Toward a Generalised Tensegrity Model Describing the Mechanical Behaviour of the Cytoskeleton Structure

The control of many cell functions including growth, migration and mechanotransduction, depends crucially on stress-induced mechanical changes in cell shape and cytoskeleton (CSK) structure. Quantitative studies have been carried out on 6-bar tensegrity models to analyse several mechanical parameters involved in the mechanical responses of adherent cells (i.e. strain hardening, internal stress and scale effects). In the present study, we attempt to generalize some characteristic mechanical laws governing spherical tensegrity structures, with a view of evaluating the mechanical behaviour of the hierarchical multi-modular CSK-structure. The numerical results obtained by studying four different tensegrity models are presented in terms of power laws and point to the existence of unique and constant relationships between the overall structural stiffness and the local properties (length, number and internal stress) of the constitutive components.     

Environmental Influences on Dall's Sheep Survival

Understanding how species respond to environmental conditions can assist with conservation strategies and harvest management, especially in arctic and boreal regions that are experiencing rapid climate change. Although climatic influences on species distributions have been studied, broad-scale effects of climate on survival are less well known. We examined the interactive effects of meteorological and remotely sensed environmental variables on survival of Dall's sheep (Ovis dalli dalli) lambs and adults by synthesizing radio-telemetry data across their range. We used data from 9 studies of adult sheep and 2 studies of lambs that were conducted between 1997 and 2012 at sites spanning the species' range in Alaska, USA, and northwestern Canada. We obtained environmental variables throughout the range of Dall's sheep, including the normalized difference vegetation index (NDVI) from optical remote sensing, freeze-thaw frequency (FTF) from passive microwave remote sensing, and gridded climate variables such as snow water equivalent, temperature, and precipitation. We used Cox proportional hazard regression to investigate the effects of environmental variables recorded during summer, winter, and the previous winter on annual survival rates of Dall's sheep lambs and adults. Summer NDVI was the most influential environmental factor affecting lamb survival, with improved lamb survival occurring in years with a high maximum NDVI. Also, lamb predation by coyotes (Canis latrans) and golden eagles (Aquila chrysaetos) decreased substantially with increasing NDVI. The previous winter FTF had the strongest effect on adult survival, with decreased survival occurring after winters with high FTF. In addition, these remotely sensed environmental factors interacted with meteorological factors to affect survival, such that effects of winter temperature depended on summer NDVI and winter FTF. Warm winters increased lamb survival only when preceded by summers with high NDVI, and warm winters increased adult survival only when winter FTF was low. Thus, potential benefits of climate warming may be counteracted if wintertime freeze-thaw events markedly increase. Correlations among environmental variables across sites were low, and regional climate cycles such as the Pacific Decadal Oscillation (PDO) had weak effects, indicating substantial local variability in climatic conditions experienced by Dall's sheep across their range. These findings can help managers anticipate how Dall's sheep populations will respond to changes in local environmental conditions. Our results also highlight the utility of multiple remotely sensed environmental conditions for ungulate management, especially passive microwave products that provide valuable information on winter icing events. © 2020 The Wildlife Society.     

Dissecting the Inter-Substrate Navigation of Migrating Glioblastoma Cells with the Stripe Assay Reveals a Causative Role of ROCK

A hallmark of gliomas is the growth and migration of cells over long distances within the brain and proliferation within selected niches, indicating that the migrating cells navigate between complex substrates. We demonstrate in the present study a differential preference for migration that depends on Rho-associated coil kinase (ROCK) signaling, using the alternating Bonhoeffer stripe assay. Membrane fractions from nonmyelinated and myelinated brain areas from female rats, purified myelin also from female rats, and commercial extracellular matrix were used as substrates, with each substrate being tested against the others. The human tumor cell lines exhibited a clear preference for extracellular matrix over all other substrates and for myelinated over nonmyelinated tissue. ROCK signaling was different when cells were cultured on either substrate. The ROCK inhibitor Y27632 significantly attenuated and neutralized the preference for extracellular matrix and myelin, indicating that ROCK controls the substrate selectivity. The findings of this study pave the way for navigation-targeted therapeutics.     

Influence of root and leaf traits on the uptake of nutrients in cover crops

Plant and Soil - The objectives of this study were to determine the spatial structure of soil respiration (Rs) in a naturally-regenerated longleaf pine forest and to assess the ecological factors...     

Tensegrity behaviour of cortical and cytosolic cytoskeletal components in twisted living adherent cells

The present study is an attempt to relate the multicomponent response of the cytoskeleton (CSK), evaluated in twisted living adherent cells, to the heterogeneity of the cytoskeletal structure - evaluated both experimentally by means of 3D reconstructions, and theoretically considering the predictions given by two tensegrity models composed of (four and six) compressive elements and (respectively 12 and 24) tensile elements. Using magnetic twisting cytometry in which beads are attached to integrin receptors linked to the actin CSK of living adherent epithelial cells, we specifically measured the elastic CSK response at quasi equilibrium state and partitioned this response in terms of cortical and cytosolic contributions with a two-component model (i.e., a series of two Voigt bodies). These two CSK components were found to be prestressed and exhibited a stress-hardening response which both characterize tensegrity behaviour with however significant differences: compared to the cytosolic component, the cortical cytoskeleton appears to be a faster responding component, being a less prestressed and easily deformable structure. The discrepancies in elastic behaviour between the cortical and cytosolic CSK components may be understood on the basis of prestress tensegrity model predictions, given that the length and number of constitutive actin elements are taken into account.     

A cellular tensegrity model to analyse the structural viscoelasticity of the cytoskeleton

This study describes the viscoelastic properties of a refined cellular-tensegrity model composed of six rigid bars connected to a continuous network of 24 viscoelastic pre-stretched cables (Voigt bodies) in order to analyse the role of the cytoskeleton spatial rearrangement on the viscoelastic response of living adherent cells. This structural contribution was determined from the relationships between the global viscoelastic properties of the tensegrity model, i.e., normalized viscosity modulus (eta(*)), normalized elasticity modulus (E(*)), and the physical properties of the constitutive elements, i.e., their normalized length (L(*)) and normalized initial internal tension (T(*)). We used a numerical method to simulate the deformation of the structure in response to different types of loading, while varying by several orders of magnitude L(*) and T(*). The numerical results obtained reveal that eta(*) remains almost independent of changes in T(*) (eta(*) proportional, variant T(*+0.1)), whereas E(*) increases with approximately the square root of the internal tension T(*) (from E(*) proportional, variant T(*+0.3) to E(*) proportional, variant T(*+0.7)). Moreover, structural viscosity eta(*) and elasticity E(*) are both inversely proportional to the square of the size of the structure (eta(*) proportional, variant L(*-2) and E(*) proportional, variant L(*-2)). These structural properties appear consistent with cytoskeleton (CSK) mechanical properties measured experimentally by various methods which are specific to the CSK micromanipulation in living adherent cells. Present results suggest, for the first time, that the effect of structural rearrangement of CSK elements on global CSK behavior is characterized by a faster cellular mechanical response relatively to the CSK element response, which thus contributes to the solidification process observed in adherent cells. In extending to the viscoelastic properties the analysis of the mechanical response of the cellular 30-element tensegrity model, the present study contributes to the understanding of recent results on the cellular-dynamic response and allows to reunify the scattered data reported for the viscoelastic properties of living adherent cells.     

Retinoic acid-induced developmental defects are mediated by RARbeta/RXR heterodimers in the pharyngeal endoderm

Fusion and hypoplasia of the first two branchial arches, a defect typically observed in retinoic acid (RA) embryopathy, is generated in cultured mouse embryos upon treatment with BMS453, a synthetic compound that exhibits retinoic acid receptor beta (RARbeta) agonistic properties in transfected cells. By contrast, no branchial arch defects are observed following treatment with synthetic retinoids that exhibit RARalpha or RARgamma agonistic properties. The BMS453-induced branchial arch defects are mediated through RAR activation, as they are similar to those generated by a selective pan-RAR agonist, are prevented by a selective pan-RAR antagonist and cannot be mimicked by exposure to a pan-RXR agonist alone. They are enhanced in the presence of a pan-RXR agonist, and cannot be generated in Rarb-null embryos. Furthermore, they are accompanied, in the morphologically altered region, by ectopic expression of Rarb and of several other direct RA target genes. Therefore, craniofacial abnormalities characteristic of the RA embryopathy are mediated through ectopic activation of RARbeta/RXR heterodimers, in which the ligand-dependent activity of RXR is subordinated to that of RARbeta. Endodermal cells lining the first two branchial arches respond to treatment with the RARbeta agonist, in contrast to neural crest cells and ectoderm, which suggests that a faulty endodermal regionalization is directly responsible for RA-induced branchial arch dysmorphologies. Additionally, we provide the first in vivo evidence that the synthetic RARbeta agonist BMS453 exhibits an antagonistic activity on the two other RAR isotypes.     

In Vivo Evidence That the Stromelysin-3 Metalloproteinase Contributes in a Paracrine Manner to Epithelial Cell Malignancy

Stromelysin-3 (ST3; Basset, P., J.P. Bellocq, C. Wolf, I. Stoll, P. Hutin, J.M. Limacher, O.L. Podhajcer, M.P. Chenard, M.C. Rio, P. Chambon. 1990. Nature. 348:699–704) is a matrix metalloproteinase (MMP) expressed in mesenchymal cells located close to epithelial cells, during physiological and pathological tissue remodeling processes. In human carcinomas, high ST3 levels are associated with a poor clinical outcome, suggesting that ST3 plays a role during malignant processes. In this study we report the ST3 gene inactivation by homologous recombination. Although ST3 null mice (ST3^−/−) were fertile and did not exhibit obvious alterations in appearance and behavior, the lack of ST3 altered malignant processes. Thus, the suppression of ST3 results in a decreased 7,12-dimethylbenzanthracene-induced tumorigenesis in ST3^−/− mice. Moreover, ST3^−/− fibroblasts have lost the capacity to promote implantation of MCF7 human malignant epithelial cells in nude mice (P < 0.008). Finally, we show that this ST3 paracrine function requires extracellular matrix (ECM)-associated growth factors. Altogether, these findings give evidence that ST3 promotes, in a paracrine manner, homing of malignant epithelial cells, a key process for both primary tumors and metastases. Therefore, ST3 represents an appropriate target for specific MMP inhibitor(s) in future therapeutical approaches directed against the stromal compartment of human carcinomas.     

Structure-based parallel medicinal chemistry approach to improve metabolic stability of benzopyran COX-2 inhibitors

Combination of the structure-based design and solid-phase parallel synthesis provided an integrated approach to rapidly develop the structure-activity relationship of benzopyran COX-2 inhibitors. Binding free energies predicted by free energy perturbation theory yielded good agreement with experimental results. New potent and selective lead compounds with improved metabolic properties were identified.