Material-driven fibronectin assembly for high-efficiency presentation of growth factors

Growth factors (GFs) are powerful signaling molecules with the potential to drive regenerative strategies, including bone repair and vascularization. However, GFs are typically delivered in soluble format at supraphysiological doses because of rapid clearance and limited therapeutic impact. These high doses have serious side effects and are expensive. Although it is well established that GF interactions with extracellular matrix proteins such as fibronectin control GF presentation and activity, a translation-ready approach to unlocking GF potential has not been realized. We demonstrate a simple, robust, and controlled material-based approach to enhance the activity of GFs during tissue healing. The underlying mechanism is based on spontaneous fibrillar organization of fibronectin driven by adsorption onto the polymer poly(ethyl acrylate). Fibrillar fibronectin on this polymer, but not a globular conformation obtained on control polymers, promotes synergistic presentation of integrin-binding sites and bound bone morphogenetic protein 2 (BMP-2), which enhances mesenchymal stem cell osteogenesis in vitro and drives full regeneration of a nonhealing bone defect in vivo at low GF concentrations. This simple and translatable technology could unlock the full regenerative potential of GF therapies while improving safety and cost-effectiveness

A Methodology to Analyze and Evaluate the Uncertainty Propagation due to Temperature and Frequency and Design Optimization for EMC Testing Instrumentation

This paper presents a study and proposes a new methodology to analyze, evaluate and reduce the overall uncertainty of instrumentations for EMC measurements. For the scope of this work, the front end of a commercial EMI receiver is chosen and variations due to tolerances, temperature and frequency response of the system are evaluated. This paper illustrates in detail how to treat each block composing the model by analyzing each discrete component, and how to evaluate their influence on the measurand. Since a model can have hundreds or even thousands of parameters, the probability distribution functions (PDFs) of some variable might be unknown. So, a method that allows to obtain in a fast and easy way the uncertainty of the measurement despite having so many variables, to then being able to evaluate the influence of each component on the measurand, is necessary for a correct design. In this way, it will be possible to indicate which discrete components have the most influence on the measurand and thus set the maximum tolerances allowed and being able to design a cost-effective solution. Furthermore, this works presents a methodology which can easily be extended and applied to estimate and compute the uncertainty for electromagnetic interferences, energy storage systems (ESS), energy production, electric machines, electric transports and power plants in genera

Engineered microenvironments for synergistic VEGF - integrin signalling during vascularization

We have engineered polymer-based microenvironments that promote vasculogenesis both in vitro and in vivo through synergistic integrin-growth factor receptor signalling. Poly(ethyl acrylate) (PEA) triggers spontaneous organization of fibronectin (FN) into nanonetworks which provide availability of critical binding domains. Importantly, the growth factor binding (FNIII12-14) and integrin binding (FNIII9-10) regions are simultaneously available on FN fibrils assembled on PEA. This material platform promotes synergistic integrin/VEGF signalling which is highly effective for vascularization events in vitro with low concentrations of VEGF. VEGF specifically binds to FN fibrils on PEA compared to control polymers (poly(methyl acrylate), PMA) where FN remains in a globular conformation and integrin/GF binding domains are not simultaneously available. The vasculogenic response of human endothelial cells seeded on these synergistic interfaces (VEGF bound to FN assembled on PEA) was significantly improved compared to soluble administration of VEGF at higher doses. Early onset of VEGF signalling (PLCγ1 phosphorylation) and both integrin and VEGF signalling (ERK1/2 phosphorylation) were increased only when VEGF was bound to FN nanonetworks on PEA, while soluble VEGF did not influence early signalling. Experiments with mutant FN molecules with impaired integrin binding site (FN-RGE) confirmed the role of the integrin binding site of FN on the vasculogenic response via combined integrin/VEGF signalling. In vivo experiments using 3D scaffolds coated with FN and VEGF implanted in the murine fat pad demonstrated pro-vascularization signalling by enhanced formation of new tissue inside scaffold pores. PEA-driven organization of FN promotes efficient presentation of VEGF to promote vascularization in regenerative medicine applications

Experimental setup and procedure for the measurement of the 7Be(n,p)7Li reaction at n_TOF

Following the completion of the second neutron beam line and the related experimental area (EAR2) at the n_TOF spallation neutron source at CERN, several experiments were planned and performed. The high instantaneous neutron flux available in EAR2 allows to investigate neutron induced reactions with charged particles in the exit channel even employing targets made out of small amounts of short-lived radioactive isotopes. After the successful measurement of the 7Be(n,) cross section, the 7Be(n,p)7Li reaction was studied in order to provide still missing cross section data of relevance for Big Bang Nucleosynthesis (BBN), in an attempt to find a solution to the cosmological Lithium abundance problem. This paper describes the experimental setup employed in such a measurement and its characterization.Séptimo Programa Marco de la Comunidad Europea de la Energía Atómica (Euratom)-Proyecto CHANDA (No. 605203)Narodowe Centrum Nauki (NCN)-UMO-2012/04/M/ST2/00700-UMO-2016/22/M/ST2/00183Croatian Science Foundation-HRZZ 168

Middle Ordovician harknessellid brachiopods (Dalmanellidina) from the Mediterranean margin of Gondwana

The family Harknessellidae Bancroft, 1928 (Orthida, Dalmanellidina) was designed to embrace an assemblage of species referred previously to Harknessella Reed, 1917, and included five genera known mainly from the Middle and Upper Ordovician of England. Herein, we suggest reassigning to this family the genus Cacemia Mitchell, 1974, widespread in the middle Darriwilian (upper Middle Ordovician) of the Iberian and Armorican massifs. Since its designation, Cacemia was placed among the dalmanellidin heterorthids, in spite of its strongly mucronate hinge line, which is totally unknown within this Mediterranean family. A new harknessellid has been identified from the upper Darriwilian beds of the Central Iberian Zone (Central Spain): Isabelella fascicostellata Reyes-Abril Villas gen. et sp. nov. It is similar to Horderleyella Bancroft, 1928 for its coarsely fascicostellate radial ornamentation and obtuse cardinal angles, although its convexoplane to convexoconcave profile allows discrimination from the typically dorsibiconvex Horderleyella. A phylogenetic analysis of the family places both Cacemia and Isabelella in basal positions of their clades, which fits with their early stratigraphic record. Based on our study, the family Harknessellidae appears to have originated in the high latitude Mediterranean margins of Gondwana during pre-Darriwilian times, before the detachment of Avalonia from Gondwana. The family reached its highest diversification in Avalonia throughout the Late Ordovician, keeping connections with the Mediterranean and Proto-Andean margins of Gondwana, as well as with the mid-latitude palaeocontinents of Baltica and South China.Peer Reviewe

Middle Ordovician harknessellid brachiopods (Dalmanellidina) from the Mediterranean margin of Gondwana

The family Harknessellidae Bancroft, 1928 (Orthida, Dalmanellidina) was designed to embrace an assemblage of species referred previously to Harknessella Reed, 1917, and included five genera known mainly from the Middle and Upper Ordovician of England. Herein, we suggest reassigning to this family the genus Cacemia Mitchell, 1974, widespread in the middle Darriwilian (upper Middle Ordovician) of the Iberian and Armorican massifs. Since its designation, Cacemia was placed among the dalmanellidin heterorthids, in spite of its strongly mucronate hinge line, which is totally unknown within this Mediterranean family. A new harknessellid has been identified from the upper Darriwilian beds of the Central Iberian Zone (Central Spain): Isabelella fascicostellata Reyes-Abril Villas gen. et sp. nov. It is similar to Horderleyella Bancroft, 1928 for its coarsely fascicostellate radial ornamentation and obtuse cardinal angles, although its convexoplane to convexoconcave profile allows discrimination from the typically dorsibiconvex Horderleyella. A phylogenetic analysis of the family places both Cacemia and Isabelella in basal positions of their clades, which fits with their early stratigraphic record. Based on our study, the family Harknessellidae appears to have originated in the high latitude Mediterranean margins of Gondwana during pre-Darriwilian times, before the detachment of Avalonia from Gondwana. The family reached its highest diversification in Avalonia throughout the Late Ordovician, keeping connections with the Mediterranean and Proto-Andean margins of Gondwana, as well as with the mid-latitude palaeocontinents of Baltica and South China

New detection systems for an enhanced sensitivity in key stellar (n,γ) measurements

Neutron capture cross-section measurements are fundamental in the study of astrophysical phenomena, such as the slow neutron capture (s-) process of nucleosynthesis operating in red-giant and massive stars. However, neutron capture measurements via the time-of-flight (TOF) technique on key s-process nuclei are often challenging. Difficulties arise from the limited mass (∼mg) available and the high sample-related background in the case of the unstable s-process branching points. Measurements on neutron magic nuclei, that act as s-process bottlenecks, are affected by low (n,γ) cross sections and a dominant neutron scattering background. Overcoming these experimental challenges requires the combination of facilities with high instantaneous flux, such as n_TOFEAR2, with detection systems with an enhanced detection sensitivity and high counting rate capabilities. This contribution reviews some of the latest detector developments in detection systems for (n,γ) measurements at n_TOF, such as i-TED, an innovative detection system which exploits the Compton imaging technique to reduce the dominant neutron scattering background and s-TED, a highly segmented total energy detector intended for high flux facilities. The discussion will be illustrated with results of the first measurement of key the s-process branching-point reaction 79Se(n,γ).European Research Council (ERC)European Union’s Horizon 2020 research and innovation programme (ERC Consolidator Grant project HYMNS, with grant agreement No. 681740)FJC2020-044688-IICJ220-045122-I funded by MCIN/AEI/ 10.13039/501100011033European Union NextGenerationEU/PRTRSpanish Ministerio de Ciencia e Innovación under grants PID2019- 104714GB-C21FPA2017-83946-C2-1-P, FIS2015-71688-ERCPIE-201750I26CERN policy in matters of scientific publications, the n_TOF Collaboratio

First report of Quaternary mammals from the Qalehjough area, Lut Desert, Eastern Iran

Taxonomic study of Quaternary mammal remains from the Qalehjough fossil site, eastern Iran, has resulted in the identification of two mammal orders, Artiodactyla and Perissodactyla, with four families and six taxa. Of particular note was the recovery of Stephanorhinus and a caballoid horse. These remains have provided the first opportunity to examine Late Quaternary faunal assemblages in the northern parts of the Lut Desert, eastern Iran. The Qalehjough faunal assemblage documents some zoogeographic characteristics of the eastern Iranian Plateau, and suggests that palaeoenvironments in this part of Iran during the Pleistocene were more humid and wooded than today. The disappearance of rhinoceroses and caballoid horses from this region is most likely a result of climate change and concomitant habitat loss

Electrochemical detection of fluoroquinolone antibiotics in milk using a magneto immunosensor

An amperometric magneto-immunosensor (AMIS) for the detection of residues of fluoroquinolone antibiotics in milk samples is described for the first time. The immunosensor presented combines magnetic beads biomodified with an antibody with a broad recognition profile of fluoroquinolones, a haptenized enzyme and a magnetic graphite-epoxy composite (m-GEC) electrode. After the immunochemical reaction with specific enzyme tracer, the antibody biomodified magnetic beads are easily captured by an electrode made of graphite-epoxy composite containing a magnet, which also acts as transducer for the electrochemical detection. In spite of the complexity of milk, the use of magnetic beads allows elimination of potential interferences caused by the matrix components; hence the AMIS could perform quantitative measurements, directly in these samples, without any additional sample cleanup or extraction step. The immunosensor is able to detect up to seven different fluoroquinolones far below the MRLs defined by the UE for milk; for example ciprofloxacin is detected directly in milk with an IC50 of 0.74 μg/L and a LOD of 0.009 μg/L. This strategy offers great promise for rapid, simple, cost-effective, and on-site analysis fluoroquinolones in complex samples. © 2014 by the authors; licensee MDPI, Basel, Switzerland.This work has been supported by the Ministry of Science and Innovation (Spain) (Contract number AGL2008-05578-C05-01 and by the European Community (FP7-FOOD-2007-211326 and FP7-OCEAN-2013-1-614168). The Nb4D group is a consolidated Grup de Recerca de la Generalitat de Catalunya and has support from the Departament d’Universitats, Recerca i Societat de la Informació la Generalitat de Catalunya (expedient 2014 SGR 1484). CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008–2011, IniciativaIngenio 2010, Consolider Program, CIBER Actions and is financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Foundation. DG had a fellowship from the Fundación EROSKI.Peer Reviewe

Functionalization of PLLA with Polymer Brushes to Trigger the Assembly of Fibronectin into Nanonetworks

[EN] Poly-l-lactic acid (PLLA) has been used as a biodegradable polymer for many years; the key characteristics of this polymer make it a versatile and useful resource for regenerative medicine. However, it is not inherently bioactive. Thus, here, a novel process is presented to functionalize PLLA surfaces with poly(ethyl acrylate) (PEA) brushes to provide biological functionality through PEA's ability to induce spontaneous organization of the extracellular matrix component fibronectin (FN) into physiological-like nanofibrils. This process allows control of surface biofunctionality while maintaining PLLA bulk properties (i.e., degradation profile, mechanical strength). The new approach is based on surface-initiated atomic transfer radical polymerization, which achieves a molecularly thin coating of PEA on top of the underlying PLLA. Beside surface characterization via atomic force microscopy, X-ray photoelectron spectroscopy and water contact angle to measure PEA grafting, the biological activity of this surface modification is investigated. PEA brushes trigger FN organization into nanofibrils, which retain their ability to enhance adhesion and differentiation of C2C12 cells. The results demonstrate the potential of this technology to engineer controlled microenvironments to tune cell fate via biologically active surface modification of an otherwise bioinert biodegradable polymer, gaining wide use in tissue engineering applications.The authors acknowledge the EPSRC (EP/P001114/1) and MRC (MR/S005412/1) funding. The authors also acknowledge the EPSRC funding as part of the Doctoral Training Centre EP/F500424/1. This work was also funded by a grant from the UK Regenerative Medicine Platform. X-ray photoelectron spectroscopy was conducted by the National EPSRC XPS Users' Service (NEXUS), Newcastle.Sprott, MR.; Ferrer, G.; Dalby, MJ.; Salmerón Sánchez, M.; Cantini, M. (2019). Functionalization of PLLA with Polymer Brushes to Trigger the Assembly of Fibronectin into Nanonetworks. Advanced Healthcare Materials (Online). 8(3):1-12. https://doi.org/10.1002/adhm.201801469S11283A. J. Rincon Lasprilla G. A. Rueda Martinez B. H. Lunelli J. E. Jaimes Figueroa A. L. Jardini R. Maciel Filho Chem. Eng. Trans 2011 985Khan, F., Tanaka, M., & Ahmad, S. R. (2015). Fabrication of polymeric biomaterials: a strategy for tissue engineering and medical devices. Journal of Materials Chemistry B, 3(42), 8224-8249. doi:10.1039/c5tb01370dXu, F. J., Yang, X. C., Li, C. Y., & Yang, W. T. (2011). Functionalized Polylactide Film Surfaces via Surface-Initiated ATRP. Macromolecules, 44(7), 2371-2377. doi:10.1021/ma200160hKhan, F., & Tanaka, M. (2017). Designing Smart Biomaterials for Tissue Engineering. 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