at ambient temperature, the honeys showed almost complete loss of hydrogen peroxide and were all significantly darker in colour, but showed varied changes in antibacterial activity. CONCLUSIONS: Heat was detrimental to the antibacterial activity of honeys, as was long-term storage at ambient temperatures for some honeys but not others.
Assuntos
Mel , Peróxido de Hidrogênio , Peróxido de Hidrogênio/farmacologia , Mel/análise , Austrália , Temperatura , Cor , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/químicaRESUMO
Staphylococcus aureus is a major foodborne pathogen that leads to various diseases due to its biofilm and virulence factors. This study aimed to investigate the inhibitory effect of 2R,3R-dihydromyricetin (DMY), a natural flavonoid compound, on the biofilm formation and virulence of S. aureus, and to explore the mode of action using transcriptomic and proteomic analyses. Microscopic observation revealed that DMY could remarkably inhibit the biofilm formation by S. aureus, leading to a collapse on the biofilm architecture and a decrease in viability of biofilm cell. Moreover, the hemolytic activity of S. aureus was reduced to 32.7% after treatment with subinhibitory concentration of DMY (p < 0.01). Bioinformation analysis based on RNA-sequencing and proteomic profiling revealed that DMY induced 262 differentially expressed genes and 669 differentially expressed proteins (p < 0.05). Many downregulated genes and proteins related to surface proteins were involved in biofilm formation, including clumping factor A (ClfA), iron-regulated surface determinants (IsdA, IsdB, and IsdC), fibrinogen-binding proteins (FnbA, FnbB), and serine protease. Meanwhile, DMY regulated a wide range of genes and proteins enriched in bacterial pathogenesis, cell envelope, amino acid metabolism, purine and pyrimidine metabolism, and pyruvate metabolism. These findings suggest that DMY targets S. aureus through multifarious mechanisms, and especially prompt that interference of surface proteins in cell envelope would lead to attenuation of biofilm and virulence.
Assuntos
Infecções Estafilocócicas , Staphylococcus aureus , Humanos , Staphylococcus aureus/genética , Virulência , Proteômica , Transcriptoma , Biofilmes , Proteínas de Membrana/genética , Antibacterianos/farmacologiaRESUMO
B7H6, a stress-induced ligand which binds to the NK cell receptor NKp30, has recently emerged as a promising candidate for immunotherapy due to its tumor-specific expression on a broad array of human tumors. NKp30 can function as a chimeric antigen receptor (CAR) extracellular domain but exhibits weak binding with a fast on and off rate to B7H6 compared to the TZ47 anti-B7H6 single-chain variable fragment (scFv). Here, directed evolution using yeast display was employed to isolate novel NKp30 variants that bind to B7H6 with higher affinity compared to the native receptor but retain its fast association and dissociation profile. Two variants, CC3 and CC5, were selected for further characterization and were expressed as soluble Fc-fusion proteins and CARs containing CD28 and CD3ς intracellular domains. We observed that Fc-fusion protein forms of NKp30 and its variants were better able to bind tumor cells expressing low levels of B7H6 than TZ47, and that the novel variants generally exhibited improved in vitro tumor cell killing relative to NKp30. Interestingly, CAR T cells expressing the engineered variants produced unique cytokine signatures in response to multiple tumor types expressing B7H6 compared to both NKp30 and TZ47. These findings suggest that natural CAR receptors can be fine-tuned to produce more desirable signaling outputs while maintaining evolutionary advantages in ligand recognition relative to scFvs.
Assuntos
Antígenos B7/química , Receptor 3 Desencadeador da Citotoxicidade Natural/química , Receptores de Antígenos Quiméricos/química , Animais , Antígenos CD28/química , Complexo CD3/química , Linhagem Celular Tumoral , Separação Celular , Citocinas/metabolismo , Citometria de Fluxo , Perfilação da Expressão Gênica , Biblioteca Gênica , Variação Genética , Células HEK293 , Humanos , Imunoterapia , Cinética , Ligantes , Camundongos , Mutação , Conformação Proteica , Anticorpos de Cadeia Única/químicaRESUMO
Inflammatory bowel disease (IBD) is a chronic gastro-intestinal disorders of unknown etiology. There are several drugs approved for treating IBD patients with active disease, including first-line use of aminosalicylates, and secondary choices of immunomodulators and other therapies. These medications might manage disease symptoms, but have also shown significant side-effects in IBD patients. Tea is the second largest beverage in the world and its main active ingredients including tea polyphenols, polysaccharides and tea pigments have been shown promising anti-inflammatory and antioxidant properties. In this review, we summarize the influence of different tea varieties including green tea, black tea and dark tea as potential nutritional therapy for preventing and treating IBD, and discuss the mechanisms of tea ingredients involved in the regulation of oxidative stress, inflammation, signaling pathways, and gut microbiota that could benefit for IBD disease management. Our observation directs further basic and clinical investigations on tea polyphenols and their derivatives as novel IBD therapeutic agents.
Assuntos
Doenças Inflamatórias Intestinais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Chá/metabolismoRESUMO
Persistent infection with gammaherpesviruses (γHV) can cause lymphomagenesis in immunocompromised patients. Murine γHV-68 (MHV-68) is an important tool for understanding immune factors contributing to γHV control; however, modeling control of γHV-associated lymphomagenesis has been challenging. Current model systems require very long incubation times or severe immune suppression, and tumor penetrance is low. In this report, we describe the generation of a B cell lymphoma on the C57BL/6 background, which is driven by the Myc oncogene and expresses an immunodominant CD8 T cell epitope from MHV-68. We determined MHV-68-specific CD8 T cells in latently infected mice use either IFN-γ or perforin/granzyme to control γHV-associated lymphoma, but perforin/granzyme is a more potent effector mechanism for lymphoma control than IFN-γ. Consistent with previous reports, CD4-depleted mice lost control of virus replication in persistently infected mice. However, control of lymphoma remained intact in the absence of CD4 T cells. Collectively, these data show the mechanisms of T cell control of B cell lymphoma in γHV-infected mice overlap with those necessary for control of virus replication, but there are also important differences. This study establishes a tool for further dissecting immune surveillance against, and optimizing adoptive T cell therapies for, γHV-associated lymphomas.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Memória Imunológica , Linfoma de Células B/imunologia , Vírus da Hepatite Murina/imunologia , Proteínas de Neoplasias/imunologia , Animais , Epitopos de Linfócito T/genética , Feminino , Linfoma de Células B/genética , Linfoma de Células B/patologia , Camundongos , Camundongos Transgênicos , Vírus da Hepatite Murina/genética , Proteínas de Neoplasias/genéticaRESUMO
Sodium salicylate, one of the non-steroidal anti-inflammatory drugs, is widely prescribed in the clinic, but a high dose of usage can cause hyperactivity in the central nervous system, including the hippocampus. At present, the neural mechanism underlying the induced hyperactivity is not fully understood, in particular, in the hippocampus under an in vivo condition. In this study, we found that systemic administration of sodium salicylate increased the field excitatory postsynaptic potential slope and the population spike amplitude in a dose-dependent manner in the hippocampal dentate gyrus area of rats with in vivo field potential extracellular recordings, which indicates that sodium salicylate enhances basal synaptic transmission and neural excitation. In the presence of picrotoxin, a GABA-A receptor antagonist, sodium salicylate failed to increase the initial slope of the field excitatory postsynaptic potential and the amplitude of the population spike in vivo. To further explore how sodium salicylate enhances the neural excitation, we made whole-cell patch-clamp recordings from hippocampal slices. We found that perfusion of the slice with sodium salicylate decreased electrically evoked GABA receptor-mediated currents, increased paired-pulse ratio, and lowered frequency and amplitude of miniature inhibitory postsynaptic currents. Together, these results demonstrate that sodium salicylate enhances the neural excitation through suppressing GABAergic synaptic transmission in presynaptic and postsynaptic mechanisms in the hippocampal dentate gyrus area. Our findings may help understand the side effects caused by sodium salicylate in the central nervous system.
Assuntos
Hipocampo , Salicilato de Sódio , Animais , Giro Denteado/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/fisiologia , Ratos , Salicilato de Sódio/farmacologia , Transmissão Sináptica/fisiologiaRESUMO
Themis (thymocyte-expressed molecule involved in selection), a member of a family of proteins with unknown functions, is highly conserved among vertebrates. Here we found that Themis had high expression in thymocytes between the pre-T cell antigen receptor (pre-TCR) and positive-selection checkpoints and low expression in mature T cells. Themis-deficient thymocytes showed defective positive selection, which resulted in fewer mature thymocytes. Negative selection was also impaired in Themis-deficient mice. A greater percentage of Themis-deficient T cells had CD4(+)CD25(+)Foxp3(+) regulatory and CD62L(lo)CD44(hi) memory phenotypes than did wild-type T cells. In support of the idea that Themis is involved in TCR signaling, this protein was phosphorylated quickly after TCR stimulation and was needed for optimal TCR-driven calcium mobilization and activation of the kinase Erk.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/fisiologia , Linhagem da Célula/fisiologia , Proteínas/metabolismo , Sequência de Aminoácidos , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Sobrevivência Celular/fisiologia , Células Cultivadas , Clonagem Molecular , Feminino , Citometria de Fluxo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Especificidade de Órgãos , Proteínas/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/fisiologiaRESUMO
OBJECTIVE: The objective of this study was to evaluate the relationship of periodontal disease with depression and anxiety via a systematic review and meta-analysis. METHOD: We systematically searched the EMBASE, PubMed, Web of Science, PsycINFO, and SinoMed databases (until August 4, 2019) with language restricted to English and Chinese. Case-control, cross-sectional, and cohort studies that calculated the risk ratio (RR), odds ratio (OR)/prevalence OR (POR), and hazard ratio (HR) of depression/anxiety with periodontal disease or the OR/POR/RR/HR of periodontal disease caused by depression/anxiety were included. Observational studies that reported the depression/anxiety scale score of patients with periodontal disease and healthy periodontal subjects aged ≥14 years were also included. We used the standard format to extract the following information from each included study: author/s, survey year, study design, age of participants, periodontal disease definition, depression/anxiety measurement, and summary of results. The Newcastle-Ottawa scale was used to ascertain the quality of the included citations. RESULTS: After screening, 40 studies were included. A meta-analysis of the case-control studies showed that periodontal disease was positively associated with depression (OR = 1.70, 95% confidence interval [CI] â= 1.01-2.83). A meta-analysis of 12 studies showed that periodontal disease was significantly correlated with anxiety (OR = 1.36, 95% CI = 1.11-1.66). A meta-analysis of 18 studies showed that subjects with periodontal disease had higher depression scale score (standardized mean difference [SMD] = 1.05, 95% CI = 0.68-1.41) and anxiety scale score (SMD = 0.70, 95% CI = 0.44-0.96). CONCLUSION: Periodontal disease is associated with emotional disorders. However, the high degree of heterogeneity among studies should be considered. More high-quality prospective studies are required to confirm the relationship.
Assuntos
Depressão , Doenças Periodontais , Idoso , Ansiedade/complicações , Ansiedade/epidemiologia , Estudos Transversais , Depressão/complicações , Depressão/epidemiologia , Humanos , Doenças Periodontais/complicações , Doenças Periodontais/epidemiologia , Estudos ProspectivosRESUMO
In this work, a green enzyme-linked immunosorbent assay (ELISA) based on the single-stranded binding protein (SSB)-assisted aptamer was designed for biosensing applications. Combined with the biotin-streptavidin (SA) system and the high catalytic activity of horseradish peroxidase (HRP), this SSB-assisted aptamer sensor was applied for the detection of aflatoxin B1, ochratoxin A, and zearalenone. In this novel ELISA, mycotoxin-protein conjugations were replaced by SSB to avoid the hazard of mycotoxin, whereas antibodies were replaced by aptamer to avoid the complex and tedious preparation of antibodies. In the absence of target mycotoxins, SSB can bind the aptamer-biotin specifically. Detection was performed using the strong combination of biotin and SA after adding SA-HRP and substrate/chromogen solution, thereby resulting in a strong yellow color signal. In the presence of target mycotoxins, the aptamer-biotin cannot bind to the SSB, thereby leading to a weak yellow color signal. Under optimal conditions, the designed method was successfully applied for the determination of real sample and exhibited high specificity and low limits of detection in corn (112 ng L-1 for aflatoxin B1, 319 ng L-1 for ochratoxin A, and 377 ng L-1 for zearalenone). The green ELISA may also be extended to the detection of other biohazardous targets by changing the aptamer.
Assuntos
Aptâmeros de Nucleotídeos/química , Biotina/química , Ensaio de Imunoadsorção Enzimática , Peroxidase do Rábano Silvestre/química , Micotoxinas/análise , Estreptavidina/química , Biotina/metabolismo , Peroxidase do Rábano Silvestre/metabolismo , Humanos , Estreptavidina/metabolismoRESUMO
This study identifies a novel mechanism linking IL-17A with colon tissue repair and tumor development. Abrogation of IL-17A signaling in mice attenuated tissue repair of dextran sulfate sodium (DSS)-induced damage in colon epithelium and markedly reduced tumor development in an azoxymethane/DSS model of colitis-associated cancer. A novel IL-17A target gene, PLET1 (a progenitor cell marker involved in wound healing), was highly induced in DSS-treated colon tissues and tumors in an IL-17RC-dependent manner. PLET1 expression was induced in LGR5+ colon epithelial cells after DSS treatment. LGR5+PLET1+ marks a highly proliferative cell population with enhanced expression of IL-17A target genes. PLET1 deficiency impaired tissue repair of DSS-induced damage in colon epithelium and reduced tumor formation in an azoxymethane/DSS model of colitis-associated cancer. Our results suggest that IL-17A-induced PLET1 expression contributes to tissue repair and colon tumorigenesis.
Assuntos
Colite/imunologia , Colo/metabolismo , Neoplasias do Colo/imunologia , Células Epiteliais/imunologia , Interleucina-17/metabolismo , Proteínas da Gravidez/metabolismo , Animais , Azoximetano , Carcinogênese , Células Cultivadas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Colite/induzido quimicamente , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Sulfato de Dextrana , Regulação Neoplásica da Expressão Gênica , Interleucina-17/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas da Gravidez/genética , Receptores de Interleucina/genética , CicatrizaçãoRESUMO
Exploring the mechanisms controlling lymphocyte trafficking is essential for understanding the function of the immune system and the pathophysiology of immunodeficiencies. The mammalian Ste20-like kinase 1 (Mst1) has been identified as a critical signaling mediator of T cell migration, and loss of Mst1 results in immunodeficiency disease. Although Mst1 is known to support T cell migration through induction of cell polarization and lamellipodial formation, the downstream effectors of Mst1 are incompletely defined. Mice deficient for the actin-bundling protein L-plastin (LPL) have phenotypes similar to mice lacking Mst1, including decreased T cell polarization, lamellipodial formation, and cell migration. We therefore asked whether LPL functions downstream of Mst1. The regulatory N-terminal domain of LPL contains a consensus Mst1 phosphorylation site at Thr(89) We found that Mst1 can phosphorylate LPL in vitro and that Mst1 can interact with LPL in cells. Removal of the Mst1 phosphorylation site by mutating Thr(89) to Ala impaired localization of LPL to the actin-rich lamellipodia of T cells. Expression of the T89A LPL mutant failed to restore migration of LPL-deficient T cells in vitro. Furthermore, expression of T89A LPL in LPL-deficient hematopoietic cells, using bone marrow chimeras, failed to rescue the phenotype of decreased thymic egress. These results identify LPL as a key effector of Mst1 and establish a novel mechanism linking a signaling intermediate to an actin-binding protein critical to T cell migration.
Assuntos
Movimento Celular , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Animais , Proteínas do Citoesqueleto , Citometria de Fluxo , Ativação Linfocitária , Linfócitos/imunologia , Camundongos , Proteínas dos Microfilamentos , Fosfoproteínas/deficiência , Fosfoproteínas/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Transporte Proteico , Pseudópodes/imunologia , Pseudópodes/fisiologiaRESUMO
In this paper, manganese carbide (MnC) and niobium carbide (NbC) are predicted as stable monolayer metallic materials, whose Young's moduli are 50.06 N m-1 and 44.07 N m-1, respectively. The ab initio molecular dynamics (AIMD) results show that both MnC and NbC could hold their structure up to 1000 K, showing favorable thermal properties. These monolayers also show good properties for promising application in Li ion batteries because of their high specific capacities and low diffusion barriers. The MnC monolayer is ferromagnetic and the Curie temperature simulated by the Monte-Carlo method is about 205 K. The electronic band of MnC shows a metal to half-metal transition by passivation of Cl or Br atoms, and the functionalization methods also cause the metallic NbC monolayer to exhibit the quantum spin Hall effect (QSHE). These novel transition metal carbide monolayers hold great promise for 2D spintronic and electronic device applications.
RESUMO
The C-3-OH, C-4 carbonyl oxygen and hydrogenation of C2=C3 bond on the C-ring of 2R,3R-dihydromyricetin (DMY) proved to be not necessary for the antibacterial activity against Staphylococcus aureus. DMY significantly decreased the intracellular ATP of S. aureus cells but had few effects on pHin, proline oxidation, succinate dehydrogenase activity or malate dehydrogenase activity.
Assuntos
Antibacterianos/química , Flavonóis/química , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacologia , Flavonóis/farmacologia , Malato Desidrogenase/metabolismo , Oxirredução , Prolina/química , Succinato Desidrogenase/metabolismoRESUMO
PURPOSE: Insomnia has become one of the foremost health concerns among workers. Despite a significant number of epidemiological studies have reported on the correlation between insomnia and job stress, comprehensive evidence remains insufficient. Therefore, this research seeks to provide evidence with greater reliability, through summarizing relevant contemporary literature via a meta-analysis. METHODS: Literature from across Europe and Asia that was of both a prospective and cross-sectional design was included, if well-controlled odds ratios were available. The meta-analysis was undertaken in accordance with the guidelines devised by PRISMA, including tests for publication bias and heterogeneity. RESULTS: High job stress was associated with a greater risk of suffering from insomnia (random OR = 1.73, 95% CI 1.46-2.05), and the correlation between effort-reward imbalance and insomnia was statistically significant (random OR = 2.63, 95% CI 1.22-5.69). Higher demand was correlated to a relatively greater risk of insomnia (random OR = 1.35, 95% CI 1.20-1.51), while the pooled effect of low control was not found to be statistically significant. The summary random odds ratio of heavy workload was 2.76, and a pooled odds ratio of 1.67 (fixed, 95% CI 1.11-2.52) was calculated in low social support. With regard to the overall population, work-family conflict was correlated with insomnia (random OR = 2.32, 95% CI 1.53-3.51). The subgroup analysis provided comparable outcomes, for both males (fixed OR = 1.97, 95% CI 1.50-2.57) and females (random OR = 2.80, 95% CI 1.30-6.05). Egger's regression indicated that publication bias may be apparent in the syntheses of effort-reward imbalance, low social support, and work-family conflict (p < 0.05). Heterogeneity was caused by design, measuring the exposure or outcome, in addition to the region where the research was conducted. CONCLUSIONS: The correlation between insomnia and higher levels of job stress, effort-reward imbalance, high demand, heavy workload, and low social support was determined. Publication bias and heterogeneity were partially observed. Furthermore, future studies with improved methodologies and a focus on mechanisms are anticipated.
Assuntos
Estresse Ocupacional/epidemiologia , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Estresse Psicológico/epidemiologia , Carga de Trabalho/estatística & dados numéricos , Adulto , Ásia , Comorbidade , Estudos Transversais , Europa (Continente) , Feminino , Humanos , Satisfação no Emprego , Masculino , Pessoa de Meia-Idade , Estresse Ocupacional/psicologia , Estudos Prospectivos , Distúrbios do Início e da Manutenção do Sono/psicologia , Apoio Social , Estresse Psicológico/psicologia , Carga de Trabalho/psicologia , Adulto JovemRESUMO
V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a negative immune-checkpoint protein that suppresses T-cell responses. To determine whether VISTA synergizes with another immune-checkpoint, programmed death 1 (PD-1), this study characterizes the immune responses in VISTA-deficient, PD-1-deficient (KO) mice and VISTA/PD-1 double KO mice. Chronic inflammation and spontaneous activation of T cells were observed in both single KO mice, demonstrating their nonredundancy. However, the VISTA/PD-1 double KO mice exhibited significantly higher levels of these phenotypes than the single KO mice. When bred onto the 2D2 T-cell receptor transgenic mice, which are predisposed to development of inflammatory autoimmune disease in the CNS, the level of disease penetrance was significantly enhanced in the double KO mice compared with in the single KO mice. Consistently, the magnitude of T-cell response toward foreign antigens was synergistically higher in the VISTA/PD-1 double KO mice. A combinatorial blockade using monoclonal antibodies specific for VISTA and PD-L1 achieved optimal tumor-clearing therapeutic efficacy. In conclusion, our study demonstrates the nonredundant role of VISTA that is distinct from the PD-1/PD-L1 pathway in controlling T-cell activation. These findings provide the rationale to concurrently target VISTA and PD-1 pathways for treating T-cell-regulated diseases such as cancer.
Assuntos
Proteínas de Membrana/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Antígenos/administração & dosagem , Antígeno B7-H1/deficiência , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Feminino , Tolerância Imunológica , Ligantes , Ativação Linfocitária , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Experimentais/imunologia , Receptor de Morte Celular Programada 1/deficiência , Receptor de Morte Celular Programada 1/genéticaRESUMO
Acoustic trauma is being reported to damage the auditory periphery and central system, and the compromised cortical inhibition is involved in auditory disorders, such as hyperacusis and tinnitus. Parvalbumin-containing neurons (PV neurons), a subset of GABAergic neurons, greatly shape and synchronize neural network activities. However, the change of PV neurons following acoustic trauma remains to be elucidated. The present study investigated how auditory cortical PV neurons change following unilateral 1 hour noise exposure (left ear, one octave band noise centered at 16 kHz, 116 dB SPL). Noise exposure elevated the auditory brainstem response threshold of the exposed ear when examined 7 days later. More detectable PV neurons were observed in both sides of the auditory cortex of noise-exposed rats when compared to control. The detectable PV neurons of the left auditory cortex (ipsilateral to the exposed ear) to noise exposure outnumbered those of the right auditory cortex (contralateral to the exposed ear). Quantification of Western blotted bands revealed higher expression level of PV protein in the left cortex. These findings of more active PV neurons in noise-exposed rats suggested that a compensatory mechanism might be initiated to maintain a stable state of the brain.