Changing the Interaction of a Single-Molecule Magnetic Moment with a Superconductor.

The exchange interaction of a brominated Co-porphyrin molecule with the Cooper pair condensate of Pb(111) is modified by reducing the Co-surface separation. The stepwise dehalogenation and dephenylation change the Co adsorption height by a few picometers. Only the residual Co-porphine core exhibits a Yu-Shiba-Rusinov bound state with low binding energy in the Bardeen-Cooper-Schrieffer energy gap. Accompanying density functional calculations reveal that the Co dz2 orbital carries the molecular magnetic moment and is responsible for the intragap state. The calculated spatial evolution of the Yu-Shiba-Rusinov wave function is compatible with the experimentally observed oscillatory attenuation of the electron-hole asymmetry with increasing lateral distance from the magnetic porphine center.

The use of adverse outcome pathways in the safety evaluation of food additives.

In the last decade, adverse outcome pathways have been introduced in the fields of toxicology and risk assessment of chemicals as pragmatic tools with broad application potential. While their use in the pharmaceutical and cosmetics sectors has been well documented, their application in the food area remains largely unexplored. In this respect, an expert group of the International Life Sciences Institute Europe has recently explored the use of adverse outcome pathways in the safety evaluation of food additives. A key activity was the organization of a workshop, gathering delegates from the regulatory, industrial and academic areas, to discuss the potentials and challenges related to the application of adverse outcome pathways in the safety assessment of food additives. The present paper describes the outcome of this workshop followed by a number of critical considerations and perspectives defined by the International Life Sciences Institute Europe expert group.

Characterizing the coverage of critical effects relevant in the safety evaluation of food additives by AOPs.

There is considerable interest in adverse outcome pathways (AOPs) as a means of organizing biological and toxicological information to assist in data interpretation and method development. While several chemical sectors have shown considerable progress in applying this approach, this has not been the case in the food sector. In the present study, safety evaluation reports of food additives listed in Annex II of Regulation (EC) No 1333/2008 of the European Union were screened to qualitatively and quantitatively characterize toxicity induced in laboratory animals. The resulting database was used to identify the critical adverse effects used for risk assessment and to investigate whether food additives share common AOPs. Analysis of the database revealed that often such scrutiny of AOPs was not possible or necessary. For 69% of the food additives, the report did not document any adverse effects in studies based on which the safety evaluation was performed. For the remaining 31% of the 326 investigated food additives, critical adverse effects and related points of departure for establishing health-based guidance values could be identified. These mainly involved effects on the liver, kidney, cardiovascular system, lymphatic system, central nervous system and reproductive system. AOPs are available for many of these apical endpoints, albeit to different degrees of maturity. For other adverse outcomes pertinent to food additives, including gastrointestinal irritation and corrosion, AOPs are lacking. Efforts should focus on developing AOPs for these particular endpoints.

FXIIa inhibitor rHA-Infestin-4: Safe thromboprotection in experimental venous, arterial and foreign surface-induced thrombosis.

Haemostasis including blood coagulation is initiated upon vessel wall injury and indispensable to limit excessive blood loss. However, unregulated pathological coagulation may lead to vessel occlusion, causing thrombotic disorders, most notably myocardial infarction and stroke. Furthermore, blood exposure to foreign surfaces activates the intrinsic pathway of coagulation. Hence, various clinical scenarios, such as extracorporeal membrane oxygenation, require robust anticoagulation consequently leading to an increased bleeding risk. This study aimed to further assess the antithrombotic efficacy of the activated factor XII (FXIIa) inhibitor, rHA-Infestin-4, in several thrombosis models. In mice, rHA-Infestin-4 decreased occlusion rates in the mechanically-induced arterial (Folt's) and the FeCl3 -induced venous thrombosis model. rHA-Infestin-4 also protected from FeCl3 -induced arterial thrombosis and from stasis-prompted venous thrombosis in rabbits. Furthermore, rHA-Infestin-4 prevented occlusion in the arterio-venous shunt model in mice and rabbits where thrombosis was induced via a foreign surface. In contrast to heparin, the haemostatic capacity in rabbits was unaffected by rHA-Infestin-4. Using rodent and non-rodent species, our data demonstrate that the FXIIa inhibitor rHA-Infestin-4 decreased arterial, venous and foreign surface-induced thrombosis without affecting physiological haemostasis. Hence, we provide further evidence that targeting FXIIa represents a potent yet safe antithrombotic treatment approach, especially in foreign surface-triggered thrombosis.

On modeling context-aware social collaboration processes.

Modeling collaboration processes is a challenging task. Existing modeling approaches are not capable of expressing the unpredictable, non-routine nature of human collaboration, which is influenced by the social context of involved collaborators. We propose a modeling approach which considers collaboration processes as the evolution of a network of collaborative documents along with a social network of collaborators. Our modeling approach, accompanied by a graphical notation and formalization, allows to capture the influence of complex social structures formed by collaborators, and therefore facilitates such activities as the discovery of socially coherent teams, social hubs, or unbiased experts. We demonstrate the applicability and expressiveness of our approach and notation, and discuss their strengths and weaknesses.

Two-dimensional versus three-dimensional CT angiography in analysis of anatomical suitability for stentgraft repair of abdominal aortic aneurysms.

BACKGROUND: The morphological analysis prior to endovascular abdominal aneurysm repair (EVAR) plays an important role in long-term outcomes. Post-imaging analysis of computed tomographic angiography (CTA) by three-dimensional reconstruction with central lumen line detection (CLL 3D-CTA) enables measurements to be made in orthogonal slices. This might be more precise than equal post-imaging analysis in axial slices by two-dimensional computed tomographic angiography (2D-CTA). PURPOSE: To evaluate the intra- and interobserver variability of CLL 3D-CTA and 2D-CTA post-imaging analysis methods and the agreement between them in pre-EVAR suitability analysis of patients with abdominal aortic aneurysm (AAA). MATERIAL AND METHODS: Anonymized CTA data-sets from 70 patients with AAA were analyzed retrospectively. Length measurements included proximal and distal aortic neck lengths and total distance from the lower renal artery to the higher iliac bifurcation. Width measurements included proximal and distal neck diameters, maximum AAA diameter and common iliac diameters just above the iliac bifurcations. The measurements were performed in random order by two vascular surgeons, twice per method with 1-month interval between readings. In the CLL 3D-CTA method we used semi-automated CLL detection by software and manual measurements on CTA slices perpendicular to CLL. The equal measurements in 2D-CTA were performed manually on axial CTA slices using a DICOM viewer workstation. The intra- and interobserver variability, as well as the agreement between the two methods were assessed by Bland-Altman test and bivariate correlation analysis. RESULTS: The intraobserver variability was significantly higher in 2D-CTA measurements for both readers. The interobserver variability was significant in 2D-CTA measurements of proximal neck dimensions while the agreement in CLL 3D-CTA analysis between the two readers was excellent in all studied parameters. The agreement between the two suitability analysis techniques was poor for both readers, especially in measurements of proximal neck's dimensions and in total aortoiliac length (p = 0.001). CONCLUSION: In pre-EVAR morphological evaluation of AAAs the CLL-3D CTA post-imaging analysis has better intra- and interobserver correlation than 2D-CTA and might represent a useful tool for the proper selection of endograft's type and size.

FogFrame: a framework for IoT application execution in the fog.

Recently, a multitude of conceptual architectures and theoretical foundations for fog computing have been proposed. Despite this, there is still a lack of concrete frameworks to setup real-world fog landscapes. In this work, we design and implement the fog computing framework FogFrame-a system able to manage and monitor edge and cloud resources in fog landscapes and to execute Internet of Things (IoT) applications. FogFrame provides communication and interaction as well as application management within a fog landscape, namely, decentralized service placement, deployment and execution. For service placement, we formalize a system model, define an objective function and constraints, and solve the problem implementing a greedy algorithm and a genetic algorithm. The framework is evaluated with regard to Quality of Service parameters of IoT applications and the utilization of fog resources using a real-world operational testbed. The evaluation shows that the service placement is adapted according to the demand and the available resources in the fog landscape. The greedy placement leads to the maximum utilization of edge devices keeping at the edge as many services as possible, while the placement based on the genetic algorithm keeps devices from overloads by balancing between the cloud and edge. When comparing edge and cloud deployment, the service deployment time at the edge takes 14% of the deployment time in the cloud. If fog resources are utilized at maximum capacity, and a new application request arrives with the need of certain sensor equipment, service deployment becomes impossible, and the application needs to be delegated to other fog resources. The genetic algorithm allows to better accommodate new applications and keep the utilization of edge devices at about 50% CPU. During the experiments, the framework successfully reacts to runtime events: (i) services are recovered when devices disappear from the fog landscape; (ii) cloud resources and highly utilized devices are released by migrating services to new devices; (iii) and in case of overloads, services are migrated in order to release resources.

Human safety review of "nano" titanium dioxide and zinc oxide.

Based on the current weight of evidence of all available data, the risk for humans from the use of nano-structured titanium dioxide (TiO(2)) or zinc oxide (ZnO) currently used in cosmetic preparations or sunscreens is considered negligible. There is a large body of information that when viewed in its entirety is considered as sufficient to demonstrate that these nano-structured ultraviolet (UV) filters, irrespective of various treatments (coatings) or crystalline structure, can be regarded as safe for use at concentrations up to 25% in cosmetic products to protect the skin from harmful effects of solar UV radiation. "Nano" TiO(2) and ZnO formulated in topically applied sunscreen products exist as aggregates of primary particles ranging from 30-150 nm in size. These aggregates are bonded such that the force of sunscreen product application onto the skin would have no impact on their structure or result in the release of primary particles. Multiple studies have shown that under exaggerated test conditions neither nano-structured TiO(2) nor ZnO penetrates beyond the stratum corneum of skin. Further, the distribution and persistence of these nano-structured metal oxides is the same compared to larger pigment-grade (i.e., >100 nm) particles, demonstrating equivalence in the recognition and elimination of such material from the body. Finally, the in vitro genotoxic and photogenotoxic profiles of these nano-structured metal oxides are of no consequence to human health. Whereas the most logical, straightforward conclusion based on data from internationally-recognized guideline studies and current 20+ year history of human use is that nano-structured TiO(2) and ZnO are safe, there will continue to be questions as "nano" conjures images of technology gone awry. Despite this rather sober view, the public health benefits of sunscreens containing nano TiO(2) and/or ZnO outweigh human safety concerns for these UV filters.

FVIII half-life extension by coadministration of a D'D3 albumin fusion protein in mice, rabbits, rats, and monkeys.

A novel mechanism for extending the circulatory half-life of coagulation factor VIII (FVIII) has been established and evaluated preclinically. The FVIII binding domain of von Willebrand factor (D'D3) fused to human albumin (rD'D3-FP) dose dependently improved pharmacokinetics parameters of coadministered FVIII in all animal species tested, from mouse to cynomolgus monkey, after IV injection. At higher doses, the half-life of recombinant FVIII (rVIII-SingleChain) was calculated to be increased 2.6-fold to fivefold compared with rVIII-SingleChain administered alone in rats, rabbits, and cynomolgus monkeys, and it was increased 3.1-fold to 9.1-fold in mice. Sustained pharmacodynamics effects were observed (ie, activated partial thromboplastin time and thrombin generation measured ex vivo). No increased risk of thrombosis was observed with coadministration of rVIII-SingleChain and rD'D3-FP compared with rVIII-SingleChain alone. At concentrations beyond the anticipated therapeutic range, rD'D3-FP reduced the hemostatic efficacy of coadministered rVIII-SingleChain. This finding might be due to scavenging of activated FVIII by the excessive amount of rD'D3-FP which, in turn, might result in a reduced probability of the formation of the tenase complex. This observation underlines the importance of a fine-tuned balance between FVIII and its binding partner, von Willebrand factor, for hemostasis in general.

Genetic fusion to albumin improves the pharmacokinetic properties of factor IX.

Haemophilia B is a X-chromosome linked disease characterised by a deficiency of functionally active coagulation Factor IX (FIX). Patients with severe haemophilia B at risk of recurrent bleeding are treated approximately twice a week in a prophylactic setting by application of FIX concentrates. To increase convenience and compliance of the therapy it is desirable to reduce the dosing frequency by improving the pharmacokinetic properties of FIX. Here a concept of rFIX (recombinant factor IX) albumin fusion proteins (rIX-FPs) with cleavable linker peptides derived from the FIX activation sequence is presented. Constructs of the genetic fusion of FIX to albumin via cleavable linkers were expressed in mammalian cells and characterised after purification. In vitro activation studies with FXIa demonstrated that cleavage of the linker and the activation peptide proceeded comparably well. In a clotting assay the rIX-FPs with cleavable linker showed a 10- to 30-fold increase in the molar specific clotting activity compared to fusion proteins with non-cleavable linkers. Furthermore, in-vivo recovery, terminal half-life and the AUC of rIX-FPs in rats and rabbits as determined by FIX antigen measurements were significantly increased compared to rFIX (BeneFIX). In FIX deficient (FIX(-/-)) mice the in-vivo recovery and the AUC were also significantly increased. The efficacy in reducing bleeding time was shown in FIX(-/-) mice by a tail tip bleeding model. The results suggest that rIX-FPs with a cleavable linker between FIX and albumin are a promising concept that may support the use of the albumin fusion technology to extend the half-life of FIX.

Surgical outcome of degenerative versus postreconstructive extracranial carotid artery aneurysms.

OBJECTIVES: Extracranial carotid artery aneurysms (ECAAs) are rare vascular lesions, and large series with short-term and long-term outcomes are seldom reported. This study compared the clinical presentation and conventional treatment outcomes of different ECAA types according to their etiology. METHODS: We retrospectively reviewed the data of 55 consecutive patients (47 men, 8 women) with 61 ECAAs who were treated from January 1986 to December 2007 by conventional surgical techniques. The patients were a mean age of 65 +/- 11 years (range, 30-92 years). Thirty-two ECAAs (52.5%) occurred postoperatively after previous carotid endarterectomy, of which 26 patients had 29 degenerative aneurysms (47.5%). Clinical presentation included cerebral stroke in three patients (4.9%) and transient ischemic attack in 26 (42.7%). Mean follow-up was 42.7 +/- 22.0 months. Statistical analysis was performed within and between degenerative and post-reconstructive ECAA subgroups of patients. RESULTS: Open aneurysm resection included 27 extended polytetrafluoroethylene interposition grafts, 12 venous grafts, and 22 closures using synthetic patch. Cumulative 1-year primary patency rates were 86.9% for the degenerative ECAAs and 96% for the postoperative ECAAs, with respective secondary patency rate at 5 years of 80% and 93.3%. The 5-year patency rate was 88.9% for synthetic grafts compared with 66.7% for vein grafts and 86.4% for synthetic patches. These differences were not statistically significant (P > .05). Complications for the degenerative ECAAs included two reconstruction thromboses <30 days, two cerebral strokes, and one myocardial infarction. The patients with postoperative ECAAs experienced one early thrombosis and two strokes postoperatively. Two patients (3.6%) from the degenerative ECAA subgroup died of cardiac decompensation (n = 1) and cerebral ischemic event (n = 1). CONCLUSIONS: Despite the different trends, no significant differences were found between degenerative ECAA and postoperative ECAA patients in clinical presentation, localization, and surgery outcomes. The good middle-term and long-term patency rates of synthetic graft reconstruction justify its use in the treatment of ECAAs, and it is less time consuming and technically demanding compared with vein interposition graft.

Prolonged in-vivo half-life of factor VIIa by fusion to albumin.

For the treatment of haemophilia patients with inhibitors, recombinant factor VIIa (rFVIIa) is available as a therapeutic option to control bleeding episodes with a good balance of safety and efficacy. However, the short in-vivo half-life of approximately 2.5 hours makes multiple injections necessary, which is inconvenient for both physicians and patients. Here we describe the generation of a recombinant FVIIa molecule with an extended half-life based on genetic fusion to human albumin. The recombinant FVII albumin fusion protein (rVII-FP) was expressed in mammalian cells and upon activation displayed a FVII activity close to that of wild type FVIIa. Pharmacokinetic studies in rats demonstrated that the half-life of the activated recombinant FVII albumin fusion protein (rVIIa-FP) was extended six- to seven-fold compared with wild type rFVIIa. The in-vitro and in-vivo efficacy was evaluated and was found to be comparable to a commercially available rFVIIa (NovoSeven((R))). The results of this study demonstrate that it is feasible to develop a half-life extended FVIIa molecule with haemostatic properties very similar to the wild-type factor.

Use of albumin fusion technology to prolong the half-life of recombinant factor VIIa.

A significant proportion of patients with haemophilia A develop inhibitors to administered factor VIII (FVIII) and require therapy with bypassing agents such as activated factor VII (FVIIa) or activated prothrombin complex concentrates. NovoSeven is a commercially available recombinant FVIIa (rFVIIa) with a very short half-life of approximately 2.4 hours. As a result, patients generally require multiple, frequent infusions for the management of bleeding episodes. Thus, there is growing interest in extending the circulating half-life of coagulation factors through the use of innovative drug delivery and formulation technologies. One such approach uses albumin fusion technology in which human albumin is genetically fused to the C-terminus of rFVIIa via a flexible glycine serine linker. The properties of this rFVIIa fusion protein (rVIIa-FP) have recently been examined in pre-clinical studies. Results from these investigations demonstrate the feasibility of this approach, which successfully extended the half-life and biological activity of rFVIIa without compromising haemostatic efficacy. These data suggest that rVIIa-FP may be a promising therapy for the treatment of haemophilia patients with inhibitors and warrants further investigation in clinical trials.

A fuzzy noise reduction method for color images.

A new fuzzy filter is presented for the reduction of additive noise for digital color images. The filter consists of two subfilters. The first subfilter computes fuzzy distances between the color components of the central pixel and its neighborhood. These distances determine in what degree each component should be corrected. All performed corrections preserve the color component distances. The goal of the second subfilter is to correct the pixels where the color components differences are corrupted so much that they appear as outliers in comparison to their environment. Experimental results show the feasibility of the proposed approach. We compare with other noise reduction methods by numerical measures and visual observations. We also illustrate the performance of the proposed method as preprocessing step for edge detection.

A new fuzzy color correlated impulse noise reduction method.

A new impulse noise reduction method for color images is presented. Color images that are corrupted with impulse noise are generally filtered by applying a grayscale algorithm on each color component separately or using a vector-based approach where each pixel is considered as a single vector. The first approach causes artefacts especially on edge and texture pixels. Vector-based methods were successfully introduced to overcome this problem. Nevertheless, they tend to cluster the noise and to receive a lower noise reduction performance. In this paper, we discuss an alternative technique which gives a good noise reduction performance while much less artefacts are introduced. The main difference between the proposed method and other classical noise reduction methods is that the color information is taken into account to develop (1) a better impulse noise detection method and (2) a noise reduction method that filters only the corrupted pixels while preserving the color and the edge sharpness. Experimental results show that the proposed method provides a significant improvement on other existing filters.

Fuzzy two-step filter for impulse noise reduction from color images.

A new framework for reducing impulse noise from digital color images is presented, in which a fuzzy detection phase is followed by an iterative fuzzy filtering technique. We call this filter the fuzzy two-step color filter. The fuzzy detection method is mainly based on the calculation of fuzzy gradient values and on fuzzy reasoning. This phase determines three separate membership functions that are passed to the filtering step. These membership functions will be used as a representation of the fuzzy set impulse noise (one function for each color component). Our proposed new fuzzy method is especially developed for reducing impulse noise from color images while preserving details and texture. Experiments show that the proposed filter can be used for efficient removal of impulse noise from color images without distorting the useful information in the image.

A fuzzy impulse noise detection and reduction method.

Removing or reducing impulse noise is a very active research area in image processing. In this paper we describe a new algorithm that is especially developed for reducing all kinds of impulse noise: fuzzy impulse noise detection and reduction method (FIDRM). It can also be applied to images having a mixture of impulse noise and other types of noise. The result is an image quasi without (or with very little) impulse noise so that other filters can be used afterwards. This nonlinear filtering technique contains two separated steps: an impulse noise detection step and a reduction step that preserves edge sharpness. Based on the concept of fuzzy gradient values, our detection method constructs a fuzzy set impulse noise. This fuzzy set is represented by a membership function that will be used by the filtering method, which is a fuzzy averaging of neighboring pixels. Experimental results show that FIDRM provides a significant improvement on other existing filters. FIDRM is not only very fast, but also very effective for reducing little as well as very high impulse noise.

A developmental toxicity study of 3S, 3'S-Astaxanthin in New Zealand white rabbits.

Astaxanthin, a naturally occurring pigment used to give the characteristic orange-pink colour to salmonid fish reared in aquaculture, is also marketed as a dietary supplement. Synthetic 3S, 3'S-Astaxanthin was tested for potential harmful effects on the in utero development of New Zealand white rabbits in a study according to international regulatory guidelines. There were two control groups, one being a placebo administration and three dose levels corresponding to 100, 200, and 400 mg of 3S, 3'S-Astaxanthin per kg body weight/day. The group sizes varied from 23 to 27 litters, providing approximately 200 fetuses per group for evaluation of developmental toxicity. There were no significant effects on the health of the does, nor on the size and viability of the litters. Malformations, both external and internal, were rare and occurred in all groups, including controls with no indication of a treatment relationship. Variations were much more common, being found in all litters. However, when examined by type and frequency, no pattern emerged indicating a relationship to administration of the test substance. It is concluded that administration of 3S, 3'S-Astaxanthin in a gelatin/carbohydrate powder formulation throughout pregnancy up to 400 mg/kg body weight/day is without harmful effects on reproduction or fetal development.

Octyl methoxycinnamate: two generation reproduction toxicity in Wistar rats by dietary administration.

Wistar rats continuously received octyl methoxycinnamate (OMC) in the diet through two successive generations at nominal doses of 0, 150, 450 or 1000 mg/kg bw/day. OMC had no adverse effects on estrous cycles, mating behavior, conception, parturition, lactation and weaning, sperm and follicle parameters, macropathology and histopathology of the sexual organs. 1000 mg/kg bw/day reduced parental food consumption and body weight (-14% to -16% in males, -4% to -5% females), increased liver weight, produced hepatic cytoplasmic eosinophilia and erosion/ulceration of glandular stomach mucosa. and led to a slightly decreased implantation rate in the top dose F0 and F1 dams. The high dose F1 and F2 pups had reduced lactation weight gain and organ weights and delayed sexual maturation landmarks. There was no evidence of a selective influence of the test compound on pups' sexual landmarks. The NOAEL (no observed adverse effect level) is 450 mg/kg bw/day for fertility and reproductive performance, for systemic parental and developmental toxicity.

Physicochemical characterisation of rVIII-SingleChain, a novel recombinant single-chain factor VIII.

rVIII-SingleChain is a novel recombinant single-chain factor VIII (FVIII) construct, comprising covalently bonded heavy and light chains. Post-translational modifications of FVIII affect physicochemical parameters, including hydrophobicity and charge. The most relevant post-translational modifications of FVIII products are N-glycosylation of asparagine residues and tyrosine sulphations. Here, the physicochemical properties, thrombin cleavage products and post-translational modifications of rVIII-SingleChain were investigated and compared against commercially available recombinant FVIII (rFVIII) products with a predominant two-chain structure (B-domain deleted rFVIII and full-length rFVIII). rVIII-SingleChain was expressed in Chinese hamster ovary (CHO) cells and purified by chromatographic methods. Physicochemical properties of rVIII-SingleChain or thrombin-derived cleavage products were assessed using size-exclusion chromatography, reversed-phase chromatography and sodium dodecyl sulphate polyacrylamide gel electrophoresis. Analysis of the respective carbohydrate structures was performed after release of N-glycans by PNGase F followed by fluorescence labelling and high-performance liquid chromatography. Proteolysis by trypsin generated the corresponding peptides, which were analysed for sulphated tyrosines by liquid chromatography-electrospray ionisation time of flight-mass spectrometry. rVIII-SingleChain was shown to be of high purity and homogeneity, and presented a well-defined single-chain molecule with predominant ß-sheet conformation. The coagulation-relevant thrombin-activation products of rVIII-SingleChain were comparable with those obtained by activation of commercially available rFVIII products. rVIII-SingleChain post-translational modifications were similar to other CHO cell-derived rFVIII products for N-glycopattern and tyrosine sulphation. In conclusion, rVIII-SingleChain is of high homogeneity and purity, and provides an expected cleavage pattern on activation, setting the basis for optimal efficacy in the patient.