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1.
Nat Commun ; 15(1): 8508, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39353943

RESUMO

Immune surveillance by cytotoxic T cells eliminates tumor cells and cells infected by intracellular pathogens. This process relies on the presentation of antigenic peptides by Major Histocompatibility Complex class I (MHC-I) at the cell surface. The loading of these peptides onto MHC-I depends on the peptide loading complex (PLC) at the endoplasmic reticulum (ER). Here, we uncovered that MHC-I antigen presentation is regulated by ER-associated degradation (ERAD), a protein quality control process essential to clear misfolded and unassembled proteins. An unbiased proteomics screen identified the PLC component Tapasin, essential for peptide loading onto MHC-I, as a substrate of the RNF185/Membralin ERAD complex. Loss of RNF185/Membralin resulted in elevated Tapasin steady state levels and increased MHC-I at the surface of professional antigen presenting cells. We further show that RNF185/Membralin ERAD complex recognizes unassembled Tapasin and limits its incorporation into PLC. These findings establish a novel mechanism controlling antigen presentation and suggest RNF185/Membralin as a potential therapeutic target to modulate immune surveillance.


Assuntos
Apresentação de Antígeno , Degradação Associada com o Retículo Endoplasmático , Retículo Endoplasmático , Antígenos de Histocompatibilidade Classe I , Proteínas de Membrana Transportadoras , Ubiquitina-Proteína Ligases , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Membrana Transportadoras/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Retículo Endoplasmático/metabolismo , Células HEK293 , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética
2.
Circulation ; 2024 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-39315436

RESUMO

The science of cardiac rehabilitation and the secondary prevention of cardiovascular disease has progressed substantially since the most recent American Heart Association and American Association of Cardiovascular and Pulmonary Rehabilitation update on the core components of cardiac rehabilitation and secondary prevention programs was published in 2007. In addition, the advent of new care models, including virtual and remote delivery of cardiac rehabilitation services, has expanded the ways that cardiac rehabilitation programs can reach patients. In this scientific statement, we update the scientific basis of the core components of patient assessment, nutritional counseling, weight management and body composition, cardiovascular disease and risk factor management, psychosocial management, aerobic exercise training, strength training, and physical activity counseling. In addition, in recognition that high-quality cardiac rehabilitation programs regularly monitor their processes and outcomes and engage in an ongoing process of quality improvement, we introduce a new core component of program quality. High-quality program performance will be essential to improve widely documented low enrollment and adherence rates and reduce health disparities in cardiac rehabilitation access.

3.
Circulation ; 150(13): 1010-1029, 2024 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-38836349

RESUMO

BACKGROUND: Cardiomyocyte growth is coupled with active protein synthesis, which is one of the basic biological processes in living cells. However, it is unclear whether the unfolded protein response transducers and effectors directly take part in the control of protein synthesis. The connection between critical functions of the unfolded protein response in cellular physiology and requirements of multiple processes for cell growth prompted us to investigate the role of the unfolded protein response in cell growth and underlying molecular mechanisms. METHODS: Cardiomyocyte-specific inositol-requiring enzyme 1α (IRE1α) knockout and overexpression mouse models were generated to explore its function in vivo. Neonatal rat ventricular myocytes were isolated and cultured to evaluate the role of IRE1α in cardiomyocyte growth in vitro. Mass spectrometry was conducted to identify novel interacting proteins of IRE1α. Ribosome sequencing and polysome profiling were performed to determine the molecular basis for the function of IRE1α in translational control. RESULTS: We show that IRE1α is required for cell growth in neonatal rat ventricular myocytes under prohypertrophy treatment and in HEK293 cells in response to serum stimulation. At the molecular level, IRE1α directly interacts with eIF4G and eIF3, 2 critical components of the translation initiation complex. We demonstrate that IRE1α facilitates the formation of the translation initiation complex around the endoplasmic reticulum and preferentially initiates the translation of transcripts with 5' terminal oligopyrimidine motifs. We then reveal that IRE1α plays an important role in determining the selectivity and translation of these transcripts. We next show that IRE1α stimulates the translation of epidermal growth factor receptor through an unannotated terminal oligopyrimidine motif in its 5' untranslated region. We further demonstrate a physiological role of IRE1α-governed protein translation by showing that IRE1α is essential for cardiomyocyte growth and cardiac functional maintenance under hemodynamic stress in vivo. CONCLUSIONS: These studies suggest a noncanonical, essential role of IRE1α in orchestrating protein synthesis, which may have important implications in cardiac hypertrophy in response to pressure overload and general cell growth under other physiological and pathological conditions.


Assuntos
Endorribonucleases , Miócitos Cardíacos , Proteínas Serina-Treonina Quinases , Animais , Miócitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Endorribonucleases/metabolismo , Endorribonucleases/genética , Humanos , Ratos , Células HEK293 , Biossíntese de Proteínas , Camundongos , Camundongos Knockout , Cardiomegalia/metabolismo , Cardiomegalia/genética , Cardiomegalia/patologia , Resposta a Proteínas não Dobradas , Células Cultivadas , Animais Recém-Nascidos , Fator de Iniciação Eucariótico 4G/metabolismo , Fator de Iniciação Eucariótico 4G/genética , Ratos Sprague-Dawley , Complexos Multienzimáticos
4.
Diagnostics (Basel) ; 14(12)2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38928705

RESUMO

In recent years, infectious disease diagnosis has increasingly turned to host-centered approaches as a complement to pathogen-directed ones. The former, however, typically requires the interpretation of complex multiple biomarker datasets to arrive at an informative diagnostic outcome. This report describes a machine learning (ML)-based classification workflow that is intended as a template for researchers seeking to apply ML approaches for developing host-based infectious disease biomarker classifiers. As an example, we built a classification model that could accurately distinguish between three disease etiology classes: bacterial, viral, and normal in human sera using host protein biomarkers of known diagnostic utility. After collecting protein data from known disease samples, we trained a series of increasingly complex Auto-ML models until arriving at an optimized classifier that could differentiate viral, bacterial, and non-disease samples. Even when limited to a relatively small training set size, the model had robust diagnostic characteristics and performed well when faced with a blinded sample set. We present here a flexible approach for applying an Auto-ML-based workflow for the identification of host biomarker classifiers with diagnostic utility for infectious disease, and which can readily be adapted for multiple biomarker classes and disease states.

5.
N Engl J Med ; 390(19): 1835, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38749052
6.
J Clin Invest ; 134(13)2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38722686

RESUMO

Group 3 innate lymphoid cells (ILC3s) are key players in intestinal homeostasis. ER stress is linked to inflammatory bowel disease (IBD). Here, we used cell culture, mouse models, and human specimens to determine whether ER stress in ILC3s affects IBD pathophysiology. We show that mouse intestinal ILC3s exhibited a 24-hour rhythmic expression pattern of the master ER stress response regulator inositol-requiring kinase 1α/X-box-binding protein 1 (IRE1α/XBP1). Proinflammatory cytokine IL-23 selectively stimulated IRE1α/XBP1 in mouse ILC3s through mitochondrial ROS (mtROS). IRE1α/XBP1 was activated in ILC3s from mice exposed to experimental colitis and in inflamed human IBD specimens. Mice with Ire1α deletion in ILC3s (Ire1αΔRorc) showed reduced expression of the ER stress response and cytokine genes including Il22 in ILC3s and were highly vulnerable to infections and colitis. Administration of IL-22 counteracted their colitis susceptibility. In human ILC3s, IRE1 inhibitors suppressed cytokine production, which was upregulated by an IRE1 activator. Moreover, the frequencies of intestinal XBP1s+ ILC3s in patients with Crohn's disease before administration of ustekinumab, an anti-IL-12/IL-23 antibody, positively correlated with the response to treatment. We demonstrate that a noncanonical mtROS-IRE1α/XBP1 pathway augmented cytokine production by ILC3s and identify XBP1s+ ILC3s as a potential biomarker for predicting the response to anti-IL-23 therapies in IBD.


Assuntos
Endorribonucleases , Imunidade Inata , Doenças Inflamatórias Intestinais , Proteínas Serina-Treonina Quinases , Proteína 1 de Ligação a X-Box , Animais , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/imunologia , Proteína 1 de Ligação a X-Box/metabolismo , Camundongos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/imunologia , Endorribonucleases/genética , Endorribonucleases/metabolismo , Endorribonucleases/imunologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Estresse do Retículo Endoplasmático/imunologia , Citocinas/metabolismo , Citocinas/imunologia , Citocinas/genética , Transdução de Sinais/imunologia , Camundongos Knockout , Masculino , Feminino
7.
Protein Sci ; 33(4): e4949, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38511500

RESUMO

Primary defects in folding of mutant proinsulin can cause dominant-negative proinsulin accumulation in the endoplasmic reticulum (ER), impaired anterograde proinsulin trafficking, perturbed ER homeostasis, diminished insulin production, and ß-cell dysfunction. Conversely, if primary impairment of ER-to-Golgi trafficking (which also perturbs ER homeostasis) drives misfolding of nonmutant proinsulin-this might suggest bi-directional entry into a common pathological phenotype (proinsulin misfolding, perturbed ER homeostasis, and deficient ER export of proinsulin) that can culminate in diminished insulin storage and diabetes. Here, we've challenged ß-cells with conditions that impair ER-to-Golgi trafficking, and devised an accurate means to assess the relative abundance of distinct folded/misfolded forms of proinsulin using a novel nonreducing SDS-PAGE/immunoblotting protocol. We confirm abundant proinsulin misfolding upon introduction of a diabetogenic INS mutation, or in the islets of db/db mice. Whereas blockade of proinsulin trafficking in Golgi/post-Golgi compartments results in intracellular accumulation of properly-folded proinsulin (bearing native disulfide bonds), impairment of ER-to-Golgi trafficking (regardless whether such impairment is achieved by genetic or pharmacologic means) results in decreased native proinsulin with more misfolded proinsulin. Remarkably, reversible ER-to-Golgi transport defects (such as treatment with brefeldin A or cellular energy depletion) upon reversal quickly restore the ER folding environment, resulting in the disappearance of pre-existing misfolded proinsulin while preserving proinsulin bearing native disulfide bonds. Thus, proper homeostatic balance of ER-to-Golgi trafficking is linked to a more favorable proinsulin folding (as well as trafficking) outcome.


Assuntos
Diabetes Mellitus , Células Secretoras de Insulina , Camundongos , Animais , Proinsulina/genética , Proinsulina/química , Dobramento de Proteína , Insulina/química , Retículo Endoplasmático , Homeostase , Dissulfetos/química
9.
Nat Commun ; 15(1): 1916, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429266

RESUMO

The striatum, known as the input nucleus of the basal ganglia, is extensively studied for its diverse behavioral roles. However, the relationship between its neuronal and vascular activity, vital for interpreting functional magnetic resonance imaging (fMRI) signals, has not received comprehensive examination within the striatum. Here, we demonstrate that optogenetic stimulation of dorsal striatal neurons or their afferents from various cortical and subcortical regions induces negative striatal fMRI responses in rats, manifesting as vasoconstriction. These responses occur even with heightened striatal neuronal activity, confirmed by electrophysiology and fiber-photometry. In parallel, midbrain dopaminergic neuron optogenetic modulation, coupled with electrochemical measurements, establishes a link between striatal vasodilation and dopamine release. Intriguingly, in vivo intra-striatal pharmacological manipulations during optogenetic stimulation highlight a critical role of opioidergic signaling in generating striatal vasoconstriction. This observation is substantiated by detecting striatal vasoconstriction in brain slices after synthetic opioid application. In humans, manipulations aimed at increasing striatal neuronal activity likewise elicit negative striatal fMRI responses. Our results emphasize the necessity of considering vasoactive neurotransmission alongside neuronal activity when interpreting fMRI signal.


Assuntos
Corpo Estriado , Imageamento por Ressonância Magnética , Humanos , Ratos , Animais , Imageamento por Ressonância Magnética/métodos , Corpo Estriado/fisiologia , Neostriado , Gânglios da Base , Neurônios Dopaminérgicos
11.
J Mol Cell Cardiol ; 189: 12-24, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38401179

RESUMO

Cardiomyocytes activate the unfolded protein response (UPR) transcription factor ATF6 during pressure overload-induced hypertrophic growth. The UPR is thought to increase ER protein folding capacity and maintain proteostasis. ATF6 deficiency during pressure overload leads to heart failure, suggesting that ATF6 protects against myocardial dysfunction by preventing protein misfolding. However, conclusive evidence that ATF6 prevents toxic protein misfolding during cardiac hypertrophy is still pending. Here, we found that activation of the UPR, including ATF6, is a common response to pathological cardiac hypertrophy in mice. ATF6 KO mice failed to induce sufficient levels of UPR target genes in response to chronic isoproterenol infusion or transverse aortic constriction (TAC), resulting in impaired cardiac growth. To investigate the effects of ATF6 on protein folding, the accumulation of poly-ubiquitinated proteins as well as soluble amyloid oligomers were directly quantified in hypertrophied hearts of WT and ATF6 KO mice. Whereas only low levels of protein misfolding was observed in WT hearts after TAC, ATF6 KO mice accumulated increased quantities of misfolded protein, which was associated with impaired myocardial function. Collectively, the data suggest that ATF6 plays a critical adaptive role during cardiac hypertrophy by protecting against protein misfolding.


Assuntos
Estenose da Valva Aórtica , Cardiomegalia , Animais , Camundongos , Cardiomegalia/patologia , Miócitos Cardíacos/metabolismo , Miocárdio/metabolismo , Fatores de Transcrição/metabolismo , Regulação da Expressão Gênica , Estenose da Valva Aórtica/metabolismo , Camundongos Knockout
12.
Mol Metab ; 80: 101874, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38211723

RESUMO

OBJECTIVES: The assembly and secretion of hepatic very low-density lipoprotein (VLDL) plays pivotal roles in hepatic and plasma lipid homeostasis. Protein disulfide isomerase A1 (PDIA1/P4HB) is a molecular chaperone whose functions are essential for protein folding in the endoplasmic reticulum. Here we investigated the physiological requirement in vivo for PDIA1 in maintaining VLDL assembly and secretion. METHODS: Pdia1/P4hb was conditionally deleted in adult mouse hepatocytes and the phenotypes characterized. Mechanistic analyses in primary hepatocytes determined how PDIA1 ablation alters MTTP synthesis and degradation as well as altering synthesis and secretion of Apolipoprotein B (APOB), along with complementary expression of intact PDIA1 vs a catalytically inactivated PDIA1 mutant. RESULTS: Hepatocyte-specific deletion of Pdia1/P4hb inhibited hepatic MTTP expression and dramatically reduced VLDL production, leading to severe hepatic steatosis and hypolipidemia. Pdia1-deletion did not affect mRNA expression or protein stability of MTTP but rather prevented Mttp mRNA translation. We demonstrate an essential role for PDIA1 in MTTP synthesis and function and show that PDIA1 interacts with APOB in an MTTP-independent manner via its molecular chaperone function to support APOB folding and secretion. CONCLUSIONS: PDIA1 plays indispensable roles in APOB folding, MTTP synthesis and activity to support VLDL assembly. Thus, like APOB and MTTP, PDIA1 is an obligatory component of hepatic VLDL production.


Assuntos
Hepatócitos , Lipoproteínas VLDL , Nucleotídeos de Timina , Animais , Camundongos , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Hepatócitos/metabolismo , Lipoproteínas VLDL/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Triglicerídeos/metabolismo
13.
Mol Ther ; 32(2): 325-339, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38053332

RESUMO

Upon viral infection of the liver, CD8+ T cell responses may be triggered despite the immune suppressive properties that manifest in this organ. We sought to identify pathways that activate responses to a neoantigen expressed in hepatocytes, using adeno-associated viral (AAV) gene transfer. It was previously established that cooperation between plasmacytoid dendritic cells (pDCs), which sense AAV genomes by Toll-like receptor 9 (TLR9), and conventional DCs promotes cross-priming of capsid-specific CD8+ T cells. Surprisingly, we find local initiation of a CD8+ T cell response against antigen expressed in ∼20% of murine hepatocytes, independent of TLR9 or type I interferons and instead relying on IL-1 receptor 1-MyD88 signaling. Both IL-1α and IL-1ß contribute to this response, which can be blunted by IL-1 blockade. Upon AAV administration, IL-1-producing pDCs infiltrate the liver and co-cluster with XCR1+ DCs, CD8+ T cells, and Kupffer cells. Analogous events were observed following coagulation factor VIII gene transfer in hemophilia A mice. Therefore, pDCs have alternative means of promoting anti-viral T cell responses and participate in intrahepatic immune cell networks similar to those that form in lymphoid organs. Combined TLR9 and IL-1 blockade may broadly prevent CD8+ T responses against AAV capsid and transgene product.


Assuntos
Linfócitos T CD8-Positivos , Fator 88 de Diferenciação Mieloide , Animais , Camundongos , Proteínas do Capsídeo , Células Dendríticas , Interleucina-1/metabolismo , Fígado/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo
14.
Cell Rep ; 43(1): 113615, 2024 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-38159280

RESUMO

The integrated stress response (ISR) is critical for cell survival under stress. In response to diverse environmental cues, eIF2α becomes phosphorylated, engendering a dramatic change in mRNA translation. The activation of ISR plays a pivotal role in the early embryogenesis, but the eIF2-dependent translational landscape in pluripotent embryonic stem cells (ESCs) is largely unexplored. We employ a multi-omics approach consisting of ribosome profiling, proteomics, and metabolomics in wild-type (eIF2α+/+) and phosphorylation-deficient mutant eIF2α (eIF2αA/A) mouse ESCs (mESCs) to investigate phosphorylated (p)-eIF2α-dependent translational control of naive pluripotency. We show a transient increase in p-eIF2α in the naive epiblast layer of E4.5 embryos. Absence of eIF2α phosphorylation engenders an exit from naive pluripotency following 2i (two chemical inhibitors of MEK1/2 and GSK3α/ß) withdrawal. p-eIF2α controls translation of mRNAs encoding proteins that govern pluripotency, chromatin organization, and glutathione synthesis. Thus, p-eIF2α acts as a key regulator of the naive pluripotency gene regulatory network.


Assuntos
Células-Tronco Embrionárias Murinas , Células-Tronco Pluripotentes , Animais , Camundongos , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias Murinas/metabolismo , Fosforilação , Células-Tronco Pluripotentes/metabolismo , RNA Mensageiro/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo
15.
Ann Med ; 55(2): 2295981, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38128485

RESUMO

INTRODUCTION: This study aimed to investigate the association between cardiorespiratory fitness (CRF) and perioperative morbidity and long-term mortality in operable patients with early-stage non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This prospective study included consecutive patients with early-stage NSCLC who underwent presurgical cardiopulmonary exercise testing between November 2014 and December 2019 (registration number: ChiCTR2100048120). Logistic and Cox proportional hazards regression were applied to evaluate the correlation between CRF and perioperative complications and long-term mortality, respectively. Propensity score overlap weighting was used to adjust for the covariates. We performed sensitivity analyses to determine the stability of our results. RESULTS: A total of 895 patients were followed for a median of 40 months [interquartile range 25]. The median age of the patients was 59 years [range 26-83], and 62.5% were male. During the study period, 156 perioperative complications and 146 deaths were observed. Low CRF was associated with a higher risk of death (62.9 versus 33.6 per 1000 person-years; weighted incidence rate difference, 29.34 [95% CI, 0.32 to 58.36] per 1000 person-years) and perioperative morbidity (241.6 versus 141.9 per 1000 surgeries; weighted incidence rate difference, 99.72 [95% CI, 34.75 to 164.70] per 1000 surgeries). A CRF of ≤ 20 ml/kg/min was significantly associated with a high risk of long-term mortality (weighted hazard ratio, 1.98 [95% CI, 1.31 to 2.98], p < 0.001) and perioperative morbidity (weighted odds ratio, 1.93 [1.28 to 2.90], p = 0.002) compared to higher CRF. CONCLUSION: The study found that low CRF is significantly associated with increased perioperative morbidity and long-term mortality in operable patients with early-stage NSCLC.


Low cardiorespiratory fitness is significantly associated with increased perioperative morbidity and long-term mortality in operable patients with early-stage non-small cell lung cancer.Future research is recommended to investigate the potential prognostic role of integrating cardiorespiratory fitness into the currently used prognosis algorithm for patients with non-small cell lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Aptidão Cardiorrespiratória , Neoplasias Pulmonares , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudos Prospectivos , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Pontuação de Propensão , Neoplasias Pulmonares/cirurgia , Teste de Esforço/métodos , Incidência , Fatores de Risco
16.
Sci Rep ; 13(1): 18840, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37914767

RESUMO

Rapid pathogen identification is a critical first step in patient isolation, treatment, and controlling an outbreak. Real-time PCR is a highly sensitive and specific approach commonly used for infectious disease diagnostics. However, mismatches in the primer or probe sequence and the target organism can cause decreased sensitivity, assay failure, and false negative results. Limited genomic sequences for rare pathogens such as Ebola virus (EBOV) can negatively impact assay performance due to undiscovered genetic diversity. We previously developed and validated several EBOV assays prior to the 2013-2016 EBOV outbreak in West Africa, and sequencing EBOV Makona identified sequence variants that could impact assay performance. Here, we assessed the impact sequence mismatches have on EBOV assay performance, finding one or two primer or probe mismatches resulted in a range of impact from minimal to almost two log sensitivity reduction. Redesigning this assay improved detection of all EBOV variants tested. Comparing the performance of the new assay with the previous assays across a panel of human EBOV samples confirmed increased assay sensitivity as reflected in decreased Cq values with detection of three positive that tested negative with the original assay.


Assuntos
Ebolavirus , Doença pelo Vírus Ebola , Humanos , Ebolavirus/genética , África Ocidental , Surtos de Doenças , Genômica
17.
Proc Natl Acad Sci U S A ; 120(49): e2308671120, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-38015848

RESUMO

Activation of neuronal protein synthesis upon learning is critical for the formation of long-term memory. Here, we report that learning in the contextual fear conditioning paradigm engenders a decrease in eIF2α (eukaryotic translation initiation factor 2) phosphorylation in astrocytes in the hippocampal CA1 region, which promotes protein synthesis. Genetic reduction of eIF2α phosphorylation in hippocampal astrocytes enhanced contextual and spatial memory and lowered the threshold for the induction of long-lasting plasticity by modulating synaptic transmission. Thus, learning-induced dephosphorylation of eIF2α in astrocytes bolsters hippocampal synaptic plasticity and consolidation of long-term memories.


Assuntos
Astrócitos , Potenciação de Longa Duração , Potenciação de Longa Duração/fisiologia , Plasticidade Neuronal/genética , Hipocampo/fisiologia , Biossíntese de Proteínas , Região CA1 Hipocampal , Memória de Longo Prazo/fisiologia
18.
J Am Coll Cardiol ; 82(15): 1499-1508, 2023 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-37793746

RESUMO

BACKGROUND: The performance of the American College of Cardiology/American Heart Association pooled cohort equation (PCE) for atherosclerotic cardiovascular disease (ASCVD) in real-world clinical practice has not been evaluated extensively. OBJECTIVES: The goal of this study was to test the performance of PCE to predict ASCVD risk in the community, and determine if including individuals with values outside the PCE range (ie, age, blood pressure, cholesterol) or statin therapy initiation over follow-up would significantly affect PCE predictive capabilities. METHODS: The PCE was validated in a community-based cohort of consecutive patients who sought primary care in Olmsted County, Minnesota, between 1997 and 2000, followed-up through 2016. Inclusion criteria were similar to those of PCE derivation. Patient information was ascertained by using the record linkage system of the Rochester Epidemiology Project. ASCVD events (nonfatal and fatal myocardial infarction and ischemic stroke) were validated in duplicate. Calculated and observed ASCVD risk and c-statistics were compared across predefined groups. RESULTS: This study included 30,042 adults, with a mean age of 48.5 ± 12.2 years; 46% were male. Median follow-up was 16.5 years, truncated at 10 years for this analysis. Mean ASCVD risk was 5.6% ± 8.73%. There were 1,555 ASCVD events (5.2%). The PCE revealed good performance overall (c-statistic 0.78) and in sex and race subgroups; it was highest among non-White female subjects (c-statistic 0.81) and lowest in White male subjects (c-statistic 0.77). Out-of-range values and initiation of statin medication did not affect model performance. CONCLUSIONS: The PCE performed well in a community cohort representing real-world clinical practice. Values outside PCE ranges and initiation of statin medication did not affect performance. These results have implications for the applicability of current strategies for the prevention of ASCVD.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Adulto , Estados Unidos/epidemiologia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/tratamento farmacológico , Fatores de Risco , Medição de Risco/métodos , Aterosclerose/tratamento farmacológico , Fatores de Risco de Doenças Cardíacas
19.
J Thromb Haemost ; 21(12): 3329-3341, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37839613

RESUMO

Remarkably, it has been 40 years since the isolation of the 2 genes involved in hemophilia A (HA) and hemophilia B (HB), encoding clotting factor (F) VIII (FVIII) and FIX, respectively. Over the years, these advances led to the development of purified recombinant protein factors that are free of contaminating viruses from human pooled plasma for hemophilia treatments, reducing the morbidity and mortality previously associated with human plasma-derived clotting factors. These discoveries also paved the way for modified factors that have increased plasma half-lives. Importantly, more recent advances have led to the development and Food and Drug Administration approval of a hepatocyte-targeted, adeno-associated viral vector-mediated gene transfer approach for HA and HB. However, major concerns regarding the durability and safety of HA gene therapy remain to be resolved. Compared with FIX, FVIII is a much larger protein that is prone to misfolding and aggregation in the endoplasmic reticulum and is poorly secreted by the mammalian cells. Due to the constraint of the packaging capacity of adeno-associated viral vector, B-domain deleted FVIII rather than the full-length protein is used for HA gene therapy. Like full-length FVIII, B-domain deleted FVIII misfolds and is inefficiently secreted. Its expression in hepatocytes activates the cellular unfolded protein response, which is deleterious for hepatocyte function and survival and has the potential to drive hepatocellular carcinoma. This review is focused on our current understanding of factors limiting FVIII secretion and the potential pathophysiological consequences upon expression in hepatocytes.


Assuntos
Hemofilia A , Hemofilia B , Animais , Humanos , Fator VIII/metabolismo , Hemofilia A/genética , Hemofilia A/terapia , Hemofilia A/metabolismo , Fatores de Coagulação Sanguínea/genética , Terapia Genética , Hemofilia B/terapia , Hemofilia B/tratamento farmacológico , Mamíferos/genética , Mamíferos/metabolismo
20.
Mol Ther Nucleic Acids ; 33: 286-295, 2023 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-37547290

RESUMO

Endoplasmic reticulum (ER) stress has been linked with various acute and chronic neurodegenerative diseases. We previously found that optic nerve (ON) injury and diseases induce neuronal ER stress in retinal ganglion cells (RGCs). We further demonstrated that germline deletion of CHOP preserves the structure and function of both RGC somata and axons in mouse glaucoma models. Here we report that RGC-specific deletion of CHOP and/or its upstream regulator ATF4 synergistically promotes RGC and ON survival and preserves visual function in mouse ON crush and silicone oil-induced ocular hypertension (SOHU) glaucoma models. Consistently, topical application of the ATF4/CHOP chemical inhibitor ISRIB or RGC-specific CRISPR-mediated knockdown of the ATF4 downstream effector Gadd45a also delivers significant neuroprotection in the SOHU glaucoma model. These studies suggest that blocking the neuronal intrinsic ATF4/CHOP axis of ER stress is a promising neuroprotection strategy for neurodegeneration.

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