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1.
Neuroimage ; 283: 120395, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37832707

RESUMO

Brain decoding aims to infer cognitive states from patterns of brain activity. Substantial inter-individual variations in functional brain organization challenge accurate decoding performed at the group level. In this paper, we tested whether accurate brain decoding models can be trained entirely at the individual level. We trained several classifiers on a dense individual functional magnetic resonance imaging (fMRI) dataset for which six participants completed the entire Human Connectome Project (HCP) task battery >13 times over ten separate fMRI sessions. We evaluated nine decoding methods, from Support Vector Machines (SVM) and Multi-Layer Perceptron (MLP) to Graph Convolutional Neural Networks (GCN). All decoders were trained to classify single fMRI volumes into 21 experimental conditions simultaneously, using ∼7 h of fMRI data per participant. The best prediction accuracies were achieved with GCN and MLP models, whose performance (57-67 % accuracy) approached state-of-the-art accuracy (76 %) with models trained at the group level on >1 K hours of data from the original HCP sample. Our SVM model also performed very well (54-62 % accuracy). Feature importance maps derived from MLP -our best-performing model- revealed informative features in regions relevant to particular cognitive domains, notably in the motor cortex. We also observed that inter-subject classification achieved substantially lower accuracy than subject-specific models, indicating that our decoders learned individual-specific features. This work demonstrates that densely-sampled neuroimaging datasets can be used to train accurate brain decoding models at the individual level. We expect this work to become a useful benchmark for techniques that improve model generalization across multiple subjects and acquisition conditions.


Assuntos
Conectoma , Humanos , Conectoma/métodos , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Redes Neurais de Computação , Aprendizagem
2.
Nat Methods ; 16(1): 111-116, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30532080

RESUMO

Preprocessing of functional magnetic resonance imaging (fMRI) involves numerous steps to clean and standardize the data before statistical analysis. Generally, researchers create ad hoc preprocessing workflows for each dataset, building upon a large inventory of available tools. The complexity of these workflows has snowballed with rapid advances in acquisition and processing. We introduce fMRIPrep, an analysis-agnostic tool that addresses the challenge of robust and reproducible preprocessing for fMRI data. fMRIPrep automatically adapts a best-in-breed workflow to the idiosyncrasies of virtually any dataset, ensuring high-quality preprocessing without manual intervention. By introducing visual assessment checkpoints into an iterative integration framework for software testing, we show that fMRIPrep robustly produces high-quality results on a diverse fMRI data collection. Additionally, fMRIPrep introduces less uncontrolled spatial smoothness than observed with commonly used preprocessing tools. fMRIPrep equips neuroscientists with an easy-to-use and transparent preprocessing workflow, which can help ensure the validity of inference and the interpretability of results.


Assuntos
Imageamento por Ressonância Magnética/métodos , Fluxo de Trabalho , Mapeamento Encefálico/métodos , Humanos , Processamento de Imagem Assistida por Computador/métodos , Reprodutibilidade dos Testes
3.
Neuroimage ; 245: 118683, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34715319

RESUMO

Inter-individual variability in the functional organization of the brain presents a major obstacle to identifying generalizable neural coding principles. Functional alignment-a class of methods that matches subjects' neural signals based on their functional similarity-is a promising strategy for addressing this variability. To date, however, a range of functional alignment methods have been proposed and their relative performance is still unclear. In this work, we benchmark five functional alignment methods for inter-subject decoding on four publicly available datasets. Specifically, we consider three existing methods: piecewise Procrustes, searchlight Procrustes, and piecewise Optimal Transport. We also introduce and benchmark two new extensions of functional alignment methods: piecewise Shared Response Modelling (SRM), and intra-subject alignment. We find that functional alignment generally improves inter-subject decoding accuracy though the best performing method depends on the research context. Specifically, SRM and Optimal Transport perform well at both the region-of-interest level of analysis as well as at the whole-brain scale when aggregated through a piecewise scheme. We also benchmark the computational efficiency of each of the surveyed methods, providing insight into their usability and scalability. Taking inter-subject decoding accuracy as a quantification of inter-subject similarity, our results support the use of functional alignment to improve inter-subject comparisons in the face of variable structure-function organization. We provide open implementations of all methods used.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Algoritmos , Humanos
4.
Neuroimage ; 229: 117742, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33454405

RESUMO

Scientific research aims to bring forward innovative ideas and constantly challenges existing knowledge structures and stereotypes. However, women, ethnic and cultural minorities, as well as individuals with disabilities, are systematically discriminated against or even excluded from promotions, publications, and general visibility. A more diverse workforce is more productive, and thus discrimination has a negative impact on science and the wider society, as well as on the education, careers, and well-being of individuals who are discriminated against. Moreover, the lack of diversity at scientific gatherings can lead to micro-aggressions or harassment, making such meetings unpleasant, or even unsafe environments for early career and underrepresented scientists. At the Organization for Human Brain Mapping (OHBM), we recognized the need for promoting underrepresented scientists and creating diverse role models in the field of neuroimaging. To foster this, the OHBM has created a Diversity and Inclusivity Committee (DIC). In this article, we review the composition and activities of the DIC that have promoted diversity within OHBM, in order to inspire other organizations to implement similar initiatives. Activities of the committee over the past four years have included (a) creating a code of conduct, (b) providing diversity and inclusivity education for OHBM members, (c) organizing interviews and symposia on diversity issues, and (d) organizing family-friendly activities and providing childcare grants during the OHBM annual meetings. We strongly believe that these activities have brought positive change within the wider OHBM community, improving inclusivity and fostering diversity while promoting rigorous, ground-breaking science. These positive changes could not have been so rapidly implemented without the enthusiastic support from the leadership, including OHBM Council and Program Committee, and the OHBM Special Interest Groups (SIGs), namely the Open Science, Student and Postdoc, and Brain-Art SIGs. Nevertheless, there remains ample room for improvement, in all areas, and even more so in the area of targeted attempts to increase inclusivity for women, individuals with disabilities, members of the LGBTQ+ community, racial/ethnic minorities, and individuals of lower socioeconomic status or from low and middle-income countries. Here, we present an overview of the DIC's composition, its activities, future directions and challenges. Our goal is to share our experiences with a wider audience to provide information to other organizations and institutions wishing to implement similar comprehensive diversity initiatives. We propose that scientific organizations can push the boundaries of scientific progress only by moving beyond existing power structures and by integrating principles of equity and inclusivity in their core values.


Assuntos
Centros Médicos Acadêmicos/métodos , Mapeamento Encefálico/métodos , Diversidade Cultural , Preconceito/etnologia , Preconceito/prevenção & controle , Sociedades Científicas , Centros Médicos Acadêmicos/tendências , Mapeamento Encefálico/tendências , Criatividade , Pessoas com Deficiência , Etnicidade , Humanos , Preconceito/psicologia , Sociedades Científicas/tendências
5.
Neuroimage ; 216: 116330, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31704292

RESUMO

Naturalistic stimuli show significant potential to inform behavioral, cognitive, and clinical neuroscience. To date, this impact is still limited by the relative inaccessibility of both generated neuroimaging data as well as the supporting naturalistic stimuli. In this perspective, we highlight currently available naturalistic datasets and technical solutions such as DataLad that continue to advance our ability to share this data. We also review scientific and sociological challenges in selecting naturalistic stimuli for reproducible research. Overall, we encourage researchers to share their naturalistic datasets to the full extent possible under local copyright law.


Assuntos
Bases de Dados Factuais/tendências , Disseminação de Informação , Neurociências/tendências , Setor Público/tendências , Humanos , Disseminação de Informação/métodos , Neurociências/métodos
6.
Cereb Cortex ; 29(12): 5269-5284, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31066899

RESUMO

Schizophrenia (SCZ) is recognized as a disorder of distributed brain dysconnectivity. While progress has been made delineating large-scale functional networks in SCZ, little is known about alterations in grey matter integrity of these networks. We used a multivariate approach to identify the structural covariance of the salience, default, motor, visual, fronto-parietal control, and dorsal attention networks. We derived individual scores reflecting covariance in each structural image for a given network. Seed-based multivariate analyses were conducted on structural images in a discovery (n = 90) and replication (n = 74) sample of SCZ patients and healthy controls. We first validated patterns across all networks, consistent with well-established functional connectivity reports. Next, across two SCZ samples, we found reliable and robust reductions in structural integrity of the fronto-parietal control and salience networks, but not default, dorsal attention, motor and sensory networks. Well-powered exploratory analyses failed to identify relationships with symptoms. These findings provide evidence of selective structural decline in associative networks in SCZ. Such decline may be linked with recently identified functional disturbances in associative networks, providing more sensitive multi-modal network-level probes in SCZ. Absence of symptom effects suggests that identified disturbances may underlie a trait-type marker in SCZ.


Assuntos
Atenção/fisiologia , Encéfalo/fisiopatologia , Rede Nervosa/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Mapeamento Encefálico/métodos , Feminino , Substância Cinzenta/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/fisiopatologia
8.
J Neurosci ; 34(42): 14108-14, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25319706

RESUMO

Substantial neuroimaging evidence suggests that spontaneous engagement of the default network impairs performance on tasks requiring executive control. We investigated whether this impairment depends on the congruence between executive control demands and internal mentation. We hypothesized that activation of the default network might enhance performance on an executive control task if control processes engage long-term memory representations that are supported by the default network. Using fMRI, we scanned 36 healthy young adult humans on a novel two-back task requiring working memory for famous and anonymous faces. In this task, participants (1) matched anonymous faces interleaved with anonymous face, (2) matched anonymous faces interleaved with a famous face, or (3) matched a famous faces interleaved with an anonymous face. As predicted, we observed a facilitation effect when matching famous faces, compared with anonymous faces. We also observed greater activation of the default network during these famous face-matching trials. The results suggest that activation of the default network can contribute to task performance during an externally directed executive control task. Our findings provide evidence that successful activation of the default network in a contextually relevant manner facilitates goal-directed cognition.


Assuntos
Encéfalo/fisiologia , Cognição/fisiologia , Objetivos , Rede Nervosa/fisiologia , Desempenho Psicomotor/fisiologia , Adulto , Feminino , Humanos , Masculino , Estimulação Luminosa/métodos , Adulto Jovem
9.
ArXiv ; 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-37744469

RESUMO

The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS.

10.
Imaging Neurosci (Camb) ; 2: 1-19, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-39308505

RESUMO

The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS.

11.
Sci Data ; 9(1): 119, 2022 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-35351925

RESUMO

Central to understanding human behavior is a comprehensive mapping of brain-behavior relations within the context of lifespan development. Reproducible discoveries depend upon well-powered samples of reliable data. We provide to the scientific community two, 10-minute, multi-echo functional MRI (ME-fMRI) runs, and structural MRI (T1-MPRAGE), from 181 healthy younger (ages 18-34 y) and 120 older adults (ages 60-89 y). T2-FLAIR MRIs and behavioral assessments are available in a majority subset of over 250 participants. Behavioral assessments include fluid and crystallized cognition, self-reported measures of personality, and socioemotional functioning. Initial quality control and validation of these data is provided. This dataset will be of value to scientists interested in BOLD signal specifically isolated from ME-fMRI, individual differences in brain-behavioral associations, and cross-sectional aging effects in healthy adults. Demographic and behavioral data are available within the Open Science Framework project "Goal-Directed Cognition in Older and Younger Adults" ( http://osf.io/yhzxe/ ), which will be augmented over time; neuroimaging data are available on OpenNeuro ( https://openneuro.org/datasets/ds003592 ).


Assuntos
Encéfalo , Imageamento por Ressonância Magnética , Neuroimagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Humanos , Pessoa de Meia-Idade , Adulto Jovem
12.
Gigascience ; 10(1)2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33481004

RESUMO

BACKGROUND: The choice of preprocessing pipeline introduces variability in neuroimaging analyses that affects the reproducibility of scientific findings. Features derived from structural and functional MRI data are sensitive to the algorithmic or parametric differences of preprocessing tasks, such as image normalization, registration, and segmentation to name a few. Therefore it is critical to understand and potentially mitigate the cumulative biases of pipelines in order to distinguish biological effects from methodological variance. METHODS: Here we use an open structural MRI dataset (ABIDE), supplemented with the Human Connectome Project, to highlight the impact of pipeline selection on cortical thickness measures. Specifically, we investigate the effect of (i) software tool (e.g., ANTS, CIVET, FreeSurfer), (ii) cortical parcellation (Desikan-Killiany-Tourville, Destrieux, Glasser), and (iii) quality control procedure (manual, automatic). We divide our statistical analyses by (i) method type, i.e., task-free (unsupervised) versus task-driven (supervised); and (ii) inference objective, i.e., neurobiological group differences versus individual prediction. RESULTS: Results show that software, parcellation, and quality control significantly affect task-driven neurobiological inference. Additionally, software selection strongly affects neurobiological (i.e. group) and individual task-free analyses, and quality control alters the performance for the individual-centric prediction tasks. CONCLUSIONS: This comparative performance evaluation partially explains the source of inconsistencies in neuroimaging findings. Furthermore, it underscores the need for more rigorous scientific workflows and accessible informatics resources to replicate and compare preprocessing pipelines to address the compounding problem of reproducibility in the age of large-scale, data-driven computational neuroscience.


Assuntos
Processamento de Imagem Assistida por Computador , Neuroimagem , Humanos , Imageamento por Ressonância Magnética , Reprodutibilidade dos Testes , Software
13.
Gigascience ; 10(8)2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34414422

RESUMO

As the global health crisis unfolded, many academic conferences moved online in 2020. This move has been hailed as a positive step towards inclusivity in its attenuation of economic, physical, and legal barriers and effectively enabled many individuals from groups that have traditionally been underrepresented to join and participate. A number of studies have outlined how moving online made it possible to gather a more global community and has increased opportunities for individuals with various constraints, e.g., caregiving responsibilities. Yet, the mere existence of online conferences is no guarantee that everyone can attend and participate meaningfully. In fact, many elements of an online conference are still significant barriers to truly diverse participation: the tools used can be inaccessible for some individuals; the scheduling choices can favour some geographical locations; the set-up of the conference can provide more visibility to well-established researchers and reduce opportunities for early-career researchers. While acknowledging the benefits of an online setting, especially for individuals who have traditionally been underrepresented or excluded, we recognize that fostering social justice requires inclusivity to actively be centered in every aspect of online conference design. Here, we draw from the literature and from our own experiences to identify practices that purposefully encourage a diverse community to attend, participate in, and lead online conferences. Reflecting on how to design more inclusive online events is especially important as multiple scientific organizations have announced that they will continue offering an online version of their event when in-person conferences can resume.

14.
Soc Cogn Affect Neurosci ; 15(5): 537-549, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32399555

RESUMO

In young adults, mentalizing about known others engages the default network, with differential brain response modulated by social closeness. While the functional integrity of the default network changes with age, few studies have investigated how these changes impact the representation of known others, across levels of closeness. Young (N = 29, 16 females) and older (N = 27, 12 females) adults underwent functional magnetic resonance imaging (fMRI) scanning while making trait judgments for social others varying in closeness. Multivariate analyses (partial least squares) identified default network activation for trait judgments across both age cohorts. For young adults, romantic partner and self-judgments differed from other levels of social closeness and were associated with activity in default and salience networks. In contrast, default network interactivity was not modulated by social closeness for older adults. In two functional connectivity analyses, both age groups demonstrated connectivity between dorsal and ventral medial prefrontal cortex and other default network regions during trait judgments. However older, but not young, adults also showed increased functional coupling between medial and lateral prefrontal brain regions that did not vary by category of known other. Mentalizing about others engages default and frontal brain regions in older adulthood, and this coupling is poorly modulated by social closeness.


Assuntos
Encéfalo/diagnóstico por imagem , Rede de Modo Padrão/diagnóstico por imagem , Julgamento , Mentalização/fisiologia , Adulto , Fatores Etários , Idoso , Encéfalo/fisiologia , Mapeamento Encefálico , Rede de Modo Padrão/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Comportamento Social , Adulto Jovem
15.
Nat Protoc ; 15(7): 2186-2202, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32514178

RESUMO

Functional magnetic resonance imaging (fMRI) is a standard tool to investigate the neural correlates of cognition. fMRI noninvasively measures brain activity, allowing identification of patterns evoked by tasks performed during scanning. Despite the long history of this technique, the idiosyncrasies of each dataset have led to the use of ad-hoc preprocessing protocols customized for nearly every different study. This approach is time consuming, error prone and unsuitable for combining datasets from many sources. Here we showcase fMRIPrep (http://fmriprep.org), a robust tool to prepare human fMRI data for statistical analysis. This software instrument addresses the reproducibility concerns of the established protocols for fMRI preprocessing. By leveraging the Brain Imaging Data Structure to standardize both the input datasets (MRI data as stored by the scanner) and the outputs (data ready for modeling and analysis), fMRIPrep is capable of preprocessing a diversity of datasets without manual intervention. In support of the growing popularity of fMRIPrep, this protocol describes how to integrate the tool in a task-based fMRI investigation workflow.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética , Animais , Encéfalo/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador/normas , Padrões de Referência , Descanso/fisiologia , Fluxo de Trabalho
17.
Neuropsychologia ; 110: 37-43, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28624521

RESUMO

As we age, the architecture of cognition undergoes a fundamental transition. Fluid intellectual abilities decline while crystalized abilities remain stable or increase. This shift has a profound impact across myriad cognitive and functional domains, yet the neural mechanisms remain under-specified. We have proposed that greater connectivity between the default network and executive control regions in lateral prefrontal cortex may underlie this shift, as older adults increasingly rely upon accumulated knowledge to support goal-directed behavior. Here we provide direct evidence for this mechanism within the domain of autobiographical memory. In a large sample of healthy adult participants (n = 103 Young; n = 80 Old) the strength of default - executive coupling reliably predicted more semanticized, or knowledge-based, recollection of autobiographical memories in the older adult cohort. The findings are consistent with the default - executive coupling hypothesis of aging and identify this shift in network dynamics as a candidate neural mechanism associated with crystalized cognition in later life that may signal adaptive capacity in the context of declining fluid cognitive abilities.


Assuntos
Encéfalo/fisiologia , Envelhecimento Cognitivo/fisiologia , Envelhecimento Cognitivo/psicologia , Memória Episódica , Semântica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Função Executiva/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Modelos Psicológicos , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiologia , Neuroimagem , Adulto Jovem
18.
Netw Neurosci ; 1(3): 302-323, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29855624

RESUMO

Structural covariance examines covariation of gray matter morphology between brain regions and across individuals. Despite significant interest in the influence of age on structural covariance patterns, no study to date has provided a complete life span perspective-bridging childhood with early, middle, and late adulthood-on the development of structural covariance networks. Here, we investigate the life span trajectories of structural covariance in six canonical neurocognitive networks: default, dorsal attention, frontoparietal control, somatomotor, ventral attention, and visual. By combining data from five open-access data sources, we examine the structural covariance trajectories of these networks from 6 to 94 years of age in a sample of 1,580 participants. Using partial least squares, we show that structural covariance patterns across the life span exhibit two significant, age-dependent trends. The first trend is a stable pattern whose integrity declines over the life span. The second trend is an inverted-U that differentiates young adulthood from other age groups. Hub regions, including posterior cingulate cortex and anterior insula, appear particularly influential in the expression of this second age-dependent trend. Overall, our results suggest that structural covariance provides a reliable definition of neurocognitive networks across the life span and reveal both shared and network-specific trajectories.

19.
J Gerontol A Biol Sci Med Sci ; 72(10): 1365-1368, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28369260

RESUMO

BACKGROUND: Age-related brain changes leading to altered socioemotional functioning may increase vulnerability to financial exploitation. If confirmed, this would suggest a novel mechanism leading to heightened financial exploitation risk in older adults. Development of predictive neural markers could facilitate increased vigilance and prevention. In this preliminary study, we sought to identify structural and functional brain differences associated with financial exploitation in older adults. METHODS: Financially exploited older adults (n = 13, 7 female) and a matched cohort of older adults who had been exposed to, but avoided, a potentially exploitative situation (n = 13, 7 female) were evaluated. Using magnetic resonance imaging, we examined cortical thickness and resting state functional connectivity. Behavioral data were collected using standardized cognitive assessments, self-report measures of mood and social functioning. RESULTS: The exploited group showed cortical thinning in anterior insula and posterior superior temporal cortices, regions associated with processing affective and social information, respectively. Functional connectivity encompassing these regions, within default and salience networks, was reduced, while between network connectivity was increased. Self-reported anger and hostility was higher for the exploited group. CONCLUSIONS: We observed financial exploitation associated with brain differences in regions involved in socioemotional functioning. These exploratory and preliminary findings suggest that alterations in brain regions implicated in socioemotional functioning may be a marker of financial exploitation risk. Large-scale, prospective studies are necessary to validate this neural mechanism, and develop predictive markers for use in clinical practice.


Assuntos
Envelhecimento/patologia , Encéfalo/patologia , Transtornos Cognitivos/patologia , Abuso de Idosos/economia , Imageamento por Ressonância Magnética , Idoso , Mapeamento Encefálico , Tomada de Decisões , Feminino , Avaliação Geriátrica , Humanos , Masculino , Competência Mental , Vias Neurais/patologia
20.
Oncogene ; 24(43): 6516-24, 2005 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-16027729

RESUMO

The activating protein-1 (AP-1) transcription factor is a converging point of multiple signal transduction pathways in many cells. We have previously demonstrated that overexpressing Tam67, a dominant-negative (DN) form of cJun, blocks AP-1 activity and inhibits breast cancer cell growth. We hypothesized that Tam67 forms dimers with other AP-1 proteins to suppress the growth of breast cancer cells. In the present study, we used immunoprecipitation-Western blotting to demonstrate that Tam67 binds all Jun and Fos proteins in breast cancer cells. In addition, we used two variants of the Tam67 mutant to investigate whether Jun or Fos protein was required for breast cancer cell growth. We created a Tam/Fos mutant in which the cJun dimerization domain was replaced by the cFos dimerization domain, and a Tam/Squelcher mutant in which the cJun dimerization domain was deleted. We then isolated MCF-7 cell lines that stably expressed these cJun-DN mutants under the control of an inducible promoter. Using AP-1-dependent reporter assays, we observed that Tam67 and Tam/Fos mutants inhibited AP-1 transcriptional activity, while the Tam/Squelcher mutant did not. We then determined whether Tam/Fos or Tam/Squelcher inhibited breast cell growth as well as Tam67. We found that while Tam67 repressed cell growth, neither Tam/Fos nor Tam/Squelcher mutant affected cell growth. These results indicate that Tam67 likely inactivates Fos family member proteins to suppress breast cancer cell growth. Finally, we performed antisense experiments to knock down the expression of individual family members (cJun or cFos). Our results demonstrated that antisense cFos inhibited breast cancer cell proliferation and colony formation, while antisense cJun did not. These results suggest that Tam67 suppresses breast cancer cell growth by interacting with Fos family members, specifically with cFos, to produce an inactive AP-1 complex.


Assuntos
Neoplasias da Mama/patologia , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células , DNA Antissenso , Dimerização , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mutação , Neuregulina-1/genética , Neuregulina-1/metabolismo , Fragmentos de Peptídeos/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo
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