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1.
Cell ; 186(5): 1026-1038.e20, 2023 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-36868208

RESUMO

Down syndrome (DS) is a neurological disorder with multiple immune-related symptoms; however, crosstalk between the CNS and peripheral immune system remains unexplored. Using parabiosis and plasma infusion, we found that blood-borne factors drive synaptic deficits in DS. Proteomic analysis revealed elevation of ß2-microglobulin (B2M), a major histocompatibility complex class I (MHC-I) component, in human DS plasma. Systemic administration of B2M in wild-type mice led to synaptic and memory defects similar to those observed in DS mice. Moreover, genetic ablation of B2m or systemic administration of an anti-B2M antibody counteracts synaptic impairments in DS mice. Mechanistically, we demonstrate that B2M antagonizes NMDA receptor (NMDAR) function through interactions with the GluN1-S2 loop; blocking B2M-NMDAR interactions using competitive peptides restores NMDAR-dependent synaptic function. Our findings identify B2M as an endogenous NMDAR antagonist and reveal a pathophysiological role for circulating B2M in NMDAR dysfunction in DS and related cognitive disorders.


Assuntos
Síndrome de Down , Receptores de N-Metil-D-Aspartato , Microglobulina beta-2 , Animais , Humanos , Camundongos , Microglobulina beta-2/metabolismo , Microglobulina beta-2/farmacologia , Disfunção Cognitiva/metabolismo , Reações Cruzadas , Parabiose , Proteômica , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Síndrome de Down/sangue , Síndrome de Down/metabolismo
2.
Nat Immunol ; 21(2): 186-198, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31932808

RESUMO

T cell homeostasis and functional responsiveness require signals from self-peptide-major histocompatibility complex (self-pMHC) and cytokines, but the mechanisms controlling this signal integration are unknown. Using a conditional deletion of the T cell lineage-specific protein Themis, we show that Themis is required for the maintenance of peripheral CD8+ T cells and for proliferative CD8+ T cell responses to low-affinity pMHC aided by cytokines. Themis-deficient peripheral T cells show a phenotype indicative of reduced tonic signaling from self-pMHC, strongly suggesting that Themis is a positive regulator of T cell receptor signal strength in response to low-affinity self-pMHC in peripheral T cells. Signals from low-affinity pMHC and cytokines synergistically induce phosphorylation of the kinase Akt, metabolic changes and c-Myc transcription factor induction in CD8+ T cells only in the presence of Themis. This function of Themis is mediated through Shp1 phosphatase, as peripheral Themis and Shp1 double deletion rescues the peripheral CD8+ T cell maintenance.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Citocinas/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Transdução de Sinais/imunologia , Animais , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout
3.
Nat Immunol ; 15(5): 465-72, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24705298

RESUMO

Regulatory T (Treg) cells, which maintain immune homeostasis and self-tolerance, form an immunological synapse (IS) with antigen-presenting cells (APCs). However, signaling events at the Treg cell IS remain unknown. Here we show that the kinase PKC-η associated with CTLA-4 and was recruited to the Treg cell IS. PKC-η-deficient Treg cells displayed defective suppressive activity, including suppression of tumor immunity but not of autoimmune colitis. Phosphoproteomic and biochemical analysis revealed an association between CTLA-4-PKC-η and the GIT2-αPIX-PAK complex, an IS-localized focal adhesion complex. Defective activation of this complex in PKC-η-deficient Treg cells was associated with reduced depletion of CD86 from APCs by Treg cells. These results reveal a CTLA-4-PKC-η signaling axis required for contact-dependent suppression and implicate this pathway as a potential cancer immunotherapy target.


Assuntos
Antígeno CTLA-4/metabolismo , Sinapses Imunológicas/metabolismo , Imunoterapia/tendências , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Complexos Multiproteicos/metabolismo , Proteína Quinase C/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Humanos , Tolerância Imunológica/genética , Células Jurkat , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Proteína Quinase C/genética , Proteômica , Transdução de Sinais
4.
Nat Immunol ; 15(11): 1055-1063, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25282159

RESUMO

TRPV1 is a Ca(2+)-permeable channel studied mostly as a pain receptor in sensory neurons. However, its role in other cell types is poorly understood. Here we found that TRPV1 was functionally expressed in CD4(+) T cells, where it acted as a non-store-operated Ca(2+) channel and contributed to T cell antigen receptor (TCR)-induced Ca(2+) influx, TCR signaling and T cell activation. In models of T cell-mediated colitis, TRPV1 promoted colitogenic T cell responses and intestinal inflammation. Furthermore, genetic and pharmacological inhibition of TRPV1 in human CD4(+) T cells recapitulated the phenotype of mouse Trpv1(-/-) CD4(+) T cells. Our findings suggest that inhibition of TRPV1 could represent a new therapeutic strategy for restraining proinflammatory T cell responses.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Inflamação/imunologia , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Canais de Cátion TRPV/genética , Anilidas/farmacologia , Animais , Linfócitos T CD4-Positivos/citologia , Cálcio/metabolismo , Canais de Cálcio/imunologia , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/imunologia , Capsaicina/farmacologia , Células Cultivadas , Cinamatos/farmacologia , Colite/imunologia , Humanos , Interleucina-10/genética , Intestinos/imunologia , Intestinos/patologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fármacos do Sistema Sensorial/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/biossíntese
5.
J Immunol ; 212(3): 397-409, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38088801

RESUMO

SHP-1 (Src homology region 2 domain-containing phosphatase 1) is a well-known negative regulator of T cells, whereas its close homolog SHP-2 is the long-recognized main signaling mediator of the PD-1 inhibitory pathway. However, recent studies have challenged the requirement of SHP-2 in PD-1 signaling, and follow-up studies further questioned the alternative idea that SHP-1 may replace SHP-2 in its absence. In this study, we systematically investigate the role of SHP-1 alone or jointly with SHP-2 in CD8+ T cells in a series of gene knockout mice. We show that although SHP-1 negatively regulates CD8+ T cell effector function during acute lymphocytic choriomeningitis virus (LCMV) infection, it is dispensable for CD8+ T cell exhaustion during chronic LCMV infection. Moreover, in contrast to the mortality of PD-1 knockout mice upon chronic LCMV infection, mice double deficient for SHP-1 and SHP-2 in CD8+ T cells survived without immunopathology. Importantly, CD8+ T cells lacking both phosphatases still differentiate into exhausted cells and respond to PD-1 blockade. Finally, we found that SHP-1 and SHP-2 suppressed effector CD8+ T cell expansion at the early and late stages, respectively, during chronic LCMV infection.


Assuntos
Coriomeningite Linfocítica , Vírus da Coriomeningite Linfocítica , Animais , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Morte Celular Programada 1/metabolismo , Exaustão das Células T
6.
Hepatology ; 79(3): 560-574, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37733002

RESUMO

BACKGROUND AND AIMS: NASH-HCC is inherently resistant to immune checkpoint blockade, but its tumor immune microenvironment is largely unknown. APPROACH AND RESULTS: We applied the imaging mass cytometry to construct a spatially resolved single-cell atlas from the formalin-fixed and paraffin-embedded tissue sections from patients with NASH-HCC, virus-HCC (HBV-HCC and HCV-HCC), and healthy donors. Based on 35 biomarkers, over 750,000 individual cells were categorized into 13 distinct cell types, together with the expression of key immune functional markers. Higher infiltration of T cells, myeloid-derived suppressor cell (MDSCs), and tumor-associated macrophages (TAMs) in HCC compared to controls. The distribution of immune cells in NASH-HCC is spatially heterogeneous, enriched at adjacent normal tissues and declined toward tumors. Cell-cell connections analysis revealed the interplay of MDSCs and TAMs with CD8 + T cells in NASH-HCC. In particular, exhausted programmed cell death 1 (PD-1 + )CD8 + T cells connected with programmed cell death-ligand 1 (PD-L1 + )/inducible T cell costimulator (ICOS + ) MDSCs and TAMs in NASH-HCC, but not in viral HCC. In contrast, CD4 + /CD8 + T cells with granzyme B positivity were reduced in NASH-HCC. Tumor cells expressed low PD-L1 and showed few connections with immune cells. CONCLUSIONS: Our work provides the first detailed spatial map of single-cell phenotypes and multicellular connections in NASH-HCC. We demonstrate that interactions between MDSCs and TAMs with effector T cells underlie immunosuppression in NASH-HCC and are an actionable target.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Antígeno B7-H1/metabolismo , Proteômica , Linfócitos T CD8-Positivos , Biomarcadores/metabolismo , Microambiente Tumoral
7.
PLoS Genet ; 18(2): e1009994, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35143487

RESUMO

Alzheimer's Disease (AD) is a neuroinflammatory disease characterized partly by the inability to clear, and subsequent build-up, of amyloid-beta (Aß). AD has a bi-directional relationship with circadian disruption (CD) with sleep disturbances starting years before disease onset. However, the molecular mechanism underlying the relationship of CD and AD has not been elucidated. Myeloid-based phagocytosis, a key component in the metabolism of Aß, is circadianly-regulated, presenting a potential link between CD and AD. In this work, we revealed that the phagocytosis of Aß42 undergoes a daily circadian oscillation. We found the circadian timing of global heparan sulfate proteoglycan (HSPG) biosynthesis was the molecular timer for the clock-controlled phagocytosis of Aß and that both HSPG binding and aggregation may play a role in this oscillation. These data highlight that circadian regulation in immune cells may play a role in the intricate relationship between the circadian clock and AD.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Ritmo Circadiano/fisiologia , Proteoglicanas de Heparan Sulfato/metabolismo , Fagocitose/fisiologia , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Relógios Circadianos , Modelos Animais de Doenças , Proteoglicanas de Heparan Sulfato/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Agregação Patológica de Proteínas/metabolismo
8.
Langmuir ; 40(19): 10217-10227, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38688028

RESUMO

The temperature dependence of the dynamic contact angles (DCAs) of water on a metallic surface remains unclear, especially under elevated pressures. Here in this work, the advancing and receding contact angles (RCAs), as well as the contact angle hysteresis (CAH), of water on stainless-steel 316 (SS316) surfaces were studied using the dynamic sessile drop method for temperatures up to 300 °C and pressures up to 10 MPa. It was found that the temperature dependence of the DCAs exhibits a different pattern as compared to the piecewise linear decline of static contact angles. The advancing contact angle (ACA) remains nearly constant and does not decrease until the temperature becomes close to the saturated temperature. The decrease in ACA is attributed to evaporation, which reduces the advancement of energy barrier. The RCA linearly declines below 120 °C and remains stable above 120 °C. The increasing temperature enhances the pinning effect and changes the droplet receding mode. Under all pressures tested, the CAH demonstrates a "increase-constant-decrease" trilinear relationship with temperature. Furthermore, the mean solid surface entropy and solid-gas interfacial tension of SS316 were estimated to be 0.1152 mJ/(m2·°C) and 61.49 mJ/m2, respectively.

9.
Clin Transplant ; 38(7): e15396, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38967600

RESUMO

INTRODUCTION: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo-geneic hematopoiesis stem cell transplantation (allo-HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome. METHODS: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF-normal (CSF-) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis. RESULTS: Compared to those in the CSF-negative group, the conventional cytology positive and MFC+ groups had comparable 8-year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia-free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS. CONCLUSION: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients.


Assuntos
Citometria de Fluxo , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Transplante Homólogo , Humanos , Feminino , Masculino , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/líquido cefalorraquidiano , Leucemia Mieloide Aguda/mortalidade , Estudos Retrospectivos , Adulto , Prognóstico , Pessoa de Meia-Idade , Seguimentos , Adolescente , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Taxa de Sobrevida , Adulto Jovem , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/líquido cefalorraquidiano , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/mortalidade , Idoso , Criança , Citologia
10.
Pacing Clin Electrophysiol ; 47(1): 167-171, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38041413

RESUMO

BACKGROUND: Atrial esophageal fistula (AEF) is a lethal complication that can occur post atrial fibrillation (AF) ablation. Esophageal injury (EI) is likely to be the initial lesion leading to AEF. Endoscopic examination is the gold standard for a diagnosis of EI but extensive endoscopic screening is invasive and costly. This study was conducted to determine whether fecal calprotectin (Fcal), a marker of inflammation throughout the intestinal tract, may be associated with the existence of esophageal injury. METHODS: This diagnostic study was conducted in a cohort of 166 patients with symptomatic AF undergoing radiofrequency catheter ablation from May 2020 to June 2021. Fcal tests were performed 1-7 days after ablation. All patients underwent endoscopic ultrasonography 1 or 2 days after ablation. RESULTS: The levels of Fcal were significantly different between the EI and non-EI groups (404.9 µg/g (IQR 129.6-723.6) vs. 40.4 µg/g (IQR 15.0-246.2), p < .001). Analysis of ROC curves revealed that a Fcal level of 125 µg/g might be the optimal cut-off value for a diagnosis of EI, giving a 78.8% sensitivity and a 65.4% specificity. The negative predictive value of Fcal was 100% for ulcerated EI. CONCLUSIONS: The level of Fcal is associated with EI post AF catheter ablation. 125 µg/g might be the optimal cut-off value for a diagnosis of EI. Negative Fcal could predict the absence of ulcerated EI, which could be considered a precursor to AEF.


Assuntos
Fibrilação Atrial , Ablação por Cateter , Fístula Esofágica , Humanos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Complexo Antígeno L1 Leucocitário , Átrios do Coração , Fístula Esofágica/etiologia , Ablação por Cateter/efeitos adversos
11.
Eur J Pediatr ; 183(8): 3359-3368, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38748253

RESUMO

The role of inflammatory cytokines in children with moderate to severe TBI (m-sTBI) is still incompletely understood. We aimed to investigate the associations between early plasma expression profiles of inflammatory cytokines and clinical outcomes in children with m-sTBI. We prospectively recruited children admitted to the intensive care unit (ICU) of a tertiary pediatric hospital due to m-sTBI from November 2022 to May 2023. Plasma interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, interferon (IFN)-α, IFN-γ and tumor necrosis factor (TNF)-α concentrations were detected by flow cytometry on admission and on days 5 to 7. The primary outcome was in-hospital mortality. The secondary outcome was the 6-month functional outcome assessed by the Glasgow Outcome Scale Extended-Pediatrics (GOS-E Peds) score, dichotomized as favorable (1-4) or unfavorable (5-8). Fifty patients and 20 healthy controls were enrolled. Baseline IL-6, IL-8 and IL-10 levels were significantly higher in TBI patients than in healthy controls. Twelve patients died in the hospital. Compared with survivors, nonsurvivors had significantly increased baseline IL-6 and IL-8 levels. Baseline IL-5, IL-6 and IL-8 levels were also significantly greater in children with unfavorable versus favorable outcomes. The area under the receiver operating characteristic curve (AUC) of the IL-6 and IL-8 levels and motor Glasgow Coma Scale (GCS) score for predicting in-hospital mortality was 0.706, 0.754, and 0.776, respectively. Baseline IL-1ß, IL-2, IL-4, IL-10, IL-12p70, IL-17A, IFN-γ, IFN-α and TNF-α levels were not associated with in-hospital mortality or an unfavorable 6-month outcome. On days 5 to 7, the IL-6 and IL-8 levels were significantly decreased in survivors but increased in nonsurvivors compared to their respective baselines. CONCLUSION: After m-sTBI, the plasma profiles of inflammatory cytokines are markedly altered in children. The trends of IL-6 and IL-8 expression vary among m-sTBI children with different outcomes. Elevated plasma IL-6 and IL-8 levels are related to in-hospital mortality and unfavorable 6-month outcomes. TRIAL REGISTRATION: This trial was registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR2200065505). Registered November 7, 2022. WHAT IS KNOWN: • Inflammation is an important secondary physiological response to TBI. WHAT IS NEW: • The plasma profiles of inflammatory cytokines are markedly altered in children with m-sTBI. Elevated IL-6 and IL-8 levels are related to mortality and unfavorable outcomes.


Assuntos
Lesões Encefálicas Traumáticas , Citocinas , Humanos , Masculino , Feminino , Estudos Prospectivos , Criança , Citocinas/sangue , Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/mortalidade , Pré-Escolar , Biomarcadores/sangue , Mortalidade Hospitalar , Estudos de Casos e Controles , Adolescente , Prognóstico , Lactente , Escala de Resultado de Glasgow
12.
Curr Pain Headache Rep ; 28(5): 439-451, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38502437

RESUMO

PURPOSE OF REVIEW: Tension-type headaches (TTH) significantly diminish patients' quality of life and increase absenteeism, thereby imposing a substantial economic burden. Animal models are essential tools for studying disease mechanisms and drug development. However, until now, little focus has been placed on summarizing the animal models of TTH and associated mechanistic studies. This narrative review discusses the current animal models of TTH and related mechanistic studies to provide insights into the pathophysiological mechanisms of and treatments for TTH. RECENT FINDINGS: The primary method for constructing an animal model of TTH involves injecting a solution of pain relievers, such as adenosine triphosphate, nerve growth factor, or a high concentration of salt solution, into the neck to initiate harmful cervical muscle responses. This model enables the examination of the interaction between peripheral muscles and central sensitization, which is crucial for understanding the pathophysiology of TTH. Mechanistic studies based on this model have investigated the effect of the P2X receptor antagonist, P2X7 receptor blockade, the P2Y1 receptor agonist 2-MESADP, P2Y1 receptor antagonist MRS2179, nitric oxide synthase inhibitors, and acetylsalicylic acid. Despite notable advancements, the current model of TTH has limitations, including surgical complexity and the inability to replicate chronic tension-type headache (CTTH). To gain a more comprehensive understanding and develop more effective treatment methods, future studies should focus on simplifying surgical procedures, examining other predisposing factors, and establishing a model for chronic TTH. This will offer a deeper insight into the pathophysiological mechanism of TTH and pave the way for improved treatment approaches.


Assuntos
Modelos Animais de Doenças , Cefaleia do Tipo Tensional , Cefaleia do Tipo Tensional/fisiopatologia , Cefaleia do Tipo Tensional/tratamento farmacológico , Cefaleia do Tipo Tensional/terapia , Animais , Humanos
13.
Nucleic Acids Res ; 50(4): 2190-2200, 2022 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-35100402

RESUMO

Unlike many other aminoacyl-tRNA synthetases, alanyl-tRNA synthetase (AlaRS) retains a conserved prototype structure throughout biology. While Caenorhabditis elegans cytoplasmic AlaRS (CeAlaRSc) retains the prototype structure, its mitochondrial counterpart (CeAlaRSm) contains only a residual C-terminal domain (C-Ala). We demonstrated herein that the C-Ala domain from CeAlaRSc robustly binds both tRNA and DNA. It bound different tRNAs but preferred tRNAAla. Deletion of this domain from CeAlaRSc sharply reduced its aminoacylation activity, while fusion of this domain to CeAlaRSm selectively and distinctly enhanced its aminoacylation activity toward the elbow-containing (or L-shaped) tRNAAla. Phylogenetic analysis showed that CeAlaRSm once possessed the C-Ala domain but later lost most of it during evolution, perhaps in response to the deletion of the T-arm (part of the elbow) from its cognate tRNA. This study underscores the evolutionary gain of C-Ala for docking AlaRS to the L-shaped tRNAAla.


Assuntos
Alanina-tRNA Ligase , Aminoacil-tRNA Sintetases , Alanina-tRNA Ligase/genética , Aminoacil-tRNA Sintetases/genética , Aminoacilação , Filogenia , RNA de Transferência/genética , RNA de Transferência/metabolismo , RNA de Transferência de Alanina/genética
14.
J Proteome Res ; 22(7): 2232-2245, 2023 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-37256709

RESUMO

Phosphoproteomics and ubiquitinomics data-independent acquisition (DIA) mass spectrometry (MS) data is typically analyzed by using a data-dependent acquisition (DDA) spectral library. The performance of various library-free strategies for analyzing phosphoproteomics and ubiquitinomics DIA MS data has not been evaluated. In this study, we systematically compare four commonly used DDA library-free approaches including Spectronaut's directDIA, DIA-Umpire, DIA-MSFragger, and in silico-predicted library for analysis of phosphoproteomics SWATH, DIA, and diaPASEF data as well as ubiquitinomics diaPASEF data. Spectronaut's directDIA shows the highest sensitivity for phosphopeptide detection not only in synthetic phosphopeptide samples but also in phosphoproteomics SWATH-MS and DIA data from real biological samples, when compared to the other three library-free strategies. For phosphoproteomics diaPASEF data, Spectronaut's directDIA and the in silico-predicted library based on DIA-NN identify almost the same number of phosphopeptides as a project-specific DDA spectral library. However, only about 30% of the total phosphopeptides are commonly identified, suggesting that the library-free strategies for phospho-diaPASEF data need further improvement in terms of sensitivity. For ubiquitinomics diaPASEF data, the in silico-predicted library performs the best among the four workflows and detects ∼50% more K-GG peptides than a project-specific DDA spectral library. Our results demonstrate that Spectronaut's directDIA is suitable for the analysis of phosphoproteomics SWATH-MS and DIA MS data, while the in silico-predicted library based on DIA-NN shows substantial advantages for ubiquitinomics diaPASEF MS data.


Assuntos
Fosfopeptídeos , Proteômica , Proteômica/métodos , Espectrometria de Massas/métodos , Proteoma/análise
15.
Small ; 19(40): e2301281, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37287345

RESUMO

The tumor microenvironment typically possesses immunosuppressive properties that hinder the effectiveness of antitumor immune responses, even in the context of immunotherapies. However, it is observed that pathogenic microorganisms can trigger strong immune responses during infection, offering a potential means to counteract the immunosuppressive environment of tumors. In this study, a protein nanocage called CpG@HBc nanocages (NCs) is developed, which mimics the structure of the hepatitis B virus and combines with an immunostimulatory component known as cytosine phosphoguanosine oligonucleotide (CpG). By delivering these immunostimulatory agents, CpG@HBc NCs are able to effectively reverse the suppressive tumor microenvironment, resulting in the inhibition of poorly immunogenic tumors in mice. Through high-dimensional mass cytometry (CyTOF) analysis, remarkable alterations in immune responses is observed induced by CpG@HBc. Treatment with immunogenic CpG@HBc NCs, along with co-injection of an OX40 agonist, sensitized colorectal cancer tumors to T cell immune responses, resulting in significant impairment of tumor growth and robust immune activation. Furthermore, CpG@HBc NCs induced long-term antitumor immunological memory, protecting tumor-cured mice from tumor rechallenge. Overall, these findings highlight the potential of a virus-inspired protein nanocage to mimic anti-viral immunity and offer a unique therapeutic approach for cancer immunotherapy.


Assuntos
Neoplasias , Oligodesoxirribonucleotídeos , Camundongos , Animais , Oligodesoxirribonucleotídeos/química , Neoplasias/terapia , Linfócitos T , Imunoterapia/métodos , Imunização , Microambiente Tumoral
16.
Immunity ; 40(2): 225-34, 2014 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-24440149

RESUMO

Recent studies demonstrate that natural killer (NK) cells have adaptive immune features. Here, we investigated the role of the costimulatory molecule DNAM-1 in the differentiation of NK cells in a mouse model of cytomegalovirus (MCMV) infection. Antibody blockade of DNAM-1 suppressed the expansion of MCMV-specific Ly49H(+) cells during viral infection and inhibited the generation of memory NK cells. Similarly, DNAM-1-deficient (Cd226(-/-)) Ly49H(+) NK cells exhibited intrinsic defects in expansion and differentiation into memory cells. Src-family tyrosine kinase Fyn and serine-threonine protein kinase C isoform eta (PKCη) signaling through DNAM-1 played distinct roles in the generation of MCMV-specific effector and memory NK cells. Thus, cooperative signaling through DNAM-1 and Ly49H are required for NK cell-mediated host defense against MCMV infection.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Diferenciação Celular , Infecções por Citomegalovirus/imunologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Animais , Infecções por Citomegalovirus/fisiopatologia , Modelos Animais de Doenças , Imunidade Inata/genética , Camundongos , Camundongos Endogâmicos C57BL , Muromegalovirus/imunologia
17.
Pacing Clin Electrophysiol ; 46(6): 548-557, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36516139

RESUMO

Permanent pacemakers are used for symptomatic bradycardia and biventricular pacing (BVP)-cardiac resynchronization therapy (BVP-CRT) is established for heart failure (HF) patients traditionally. According to guidelines, patients' selection for CRT is based on QRS duration (QRSd) and morphology by surface electrocardiogram (ECG). Cardiovascular imaging techniques evaluate cardiac structure and function as well as identify pathophysiological substrate changes including the presence of scar. Cardiovascular imaging helps by improving the selection of candidates, guiding left ventricular (LV) lead placement, and optimization devices during the follow-up. Conduction system pacing (CSP) includes His bundle pacing (HBP) and left bundle branch pacing (LBBP) which is screwed into the interventricular septum. CSP maintains and restores ventricular synchrony in patients with native narrow QRSd and left bundle branch block (LBBB), respectively. LBBP is more feasible than HBP due to a wider target area. This review highlights the role of multimodality cardiovascular imaging including fluoroscopy, echocardiography, cardiac magnetic resonance (CMR), myocardial scintigraphy, and computed tomography (CT) in the pre-procedure assessment for CSP, better selection for CSP candidates, the guidance of CSP lead implantation, and the optimization of devices programming after the procedure. We also compare the different characteristics of multimodality imaging and discuss their potential roles in future CSP implantation.


Assuntos
Fascículo Atrioventricular , Terapia de Ressincronização Cardíaca , Humanos , Estimulação Cardíaca Artificial/métodos , Sistema de Condução Cardíaco , Doença do Sistema de Condução Cardíaco , Bloqueio de Ramo/diagnóstico por imagem , Bloqueio de Ramo/terapia , Terapia de Ressincronização Cardíaca/métodos , Eletrocardiografia/métodos , Resultado do Tratamento , Função Ventricular Esquerda/fisiologia
18.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 45(4): 563-570, 2023 Aug.
Artigo em Zh | MEDLINE | ID: mdl-37654136

RESUMO

Objective To study the expression of selenoprotein genes in human immunodeficiency virus(HIV)infection and its mother-to-child transmission,so as to provide a theoretical basis for the prevention,diagnosis,and treatment of acquired immunodeficiency syndrome.Methods The dataset GSE4124 was downloaded from the Gene Expression Omnibus(GEO).Two groups of HIV-positive mothers(n=25)and HIV-negative mothers(n=20)were designed.HIV-positive mothers included a subset of transmitter(TR)mothers(n=11)and non-transmitter(NTR)mothers(n=14).Then,t-test was carried out to compare the expression levels of selenoprotein genes between the four groups(HIV-positive vs. HIV-negative,NTR vs. HIV-negative,TR vs. HIV-negative,TR vs. NTR).Univariate and multivariate Logistic regression were adopted to analyze the effects of differentially expressed genes on HIV infection and mother-to-child transmission.R software was used to establish a nomogram prediction model and evaluate the model performance.Results Compared with the HIV-negative group,HIV-positive,NTR,and TR groups had 8,5 and 8 down-regulated selenoprotein genes,respectively.Compared with the NTR group,the TR group had 4 down-regulated selenoprotein genes.Univariate Logistic regression analysis showed that abnormally high expression of GPX1,GPX3,GPX4,TXNRD1,TXNRD3,and SEPHS2 affected HIV infection and had no effect on mother-to-child transmission.The multivariate Logistic regression analysis showed that the abnormally high expression of TXNRD3(OR=0.032,95%CI=0.002-0.607,P=0.022)was positively correlated with HIV infection.As for the nomogram prediction model,the area under the receiver-operating characteristic curve for 1-year survival of HIV-infected patients was 0.840(95%CI=0.690-1.000),and that for 3-year survival of HIV-infected patients was 0.870(95%CI=0.730-1.000).Conclusions Multiple selenoprotein genes with down-regulated expression levels were involved in the regulation of HIV infection and mother-to-child transmission.The abnormal high expression of TXNRD3 was positively correlated with HIV infection.The findings provide new ideas for the prevention,diagnosis,and treatment of acquired immunodeficiency syndrome.


Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Humanos , Feminino , Transmissão Vertical de Doenças Infecciosas , Nomogramas , Selenoproteínas/genética
19.
Zhongguo Zhong Yao Za Zhi ; 48(20): 5668-5674, 2023 Oct.
Artigo em Zh | MEDLINE | ID: mdl-38114160

RESUMO

Lixuwang~® Xuesaitong Soft Capsules(referred to as "Xuesaitong Soft Capsules") have the effects of promoting blood circulation, resolving blood stasis, and dredging meridians and collaterals. They are widely used in the prevention and treatment of cardiovascular and cerebrovascular diseases in clinical practice. Through years of clinical observation, they have shown significant efficacy in ischemic stroke, coronary heart disease, and other diseases, and have been recommended by multiple guidelines, consensus statements, and monographs. Based on the summary of clinical application experience by doctors and existing evidence-based research, following the Technical Specifications for Consensus Development of Chinese Patent Medicine by Clinical Experts issued by Standardization Office of the Chinese Association of Traditional Chinese Medicine, a nominal group method was used to reach 19 recommended opinions/consensus suggestions. This document proposes the timing of medication, syndrome differentiation for medication, therapeutic effects, dosage and administration, treatment duration, economic considerations, and safety considerations in the use of Xuesaitong Soft Capsules for the treatment of ischemic stroke and angina pectoris in coronary heart disease. It is intended for doctors in internal medicine, encephalopathy(neurology), cardiovascular medicine, geriatrics, emergency medicine, general practice, and traditional Chinese medicine departments of various medical institutions, as well as pharmacists in hospitals and pharmacies, as a medication reference when using Xuesaitong Soft Capsules. It is hoped that the widespread application of this consensus can improve the clinical efficacy of Xuesaitong Soft Capsules in the treatment of ischemic stroke and coronary heart disease, promote rational drug use, and reduce medication risks. This consensus has been reviewed and published by the China Association of Traditional Chinese Medicine, with the identification number GS/CACM 323-2023.


Assuntos
Doença das Coronárias , Medicamentos de Ervas Chinesas , AVC Isquêmico , Humanos , Consenso , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Doença das Coronárias/tratamento farmacológico , AVC Isquêmico/tratamento farmacológico , Cápsulas
20.
Catheter Cardiovasc Interv ; 99 Suppl 1: 1440-1447, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35077596

RESUMO

OBJECTIVES: To investigate the potential predictors and clinical significance of periprocedural myocardial infarction (PMI), as defined by the latest Fourth Universal Definition of Myocardial Infarction (2018), following rotational atherectomy (RA). BACKGROUND: PMI is not uncommon in patients undergoing RA, although the predictors and prognostic impact are unknown. METHODS: Data from 229 consecutive patients who had undergone RA before drug-eluting stent (DES) implantation in a single center were analyzed. Patients' demographic information, clinical, angiographic, and procedural characteristics, and 1-year follow-up outcomes were collected retrospectively. RESULTS: The overall incidence of PMI in patients undergoing RA was 48.5%. Age (adjusted odds ratio [OR]: 1.024, 95% confidence interval [CI]: 1.001-1.047, p = 0.043) and ejection fraction (adjusted OR: 0.977, 95% CI: 0.962-0.993, p = 0.004) were independent predictors of PMI in RA, although PMI was not associated with an increased risk of major adverse cardiovascular and cerebrovascular events (MACCEs) at the 1-year follow-up in patients undergoing RA. CONCLUSION: Age and ejection fraction were independently associated with an elevated risk of PMI in patients undergoing RA. However, post-RA microinfarcts were not associated with an increased risk of MACCEs over the short-term follow-up period.


Assuntos
Aterectomia Coronária , Doença da Artéria Coronariana , Stents Farmacológicos , Infarto do Miocárdio , Intervenção Coronária Percutânea , Aterectomia Coronária/efeitos adversos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/terapia , Stents Farmacológicos/efeitos adversos , Humanos , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
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