RESUMEN
Heterogeneity plays an important role in diversifying neural responses to support brain function. Adult neurogenesis provides the dentate gyrus with a heterogeneous population of granule cells (GCs) that were born and developed their properties at different times. Immature GCs have distinct intrinsic and synaptic properties than mature GCs and are needed for correct encoding and discrimination in spatial tasks. How immature GCs enhance the encoding of information to support these functions is not well understood. Here, we record the responses to fluctuating current injections of GCs of different ages in mouse hippocampal slices to study how they encode stimuli. Immature GCs produce unreliable responses compared to mature GCs, exhibiting imprecise spike timings across repeated stimulation. We use a statistical model to describe the stimulus-response transformation performed by GCs of different ages. We fit this model to the data and obtain parameters that capture GCs' encoding properties. Parameter values from this fit reflect the maturational differences of the population and indicate that immature GCs perform a differential encoding of stimuli. To study how this age heterogeneity influences encoding by a population, we perform stimulus decoding using populations that contain GCs of different ages. We find that, despite their individual unreliability, immature GCs enhance the fidelity of the signal encoded by the population and improve the discrimination of similar time-dependent stimuli. Thus, the observed heterogeneity confers the population with enhanced encoding capabilities.
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Giro Dentado , Neuronas , Ratones , Animales , Giro Dentado/fisiología , Neuronas/fisiología , Hipocampo , Neurogénesis/fisiologíaRESUMEN
Apoptosis is a mechanism of programmed cell death in which cells engage in a controlled demolition and prepare to be digested without damaging their environment. In normal conditions, apoptosis is repressed until it is irreversibly induced by an appropriate signal. In adult organisms, apoptosis is a natural way to dispose of damaged cells and its disruption or excess is associated with cancer and autoimmune diseases. Apoptosis is regulated by a complex signaling network controlled by caspases, specialized enzymes that digest essential cellular components and promote the degradation of genomic DNA. In this work, we propose an effective description of the signaling network focused on caspase-3 as a readout of cell fate. We integrate intermediate network interactions into a nonlinear feedback function acting on caspase-3 and introduce the effect of pro-apoptotic stimuli and regulatory elements as a saturating activation function. We show that activation dynamics in the theory is similar to previously reported experimental results. We compute bifurcation diagrams and obtain cell fate maps describing how stimulus intensity and feedback strength affect cell survival and death fates. These fates overlap within a bistable region that depends on total caspase concentration, regulatory elements, and feedback nonlinearity. We study a strongly nonlinear regime to obtain analytical expressions for bifurcation curves and fate map boundaries. For a broad range of parameters, strong stimuli can induce an irreversible switch to the death fate. We use the theory to explore dynamical stimulation conditions and determine how cell fate depends on stimulation temporal patterns. This analysis predicts a critical relation between transient stimuli intensity and duration to trigger irreversible apoptosis. We derive an analytical expression for this critical relation, valid for short stimuli. Our description provides distinct predictions and offers a framework to study how this signaling network processes different stimuli to make a cell fate decision.
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Apoptosis , Modelos Biológicos , Transducción de SeñalRESUMEN
Individual biological oscillators can synchronize to generate a collective rhythm. During vertebrate development, mobile cells exchange signals to synchronize a rhythmic pattern generator that makes the embryonic segments. Previous theoretical works have shown that cell mobility can enhance synchronization of coupled oscillators when signal exchange is instantaneous. However, in vertebrate segmentation, the exchange of signals is thought to comprise delays from signal sending and processing, which could alter the effect of mobility on synchronization. Here, we study synchronization dynamics of mobile phase oscillators in the presence of coupling delays. We find that mobility can speed up synchronization when coupling delays are present. We derive an analytical expression for the characteristic time of synchronization dynamics, which is in very good agreement with numerical simulations. This analytical expression suggests a subdivision of the mobility range into different dynamical regimes and reveals that, with delayed coupling, synchronization is enhanced at a lower mobility rate than with instantaneous coupling. We argue that these results may be relevant to the synchronization of mobile oscillators in vertebrate segmentation.
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Embryonic morphogenesis is organized by an interplay between intercellular signaling and cell movements. Both intercellular signaling and cell movement involve multiple timescales. A key timescale for signaling is the time delay caused by preparation of signaling molecules and integration of received signals into cells' internal state. Movement of cells relative to their neighbors may introduce exchange of positions between cells during signaling. When cells change their relative positions in a tissue, the impact of signaling delays on intercellular signaling increases because the delayed information that cells receive may significantly differ from the present state of the tissue. The time it takes to perform a neighbor exchange sets a timescale of cell mixing that may be important for the outcome of signaling. Here we review recent theoretical work on the interplay of timescales between cell mixing and signaling delays adopting the zebrafish segmentation clock as a model system. We discuss how this interplay can lead to spatial patterns of gene expression that could disrupt the normal formation of segment boundaries in the embryo. The effect of cell mixing and signaling delays highlights the importance of theoretical and experimental frameworks to understand collective cellular behaviors arising from the interplay of multiple timescales in embryonic developmental processes.
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Movimiento Celular , Desarrollo Embrionario , Transducción de Señal , HumanosRESUMEN
PURPOSE: To describe a novel technique designed to safely and precisely deploy the Supera stent accurately at the ostium of the proximal superficial femoral artery (SFA) without compromising the profunda and common femoral arteries. TECHNIQUE: After antegrade crossing of the chronic total occlusion (CTO) at the SFA ostium and accurate predilation of the entire SFA lesion, a retrograde arterial access is obtained. The Supera stent is navigated in retrograde fashion to position the first crown to be released just at the SFA ostium. Antegrade dilation is performed across the retrograde access site to obtain adequate hemostasis. The technique has been applied successfully in 21 patients (mean age 78.1±8.2 years; 13 men) with critical limb ischemia using retrograde Supera stenting from the proximal anterior tibial artery (n=6), the posterior tibial artery (n=2), retrograde stent puncture in the mid to distal SFA (n=2), the native distal SFA/proximal popliteal segment (n=6), and the distal anterior tibial artery (n=5). No complications were observed. CONCLUSION: Distal retrograde Supera stent passage and reverse deployment allow precise and safe Supera stenting at the SFA ostium.
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Angioplastia de Balón/instrumentación , Arteria Femoral , Isquemia/terapia , Enfermedad Arterial Periférica/terapia , Stents , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Constricción Patológica , Costa Rica , Enfermedad Crítica , Femenino , Arteria Femoral/diagnóstico por imagen , Humanos , Isquemia/diagnóstico por imagen , Italia , Masculino , Enfermedad Arterial Periférica/diagnóstico por imagen , Diseño de Prótesis , Resultado del Tratamiento , Estados UnidosRESUMEN
Cells may control fluctuations in protein levels by means of negative autoregulation, where transcription factors bind DNA sites to repress their own production. Theoretical studies have assumed a single binding site for the repressor, while in most species it is found that multiple binding sites are arranged in clusters. We study a stochastic description of negative autoregulation with multiple binding sites for the repressor. We find that increasing the number of binding sites induces regular bursting of gene products. By tuning the threshold for repression, we show that multiple binding sites can also suppress fluctuations. Our results highlight possible roles for the presence of multiple binding sites of negative autoregulators.
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Modelos Genéticos , Factores de Transcripción/metabolismo , Sitios de Unión , ADN/metabolismo , Regulación de la Expresión Génica/fisiología , Cinética , Proteolisis , Procesos EstocásticosRESUMEN
We study the dynamics of mobile, locally coupled identical oscillators in the presence of coupling delays. We find different kinds of chimera states in which coherent in-phase and antiphase domains coexist with incoherent domains. These chimera states are dynamic and can persist for long times for intermediate mobility values. We discuss the mechanisms leading to the formation of these chimera states in different mobility regimes. This finding could be relevant for natural and technological systems composed of mobile communicating agents.
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We study the effects of multiple binding sites in the promoter of a genetic oscillator. We evaluate the regulatory function of a promoter with multiple binding sites in the absence of cooperative binding, and consider different hypotheses for how the number of bound repressors affects transcription rate. Effective Hill exponents of the resulting regulatory functions reveal an increase in the nonlinearity of the feedback with the number of binding sites. We identify optimal configurations that maximize the nonlinearity of the feedback. We use a generic model of a biochemical oscillator to show that this increased nonlinearity is reflected in enhanced oscillations, with larger amplitudes over wider oscillatory ranges. Although the study is motivated by genetic oscillations in the zebrafish segmentation clock, our findings may reveal a general principle for gene regulation.
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Introdução: Insatisfação dos pacientes com resultado de mamoplastia redutora pode ser identificado em alguns casos, especialmente quando apresentam ptose acompanhada de flacidez excessive, estrias, e ainda, componente mamário mais gorduroso que glandular. Nesses tipos de pacientes, é muito difícil conseguir bons resultados por longo período. Implantes mamários de pequeno volume, podem ser colocados no mesmo tempo da mamoplastia redutora com o objetivo de se obter melhor forma, contorno e projeção das mamas, com maior satisfação a longo prazo. Método: No período de 1997 a 2012, duzentos e sessenta e quatro pacientes com idade entre 27e 55 anos (idade média de 38), foram submetidas à mamoplastia redutora com imediata colocação de implante mamário. Resultados: Foram obtidos resultados satisfatórios, com adequado preenchimento do pólo superior, mamas firmes e reduzida estatística de ptose pós-operatória. Foram identificados dois casos de carcinoma in sito, como achados no anátomo-patológico. Conclusão: Mastoplastia redutora associada a implantes de silicone é um procedimento seguro para casos selecionados.
INTRODUCTION: Patient dissatisfaction with reduction mammoplasty outcomes can occur, especially in cases of ptosis accompanied by excessive flaccidity, striations, and a higher fat than glandular content. In such cases, achieving long-lasting results is very difficult. Small-volume breast implants can be placed during the reduction mammoplasty with the purpose of obtaining better breast shape, contour, and projection as well as greater long-term satisfaction. METHOD: Between 1997 and 2012, 264 patients aged 27-55 years (mean, 38) underwent reduction mammoplasty with immediate placement of breast implants. RESULTS: Satisfactory results were obtained, with adequate filling of the upper pole, increased breast firmness, and statistical reduction in postoperative ptosis. Two cases of carcinoma in situ were identified in the pathological exam. CONCLUSION: Reduction mastoplasty associated with silicone implants is safe for selected cases.
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Humanos , Femenino , Adulto , Persona de Mediana Edad , Historia del Siglo XXI , Complicaciones Posoperatorias , Siliconas , Mama , Neoplasias de la Mama , Mamoplastia , Implantes de Mama , Procedimientos de Cirugía Plástica , Glándulas Mamarias Humanas , Estética , Hipertrofia , Complicaciones Posoperatorias/cirugía , Complicaciones Posoperatorias/patología , Siliconas/uso terapéutico , Siliconas/química , Mama/cirugía , Mama/lesiones , Neoplasias de la Mama/cirugía , Mamoplastia/efectos adversos , Mamoplastia/métodos , Implantes de Mama/efectos adversos , Implantes de Mama/normas , Procedimientos de Cirugía Plástica/métodos , Glándulas Mamarias Humanas/cirugía , Glándulas Mamarias Humanas/lesiones , Hipertrofia/cirugía , Hipertrofia/complicacionesRESUMEN
Introdução: Muito tem sido discutido a respeito das várias técnicas e vias de acesso em rinoplastia. Todas as técnicas buscam um resultado previsível e reprodutível, associado à melhora estética e funcional do nariz. Nesse trabalho, foi avaliado o nível de satisfação dos pacientes submetidos à rinoplastia nos últimos cinco anos: rinoplastia reducional por via endonasal associada ou não a rinodinâmica. Método: Por meio de um estudo retrospectivo foram identificados 201 pacientes submetidos à rinoplastia endonasal entre 2005 e 2010. Todos os procedimentos foram realizados com a mesma rotina cirúrgica, conforme indicação. Os pacientes foram avaliados de maneira objetiva quanto à cirurgia realizada e, de maneira subjetiva, a respeito de sua função respiratória anterior e posterior à intervenção cirúrgica e o grau de satisfação quanto à estética nasal por meio de um questionário. Resultados: A idade dos pacientes variou de 14 a 68 anos; com predominância da raça branca (96,75%). Referiram melhora no padrão respiratório após a cirurgia, 83,87% dos pacientes estudados.Em relação à estética nasal, 30 (32,26%) pacientes tiveram suas expectativas superadas, 42(45,16%) consideraram muito boa, 18 (19,36%), como boa e três (3,22%), como abaixo do esperado. Conclusão: O procedimento resultou em melhora da função respiratória em quase 90% dos pacientes, além disso, o alto grau de satisfação com a estética exposto pelos pacientes permite concluir que rinoplastia endonasal tem apresentado ótimos resultados até o momento.
Background: Much has been discussed about the various techniques and access routes in rhinoplasty. All seek a predictable and reproducible associated with improved aesthetic and functional nose. This study evaluated the level of satisfaction of patients under going rhinoplastyin the past five years: by endonasal reductional rhinoplasty associated or not to rhinodynamic. Methods: Through a retrospective study identified 201 patients who under went endonasal rhinoplasty the period between 2005 and 2010. All procedures were performed with the same routine as surgical indication. Were evaluated in an objective manner about the surgery and subjectively about their lung function before and after surgery and the degree of satisfaction with the nasal aesthetics through a questionnaire. Results: The age ranged between 14 and 68 years of age; predominant among Caucasians (96.75%). 83.87% of the patients changed their minds after surgery, indicating improvement in breathing pattern. Regarding the nasal aesthetic, 30 (32.26%) patients had exceeded their expectations, 42(45.16%) felt very good, 18 (19.36%) looked as good and three (3.22%) evaluated with lower than expected. Conclusion: The high degree of satisfaction with the aesthetics espoused by patients as well as lead to an improvement of respiratory function in 90% notest hat the procedure performed has great result so far.