A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Defining evacuation travel times and safety areas in a debris flow hazard scenario.

Debris flows are one of the most hazardous types of landslides in mountain regions. In the upper part of the Zêzere valley (Serra da Estrela, Portugal) several debris flows events occurred in the last 200 years, some of them causing loss of lives and material damages. In this work, a methodology for pedestrian evacuation modelling, in a debris flow hazard scenario, was implemented. A dynamic run-out model, developed in previous studies, was used to evaluate the debris flows velocities, thickness of the deposits and extent of the mobilized material. The buildings potentially affected by the impact of debris flows were identified and the potentially exposed population was estimated by applying a dasymetric distribution. The results lead to the conclusion that, in the study area, the elderly are those who are most exposed to debris flows. Furthermore, the time lapse between the debris flows initiation and the arrival at the buildings at risk was estimated, allowing to account for the overall number of buildings where the evacuation time takes longer than the debris flows arrival. Additionally, the safe areas within the study area were identified, and several safe public buildings with the capacity to gather a large number of persons were selected. Considering that the study area is located in a mountain region, characterized by steep slopes, the evacuation modelling was performed based on an anisotropic approach, in order to consider the influence of slope direction on travel costs. At the end, three pedestrian evacuation travel time scenarios, based on different walking speeds to accommodate residents with different ages in safer places, were compared and the results mapped. The implemented methodology is not local dependent, which allows its reproduction elsewhere.

Silver activation on thin films of Ag-ZrCN coatings for antimicrobial activity.

Nowadays, with the increase of elderly population and related health problems, knee and hip joint prosthesis are being widely used worldwide. However, failure of these invasive devices occurs in a high percentage thus demanding the revision of the chirurgical procedure. Within the reasons of failure, microbial infections, either hospital or subsequently-acquired, contribute in high number to the statistics. Staphylococcus epidermidis (S. epidermidis) has emerged as one of the major nosocomial pathogens associated with these infections. Silver has a historic performance in medicine due to its potent antimicrobial activity, with a broad-spectrum on the activity of different types of microorganisms. Consequently, the main goal of this work was to produce Ag-ZrCN coatings with antimicrobial activity, for the surface modification of hip prostheses. Thin films of ZrCN with several silver concentrations were deposited onto stainless steel 316 L, by DC reactive magnetron sputtering, using two targets, Zr and Zr with silver pellets (Zr+Ag target), in an atmosphere containing Ar, C2H2 and N2. The antimicrobial activity of the modified surfaces was tested against S. epidermidis and the influence of an activation step of silver was assessed by testing samples after immersion in a 5% (w/v) NaClO solution for 5 min. The activation procedure revealed to be essential for the antimicrobial activity, as observed by the presence of an inhibition halo on the surface with 11 at.% of Ag. The morphology analysis of the surface before and after the activation procedure revealed differences in silver distribution indicating segregation/diffusion of the metallic element to the film's surface. Thus, the results indicate that the silver activation step is responsible for an antimicrobial effect of the coatings, due to silver oxidation and silver ion release.

Influence of albumin on the tribological behavior of Ag-Ti (C, N) thin films for orthopedic implants.

With the increase of elderly population and the health problems arising nowadays, such as cancer, knee and hip joint prostheses are widely used worldwide. It is estimated that 20% of hip replacement surgeries simply fail after 5years, due to wear loosening, instability and infection. In this paper it is reported the study of advanced materials with the ability to overcome some of these drawbacks. The development of ceramic coatings, based on carbonitrides of transition metals, such as TiCN, doped with silver, Ag, may represent an effective solution. Thin films of Ag-TiCN were produced by dc reactive magnetron sputtering with silver contents ranging from 4 to 8at.%. The physical, chemical, structural, morphological/topographical, mechanical and tribological properties were evaluated. The tribological tests were performed in a unidirectional wear simulator, pin on disk, being the antagonists of a ceramic Al2O3 ball, and using simulate body fluids as lubricant. Hank's Balanced Salt Solution (HBSS) and bovine serum albumin (BSA) in HBSS were chosen, in order to evaluate the lubrication ability of the solution containing the protein, albumin. The results revealed that the coatings with Ag content ranging from 4 to 8at.%, were the most promising, as the tribological properties were superior to the results reported by other authors, which also developed Ag-TiCN coatings containing similar Ag contents and using similar test conditions. The presence of albumin leads to a lower wear in all the test conditions, and this enhancement was higher in the hydrophobic surfaces.

Dexamethasone-loaded poly(ε-caprolactone)/silica nanoparticles composites prepared by supercritical CO2 foaming/mixing and deposition.

A supercritical carbon dioxide (scCO2)-assisted foaming/mixing method (SFM) was implemented for preparing dexamethasone (DXMT)-loaded poly(ε-caprolactone)/silica nanoparticles (PCL/SNPs) composite materials suitable for bone regeneration. The composites were prepared from PCL and mesoporous SNPs (MCM-41/SBA-15) by means of scCO2-assisted SFM at several operational pressures, processing times and depressurization conditions. DXMT was loaded into SNPs (applying a scCO2 solvent impregnation/deposition method - SSID) and into PCL/SNPs composites (using the SFM method). The effects of the employed operational and compositional variables on the physicochemical and morphological features as well as in the in vitro release profiles of DXMT were analyzed in detail. This work demonstrates that the above-referred scCO2-based methods can be very useful for the preparation of DXMT-loaded PCL/SNPs composites with tunable physicochemical, thermomechanical, morphological and drug release properties and suitable for hard-tissue regeneration applications.

Mechanical characterization of a functionally graded nanocomposite thin film.

Functionally graded nanocomposite thin films (2D-FGM), of sub-micrometric thickness, were co-deposited from austenitic stainless steel (316L (AISI)) and poly(tetrafluoroethylene) targets by r.f. magnetron sputtering. All the deposition parameters were kept constant except for the electrical characteristics applied to polymeric target. XPS revealed in the films fluorine contents between 0 and 60 at%. The TEM analysis revealed the evolution towards a nanocomposite structure with an increase in fluorine content (from 0 to 20 at%). For the higher fluorine contents the formation of a ceramic phase, FeF2, is the main structural feature. The hardness is higher for the films with the lowest fluorine concentration due to higher chromium carbides content. The residual stresses of the 2D-FGM are essentially compressive with values up to 2.2 GPa. The values of the friction coefficient of the nanocomposite thin films are in the range of 0.66-0.71, an exception is for the highest fluorine content where the value is 0.31.

Thin films with chemically graded functionality based on fluorine polymers and stainless steel.

Thin films of stainless steel and poly(tetrafluoroethylene) were co-deposited, by radiofrequency magnetron sputtering, in an inert atmosphere in order to produce a functionally graded material as a coating on a traditional biomaterial, where non-ferromagnetic characteristics and improved wettability must be ensured. These thin films are intended to modify the surface of SS316L used in stents, where the bulk/thin film couple should be regarded as a single material. This requires excellent adhesion of the coating to the substrate. All coatings were deposited with an average thickness of 500 nm. The chemical and phase characterization of the surface revealed that, with the increase in F content, the thin film evolves from a ferritic phase (alpha) to an amorphous phase with dispersion of a new crystalline ceramic phase (FeF(2)). For intermediate F content values, an austenitic (111) phase (gamma) was present. Bearing in mind the envisaged application, the best results were attained for thin films with a fluorine content between 10 and 20 at.%.

Covalent binding of urease on ammonium-selective potentiometric membranes.

As part of the development of disposable urea bioselective probes, the covalent binding of urease on ammonium-selective potentiometric membranes has been assessed. Nonactin/bis(1-butylpentyl)adipate/poly(vinylchloride) (PVC) membranes, directly applied to an internal solid contact (conductive epoxy-graphite composite), has been used as a support for covalent immobilization of urease. Two types of all-solid-state construction process have been assayed: thin layers of cellulose acetate (CA) were coated on the PVC ammonium-selective membranes (type 1) and blends of PVC and CA at various ratios were used as ammonium-selective membrane matrices (type 2). Urease was covalently attached to CA via aldehyde groups. These groups were created on the polysaccharide with sodium periodate to which the enzyme was immobilized through a spacer (hexamethylenediamine). The viability of both types of probe for the determination of ammonium ions was assessed after each step of the activation process. Results indicated that type 2 potentiometric probes are altered after the treatment with sodium periodate. Good results were obtained with type 1 probes. Their dynamic concentration range of response to urea was from 2 x 10(-5) to 0.01 M with a sensibility of 50 mV/decade.