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1.
Commun Med (Lond) ; 4(1): 62, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570605

RESUMO

BACKGROUND: The fight against COVID-19 requires mass vaccination strategies, and vaccines inducing durable cross-protective responses are still needed. Inactivated vaccines have proven lasting efficacy against many pathogens and good safety records. They contain multiple protein antigens that may improve response breadth and can be easily adapted every year to maintain preparedness for future seasonally emerging variants. METHODS: The vaccine dose was determined using ELISA and pseudoviral particle-based neutralization assay in the mice. The immunogenicity was assessed in the non-human primates with multiplex ELISA, neutralization assays, ELISpot and intracellular staining. The efficacy was demonstrated by viral quantification in fluids using RT-qPCR and respiratory tissue lesions evaluation. RESULTS: Here we report the immunogenicity and efficacy of VLA2001 in animal models. VLA2001 formulated with alum and the TLR9 agonist CpG 1018™ adjuvant generate a Th1-biased immune response and serum neutralizing antibodies in female BALB/c mice. In male cynomolgus macaques, two injections of VLA2001 are sufficient to induce specific and polyfunctional CD4+ T cell responses, predominantly Th1-biased, and high levels of antibodies neutralizing SARS-CoV-2 infection in cell culture. These antibodies also inhibit the binding of the Spike protein to human ACE2 receptor of several variants of concern most resistant to neutralization. After exposure to a high dose of homologous SARS-CoV-2, vaccinated groups exhibit significant levels of protection from viral replication in the upper and lower respiratory tracts and from lung tissue inflammation. CONCLUSIONS: We demonstrate that the VLA2001 adjuvanted vaccine is immunogenic both in mouse and NHP models and prevent cynomolgus macaques from the viruses responsible of COVID-19.


Mass vaccination in response to the COVID-19 pandemic has substantially reduced the number of severe cases and hospitalizations. As the virus continues to evolve and give rise to new variants that cause local outbreaks, there is a need to develop new vaccine candidates capable of stopping the viral transmission. In this study, we explore the immune responses induced by the vaccine candidate VLA2001 in animal models. We highlight the vaccine's ability to induce an immune response capable of blocking the virus and eliminating infected cells. We show that it can protect the host from developing severe disease.

2.
Infect Dis Poverty ; 13(1): 16, 2024 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-38369483

RESUMO

BACKGROUND: Current soil-transmitted helminth (STH) control guidelines endorse the use of albendazole or mebendazole for school-based targeted preventive chemotherapy (PC), yet their reduced efficacy against Strongyloides stercoralis and Trichuris trichiura presents significant limitations. Emerging evidence indicates that community-wide PC [or mass drug administration (MDA)] using ivermectin, commonly used in other neglected tropical disease (NTD) control programs, may play an important role in controlling these parasites. We conducted a systematic review and meta-analysis to evaluate the effectiveness of ivermectin PC in reducing STH prevalence in endemic populations. METHODS: We searched Pubmed, EMBASE, and Web of Science on February 14, 2023, for studies that investigated the effectiveness of ivermectin PC, either alone or in combination with other anthelmintic drugs, on STH infections, and provided a measure of STH prevalence before and after PC. We calculated pooled prevalence reductions for each STH using random-effects meta-analyses. Our protocol is available on PROSPERO (registration number CRD42023401219). RESULTS: A total of 21 were eligible for the systematic review, of which 15 were eligible for meta-analysis. All studies delivered ivermectin through MDA. The pooled prevalence reduction of S. stercoralis following MDA with ivermectin alone was 84.49% (95% CI 54.96-94.66) across five studies and 81.37% (95% CI 61.62-90.96) across seven studies with or without albendazole. The prevalence reduction of T. trichiura was 49.93% (95% CI 18.23-69.34) across five studies with ivermectin alone, and 89.40% (95% CI 73.66-95.73) across three studies with the addition of albendazole. There was high heterogeneity for all syntheses (I2 > 65%). CONCLUSIONS: This study underscores the key role of ivermectin-based MDA in addressing limitations in current global STH guidelines in terms of limited efficacy against S. stercoralis and T. trichiura. Based on these findings, revising international STH guidelines to include ivermectin is a promising option to progress the control and eventual elimination of STHs and other NTDs.


Assuntos
Anti-Helmínticos , Helmintíase , Helmintos , Animais , Humanos , Ivermectina/uso terapêutico , Albendazol/uso terapêutico , Administração Massiva de Medicamentos , Solo/parasitologia , Helmintíase/tratamento farmacológico , Helmintíase/epidemiologia , Helmintíase/prevenção & controle , Anti-Helmínticos/uso terapêutico , Prevalência
3.
Front Cell Infect Microbiol ; 12: 979641, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405962

RESUMO

We evaluated the immunogenicity and protective ability of a chimpanzee replication-deficient adenovirus vectored COVID-19 vaccine (BV-AdCoV-1) expressing a stabilized pre-fusion SARS-CoV-2 spike glycoprotein in golden Syrian hamsters. Intranasal administration of BV-AdCoV-1 elicited strong humoral and cellular immunity in the animals. Furthermore, vaccination prevented weight loss, reduced SARS-CoV-2 infectious virus titers in the lungs as well as lung pathology and provided protection against SARS-CoV-2 live challenge. In addition, there was no vaccine-induced enhanced disease nor immunopathological exacerbation in BV-AdCoV-1-vaccinated animals. Furthermore, the vaccine induced cross-neutralizing antibody responses against the ancestral strain and the B.1.617.2, Omicron(BA.1), Omicron(BA.2.75) and Omicron(BA.4/5) variants of concern. These results demonstrate that BV-AdCoV-1 is potentially a promising candidate vaccine to prevent SARS-CoV-2 infection, and to curtail pandemic spread in humans.


Assuntos
COVID-19 , Vacinas Virais , Cricetinae , Animais , Humanos , Mesocricetus , Administração Intranasal , Pan troglodytes , COVID-19/prevenção & controle , Anticorpos Antivirais , Vacinas contra COVID-19 , SARS-CoV-2/genética , Adenoviridae/genética
4.
iScience ; 25(12): 105516, 2022 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-36419855

RESUMO

Intrusive memories hijack consciousness and their control may lead to forgetting. However, the contribution of reflexive attention to qualifying a memory signal as interfering is unknown. We used machine learning to decode the brain's electrical activity and pinpoint the otherwise hidden emergence of intrusive memories reported during a memory suppression task. Importantly, the algorithm was trained on an independent attentional model of visual activity, mimicking either the abrupt and interfering appearance of visual scenes into conscious awareness or their deliberate exploration. Intrusion of memories into conscious awareness were decoded above chance. The decoding accuracy increased when the algorithm was trained using a model of reflexive attention. Conscious detection of intrusive activity decoded from the brain signal was central to the future silencing of suppressed memories and later forgetting. Unwanted memories require the reflexive orienting of attention and access to consciousness to be suppressed effectively by inhibitory control.

5.
Biol Psychol ; 170: 108325, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35358604

RESUMO

The ability to sense, monitor, and control respiration - e.g., respiratory interoception (henceforth, respiroception) is a core homeostatic ability. Beyond the regulation of gas exchange, enhanced awareness of respiratory sensations is directly related to psychiatric symptoms such as panic and anxiety. Indeed, chronic breathlessness (dyspnea) is associated with a fourfold increase in the risk of developing depression and anxiety, and the regulation of the breath is a key aspect of many mindfulness-based approaches to the treatment of mental illness. Physiologically speaking, the ability to accurately monitor respiratory sensations is important for optimizing cardiorespiratory function during athletic exertion, and can be a key indicator of illness. Given the important role of respiroception in mental and physical health, it is unsurprising that there is increased interest in the quantification of respiratory psychophysiology across different perceptual and metacognitive levels of the psychological hierarchy. Compared to other more popular modalities of interoception, such as in the cardiac domain, there are relatively few methods available for measuring aspects of respiroception. Existing inspiratory loading tasks are difficult to administer and frequently require expensive medical equipment, or offer poor granularity in their quantification of respiratory-related perceptual ability. To facilitate the study of respiroception, we here present a new, fully automated and computer-controlled apparatus and psychophysiological method, which can flexibly and easily measure respiratory-related interoceptive sensitivity, bias and metacognition, in as little as 30 min of testing, using easy to make 3D printable parts.


Assuntos
Interocepção , Metacognição , Ansiedade , Conscientização , Dispneia , Frequência Cardíaca/fisiologia , Humanos , Interocepção/fisiologia , Metacognição/fisiologia , Taxa Respiratória
6.
Clin Microbiol Rev ; 35(2): e0007821, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-35195446

RESUMO

Human T-lymphotropic virus type 1 (HTLV-1) is estimated to affect 5 to 10 million people globally and can cause severe and potentially fatal disease, including adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The burden of HTLV-1 infection appears to be geographically concentrated, with high prevalence in discrete regions and populations. While most high-income countries have introduced HTLV-1 screening of blood donations, few other public health measures have been implemented to prevent infection or its consequences. Recent advocacy from concerned researchers, clinicians, and community members has emphasized the potential for improved prevention and management of HTLV-1 infection. Despite all that has been learned in the 4 decades following the discovery of HTLV-1, gaps in knowledge across clinical and public health aspects persist, impeding optimal control and prevention, as well as the development of policies and guidelines. Awareness of HTLV-1 among health care providers, communities, and affected individuals remains limited, even in countries of endemicity. This review provides a comprehensive overview on HTLV-1 epidemiology and on clinical and public health and highlights key areas for further research and collaboration to advance the health of people with and at risk of HTLV-1 infection.


Assuntos
Infecções por HTLV-I , Vírus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T do Adulto , Paraparesia Espástica Tropical , Adulto , Infecções por HTLV-I/diagnóstico , Infecções por HTLV-I/epidemiologia , Infecções por HTLV-I/prevenção & controle , Humanos , Leucemia-Linfoma de Células T do Adulto/epidemiologia , Paraparesia Espástica Tropical/epidemiologia , Paraparesia Espástica Tropical/patologia , Saúde Pública
7.
J Antimicrob Chemother ; 77(4): 1094-1101, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35022753

RESUMO

BACKGROUND: Studies of antiretroviral drug (ARV) tissue distribution in preclinical models, such as mice, are key to understanding viral persistence. OBJECTIVES: To determine the plasma and tissue pharmacokinetics and tissue distributions of tenofovir, emtricitabine and dolutegravir in mice. METHODS: ARVs were simultaneously administered to two different strains, and their levels in plasma and tissue samples were determined by a validated LC-MS/MS method. A non-compartmental analysis was performed to estimate the main pharmacokinetic parameters. A tissue penetration factor (TPF) was calculated as the ratio of the concentration in the tissue concerned to that in plasma. RESULTS: ARV plasma pharmacokinetic parameters in both strains were similar to those estimated in the clinical context. Tissue concentrations were highest in the digestive tract, followed by the liver and kidneys, lymphatic system, pancreas, adipose tissue and lungs. Tissue concentrations were lowest in the brain. Triple therapy could not be considered effective in any of the tissues considered. The TPF values obtained showed that tenofovir diffused widely, especially in the digestive tract, liver and kidneys. Emtricitabine had a TPF above 100% in two-thirds of the tissues. Dolutegravir was poorly distributed to all tissues. CONCLUSIONS: Drug specificity was observed, with higher levels of exposure to tenofovir than to emtricitabine or dolutegravir. Tissue specificity was also observed, with strong penetration of the digestive tract and weak penetration of the brain. These data have important implications for future preclinical and clinical studies for developing new HIV therapies with the goal of an HIV cure.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Animais , Fármacos Anti-HIV/uso terapêutico , Cromatografia Líquida/métodos , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis , Camundongos , Oxazinas , Piperazinas , Piridonas , Espectrometria de Massas em Tandem/métodos , Tenofovir/uso terapêutico , Distribuição Tecidual
8.
Biol Psychol ; 168: 108239, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34902450

RESUMO

Interoception - the physiological sense of our inner bodies - has risen to the forefront of psychological and psychiatric research. Much of this research utilizes tasks that attempt to measure the ability to accurately detect cardiac signals. Unfortunately, these approaches are confounded by well-known issues limiting their validity and interpretation. At the core of this controversy is the role of subjective beliefs about the heart rate in confounding measures of interoceptive accuracy. Here, we recast these beliefs as an important part of the causal machinery of interoception, and offer a novel psychophysical "heart rate discrimination" method to estimate their accuracy and precision. By applying this task in 223 healthy participants, we demonstrate that cardiac interoceptive beliefs are more biased, less precise, and are associated with poorer metacognitive insight relative to an exteroceptive control condition. Our task, provided as an open-source python package, offers a robust approach to quantifying cardiac beliefs.


Assuntos
Interocepção , Metacognição , Conscientização/fisiologia , Voluntários Saudáveis , Coração , Frequência Cardíaca/fisiologia , Humanos , Interocepção/fisiologia
9.
Viruses ; 13(12)2021 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-34960758

RESUMO

BACKGROUND: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. METHODS: Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. RESULTS: While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFNα-remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFNα combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. CONCLUSIONS: Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections.


Assuntos
Antivirais/farmacologia , Interferon-alfa/farmacologia , SARS-CoV-2/efeitos dos fármacos , Linhagem Celular , Sinergismo Farmacológico , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/virologia , Metaboloma/efeitos dos fármacos , Organoides , RNA Viral/biossíntese , RNA Viral/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Vírus/classificação , Vírus/efeitos dos fármacos
10.
Viruses ; 13(9)2021 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-34578348

RESUMO

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here, we address these challenges by combining Pegasys (IFNα) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNα and that both Serpin E1 and nafamostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Benzamidinas/farmacologia , COVID-19/metabolismo , COVID-19/virologia , Guanidinas/farmacologia , Interferon-alfa/farmacologia , SARS-CoV-2/efeitos dos fármacos , Serina Endopeptidases/metabolismo , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Benzamidinas/uso terapêutico , Cricetinae , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Guanidinas/uso terapêutico , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Interferon-alfa/uso terapêutico , Replicação Viral/efeitos dos fármacos , Tratamento Farmacológico da COVID-19
11.
Cogn Emot ; 35(4): 705-721, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33342362

RESUMO

Emotion alters how we feel, see, and experience the world. In the domain of memory, the emotional valence and arousal of memorised stimuli can modulate both the acuity and content of episodic recall. However, no experiment has investigated whether arousal and valence also influence metacognition for memory (i.e. the process of self-monitoring memories). In a pre-registered study, we applied a novel psychophysiological design together with computational models of metacognition to assess the influence of stimulus valence and arousal on the sensitivity, bias, and efficiency of metamemory. To estimate the role of physiological arousal in mediating these effects, we recorded cardiac measures through pulse oximetry. We found that negative valence substantially decreased both memory performance and subjective confidence, in particular for low arousal words. Simultaneously, we found that emotional valence modulated both heart rate and heart-rate variability (HRV) during recognition memory. Exploratory trial-level analyses further revealed that subjective confidence was encoded in instantaneous heart-rate fluctuations and that this relationship was also modulated by emotional valence. Our results demonstrate that recognition memory and metacognition are influenced by the emotional valence of encoded items and that this correlation is in part related to cardiac activity.


Assuntos
Metacognição , Nível de Alerta , Emoções , Humanos , Rememoração Mental , Reconhecimento Psicológico
12.
Sci Rep ; 10(1): 15008, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929105

RESUMO

Efforts to exclude past experiences from conscious awareness can lead to forgetting. Memory suppression is central to affective disorders, but we still do not really know whether emotions, including their physiological causes, are also impacted by this process in normal functioning individuals. In two studies, we measured the after-effects of suppressing negative memories on cardiac response in healthy participants. Results of Study 1 revealed that efficient control of memories was associated with long-term inhibition of the cardiac deceleration that is normally induced by disgusting stimuli. Attempts to suppress sad memories, by contrast, aggravated the cardiac response, an effect that was closely related to the inability to forget this specific material. In Study 2, electroencephalography revealed a reduction in power in the theta (3-8 Hz), alpha (8-12 Hz) and low-beta (13-20 Hz) bands during the suppression of unwanted memories, compared with their voluntary recall. Interestingly, however, the reduction of power in the theta frequency band during memory control was related to a subsequent inhibition of the cardiac response. These results provide a neurophysiological basis for the influence of memory control mechanisms on the cardiac system, opening up new avenues and questions for treating intrusive memories using motivated forgetting.


Assuntos
Emoções/fisiologia , Coração/fisiologia , Memória/fisiologia , Adolescente , Adulto , Eletroencefalografia , Feminino , Frequência Cardíaca , Humanos , Masculino , Experimentação Humana não Terapêutica , Fatores de Tempo , Adulto Jovem
13.
Behav Brain Sci ; 43: e91, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32460937

RESUMO

The Bayesian brain hypothesis, as formalized by the free-energy principle, is ascendant in cognitive science. But, how does the Bayesian brain obtain prior beliefs? Veissière and colleagues argue that sociocultural interaction is one important source. We offer a complementary model in which "interoceptive self-inference" guides the estimation of expected uncertainty both in ourselves and in our social conspecifics.


Assuntos
Encéfalo , Ciência Cognitiva , Teorema de Bayes , Humanos , Incerteza
14.
J Leukoc Biol ; 107(1): 27-42, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31378988

RESUMO

This work sought to confirm the human-like expression of exhaustion and senescence markers in a mouse model with a humanized immune system (HIS): the Balb/c Rag2KO IL2rgcKO SirpαNOD Flk2KO HLA-A2HHD (BRGSF-A2) mouse reconstituted with human CD34+ cord blood cells. With regard to senescence markers, the percentage of CD57+ T cells was higher in the bone marrow (BM) than in the spleen or blood. The same was true for KLRG1+ hCD8+ T cells. With regard to exhaustion markers, the percentage of programmed death 1 (PD-1+ ) T cells was higher in the BM than in the spleen or blood; the same was true for TIGIT+ hCD4+ cells. These tissue-specific differences were related to both higher proportions of memory T cells in BM and intrinsic differences in expression within the memory fraction. In blood samples from HIS mice and healthy human donors (HDs), we found that the percentage of KLRG1+ cells among hCD8+ T cells was lower in HIS compared to HDs. The opposite was true for CD4+ T cells. Unexpectedly, a high frequency of KLRG1+ cells was observed among naive T cells in HIS mice. CD57 expression on T cells was similar in blood samples from HIS mice and HDs. Likewise, PD-1 expression was similar in the two systems, although a relatively low proportion of HIS hCD4+ T cells expressed TIGIT. The BRGSF-A2 HIS mouse's exhaustion and senescence profile was tissue specific and relatively human like; hence, this mouse might be a valuable tool for determining the preclinical efficacy of immunotherapies.


Assuntos
Biomarcadores/análise , Senescência Celular , Proteínas de Ligação a DNA/fisiologia , Antígeno HLA-A2/fisiologia , Subunidade gama Comum de Receptores de Interleucina/fisiologia , Receptores Imunológicos/fisiologia , Linfócitos T/imunologia , Tirosina Quinase 3 Semelhante a fms/fisiologia , Adulto , Idoso , Animais , Feminino , Voluntários Saudáveis , Humanos , Leucócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Knockout , Pessoa de Meia-Idade , Receptores Imunológicos/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo
15.
Eur J Immunol ; 49(6): 954-965, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30888052

RESUMO

Human immune system (HIS) mouse models provide a robust in vivo platform to study human immunity. Nevertheless, the signals that guide human lymphocyte differentiation in HIS mice remain poorly understood. Here, we have developed a novel Balb/c Rag2-/- Il2rg-/- SirpaNOD (BRGS) HIS mouse model expressing human HLA-A2 and -DR2 transgenes (BRGSA2DR2). When comparing BRGS and BRGSA2DR2 HIS mice engrafted with human CD34+ stem cells, a more rapid emergence of T cells in the circulation of hosts bearing human HLA was shown, which may reflect a more efficient human T-cell development in the mouse thymus. Development of CD4+ and CD8+ T cells was accelerated in BRGSA2DR2 HIS mice and generated more balanced B and T-cell compartments in peripheral lymphoid organs. Both B- and T-cell function appeared enhanced in the presence of human HLA transgenes with higher levels of class switched Ig, increased percentages of polyfunctional T cells and clear evidence for antigen-specific T-cell responses following immunization. Taken together, the presence of human HLA class I and II molecules can improve multiple aspects of human B- and T-cell homeostasis and function in the BRGS-based HIS mouse model.


Assuntos
Modelos Animais de Doenças , Linfopoese/imunologia , Camundongos Transgênicos , Linfócitos T , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Antígeno HLA-A2/genética , Antígeno HLA-A2/imunologia , Antígeno HLA-DR2/genética , Antígeno HLA-DR2/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/citologia , Linfócitos T/imunologia
16.
Clocks Sleep ; 1(3): 332-351, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33089173

RESUMO

Prospective memory (PM) refers to our ability to perform actions at the appropriate moment, either when a predetermined event occurs (event-based, EB) or after a predetermined amount of time (time-based, TB). Sleep favors the consolidation of both EB and TB intentions, but whether this benefit is preserved during ageing is still subject to debate. PM was assessed in 28 young and 27 older healthy volunteers using a virtual environment. Participants had to learn and execute intentions after intervals filled with either daytime wakefulness or nighttime sleep. Intentions consisted of four TB, four EB with a strong link between the cue triggering retrieval and the action to be performed (EB-link) and four with no link (EB-nolink). PM was not affected by age, whatever the type of intention and the nature of the retention interval. While sleep reinforced all types of intentions in young participants, this benefit was only observed for TB and EB-link intentions in older adults. Sleep also reinforced the intrinsic PM components in both groups. Thus, when assessed using complex realistic situations, PM is not impaired in ageing. Results are discussed in the light of memory schema theory and the possible impact of cognitive reserve on sleep and memory.

17.
Eur J Immunol ; 46(5): 1291-9, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26865269

RESUMO

Humanized mice harboring human immune systems (HIS) represent a platform to study immune responses against pathogens and to screen vaccine candidates and novel immunotherapeutics. Innate and adaptive immune responses are suboptimal in HIS mice, possibly due to poor reconstitution of human antigen-presenting cells, including dendritic cells (DCs). DC homeostasis is regulated by cytokine availability, and Flt3-ligand (Flt3L) is one factor that conditions this process. Mouse myelopoiesis is essentially normal in most current HIS models. As such, developing mouse myeloid cells may limit human DC reconstitution by reducing available Flt3L and by cellular competition for specific "niches." To address these issues, we created a novel HIS model that compromises host myeloid cell development via deficiency in the receptor tyrosine kinase Flk2/Flt3. In Balb/c Rag2(-/-) Il2rg(-/-) Flt3(-/-) (BRGF) recipients, human conventional DCs and plasmacytoid DCs develop from hCD34(+) precursors and can be specifically boosted with exogenous Flt3L. Human DCs that develop in this context normally respond to TLR stimulation, and improved human DC homeostasis is associated with increased numbers of human NK and T cells. This new HIS-DC model should provide a means to dissect human DC differentiation and represents a novel platform to screen immune adjuvants and DC targeting therapies.


Assuntos
Diferenciação Celular , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Tirosina Quinase 3 Semelhante a fms/deficiência , Adjuvantes Imunológicos , Animais , Homeostase , Humanos , Imunidade Inata , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Mieloides/fisiologia , Células T Matadoras Naturais/fisiologia , Linfócitos T/fisiologia , Tirosina Quinase 3 Semelhante a fms/genética
18.
Anal Chim Acta ; 897: 96-101, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26515010

RESUMO

Protein post-translational modifications (PTMs) are regulatory mechanisms carried out by different enzymes in a cell. Kinase catalyzed phosphorylation is one of the most important PTM affecting the protein activity and function. We have developed a single-label quenching resonance energy transfer (QRET) assay to monitor tyrosine phosphorylation in a homogeneous high throughput compatible format. Epidermal growth factor receptor (EGFR) induced phosphorylation was monitored using Eu(3+)-chelate labeled peptide and label-free phosphotyrosine specific antibody in presence of a soluble quencher molecule. In the QRET kinase assay, antibody binding to phosphorylated Eu(3+)-peptide protects the Eu(3+)-chelate from luminescence quenching, monitoring high time-resolved luminescence (TRL) signals. In the presence of specific kinase inhibitor, antibody recognition and Eu(3+)-chelate protection is prevented, allowing an efficient luminescence quenching. The assay functionality was demonstrated with a panel of EGFR inhibitors (AG-1478, compound 56, erlotinib, PD174265, and staurosporine). The monitored IC50 values ranged from 0.08 to 155.3 nM and were comparable to those found in the literature. EGFR activity and inhibition assays were performed using low nanomolar enzyme and antibody concentration in a 384-well plate format, demonstrating its compatibility for high throughput screening (HTS).


Assuntos
Ensaios Enzimáticos/métodos , Receptores ErbB/metabolismo , Ensaios de Triagem em Larga Escala/métodos , Ativação Enzimática , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Európio/química , Transferência Ressonante de Energia de Fluorescência , Luminescência , Peptídeos/química , Fosforilação , Tirosina/metabolismo
19.
PLoS One ; 10(3): e0119820, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25782010

RESUMO

Hepatic infections by hepatitis B virus (HBV), hepatitis C virus (HCV) and Plasmodium parasites leading to acute or chronic diseases constitute a global health challenge. The species tropism of these hepatotropic pathogens is restricted to chimpanzees and humans, thus model systems to study their pathological mechanisms are severely limited. Although these pathogens infect hepatocytes, disease pathology is intimately related to the degree and quality of the immune response. As a first step to decipher the immune response to infected hepatocytes, we developed an animal model harboring both a human immune system (HIS) and human hepatocytes (HUHEP) in BALB/c Rag2-/- IL-2Rγc-/- NOD.sirpa uPAtg/tg mice. The extent and kinetics of human hepatocyte engraftment were similar between HUHEP and HIS-HUHEP mice. Transplanted human hepatocytes were polarized and mature in vivo, resulting in 20-50% liver chimerism in these models. Human myeloid and lymphoid cell lineages developed at similar frequencies in HIS and HIS-HUHEP mice, and splenic and hepatic compartments were humanized with mature B cells, NK cells and naïve T cells, as well as monocytes and dendritic cells. Taken together, these results demonstrate that HIS-HUHEP mice can be stably (> 5 months) and robustly engrafted with a humanized immune system and chimeric human liver. This novel HIS-HUHEP model provides a platform to investigate human immune responses against hepatotropic pathogens and to test novel drug strategies or vaccine candidates.


Assuntos
Modelos Animais de Doenças , Hepatócitos/imunologia , Sistema Imunitário/fisiologia , Hepatopatias/imunologia , Camundongos , Animais , Linfócitos B/imunologia , Linfócitos B/fisiologia , Linfócitos B/transplante , Linhagem da Célula , Células Cultivadas , Quimerismo , Hepatócitos/parasitologia , Hepatócitos/virologia , Humanos , Sistema Imunitário/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Células Matadoras Naturais/transplante , Cinética , Hepatopatias/parasitologia , Hepatopatias/virologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Linfócitos T/imunologia , Linfócitos T/fisiologia , Linfócitos T/transplante
20.
Biol Aujourdhui ; 209(3): 273-86, 2015.
Artigo em Francês | MEDLINE | ID: mdl-26820833

RESUMO

During the last two decades, the effect of intersubjective relationships on cognition has been an emerging topic in cognitive neurosciences leading through a so-called "social turn" to the formation of new domains integrating society and cultures to this research area. Such inquiry has been recently extended to collective memory studies. Collective memory refers to shared representations that are constitutive of the identity of a group and distributed among all its members connected by a common history. After briefly describing those evolutions in the study of human brain and behaviors, we review recent researches that have brought together cognitive psychology, neuroscience and social sciences into collective memory studies. Using the reemerging concept of memory schema, we propose a theoretical framework allowing to account for collective memories formation with a specific focus on the encoding process of historical events. We suggest that (1) if the concept of schema has been mainly used to describe rather passive framework of knowledge, such structure may also be implied in more active fashions in the understanding of significant collective events. And, (2) if some schema researches have restricted themselves to the individual level of inquiry, we describe a strong coherence between memory and cultural frameworks. Integrating the neural basis and properties of memory schema to collective memory studies may pave the way toward a better understanding of the reciprocal interaction between individual memories and cultural resources such as media or education.


Assuntos
Encéfalo/fisiologia , Cultura , Conhecimento , Memória/fisiologia , Neurociências , Comportamento Social , História do Século XX , História do Século XXI , Humanos , Neurociências/história , Neurociências/tendências , Comportamento Social/história , Mudança Social , Fatores Sociológicos
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