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1.
Cureus ; 15(8): e44070, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37638261

RESUMO

Eyebrow micropigmentation, also known as eyebrow microblading or embroidery, is a new technique in the field of semi-permanent cosmetics that are used for therapeutic and aesthetic purposes to recreate eyebrow structure and definition. It uses synthetic pigment that is deposited through fine needles into the papillary dermis and remains till the body metabolizes the pigment and clinically fades away by 12-18 months. Similar to other tattooing procedures, microblading involves risks including local inflammation, infection, allergic contact dermatitis, and granulomatous reactions that can occur from months to years after the procedure. We describe herein a case of a 49-year-old female who has persistent erythematous and indurated plaques on both eyebrows after a microblading procedure performed over a year and a half prior to her initial visit.

2.
J Int Bus Stud ; : 1-18, 2022 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-36531905

RESUMO

Africa is rising, but IB scholars have largely failed to take notice. We argue that this is a missed opportunity. Not only is Africa a dynamic and distinctive region, but its rise presents a number of puzzles for international business (IB) research, with phenomena that seem to challenge fundamental assumptions underlying IB theories. In order to unravel these puzzles and better explain business dynamics on the continent, we contend that there is a need for IB theorizing to place greater emphasis on the role of people, to balance IB's traditional emphasis on institutions, location-specific assets, and other macro-level attributes. We explore how this conceptual shift presents new avenues for inquiry into issues that are of importance for IB but have received limited attention to date. Such issues include entrepreneurial human capital, social networks, institutional co-evolution, and the informal economy. As such, we argue that, while extant theories in IB inform explanations and predictions regarding business activity across the continent, Africa's diverse and distinctive characteristics offer the potential to serve as a context for testing and developing generalizable, cutting-edge IB theory. Supplementary Information: The online version contains supplementary material available at 10.1057/s41267-022-00581-z.


L'Afrique est en plein essor, mais les chercheurs en affaires internationales (International Business­IB) n'ont pas réussi à en tenir compte. Nous argumentons qu'il s'agit là d'une occasion manquée. Non seulement l'Afrique est une région dynamique et distincte, mais son essor présente un certain nombre d'énigmes pour la recherche en IB, avec des phénomènes susceptibles de remettre en question les postulats fondamentaux sous-tendant les théories de l'IB. Afin d'élucider ces énigmes et de mieux expliquer la dynamique des affaires sur le continent, nous soutenons qu'il est nécessaire que la conception théorique en IB mette davantage l'accent sur le rôle de l'homme, pour contrebalancer l'importance traditionnelle accordée par l'IB aux institutions, aux actifs spécifiques localisés et à d'autres attributs au niveau macro. Nous explorons comment cette mutation conceptuelle ouvre de nouvelles voies d'investigation sur des questions qui ont de l'importance pour l'IB, mais n'ont pourtant reçu qu'une attention limitée jusqu'à présent. Ces questions comportent le capital humain entrepreneurial, les réseaux sociaux, la co-évolution institutionnelle et l'économie informelle. À ce titre, nous argumentons que, si les théories existantes de l'IB permettent d'expliquer et de prédire les affaires des entreprises sur le continent, les caractéristiques diverses et distinctives de l'Afrique offrent la possibilité d'utiliser celles-ci en tant que contexte pour tester et développer une théorie de l'IB généralisable et avant-gardiste.


África está en ascenso, pero los académicos de negocios internacionales no se han dado por enterados. Nosotros sostenemos que se trata de una oportunidad perdida. África no sólo es una región dinámica y distintiva, sino que su auge presenta una serie de rompecabezas para la investigación de los negocios internacionales, con fenómenos que parecen desafiar los supuestos fundamentales en los que se basan las teorías de los negocios internacionales. Para desentrañar estos rompecabezas y explicar mejor la dinámica empresarial en el continente, sostenemos que es necesario que la teoría de los negocios internacionales haga más hincapié en el papel de las personas, para equilibrar el énfasis tradicional de los negocios internacionales en las instituciones, los activos específicos de la ubicación y otros atributos a nivel macro. Exploramos cómo este cambio conceptual presenta nuevas vías de investigación sobre cuestiones que son importantes para negocios internacionales pero que han recibido poca atención hasta la fecha. Entre estas cuestiones se encuentran el capital humano empresarial, las redes sociales, la coevolución institucional y la economía informal. En este sentido, sostenemos que, si bien las teorías existentes de negocios internacionales informan sobre las explicaciones y predicciones relativas a la actividad empresarial en todo el continente, las características diversas y distintivas de África ofrecen el potencial de servir como contexto para poner a prueba y desarrollar una teoría de negocios internacionales generalizable y de vanguardia.


A África está crescendo, mas estudiosos de IB majoritariamente não perceberam. Argumentamos que esta é uma oportunidade perdida. A África não é apenas uma região dinâmica e distinta, mas sua ascensão apresenta uma série de enigmas para a pesquisa em negócios internacionais (IB), com fenômenos que parecem desafiar pressupostos fundamentais subjacentes a teorias de IB. A fim de desvendar esses enigmas e explicar melhor a dinâmica dos negócios no continente, afirmamos que é necessário que a teorização em IB dedique maior ênfase no papel de pessoas para equilibrar a ênfase tradicional de IB em instituições, ativos de localização específica e outros atributos de nível macro. Exploramos como essa mudança conceitual apresenta novos caminhos para a investigação de questões relevantes para IB, mas que receberam atenção limitada até o momento. Tais questões incluem capital humano empreendedor, redes sociais, coevolução institucional e economia informal. De tal forma, argumentamos que, embora teorias existentes em IB forneçam explicações e previsões sobre a atividade empresarial em todo o continente, características diversas e distintas da África ofereçam o potencial para servir como um contexto para testar e desenvolver teorias generalizáveis e de ponta em IB.

3.
Proc Natl Acad Sci U S A ; 117(26): 15221-15229, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32546524

RESUMO

The balance between proliferation and differentiation of stem cells and progenitors determines the size of an adult brain region. While the molecular mechanisms regulating proliferation and differentiation of cortical progenitors have been intensively studied, an analysis of the kinetics of progenitor choice between self-renewal and differentiation in vivo is, due to the technical difficulties, still unknown. Here we established a descriptive mathematical model to estimate the probability of self-renewal or differentiation of cortical progenitor behaviors in vivo, a variable we have termed the expansion coefficient. We have applied the model, one which depends only on experimentally measured parameters, to the developing mouse cortex where the expansive neuroepithelial cells and neurogenic radial glial progenitors are coexisting. Surprisingly, we found that the expansion coefficients of both neuroepithelium cells and radial glial progenitors follow the same developmental trajectory during cortical development, suggesting a common rule governing self-renewal/differentiation behaviors in mouse cortical progenitor differentiation.


Assuntos
Diferenciação Celular/fisiologia , Córtex Cerebral/citologia , Modelos Biológicos , Células-Tronco Neurais/fisiologia , Animais , Ciclo Celular/fisiologia , Feminino , Camundongos , Camundongos Endogâmicos ICR
4.
Curr Biol ; 29(15): 2533-2540.e7, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31327712

RESUMO

Identifying shared quantitative features of a neural circuit across species is important for 3 reasons. Often expressed in the form of power laws and called scaling relationships [1, 2], they reveal organizational principles of circuits, make insights gleaned from model systems widely applicable, and explain circuit performance and function, e.g., visual circuits [3, 4]. The visual circuit is topographic [5, 6], wherein retinal neurons target and activate predictable spatial loci in primary visual cortex. The brain, however, contains many circuits, where neuronal targets and activity are unpredictable and distributed throughout the circuit, e.g., olfactory circuits, in which glomeruli (or mitral cells) in the olfactory bulb synapse with neurons distributed throughout the piriform cortex [7-10]. It is unknown whether such circuits, which we term distributed circuits, are scalable. To determine whether distributed circuits scale, we obtained quantitative descriptions of the olfactory bulb and piriform cortex in six mammals using stereology techniques and light microscopy. Two conserved features provide evidence of scalability. First, the number of piriform neurons n and bulb glomeruli g scale as n∼g3/2. Second, the average number of synapses between a bulb glomerulus and piriform neuron is invariant at one. Using theory and modeling, we show that these two features preserve the discriminatory ability and precision of odor information across the olfactory circuit. As both abilities depend on circuit size, manipulating size provides evolution with a way to adapt a species to its niche without designing developmental programs de novo. These principles might apply to other distributed circuits like the hippocampus.


Assuntos
Bulbo Olfatório/fisiologia , Condutos Olfatórios/fisiologia , Córtex Piriforme/fisiologia , Animais , Gatos/fisiologia , Furões/fisiologia , Cobaias/fisiologia , Camundongos/fisiologia , Monodelphis/fisiologia , Neurônios/fisiologia , Ratos/fisiologia , Sinapses/fisiologia
5.
Proc Natl Acad Sci U S A ; 116(14): 6969-6974, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30886088

RESUMO

Sudden unexpected death of an infant (SUDI) is a devastating occurrence for families. To investigate the genetic pathogenesis of SUDI, we sequenced >70 genes from 191 autopsy-negative SUDI victims. Ten infants sharing a previously unknown variant in troponin I (TnI) were identified. The mutation (TNNI1 R37C+/-) is in the fetal/neonatal paralog of TnI, a gene thought to be expressed in the heart up to the first 24 months of life. Using phylogenetic analysis and molecular dynamics simulations, it was determined that arginine at residue 37 in TNNI1 may play a critical functional role, suggesting that the variant may be pathogenic. We investigated the biophysical properties of the TNNI1 R37C mutation in human reconstituted thin filaments (RTFs) using fluorometry. RTFs reconstituted with the mutant R37C TnI exhibited reduced Ca2+-binding sensitivity due to an increased Ca2+ off-rate constant. Furthermore, we generated TNNI1 R37C+/- mutants in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) using CRISPR-Cas9. In monolayers of hiPSC-CMs, we simultaneously monitored voltage and Ca2+ transients through optical mapping and compared them to their isogenic controls. We observed normal intrinsic beating patterns under control conditions in TNNI1 R37C+/- at stimulation frequencies of 55 beats/min (bpm), but these cells showed no restitution with increased stimulation frequency to 65 bpm and exhibited alternans at >75 bpm. The WT hiPSC-CMs did not exhibit any sign of arrhythmogenicity even at stimulation frequencies of 120 bpm. The approach used in this study provides critical physiological and mechanistic bases to investigate sarcomeric mutations in the pathogenesis of SUDI.


Assuntos
Células-Tronco Pluripotentes Induzidas/metabolismo , Simulação de Dinâmica Molecular , Mutação de Sentido Incorreto , Miócitos Cardíacos/metabolismo , Morte Súbita do Lactente/genética , Troponina I , Cálcio/química , Cálcio/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Recém-Nascido , Contração Miocárdica/genética , Miócitos Cardíacos/patologia , Sarcômeros/genética , Sarcômeros/metabolismo , Sarcômeros/patologia , Morte Súbita do Lactente/patologia , Troponina I/química , Troponina I/genética , Troponina I/metabolismo
6.
Proc Natl Acad Sci U S A ; 115(51): 13093-13098, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30509984

RESUMO

Novelty detection is a fundamental biological problem that organisms must solve to determine whether a given stimulus departs from those previously experienced. In computer science, this problem is solved efficiently using a data structure called a Bloom filter. We found that the fruit fly olfactory circuit evolved a variant of a Bloom filter to assess the novelty of odors. Compared with a traditional Bloom filter, the fly adjusts novelty responses based on two additional features: the similarity of an odor to previously experienced odors and the time elapsed since the odor was last experienced. We elaborate and validate a framework to predict novelty responses of fruit flies to given pairs of odors. We also translate insights from the fly circuit to develop a class of distance- and time-sensitive Bloom filters that outperform prior filters when evaluated on several biological and computational datasets. Overall, our work illuminates the algorithmic basis of an important neurobiological problem and offers strategies for novelty detection in computational systems.


Assuntos
Algoritmos , Drosophila/fisiologia , Redes Neurais de Computação , Odorantes , Condutos Olfatórios , Animais , Modelos Biológicos , Rede Nervosa
7.
J Neurosci ; 38(34): 7365-7374, 2018 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-30006366

RESUMO

Animals successfully thrive in noisy environments with finite resources. The necessity to function with resource constraints has led evolution to design animal brains (and bodies) to be optimal in their use of computational power while being adaptable to their environmental niche. A key process undergirding this ability to adapt is the process of learning. Although a complete characterization of the neural basis of learning remains ongoing, scientists for nearly a century have used the brain as inspiration to design artificial neural networks capable of learning, a case in point being deep learning. In this viewpoint, we advocate that deep learning can be further enhanced by incorporating and tightly integrating five fundamental principles of neural circuit design and function: optimizing the system to environmental need and making it robust to environmental noise, customizing learning to context, modularizing the system, learning without supervision, and learning using reinforcement strategies. We illustrate how animals integrate these learning principles using the fruit fly olfactory learning circuit, one of nature's best-characterized and highly optimized schemes for learning. Incorporating these principles may not just improve deep learning but also expose common computational constraints. With judicious use, deep learning can become yet another effective tool to understand how and why brains are designed the way they are.


Assuntos
Aprendizado Profundo , Modelos Neurológicos , Vias Aferentes/fisiologia , Animais , Aprendizagem por Associação/fisiologia , Aprendizagem da Esquiva/fisiologia , Condicionamento Clássico/fisiologia , Condicionamento Operante/fisiologia , Drosophila melanogaster/fisiologia , Meio Ambiente , Corpos Pedunculados/fisiologia , Rede Nervosa/fisiologia , Neurópilo/fisiologia , Odorantes , Percepção Olfatória/fisiologia , Neurônios Receptores Olfatórios/fisiologia , Reforço Psicológico , Recompensa , Detecção de Sinal Psicológico/fisiologia , Razão Sinal-Ruído , Sinapses/fisiologia
8.
J Comp Neurol ; 526(17): 2725-2743, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30014545

RESUMO

Distributed circuits wherein connections between subcircuit components seem randomly distributed are common to the olfactory circuit, hippocampus, and cerebellum. In such circuits, activation patterns seem random too, showing no detectable spatial preference, and contrast with regions that have topographic connections between subcircuits and topographic activation patterns. Quantitative studies of topographic circuits in the neocortex have yielded common principles of organization. Whether distributed circuits share similar principles of organization is unknown because similar quantitative information is missing and understanding the way they encode information remains a challenge. We addressed these needs by providing a quantitative description of the mouse piriform cortex, a paleocortical distributed circuit that subserves olfaction. The quantitative information provided two insights. First, with a nearly parameter-free model of the olfactory circuit, we show that the piriform cortex robustly maintains odor information and discrimination ability present in the olfactory bulb. Second, the paleocortex is quantitatively different from the neocortex: it has a lower surface area density, which decreases from the anterior to posterior paleocortex contrasting with the uniform neuronal density of the neocortex. These insights might also apply to other distributed circuits.


Assuntos
Discriminação Psicológica/fisiologia , Condutos Olfatórios/fisiologia , Percepção Olfatória/fisiologia , Córtex Piriforme/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neocórtex/fisiologia , Neurônios/fisiologia , Odorantes , Bulbo Olfatório/citologia , Bulbo Olfatório/fisiologia , Condutos Olfatórios/citologia , Córtex Piriforme/citologia , Sinapses/fisiologia
9.
Proc Natl Acad Sci U S A ; 115(3): 584-588, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29295918

RESUMO

A recent paper demonstrated that the pattern of firing rates across ∼100 neurons in the anterior medial face patch is closely related to which human face (of 2,000) had been presented to a monkey [Chang L, Tsao DY (2017) Cell 169:1013-1028]. In addition, the firing rates for these neurons can be predicted for a novel human face. Although it is clear from this work that the firing rates of these face patch neurons encode faces, the properties of the face code have not yet been fully described. Based on an analysis of 98 neurons responding to 2,000 faces, I conclude that the anterior medial face patch uses a combinatorial rate code, one with an exponential distribution of neuron rates that has a mean rate conserved across faces. Thus, the face code is maximally informative (technically, maximum entropy) and is very similar to the code used by the fruit fly olfactory system.


Assuntos
Face , Neurônios/fisiologia , Reconhecimento Visual de Modelos , Animais , Humanos , Modelos Neurológicos , Neurônios/química , Córtex Visual/fisiologia
10.
Science ; 358(6364): 793-796, 2017 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-29123069

RESUMO

Similarity search-for example, identifying similar images in a database or similar documents on the web-is a fundamental computing problem faced by large-scale information retrieval systems. We discovered that the fruit fly olfactory circuit solves this problem with a variant of a computer science algorithm (called locality-sensitive hashing). The fly circuit assigns similar neural activity patterns to similar odors, so that behaviors learned from one odor can be applied when a similar odor is experienced. The fly algorithm, however, uses three computational strategies that depart from traditional approaches. These strategies can be translated to improve the performance of computational similarity searches. This perspective helps illuminate the logic supporting an important sensory function and provides a conceptually new algorithm for solving a fundamental computational problem.


Assuntos
Algoritmos , Drosophila , Rede Nervosa , Redes Neurais de Computação , Córtex Olfatório , Olfato , Animais , Odorantes
11.
Circ Cardiovasc Genet ; 10(4)2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28807990

RESUMO

BACKGROUND: Inherited arrhythmia syndromes are responsible for a significant portion of autopsy-negative sudden unexpected death (SUD) cases, but molecular autopsy used to identify potentially causal variants is not routinely included in SUD investigations. We collaborated with a medical examiner's office to assist in finding a diagnosis for their autopsy-negative child SUD cases. METHODS AND RESULTS: 191 child SUD cases (<5 years of age) were selected for analyses. Our next generation sequencing panel incorporated 38 inherited arrhythmia syndrome candidate genes and another 33 genes not previously investigated for variants that may underlie SUDY pathophysiology. Overall, we identified 11 potentially causal disease-associated variants in 12 cases, for an overall yield of 6.3%. We also identified 31 variants of uncertain significance in 36 cases and 16 novel variants predicted to be pathogenic in silico in 15 cases. The disease-associated variants were reported to the medical examiner to notify surviving relatives and recommend clinical assessment. CONCLUSIONS: We have identified variants that may assist in the diagnosis of at least 6.3% of autopsy-negative child SUD cases and reduce risk of future SUD in surviving relatives. We recommend a cautious approach to variant interpretation. We also suggest inclusion of cardiomyopathy genes as well as other candidate SUD genes in molecular autopsy analyses.


Assuntos
Arritmias Cardíacas/genética , Morte Súbita Cardíaca/patologia , Arritmias Cardíacas/diagnóstico , Pré-Escolar , Estudos de Coortes , DNA/química , DNA/isolamento & purificação , DNA/metabolismo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Placofilinas/genética , Análise de Sequência de DNA , Trocador de Sódio e Cálcio/genética , Troponina I/genética
12.
Curr Biol ; 27(14): 2078-2088.e3, 2017 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-28690115

RESUMO

Plant architectures can be characterized statistically by their spatial density function, which specifies the probability of finding a branch at each location in the territory occupied by a plant. Using high-precision 3D scanning, we analyzed 557 plant shoot architectures, representing three species, grown across three to five environmental conditions, and through 20-30 developmental time points. We found two elegant properties in the spatial density functions of these architectures: all functions could be nearly modified in one direction without affecting the density in orthogonal directions (called "separability"), and all functions shared the same underlying shape, aside from stretching and compression (called "self-similarity"). Surprisingly, despite their striking visual diversity, we discovered that all architectures could be described as variations on a single underlying function: a Gaussian density function truncated at roughly two SDs. We also observed systematic variation in the spatial density functions across species, growth conditions, and time, which suggests functional specialization despite following the same general design form.


Assuntos
Nicotiana/crescimento & desenvolvimento , Brotos de Planta/crescimento & desenvolvimento , Solanum lycopersicum/crescimento & desenvolvimento , Sorghum/crescimento & desenvolvimento , Imageamento Tridimensional
13.
J Biol Chem ; 292(28): 11915-11926, 2017 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-28533433

RESUMO

Cardiac troponin C (cTnC) is the regulatory protein that initiates cardiac contraction in response to Ca2+ TnC binding Ca2+ initiates a cascade of protein-protein interactions that begins with the opening of the N-terminal domain of cTnC, followed by cTnC binding the troponin I switch peptide (TnISW). We have evaluated, through isothermal titration calorimetry and molecular-dynamics simulation, the effect of several clinically relevant mutations (A8V, L29Q, A31S, L48Q, Q50R, and C84Y) on the Ca2+ affinity, structural dynamics, and calculated interaction strengths between cTnC and each of Ca2+ and TnISW Surprisingly the Ca2+ affinity measured by isothermal titration calorimetry was only significantly affected by half of these mutations including L48Q, which had a 10-fold higher affinity than WT, and the Q50R and C84Y mutants, each of which had affinities 3-fold higher than wild type. This suggests that Ca2+ affinity of the N-terminal domain of cTnC in isolation is insufficient to explain the pathogenicity of these mutations. Molecular-dynamics simulation was used to evaluate the effects of these mutations on Ca2+ binding, structural dynamics, and TnI interaction independently. Many of the mutations had a pronounced effect on the balance between the open and closed conformations of the TnC molecule, which provides an indirect mechanism for their pathogenic properties. Our data demonstrate that the structural dynamics of the cTnC molecule are key in determining myofilament Ca2+ sensitivity. Our data further suggest that modulation of the structural dynamics is the underlying molecular mechanism for many disease mutations that are far from the regulatory Ca2+-binding site of cTnC.


Assuntos
Sinalização do Cálcio , Cardiomiopatia Hipertrófica Familiar/genética , Cardiomiopatia Hipertrófica/genética , Modelos Moleculares , Mutação , Troponina C/metabolismo , Troponina I/metabolismo , Substituição de Aminoácidos , Sítios de Ligação , Calorimetria , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica Familiar/metabolismo , Transferência de Energia , Humanos , Cinética , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Redobramento de Proteína , Estabilidade Proteica , Desdobramento de Proteína , Proteínas Recombinantes/metabolismo , Titulometria , Troponina C/antagonistas & inibidores , Troponina C/química , Troponina C/genética , Troponina I/química
14.
Rev Physiol Biochem Pharmacol ; 171: 99-136, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27538987

RESUMO

Zebrafish (Danio rerio) are widely used as vertebrate model in developmental genetics and functional genomics as well as in cardiac structure-function studies. The zebrafish heart has been increasingly used as a model of human cardiac function, in part, due to the similarities in heart rate and action potential duration and morphology with respect to humans. The teleostian zebrafish is in many ways a compelling model of human cardiac function due to the clarity afforded by its ease of genetic manipulation, the wealth of developmental biological information, and inherent suitability to a variety of experimental techniques. However, in addition to the numerous advantages of the zebrafish system are also caveats related to gene duplication (resulting in paralogs not present in human or other mammals) and fundamental differences in how zebrafish hearts function. In this review, we discuss the use of zebrafish as a cardiac function model through the use of techniques such as echocardiography, optical mapping, electrocardiography, molecular investigations of excitation-contraction coupling, and their physiological implications relative to that of the human heart. While some of these techniques (e.g., echocardiography) are particularly challenging in the zebrafish because of diminutive size of the heart (~1.5 mm in diameter) critical information can be derived from these approaches and are discussed in detail in this article.


Assuntos
Coração/fisiologia , Modelos Animais , Peixe-Zebra/fisiologia , Potenciais de Ação/fisiologia , Animais , Ecoencefalografia , Eletrocardiografia , Acoplamento Excitação-Contração/fisiologia , Coração/anatomia & histologia , Coração/inervação , Sistema de Condução Cardíaco/fisiologia , Frequência Cardíaca/fisiologia , Humanos , Miócitos Cardíacos/fisiologia , Imagens com Corantes Sensíveis à Voltagem , Peixe-Zebra/genética
15.
Biophys J ; 111(1): 38-49, 2016 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-27410732

RESUMO

Zebrafish, as a model for teleost fish, have two paralogous troponin C (TnC) genes that are expressed in the heart differentially in response to temperature acclimation. Upon Ca(2+) binding, TnC changes conformation and exposes a hydrophobic patch that interacts with troponin I and initiates cardiac muscle contraction. Teleost-specific TnC paralogs have not yet been functionally characterized. In this study we have modeled the structures of the paralogs using molecular dynamics simulations at 18°C and 28°C and calculated the different Ca(2+)-binding properties between the teleost cardiac (cTnC or TnC1a) and slow-skeletal (ssTnC or TnC1b) paralogs through potential-of-mean-force calculations. These values are compared with thermodynamic binding properties obtained through isothermal titration calorimetry (ITC). The modeled structures of each of the paralogs are similar at each temperature, with the exception of helix C, which flanks the Ca(2+) binding site; this region is also home to paralog-specific sequence substitutions that we predict have an influence on protein function. The short timescale of the potential-of-mean-force calculation precludes the inclusion of the conformational change on the ΔG of Ca(2+) interaction, whereas the ITC analysis includes the Ca(2+) binding and conformational change of the TnC molecule. ITC analysis has revealed that ssTnC has higher Ca(2+) affinity than cTnC for Ca(2+) overall, whereas each of the paralogs has increased affinity at 28°C compared to 18°C. Microsecond-timescale simulations have calculated that the cTnC paralog transitions from the closed to the open state more readily than the ssTnC paralog, an unfavorable transition that would decrease the ITC-derived Ca(2+) affinity while simultaneously increasing the Ca(2+) sensitivity of the myofilament. We propose that the preferential expression of cTnC at lower temperatures increases myofilament Ca(2+) sensitivity by this mechanism, despite the lower Ca(2+) affinity that we have measured by ITC.


Assuntos
Simulação de Dinâmica Molecular , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Homologia de Sequência de Aminoácidos , Troponina C/química , Troponina C/metabolismo , Peixe-Zebra , Sequência de Aminoácidos , Animais , Cálcio/metabolismo , Calorimetria , Temperatura , Proteínas de Peixe-Zebra/química , Proteínas de Peixe-Zebra/metabolismo
16.
Proc Natl Acad Sci U S A ; 113(24): 6737-42, 2016 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-27247407

RESUMO

I have reanalyzed the data presented by Hallem and Carlson [Hallem EA, Carlson JR (2006) Cell 125(1):143-160] and shown that the combinatorial odor code supplied by the fruit fly antenna is a very simple one in which nearly all odors produce, statistically, the same neuronal response; i.e., the probability distribution of sensory neuron firing rates across the population of odorant sensory neurons is an exponential for nearly all odors and odor mixtures, with the mean rate dependent on the odor concentration. Between odors, then, the response differs according to which sensory neurons are firing at what individual rates and with what mean population rate, but not in the probability distribution of firing rates. This conclusion is independent of adjustable parameters, and holds both for monomolecular odors and complex mixtures. Because the circuitry in the antennal lobe constrains the mean firing rate to be the same for all odors and concentrations, the odor code is what is known as maximum entropy.


Assuntos
Dípteros/fisiologia , Modelos Neurológicos , Odorantes , Percepção Olfatória/fisiologia , Células Receptoras Sensoriais/fisiologia , Animais , Comportamento Animal/fisiologia
17.
BMC Biol ; 14: 40, 2016 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-27197636

RESUMO

The mechanism of memory remains one of the great unsolved problems of biology. Grappling with the question more than a hundred years ago, the German zoologist Richard Semon formulated the concept of the engram, lasting connections in the brain that result from simultaneous "excitations", whose precise physical nature and consequences were out of reach of the biology of his day. Neuroscientists now have the knowledge and tools to tackle this question, however, and this Forum brings together leading contemporary views on the mechanisms of memory and what the engram means today.


Assuntos
Encéfalo/fisiologia , Memória/fisiologia , Animais , Epigenômica , Hipocampo/fisiologia , Humanos , Modelos Animais , Neurônios/fisiologia , Coluna Vertebral/fisiologia , Sinapses/fisiologia
18.
Genome Biol Evol ; 8(4): 994-1011, 2016 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-26979795

RESUMO

Gene duplication results in extra copies of genes that must coevolve with their interacting partners in multimeric protein complexes. The cardiac troponin (Tn) complex, containing TnC, TnI, and TnT, forms a distinct functional unit critical for the regulation of cardiac muscle contraction. In teleost fish, the function of the Tn complex is modified by the consequences of differential expression of paralogs in response to environmental thermal challenges. In this article, we focus on the interaction between TnI and TnC, coded for by genes that have independent evolutionary origins, but the co-operation of their protein products has necessitated coevolution. In this study, we characterize functional divergence of TnC and TnI paralogs, specifically the interrelated roles of regulatory subfunctionalization and structural subfunctionalization. We determined that differential paralog transcript expression in response to temperature acclimation results in three combinations of TnC and TnI in the zebrafish heart: TnC1a/TnI1.1, TnC1b/TnI1.1, and TnC1a/TnI1.5. Phylogenetic analysis of these highly conserved proteins identified functionally divergent residues in TnI and TnC. The structural and functional effect of these Tn combinations was modeled with molecular dynamics simulation to link divergent sites to changes in interaction strength. Functional divergence in TnI and TnC were not limited to the residues involved with TnC/TnI switch interaction, which emphasizes the complex nature of Tn function. Patterns in domain-specific divergent selection and interaction energies suggest that substitutions in the TnI switch region are crucial to modifying TnI/TnC function to maintain cardiac contraction with temperature changes. This integrative approach introduces Tn as a model of functional divergence that guides the coevolution of interacting proteins.


Assuntos
Evolução Molecular , Troponina C/genética , Troponina I/genética , Peixe-Zebra/genética , Aclimatação , Sequência de Aminoácidos , Animais , Temperatura Baixa , Perfilação da Expressão Gênica , Modelos Moleculares , Filogenia , Mapas de Interação de Proteínas , Seleção Genética , Troponina C/análise , Troponina C/metabolismo , Troponina I/análise , Troponina I/metabolismo , Peixe-Zebra/fisiologia
19.
Proc Natl Acad Sci U S A ; 112(30): 9460-5, 2015 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-26150492

RESUMO

The fly olfactory system has a three-layer architecture: The fly's olfactory receptor neurons send odor information to the first layer (the encoder) where this information is formatted as combinatorial odor code, one which is maximally informative, with the most informative neurons firing fastest. This first layer then sends the encoded odor information to the second layer (decoder), which consists of about 2,000 neurons that receive the odor information and "break" the code. For each odor, the amplitude of the synaptic odor input to the 2,000 second-layer neurons is approximately normally distributed across the population, which means that only a very small fraction of neurons receive a large input. Each odor, however, activates its own population of large-input neurons and so a small subset of the 2,000 neurons serves as a unique tag for the odor. Strong inhibition prevents most of the second-stage neurons from firing spikes, and therefore spikes from only the small population of large-input neurons is relayed to the third stage. This selected population provides the third stage (the user) with an odor label that can be used to direct behavior based on what odor is present.


Assuntos
Encéfalo/fisiologia , Neurônios/fisiologia , Percepção Olfatória/fisiologia , Olfato/fisiologia , Animais , Axônios/fisiologia , Mapeamento Encefálico , Drosophila melanogaster , Modelos Neurológicos , Odorantes , Condutos Olfatórios/fisiologia , Neurônios Receptores Olfatórios/fisiologia , Probabilidade
20.
Proc Natl Acad Sci U S A ; 112(25): 7815-20, 2015 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-26056277

RESUMO

Three decades ago, Rockel et al. proposed that neuronal surface densities (number of neurons under a square millimeter of surface) of primary visual cortices (V1s) in primates is 2.5 times higher than the neuronal density of V1s in nonprimates or many other cortical regions in primates and nonprimates. This claim has remained controversial and much debated. We replicated the study of Rockel et al. with attention to modern stereological precepts and show that indeed primate V1 is 2.5 times denser (number of neurons per square millimeter) than many other cortical regions and nonprimate V1s; we also show that V2 is 1.7 times as dense. As primate V1s are denser, they have more neurons and thus more pinwheels than similar-sized nonprimate V1s, which explains why primates have better visual acuity.


Assuntos
Acuidade Visual , Córtex Visual/anatomia & histologia , Animais , Humanos , Córtex Visual/fisiologia
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