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1.
Mem Cognit ; 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33650022

RESUMO

Intentional forgetting of unwanted items is effortful, yet directed forgetting seems to improve when a secondary task is performed. According to the cognitive load hypothesis of directed forgetting, allocating attentional resources to another task improves forgetting by restricting unwanted encoding of to-be-forgotten (TBF) items. Alternatively, it might be that anything that makes studying more difficult will encourage greater effort to perform the task well and therefore lead to improved intentional forgetting. To assess these proposals we imposed data-processing limitations on study words in an item-method directed forgetting paradigm. Across six experiments, the perceptual quality of study words was manipulated by varying: (1) the duration of study word presentation (Experiments 1-4); (2) the contrast of the displayed word against its visual background (Experiment 5); or (3) the amount of visual background noise on which the word was presented (Experiment 6). In Experiments 4-6, a lexical decision task corroborated the difficulty of study word processing. Despite evidence that relatively low visual contrast and relatively high visual background noise, in particular, create challenging conditions, we found no evidence that perceptual quality impacts the magnitude of the directed forgetting effect. This work suggests that data limitations have no discernible effect on forgetting and corroborate that only attentional resource limitations improve directed forgetting.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33409904

RESUMO

This study embedded attentional cues in the study phase of an item-method directed forgetting task. We used an unpredictive onset cue (Experiment 1), a predictive onset cue (Experiment 2), or a predictive central cue (Experiments 3-6) to direct attention to the left or right. In Experiments 1-5, this was followed by a pink or blue study word that required a speeded colour discrimination; in Experiment 6, it was followed by a pink or blue word or nonword that required a lexical decision. Each study word was followed by an instruction to Remember or Forget. A yes-no recognition test confirmed better recognition of to-be-remembered words than to-be-forgotten words; a cueing effect confirmed the effectiveness of predictive cues in allocating attentional resources. There was, however, no evidence that the directed forgetting effect differed for attended and unattended words: Encoding depends more on the memory intention formed after a study word has disappeared than on the availability of processing resources when that word first appears.

3.
J Med Chem ; 64(3): 1454-1480, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33492963

RESUMO

Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P1-5). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P1 has been shown to result in lymphopenia. As a result, agonists of this type hold promise as therapeutics for autoimmune disorders. The previously disclosed differentiated S1P1 modulator BMS-986104 (1) exhibited improved preclinical cardiovascular and pulmonary safety profiles as compared to earlier full agonists of S1P1; however, it demonstrated a long pharmacokinetic half-life (T1/2 18 days) in the clinic and limited formation of the desired active phosphate metabolite. Optimization of this series through incorporation of olefins, ethers, thioethers, and glycols into the alkyl side chain afforded an opportunity to reduce the projected human T1/2 and improve the formation of the active phosphate metabolite while maintaining efficacy as well as the improved safety profile. These efforts led to the discovery of 12 and 24, each of which are highly potent, biased agonists of S1P1. These compounds not only exhibited shorter in vivo T1/2 in multiple species but are also projected to have significantly shorter T1/2 values in humans when compared to our first clinical candidate. In models of arthritis, treatment with 12 and 24 demonstrated robust efficacy.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Pró-Proteína Convertases/efeitos dos fármacos , Serina Endopeptidases/efeitos dos fármacos , Animais , Artrite Experimental/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Biotransformação , Compostos Bicíclicos com Pontes/efeitos adversos , Líquido da Lavagem Broncoalveolar , Quimiotaxia de Leucócito/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Pneumopatias/induzido quimicamente , Pneumopatias/patologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Fosforilação , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade
4.
PLoS One ; 15(11): e0241959, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33166373

RESUMO

The coronavirus disease 2019 (Covid-19) pandemic, caused by SARS-CoV-2, has resulted in a global testing supply shortage. In response, pooled testing has emerged as a promising strategy that can immediately increase testing capacity. In pooled sample testing, multiple samples are combined (or pooled) together and tested as a single unit. If the pool is positive, the individual samples can then be individually tested to identify the positive case(s). Here, we provide support for the adoption of sample pooling with the point-of-care Cepheid Xpert® Xpress SARS-CoV-2 molecular assay. Corroborating previous findings, the limit of detection of this assay was comparable to laboratory-developed reverse-transcription quantitative PCR SARS-CoV-2 tests, with observed detection below 100 copies/mL. The Xpert® Xpress assay detected SARS-CoV-2 after samples with minimum viral loads of 461 copies/mL were pooled in groups of six. Based on these data, we recommend the adoption of pooled testing with the Xpert® Xpress SARS-CoV-2 assay where warranted based on public health needs. The suggested number of samples per pool, or the pooling depth, is unique for each point-of-care testing site and can be determined by the positive test rates. To statistically determine appropriate pooling depth, we have calculated the pooling efficiency for numerous combinations of pool sizes and test rates. This information is included as a supplemental dataset that we encourage public health authorities to use as a guide to make recommendations that will maximize testing capacity and resource conservation.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , RNA Viral/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Humanos , Pandemias , Pneumonia Viral/virologia , Testes Imediatos , RNA Viral/genética , Kit de Reagentes para Diagnóstico , Manejo de Espécimes , Carga Viral
5.
ACS Med Chem Lett ; 11(11): 2195-2203, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33214829

RESUMO

Bruton's tyrosine kinase (BTK) has been shown to play a key role in the pathogenesis of autoimmunity. Therefore, the inhibition of the kinase activity of BTK with a small molecule inhibitor could offer a breakthrough in the clinical treatment of many autoimmune diseases. This Letter describes the discovery of BMS-986143 through systematic structure-activity relationship (SAR) development. This compound benefits from defined chirality derived from two rotationally stable atropisomeric axes, providing a potent and selective single atropisomer with desirable efficacy and tolerability profiles.

6.
ACS Med Chem Lett ; 11(9): 1766-1772, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32944145

RESUMO

Efforts aimed at increasing the in vivo potency and reducing the elimination half-life of 1 and 2 led to the identification of aryl ether and thioether-derived bicyclic S1P1 differentiated modulators 3-6. The effects of analogs 3-6 on lymphocyte reduction in the rat (desired pharmacology) along with pulmonary- and cardiovascular-related effects (undesired pharmacology) are described. Optimization of the overall properties in the aryl ether series yielded 3d, and the predicted margin of safety against the cardiovascular effects of 3d would be large enough for human studies. Importantly, compared to 1 and 2, compound 3d had a better profile in both potency (ED50 < 0.05 mg/kg) and predicted human half-life (t 1/2 ∼ 5 days).

7.
Viruses ; 12(6)2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32532083

RESUMO

Next-generation sequencing (NGS)-based HIV drug resistance (HIVDR) assays outperform conventional Sanger sequencing in scalability, sensitivity, and quantitative detection of minority resistance variants. Thus far, HIVDR assays have been applied primarily in research but rarely in clinical settings. One main obstacle is the lack of standardized validation and performance evaluation systems that allow regulatory agencies to benchmark and accredit new assays for clinical use. By revisiting the existing principles for molecular assay validation, here we propose a new validation and performance evaluation system that helps to both qualitatively and quantitatively assess the performance of an NGS-based HIVDR assay. To accomplish this, we constructed a 70-specimen proficiency test panel that includes plasmid mixtures at known ratios, viral RNA from infectious clones, and anonymized clinical specimens. We developed assessment criteria and benchmarks for NGS-based HIVDR assays and used these to assess data from five separate MiSeq runs performed in two experienced HIVDR laboratories. This proposed platform may help to pave the way for the standardization of NGS HIVDR assay validation and performance evaluation strategies for accreditation and quality assurance purposes in both research and clinical settings.

8.
mBio ; 10(5)2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641086

RESUMO

The 1918 influenza virus, subtype H1N1, was the causative agent of the most devastating pandemic in the history of infectious diseases. In vitro studies have confirmed that extreme virulence is an inherent property of this virus. Here, we utilized the macaque model for evaluating the efficacy of oseltamivir phosphate against the fully reconstructed 1918 influenza virus in a highly susceptible and relevant disease model. Our findings demonstrate that oseltamivir phosphate is effective in preventing severe disease in macaques but vulnerable to virus escape through emergence of resistant mutants, especially if given in a treatment regimen. Nevertheless, we conclude that oseltamivir would be highly beneficial to reduce the morbidity and mortality rates caused by a highly pathogenic influenza virus although it would be predicted that resistance would likely emerge with sustained use of the drug.IMPORTANCE Oseltamivir phosphate is used as a first line of defense in the event of an influenza pandemic prior to vaccine administration. Treatment failure through selection and replication of drug-resistant viruses is a known complication in the field and was also demonstrated in our study with spread of resistant 1918 influenza virus in multiple respiratory tissues. This emphasizes the importance of early treatment and the possibility that noncompliance may exacerbate treatment effectiveness. It also demonstrates the importance of implementing combination therapy and vaccination strategies as soon as possible in a pandemic situation.


Assuntos
Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Infecções por Orthomyxoviridae/tratamento farmacológico , Oseltamivir/uso terapêutico , Animais , Macaca , Infecções por Orthomyxoviridae/virologia
9.
Can J Exp Psychol ; 73(4): 254-264, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31393154

RESUMO

The production effect is defined as better memory for items that were read aloud compared with items that were read silently. Quinlan and Taylor (2013) expanded the findings of the production effect by demonstrating that singing items produces even better recognition performance than reading aloud, and argued that this was due to enhanced relative distinctiveness. The current study tested three alternative accounts. In Experiment 1, we explored whether singing results in a larger production effect because it is deemed more bizarre than reading aloud. To address this, we tested a sample for whom singing does not seem bizarre: experienced singers. They also showed better recognition of items that were sung compared with those that were read aloud. In Experiment 2, we determined that singing appears to take longer than either reading aloud or reading silently; however, the possible effect of production time was further explored in Experiment 3. We did this by instructing participants to sing quickly, read aloud slowly, or read silently. Altering relative production times resulted in no discernible changes in subsequent recognition performance. Finally, in Experiment 4, we explored whether singing might strengthen the memory trace relative to reading aloud. We tested this by manipulating the production instruction between subjects. This eliminated the recognition advantage for both reading items aloud as well as for singing them aloud. Having ruled out these alternatives, we argue that singing improves subsequent recognition because it offers more distinctive elements than either reading aloud or reading silently. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Rememoração Mental/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Leitura , Reconhecimento Psicológico/fisiologia , Canto/fisiologia , Adulto , Humanos , Adulto Jovem
10.
Sci Rep ; 9(1): 8970, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31222149

RESUMO

Conventional HIV drug resistance (HIVDR) genotyping utilizes Sanger sequencing (SS) methods, which are limited by low data throughput and the inability of detecting low abundant drug resistant variants (LADRVs). Here we present a next generation sequencing (NGS)-based HIVDR typing platform that leverages the advantages of Illumina MiSeq and HyDRA Web. The platform consists of a fully validated sample processing protocol and HyDRA web, an open web portal that allows automated customizable NGS-based HIVDR data processing. This platform was characterized and validated using a panel of HIV-spiked plasma representing all major HIV-1 subtypes, pedigreed plasmids, HIVDR proficiency specimens and clinical specimens. All examined major HIV-1 subtypes were consistently amplified at viral loads of ≥1,000 copies/ml. The gross error rate of this platform was determined at 0.21%, and minor variations were reliably detected down to 0.50% in plasmid mixtures. All HIVDR mutations identifiable by SS were detected by the MiSeq-HyDRA protocol, while LADRVs at frequencies of 1~15% were detected by MiSeq-HyDRA only. As compared to SS approaches, the MiSeq-HyDRA platform has several notable advantages including reduced cost and labour, and increased sensitivity for LADRVs, making it suitable for routine HIVDR monitoring for both patient care and surveillance purposes.


Assuntos
Farmacorresistência Viral , Genótipo , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Genes Virais , Infecções por HIV/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação , Vigilância em Saúde Pública , RNA Viral , Reprodutibilidade dos Testes , Carga Viral
11.
ACS Med Chem Lett ; 10(3): 383-388, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891145

RESUMO

In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

12.
J Med Chem ; 62(7): 3228-3250, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30893553

RESUMO

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Descoberta de Drogas , Indóis/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Artrite Reumatoide/tratamento farmacológico , Relação Dose-Resposta a Droga , Humanos , Indóis/farmacocinética , Indóis/uso terapêutico , Concentração Inibidora 50 , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Macaca fascicularis , Camundongos , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico
13.
J Med Chem ; 62(5): 2265-2285, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30785748

RESUMO

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.


Assuntos
Ensaios Clínicos como Assunto , Naftalenos/farmacologia , Receptores de Esfingosina-1-Fosfato/agonistas , Tetra-Hidronaftalenos/farmacologia , Animais , Líquido da Lavagem Broncoalveolar , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Naftalenos/química , Naftalenos/farmacocinética , Ratos , Ratos Endogâmicos Lew , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacocinética
14.
Atten Percept Psychophys ; 81(1): 237-252, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30194621

RESUMO

In an item-method directed forgetting task, attentional resources are withdrawn from forget item processing (e.g., Taylor & Fawcett in Attention, Perception, & Psychophysics, 73, 1790-1814, 2011). Taylor and Hamm (Attention, Perception, & Psychophysics, 78, 168-186, 2016) demonstrated that there is no corresponding increase in the proclivity for exogenous attention to be captured following a forget instruction. This means either that the attentional resources withdrawn from the forget item are reallocated immediately (and therefore not especially vulnerable to capture) or that it is not exogenous attention that is withdrawn. Given that endogenous attention is distinct from exogenous attention, we therefore extended the Taylor and Hamm study by using endogenous orienting rather than exogenous orienting. Words appeared individually in a peripheral location (Exp. 1) or in a central location (Exp. 2), followed by an instruction to either remember or forget. After a short (50-ms) or long (250-ms) interstimulus interval (ISI), a central cue (80% accurate) directed participants to allocate their attention to the left or right. This was followed by a discrimination target that appeared at a 1,000-ms cue-target stimulus onset asynchrony. A subsequent yes-no recognition test assessed memory for all study items. In both experiments, we observed better recognition of remember words than forget words-a directed forgetting effect. We also found a cueing effect, revealed as faster reaction times to discriminate cued targets than to discriminate uncued targets. There was not, however, an effect of memory instruction (and/or instruction-cue ISI) on the magnitude of this cueing effect. Thus, neither exogenous attention nor endogenous attention remains in an unengaged state following an instruction to forget.


Assuntos
Estimulação Acústica/métodos , Sinais (Psicologia) , Rememoração Mental/fisiologia , Orientação Espacial/fisiologia , Estimulação Luminosa/métodos , Adulto , Atenção/fisiologia , Humanos , Masculino , Memória/fisiologia , Psicofísica , Tempo de Reação/fisiologia , Adulto Jovem
15.
Acta Psychol (Amst) ; 188: 39-54, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29857288

RESUMO

Using an item-method directed forgetting task, we presented homographic homophonic nouns embedded in sentences. At study, each sentence was followed by an instruction to remember or forget the embedded word. On a subsequent yes-no recognition test, each word was again embedded within a sentence. In Experiments 1, 2, and 4 we varied the embedding sentence at test so that it was identical to that at study, changed but retained the meaning of the studied word, or changed to alter the meaning of the studied word. Repeated context - whether the sentence and/or the word meaning - proved to be as useful a retrieval cue for TBF items as for TBR items. In Experiment 3, we demonstrated that physical repetition was insufficient to produce context effects for either TBR or TBF items. And, in Experiment 4, we determined that participants were equally accurate in reporting context repetition/change following the correct recognition of TBR and TBF items. When considered in light of the existing literature, our results suggest that when context can be dissociated from the study item, it is encoded in "one shot" and not vulnerable to subsequent efforts to limit unwanted encoding.


Assuntos
Memória/fisiologia , Rememoração Mental , Reconhecimento Psicológico , Sinais (Psicologia) , Feminino , Humanos , Aprendizagem , Masculino , Semântica , Adulto Jovem
16.
Atten Percept Psychophys ; 80(6): 1489-1503, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29691764

RESUMO

This study used rapid serial visual presentation (RSVP) to determine whether, in an item-method directed forgetting task, study word processing ends earlier for forget words than for remember words. The critical manipulation required participants to monitor an RSVP stream of black nonsense strings in which a single blue word was embedded. The next item to follow the word was a string of red fs that instructed the participant to forget the word or green rs that instructed the participant to remember the word. After the memory instruction, a probe string of black xs or os appeared at postinstruction positions 1-8. Accuracy in reporting the identity of the probe string revealed an attenuated attentional blink following instructions to forget. A yes-no recognition task that followed the study trials confirmed a directed forgetting effect, with better recognition of remember words than forget words. Considered in the context of control conditions that required participants to commit either all or none of the study words to memory, the pattern of probe identification accuracy following the directed forgetting task argues that an intention to forget releases limited-capacity attentional resources sooner than an instruction to remember-despite participants needing to maintain an ongoing rehearsal set in both cases.


Assuntos
Intermitência na Atenção Visual/fisiologia , Rememoração Mental/fisiologia , Análise e Desempenho de Tarefas , Adulto , Humanos , Intenção , Aprendizagem , Masculino , Memória , Adulto Jovem
18.
Mem Cognit ; 46(1): 132-147, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29214552

RESUMO

Using an item-method directed forgetting task, we presented negative, neutral, and positive photographic pictures, one at a time, each followed by an instruction to remember or forget. We determined that the directed forgetting effect, defined as better subsequent recognition of to-be-remembered (TBR) items than to-be-forgotten (TBF) items, was equivalent across negative, neutral, and positive pictures. To disentangle the underlying costs (i.e., decrease in memory for TBF items) and benefits (i.e., increase in memory for TBR items), we compared recognition memory performance in the directed forgetting task to that of a novel within-subjects remember-all control condition (Experiment 1) and to a between-subjects remember-all control group (Experiment 2). We observed costs without benefits across all three emotions-negative, neutral, and positive-in both experiments. These results demonstrate that equivalent directed forgetting effects for emotional stimuli are not attributable to different underlying component processes. Instead, our results suggest that selection for encoding is accomplished in similar ways, regardless of emotional content.


Assuntos
Emoções/fisiologia , Intenção , Rememoração Mental/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Reconhecimento Psicológico/fisiologia , Adulto , Humanos , Adulto Jovem
19.
Acta Psychol (Amst) ; 183: 116-123, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29275948

RESUMO

In an item-method directed forgetting paradigm, words are presented one at a time, each followed by an instruction to Remember or Forget; a directed forgetting effect is measured as better subsequent memory for Remember words than Forget words. The dominant view is that the directed forgetting effect arises during encoding due to selective rehearsal of Remember over Forget items. In three experiments we attempted to falsify a strong view that directed forgetting effects in recognition are due only to encoding mechanisms when an item method is used. Across 3 experiments we tested for retrieval-based processes by colour-coding the recognition test items. Black colour provided no information; green colour cued a potential Remember item; and, red colour cued a potential Forget item. Recognition cues were mixed within-blocks in Experiment 1 and between-blocks in Experiments 2 and 3; Experiment 3 added explicit feedback on the accuracy of the recognition decision. Although overall recognition improved with cuing when explicit test performance feedback was added in Experiment 3, in no case was the magnitude of the directed forgetting effect influenced by recognition cueing. Our results argue against a role for retrieval-based strategies that limit recognition of Forget items at test and posit a role for encoding intentions only.


Assuntos
Aprendizagem/fisiologia , Memória/fisiologia , Rememoração Mental/fisiologia , Reconhecimento Psicológico/fisiologia , Sinais (Psicologia) , Feminino , Humanos , Masculino , Adulto Jovem
20.
PLoS One ; 12(7): e0181782, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28742141

RESUMO

Bruton's tyrosine kinase (BTK) regulates critical signal transduction pathways involved in the pathobiology of rheumatoid arthritis (RA) and other autoimmune disorders. BMS-986142 is a potent and highly selective reversible small molecule inhibitor of BTK currently being investigated in clinical trials for the treatment of both RA and primary Sjögren's syndrome. In the present report, we detail the in vitro and in vivo pharmacology of BMS-986142 and show this agent provides potent and selective inhibition of BTK (IC50 = 0.5 nM), blocks antigen receptor-dependent signaling and functional endpoints (cytokine production, co-stimulatory molecule expression, and proliferation) in human B cells (IC50 ≤ 5 nM), inhibits Fcγ receptor-dependent cytokine production from peripheral blood mononuclear cells, and blocks RANK-L-induced osteoclastogenesis. Through the benefits of impacting these important drivers of autoimmunity, BMS-986142 demonstrated robust efficacy in murine models of rheumatoid arthritis (RA), including collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). In both models, robust efficacy was observed without continuous, complete inhibition of BTK. When a suboptimal dose of BMS-986142 was combined with other agents representing the current standard of care for RA (e.g., methotrexate, the TNFα antagonist etanercept, or the murine form of CTLA4-Ig) in the CIA model, improved efficacy compared to either agent alone was observed. The results suggest BMS-986142 represents a potential therapeutic for clinical investigation in RA, as monotherapy or co-administered with agents with complementary mechanisms of action.


Assuntos
Artrite Experimental/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Animais , Formação de Anticorpos/efeitos dos fármacos , Artrite Experimental/imunologia , Artrite Experimental/patologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Camundongos Endogâmicos BALB C , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteoclastos/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/imunologia , Ligante RANK/imunologia
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