422 research outputs found
Mechanical cell-matrix feedback explains pairwise and collective endothelial cell behavior in vitro
In vitro cultures of endothelial cells are a widely used model system of the
collective behavior of endothelial cells during vasculogenesis and
angiogenesis. When seeded in an extracellular matrix, endothelial cells can
form blood vessel-like structures, including vascular networks and sprouts.
Endothelial morphogenesis depends on a large number of chemical and mechanical
factors, including the compliancy of the extracellular matrix, the available
growth factors, the adhesion of cells to the extracellular matrix, cell-cell
signaling, etc. Although various computational models have been proposed to
explain the role of each of these biochemical and biomechanical effects, the
understanding of the mechanisms underlying in vitro angiogenesis is still
incomplete. Most explanations focus on predicting the whole vascular network or
sprout from the underlying cell behavior, and do not check if the same model
also correctly captures the intermediate scale: the pairwise cell-cell
interactions or single cell responses to ECM mechanics. Here we show, using a
hybrid cellular Potts and finite element computational model, that a single set
of biologically plausible rules describing (a) the contractile forces that
endothelial cells exert on the ECM, (b) the resulting strains in the
extracellular matrix, and (c) the cellular response to the strains, suffices
for reproducing the behavior of individual endothelial cells and the
interactions of endothelial cell pairs in compliant matrices. With the same set
of rules, the model also reproduces network formation from scattered cells, and
sprouting from endothelial spheroids. Combining the present mechanical model
with aspects of previously proposed mechanical and chemical models may lead to
a more complete understanding of in vitro angiogenesis.Comment: 25 pages, 6 figures, accepted for publication in PLoS Computational
Biolog
Melatonin treatment in children with therapy-resistant monosymptomatic nocturnal enuresis
Objective: To evaluate the effects of exogenous melatonin on the frequency of wet nights, on the sleep-wake cycle, and on the melatonin profile in children with therapy-resistant MNE. Patients and methods: 24 patients were included. Patients had to maintain a diary including time of sleep and arousal, and whether they had a dry or a wet bed in the morning. We measured baseline melatonin profiles in saliva. Hereafter, patients were randomized to synthetic melatonin or placebo. After 3 and 6 months we evaluated the frequency of enuresis and the melatonin profiles. Results: 11 patients were randomized to melatonin, 13 to placebo. We evaluated melatonin profiles of 7 patients in the melatonin group and of 8 in the placebo group. We observed a change in profile in the melatonin group, but we did not observe a difference in the sleep-wake cycle or the frequency of wet nights in either group. Conclusion: This is the first time exogenous melatonin has been evaluated in the treatment of MNE. Although we observed a change in melatonin profile after the use of exogenous melatonin, we did not observe a change in enuresis frequency or in the sleep-wake cycle of this select group of patients. (C) 2011 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved
Emergence of tissue polarization from synergy of intracellular and extracellular auxin signaling
Here, we provide a novel mechanistic framework for cell polarization during auxin-driven plant development that combines intracellular auxin signaling for regulation of expression of PINFORMED (PIN) auxin efflux transporters and the theoretical assumption of extracellular auxin signaling for regulation of PIN subcellular dynamics.The competitive utilization of auxin signaling component in the apoplast might account for the elusive mechanism for cell-to-cell communication for tissue polarization.Computer model simulations faithfully and robustly recapitulate experimentally observed patterns of tissue polarity and asymmetric auxin distribution during formation and regeneration of vascular systems, and during the competitive regulation of shoot branching by apical dominance.Our model generated new predictions that could be experimentally validated, highlighting a mechanistically conceivable explanation for the PIN polarization and canalization of the auxin flow in plants
Deformability and collision-induced reorientation enhance cell topotaxis in dense microenvironments
In vivo, cells navigate through complex environments filled with obstacles.
Recently, the term 'topotaxis' has been introduced for navigation along
topographic cues such as obstacle density gradients. Experimental and
mathematical efforts have analyzed topotaxis of single cells in pillared grids
with pillar density gradients. A previous model based on active Brownian
particles has shown that ABPs perform topotaxis, i.e., drift towards lower
pillar densities, due to decreased effective persistence lengths at high
pillars densities. The ABP model predicted topotactic drifts of up to 1% of the
instantaneous speed, whereas drifts of up to 5% have been observed
experimentally. We hypothesized that the discrepancy between the ABP and the
experimental observations could be in 1) cell deformability, and 2) more
complex cell-pillar interactions. Here, we introduce a more detailed model of
topotaxis, based on the Cellular Potts model. To model persistent cells we use
the Act model, which mimicks actin-polymerization driven motility, and a hybrid
CPM-ABP model. Model parameters were fitted to simulate the experimentally
found motion of D. discoideum on a flat surface. For starved D. discoideum,
both CPM variants predict topotactic drifts closer to the experimental results
than the previous ABP model, due to a larger decrease in persistence length.
Furthermore, the Act model outperformed the hybrid model in terms of topotactic
efficiency, as it shows a larger reduction in effective persistence time in
dense pillar grids. Also pillar adhesion can slow down cells and decrease
topotaxis. For slow and less persistent vegetative D. discoideum cells, both
CPMs predicted a similar small topotactic drift. We conclude that deformable
cell volume results in higher topotactic drift compared to ABPs, and that
feedback of cell-pillar collisions on cell persistence increases drift only in
highly persistent cells
Simulation of organ patterning on the floral meristem using a polar auxin transport model
An intriguing phenomenon in plant development is the timing and positioning of lateral organ initiation,
which is a fundamental aspect of plant architecture. Although important progress has been made in
elucidating the role of auxin transport in the vegetative shoot to explain the phyllotaxis of leaf formation
in a spiral fashion, a model that explains the whorled organ patterning in the expanding floral meristem
is not available yet. We present an initial simulation approach to study the mechanisms that are expected
to play an important role. Starting point is a confocal imaging study of Arabidopsis floral meristems
at consecutive time points during flower development. These images reveal auxin accumulation patterns
at the positions of the organs, which strongly suggests that the role of auxin in the floral meristem is
similar to the role it plays in the shoot apical meristem. This is the basis for a simulation study of auxin
transport through a growing floral meristem, which may answer the question whether auxin transport can
in itself be responsible for the typical whorled floral pattern. We combined a cellular growth model for
the meristem with a polar auxin transport model. The model predicts that sepals are initiated by auxin maxima arising early during meristem outgrowth. These form a pre-pattern relative to which a series of
smaller auxin maxima are positioned, which partially overlap with the anlagen of petals, stamens, and
carpels. We adjusted the model parameters corresponding to properties of floral mutants and found that
the model predictions agree with the observed mutant patterns. The predicted timing of the primordia
outgrowth and the timing and positioning of the sepal primordia show remarkable similarities with a
developing flower in nature
A multiscale hybrid model for pro-angiogenic calcium signals in a vascular endothelial cell
Cytosolic calcium machinery is one of the principal signaling mechanisms by which endothelial cells (ECs) respond to external stimuli during several biological processes, including vascular progression in both physiological and pathological conditions. Low concentrations of angiogenic factors (such as VEGF) activate in fact complex pathways involving, among others, second messengers arachidonic acid (AA) and nitric oxide (NO), which in turn control the activity of plasma membrane calcium channels. The subsequent increase in the intracellular level of the ion regulates fundamental biophysical properties of ECs (such as elasticity, intrinsic motility, and chemical strength), enhancing their migratory capacity. Previously, a number of continuous models have represented cytosolic calcium dynamics, while EC migration in angiogenesis has been separately approached with discrete, lattice-based techniques. These two components are here integrated and interfaced to provide a multiscale and hybrid Cellular Potts Model (CPM), where the phenomenology of a motile EC is realistically mediated by its calcium-dependent subcellular events. The model, based on a realistic 3-D cell morphology with a nuclear and a cytosolic region, is set with known biochemical and electrophysiological data. In particular, the resulting simulations are able to reproduce and describe the polarization process, typical of stimulated vascular cells, in various experimental conditions.Moreover, by analyzing the mutual interactions between multilevel biochemical and biomechanical aspects, our study investigates ways to inhibit cell migration: such strategies have in fact the potential to result in pharmacological interventions useful to disrupt malignant vascular progressio
New perspectives for eye-sparing treatment strategies in primary uveal melanoma
Uveal melanoma is the most common intraocular malignancy and arises from melanocytes in the choroid, ciliary body, or iris. The current eye-sparing treatment options include surgical treatment, plaque brachytherapy, proton beam radiotherapy, stereotactic photon radiotherapy, or photodynamic therapy. However, the efficacy of these methods is still unsatisfactory. This article reviews several possible new treatment options and their potential advantages in treating localized uveal melanoma. These methods may be based on the physical destruction of the cancerous cells by applying ultrasounds. Two examples of such an approach are High-Intensity Focused Ultrasound (HIFU)—a promising technology of thermal destruction of solid tumors located deep under the skin and sonodynamic therapy (SDT) that induces reactive oxygen species. Another approach may be based on improving the penetration of anti-cancer agents into UM cells. The most promising technologies from this group are based on enhancing drug delivery by applying electric current. One such approach is called transcorneal iontophoresis and has already been shown to increase the local concentration of several different therapeutics. Another technique, electrically enhanced chemotherapy, may promote drug delivery from the intercellular space to cells. Finally, new advanced nanoparticles are developed to combine diagnostic imaging and therapy (i.e., theranostics). However, development. these methods More are mostly advanced at an and early targeted stage of preclinical development. studies More and advanced clinical trials and targeted would be preclinical needed to studies introduce and some clinical of trials these would techniques be needed to routine to introduce clinical practice. some of these techniques to routine clinical practice
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