Lobe specific Ca2+-calmodulin nano-domain in neuronal spines: a single molecule level analysis.

Calmodulin (CaM) is a ubiquitous Ca(2+) buffer and second messenger that affects cellular function as diverse as cardiac excitability, synaptic plasticity, and gene transcription. In CA1 pyramidal neurons, CaM regulates two opposing Ca(2+)-dependent processes that underlie memory formation: long-term potentiation (LTP) and long-term depression (LTD). Induction of LTP and LTD require activation of Ca(2+)-CaM-dependent enzymes: Ca(2+)/CaM-dependent kinase II (CaMKII) and calcineurin, respectively. Yet, it remains unclear as to how Ca(2+) and CaM produce these two opposing effects, LTP and LTD. CaM binds 4 Ca(2+) ions: two in its N-terminal lobe and two in its C-terminal lobe. Experimental studies have shown that the N- and C-terminal lobes of CaM have different binding kinetics toward Ca(2+) and its downstream targets. This may suggest that each lobe of CaM differentially responds to Ca(2+) signal patterns. Here, we use a novel event-driven particle-based Monte Carlo simulation and statistical point pattern analysis to explore the spatial and temporal dynamics of lobe-specific Ca(2+)-CaM interaction at the single molecule level. We show that the N-lobe of CaM, but not the C-lobe, exhibits a nano-scale domain of activation that is highly sensitive to the location of Ca(2+) channels, and to the microscopic injection rate of Ca(2+) ions. We also demonstrate that Ca(2+) saturation takes place via two different pathways depending on the Ca(2+) injection rate, one dominated by the N-terminal lobe, and the other one by the C-terminal lobe. Taken together, these results suggest that the two lobes of CaM function as distinct Ca(2+) sensors that can differentially transduce Ca(2+) influx to downstream targets. We discuss a possible role of the N-terminal lobe-specific Ca(2+)-CaM nano-domain in CaMKII activation required for the induction of synaptic plasticity.

Structural plasticity can produce metaplasticity.

BACKGROUND: Synaptic plasticity underlies many aspect of learning memory and development. The properties of synaptic plasticity can change as a function of previous plasticity and previous activation of synapses, a phenomenon called metaplasticity. Synaptic plasticity not only changes the functional connectivity between neurons but in some cases produces a structural change in synaptic spines; a change thought to form a basis for this observed plasticity. Here we examine to what extent structural plasticity of spines can be a cause for metaplasticity. This study is motivated by the observation that structural changes in spines are likely to affect the calcium dynamics in spines. Since calcium dynamics determine the sign and magnitude of synaptic plasticity, it is likely that structural plasticity will alter the properties of synaptic plasticity. METHODOLOGY/PRINCIPAL FINDINGS: In this study we address the question how spine geometry and alterations of N-methyl-D-aspartic acid (NMDA) receptors conductance may affect plasticity. Based on a simplified model of the spine in combination with a calcium-dependent plasticity rule, we demonstrated that after the induction phase of plasticity a shift of the long term potentiation (LTP) or long term depression (LTD) threshold takes place. This induces a refractory period for further LTP induction and promotes depotentiation as observed experimentally. That resembles the BCM metaplasticity rule but specific for the individual synapse. In the second phase, alteration of the NMDA response may bring the synapse to a state such that further synaptic weight alterations are feasible. We show that if the enhancement of the NMDA response is proportional to the area of the post synaptic density (PSD) the plasticity curves most likely return to the initial state. CONCLUSIONS/SIGNIFICANCE: Using simulations of calcium dynamics in synaptic spines, coupled with a biophysically motivated calcium-dependent plasticity rule, we find under what conditions structural plasticity can form the basis of synapse specific metaplasticity.

Large scale multiphysics modeling of neurites

Situado en el límite entre Ingeniería, Informática y Biología, la mecánica computacional de las neuronas aparece como un nuevo campo interdisciplinar que potencialmente puede ser capaz de abordar problemas clínicos desde una perspectiva diferente. Este campo es multiescala por naturaleza, yendo desde la nanoescala (como, por ejemplo, los dímeros de tubulina) a la macroescala (como, por ejemplo, el tejido cerebral), y tiene como objetivo abordar problemas que son complejos, y algunas veces imposibles, de estudiar con medios experimentales. La modelización computacional ha sido ampliamente empleada en aplicaciones Neurocientíficas tan diversas como el crecimiento neuronal o la propagación de los potenciales de acción compuestos. Sin embargo, en la mayoría de los enfoques de modelización hechos hasta ahora, la interacción entre la célula y el medio/estímulo que la rodea ha sido muy poco explorada. A pesar de la tremenda importancia de esa relación en algunos desafíos médicos—como, por ejemplo, lesiones traumáticas en el cerebro, cáncer, la enfermedad del Alzheimer—un puente que relacione las propiedades electrofisiológicas-químicas y mecánicas desde la escala molecular al nivel celular todavía no existe. Con ese objetivo, esta investigación propone un marco computacional multiescala particularizado para dos escenarios respresentativos: el crecimiento del axón y el acomplamiento electrofisiológicomecánico de las neuritas. En el primer caso, se explora la relación entre los constituyentes moleculares del axón durante su crecimiento y sus propiedades mecánicas resultantes, mientras que en el último, un estímulo mecánico provoca deficiencias funcionales a nivel celular como consecuencia de sus alteraciones electrofisiológicas-químicas. La modelización computacional empleada en este trabajo es el método de las diferencias finitas, y es implementada en un nuevo programa llamado Neurite. Aunque el método de los elementos finitos es también explorado en parte de esta investigación, el método de las diferencias finitas tiene la flexibilidad y versatilidad necesaria para implementar mode los biológicos, así como la simplicidad matemática para extenderlos a simulaciones a gran escala con un coste computacional bajo. Centrándose primero en el efecto de las propiedades electrofisiológicas-químicas sobre las propiedades mecánicas, una versión adaptada de Neurite es desarrollada para simular la polimerización de los microtúbulos en el crecimiento del axón y proporcionar las propiedades mecánicas como función de la ocupación de los microtúbulos. Después de calibrar el modelo de crecimiento del axón frente a resultados experimentales disponibles en la literatura, las características mecánicas pueden ser evaluadas durante la simulación. Las propiedades mecánicas del axón muestran variaciones dramáticas en la punta de éste, donde el cono de crecimiento soporta las señales químicas y mecánicas. Bansándose en el conocimiento ganado con el modelo de diferencias finitas, y con el objetivo de ir de 1D a 3D, este esquema preliminar pero de una naturaleza innovadora allana el camino a futuros estudios con el método de los elementos finitos. Centrándose finalmente en el efecto de las propiedades mecánicas sobre las propiedades electrofisiológicas- químicas, Neurite es empleado para relacionar las cargas mecánicas macroscópicas con las deformaciones y velocidades de deformación a escala microscópica, y simular la propagación de la señal eléctrica en las neuritas bajo carga mecánica. Las simulaciones fueron calibradas con resultados experimentales publicados en la literatura, proporcionando, por tanto, un modelo capaz de predecir las alteraciones de las funciones electrofisiológicas neuronales bajo cargas externas dañinas, y uniendo lesiones mecánicas con las correspondientes deficiencias funcionales. Para abordar simulaciones a gran escala, aunque otras arquitecturas avanzadas basadas en muchos núcleos integrados (MICs) fueron consideradas, los solvers explícito e implícito se implementaron en unidades de procesamiento central (CPU) y unidades de procesamiento gráfico (GPUs). Estudios de escalabilidad fueron llevados acabo para ambas implementaciones mostrando resultados prometedores para casos de simulaciones extremadamente grandes con GPUs. Esta tesis abre la vía para futuros modelos mecánicos con el objetivo de unir las propiedades electrofisiológicas-químicas con las propiedades mecánicas. El objetivo general es mejorar el conocimiento de las comunidades médicas y de bioingeniería sobre la mecánica de las neuronas y las deficiencias funcionales que aparecen de los daños producidos por traumatismos mecánicos, como lesiones traumáticas en el cerebro, o enfermedades neurodegenerativas como la enfermedad del Alzheimer. ABSTRACT Sitting at the interface between Engineering, Computer Science and Biology, Computational Neuron Mechanics appears as a new interdisciplinary field potentially able to tackle clinical problems from a new perspective. This field is multiscale by nature, ranging from the nanoscale (e.g., tubulin dimers) to the macroscale (e.g., brain tissue), and aims at tackling problems that are complex, and sometime impossible, to study through experimental means. Computational modeling has been widely used in different Neuroscience applications as diverse as neuronal growth or compound action potential propagation. However, in the majority of the modeling approaches done in this field to date, the interactions between the cell and its surrounding media/stimulus have been rarely explored. Despite of the tremendous importance of such relationship in several medical challenges—e.g., traumatic brain injury (TBI), cancer, Alzheimer’s disease (AD)—a bridge between electrophysiological-chemical and mechanical properties of neurons from the molecular scale to the cell level is still lacking. To this end, this research proposes a multiscale computational framework particularized for two representative scenarios: axon growth and electrophysiological-mechanical coupling of neurites. In the former case, the relation between the molecular constituents of the axon during its growth and its resulting mechanical properties is explored, whereas in the latter, a mechanical stimulus provokes functional deficits at cell level as a consequence of its electrophysiological-chemical alterations. The computational modeling approach chosen in this work is the finite difference method (FDM), and was implemented in a new program called Neurite. Although the finite element method (FEM) is also explored as part of this research, the FDM provides the necessary flexibility and versatility to implement biological models, as well as the mathematical simplicity to extend them to large scale simulations with a low computational cost. Focusing first on the effect of electrophysiological-chemical properties on the mechanical proper ties, an adaptation of Neurite was developed to simulate microtubule polymerization in axonal growth and provide the axon mechanical properties as a function of microtubule occupancy. After calibrating the axon growth model against experimental results available in the literature, the mechanical characteristics can be tracked during the simulation. The axon mechanical properties show dramatic variations at the tip of the axon, where the growth cone supports the chemical and mechanical signaling. Based on the knowledge gained from the FDM scheme, and in order to go from 1D to 3D, this preliminary yet novel scheme paves the road for future studies with FEM. Focusing then on the effect of mechanical properties on the electrophysiological-chemical properties, Neurite was used to relate macroscopic mechanical loading to microscopic strains and strain rates, and simulate the electrical signal propagation along neurites under mechanical loading. The simulations were calibrated against experimental results published in the literature, thus providing a model able to predict the alteration of neuronal electrophysiological function under external damaging load, and linking mechanical injuries to subsequent acute functional deficits. To undertake large scale simulations, although other state-of-the-art architectures based on many integrated cores (MICs) were considered, the explicit and implicit solvers were implemented for central processing units (CPUs) and graphics processing units (GPUs). Scalability studies were done for both implementations showing promising results for extremely large scale simulations with GPUs. This thesis opens the avenue for future mechanical modeling approaches aimed at linking electrophysiological- chemical properties to mechanical properties. Its overarching goal is to enhance the bioengineering and medical communities knowledge on neuronal mechanics and functional deficits arising from damages produced by direct mechanical insults, such as TBI, or neurodegenerative evolving illness, such as AD.

Evidence for a Myotomal Hox/Myf Cascade Governing Nonautonomous Control of Rib Specification within Global Vertebral Domains

Hox genes are essential for the patterning of the axial skeleton. Hox group 10 has been shown to specify the lumbar domain by setting a rib-inhibiting program in the presomitic mesoderm (PSM). We have now produced mice with ribs in every vertebra by ectopically expressing Hox group 6 in the PSM, indicating that Hox genes are also able to specify the thoracic domain. We show that the information provided by Hox genes to specify rib-containing and rib-less areas is first interpreted in the myotome through the regional-specific control of Myf5 and Myf6 expression. This information is then transmitted to the sclerotome by a system that includes FGF and PDGF signaling to produce vertebrae with or without ribs at different axial levels. Our findings offer a new perspective of how Hox genes produce global patterns in the axial skeleton and support a redundant nonmyogenic role of Myf5 and Myf6 in rib formation.

Design and evaluation of a terrestrial model ecosystem for evaluation substitute pesticide chemicals /

Mode of access: Internet.

A two compartmental model of the respiratory system /

"UIUCDCS-R-73-616"

Modelling of wastewater treatment plants:how far shall we go with sophisticated modelling tools?

Several levels of complexity are available for modelling of wastewater treatment plants. Modelling local effects rely on computational fluid dynamics (CFD) approaches whereas activated sludge models (ASM) represent the global methodology. By applying both modelling approaches to pilot plant and full scale systems, this paper evaluates the value of each method and especially their potential combination. Model structure identification for ASM is discussed based on a full-scale closed loop oxidation ditch modelling. It is illustrated how and for what circumstances information obtained via CFD (computational fluid dynamics) analysis, residence time distribution (RTD) and other experimental means can be used. Furthermore, CFD analysis of the multiphase flow mechanisms is employed to obtain a correct description of the oxygenation capacity of the system studied, including an easy implementation of this information in the classical ASM modelling (e.g. oxygen transfer). The combination of CFD and activated sludge modelling of wastewater treatment processes is applied to three reactor configurations, a perfectly mixed reactor, a pilot scale activated sludge basin (ASB) and a real scale ASB. The application of the biological models to the CFD model is validated against experimentation for the pilot scale ASB and against a classical global ASM model response. A first step in the evaluation of the potential of the combined CFD-ASM model is performed using a full scale oxidation ditch system as testing scenario.

Migration, prospecting, dispersal? What host movement matters for infectious agent circulation?

Spatial disease ecology is emerging as a new field that requires the integration of complementary approaches to address how the distribution and movements of hosts and parasites may condition the dynamics of their interactions. In this context, migration, the seasonal movement of animals to different zones of their distribution, is assumed to play a key role in the broad scale circulation of parasites and pathogens. Nevertheless, migration is not the only type of host movement that can influence the spatial ecology, evolution, and epidemiology of infectious diseases. Dispersal, the movement of individuals between the location where they were born or bred to a location where they breed, has attracted attention as another important type of movement for the spatial dynamics of infectious diseases. Host dispersal has notably been identified as a key factor for the evolution of host-parasite interactions as it implies gene flow among local host populations and thus can alter patterns of coevolution with infectious agents across spatial scales. However, not all movements between host populations lead to dispersal per se. One type of host movement that has been neglected, but that may also play a role in parasite spread is prospecting, i.e., movements targeted at selecting and securing new habitat for future breeding. Prospecting movements, which have been studied in detail in certain social species, could result in the dispersal of infectious agents among different host populations without necessarily involving host dispersal. In this article, we outline how these various types of host movements might influence the circulation of infectious disease agents and discuss methodological approaches that could be used to assess their importance. We specifically focus on examples from work on colonial seabirds, ticks, and tick-borne infectious agents. These are convenient biological models because they are strongly spatially structured and involve relatively simple communities of interacting species. Overall, this review emphasizes that explicit consideration of the behavioral and population ecology of hosts and parasites is required to disentangle the relative roles of different types of movement for the spread of infectious diseases.

Impacto de la biología en los modelos de gestión y control organizacional

Desde el inicio de las organizaciones han existido modelos de control rígidos como los sistemas mecanicistas y formales en donde la perspectiva racional sobresale y no se tienen en cuenta los aspectos humanos en el diseño de los sistemas. Estos modelos de control rígidos, estandarizados y centralizados suponen un problema para el adecuado desarrollo estratégico y operativo de las organizaciones. Sin embargo, desde los sistemas biológicos se pueden observar aportes de autores que destacan la ausencia de control y su consecuente funcionamiento armónico a través de propiedades como la auto-organización y la emergencia. De esta forma, este artículo de revisión tiene como objetivo identificar las aproximaciones teóricas que se han realizado en torno a los principales aportes que los modelos biológicos han hecho a la gestión administrativa y específicamente al control organizacional mediante el análisis de la producción bibliográfica realizada en los últimos 10 años.

Toxicological assessment of novel green biocides for cultural heritage.

The damaging of buildings and monuments by biological contamination is a cause of serious concern. Biocides based on chemical toxic compounds have been used to mitigate this problem. However, in the past decade many of the most effective biocides have been banned due to their environmental and health hazards. Therefore, proper remediation actions for microbiologically contaminated historic materials based on environmentally safe solution is of vital importance. Bacillus species are emerging as a promising alternative for built heritage treatment. They produce a great diversity of secondary metabolites with biological activity, well known to possess antagonistic activities against many fungal pathogens. In order to evaluate the antifungal activity of the novel biocides produced in our laboratory by cultures of selected bacterial strains, liquid interaction assays using four biodeteriogenic fungi were achieved, revealing a nearly 100% of inhibitory capacity to fungal proliferation. To confirm their effective safe toxicological properties, in vivo tests using two different biological models were performed. The lyophilized supernatant of the Bacillus culture broth showed no lethality against brine shrimp and also no toxicological effects in Swiss mice through administration of acute dose of 5000 mg/kg by oral gavage. In fact, the bioactive compounds were no lethal at the tested dose unlike Preventol® (commercial biocide) that induced acute toxicity with 10 times minor concentration dose administrated in the same conditions. Therefore, the new bioactive compounds that suppress growth of biodeteriogenic fungi on historical artworks, presenting at the same time no toxicity against other living organisms, constituting an efficient and green safe solution for biodegradation/biodeterioration treatment of Cultural Heritage.

Amyotrophic Lateral Sclerosis:Mammalian Cell Models,Copper-Zinc Superoxide Dismutaseand Biological Characteristics

"Amyotrophic Lateral Sclerosis (ALS) is the most severe and common adult onset disorder that affects motor neurons in the spinal cord, brainstem and cortex, resulting in progressive weakness and death from respiratory failure within two to five years of symptoms onset(...)

Modelos Mixtos-Aditivos Generalizados para el Estudio de Fenómenos Biológicos y Sociales Descriptos por Datos Agregados y/o Longitudinales. Generalized Mixed Additive Models for the Study of Biological and Social Phenomenons from Longitudinal and/or Aggregated Data.

Este proyecto propone extender y generalizar los procesos de estimación e inferencia de modelos aditivos generalizados multivariados para variables aleatorias no gaussianas, que describen comportamientos de fenómenos biológicos y sociales y cuyas representaciones originan series longitudinales y datos agregados (clusters). Se genera teniendo como objeto para las aplicaciones inmediatas, el desarrollo de metodología de modelación para la comprensión de procesos biológicos, ambientales y sociales de las áreas de Salud y las Ciencias Sociales, la condicionan la presencia de fenómenos específicos, como el de las enfermedades.Es así que el plan que se propone intenta estrechar la relación entre la Matemática Aplicada, desde un enfoque bajo incertidumbre y las Ciencias Biológicas y Sociales, en general, generando nuevas herramientas para poder analizar y explicar muchos problemas sobre los cuales tienen cada vez mas información experimental y/o observacional.Se propone, en forma secuencial, comenzando por variables aleatorias discretas (Yi, con función de varianza menor que una potencia par del valor esperado E(Y)) generar una clase unificada de modelos aditivos (paramétricos y no paramétricos) generalizados, la cual contenga como casos particulares a los modelos lineales generalizados, no lineales generalizados, los aditivos generalizados, los de media marginales generalizados (enfoques GEE1 -Liang y Zeger, 1986- y GEE2 -Zhao y Prentice, 1990; Zeger y Qaqish, 1992; Yan y Fine, 2004), iniciando una conexión con los modelos lineales mixtos generalizados para variables latentes (GLLAMM, Skrondal y Rabe-Hesketh, 2004), partiendo de estructuras de datos correlacionados. Esto permitirá definir distribuciones condicionales de las respuestas, dadas las covariables y las variables latentes y estimar ecuaciones estructurales para las VL, incluyendo regresiones de VL sobre las covariables y regresiones de VL sobre otras VL y modelos específicos para considerar jerarquías de variación ya reconocidas. Cómo definir modelos que consideren estructuras espaciales o temporales, de manera tal que permitan la presencia de factores jerárquicos, fijos o aleatorios, medidos con error como es el caso de las situaciones que se presentan en las Ciencias Sociales y en Epidemiología, es un desafío a nivel estadístico. Se proyecta esa forma secuencial para la construcción de metodología tanto de estimación como de inferencia, comenzando con variables aleatorias Poisson y Bernoulli, incluyendo los existentes MLG, hasta los actuales modelos generalizados jerárquicos, conextando con los GLLAMM, partiendo de estructuras de datos correlacionados. Esta familia de modelos se generará para estructuras de variables/vectores, covariables y componentes aleatorios jerárquicos que describan fenómenos de las Ciencias Sociales y la Epidemiología.

Impact of biological and environmental variabilities on biological monitoring: an approach using toxicokinetic models

Biological monitoring of occupational exposure is characterized by important variability, due both to variability in the environment and to biological differences between workers. A quantitative description and understanding of this variability is important for a dependable application of biological monitoring. This work describes this variability,using a toxicokinetic model, for a large range of chemicals for which reference biological reference values exist. A toxicokinetic compartmental model describing both the parent compound and its metabolites was used. For each chemical, compartments were given physiological meaning. Models were elaborated based on physiological, physicochemical, and biochemical data when available, and on half-lives and central compartment concentrations when not available. Fourteen chemicals were studied (arsenic, cadmium, carbon monoxide, chromium, cobalt, ethylbenzene, ethyleneglycol monomethylether, fluorides, lead, mercury, methyl isobutyl ketone, penthachlorophenol, phenol, and toluene), representing 20 biological indicators. Occupational exposures were simulated using Monte Carlo techniques with realistic distributions of both individual physiological parameters and exposure conditions. Resulting biological indicator levels were then analyzed to identify the contribution of environmental and biological variability to total variability. Comparison of predicted biological indicator levels with biological exposure limits showed a high correlation with the model for 19 out of 20 indicators. Variability associated with changes in exposure levels (GSD of 1.5 and 2.0) is shown to be mainly influenced by the kinetics of the biological indicator. Thus, with regard to variability, we can conclude that, for the 14 chemicals modeled, biological monitoring would be preferable to air monitoring. For short half-lives (less than 7 hr), this is very similar to the environmental variability. However, for longer half-lives, estimated variability decreased. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: tables detailing the CBTK models for all 14 chemicals and the symbol nomenclature that was used.] [Authors]

Bayesian L-optimal exact design of experiments for biological kinetic models

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Predicting biological parameters of estuarine benthic communities using models based on environmental data

Este trabalho objetivou predizer parâmetros da estrutura de associações macrobentônicas (composição específica, abundância, riqueza, diversidade e equitatividade) em estuários do Sul do Brasil, utilizando modelos baseados em dados ambientais (características dos sedimentos, salinidade, temperaturas do ar e da água, e profundidade). As amostragens foram realizadas sazonalmente em cinco estuários entre o inverno de 1996 e o verão de 1998. Em cada estuário as amostras foram coletadas em áreas não poluídas, com características semelhantes quanto a presença ou ausência de vegetação, profundidade e distância da desenbocadura. Para a obtenção dos modelos de predição, foram utilizados dois métodos: o primeiro baseado em Análise Discriminante Múltipla (ADM) e o segundo em Regressão Linear Múltipla (RLM). Os modelos baseados em ADM apresentaram resultados melhores do que os baseados em regressão linear. Os melhores resultados usando RLM foram obtidos para diversidade e riqueza. É possível então, concluir que modelos como aqui derivados podem representar ferramentas muito úteis em estudos de monitoramento ambiental em estuários.