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Studying the complex interactions between different brain regions is crucial in neuroscience. Various statistical methods have explored the latent communication across multiple brain regions. Two main categories are the Gaussian Process (GP) and Linear Dynamical System (LDS), each with unique strengths. The GP-based approach effectively discovers latent variables with frequency bands and communication directions. Conversely, the LDS-based approach is computationally efficient but lacks powerful expressiveness in latent representation. In this study, we merge both methodologies by creating an LDS mirroring a multi-output GP, termed Multi-Region Markovian Gaussian Process (MRM-GP). Our work establishes a connection between an LDS and a multi-output GP that explicitly models frequencies and phase delays within the latent space of neural recordings. Consequently, the model achieves a linear inference cost over time points and provides an interpretable low-dimensional representation, revealing communication directions across brain regions and separating oscillatory communications into different frequency bands.
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Background: Patients with type 2 diabetes mellitus (T2DM) experience a decline in cardiac function, resulting in poor prognosis. Therefore, restoration of cardiac function and improvement of myocardial fibrosis is an important treatment goal for patients with T2DM. Material and methods: The chemical structure of oleanolic acid(OA) was downloaded from PubChem and uploaded to PharmMapper. GeneCards and OMIM databases were searched for genes related to OA and disease and plotted into a Venn diagram. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using R software. Then, a mouse model of diabetes mellitus was established, and ELISA, echocardiographic analysis of cardiac function, TUNEL assay, and reactive oxygen species assay were performed. Results: Network pharmacology analysis identified the related targets and potential molecular mechanisms underlying the effects of OA in T2DM. ELISA, echocardiographic analysis of cardiac function, and TUNEL assay results showed that OA inhibits apoptosis and improves apoptotic indexes in mice with T2DM-induced myocardial injury. Conclusion: The results demonstrate the myocardial protective effect of OA in this mouse model.
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Rhizoma Panacis Japonici (RPJ) is an ancient herbal medicine from China that has long been employed for its medicinal benefits in relieving arthritis physical debility and diverse afflictions. The primary bioactive constituents found in RPJ are triterpene saponins, which exhibit numerous pharmacological actions, including anti-inflammatory, antioxidant, and immunomodulating effects. The present study established a straightforward and effective approach for characterizing triterpene saponins in RPJ. An offline HILIC × RP LC/QTOF-MS method was developed, along with a self-constructed in-house database containing 612 saponins reported in the Panax genus and 228 predicted metabolites. The approach achieved good chromatographic performance in isolating triterpene saponins of RPJ, with the HILIC column as the first dimension (1D) and the BEH C18 column as the second dimension (2D). The developed two-dimensional liquid chromatography system exhibited an orthogonality of 0.61 and a peak capacity of 1249. Detection was performed using a QTOF mass spectrometer in a data-independent manner (MSE) in a negative ion mode. Using the in-house database, the collected MS data were processed by an automatic workflow on UNIFI 1.8.2 software, which included data correction, matching of precursor and product ions, and peak annotation. In this study, 307 saponins were characterized from RPJ and 76 saponins were identified for the first time in Panax japonicus. This research not only enhances our understanding of the chemical characteristics of RPJ but also offers a simple and efficient method for analyzing the complex composition of herbal medicine.
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Medicamentos de Ervas Chinesas , Panax , Plantas Medicinais , Saponinas , Triterpenos , Saponinas/química , Triterpenos/química , Cromatografia Líquida de Alta Pressão/métodos , Extratos Vegetais/química , Espectrometria de Massas , Plantas Medicinais/químicaRESUMO
The issue of hypersonic boundary layer transition prediction is a critical aerodynamic concern that must be addressed during the aerodynamic design process of high-speed vehicles. In this context, we propose an advanced mesoscopic method that couples the gas kinetic scheme (GKS) with the Langtry-Menter transition model, including its three high-speed modification methods, tailored for accurate predictions of high-speed transition flows. The new method incorporates the turbulent kinetic energy term into the Maxwellian velocity distribution function, and it couples the effects of high-speed modifications on turbulent kinetic energy within the computational framework of the GKS solver. This integration elevates both the transition model and its high-speed enhancements to the mesoscopic level, enhancing the method's predictive capability. The GKS-coupled mesoscopic method is validated through a series of test cases, including supersonic flat plate simulation, multiple hypersonic cone cases, the Hypersonic International Flight Research Experimentation (HIFiRE)-1 flight test, and the HIFiRE-5 case. The computational results obtained from these cases exhibit favorable agreement with experimental data. In comparison with the conventional Godunov method, the new approach encompasses a broader range of physical mechanisms, yielding computational results that closely align with the true physical phenomena and marking a notable elevation in computational fidelity and accuracy. This innovative method potentially satisfies the compelling demand for developing a precise and rapid method for predicting hypersonic boundary layer transition, which can be readily used in engineering applications.
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Seeking organic cathode materials with low cost and long cycle life that can be employed for large-scale energy storage remains a significant challenge. This work has synthesized an organic compound, triphenazino[2,3-b](1,4,5,8,9,12-hexaazatriphenylene) (TPHATP), with as high as 87.16% yield. This compound has a highly π-conjugated and rigid molecular structure, which is synthesized by capping hexaketocyclohexane with three molecules of 2,3-diaminophenazine derived from low-cost o-phenylenediamine, and is used as a cathode material for assembling aqueous rechargeable zinc ion batteries. Both experiments and DFT calculations demonstrate that the redox mechanism of TPHATP is predominantly governed by H+ storage. The Zn-intercalation product of nitride-type compound, is too unstable to form in water. Moreover, the TPHATP cathode exhibits a capacity of as high as 318.3 mAh g-1 at 0.1 A g-1 , and maintained a stable capacity of 111.9 mAh g-1 at a large current density of 10 A g-1 for 5000 cycles with only a decay of 0.000512% per cycle. This study provides new insights into understanding pyrazine as an active redox group and offers a potential affordable aqueous battery system for grid-scale energy storage.
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Synthesis of regular morphology catalysts with self-growing substrates is one of the effective methods to solve the problem of easy shedding of heterogeneous catalysts. In this study, Fe-doped Ni12P5 nanorods were prepared by depositing 1,1' -bis (diphenylphosphine) ferrocene (DPPF) on N-doped C/NF. The bottom-up growth of the nanorod is ascribed to the preferential adsorption of DPPF with a P site to NF that is surface-doped with the solid-solving C, and the length of nanorods can reach tens of microns and has good robustness. The N-doped carbon-constrained rod-shaped Fe-doped Ni12P5 catalyst (Fe-Ni12P5/NdC/NF-800) that grows on NF has excellent catalytic performance for the urea oxidation reaction. In addition, the current density can be maintained as high as 100 mA cm-2 and the current attenuation is weak for 12 h, and the rod shape remains good. This work provides a new idea for synthesizing self-growing catalysts with regular morphology to improve the performance of heterogeneous catalysts.
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Small-molecule induction can lead to the oriented migration of metal elements, which affords functional materials with synergistic components. In this study, phosphating nickel foam (NF)-supported octahedral WO3 with phosphine affords P-WO3 /NF electrocatalyst. Ni is found to form Ni-P bonds that migrate from NF to WO3 under the induction of P, resulting in the complex oxides W1.3 Ni0.24 O4 and Ni2 P2 O7 in the particle interior and nickel phosphide on the octahedral grain surface. The catalytic activity of P-WO3 /NF in the urea oxidation reaction (UOR) is improved by synergistic action of the components in the synthesized hybrid particles. A current density of 10â mA cm-2 can be reached at a potential of 1.305â V, the double layer capacitance of the catalyst is significantly increased, and the electron transfer impedance in catalytic UOR is reduced. This work demonstrates that small-molecule induction is suitable for constructing co-catalysts with complex components in a simple protocol, which provides a new route for the design of highly efficient urea oxidation electrocatalysts.
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Níquel , Óxidos , Oxirredução , Transporte de Elétrons , UreiaRESUMO
Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer associated with an unstable prognosis. Thus, there is an urgent demand for the identification of novel diagnostic and prognostic biomarkers as well as targeted drugs for LUAD. The present study aimed to identify potential new biomarkers associated with the pathogenesis and prognosis of LUAD. Three microarray datasets (GSE10072, GSE31210, and GSE40791) from the Gene Expression Omnibus database were integrated to identify the differentially expressed genes (DEGs) in normal and LUAD samples using the limma package. Bioinformatics tools were used to perform functional and signaling pathway enrichment analyses for the DEGs. The expression and prognostic values of the hub genes were further evaluated by Gene Expression Profiling Interactive Analysis and real-time quantitative polymerase chain reaction. Furthermore, we mined the "Connectivity Map" (CMap) to explore candidate small molecules that can reverse the tumoral of LUAD based on the DEGs. A total of 505 DEGs were identified, which included 337 downregulated and 168 upregulated genes. The PPI network was established with 1,860 interactions and 373 nodes. The most significant pathway and functional enrichment associated with the genes were cell adhesion and extracellular matrix-receptor interaction, respectively. Seven DEGs with high connectivity degrees (ZWINT, RRM2, NDC80, KIF4A, CEP55, CENPU, and CENPF) that were significantly associated with worse survival were chosen as hub genes. Lastly, top 20 most important small molecules which reverses the LUAD gene expressions were identified. The findings contribute to revealing the molecular mechanisms of the initiation and progression of LUAD and provide new insights for integrating multiple biomarkers in clinical practice.
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Oxygen glucose deprivation (OGD)/re-oxygenation (OGDR) induces profound oxidative injury and neuronal cell death. It mimics ischemia-reperfusion neuronal injury. CPI-1189 is a novel tumor necrosis factor alpha-inhibiting compound with potential neuroprotective function. Here in SH-SY5Y neuronal cells and primary murine cortical neurons, CPI-1189 pretreatment potently inhibited OGDR-induced viability reduction and cell death. In OGDR-stimulated neuronal cells, p38 phosphorylation was blocked by CPI-1189. In addition, CPI-1189 alleviated OGDR-induced reactive oxygen species production, lipid peroxidation, and glutathione consumption. OGDR-induced neuronal cell apoptosis was also inhibited by CPI-1189 pretreatment. Furthermore, in SH-SY5Y cells and cortical neurons, CPI-1189 alleviated OGDR-induced programmed necrosis by inhibiting mitochondrial p53-cyclophilin D-adenine nucleotide translocase 1 association, mitochondrial depolarization, and lactate dehydrogenase release to the medium. In summary, CPI-1189 potently inhibited OGDR-induced oxidative injury and neuronal cell death.
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Butanos/farmacologia , Glucose/metabolismo , Neurônios/efeitos dos fármacos , Oxigênio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
OBJECTIVE: To determine the prevalence of cochlear-facial dehiscence (CFD) and to examine the influence of otic capsule area, age, sex, and race on CFD. STUDY DESIGN: Descriptive study of archived temporal bone specimens. MATERIALS AND METHODS: Targeted sections from 1,020 temporal bone specimens were scanned and examined for CFD. Cochlear-facial partition width (CFPW) and otic capsule area (OCA), a marker of bone thickness, were measured using image analysis software. Demographic data were analyzed using multiple linear regression analysis. RESULTS: The mean CFPW was 0.23âmm (range, 0-0.92âmm; SD, 0.15âmm). Six patients were completely dehiscent (0.59%). Fallopian canal width, age, sex, race, and OCA were found to be significant predictors of CFPW. Age was found to be negatively correlated with CFPW (ßâ=â-0.001) (pâ<â0.005). Thicker CFPW was associated with males (ßâ=â0.024) and non-Caucasian individuals (ßâ=â0.031). The mean OCA for dehiscent specimens (mean, 9.48 mm; range, 6.65-11.58 mm; SD 3.21 mm) was significantly smaller than the mean OCA for nondehiscent specimens, (mean, 12.88 mm; range, 6.63-21.92 mm; SD, 2.47 mm) (pâ<â0.01). CONCLUSION: CFD occurred in nearly 0.6% of specimens in this temporal bone collection. Close to 35% of patients were sufficiently thin (<0.1âmm) to appear dehiscent on computed tomography scanning. Smaller OCA correlated with thinner CFPW, suggesting a developmental factor. Older, female, and Caucasian patients may have a greater risk for CFD and its associated symptoms.
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Nervo Coclear/patologia , Doenças do Nervo Facial/epidemiologia , Nervo Facial/patologia , Doenças do Nervo Vestibulococlear/epidemiologia , Feminino , Humanos , Masculino , Prevalência , Osso Temporal/anatomia & histologiaRESUMO
Three-dimensional conformal radiotherapy in combination with transarterial chemoembolization (TACE) has been beneficial in patients with unresectable hepatocellular carcinoma (HCC). There have been few clinical reports on the use of intensity-modulated radiotherapy (IMRT) in combination with TACE for these patients. The purpose of this study was to assess the efficacy and toxicity of IMRT following TACE in unresectable HCC.The medical records of consecutive patients with unresectable HCC, who underwent IMRT following TACE from January 2009 to June 2014, were retrospectively reviewed in order to assess the overall survival (OS), progression-free survival (PFS), tumor response, and treatment-associated toxicity.A total of 64 lesions in 54 patients were included in the analysis. IMRT was delivered at a median dose of 50 Gy (range 44-70 Gy) at 1.8 to 2.0 Gy per fraction. The overall response rate was achieved in 64.8% of patients with complete response in 20.4% of patients at 3 months after completion of IMRT. The median OS was 20.2 months (95% CIâ=â8.6-31.9), and the actuarial 1-, 2-, and 3-year OS rates were 84.6%, 49.7%, and 36.7%, respectively. The median PFS was 10.5 months (95% CIâ=â7.3-13.7) and the 1-, 2-, and 3-year PFS rates were 44.2%, 23.4%, and 14.6%, respectively. The responders had a significantly higher OS rate than the nonresponders (3-year OS 48.0% vs 14.4%, Pâ=â0.001). During and the first month following IMRT, 10 (18.5%) patients developed grade 3 hematological toxicity, and 3 (5.6%) developed grade 3 hepatic toxicity. No patient experienced grade 4 or 5 toxicity. Radiation-induced liver disease was not observed.Our findings suggest that IMRT following TACE could be a favorable treatment option for both its safety profile and clinical benefit in patients with unresectable HCC.
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Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Radioterapia de Intensidade Modulada/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/radioterapia , Quimioembolização Terapêutica/métodos , China , Terapia Combinada , Feminino , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/radioterapia , Masculino , Pessoa de Meia-Idade , Radioterapia de Intensidade Modulada/efeitos adversos , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Curing type 1 diabetes (T1D) will require lasting control of the autoimmune response that destroys insulin-producing islet ß-cells. Re-establishing tolerance by restoring/replacing Tregs has significant potential for treatment of T1D but will require strategies to augment and maintain their efficacy. We previously showed that polyclonal in vitro-induced Tregs can reverse recent onset of T1D in â¼ 50% of NOD mice. Here we report that treatment of newly hyperglycemic animals with a short course of anti-CD44 at the time of Treg transfer improved diabetes reversal to >90%. Anti-CD44 treatment alone delayed diabetes onset and increased the frequencies of pancreatic CD4(+) T cells producing IL-2 or TGF-ß, cytokines that support Treg function and survival, without altering production of IFN-γ. These anti-CD44 effects on endogenous T cells were also observed in the context of polyclonal Treg transfer, and the combination treatment also reduced pancreatic infiltrates. The results provide compelling evidence that approaches to modulate the pancreatic milieu to support Treg function and counteract inflammation in the pancreas can greatly enhance the efficacy of adoptively transferred Tregs, and suggest that approaches achieving these outcomes hold promise for long-term control of autoimmunity in T1D.
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Anticorpos Bloqueadores/imunologia , Diabetes Mellitus Tipo 1/imunologia , Receptores de Hialuronatos/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Anticorpos Bloqueadores/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Terapia Combinada , Diabetes Mellitus Tipo 1/prevenção & controle , Feminino , Citometria de Fluxo , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-2/imunologia , Interleucina-2/metabolismo , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/metabolismo , Linfócitos T Reguladores/transplante , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic ß-cells. Although Th1 cells are key orchestrators of T1D, the function(s) of the more recently identified Th17 subset are unclear due to inherent plasticity. In this study, we analyzed Th17 cells for stability and diabetogenicity in NOD mice. We found that like Th1 cells, Th17 are a distinct population throughout the prediabetic phase. At diabetes onset, there were marked increases in IL-17-producing Th17 cells and IFN-γ-producing Th1 cells in the pancreas as well as in the serum levels of these cytokines, indicating that these proinflammatory mediators serve as biomarkers of advanced autoimmunity. Although naturally occurring Th17 cells in diabetic mice did not contribute to diabetes development in transfer models, islet-specific Th17 cells were diabetogenic independently of IL-17 and displayed inflammation-induced Th17-to-Th1 reprogramming that could be elicited by Th1 cells. However, an inability to generate Th1 cells because of Stat4, Ifngr, and Ifng deficiencies did not prevent diabetes. Instead, TNF-α could mediate diabetes in response to either Th17 cells or Th1 cells. The results identify a previously unknown mechanism by which Th17 cells can contribute to T1D. Our studies also suggest that when developing interventions for T1D, it will be potentially advantageous to focus on mechanisms common to effector T cells rather than on the signature cytokines of various subsets.
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Diabetes Mellitus Tipo 1/imunologia , Células Secretoras de Insulina/imunologia , Células Th17/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Autoimunidade/imunologia , Biomarcadores/sangue , Inflamação/imunologia , Interferon gama/sangue , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-17/sangue , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pâncreas/imunologia , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Fator de Transcrição STAT4/deficiência , Fator de Transcrição STAT4/genética , Células Th1/imunologia , Receptor de Interferon gamaRESUMO
Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing ß-cells in the pancreatic islets. There is an immediate need to restore both ß-cell function and immune tolerance to control disease progression and ultimately cure T1D. Currently, there is no effective treatment strategy to restore glucose regulation in patients with T1D. FoxP3-expressing CD4(+) regulatory T cells (Tregs) are potential candidates to control autoimmunity because they play a central role in maintaining self-tolerance. However, deficiencies in either naturally occurring Tregs (nTregs) themselves and/or their ability to control pathogenic effector T cells have been associated with T1D. Here, we hypothesize that nTregs can be replaced by FoxP3(+) adaptive Tregs (aTregs), which are uniquely equipped to combat autoreactivity in T1D. Unlike nTregs, aTregs are stable and provide long-lived protection. In this review, we summarize the current understanding of aTregs and their potential for use as an immunological intervention to treat T1D.
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Autoimunidade , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Diabetes Mellitus Tipo 1/patologia , Progressão da Doença , Fatores de Transcrição Forkhead/imunologia , Humanos , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Cadeias beta de Integrinas/imunologia , Interleucina-2/imunologia , Camundongos , Tolerância a Antígenos Próprios , Fator de Crescimento Transformador beta/imunologiaRESUMO
Type 1 diabetes (T1D) develops as a consequence of a progressive autoimmune response that destroys insulin-producing ß-cells in pancreatic islets. Because of their role(s) in controlling immune responses, considerable effort has been directed toward resolving whether regulatory T cells (Tregs) offer a clinical treatment to restore tolerance in T1D. We previously reported that in vitro-induced adaptive Treg cells (aTregs) can reverse T1D and persist as protective memory cells in the NOD mouse model. In the current study, we investigated mechanisms that regulate aTregs. We found that these FoxP3(+) aTregs expressed high levels of the IL-7 receptor, IL-7Rα, without the high affinity receptor for IL-2, CD25, which is found on natural Treg cells (nTregs). IL-7Rα expression was mirrored by the dependency of aTregs on IL-7 for persistence. IL-10 and TGF-ß, effector cytokines of aTregs, were not essential for their maintenance at the level of systemic antibody blocking. Nevertheless, IL-10 modulated cytokine production by aTregs and TGF-ß was critical for protection. aTregs were found to infiltrate islets and the expression of integrin-ß7 was required for their localization in the pancreas. Furthermore, blocking aTreg entry into the pancreas prevented their control of diabetogenic effector T cells, implying the need for local control of the autoimmune response. The distinct homeostatic regulation of aTregs independently of a response to IL-2, which is defective in T1D patients, suggests that these cells represent a translatable candidate to control the autoimmune response.
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Imunidade Adaptativa , Diabetes Mellitus Tipo 1/imunologia , Cadeias beta de Integrinas/imunologia , Interleucina-7/imunologia , Pâncreas/imunologia , Receptores de Interleucina-7/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores , Transferência Adotiva , Animais , Autoimunidade , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Humanos , Cadeias beta de Integrinas/genética , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-2/imunologia , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-7/deficiência , Interleucina-7/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Pâncreas/metabolismo , Receptores de Interleucina-7/deficiência , Receptores de Interleucina-7/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Optimal immunity to microorganisms depends upon the regulated death of clonally expanded effector cells and the survival of a cohort of cells that become memory cells. After activation of naive T cells, CD44, a widely expressed receptor for extracellular matrix components, is upregulated. High expression of CD44 remains on memory cells and despite its wide usage as a "memory marker," its function is unknown. Here we report that CD44 was essential for the generation of memory T helper 1 (Th1) cells by promoting effector cell survival. This dependency was not found in Th2, Th17, or CD8(+) T cells despite similar expression of CD44 and the absence of splice variants in all subsets. CD44 limited Fas-mediated death in Th1 cells and its ligation engaged the phosphoinositide 3-kinase-Akt kinase signaling pathway that regulates cell survival. The difference in CD44-regulated apoptosis resistance in T cell subpopulations has important implications in a broad spectrum of diseases.
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Receptores de Hialuronatos/imunologia , Memória Imunológica/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th1/imunologia , Animais , Apoptose/imunologia , Receptores de Hialuronatos/metabolismo , Immunoblotting , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th1/metabolismoRESUMO
CD44 is a widely-expressed adhesion receptor that is associated with diverse biological processes involving migrating cells, including inflammation, angiogenesis, bone metabolism and wound healing. In the immune system, CD44 is upregulated after activation of naive T lymphocytes during their responses against invading microbes. Once an infection is cleared, elevated levels of CD44 remain on the surface of memory T cells that mediate protection against re-infection. While this has led to the use of highly sustained CD44 expression on T cells as an indicator of a previous immune response, the relevance to T-cell responses or homeostasis has been largely unexplored. Our recent studies demonstrate that CD44 selectively regulates the survival of the Th1 subset of CD4 T cells, but not other T-cell subpopulations. These findings, together with studies of CD44 in other cell types, suggest that differences in the engagement of signaling mechanisms are likely to underlie differential regulation of T-cell responses and underscore the importance of this adhesion receptor to immune cell regulation and protection against viruses and intracellular bacteria.
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T cell homeostatic proliferation occurs on transfer of T cells into lymphopenic recipients; transferred cells undergo several rounds of division in the absence of specific antigen stimulation. For a quantitative analysis of this phenomenon, we applied a mathematical method to describe proliferating T cells to match peak distributions from actual CFSE dilution data. For in vitro stimulation of T cells with anti-CD3/anti-CD28, our simulation confirmed a high proportion of cells entering cell cycle with a low proportion undergoing apoptosis. When applied to homeostatic proliferation, it described striking differences in CD4 and CD8 T cell proliferation rates, and accurately predicted that successive divisions were accompanied by higher rates of apoptosis, limiting the accumulation of proliferating cells. Thus, the presence of multiple CFSE dilution peaks cannot be considered equivalent to lymphocyte expansion. Finally, genetic effects were identified that may help explain links between homeostatic proliferation and autoimmunity.
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Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Proliferação de Células , Homeostase , Modelos Imunológicos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Contagem de Células , Células Cultivadas , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
Itk, a member of the Tec family of tyrosine kinases, is critical for TCR signaling, leading to the activation of phospholipase C gamma1. Early biochemical studies performed in tumor cell lines also implicated Itk in CD28 signaling. These data were complemented by functional studies on primary Itk-/- T cells that suggested a negative role for Itk in CD28 signaling. In this report, we describe a thorough analysis of CD28-mediated responses in T cells lacking Itk. Using purified naive CD4+ T cells from Itk-/- mice, we examine a range of responses dependent on CD28 costimulation. We also analyze Akt and glycogen synthase kinase-3beta phosphorylation in response to stimulation of CD28 alone. Overall, these experiments demonstrate that CD28 signaling, as well as CD28-mediated costimulation of TCR signaling, function efficiently in the absence of Itk. These findings indicate that Itk is not essential for CD28 signaling in primary naive CD4+ T cells.