Matrix Rigidity Regulates Cancer Cell Growth and Cellular Phenotype

Background: The mechanical properties of the extracellular matrix have an important role in cell growth and differentiation. However, it is unclear as to what extent cancer cells respond to changes in the mechanical properties (rigidity/stiffness) of the microenvironment and how this response varies among cancer cell lines. Methodology/Principal Findings: In this study we used a recently developed 96-well plate system that arrays extracellular matrix-conjugated polyacrylamide gels that increase in stiffness by at least 50-fold across the plate. This plate was used to determine how changes in the rigidity of the extracellular matrix modulate the biological properties of tumor cells. The cell lines tested fall into one of two categories based on their proliferation on substrates of differing stiffness: ‘‘rigidity dependent’ ’ (those which show an increase in cell growth as extracellular rigidity is increased), and ‘‘rigidity independent’’ (those which grow equally on both soft and stiff substrates). Cells which grew poorly on soft gels also showed decreased spreading and migration under these conditions. More importantly, seeding the cell lines into the lungs of nude mice revealed that the ability of cells to grow on soft gels in vitro correlated with their ability to grow in a soft tissue environment in vivo. The lung carcinoma line A549 responded to culture on soft gels by expressing the differentiated epithelial marker E-cadherin and decreasing the expression of the mesenchymal transcription factor Slug. Conclusions/Significance: These observations suggest that the mechanical properties of the matrix environment play

High throughput screening for discovery of materials that control stem cell fate

Insights into the complex stem cell niche have identified the cell–material interface to be a potent regulator of stem cell fate via material properties such as chemistry, topography and stiffness. In light of this, materials scientists have the opportunity to develop bioactive materials for stem cell culture that elicit specific cellular responses. To accelerate materials discovery, high throughput screening platforms have been designed which can rapidly evaluate combinatorial material libraries in two and three-dimensional environments. In this review, we present screening platforms for the discovery of material properties that influence stem cell behavior

Protection and consolidation of stone heritage by self-inoculation with indigenous carbonatogenic bacterial communities

Enhanced salt weathering resulting from global warming and increasing environmental pollution is endangering the survival of stone monuments and artworks. To mitigate the effects of these deleterious processes, numerous conservation treatments have been applied that, however, show limited efficacy. Here we present a novel, environmentally friendly, bacterial self-inoculation approach for the conservation of stone, based on the isolation of an indigenous community of carbonatogenic bacteria from salt damaged stone, followed by their culture and re-application back onto the same stone. This method results in an effective consolidation and protection due to the formation of an abundant and exceptionally strong hybrid cement consisting of nanostructured bacterial CaCO3 and bacterially derived organics, and the passivating effect of bacterial exopolymeric substances (EPS) covering the substrate. The fact that the isolated and identified bacterial community is common to many stone artworks may enable worldwide application of this novel conservation methodology.This work was supported by the Spanish Government (Grants MAT2012-37584, CGL2012-35992 and CGL2015-70642-R), the Junta de Andalucía through Proyecto de excelencia RNM-3493 and Project P11-RNM-7550, the Research Groups BIO 103 and RNM-179, and the University of Granada (Unidad Científica de Excelencia UCE-PP2016-05). Additional funds were provided by the Molecular Foundry (Lawrence Berkeley National Laboratory, LBNL, University of California, Berkeley, CA) for a research stay of M.S. (project #1451; User Agreement No. NPUSR009206)

Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a

This is the final version. Available on open access from Nature Research via the DOI in this recordThe SLC12A cation-Clcotransporters (CCC), including NKCC1 and the KCCs, are important determinants of brain ionic homeostasis. SPAK kinase (STK39) is the CCC master regulator, which stimulates NKCC1 ionic influx and inhibits KCC-mediated efflux via phosphorylation at conserved, shared motifs. Upregulation of SPAK-dependent CCC phosphorylation has been implicated in several neurological diseases. Using a scaffold-hybrid strategy, we develop a novel potent and selective SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxybenzamide ("ZT-1a"). ZT-1a inhibits NKCC1 and stimulates KCCs by decreasing their SPAK-dependent phosphorylation. Intracerebroventricular delivery of ZT-1adecreases inflammation-induced CCC phosphorylation in the choroid plexus and reduces cerebrospinal fluid (CSF) hypersecretion in a model of post-hemorrhagic hydrocephalus. Systemically administered ZT-1a reduces ischemia-induced CCC phosphorylation, attenuates cerebral edema, protects against brain damage, and improves outcomes in a model of stroke. These results suggest ZT-1a or related compounds may be effective CCC modulators with therapeutic potential for brain disorders associated with impaired ionic homeostasis.National Key R&D ProgramNational Natural Science Foundation of ChinaFundamental Research Funds for the Central Universities of ChinaHydrocephalus FoundationSimons Foundatio

Recon3D enables a three-dimensional view of gene variation in human metabolism

Genome-scale network reconstructions have helped uncover the molecular basis of metabolism. Here we present Recon3D, a computational resource that includes three-dimensional (3D) metabolite and protein structure data and enables integrated analyses of metabolic functions in humans. We use Recon3D to functionally characterize mutations associated with disease, and identify metabolic response signatures that are caused by exposure to certain drugs. Recon3D represents the most comprehensive human metabolic network model to date, accounting for 3,288 open reading frames (representing 17% of functionally annotated human genes), 13,543 metabolic reactions involving 4,140 unique metabolites, and 12,890 protein structures. These data provide a unique resource for investigating molecular mechanisms of human metabolism. Recon3D is available at http://vmh.life

Ritual plants of Muslim graveyards in northern Israel

This article surveys the botanical composition of 40 Muslim graveyards in northern Israel, accompanied by an ethnobotanical study of the folkloristic traditions of the use of these plants in cemeteries. Three groups of plants were found to be repeated systematically and were also recognized for their ritual importance: aromatics herbs (especially Salvia fruticosa and Rosmarinus officinalis), white flowered plants (mainly Narcissus tazetta, Urginea maritima, Iris spp. and Pancratium spp.) and Cupressus sempervirens as the leading cemetery tree. As endemic use we can indicate the essential role of S. fruticosa as the main plant used in all human rites of passage symbolizing the human life cycle. The rosemary is of European origin while the use of basil is of Indian influence. The use of white flowers as cemeteries plants reflects an old European influence and almost the same species are used or their congeners. Most of the trees and shrubs that are planted in Muslim cemeteries in Israel have the same use in ancient as well in modern European cultures. In conclusion, our findings on the occurrence of plants in graveyards reflect the geographic situation of Israel as a crossroads in the cultural arena between Asia and Europe. Most of the traditions are common to the whole Middle East showing high relatedness to the classical world as well as to the present-day Europe

Transition, Integration and Convergence. The Case of Romania

This volume comprises several studies and papers published in the last decades. They have been selected and ranged so that to provide a minimum of coherence concerning the phases which Romania has crossed in her way to the advanced socio-economic system of European type: transition to the market economy, accession to the EU, the economic convergence in the three fundamental domains: institutions, real economy, and nominal economy. The readers may find in this volume a description of debates, difficulties and solutions adopted for building-up the market economy by a state being in a profound transformation from weak transition institutions towards hard democratic institutions. Because the transition to the market economy and the association of Romania with the EU and then the integration presenting strategic political decisions, I have included in this work two studies devoted to the political forces state and political parties that elaborated and applied these strategic decisions underlining their structure, role and function and their transformation. Integration into the EU of a country like Romania, which emerged from a different system comparing with the West-European one, has proved to be difficult and lasting many years because of the structural transformations. In five chapters I am referring to the essential characteristics of the integration process, such as: market liberalization, competitiveness of the local (national) firms on the national and EU markets, institutional reforms so that the institutions of candidate countries have to become compatible with those of the EU and finally the perspective assessment to find out the real and nominal convergence. Putting into practice the EU competitivity and cohesion principles, Romania has good prospects to close, in a reasonable time, the economic gap and to be admitted into the Euro Zone. Although the real convergence of Romania with the EU requires higher growth rates for the former, a new approach is compulsory to take into consideration the environment quality, the natural resources and the equity between the present and the future generations as natural resource consumers. Just these problems have determined me to include in this volume the last two chapters which, on the one hand, try to prove the necessity of the economy growth harmonization with the environment evolution as well as the saving of the energy resources, and, on the other hand, to point out the main ways to be followed and instruments to be used