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Understanding the neural implementation of value-based choice has been an important focus of neuroscience for several decades. Although a consensus has emerged regarding the brain regions involved, including ventromedial prefrontal cortex (vmPFC), posterior parietal cortex (PPC), and the ventral striatum (vSTR), the multifaceted nature of decision processes is one cause of persistent debate regarding organization of the value-based choice network. In the current study, we isolate neural activity related to valuation and choice selection using a gambling task where expected gains and losses are dissociated from choice outcomes. We apply multilevel mediation analysis to formally test whether brain regions identified as part of the value-based choice network mediate between perceptions of expected value and choice to accept or decline a gamble. Our approach additionally makes predictions regarding interregional relationships to elucidate the chain of processing events within the value-based decision network. Finally, we use dynamic causal modelling (DCM) to compare plausible models of interregional relationships in value-based choice. We observe that activity in vmPFC does not predict take/pass choices, but rather is highly associated with outcome evaluation. By contrast, both PPC and bilateral vSTR (bilaterally) mediate the relationship between expected value and choice. Interregional mediation analyses reveal that vSTR fully mediates between PPC and choice, and this is supported by DCM. Together these results suggest that vSTR, and not vmPFC nor PPC, functions as an important driver of choice.
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Mapeamento Encefálico/métodos , Comportamento de Escolha/fisiologia , Processamento de Imagem Assistida por Computador/métodos , Vias Neurais/fisiologia , Estriado Ventral/fisiologia , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Lobo Parietal/fisiologia , Córtex Pré-Frontal/fisiologia , RecompensaRESUMO
Testing older adults in the morning generally improves behavioral performance relative to afternoon testing. Morning testing is also associated with brain activity similar to that of young adults. Here, we used graph theory to explore how time of day (TOD) affects the organization of brain networks in older adults across rest and task states. We used nodes from the automated anatomical labeling atlas to construct participant-specific correlation matrices of fMRI data obtained during 1-back tasks with interference and rest. We computed pairwise group differences for key graph metrics, including small-worldness and modularity. We found that older adults tested in the morning and young adults did not differ on any graph metric. Both of these groups differed from older adults tested in the afternoon during the tasks-but not rest. Specifically, the latter group had lower modularity and small-worldness (indices of more efficient network organization). Across all groups, higher modularity and small-worldness strongly correlated with reduced distractibility on an implicit priming task. Increasingly, TOD is seen as important for interpreting and reproducing neuroimaging results. Our study emphasizes how TOD affects brain network organization and executive control in older adults.
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Envelhecimento/fisiologia , Envelhecimento/psicologia , Encéfalo/fisiologia , Ritmo Circadiano/fisiologia , Idoso , Análise de Variância , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Função Executiva/fisiologia , Humanos , Imageamento por Ressonância Magnética , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiologia , Plasticidade Neuronal , Testes Neuropsicológicos , Fotoperíodo , Descanso , Fatores de Tempo , Adulto JovemRESUMO
UNLABELLED: Infection with human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and tropical spastic paraparesis. Type I interferons (IFNs) are key effectors of the innate antiviral response, and IFN-α combined with the nucleoside reverse transcriptase inhibitor zidovudine is considered the standard first-line therapy for ATL. HTLV-1 oncoprotein Tax is known to suppress innate IFN production and response but the underlying mechanisms remain to be fully established. In this study, we report on the suppression of type I IFN production by HTLV-1 Tax through interaction with and inhibition of TBK1 kinase that phosphorylates IRF3. Induced transcription of IFN-ß was severely impaired in HTLV-1-transformed ATL cells and freshly infected T lymphocytes. The ability to suppress IRF3 activation was ascribed to Tax. The expression of Tax alone sufficiently repressed the induction of IFN production by RIG-I plus PACT, cGAMP synthase plus STING, TBK1, IKKε, IRF3, and IRF7, but not by IRF3-5D, a dominant-active phosphomimetic mutant. This suggests that Tax perturbs IFN production at the step of IRF3 phosphorylation. Tax mutants deficient for CREB or NF-κB activation were fully competent in the suppression of IFN production. Coimmunoprecipitation experiments confirmed the association of Tax with TBK1, IKKε, STING, and IRF3.In vitrokinase assay indicated an inhibitory effect of Tax on TBK1-mediated phosphorylation of IRF3. Taken together, our findings suggested a new mechanism by which HTLV-1 oncoprotein Tax circumvents the production of type I IFNs in infected cells. Our findings have implications in therapeutic intervention of ATL. IMPORTANCE: Human T-cell leukemia virus type 1 (HTLV-1) is the cause of adult T-cell leukemia (ATL), an aggressive and fatal blood cancer, as well as another chronic disabling disease of the spinal cord. Treatments are unsatisfactory, and options are limited. A combination of antiviral cellular protein alpha interferon and zidovudine, which is an inhibitor of a viral enzyme called reverse transcriptase, has been recommended as the standard first-line therapy for ATL. Exactly how HTLV-1 interacts with the cellular machinery for interferon production and action is not well understood. Our work sheds light on the mechanism of action for the inhibition of interferon production by an HTLV-1 oncogenic protein called Tax. Our findings might help to improve interferon-based anti-HTLV-1 and anti-ATL therapy.
Assuntos
Produtos do Gene tax/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Fator Regulador 3 de Interferon/antagonistas & inibidores , Interferon beta/antagonistas & inibidores , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Produtos do Gene tax/genética , Células HEK293 , Humanos , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/biossíntese , Células Jurkat , Leucemia-Linfoma de Células T do Adulto/virologia , NF-kappa B/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/metabolismo , Linfócitos T/virologiaRESUMO
OBJECTIVES: Bipolar disorder (BD) is associated with elevated reward sensitivity and persistent positive affect, yet the neural mechanisms underlying these patterns are not well understood. In the present study, we examined putative disruptions in communication within a well-known cortico-limbic reward circuit during reward processing as a potential contributing mechanism to these symptoms. METHODS: The present investigation employed a within- and between-subjects design utilizing a monetary and social incentive delay task among adults with bipolar disorder type I (BD; N = 24) and a healthy non-psychiatric control group (HC; N = 25) during functional magnetic resonance imaging (fMRI). Participants in the BD group were remitted at the time of testing. RESULTS: Functional connectivity analyses revealed increased connectivity between the ventral striatum (VS) seed region and orbitofrontal cortex (OFC) as well as the amygdala during processing of reward receipt in the BD group. After omission of expected rewards, the BD group showed decreased functional connectivity between the VS and a medial frontopolar cortex (mFPC) region associated with consideration of behavioral alternatives. Follow-up analyses within the BD group showed that increased VS-OFC connectivity after reward receipt, and decreased VS-mFPC connected after reward omission, were associated with higher levels of subthreshold mania symptoms. CONCLUSIONS: Results point toward potential mechanisms implicated in elevated reward sensitivity in BD. Enhanced VS-OFC connectivity after reward receipt may be involved in elevated valuation of rewards whereas blunted VS-mFPC connectivity after reward omission may reflect a failure to consider behavioral alternatives to reward pursuit.
Assuntos
Transtorno Bipolar , Córtex Cerebral , Sistema Límbico , Adulto , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/fisiopatologia , Transtorno Bipolar/psicologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Conectoma/métodos , Feminino , Humanos , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Motivação , Recompensa , Estatística como AssuntoRESUMO
UNLABELLED: Human T-cell leukemia virus type 1 (HTLV-1)-associated diseases are poorly treatable, and HTLV-1 vaccines are not available. High proviral load is one major risk factor for disease development. HTLV-1 encodes Tax oncoprotein, which activates transcription from viral long terminal repeats (LTR) and various types of cellular promoters. Counteracting Tax function might have prophylactic and therapeutic benefits. In this work, we report on the suppression of Tax activation of HTLV-1 LTR by SIRT1 deacetylase. The transcriptional activity of Tax on the LTR was largely ablated when SIRT1 was overexpressed, but Tax activation of NF-κB was unaffected. On the contrary, the activation of the LTR by Tax was boosted when SIRT1 was depleted. Treatment of cells with resveratrol shunted Tax activity in a SIRT1-dependent manner. The activation of SIRT1 in HTLV-1-transformed T cells by resveratrol potently inhibited HTLV-1 proviral transcription and Tax expression, whereas compromising SIRT1 by specific inhibitors augmented HTLV-1 mRNA expression. The administration of resveratrol also decreased the production of cell-free HTLV-1 virions from MT2 cells and the transmission of HTLV-1 from MT2 cells to uninfected Jurkat cells in coculture. SIRT1 associated with Tax in HTLV-1-transformed T cells. Treatment with resveratrol prevented the interaction of Tax with CREB and the recruitment of CREB, CRTC1, and p300 to Tax-responsive elements in the LTR. Our work demonstrates the negative regulatory function of SIRT1 in Tax activation of HTLV-1 transcription. Small-molecule activators of SIRT1 such as resveratrol might be considered new prophylactic and therapeutic agents in HTLV-1-associated diseases. IMPORTANCE: Human T-cell leukemia virus type 1 (HTLV-1) causes a highly lethal blood cancer or a chronic debilitating disease of the spinal cord. Treatments are unsatisfactory, and vaccines are not available. Disease progression is associated with robust expression of HTLV-1 genes. Suppressing HTLV-1 gene expression might have preventive and therapeutic benefits. It is therefore critical that host factors controlling HTLV-1 gene expression be identified and characterized. This work reveals a new host factor that suppresses HTLV-1 gene expression and a natural compound that activates this suppression. Our findings not only provide new knowledge of the host control of HTLV-1 gene expression but also suggest a new strategy of using natural compounds for prevention and treatment of HTLV-1-associated diseases.
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Regulação Viral da Expressão Gênica/fisiologia , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Sirtuína 1/metabolismo , Imunoprecipitação da Cromatina , Células HEK293 , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Células Jurkat , Interferência de RNA , Reação em Cadeia da Polimerase em Tempo Real , Resveratrol , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sirtuína 1/antagonistas & inibidores , Estilbenos/farmacologia , Sequências Repetidas Terminais/genética , Vírion/efeitos dos fármacosRESUMO
Most unwanted RNA transcripts in the nucleus of eukaryotic cells, such as splicing-defective pre-mRNAs and spliced-out introns, are rapidly degraded by the nuclear exosome. In budding yeast, a number of these unwanted RNA transcripts, including spliced-out introns, are first recognized by the nuclear exosome cofactor Trf4/5p-Air1/2p-Mtr4p polyadenylation (TRAMP) complex before subsequent nuclear-exosome-mediated degradation. However, it remains unclear when spliced-out introns are recognized by TRAMP, and whether TRAMP may have any potential roles in pre-mRNA splicing. Here, we demonstrated that TRAMP is cotranscriptionally recruited to nascent RNA transcripts, with particular enrichment at intronic sequences. Deletion of TRAMP components led to further accumulation of unspliced pre-mRNAs even in a yeast strain defective in nuclear exosome activity, suggesting a novel stimulatory role of TRAMP in splicing. We also uncovered new genetic and physical interactions between TRAMP and several splicing factors, and further showed that TRAMP is required for optimal recruitment of the splicing factor Msl5p. Our study provided the first evidence that TRAMP facilitates pre-mRNA splicing, and we interpreted this as a fail-safe mechanism to ensure the cotranscriptional recruitment of TRAMP before or during splicing to prepare for the subsequent targeting of spliced-out introns to rapid degradation by the nuclear exosome.
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Íntrons , Precursores de RNA/metabolismo , Splicing de RNA , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , RNA Helicases DEAD-box/metabolismo , DNA Polimerase Dirigida por DNA/genética , DNA Polimerase Dirigida por DNA/metabolismo , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Deleção de Genes , Genes Reporter , Fatores de Processamento de RNA , RNA Nuclear Pequeno/metabolismo , Ribonucleoproteína Nuclear Pequena U2/genética , Ribonucleoproteínas/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Fator de Processamento U2AF , Elongação da Transcrição Genética , Transcrição Gênica , beta-Galactosidase/genéticaRESUMO
Transcription of hepatitis B virus (HBV) from the covalently closed circular DNA (cccDNA) template is essential for its replication. Suppressing the level and transcriptional activity of cccDNA might have anti-HBV effect. Although cellular transcription factors, such as CREB, which mediate HBV transcription, have been well described, transcriptional coactivators that facilitate this process are incompletely understood. In this study we showed that CREB-regulated transcriptional coactivator 1 (CRTC1) is required for HBV transcription and replication. The steady-state levels of CRTC1 protein were elevated in HBV-positive hepatoma cells and liver tissues. Ectopic expression of CRTC1 or its homolog CRTC2 or CRTC3 in hepatoma cells stimulated the activity of the preS2/S promoter of HBV, whereas overexpression of a dominant inactive form of CRTC1 inhibited HBV transcription. CRTC1 interacts with CREB and they are mutually required for the recruitment to the preS2/S promoter on cccDNA and for the activation of HBV transcription. Accumulation of pregenomic RNA (pgRNA) and cccDNA was observed when CRTC1 or its homologs were overexpressed, whereas the levels of pgRNA, cccDNA and secreted HBsAg were diminished when CRTC1 was compromised. In addition, HBV transactivator protein HBx stabilized CRTC1 and promoted its activity on HBV transcription. Our work reveals an essential role of CRTC1 coactivator in facilitating and supporting HBV transcription and replication.
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Regulação Viral da Expressão Gênica , Vírus da Hepatite B/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional , Linhagem Celular Tumoral , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Vírus da Hepatite B/metabolismo , Vírus da Hepatite B/fisiologia , Humanos , Transativadores/metabolismo , Proteínas Virais Reguladoras e Acessórias , Replicação ViralRESUMO
Activating transcription factor 4 (ATF4) is a master regulator of genes involved in unfolded protein response (UPR) and its translation is regulated through reinitiation at upstream open reading frames. Here, we demonstrate internal ribosome entry site (IRES)-mediated translation of an alternatively spliced variant of human ATF4. This variant that contains four upstream open reading frames in the 5' leader region was expressed in leukocytes and other tissues. mRNA and protein expression of this variant was activated in the UPR. Its translation was neither inhibited by steric hindrance nor affected by eIF4G1 inactivation, indicating a cap-independent and IRES-dependent mechanism not mediated by ribosome scanning-reinitiation. The IRES activity mapped to a highly structured region that partially overlaps with the third and fourth open reading frames was unlikely attributed to cryptic promoter or splicing, but was activated by PERK-induced eIF2α phosphorylation. Taken together, our findings reveal a new mechanism for translational regulation of ATF4 in mammalian UPR.
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Fator 4 Ativador da Transcrição/genética , Processamento Alternativo/genética , Regulação da Expressão Gênica , Biossíntese de Proteínas , Ribossomos/metabolismo , Resposta a Proteínas não Dobradas/genética , Western Blotting , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Células HeLa , Humanos , Luciferases/metabolismo , Fosforilação , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribossomos/genéticaRESUMO
PURPOSE: In 15 patients with idiopathic uveitis associated with retinal vasculitis, HLA DRB1 gene testing was performed to detect a possible association. 11 patients tested positive and 4 negative for the HLA DRB1 × 15 allele. The presence of the HLA DRB1 × 15 haplotype might be associated with a higher susceptibility to develop Multiple Sclerosis (MS). METHODS: In this case series, we describe the ophthalmological and neurological findings in 10 HLA DR15-positive patients and 4 HLA DR15-negative patients that had neurological workup, including Magnetic Resonance Imaging (MRI) of the brain. RESULTS: All patients had granulomatous ocular inflammation with either panuveitis or intermediate uveitis. MRI of the brain showed white matter lesions in 13 patients (9/10 and 4/4 respectively) of which 4 patients were eventually diagnosed with MS (3/10 and 1/4 respectively). CONCLUSION: Although the majority of tested patients was carrying at least one HLA DRB1-15 allele, there was no difference in ophthalmological and neurological findings in both groups.
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PURPOSE: Accurate staging of ovarian cancer is critical to guide optimal management pathways. North American guidelines recommend contrast-enhanced CT as the primary work-up for staging ovarian cancer. This meta-analysis aims to compare the diagnostic accuracy of contrast-enhanced CT alone to PET/CT for detecting abdominal metastases in patients with a new or suspected diagnosis of ovarian cancer. MATERIALS AND METHODS: A systematic review of MEDLINE, EMBASE, Scopus, the Cochrane Library, and the gray literature from inception to October 2022 was performed. Studies with a minimum of 5 patients evaluating the diagnostic accuracy of contrast-enhanced CT and/or PET/CT for detecting stage 3 ovarian cancer as defined by a surgical/histopathological reference standard ± clinical follow-up were included. Study, clinical, imaging, and accuracy data for eligible studies were independently acquired by two reviewers. Primary meta-analysis was performed in studies reporting accuracy on a per-patient basis using a bivariate mixed-effects regression model. Risk of bias was evaluated using QUADAS-2. RESULTS: From 3701 citations, 15 studies (918 patients with mean age ranging from 51 to 65 years) were included in the systematic review. Twelve studies evaluated contrast-enhanced CT (6 using a per-patient assessment and 6 using a per-region assessment) and 11 studies evaluated PET/CT (7 using a per-patient assessment and 4 using a per-region assessment). All but one reporting study used consensus reading. Respective sensitivity and specificity values on a per-patient basis were 82% (67-91%, 95% CI) and 72% (59-82%) for contrast-enhanced CT and 87% (75-94%) and 90% (82-95%) for PET/CT. There was no significant difference in sensitivities between modalities (p = 0.29), but PET/CT was significantly more specific than CT (p < 0.01). Presumed variability could not be assessed in any single category due to limited studies using per-patient assessment. Studies were almost entirely low risk for bias and applicability concerns using QUADAS-2. CONCLUSION: Contrast-enhanced CT demonstrates non-inferior sensitivity compared to PET/CT, although PET/CT may still serve as an alternative and/or supplement to CT alone prior to and/or in lieu of diagnostic laparoscopy in patients with ovarian cancer. Future revisions to existing guidelines should consider these results to further refine the individualized pretherapeutic diagnostic pathway.
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Meios de Contraste , Estadiamento de Neoplasias , Neoplasias Ovarianas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia Computadorizada por Raios X , Humanos , Feminino , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia Computadorizada por Raios X/métodos , Sensibilidade e EspecificidadeRESUMO
The value and uncertainty associated with choice alternatives constitute critical features relevant for decisions. However, the manner in which reward and risk representations are temporally organized in the brain remains elusive. Here we leverage the spatiotemporal precision of intracranial electroencephalography, along with a simple card game designed to elicit the unfolding computation of a set of reward and risk variables, to uncover this temporal organization. Reward outcome representations across wide-spread regions follow a sequential order along the anteroposterior axis of the brain. In contrast, expected value can be decoded from multiple regions at the same time, and error signals in both reward and risk domains reflect a mixture of sequential and parallel encoding. We further highlight the role of the anterior insula in generalizing between reward prediction error and risk prediction error codes. Together our results emphasize the importance of neural dynamics for understanding value-based decisions under uncertainty.
Assuntos
Encéfalo , Recompensa , Humanos , Encéfalo/diagnóstico por imagemRESUMO
BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and tropical spastic paraparesis. HTLV-1 encodes transactivator protein Tax that interacts with various cellular factors to modulate transcription and other biological functions. Additional cellular mediators of Tax-mediated transcriptional activation of HTLV-1 long terminal repeats (LTR) remain to be identified and characterized. RESULTS: In this study, we investigated the regulatory role of group I p21-activated kinases (Paks) in Tax-induced LTR activation. Both wild-type and kinase-dead mutants of Pak3 were capable of potentiating the activity of Tax to activate LTR transcription. The effect of Paks on the LTR was attributed to the N-terminal regulatory domain and required the action of CREB, CREB-regulating transcriptional coactivators (CRTCs) and p300/CREB-binding protein. Paks physically associated with Tax and CRTCs. Paks were recruited to the LTR in the presence of Tax. siRNAs against either Pak1 or Pak3 prevented the interaction of Tax with CRTC1 and the recruitment of Tax to the LTR. These siRNAs also inhibited LTR-dependent transcription in HTLV-1-transformed MT4 cells and in cells transfected with an infectious clone of HTLV-1. CONCLUSION: Group I Paks augment Tax-mediated transcriptional activation of HTLV-1 LTR in a kinase-independent manner.
Assuntos
Produtos do Gene tax/metabolismo , Interações Hospedeiro-Patógeno , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Sequências Repetidas Terminais , Ativação Transcricional , Replicação Viral , Quinases Ativadas por p21/metabolismo , Células HeLa , Humanos , Ligação Proteica , Mapeamento de Interação de ProteínasRESUMO
BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Treatment options are limited and prophylactic agents are not available. We have previously demonstrated an essential role for CREB-regulating transcriptional coactivators (CRTCs) in HTLV-1 transcription. RESULTS: In this study we report on the negative regulatory role of LKB1 tumor suppressor and salt-inducible kinases (SIKs) in the activation of HTLV-1 long terminal repeats (LTR) by the oncoprotein Tax. Activation of LKB1 and SIKs effectively blunted Tax activity in a phosphorylation-dependent manner, whereas compromising these kinases, but not AMP-dependent protein kinases, augmented Tax function. Activated LKB1 and SIKs associated with Tax and suppressed Tax-induced LTR activation by counteracting CRTCs and CREB. Enforced expression of LKB1 or SIK1 in cells transfected with HTLV-1 molecular clone pX1MT repressed proviral transcription. On the contrary, depletion of LKB1 in pX1MT-transfected cells and in HTLV-1-transformed T cells boosted the expression of Tax. Treatment of HTLV-1 transformed cells with metformin led to LKB1/SIK1 activation, reduction in Tax expression, and inhibition of cell proliferation. CONCLUSIONS: Our findings revealed a new function of LKB1 and SIKs as negative regulators of HTLV-1 transcription. Pharmaceutical activation of LKB1 and SIKs might be considered as a new strategy in anti-HTLV-1 and anti-ATL therapy.
Assuntos
Regulação Viral da Expressão Gênica , Produtos do Gene tax/antagonistas & inibidores , Interações Hospedeiro-Patógeno , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Transcrição Gênica , Quinases Proteína-Quinases Ativadas por AMP , Linhagem Celular , HumanosRESUMO
The value and uncertainty associated with choice alternatives constitute critical features along which decisions are made. While the neural substrates supporting reward and risk processing have been investigated, the temporal organization by which these computations are encoded remains elusive. Here we leverage the high spatiotemporal precision of intracranial electroencephalography (iEEG) to uncover how representations of decision-related computations unfold in time. We present evidence of locally distributed representations of reward and risk variables that are temporally organized across multiple regions of interest. Reward outcome representations across wide-spread regions follow a temporally cascading order along the anteroposterior axis of the brain. In contrast, expected value can be decoded from multiple regions at the same time, and error signals in both reward and risk domains reflect a mixture of sequential and parallel encoding. We highlight the role of the anterior insula in generalizing between reward prediction error (RePE) and risk prediction error (RiPE), within which the encoding of RePE in the distributed iEEG signal predicts RiPE. Together our results emphasize the utility of uncovering temporal dynamics in the human brain for understanding how computational processes critical for value-based decisions under uncertainty unfold.
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The heterogeneous nuclear ribonucleoprotein Npl3p of budding yeast is a substrate of arginine methyltransferase Hmt1p, but the role of Hmt1p in regulating Npl3p's functions in transcription antitermination and elongation were unknown. We found that mutants lacking Hmt1p methyltransferase activity exhibit reduced recruitment of Npl3p, but elevated recruitment of a component of mRNA cleavage/termination factor CFI, to the activated GAL10-GAL7 locus. Consistent with this, hmt1 mutants displayed increased termination at the defective gal10-Delta56 terminator. Remarkably, hmt1Delta cells also exhibit diminished recruitment of elongation factor Tho2p and a reduced rate of transcription elongation in vivo. Importantly, the defects in Npl3p and Tho2p recruitment, antitermination and elongation in hmt1Delta cells all were mitigated by substitutions in Npl3p RGG repeats that functionally mimic arginine methylation by Hmt1p. Thus, Hmt1p promotes elongation and suppresses termination at cryptic terminators by methylating RGG repeats in Npl3p. As Hmt1p stimulates dissociation of Tho2p from an Npl3p-mRNP complex, it could act to recycle these elongation and antitermination factors back to sites of ongoing transcription.
Assuntos
Regulação da Expressão Gênica , Proteínas Nucleares/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Transcrição Gênica , Deleção de Genes , Metilação , Proteínas Nucleares/química , Proteína-Arginina N-Metiltransferases/genética , Proteínas de Ligação a RNA/química , Sequências Repetitivas de Aminoácidos , Proteínas Repressoras/genética , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Transativadores/genética , Fatores de Transcrição/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/metabolismoRESUMO
Peroxiredoxins are a family of antioxidant enzymes critically involved in cellular defense and signaling. Particularly, yeast peroxiredoxin Tsa1p is thought to play a role in the maintenance of genome integrity, but the underlying mechanism is not understood. In this study, we took a genetic approach to investigate the cause of genome instability in tsa1Delta cells. Strong genetic interactions of TSA1 with DNA damage checkpoint components DUN1, SML1, and CRT1 were found when mutant cells were analyzed for either sensitivity to DNA damage or rate of spontaneous base substitutions. An elevation in intracellular dNTP production was observed in tsa1Delta cells. This was associated with constitutive activation of the DNA damage checkpoint as indicated by phosphorylation of Rad9/Rad53p, reduced steady-state amount of Sml1p, and induction of RNR and HUG1 genes. In addition, defects in the DNA damage checkpoint did not modulate intracellular level of reactive oxygen species, but suppressed the mutator phenotype of tsa1Delta cells. On the contrary, overexpression of RNR1 exacerbated this phenotype by increasing dNTP levels. Taken together, our findings uncover a new role of TSA1 in preventing the overproduction of dNTPs, which is a root cause of genome instability.
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Dano ao DNA , Instabilidade Genômica , Nucleotídeos/metabolismo , Peroxidases/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Reparo do DNA , Mutação , Peroxidases/genética , Proteínas de Saccharomyces cerevisiae/genéticaRESUMO
Both novelty and uncertainty are potent features guiding exploration; however, they are often experimentally conflated, and an understanding of how they interact to regulate the balance between exploration and exploitation has proved elusive. Using a task designed to decouple the influence of novelty and uncertainty, we identify separable mechanisms through which exploration is directed. We show that uncertainty-directed exploration is sensitive to the prospective benefit offered by new information, whereas novelty-directed exploration is maintained regardless of its potential advantage. Using a computational framework in conjunction with fMRI, we show that uncertainty-directed choice is rooted in an adaptive bias indexing the prospective utility of exploration. In contrast, novelty persistently promotes exploration by optimistically inflating reward expectations while simultaneously dampening uncertainty signals. Our results identify separable neural substrates charged with balancing the explore/exploit trade-off to foster a manageable decomposition of an otherwise intractable problem.
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Comportamento Exploratório , Recompensa , Encéfalo/diagnóstico por imagem , Tomada de Decisões , Comportamento Exploratório/fisiologia , Cabeça , Humanos , IncertezaRESUMO
Psychological theories posit that affective experiences can be decomposed into component constituents, yet disagree on the level of representation of these components. Affective experiences have been previously described as emerging from core dimensions of valence and arousal. However, this view needs to be reconciled with accounts of valence processing in appetitive and aversive circuits from the neuroscience literature. Here we offer an account of affect that allows for both perspectives but compares across levels of analysis. At one level of analysis, valence and arousal are observed already in the properties of encountered stimuli and the appetitive and aversive neural circuits that engage accordingly. At another level of analysis, the explicit experiential aspect of affective processes are compressed and appraised in a manner that allows these experiences to be organized along valence and arousal axes. We review both the behavioral neuroscience evidence on appetitive and aversive circuits as well as the cognitive neuroscience literature on compression in information coding across multiple domains of processing. We argue that these processes are domain-general and adapt these principles to provide a perspective on how valence can be represented at multiple scales in the brain.
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Nível de Alerta , Neurociências , Afeto , Encéfalo , HumanosRESUMO
To reveal the putative cellular factors involved in SARS coronavirus replication, the helicase (Hel, nsp13) of SARS coronavirus was used to screen the cDNA library of rat pulmonary epithelial cells using the yeast two-hybrid system. Positively interacting proteins were further tested using a mammalian cell hybrid system and co-immunoprecipitation in the human A549 cell line, which has been shown to support SARS coronavirus replication. Out of the seven positive clones observed by yeast two-hybrid assay, only the Ddx5 (Asp-Glu-Ala-Asp box polypeptide 5) protein showed specific interaction with SARS-CoV helicase. When expression of DdX5 was knocked down by small interfering RNA (siRNA), SARS coronavirus replication was significantly inhibited in fetal rhesus kidney (FRhK-4) cells. Since Ddx5 is a multifunctional protein that plays important roles in transcriptional regulation, its interaction with SARS coronavirus helicase provides interesting clues for studying virus-host cell interactions in SARS-CoV infections.
Assuntos
RNA Helicases DEAD-box/metabolismo , Metiltransferases/metabolismo , Mapeamento de Interação de Proteínas , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/fisiologia , Animais , Linhagem Celular , Técnicas de Silenciamento de Genes , Humanos , Macaca mulatta , Ligação Proteica , RNA Helicases , Ratos , Técnicas do Sistema de Duplo-Híbrido , Proteínas não Estruturais Virais , Replicação ViralRESUMO
We have previously shown that the connectivity of the hippocampus to other regions of the default mode network (DMN) is a strong indicator of memory ability in people with temporal lobe epilepsy (TLE). Recent work in the cognitive neuroscience literature has suggested that the anterior and posterior aspects of the hippocampus have distinct connections to the rest of the DMN and may support different memory operations. Further, structural analysis of epileptogenic hippocampi has found greater atrophy, characterized by mesial temporal sclerosis, in the anterior region of the hippocampus. Here, we used resting state FMRI data to parcellate the hippocampus according to its functional connectivity to the rest of the brain in people with left lateralized TLE (LTLE) and right lateralized TLE (RTLE), and in a group of neurologically healthy controls. We found similar anterior and posterior compartments in all groups. However, there was weaker connectivity of the epileptogenic hippocampus to multiple regions of the DMN. Both TLE groups showed reduced connectivity of the posterior hippocampus to key hubs of the DMN, the posterior cingulate cortex (PCC) and the medial pre-frontal cortex (mPFC). In the LTLE group, the anterior hippocampus also showed reduced connectivity to the DMN, and this effect was influenced by the presence of mesial temporal sclerosis. When we explored brain-behavior relationships, we found that reduced connectivity of the left anterior hippocampus to the DMN hubs related to poorer verbal memory ability in people with LTLE, and reduced connectivity of the right posterior hippocampus to the PCC related to poorer visual memory ability in those with RTLE. These findings may inform models regarding functional distinctions of the hippocampal anteroposterior axis.