Cell biophysical stimuli in lobodopodium formation: a computer based approach

Different cell migration modes have been identified in 3D environments, e.g., modes incorporating lamellopodia or blebs. Recently, a new type of cellular migration has been investigated: lobopodia-based migration, which appears only in three-dimensional matrices under certain conditions. The cell creates a protrusion through which the nucleus slips, dividing the cell into two parts (front and rear) with different hydrostatic pressures. In this work, we elucidate the mechanical conditions that favour this type of migration. One of the hypotheses about this type of migration is that it depends on the mechanical properties of the extracellular matrix. That is, lobopodia-based migration is dependent on whether the extracellular matrix is linearly elastic or non-linearly elastic. To determine whether the mechanical properties of the extracellular matrix are crucial in the choice of cell migration mode and which mechanotransduction mechanism the cell might use, we develop a finite element model. From our simulations, we identify two different possible mechanotransduction mechanisms that could regulate the cell to switch from a lobopodial to a lamellipodial migration mode. The first relies on a differential pressure increase inside the cytoplasm while the cell contracts, and the second relies on a change in the fluid flow direction in non-linearly elastic extracellular matrices but not in linearly elastic matrices. The biphasic nature of the cell has been determined to mediate this mechanism and the different behaviours of cells in linearly elastic and non-linearly elastic matrices

Modelling actin polymerization: the effect on confined cell migration

The aim of this work is to model cell motility under conditions of mechanical confinement. This cell migration mode may occur in extravasation of tumour and neutrophil-like cells. Cell migration is the result of the complex action of different forces exerted by the interplay between myosin contractility forces and actin processes. Here, we propose and implement a finite element model of the confined migration of a single cell. In this model, we consider the effects of actin and myosin in cell motility. Both filament and globular actin are modelled. We model the cell considering cytoplasm and nucleus with different mechanical properties. The migration speed in the simulation is around 0.1 µm/min, which is in agreement with existing literature. From our simulation, we observe that the nucleus size has an important role in cell migration inside the channel. In the simulation the cell moves further when the nucleus is smaller. However, this speed is less sensitive to nucleus stiffness. The results show that the cell displacement is lower when the nucleus is stiffer. The degree of adhesion between the channel walls and the cell is also very important in confined migration. We observe an increment of cell velocity when the friction coefficient is higher

In silico mechano-chemical model of bone healing for the regeneration of critical defects: The effect of BMP-2

The healing of bone defects is a challenge for both tissue engineering and modern ortho- paedics. This problem has been addressed through the study of scaffold constructs com- bined with mechanoregulatory theories, disregarding the influence of chemical factors and their respective delivery devices. Of the chemical factors involved in the bone healing pro- cess, bone morphogenetic protein-2 (BMP-2) has been identified as one of the most power- ful osteoinductive proteins. The aim of this work is to develop and validate a mechano- chemical regulatory model to study the effect of BMP-2 on the healing of large bone defects in silico. We first collected a range of quantitative experimental data from the literature con- cerning the effects of BMP-2 on cellular activity, specifically proliferation, migration, differen- tiation, maturation and extracellular matrix production. These data were then used to define a model governed by mechano-chemical stimuli to simulate the healing of large bone de- fects under the following conditions: natural healing, an empty hydrogel implanted in the de- fect and a hydrogel soaked with BMP-2 implanted in the defect. For the latter condition, successful defect healing was predicted, in agreement with previous in vivo experiments. Further in vivo comparisons showed the potential of the model, which accurately predicted bone tissue formation during healing, bone tissue distribution across the defect and the quantity of bone inside the defect. The proposed mechano-chemical model also estimated the effect of BMP-2 on cells and the evolution of healing in large bone defects. This novel in silico tool provides valuable insight for bone tissue regeneration strategies

Computational model of mesenchymal migration in 3D under chemotaxis

Cell chemotaxis is an important characteristic of cellular migration, which takes part in crucial aspects of life and development. In this work, we propose a novel in silico model of mesenchymal 3D migration with competing protrusions under a chemotactic gradient. Based on recent experimental observations, we identify three main stages that can regulate mesenchymal chemotaxis: chemosensing, dendritic protrusion dynamics and cell–matrix interactions. Therefore, each of these features is considered as a different module of the main regulatory computational algorithm. The numerical model was particularized for the case of fibroblast chemotaxis under a PDGF-bb gradient. Fibroblasts migration was simulated embedded in two different 3D matrices – collagen and fibrin – and under several PDGF-bb concentrations. Validation of the model results was provided through qualitative and quantitative comparison with in vitro studies. Our numerical predictions of cell trajectories and speeds were within the measured in vitro ranges in both collagen and fibrin matrices. Although in fibrin, the migration speed of fibroblasts is very low, because fibrin is a stiffer and more entangling matrix. Testing PDGF-bb concentrations, we noticed that an increment of this factor produces a speed increment. At 1 ng mL-1 a speed peak is reached after which the migration speed diminishes again. Moreover, we observed that fibrin exerts a dampening behavior on migration, significantly affecting the migration efficiency

Flood frequency analysis of historical flood data under stationary and non-stationary modelling

Historical records are an important source of information on extreme and rare floods and fundamental to establish a reliable flood return frequency. The use of long historical records for flood frequency analysis brings in the question of flood stationarity, since climatic and land-use conditions can affect the relevance of past flooding as a predictor of future flooding. In this paper, a detailed 400 yr flood record from the Tagus River in Aranjuez (central Spain) was analysed under stationary and non-stationary flood frequency approaches, to assess their contribution within hazard studies. Historical flood records in Aranjuez were obtained from documents (Proceedings of the City Council, diaries, chronicles, memoirs, etc.), epigraphic marks, and indirect historical sources and reports. The water levels associated with different floods (derived from descriptions or epigraphic marks) were computed into discharge values using a one-dimensional hydraulic model. Secular variations in flood magnitude and frequency, found to respond to climate and environmental drivers, showed a good correlation between high values of historical flood discharges and a negative mode of the North Atlantic Oscillation (NAO) index. Over the systematic gauge record (1913–2008), an abrupt change on flood magnitude was produced in 1957 due to constructions of three major reservoirs in the Tagus headwaters (Bolarque, Entrepeñas and Buendia) controlling 80% of the watershed surface draining to Aranjuez. Two different models were used for the flood frequency analysis: (a) a stationary model estimating statistical distributions incorporating imprecise and categorical data based on maximum likelihood estimators, and (b) a time-varying model based on "generalized additive models for location, scale and shape" (GAMLSS) modelling, which incorporates external covariates related to climate variability (NAO index) and catchment hydrology factors (in this paper a reservoir index; RI). Flood frequency analysis using documentary data (plus gauged records) improved the estimates of the probabilities of rare floods (return intervals of 100 yr and higher). Under non-stationary modelling flood occurrence associated with an exceedance probability of 0.01 (i.e. return period of 100 yr) has changed over the last 500 yr due to decadal and multi-decadal variability of the NAO. Yet, frequency analysis under stationary models was successful in providing an average discharge around which value flood quantiles estimated by non-stationary models fluctuate through time

Constructing 3D crystal templates for photonic band gap materials using holographic optical tweezers

A simple and robust method is presented for the construction of 3-dimensional crystals from silica and polystyrene microspheres. The crystals are suitable for use as templates in the production of three-dimensional photonic band gap (PBG) materials. Manipulation of the microspheres was achieved using a dynamic holographic assembler (DHA) consisting of computer controlled holographic optical tweezers. Attachment of the microspheres was achieved by adjusting their colloidal interactions during assembly. The method is demonstrated by constructing a variety of 3-dimensional crystals using spheres ranging in size from 3 µm down to 800 nm. A major advantage of the technique is that it may be used to build structures that cannot be made using self-assembly. This is illustrated through the construction of crystals in which line defects have been deliberately included, and by building simple cubic structures

Estudio de la capacidad estabilizadora del peroné en fracturas de tibia de conejo

El objetivo de este trabajo es estudiar la capacidad estabilizadora del peroné en fracturas de tibia. Si dicha capacidad es suficiente, sería posible evitar el uso de sistemas de fijación en los experimentos de laboratorio con este tipo de fracturas. Para comprobarlo se ha realizado una simulación computacional por elementos finitos de la tibia y el peroné de un conejo, con una fractura en el tercio medio superior de la diáfisis sin ningún elemento estabilizador. El conjunto ha sido sometido a las cargas más desfavorables del proceso de salto comprobándose que en este caso el peroné fracturaría en su parte inferior del mismo modo que sucede en la experimentación en laboratorio

Modelado del proceso de angiogénesis en cicatrización de heridas por el Método de los Elementos Finitos

El proceso de angiogénesis consiste en la formación de nuevos vasos sanguíneos a partir devasos preexistentes. Este fenómeno está presente en numerosos procesos biológicos, talescomo la regeneración de tejidos (piel y hueso) y el crecimiento de tumores, y realiza un papelmuy importante en los mismos. En este trabajo se ha estudiado el proceso de angiogénesis enla cicatrización de heridas en la piel ya que la capacidad de las heridas para cicatrizar dependeen gran medida de la capacidad de los nuevos vasos para formarse. El proceso de cicatrizaciónestá formado por tres etapas: inflamación, proliferación y remodelación. Dentro de la segundaetapa se produce el fenómeno de angiogénesis. Este proceso está regulado tanto por factoresbiológicos (células) y químicos (oxígeno, factores de crecimiento) como por estímulosmecánicos. En este trabajo se ha realizado la implementación de un modelo numérico conelementos finitos del proceso de angiogenésis para estudiar su efecto en heridas planas en dosdimensiones. Para ello se han incorpordo diferentes factores bioquímicos y mecánicos demanera desacoplada y se ha estudiado su efecto en el proceso de angiogenesis y en el cambiode geometría de la herida

An approach for identifyation of areas with higher expected damage and definition of priority levels for prevention plans in Murcia Province (SE Spain)

The Murcia Region is one of the most active zones in Spain, where three earthquakes took place in 1999, 2002 and 2005. In spite of their low magnitudes (Mw 4.8), these earthquakes caused important damage, the last one reaching an EMS-98 intensity of VII. After that event, the RISMUR project started, aimed at providing a general picture of the seismic risk, which allows us to identify zones requiring a more detailed analysis of where prevention plans should be prioritized. A multidisciplinary study, starting with the seismic hazard assessment, which follows the Probabilistic Seismic Hazard Assessment methodology has been carried out at a regional scale. The expected ground motion (rock sites), for a return period of 475 years, has been characterized in terms of PGA and spectral ordinates and the corresponding maps have been drawn. In addition, a regional geotechnical study has been done and a classification of eight types of soils has been proposed, with the corresponding amplification factors. The combination of previous maps and factors, gives a new hazard map which already includes local effects. In parallel, a vulnerability assessment of the Murcian building stock is carried out, based fundamentally on the age of construction and following the EMS-98 criteria. Taking into account the expected ground motions and building vulnerabilities, the distribution of expected damage is estimated by the application of probability damage matrixes. A suite of maps representing seismic risk in terms of damage parameters for the entire region and from which we can identify the locations with higher expected damage have been obtained. We use the Coulomb stress transfer map of the region as additional criteria for defining priority areas where detailed studies should be performed. This gives information about the zones with stress load due to the previous seismicity and where new events could be triggered. The superposition of this map with the active faults of the region and the locations with higher expected damage allows us to establish a four-level priority ranking where future local-scale analyses should be made

Primeros datos del magmatismo pérmico medio-superior del SE de la Cordillera Ibérica: caracterización y comparación con magmatismos contemporáneos del Tethys occidental

A multiple basic to intermediate sill is reported for the first time in the south-eastern Iberian Ranges. It is composed of several tabular to irregular levels intercalated within the fluvial sediments of the Alcotas Formation (Middle-Upper Permian). The sill could represent the youngest Paleozoic subvolcanic intrusion in the Iberian Ranges. The igneous rocks are classified as basaltic andesites. They show a subophitic microstructure constituted by plagioclase (An62 – An6), augite (En48Wo44Fs7 –En46Wo39Fs15), pseudomorphosed olivine, minor amounts of oxides (magnetite and ilmenite) and accessory F-apatite. According to the mineralogy and whole-rock composition, their geochemical affinity is transitional from subalkaline to alkaline. Radiometric dating of the sill is not feasible due to its significant alteration. Field criteria, however, suggest an emplacement coeval to the deposition of the Alcotas Formation (Middle-Upper Permian). This hypothesis is supported by the transitional affinity of these rocks, similar to other Middle-Upper Permian magmatisms in the western Tethys, e.g., from the Pyrenees. Taking into account their isotopic signature (εSr: -6.8 to -9.2; εNd: +1.7 to +8.3), an enriched mantle source with the involvement of a HIMU component has been identified. This interpretation is supported by the trace element contents. Some of these HIMU characteristics have been recognised in the Middle-Upper Permian magmatisms of the Central Pyrenees (Anayet Basin) and the High Atlas (Argana Basin). However, none of these source features are shared with other Middle-Upper Permian magmatisms of the western Tethys (Catalonian Coastal Ranges, Corsica-Sardinia and southern France), nor with the Lower Permian magmatism of the Iberian Ranges. These differences support the presence of a heterogeneous mantle in the western Tethys during the Permian.Se describe por primera vez en el sudeste de la Cordillera Ibérica un sill múltiple de carácter básico a intermedio. Está compuesto por varios cuerpos tabulares a irregulares intercalados entre los sedimentos de origen fluvial de la Formación Alcotas (Pérmico Medio-Superior). El sill podría representar la intrusión subvolcánica paleozoica más reciente en la Cordillera Ibérica. Estas rocas subvolcánicas se clasifican como andesitas basálticas. Muestran una textura subofítica constituida por plagioclasa (An62 – An6), augita (En48Wo44Fs7 –En46Wo39Fs15), pseudomorfos de olivino, minerales opacos (magnetita e ilmenita) y F-apatito accesorio. De acuerdo con su composición mineral y de roca total, su afinidad geoquímica es transicional entre subalcalina y alcalina. La datación radiométrica del sill no es posible debido a su elevado grado de alteración. No obstante, los criterios de campo sugieren un emplazamiento contemporáneo con el depósito de la Formación Alcotas (Pérmico Medio-Superior). Esta hipótesis está apoyada por la afinidad transicional de estas rocas, similar a otros episodios magmáticos del Pérmico Medio-Superior en el Tethys occidental, como los que afloran en los Pirineos. Teniendo en cuenta su signatura isotópica (εSr: -6.8 a -9.2; εNd: +1.7 a +8.3), se propone un origen a partir de un manto enriquecido, con la participación de un componente de tipo HIMU. Esta interpretación está apoyada por sus contenidos en elementos traza. Algunas de estas características del protolito han sido reconocidas en los magmatismos del Pérmico Medio-Superior del Pirineo (cuenca del Anayet) y del Alto Atlas (cuenca de Argana), pero no son habituales en otros magmatismos de edad Pérmico Medio-Superior del Tethys occidental (Cadenas Costero Catalanas, Córcega-Cerdeña y Sur de Francia), ni en el magmatismo Pérmico Inferior de la Cordillera Ibérica. Estas diferencias apoyan la presencia de un manto heterogéneo en el Tethys occidental durante el Pérmico