Regional development agencies are confronted with a plethora of research funding programs that provide opportunities for regional research groups and SMEs. This paper describes the practical benefits and technological building blocks of an online matching service of research profiles with funding opportunities. It gives an overview of the infrastructure for data sourcing and processing based on a scalable cloud computing platform. It then describes how data is consolidated, analyzed, and interlinked so as to facilitate the finding and matching of funding opportunities. Integrating concepts and themes with those available as Linked Open Data (LOD) adds value to finding and matching by interlinking results with publicly available data resources, and to improve search performance for related content on the internet. In order to optimize matching, the paper describes the user-profiling capabilities based on statistical analyses and machine learning. The paper concludes by discussing the lessons learned so far as well as possible extensions into other application areas.

Regional development agencies are confronted with a plethora of research funding programs that provide opportunities for regional research groups and SMEs. This paper describes the practical benefits and technological building blocks of an online matching service of research profiles with funding opportunities. It gives an overview of the infrastructure for data sourcing and processing based on a scalable cloud computing platform. It then describes how data is consolidated, analyzed, and interlinked so as to facilitate the finding and matching of funding opportunities. Integrating concepts and themes with those available as Linked Open Data (LOD) adds value to finding and matching by interlinking results with publicly available data resources, and to improve search performance for related content on the internet. In order to optimize matching, the paper describes the user-profiling capabilities based on statistical analyses and machine learning. The paper concludes by discussing the lessons learned so far as well as possible extensions into other application areas.

Cyclosporine A (CsA) has been demonstrated to be effective for the treatment of a variety of ophthalmological conditions, including ocular surface disorders such as the dry eye disease (DED). Since CsA is characterised by its low water solubility, the development of a topical ophthalmic formulation represents an interesting pharmaceutical question. In the present study, two different strategies to address this challenge were studied and compared: (i) a water-soluble CsA prodrug formulated within an aqueous solution and (ii) a CsA oil-in-water emulsion (Restasis (R), Allergan Inc., Irvine, CA). First, the prodrug formulation was shown to have an excellent ocular tolerance as well as no influence on the basal tear production; maintaining the ocular surface properties remained unchanged. Then, in order to allow in vivo investigations, a specific analytical method based on ultra high pressure liquid chromatography coupled with triple quadrupole mass spectrometer (UHPLC-MS/MS) was developed and optimised to quantify CsA in ocular tissues and fluids. The CsA ocular kinetics in lachrymal fluid for both formulations were found to be similar between 15 min and 48 h. The CsA ocular distribution study evidenced the ability of the prodrug formulation to penetrate into the eye, achieving therapeutically active CsA levels in tissues of both the anterior and posterior segments. In addition, the detailed analysis of the in vivo data using a bicompartmental model pointed out a higher bioavailability and lower elimination rate for CsA when it is generated from the prodrug than after direct application as an emulsion. The interesting in vivo properties displayed by the prodrug solution make it a safe and suitable option for the treatment of DED. (C) 2011 Elsevier B.V. All rights reserved.

REQUIRED) The case presented in this paper describes an early prototype and next steps for developing a user-adaptive recommender system using semantic analysis and matching of user profiles and content. Machine learning methods optimize semantic analysis and matching based on implicit and explicit feedback of users. The constant interaction with users provides a valuable data source that is used to improve human-computer interaction and for adapting to specific user preferences. This can lead to, among others, higher accuracy and relevance in content matching, more intuitive graphical user interfaces, improved system performance, and better prioritization of tasks.

As the amount of information which becomes available to users grows, finding condensed sets of useful information becomes more difficult. The manual evaluation and discovery for content valuable to individual users needs thus grows in conjunction with the size of the dataset. Ideally, providing as condensed set of accurate information as possible results in a significant increase in user productivity and with decreased mental effort. While this concept of information foraging has been in the literature since the 1990's, its application to specific information domains has proven to be of a continual challenge. In this paper we examine the process of global matchmaking across the whole spectrum of activities between research development, innovation. As a concrete example, we investigate the European Research Area and introduce a three tiered search approach embedded in a tool called The Opportunity Finder, which increases the ease of finding matches in a user friendly and intuitive manner.

Bacterial poly(hydroxyalkanoates) (PHAs) vary in the composition of their monomeric units. Besides saturated side-chains, unsaturated ones can also be found. The latter leads to unwanted by-products (THF ester, secondary alcohols) during acidic cleavage of the polymer backbone in the conventional analytical assays. To prevent these problems, we developed a new method for the reductive depolymerization of medium chain-length PHAs, leading to monomeric diols that can be separated and quantified by HPLC/MS. Reduction is performed at room temperature with lithium aluminum hydride within 5-15 min. The new method is faster and simpler than the previous ones and is quantitative. The results are consistent with the ones obtained by quantitative (1)H NMR.

Standard chromatographic methods for the quantification of bacterial poly(3-hydroxyalkanoate) (PHA) proved to be inappropriate for the analysis of medium-chain-length PHA (mcl-PHA). Transesterification catalyzed by protic acids is not quantitative for mcl-PHA under common conditions due to slow reaction kinetics and formation of side-products in case of functionalized side-chains. To circumvent these limitations, an improved method for the quantification of mcl-PHA by GC-FID was developed. Boron trifluoride in methanol was successfully applied to quantitatively methanolyse different mcl-PHA (recovery >94%). This novel method is well-suited for the analysis of purified mcl-PHA as well as for mcl-PHA in biomass.

Bacterial polyhydroxyalkanoate (PHA) is an attractive biopolyester for medical applications due to its biocompatibility. However, inappropriate extraction of PHA from bacterial biomass results in contamination by pyrogenic compounds (e.g. lipopolysaccharides) and thus influences medical testing. This problem was solved by a temperature-controlled method for the recovery of poly(3-hydroxyoctanoate-co-3-hydroxyhexanaote) (PHO) from Pseudomonas pittida GPo1. In contrast to other methods, precipitation of PHO was triggered by cooling the hot solution to a particular temperature. N-hexane and 2-propanol were found to be optimal solvents for such procedure. Quantitative extraction with n-hexane took place at 50 degrees C and optimal precipitation occurred between 0 and 5 degrees C. The purity was > 97% (w/w) and the endotoxicity between 10 and 15 EU/g PHO. Additional re-dissolution in 2-propanol at 45 degrees C and precipitation at 10 degrees C resulted in a purity of close to 100% (w/w) and the-minimal endotoxicity of 2 EU/g PHO. The polydispersity (M-w/M-n) of PHO was decreased from 2.0 to 1.5 for this optimized procedure. (c) 2007 Elsevier B.V. All rights reserved.

The purpose of this study is to demonstrate that a novel water-soluble prodrug of cyclosporine A (CsA) intended for topical ocular administration, does not induce eye irritation in a rabbit model and is able to generate therapeutic concentrations of CsA in the precorneal area immediately after administration. The eye irritancy of the prodrug and CsA control solution was assessed by the Draize test and by confocal laser ophthalmoscopy (CLSO). Residence time and tear concentrations of prodrug and CsA in the rabbit eye were assessed by HPLC. The Draize test showed an excellent tolerance for the prodrug solution while the reference CsA oil solution induced lachrymation and irritation. The CLSO-measured corneal lesions, subsequent to treatment with the prodrug and reference solutions, were 3% and 9%, respectively. The prodrug transformed rapidly, leading to relatively stable CsA concentrations in tears with a maximal concentration of 94 μg ml−1 over the observation period. This study demonstrated that the prodrug solution was well tolerated and that clinically significant CsA tear concentrations were achieved. UNIL088 is a promising molecule in the treatment of immune-related disorders of the eye.

Laser assisted refractive surgery is a common procedure for the correction of visual defects. However, this technique is sometimes associated with complications such as recurrent erosion scars or late-onset corneal haze formation due to irregular wound healing. In order to improve the risk/benefit ratio of this surgery, a better understanding of the wound healing process is absolutely necessary. The aim of the present study was to investigate in an animal model the influence of biopolymeric hydrogels in the modulation of the wound healing. Mechanical wounds were generated in rabbit cornea with the aid of an Algerbrush burr. The closure of the wound was monitored after staining with fluorescein by means of a confocal microscope. A hydrogel based on 1 % xanthan gum stimulated significantly corneal wound healing whereas other viscosified solutions or hydrogels based on lower concentrations of xanthan gum or on hyaluronic acid did not promote wound healing.

Two n-octenylsuccinate starch (AS) types of unknown molecular weights were assessed for ocular tolerance. Irritation potential of different solutions (containing 2 and 15% (w/w) AS) and AS stabilized emulsions (containing 15% (w/w) AS) was evaluated in vivo in rabbit eyes, using a confocal laser scanning microscope, and in vitro on treated excised pig corneas by light microscopy of histological cross sections. Both AS types were previously characterized by viscosity, osmolality and surface tension measurements. All tested solutions and emulsions showed good eye tolerance regardless of concentration and emulsifying properties suggesting AS to be a good alternative to commonly used solubilizing or emulsifying agents in ophthalmic formulations.

This study was conducted to evaluate UNIL088, a water-soluble prodrug of cyclosporine A (CsA), formulated as an aqueous eyedrop solution for topical ocular delivery. The ocular tolerance, evaluated by the Draize test and confocal laser ophthalmoscopy (CLSO), was found to be excellent. Ex vivo conversion rate of BD088 into CsA showed that hydrolysis was rapid and enzyme-activated. In vivo kinetics in the rabbit eye demonstrated that the prodrug generated high concentrations of CsA in the tears within a minute. Therapeutic efficacy was assessed by comparing i.m. injections of CsA (10 mg/day) to topical prodrug administrations (15 mu L; 5 times/day) for the prevention of corneal graft rejection after heterologous keratoplasty in rats. Topical administration of UNIL088 achieved a comparable prevention of graft rejection as i.m. CsA (56 % vs 50 % rejected grafts). UNIL088 is a promising candidate for the topical delivery of CsA to the eye.

Eye drops are multiple dosage forms protected against microbial contamination by means of preservatives. However, the ocular tolerance of these chemicals can vary and this may result in adverse toxic or allergic reactions. This overview presents the pharmacopoeial requirements for the preservation of eye drops, the factors affecting ocular tolerance as well as the adverse external ocular effects induced by preservatives. The alternatives to the use of preservatives are also discussed, including the recent progress in eye drops packaging.

Little is known about the dynamics of chromosomes in interphase nuclei. By tagging four chromosomal regions with a green fluorescent protein fusion to lac repressor, we monitored the movement and subnuclear position of specific sites in the yeast genome, sampling at short time intervals. We found that early and late origins of replication are highly mobile in G 1 phase, frequently moving at or faster than 0.5 micrometers/10 seconds, in an energy-dependent fashion. The rapid diffusive movement of chromatin detected in G 1 becomes constrained in S phase through a mechanism dependent on active DNA replication. In contrast, telomeres and centromeres provide replication-independent constraint on chromatin movement in both G 1 and S phases.

Purpose: Ophthalmic preparations can cause toxic ocular reactions, often associated with the use of preservatives. The aim of this study was to compare the ocular tolerance of three ophthalmic preparations based on timolol: a preservative free ophthalmic preparation (Timabak(R)) and two other commercially available preserved preparations (Timoptol(R) and Timoptol(R)LP).Methods: The effect of repeatedly instilling eye drops for 28 days on rabbit eyes was assessed in vivo by mean of a confocal laser scanning ophthalmoscope. The corneal microlesions were selectively marked by fluorescein.Results and conclusion: The overall results show the good ocular tolerance of the three tested products. However, a closer comparison between the products brought out differences in the extent of lesions among the tested products depending on their composition. Indeed the preservative free eye drops appeared better tolerated than the two preserved preparations.

An ocular irritation test using confocal laser scanning ophthalmoscopy has been developed in which corneal lesions subsequent to instillation of surfactants are specifically marked by fluorescein and assessed by digital image processing. The sum of the observed fluorescent corneal areas is taken into account as an endpoint of ocular irritation. Eight currently used nonionic, cationic and anionic surfactants were applied onto the cornea of rabbits and mice, four times per day during 3 days at various concentrations. Benzalkonium chloride, a cationic surfactant, at a concentration range of 0.01–0.5%, was tested in the same manner. The cornea was evaluated in vivo for ocular tolerance by confocal microscopy. In both rabbits and mice, the test revealed following irritation rankings: cationic>anionic>nonionic surfactants. Furthermore, in both animal models, the ocular damage increased with the concentration of benzalkonium. The test was sensitive enough to detect ocular microlesions at concentrations of surfactants as low as 0.01% for benzalkonium. These findings demonstrate the usefulness of confocal microscopy for the non-invasive, in situ evaluation of ocular tolerance.

A recent Random Samples contribution “Locked but not knotted” (12 Feb. p. 931) describes a mathematically interesting result about locked, unknotted hexagons. We believe, however, that the statement that DNA is like “chains or loops of linked rigid pieces, like bits of uncooked spaghetti joined by hinges,” rather than the more familiar “overcooked spaghetti” is misleading. Piece-wise linear models of polymers were introduced by Kuhn in the 1930s to provide a tractable model simpler than the continuous description that he knew was closer to reality. His approximation and subsequent refinements have successfully allowed relatively simple mathematical and numerical treatments of physical phenomena in DNA. However, the effective physical properties of DNA are relatively uniform along the backbone and, in reality, there are no hinges interspersed with rigid regions (unless perhaps one reduces to a single base pair-level description). Electron microscopy of DNA has shown that on the wide range of viewable length scales the double helix appears as a continuous curve (Fig. 1). Any such smooth curve (in yellow) can be well approximated by n line segments, with n sufficiently large (the case n = 6 shown in red seems inadequate). The question of how large n needs to be depends on the smoothness of the underlying curve, or whether the spaghetti is cooked al dente or scotti. For models of DNA, this smoothness depends on the number of base pairs represented by the continuous curve (2686 for the data shown). ![Fig. 1.][1] Fig. 1. DNA model. We know of no realistic application involving a piece-wise linear model of a DNA loop where the number of links, n , can be as few as 6. Moreover, any conclusion that depends sensitively on n —for example, rigidity—for n = 6, which disappears for n = 7, cannot be physically pertinent for DNA. # DNA: Uncooked, al Dente, or Scotti ? {#article-title-2} The point of Stasiak et al. that DNA does not resemble a polygon of 6 or 7 rigid segments is absolutely correct. Such a model may be more realistic for an artificially synthesized polymer, and several mathematicians I spoke with suggested that this might be an interesting project for chemists to work on (similar to the synthesis of “rotaxanes,” in which two loops are geometrically linked without being topologically linked). For DNA, the best model may indeed be one that depends on the details of how the spaghetti is cooked, as Stasiak et al. suggest. The mathematical treatment of large molecules with a certain amount of rigidity is still very much in its infancy. If mathematicians continue to study models of molecules that are in some respects outdated or oversimplified, the reason is that there are still interesting questions about them that have not been answered. The mathematicians I spoke with felt that the shape presented by Jason Cantarella was a useful step toward understanding the effect of rigidity on conformation. The conclusion: Rigidity matters. [1]: pending:yes

Chemically modified DNA oligonucleotides have been crucial to the success of antisense therapeutics. Although such modifications are ubiquitous in the clinic, high-resolution structural studies of pharmaceutically relevant derivatives have been limited to only a few molecules. We have completed a high-resolution NMR structural study of three DNA.RNA hybrids with the sequence d(CCTATAATCC). r(GGAUUAUAGG). All hybrids contain an unmodified RNA strand, whereas the DNA strand of each hybrid contains one of three different sugar-phosphate backbone linkages at each nucleotide: (1) phosphate, (2) [Rp]-phosphorothioate, or (3) phosphorodithioate. The UV and NMR melting profiles revealed that the normal hybrid is more stable than the [Rp]-phosphorothioate, which in turn is more stable than the phosphorodithioate. Homonuclear two-dimensional nuclear Overhauser effect spectroscopy and double quantum-filtered correlation spectroscopy afforded nearly complete non-labile proton assignments. The three molecules show nearly equivalent chemical shifts, with the exception of H3' protons, which are shifted downfield in a manner that appears correlated with the degree of sulfur substitution at phosphate. All three hybrids exhibit unusually broad linewidths for deoxyribose protons H2' and H2".Distance restraints were calculated from NOE cross-peak intensities via a complete relaxation matrix approach using the program RANDMARDI. Detailed comparison of interproton distances from each hybrid indicates that the three molecules share a common structure, with neither strand in canonical A or B form. Correlation of R factors, calculated using the program CORMA with DNA H2'-base and H3'-base distances, revealed a relative increase in the population of B-type sugar conformations for deoxyriboses in the A+T-rich center of the hybrid sequence. It is widely known that the activity of enzymes which act upon DNA.RNA hybrid substrates (e.g. ribonuclease H) is impacted when the hybrids contain phosphorothioate or phosphorodithioate substitutions. The structural similarity of the three hybrids examined here suggests that factors other than global structure may mediate the activity of these enzymes.

The mucoadhesive polysaccharide chitosan was evaluated as a potential component in ophthalmic gels for enabling increased precorneal drug residence times. This cationic vehicle was expected to slow down drug elimination by the lacrymal flow both by increasing solution viscosity and by interacting with the negative charges of the mucus. The molecular weight (Mw) and concentration of polysaccharide were studied in four types of chitosan as parameters that might influence ocular tolerability and precorneal residence time of formulations containing tobramycin as therapeutic agent. An ocular irritation test, using confocal laser scanning ophthalmoscopy (CLSO) combined with corneal fluorescein staining, clearly demonstrated the excellent tolerance of chitosan after topical administration onto the corneal surface. Gamma scintigraphic data showed that the clearance of the formulations labelled with 99mTc-DTPA was significantly delayed in the presence of chitosan with respect to the commercial collyrium (Tobrex®), regardless of the concentration and of the molecular weight of chitosan in solution. At least a 3-fold increase of the corneal residence time was achieved in the presence of chitosan when compared to Tobrex®.