Are Podoplanin and Ezrin Involved in the Invasion Process of the Ameloblastomas?

The association between podoplanin and ezrin in the process of odontogenic tumors invasion has been suggested, but was not studied yet. Our purpose was to investigate the relationship between podoplanin and ezrin expressions in the odontogenic epithelium of ameloblastomas. Forty-seven ameloblastomas were analyzed by immunohistochemistry using anti-podoplanin and anti-ezrin antibodies. The expressions of both proteins were evaluated using a score method and the comparison and association between these proteins were verified, respectively, by Wilcoxon Signed-Rank test and by Spearman’s rank correlation coefficient, using a statistical significance level of 0.05. The majority of tumors (87.2%) exhibited strong membranous expression of podoplanin in the peripheral cells. Cytoplasmic expression of ezrin in the peripheral cells of ameloblastomas was stronger than its membranous expression. No statistically significant correlation was observed between podoplanin and ezrin. However, there was statistically significant difference between membranous podoplanin and membranous ezrin expressions, between cytoplasmic podoplanin and membranous ezrin expressions, and between cytoplasmic podoplanin and cytoplasmic ezrin expressions. There was no statistical difference between membranous podoplanin and cytoplasmic ezrin expressions. These results suggest a synergistic role of both proteins in the process of invasion of ameloblastomas.Key words: Odontogenic tumor, ameloblastoma, podoplanin, ezrin, adhesion molecule     

Ecological Invasion,Roughened Fronts,and a Competitor’s Extreme Advance: Integrating Stochastic Spatial-Growth Models

Both community ecology and conservation biology seek further understanding of factors governing the advance of an invasive species. We model biological invasion as an individual-based, stochastic process on a two-dimensional landscape. An ecologically superior invader and a resident species compete for space preemptively. Our general model includes the basic contact process and a variant of the Eden model as special cases. We employ the concept of a “roughened” front to quantify effects of discreteness and stochasticity on invasion; we emphasize the probability distribution of the front-runner’s relative position. That is, we analyze the location of the most advanced invader as the extreme deviation about the front’s mean position. We find that a class of models with different assumptions about neighborhood interactions exhibits universal characteristics. That is, key features of the invasion dynamics span a class of models, independently of locally detailed demographic rules. Our results integrate theories of invasive spatial growth and generate novel hypotheses linking habitat or landscape size (length of the invading front) to invasion velocity, and to the relative position of the most advanced invader.     

Invasion waves and pinning in the Kirkpatrick–Barton model of evolutionary range dynamics

Journal of Mathematical Biology - The Kirkpatrick–Barton model, well known to invasion biologists, is a pair of reaction–diffusion equations for the joint evolution of population...     

WAVE3-NFκB Interplay Is Essential for the Survival and Invasion of Cancer Cells

The WAVE3 cytoskeletal protein promotes cancer invasion and metastasis. We have shown that the WAVE3-mediated activation of cancer cell invasion is due, in part, to its regulation of expression and activity of key metalloproteinases (MMPs), including MMP9, which is centrally involved in invadopodia-mediated degradation of the extracellular matrix (ECM). MMP9 is also a major NFκB target gene, suggesting a potential linkage of WAVE3 to this pathway, which we sought to investigate. Mechanistically, we found that loss of WAVE3 in cancer cells leads to inhibition of NFκB signaling as a result of a decrease in the nuclear translocation of NFκB and therefore loss of activation of NFκB target genes. Conversely, overexpression of WAVE3 was sufficient to enhance NFκB activity. Both pharmacologic and genetic manipulations of NFκB effector molecules show that the biological consequence of loss of WAVE3 function in the NFκB pathway result the inhibition of invadopodia formation and ECM degradation by cancer cells, and these changes are a consequence of decreased MMP9 expression and activity. Loss of WAVE3 also sensitized cancer cells to apoptosis and cell death driven by TNFα, through the inhibition of the AKT pro-survival pathway. Our results identify a novel function of WAVE3 in NFκB signaling, where its activity is essential for the regulation of invadopodia and ECM degradation. Therefore, targeted therapeutic inhibition of WAVE3 will sensitize cancer cells to apoptosis and cell death, and suppress cancer invasion and metastasis.     

Does Invasion of Exotic Plants Promote Invasion of Exotic Flower Visitors? A Case Study from the Temperate Forests of the Southern Andes

Habitat disturbance, particularly of human origin, promotes the invasion of exotic plants, which in turn might foster the invasion of alien-interacting animals. Here we assess whether the invasion of exotic plants – mostly mediated by habitat disturbance – facilitates the invasion of exotic flower visitors in temperate forests of the southern Andes, Argentina. We recorded visit frequencies and the identity of visitors to the flowers of 15 native and 15 exotic plant species occurring in different highly disturbed and less disturbed habitats. We identified three alien flower visitors, the hymenopterans Apis mellifera, Bombus ruderatus, and Vespula germanica. We found significantly more visitation by exotic insects in disturbed habitats. This pattern was explained, at least in part, by the association between alien flower visitors and flowers of exotic plants, which occurred more frequently in disturbed habitats. However, this general pattern masked different responses between the two main alien flower visitors. Apis mellifera exploited almost exclusively the flowers of a subset of herbaceous exotic plants that thrive under disturbance, whereas B. ruderatus visited equally flowers of both exotic and native plants in both disturbed and undisturbed habitats. We did not find any strong evidence that flowers of exotic plants were more generalist than those of native plants, or that exotic flower visitors were more generalist than their native counterparts. Our results suggest that alien plant species could facilitate the invasion of at least some exotic flower visitors to disturbed habitats. Because flowering plants as well as flower visitors benefit from this mutualism, this association may enhance, through a positive feedback, successful establishment of both exotic partners.     

Is Switzerland Suitable for the Invasion of Aedes albopictus?

Background

Over the last 30 years, the Asian tiger mosquito, Aedes albopictus, has rapidly spread around the world. The European distribution comprises the Mediterranean basin with a first appearance in Switzerland in 2003. Early identification of the most suitable areas in Switzerland allowing progressive invasion by this species is considered crucial to suggest adequate surveillance and control plans.

Methodology/Principal Findings

We identified the most suitable areas for invasion and establishment of Ae. albopictus in Switzerland. The potential distribution areas linked to the current climatic suitability were assessed using remotely sensed land surface temperature data recorded by the MODIS satellite sensors. Suitable areas for adult survival and overwintering of diapausing eggs were also identified for future climatic conditions, considering two different climate change scenarios (A1B, A2) for the periods 2020–2049 and 2045–2074. At present, the areas around Lake Geneva in western Switzerland provide suitable climatic conditions for Ae. albopictus. In northern Switzerland, parts of the Rhine valley, around Lake Constance, as well as the surroundings of Lake Neuchâtel, appear to be suitable for the survival at least of adult Ae. albopictus. However, these areas are characterized by winters currently being too cold for survival and development of diapausing eggs. In southern Switzerland, Ae. albopictus is already well-established, especially in the Canton of Ticino. For the years 2020–2049, the predicted possible spread of the tiger mosquito does not differ significantly from its potential current distribution. However, important expansions are obtained if the period is extended to the years 2045–2074, when Ae. albopictus may invade large new areas.

Conclusions/Significance

Several parts of Switzerland provide suitable climatic conditions for invasion and establishment of Ae. albopictus. The current distribution and rapid spread in other European countries suggest that the tiger mosquito will colonize new areas in Switzerland in the near future.     

Models of β-amyloid induced Tau-pathology: the long and “folded” road to understand the mechanism

The amyloid cascade hypothesis has been the prevailing hypothesis in Alzheimer’s Disease research, although the final and most wanted proof i.e. fully successful anti-amyloid clinical trials in patients, is still lacking. This may require a better in depth understanding of the cascade. Particularly, the exact toxic forms of Aβ and Tau, the molecular link between them and their respective contributions to the disease process need to be identified in detail. Although the lack of final proof has raised substantial criticism on the hypothesis per se, accumulating experimental evidence in in vitro models, in vivo models and from biomarkers analysis in patients supports the amyloid cascade and particularly Aβ-induced Tau-pathology, which is the focus of this review. We here discuss available models that recapitulate Aβ-induced Tau-pathology and review some potential underlying mechanisms. The availability and diversity of these models that mimic the amyloid cascade partially or more complete, provide tools to study remaining questions, which are crucial for development of therapeutic strategies for Alzheimer’s Disease.     

Framework Models of Ion Permeation Through Membrane Channels and the Generalized King–Altman Method

A modern approach to studying the detailed dynamics of biomolecules is to simulate them on computers. Framework models have been developed to incorporate information from these simulations in order to calculate properties of the biomolecules on much longer time scales than can be achieved by the simulations. They also provide a simple way to think about the simulated dynamics. This article develops a method for the solution of framework models, which generalizes the King–Altman method of enzyme kinetics. The generalized method is used to construct solutions of two framework models which have been introduced previously, the single-particle and Grotthuss (proton conduction) models. The solution of the Grotthuss model is greatly simplified in comparison with direct integration. In addition, a new framework model is introduced, generalizing the shaking stack model of ion conduction through the potassium channel.     

Isorhamnetin Inhibits Proliferation and Invasion and Induces Apoptosis through the Modulation of Peroxisome Proliferator-activated Receptor γ Activation Pathway in Gastric Cancer

Gastric cancer (GC) is a lethal malignancy and the second most common cause of cancer-related deaths. Although treatment options such as chemotherapy, radiotherapy, and surgery have led to a decline in the mortality rate due to GC, chemoresistance remains as one of the major causes for poor prognosis and high recurrence rate. In this study, we investigated the potential effects of isorhamnetin (IH), a 3′-O-methylated metabolite of quercetin on the peroxisome proliferator-activated receptor γ (PPAR-γ) signaling cascade using proteomics technology platform, GC cell lines, and xenograft mice model. We observed that IH exerted a strong antiproliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of GC cells, which could be reversed in the presence of PPAR-γ inhibitor. We found that IH increased PPAR-γ activity and modulated the expression of PPAR-γ regulated genes in GC cells. Also, the increase in PPAR-γ activity was reversed in the presence of PPAR-γ-specific inhibitor and a mutated PPAR-γ dominant negative plasmid, supporting our hypothesis that IH can act as a ligand of PPAR-γ. Using molecular docking analysis, we demonstrate that IH formed interactions with seven polar residues and six nonpolar residues within the ligand-binding pocket of PPAR-γ that are reported to be critical for its activity and could competitively bind to PPAR-γ. IH significantly increased the expression of PPAR-γ in tumor tissues obtained from xenograft model of GC. Overall, our findings clearly indicate that antitumor effects of IH may be mediated through modulation of the PPAR-γ activation pathway in GC.     

Pancreatic Cancer Cell Glycosylation Regulates Cell Adhesion and Invasion through the Modulation of α2β1 Integrin and E-Cadherin Function

In our previous studies we have described that ST3Gal III transfected pancreatic adenocarcinoma Capan-1 and MDAPanc-28 cells show increased membrane expression levels of sialyl-Lewis x (SLe^x) along with a concomitant decrease in α2,6-sialic acid compared to control cells. Here we have addressed the role of this glycosylation pattern in the functional properties of two glycoproteins involved in the processes of cancer cell invasion and migration, α2β1 integrin, the main receptor for type 1 collagen, and E-cadherin, responsible for cell-cell contacts and whose deregulation determines cell invasive capabilities. Our results demonstrate that ST3Gal III transfectants showed reduced cell-cell aggregation and increased invasive capacities. ST3Gal III transfected Capan-1 cells exhibited higher SLe^x and lower α2,6-sialic acid content on the glycans of their α2β1 integrin molecules. As a consequence, higher phosphorylation of focal adhesion kinase tyrosine 397, which is recognized as one of the first steps of integrin-derived signaling pathways, was observed in these cells upon adhesion to type 1 collagen. This molecular mechanism underlies the increased migration through collagen of these cells. In addition, the pancreatic adenocarcinoma cell lines as well as human pancreatic tumor tissues showed colocalization of SLe^x and E-cadherin, which was higher in the ST3Gal III transfectants. In conclusion, changes in the sialylation pattern of α2β1 integrin and E-cadherin appear to influence the functional role of these two glycoproteins supporting the role of these glycans as an underlying mechanism regulating pancreatic cancer cell adhesion and invasion.     

Neurologic Abnormalities in Mouse Models of the Lysosomal Storage Disorders Mucolipidosis II and Mucolipidosis III γ

UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase is an α₂β₂γ₂ hexameric enzyme that catalyzes the synthesis of the mannose 6-phosphate targeting signal on lysosomal hydrolases. Mutations in the α/β subunit precursor gene cause the severe lysosomal storage disorder mucolipidosis II (ML II) or the more moderate mucolipidosis III alpha/beta (ML III α/β), while mutations in the γ subunit gene cause the mildest disorder, mucolipidosis III gamma (ML III γ). Here we report neurologic consequences of mouse models of ML II and ML III γ. The ML II mice have a total loss of acid hydrolase phosphorylation, which results in depletion of acid hydrolases in mesenchymal-derived cells. The ML III γ mice retain partial phosphorylation. However, in both cases, total brain extracts have normal or near normal activity of many acid hydrolases reflecting mannose 6-phosphate-independent lysosomal targeting pathways. While behavioral deficits occur in both models, the onset of these changes occurs sooner and the severity is greater in the ML II mice. The ML II mice undergo progressive neurodegeneration with neuronal loss, astrocytosis, microgliosis and Purkinje cell depletion which was evident at 4 months whereas ML III γ mice have only mild to moderate astrocytosis and microgliosis at 12 months. Both models accumulate the ganglioside GM2, but only ML II mice accumulate fucosylated glycans. We conclude that in spite of active mannose 6-phosphate-independent targeting pathways in the brain, there are cell types that require at least partial phosphorylation function to avoid lysosomal dysfunction and the associated neurodegeneration and behavioral impairments.     

Pin1 Promotes Transforming Growth Factor-��-induced Migration and Invasion

Transforming growth factor-β (TGF-β) regulates a wide variety of biological activities. It induces potent growth-inhibitory responses in normal cells but promotes migration and invasion of cancer cells. Smads mediate the TGF-β responses. TGF-β binding to the cell surface receptors leads to the phosphorylation of Smad2/3 in their C terminus as well as in the proline-rich linker region. The serine/threonine phosphorylation sites in the linker region are followed by the proline residue. Pin1, a peptidyl-prolyl cis/trans isomerase, recognizes phosphorylated serine/threonine-proline motifs. Here we show that Smad2/3 interacts with Pin1 in a TGF-β-dependent manner. We further show that the phosphorylated threonine 179-proline motif in the Smad3 linker region is the major binding site for Pin1. Although epidermal growth factor also induces phosphorylation of threonine 179 and other residues in the Smad3 linker region the same as TGF-β, Pin1 is unable to bind to the epidermal growth factor-stimulated Smad3. Further analysis suggests that phosphorylation of Smad3 in the C terminus is necessary for the interaction with Pin1. Depletion of Pin1 by small hairpin RNA does not significantly affect TGF-β-induced growth-inhibitory responses and a number of TGF-β/Smad target genes analyzed. In contrast, knockdown of Pin1 in human PC3 prostate cancer cells strongly inhibited TGF-β-mediated migration and invasion. Accordingly, TGF-β induction of N-cadherin, which plays an important role in migration and invasion, is markedly reduced when Pin1 is depleted in PC3 cells. Because Pin1 is overexpressed in many cancers, our findings highlight the importance of Pin1 in TGF-β-induced migration and invasion of cancer cells.     

Electrodiffusion Models of Neurons and Extracellular Space Using the Poisson-Nernst-Planck Equations—Numerical Simulation of the Intra- and?Extracellular Potential for an Axon Model

In neurophysiology, extracellular signals—as measured by local field potentials (LFP) or electroencephalography—are of great significance. Their exact biophysical basis is, however, still not fully understood. We present a three-dimensional model exploiting the cylinder symmetry of a single axon in extracellular fluid based on the Poisson-Nernst-Planck equations of electrodiffusion. The propagation of an action potential along the axonal membrane is investigated by means of numerical simulations. Special attention is paid to the Debye layer, the region with strong concentration gradients close to the membrane, which is explicitly resolved by the computational mesh. We focus on the evolution of the extracellular electric potential. A characteristic up-down-up LFP waveform in the far-field is found. Close to the membrane, the potential shows a more intricate shape. A comparison with the widely used line source approximation reveals similarities and demonstrates the strong influence of membrane currents. However, the electrodiffusion model shows another signal component stemming directly from the intracellular electric field, called the action potential echo. Depending on the neuronal configuration, this might have a significant effect on the LFP. In these situations, electrodiffusion models should be used for quantitative comparisons with experimental data.     

Animal Models and Experimental Medicine被PubMed Central收录

Animal Models and Experimental Medicine (简称AMEM,《动物模型与实验医学(英文)》)主管单位是中国科学技术协会,由中国实验动物学会、中国医学科学院医学实验动物研究所共同主办,与国际著名出版集团Wiley合作出版。AMEM获"中国科技期刊国际影响力提升计划"D类项目支持,于2018年3月创刊,季刊,主编为中国实验动物学会理事长、中国医学科学院医学实验动物研究所所长秦川教授。     

On the Modelling of Biological Patterns with Mechanochemical Models: Insights from Analysis and Computation

The diversity of biological form is generated by a relatively small number of underlying mechanisms. Consequently, mathematical and computational modelling can, and does, provide insight into how cellular level interactions ultimately give rise to higher level structure. Given cells respond to mechanical stimuli, it is therefore important to consider the effects of these responses within biological self-organisation models. Here, we consider the self-organisation properties of a mechanochemical model previously developed by three of the authors in Acta Biomater. 4, 613–621 (2008), which is capable of reproducing the behaviour of a population of cells cultured on an elastic substrate in response to a variety of stimuli. In particular, we examine the conditions under which stable spatial patterns can emerge with this model, focusing on the influence of mechanical stimuli and the interplay of non-local phenomena. To this end, we have performed a linear stability analysis and numerical simulations based on a mixed finite element formulation, which have allowed us to study the dynamical behaviour of the system in terms of the qualitative shape of the dispersion relation. We show that the consideration of mechanotaxis, namely changes in migration speeds and directions in response to mechanical stimuli alters the conditions for pattern formation in a singular manner. Furthermore without non-local effects, responses to mechanical stimuli are observed to result in dispersion relations with positive growth rates at arbitrarily large wavenumbers, in turn yielding heterogeneity at the cellular level in model predictions. This highlights the sensitivity and necessity of non-local effects in mechanically influenced biological pattern formation models and the ultimate failure of the continuum approximation in their absence.     

Models for dioxygen activation by the CuB site of dopamine β-monooxygenase and peptidylglycine α-hydroxylating monooxygenase

On the basis of spectroscopic and crystallographic data for dopamine beta-monooxygenase and peptidylglycine alpha-hydroxylating monooxygenase (PHM), a variety of ligand sets have been used to model the oxygen-binding Cu site in these enzymes. Calculations which employed a combination of density functional and multireference second-order perturbation theory methods provided insights into the optimal ligand set for supporting eta (1) superoxo coordination as seen in a crystal structure of a precatalytic Cu/O(2) complex for PHM (Prigge et al. in Science 304:864-867, 2004). Anionic ligand sets stabilized eta (2) dioxygen coordination and were found to lead to more peroxo-like Cu-O(2) complexes with relatively exergonic binding free energies, suggesting that these adducts may be unreactive towards substrates. Neutral ligand sets (including a set of two imidazoles and a thioether), on the other hand, energetically favored eta (1) dioxygen coordination and exhibited limited dioxygen reduction. Binding free energies for the 1:1 adducts with Cu supported by the neutral ligand sets were also higher than with their anionic counterparts. Deviations between the geometry and energetics of the most analogous models and the PHM crystal structures suggest that the protein environment influences the coordination geometry at the Cu(B) site and increases the lability of water bound to the preoxygenated reduced form. Another implication is that a neutral ligand set will be critical in biomimetic models in order to stabilize eta (1) dioxygen coordination.     

Does Mutualism Drive the Invasion of Two Alien Species? The Case of Solenopsis invicta and Phenacoccus solenopsis

Although mutualism between ants and honeydew-producing hemipterans has been extensively recognized in ecosystem biology, however few attempts to test the hypothesis that mutualism between two alien species leads to the facilitation of the invasion process. To address this problem, we focus on the conditional mutualism between S. invicta and P. solenopsis by field investigations and indoor experiments. In the laboratory, ant colony growth increased significantly when ants had access to P. solenopsis and animal-based food. Honeydew produced by P. solenopsis also improved the survival of ant workers. In the field, colony density of P. solenopsis was significantly greater on plots with ants than on plots without ants. The number of mealybug mummies on plants without fire ants was almost three times that of plants with fire ants, indicating a strong effect of fire ants on mealybug survival. In addition, the presence of S. invicta successfully contributed to the spread of P. solenopsis. The quantity of honeydew consumption by S. invicta was significantly greater than that of a presumptive native ant, Tapinoma melanocephalum. When compared with the case without ant tending, mealybugs tended by ants matured earlier and their lifespan and reproduction increased. T. melanocephalum workers arrived at honeydew more quickly than S. invicta workers, while the number of foraging S. invicta workers on plants steadily increased, eventually exceeding that number of T. melanocephalum foragers. Overall, these results suggest that the conditional mutualism between S. invicta and P. solenopsis facilitates population growth and fitness of both species. S. invicta tends to acquire much more honeydew and drive away native ants, promoting their predominance. These results suggest that the higher foraging tempo of S. invicta may provide more effective protection of P. solenopsis than native ants. Thus mutualism between these two alien species may facilitate the invasion success of both species.     

Podocalyxin Promotes Glioblastoma Multiforme Cell Invasion and Proliferation via β-Catenin Signaling

Both podocalyxin (PODX) and β-catenin (β-cat) signaling reportedly play important roles in glioblastoma multiforme (GBM) progression. In this study, we for the first time explored crosstalk between PODX and β-cat signaling in GBM cells, and assessed its impact on GBM cell invasion and proliferation. Stable overexpression of PODX in LN-229 and U-118 MG human GBM cells increased the soluble/intracellular β-cat level, TOPflash luciferase reporter activity, the mRNA levels of β-cat signaling target genes, matrix metalloproteinase 9 (MMP9) expression/activity, and cell invasion and proliferation, which was abolished by selective p38 mitogen-activated protein kinase (MAPK) inhibitor PD169316 and selective β-cat signaling inhibitor CCT031374. On the other hand, stable knockdown of PODX in LN-229 and U-118 MG cells decreased the soluble β-cat level, TOPflash luciferase reporter activity, the mRNA levels of β-cat signaling target genes, MMP9 expression/activity, and cell invasion and proliferation, which was completely reversed by overexpression of a constitutively active β-cat mutant. In addition, overexpression of PODX induced p38 MAPK activity and inactivating phosphorylation of glycogen synthase kinase-3β (GSK-3β) at serine 389 in LN-229 and U-118 MG cells, which was abolished by PD169316, but not CCT031374; knockdown of PODX decreased p38 MAPK activity and inactivating phosphorylation of GSK-3β at serine 389 in both cell lines, which was not significantly affected by overexpression of constitutively active β-cat. In conclusion, this study indicates that PODX promotes GBM cell invasion and proliferation by elevating the soluble β-cat level/β-cat signaling through the p38 MAPK/GSK-3β pathway. Uncovering the PODX/β-cat signaling axis adds new insights not only into the biological functions of PODX and β-cat, but also into the molecular mechanisms underlying GBM progression.