Molecular mechanism of Ena/VASP-mediated actin-filament elongation

Ena/VASP proteins have important functions in actin-dependent processes. A model for the actin elongation activity of Ena/VASP based on the affinity and saturation state of WH2-domain-mediated actin monomer binding is presented

Black holes, gravitational waves and fundamental physics: a roadmap

The grand challenges of contemporary fundamental physics—dark matter, dark energy, vacuum energy, inflation and early universe cosmology, singularities and the hierarchy problem—all involve gravity as a key component. And of all gravitational phenomena, black holes stand out in their elegant simplicity, while harbouring some of the most remarkable predictions of General Relativity: event horizons, singularities and ergoregions. The hitherto invisible landscape of the gravitational Universe is being unveiled before our eyes: the historical direct detection of gravitational waves by the LIGO-Virgo collaboration marks the dawn of a new era of scientific exploration. Gravitational-wave astronomy will allow us to test models of black hole formation, growth and evolution, as well as models of gravitational-wave generation and propagation. It will provide evidence for event horizons and ergoregions, test the theory of General Relativity itself, and may reveal the existence of new fundamental fields. The synthesis of these results has the potential to radically reshape our understanding of the cosmos and of the laws of Nature. The purpose of this work is to present a concise, yet comprehensive overview of the state of the art in the relevant fields of research, summarize important open problems, and lay out a roadmap for future progress. This write-up is an initiative taken within the framework of the European Action on 'Black holes, Gravitational waves and Fundamental Physics'

Cost-effectiveness of early intervention: comparison between intraluminal bronchoscopic treatment and surgical resection for T1N0 lung cancer patients.

BACKGROUND: For patients with early-stage lung cancer (ESLC) and severe comorbidities, the cost-effectiveness of early intervention may be reduced by screening and treatment-related morbidity and mortality in addition to the risk for non-cancer-related deaths. OBJECTIVES: The use of bronchoscopic treatment (BT) for centrally located ESLC as minimally invasive technique has raised questions whether this approach will be more cost-effective than standard surgical resection in the above-mentioned cohort of patients. METHODS: The cost-effectiveness of BT of 32 medically inoperable patients with intraluminal tumor has been compared to a matched control group of surgically treated stage IA cancer patients. RESULTS: Median follow-up after BT for ESLC has been 5 years (range 2-10) versus 6.7 years (range 2-10) for the surgical group. Five patients (16%) developed subsequent primaries/local recurrences after BT versus 4 (12.5%) in the surgical group. The respective percentages of actual survival during follow-up have been 50 and 41%, non-lung-cancer-related death 22 and 31% and lung-cancer-related death 28% in both groups, respectively. So far, the average costs per individual for early management by BT have been Euro 22,638 by surgery, and total expenses have been Euro 209,492 and Euro 724,403, respectively. CONCLUSIONS: Despite the worse initial health status of patients treated with BT, actual survival rates and costs for early intervention underscore the superior cost-effectiveness of BT as early intervention in properly selected individuals with ESLC in the central airways

Spatially Controlled Surface Modification of Porous Silicon for Sustained Drug Delivery Applications

Abstract A new and facile approach to selectively functionalize the internal and external surfaces of porous silicon (pSi) for drug delivery applications is reported. To provide a surface that is suitable for sustained drug release of the hydrophobic cancer chemotherapy drug camptothecin (CPT), the internal surfaces of pSi films were first modified with 1-dodecene. To further modify the external surface of the pSi samples, an interlayer was applied by silanization with (3-aminopropyl)triethoxysilane (APTES) following air plasma treatment. In addition, copolymers of N-(2-hydroxypropyl) acrylamide (HPAm) and N-benzophenone acrylamide (BPAm) were grafted onto the external pSi surfaces by spin-coating and UV crosslinking. Each modification step was verified using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy, water contact angle (WCA) measurements, X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). In order to confirm that the air plasma treatment and silanization step only occurred on the top surface of pSi samples, confocal microscopy was employed after fluorescein isothiocyanate (FITC) conjugation. Drug release studies carried out over 17 h in PBS demonstrated that the modified pSi reservoirs released CPT continuously, while showing excellent stability. Furthermore, protein adsorption and cell attachment studies demonstrated the ability of the graft polymer layer to reduce both significantly. In combination with the biocompatible pSi substrate material, the facile modification strategy described in this study provides access to new multifunctional drug delivery systems (DDS) for applications in cancer therapy

Polymerizable Peptide Copolymer Coatings for the Control of Biointerfacial Interactions

The effective control over biointerfacial interactions is essential for a broad range of biomedical applications in vitro and in vivo such as biosensors, cell culture tools and implantable devices. Here, our aim was to develop a coating strategy that is transferable between different substrate materials and can effectively suppress nonspecific protein adsorption and hence reduce cell attachment while also presenting bioactive signals to enable specific cell–material interactions. In a first step an allylamine plasma polymer coating was applied, followed by the covalent immobilization of a macroinitiator carrying iniferter functionalities in the side chains. Subsequently, copolymers with different molar ratios of acrylamide and a polymerizable peptide containing the sequence Arg-Gly-Asp (RGD) were grafted via surface initiated free radical polymerization. X-ray photoelectron spectroscopy (XPS) was used to confirm the success of each coating step. The cellular response to these coatings was evaluated using L929 mouse fibroblast cell culture assays for up to 24 h. Cell attachment was significantly reduced on acrylamide homopolymer coatings and negative control surfaces representing a polymerizable peptide containing the nonbioactive Arg-Ala-Asp (RAD) sequence. In contrast, cell attachment was increased with increasing polymerizable RGD peptide ratios in the copolymer. The combination of acrylamide-terminated peptide sequences in combination with acrylamide provides a simple and versatile route to surfaces that combine low nonspecific protein adsorption and the display of controlled densities of bioactive signals and is expected to be translated into a number of biomedical applications in vitro and in vivo

The in vivo performance of an enzyme-assisted self-assembled peptide/protein hydrogel

We demonstrate the distribution of the important extracellular matrix protein laminin in a novel biomaterial consisting of a hydrogel underpinned by nanofibrillar networks. These are formed by the immobilised enzyme mediated self-assembly of fmoc-L (9-fluorenylmethoxycarbonyl-tri-leucine). The peptide assembly yields nanofibrils formed of β-sheets that are locked together via π-stacking interactions. This ordering allows the localisation of the peptide sidechains on the surface, creating a hydrophobic environment. This induces the formation of bundles of these nanofibrils producing a clear hydrogel. This mechanism enables the three dimensional distribution of laminin throughout the network via supramolecular interactions. These forces favour the formation and improve the order of the network itself, as observed by spectroscopic and mechanical testing. In order to test the stability and suitability of this class of material for in vivo applications, we utilise microinjection to deliver the biomaterial under fine spatial control into a dystrophic zebrafish model organism, which lacks laminin as a result of a genetic mutation. Using confocal and transmission electron microscopy, we confirm that the biomaterial remains stable structurally, and is confined spatially to the site of injection