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1.
Int J Mol Sci ; 24(12)2023 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-37373366

RESUMO

The foraging (for) gene of Drosophila melanogaster encodes a cGMP-dependent protein kinase (PKG), which is a major effector of the cGMP signaling pathway involved in the regulation of behaviour and metabolic traits. Despite being well studied at the transcript level, little is known about the for gene at the protein level. Here, we provide a detailed characterization of the for gene protein (FOR) products and present new tools for their study, including five isoform-specific antibodies and a transgenic strain that carries an HA-labelled for allele (forBAC::HA). Our results showed that multiple FOR isoforms were expressed in the larval and adult stages of D. melanogaster and that the majority of whole-body FOR expression arises from three (P1, P1α, and P3) of eight putative protein isoforms. We found that FOR expression differed between the larval and adult stages and between the dissected larval organs we analyzed, which included the central nervous system (CNS), fat body, carcass, and intestine. Moreover, we showed that the FOR expression differed between two allelic variants of the for gene, namely, fors (sitter) and forR (rover), that are known to differ in many food-related traits. Together, our in vivo identification of FOR isoforms and the existence of temporal, spatial, and genetic differences in their expression lay the groundwork for determining their functional significance.


Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Animais , Drosophila melanogaster/metabolismo , Comportamento Alimentar/fisiologia , Animais Geneticamente Modificados , Fenótipo , Isoformas de Proteínas/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo
2.
Ann N Y Acad Sci ; 1526(1): 99-113, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37350250

RESUMO

Genes are often pleiotropic and plastic in their expression, features which increase and diversify the functionality of the genome. The foraging (for) gene in Drosophila melanogaster is highly pleiotropic and a long-standing model for studying individual differences in behavior and plasticity from ethological, evolutionary, and genetic perspectives. Its pleiotropy is known to be linked to its complex molecular structure; however, the downstream pathways and interactors remain mostly elusive. To uncover these pathways and interactors and gain a better understanding of how pleiotropy and plasticity are achieved at the molecular level, we explore the effects of different for alleles on gene expression at baseline and in response to 4 h of food deprivation, using RNA sequencing analysis in different Drosophila larval tissues. The results show tissue-specific transcriptomic dynamics influenced by for allelic variation and food deprivation, as well as genotype by treatment interactions. Differentially expressed genes yielded pathways linked to previously described for phenotypes and several potentially novel phenotypes. Together, these findings provide putative genes and pathways through which for might regulate its varied phenotypes in a pleiotropic, plastic, and gene-structure-dependent manner.


Assuntos
Drosophila melanogaster , Transcriptoma , Animais , Drosophila melanogaster/genética , Fenótipo , Larva/fisiologia , Pleiotropia Genética
3.
Fly (Austin) ; 16(1): 68-84, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-34852730

RESUMO

An organism's behaviour is influenced by its social environment. Experiences such as social isolation or crowding may have profound short or long-term effects on an individual's behaviour. The composition of the social environment also depends on the genetics and previous experiences of the individuals present, leading to additional potential outcomes from each social interaction. In this article, we review selected literature related to the social environment of the model organism Drosophila melanogaster, and how Drosophila respond to variation in their social experiences throughout their lifetimes. We focus on the effects of social environment on behavioural phenotypes such as courtship, aggression, and group dynamics, as well as other phenotypes such as development and physiology. The consequences of phenotypic plasticity due to social environment are discussed with respect to the ecology and evolution of Drosophila. We also relate these studies to laboratory research practices involving Drosophila and other animals.


Assuntos
Drosophila melanogaster , Drosophila , Agressão , Animais , Corte , Drosophila melanogaster/genética
4.
J Neurogenet ; 35(3): 192-212, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34382904

RESUMO

The foraging gene in Drosophila melanogaster, which encodes a cGMP-dependent protein kinase, is a highly conserved, complex gene with multiple pleiotropic behavioral and physiological functions in both the larval and adult fly. Adult foraging expression is less well characterized than in the larva. We characterized foraging expression in the brain, gastric system, and reproductive systems using a T2A-Gal4 gene-trap allele. In the brain, foraging expression appears to be restricted to multiple sub-types of glia. This glial-specific cellular localization of foraging was supported by single-cell transcriptomic atlases of the adult brain. foraging is extensively expressed in most cell types in the gastric and reproductive systems. We then mapped multiple cis-regulatory elements responsible for parts of the observed expression patterns by a nested cloned promoter-Gal4 analysis. The mapped cis-regulatory elements were consistently modular when comparing the larval and adult expression patterns. These new data using the T2A-Gal4 gene-trap and cloned foraging promoter fusion GAL4's are discussed with respect to previous work using an anti-FOR antibody, which we show here to be non-specific. Future studies of foraging's function will consider roles for glial subtypes and peripheral tissues (gastric and reproductive systems) in foraging's pleiotropic behavioral and physiological effects.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/biossíntese , Proteínas de Drosophila/biossíntese , Drosophila melanogaster/fisiologia , Transcriptoma , Animais , Encéfalo/metabolismo , Genitália/metabolismo , Estômago/metabolismo
5.
Nucleic Acids Res ; 49(16): 9097-9116, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34403484

RESUMO

Sex is a modulator of health that has been historically overlooked in biomedical research. Recognizing this knowledge gap, funding agencies now mandate the inclusion of sex as a biological variable with the goal of stimulating efforts to illuminate the molecular underpinnings of sex biases in health and disease. DNA methylation (DNAm) is a strong molecular candidate for mediating such sex biases; however, a robust and well characterized annotation of sex differences in DNAm is yet to emerge. Beginning with a large (n = 3795) dataset of DNAm profiles from normative adult whole blood samples, we identified, validated and characterized autosomal sex-associated co-methylated genomic regions (sCMRs). Strikingly, sCMRs showed consistent sex differences in DNAm over the life course and a subset were also consistent across cell, tissue and cancer types. sCMRs included sites with known sex differences in DNAm and links to health conditions with sex biased effects. The robustness of sCMRs enabled the generation of an autosomal DNAm-based predictor of sex with 96% accuracy. Testing this tool on blood DNAm profiles from individuals with sex chromosome aneuploidies (Klinefelter [47,XXY], Turner [45,X] and 47,XXX syndrome) revealed an intimate relationship between sex chromosomes and sex-biased autosomal DNAm.


Assuntos
Metilação de DNA , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Processos de Determinação Sexual/genética , Cromossomos/genética , Ilhas de CpG , Feminino , Humanos , Masculino
6.
J Neurogenet ; 35(3): 249-261, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34121597

RESUMO

Drosophila melanogaster displays social behaviors including courtship, mating, aggression, and group foraging. Recent studies employed social network analyses (SNAs) to show that D. melanogaster strains differ in their group behavior, suggesting that genes influence social network phenotypes. Aside from genes associated with sensory function, few studies address the genetic underpinnings of these networks. The foraging gene (for) is a well-established example of a pleiotropic gene that regulates multiple behavioral phenotypes and their plasticity. In D. melanogaster, there are two naturally occurring alleles of for called rover and sitter that differ in their larval and adult food-search behavior as well as other behavioral phenotypes. Here, we hypothesize that for affects behavioral elements required to form social networks and the social networks themselves. These effects are evident when we manipulate gene dosage. We found that flies of the rover and sitter strains exhibit differences in duration, frequency, and reciprocity of pairwise interactions, and they form social networks with differences in assortativity and global efficiency. Consistent with other adult phenotypes influenced by for, rover-sitter heterozygotes show intermediate patterns of dominance in many of these characteristics. Multiple generations of backcrossing a rover allele into a sitter strain showed that many but not all of these rover-sitter differences may be attributed to allelic variation at for. Our findings reveal the significant role that for plays in affecting social network properties and their behavioral elements in Drosophila melanogaster.


Assuntos
Comportamento Animal/fisiologia , Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/fisiologia , Comportamento Social , Animais
7.
J Neurogenet ; 35(3): 179-191, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33944658

RESUMO

The foraging (for) gene has been extensively studied in many species for its functions in development, physiology, and behavior. It is common for genes that influence behavior and development to be essential genes, and for has been found to be an essential gene in both fruit flies and mammals, with for mutants dying before reaching the adult stage. However, the biological process underlying the lethality associated with this gene is not known. Here, we show that in Drosophila melanogaster, some but not all gene products of for are essential for survival. Specifically, we show that promoter 3 of for, but not promoters 1, 2, and 4 are required for survival past pupal stage. We use full and partial genetic deletions of for, and temperature-restricted knock-down of the gene to further investigate the stage of lethality. While deletion analysis shows that flies lacking for die at the end of pupal development, as pharate adults, temperature-restricted knock-down shows that for is only required at the start of pupal development, for normal adult emergence (AE) and viability. We further show that the inability of these mutants to emerge from their pupal cases is linked to deficiencies in emergence behaviors, caused by a possible energy deficiency, and finally, that the lethality of for mutants seems to be linked to protein isoform P3, transcribed from for promoter 3.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Metamorfose Biológica/genética , Animais
8.
J Neurogenet ; 35(3): 213-220, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33998378

RESUMO

A cGMP-dependent protein kinase (PKG) encoded by the Drosophila foraging (for) gene regulates both synaptic structure (nerve terminal growth) and function (neurotransmission) through independent mechanisms at the Drosophila larval neuromuscular junction (nmj). Glial for is known to restrict nerve terminal growth, whereas presynaptic for inhibits synaptic vesicle (SV) exocytosis during low frequency stimulation. Presynaptic for also facilitates SV endocytosis during high frequency stimulation. for's effects on neurotransmission can occur independent of any changes in nerve terminal growth. However, it remains unclear if for's effects on neurotransmission affect nerve terminal growth. Furthermore, it's possible that for's effects on synaptic structure contribute to changes in neurotransmission. In the present study, we examined these questions using RNA interference to selectively knockdown for in presynaptic neurons or glia at the Drosophila larval nmj. Consistent with our previous findings, presynaptic knockdown of for impaired SV endocytosis, whereas knockdown of glial for had no effect on SV endocytosis. Surprisingly, we found that knockdown of either presynaptic or glial for increased neurotransmitter release in response to low frequency stimulation. Knockdown of presynaptic for did not affect nerve terminal growth, demonstrating that for's effects on neurotransmission does not alter nerve terminal growth. In contrast, knockdown of glial for enhanced nerve terminal growth. This enhanced nerve terminal growth was likely the cause of the enhanced neurotransmitter release seen following knockdown of glial for. Overall, we show that for can affect neurotransmitter release by regulating both synaptic structure and function.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/fisiologia , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/fisiologia , Junção Neuromuscular/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais
9.
Fly (Austin) ; 15(1): 47-59, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33704003

RESUMO

Evolved metabolic thriftiness in humans is a proposed contributor to the obesity epidemic. Insect models have been shown to evolve both 'metabolic thrift' in response to rearing on high-protein diets that promote leanness, and 'obesity resistance' when reared on fattening high-carbohydrate, low-protein foods. Despite the hypothesis that human obesity is caused by evolved metabolic thrift, genetic contributions to this physiological trait remain elusive. Here we conducted a pilot study to determine whether thrift and obesity resistance can arise under laboratory based 'quasi-natural selection' in the genetic model organism Drosophila melanogaster. We found that both these traits can evolve within 16 generations. Contrary to predictions from the 'thrifty genotype/phenotype' hypothesis, we found that when animals from a metabolic thrift inducing high-protein environment are mismatched to fattening high-carbohydrate foods, they did not become 'obese'. Rather, they accumulate less triglyceride than control animals, not more. We speculate that this may arise through as yet un-quantified parental effects - potentially epigenetic. This study establishes that D. melanogaster could be a useful model for elucidating the role of the trans- and inter-generational effects of diet on the genetics of metabolic traits in higher animals.


Assuntos
Modelos Animais de Doenças , Drosophila melanogaster/genética , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Obesidade/genética , Adaptação Fisiológica/genética , Ração Animal/análise , Animais , Evolução Biológica , Epigenômica , Projetos Piloto , Seleção Genética
10.
Proc Natl Acad Sci U S A ; 117(38): 23235-23241, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32967067

RESUMO

A now substantial body of science implicates a dynamic interplay between genetic and environmental variation in the development of individual differences in behavior and health. Such outcomes are affected by molecular, often epigenetic, processes involving gene-environment (G-E) interplay that can influence gene expression. Early environments with exposures to poverty, chronic adversities, and acutely stressful events have been linked to maladaptive development and compromised health and behavior. Genetic differences can impart either enhanced or blunted susceptibility to the effects of such pathogenic environments. However, largely missing from present discourse regarding G-E interplay is the role of time, a "third factor" guiding the emergence of complex developmental endpoints across different scales of time. Trajectories of development increasingly appear best accounted for by a complex, dynamic interchange among the highly linked elements of genes, contexts, and time at multiple scales, including neurobiological (minutes to milliseconds), genomic (hours to minutes), developmental (years and months), and evolutionary (centuries and millennia) time. This special issue of PNAS thus explores time and timing among G-E transactions: The importance of timing and timescales in plasticity and critical periods of brain development; epigenetics and the molecular underpinnings of biologically embedded experience; the encoding of experience across time and biological levels of organization; and gene-regulatory networks in behavior and development and their linkages to neuronal networks. Taken together, the collection of papers offers perspectives on how G-E interplay operates contingently within and against a backdrop of time and timescales.


Assuntos
Interação Gene-Ambiente , Animais , Evolução Biológica , Epigênese Genética , Regulação da Expressão Gênica , Humanos , Tempo
11.
Proc Natl Acad Sci U S A ; 117(38): 23270-23279, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32661177

RESUMO

Neuronal networks are the standard heuristic model today for describing brain activity associated with animal behavior. Recent studies have revealed an extensive role for a completely distinct layer of networked activities in the brain-the gene regulatory network (GRN)-that orchestrates expression levels of hundreds to thousands of genes in a behavior-related manner. We examine emerging insights into the relationships between these two types of networks and discuss their interplay in spatial as well as temporal dimensions, across multiple scales of organization. We discuss properties expected of behavior-related GRNs by drawing inspiration from the rich literature on GRNs related to animal development, comparing and contrasting these two broad classes of GRNs as they relate to their respective phenotypic manifestations. Developmental GRNs also represent a third layer of network biology, playing out over a third timescale, which is believed to play a crucial mediatory role between neuronal networks and behavioral GRNs. We end with a special emphasis on social behavior, discuss whether unique GRN organization and cis-regulatory architecture underlies this special class of behavior, and review literature that suggests an affirmative answer.


Assuntos
Comportamento , Encéfalo/fisiologia , Redes Reguladoras de Genes , Animais , Encéfalo/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Humanos
13.
Proc Natl Acad Sci U S A ; 117(38): 23286-23291, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-31213548

RESUMO

Painful or threatening experiences trigger escape responses that are guided by nociceptive neuronal circuitry. Although some components of this circuitry are known and conserved across animals, how this circuitry is regulated at the genetic and developmental levels is mostly unknown. To escape noxious stimuli, such as parasitoid wasp attacks, Drosophila melanogaster larvae generate a curling and rolling response. Rover and sitter allelic variants of the Drosophila foraging (for) gene differ in parasitoid wasp susceptibility, suggesting a link between for and nociception. By optogenetically activating cells associated with each of for's promoters (pr1-pr4), we show that pr1 cells regulate larval escape behavior. In accordance with rover and sitter differences in parasitoid wasp susceptibility, we found that rovers have higher pr1 expression and increased sensitivity to nociception relative to sitters. The for null mutants display impaired responses to thermal nociception, which are rescued by restoring for expression in pr1 cells. Conversely, knockdown of for in pr1 cells phenocopies the for null mutant. To gain insight into the circuitry underlying this response, we used an intersectional approach and activity-dependent GFP reconstitution across synaptic partners (GRASP) to show that pr1 cells in the ventral nerve cord (VNC) are required for the nociceptive response, and that multidendritic sensory nociceptive neurons synapse onto pr1 neurons in the VNC. Finally, we show that activation of the pr1 circuit during development suppresses the escape response. Our data demonstrate a role of for in larval nociceptive behavior. This function is specific to for pr1 neurons in the VNC, guiding a developmentally plastic escape response circuit.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Reação de Fuga , Larva/crescimento & desenvolvimento , Nociceptores/metabolismo , Animais , Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Temperatura Alta , Larva/genética , Larva/fisiologia , Plasticidade Neuronal , Nociceptividade , Regiões Promotoras Genéticas , Vespas/fisiologia
15.
Proc Natl Acad Sci U S A ; 117(38): 23261-23269, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-31624126

RESUMO

Biological embedding occurs when life experience alters biological processes to affect later life health and well-being. Although extensive correlative data exist supporting the notion that epigenetic mechanisms such as DNA methylation underlie biological embedding, causal data are lacking. We describe specific epigenetic mechanisms and their potential roles in the biological embedding of experience. We also consider the nuanced relationships between the genome, the epigenome, and gene expression. Our ability to connect biological embedding to the epigenetic landscape in its complexity is challenging and complicated by the influence of multiple factors. These include cell type, age, the timing of experience, sex, and DNA sequence. Recent advances in molecular profiling and epigenome editing, combined with the use of comparative animal and human longitudinal studies, should enable this field to transition from correlative to causal analyses.


Assuntos
Epigênese Genética , Animais , Metilação de DNA , Epigenômica , Interação Gene-Ambiente , Humanos
16.
Annu Rev Genet ; 53: 373-392, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31487469

RESUMO

The Drosophila melanogaster foraging (for) gene is a well-established example of a gene with major effects on behavior and natural variation. This gene is best known for underlying the behavioral strategies of rover and sitter foraging larvae, having been mapped and named for this phenotype. Nevertheless, in the last three decades an extensive array of studies describing for's role as a modifier of behavior in a wide range of phenotypes, in both Drosophila and other organisms, has emerged. Furthermore, recent work reveals new insights into the genetic and molecular underpinnings of how for affects these phenotypes. In this article, we discuss the history of the for gene and its role in natural variation in behavior, plasticity, and behavioral pleiotropy, with special attention to recent findings on the molecular structure and transcriptional regulation of this gene.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/fisiologia , Comportamento Alimentar/fisiologia , Interação Gene-Ambiente , Pleiotropia Genética , Animais , Formigas/fisiologia , Drosophila melanogaster/genética , Larva/fisiologia , Memória/fisiologia , Sono/genética , Sono/fisiologia , Comportamento Social , Termotolerância/fisiologia
18.
J Cell Sci ; 132(7)2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837290

RESUMO

Sustained neurotransmission requires the tight coupling of synaptic vesicle (SV) exocytosis and endocytosis. The mechanisms underlying this coupling are poorly understood. We tested the hypothesis that a cGMP-dependent protein kinase (PKG), encoded by the foraging (for) gene in Drosophila melanogaster, is critical for this process using a for null mutant, genomic rescues and tissue-specific rescues. We uncoupled the exocytic and endocytic functions of FOR in neurotransmission using a temperature-sensitive shibire mutant in conjunction with fluorescein-assisted light inactivation of FOR. We discovered a dual role for presynaptic FOR, in which FOR inhibits SV exocytosis during low-frequency stimulation by negatively regulating presynaptic Ca2+ levels and maintains neurotransmission during high-frequency stimulation by facilitating SV endocytosis. Additionally, glial FOR negatively regulated nerve terminal growth through TGF-ß signalling, and this developmental effect was independent of the effects of FOR on neurotransmission. Overall, FOR plays a critical role in coupling SV exocytosis and endocytosis, thereby balancing these two components to maintain sustained neurotransmission.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Proteínas de Drosophila/metabolismo , Junção Neuromuscular/metabolismo , Transmissão Sináptica , Vesículas Sinápticas/metabolismo , Animais , Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas de Drosophila/genética , Drosophila melanogaster , Endocitose , Exocitose , Mutação , Terminações Pré-Sinápticas/metabolismo , Transdução de Sinais , Vesículas Sinápticas/genética , Fator de Crescimento Transformador beta/metabolismo
19.
Proc Natl Acad Sci U S A ; 116(10): 4434-4439, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30782798

RESUMO

Foraging is a goal-directed behavior that balances the need to explore the environment for resources with the need to exploit those resources. In Drosophila melanogaster, distinct phenotypes have been observed in relation to the foraging gene (for), labeled the rover and sitter. Adult rovers explore their environs more extensively than do adult sitters. We explored whether this distinction would be conserved in humans. We made use of a distinction from regulatory mode theory between those who "get on with it," so-called locomotors, and those who prefer to ensure they "do the right thing," so-called assessors. In this logic, rovers and locomotors share similarities in goal pursuit, as do sitters and assessors. We showed that genetic variation in PRKG1, the human ortholog of for, is associated with preferential adoption of a specific regulatory mode. Next, participants performed a foraging task to see whether genetic differences associated with distinct regulatory modes would be associated with distinct goal pursuit patterns. Assessors tended to hug the boundary of the foraging environment, much like behaviors seen in Drosophila adult sitters. In a patchy foraging environment, assessors adopted more cautious search strategies maximizing exploitation. These results show that distinct patterns of goal pursuit are associated with particular genotypes of PRKG1, the human ortholog of for.


Assuntos
Proteína Quinase Dependente de GMP Cíclico Tipo I/genética , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Variação Genética , Adolescente , Adulto , Animais , Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Feminino , Humanos , Masculino
20.
Neuron ; 101(3): 370-374, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30731060

RESUMO

Building on Canada's strong traditions in neuroscience and ethics, neuroethics provides a backbone for the evolving Canadian Brain Research Strategy (CBRS) that, from the outset, incorporates ethically responsible discoveries in brain science into clinical, societal, educational, and commercial innovation.


Assuntos
Neurologia/ética , Neurociências/ética , Psiquiatria/ética , Canadá , Humanos , Neurologia/normas , Neurociências/normas , Guias de Prática Clínica como Assunto , Psiquiatria/normas
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