Calculating path algorithms

AbstractA calculational derivation is given of two abstract path algorithms. The first is an all-pairs algorithm, two well-known instances of which are Warshall's (reachability) algorithm and Floyd's shortest-path algorithm; instances of the second are Dijkstra's shortest-path algorithm and breadth-first/depth-first search of a directed graph. The basis for the derivations is the algebra of regular languages

Good care during COVID-19: a narrative approach to care home staff's experiences of the pandemic

Due to its major impact on Dutch care homes for older people, the COVID-19 pandemic has presented care staff with unprecedented challenges. Studies investigating the experiences of care staff during the COVID-19 pandemic have shown its negative impact on their wellbeing. We aimed to supplement this knowledge by taking a narrative approach. We drew upon 424 personal narratives written by care staff during their work in a Dutch care home during the COVID-19 pandemic. Firstly, our results show that care staff have a relational-moral approach to good care. Residents' wellbeing is their main focus, which they try to achieve through personal relationships within the triad of care staff-resident-significant others (SOs). Secondly, our results indicate that caregivers experience the COVID-19 mitigation measures as obstructions to relational-moral good care, as they limit residents' wellbeing, damage the triadic care staff-residents-SOs relationship and leave no room for dialogue about good care. Thirdly, the results show that care staff experiences internal conflict when enforcing the mitigation measures, as the measures contrast with their relational-moral approach to care. We conclude that decisions about mitigation measures should be the result of a dialogic process on multiple levels so that a desired balance between practical good care and relational-moral good care can be determined

Transbilayer Phospholipid Movements in ABCA1-Deficient Cells

Tangier disease is an inherited disorder that results in a deficiency in circulating levels of HDL. Although the disease is known to be caused by mutations in the ABCA1 gene, the mechanism by which lesions in the ABCA1 ATPase effect this outcome is not known. The inability of ABCA1 knockout mice (ABCA1−/−) to load cholesterol and phospholipids onto apoA1 led to a proposal that ABCA1 mediates the transbilayer externalization of phospholipids, an activity integral not only to the formation of HDL particles but also to another, distinct process: the recognition and clearance of apoptotic cells by macrophages. Expression of phosphatidylserine (PS) on the surface of both macrophages and their apoptotic targets is required for efficient engulfment of the apoptotic cells, and it has been proposed that ABCA1 is required for transbilayer externalization of PS to the surface of both cell types. To determine whether ABCA1 is responsible for any of the catalytic activities known to control transbilayer phospholipid movements, these activities were measured in cells from ABCA1−/− mice and from Tangier individuals as well as ABCA1-expressing HeLa cells. Phospholipid movements in either normal or apoptotic lymphocytes or in macrophages were not inhibited when cells from knockout and wildtype mice or immortalized cells from Tangier individuals vs normal individuals were compared. Exposure of PS on the surface of normal thymocytes, apoptotic thymocytes and elicited peritoneal macrophages from wildtype and knockout mice or B lymphocytes from normal and Tangier individuals, as measured by annexin V binding, was also unchanged. No evidence was found of ABCA1-stimulated active PS export, and spontaneous PS movement to the outer leaflet in the presence or absence of apoA1 was unaffected by the presence or absence of ABCA1. Normal or Tangier B lymphocytes and macrophages were also identical in their ability to serve as targets or phagocytes, respectively, in apoptotic cell clearance assays. No evidence was found to support the suggestion that ABCA1 is involved in transport to the macrophage cell surface of annexins I and II, known to enhance phagocytosis of apoptotic cells. These results show that mutations in ABCA1 do not measurably reduce the rate of transbilayer movements of phospholipids in either the engulfing macrophage or the apoptotic target, thus discounting catalysis of transbilayer movements of phospholipids as the mechanism by which ABCA1 facilitates loading of phospholipids and cholesterol onto apoA1

Snake Cytotoxins Bind to Membranes via Interactions with Phosphatidylserine Head Groups of Lipids

The major representatives of Elapidae snake venom, cytotoxins (CTs), share similar three-fingered fold and exert diverse range of biological activities against various cell types. CT-induced cell death starts from the membrane recognition process, whose molecular details remain unclear. It is known, however, that the presence of anionic lipids in cell membranes is one of the important factors determining CT-membrane binding. In this work, we therefore investigated specific interactions between one of the most abundant of such lipids, phosphatidylserine (PS), and CT 4 of Naja kaouthia using a combined, experimental and modeling, approach. It was shown that incorporation of PS into zwitterionic liposomes greatly increased the membrane-damaging activity of CT 4 measured by the release of the liposome-entrapped calcein fluorescent dye. The CT-induced leakage rate depends on the PS concentration with a maximum at approximately 20% PS. Interestingly, the effects observed for PS were much more pronounced than those measured for another anionic lipid, sulfatide. To delineate the potential PS binding sites on CT 4 and estimate their relative affinities, a series of computer simulations was performed for the systems containing the head group of PS and different spatial models of CT 4 in aqueous solution and in an implicit membrane. This was done using an original hybrid computational protocol implementing docking, Monte Carlo and molecular dynamics simulations. As a result, at least three putative PS-binding sites with different affinities to PS molecule were delineated. Being located in different parts of the CT molecule, these anion-binding sites can potentially facilitate and modulate the multi-step process of the toxin insertion into lipid bilayers. This feature together with the diverse binding affinities of the sites to a wide variety of anionic targets on the membrane surface appears to be functionally meaningful and may adjust CT action against different types of cells

Phosphatidylserine targeting for diagnosis and treatment of human diseases

Cells are able to execute apoptosis by activating series of specific biochemical reactions. One of the most prominent characteristics of cell death is the externalization of phosphatidylserine (PS), which in healthy cells resides predominantly in the inner leaflet of the plasma membrane. These features have made PS-externalization a well-explored phenomenon to image cell death for diagnostic purposes. In addition, it was demonstrated that under certain conditions viable cells express PS at their surface such as endothelial cells of tumor blood vessels, stressed tumor cells and hypoxic cardiomyocytes. Hence, PS has become a potential target for therapeutic strategies aiming at Targeted Drug Delivery. In this review we highlight the biomarker PS and various PS-binding compounds that have been employed to target PS for diagnostic purposes. We emphasize the 35 kD human protein annexin A5, that has been developed as a Molecular Imaging agent to measure cell death in vitro, and non-invasively in vivo in animal models and in patients with cardiovascular diseases and cancer. Recently focus has shifted from diagnostic towards therapeutic applications employing annexin A5 in strategies to deliver drugs to cells that express PS at their surface

Integrating geomatics in archaeological research at the site of Thorikos (Greece)

Archaeological excavation is a destructive process, making accurate, fast and efficient 3D documentation of information essential. With this in mind, our research uses an integrated workflow of topographic measurements and image-based 3D modelling to generate highly accurate reconstructions of archaeological features at the site of Thorikos, Greece. Topographic ground control points and images are acquired using a total station and consumer digital camera respectively, and processed in a highly automated workflow using Structure from Motion and Multiview Stereo reconstruction software. These models were generated on a daily basis in order to map the on-going of a field campaign at this archaeological site in 2012. Moreover, a management system is presented as a consultation and analysis application, enabling the interaction with the 3D models, accompanied with attribute data and metadata. For the efficiency of the management system it was essential to integrate the 3D models in a Harris matrix. This matrix functions as an intermediate between a graphical user interface and the database system. Additionally, two applications of these 3D models are presented, focussing on capacity calculations and in situ mapping (orthophoto mapping) of stone wall remains. The presented management system, the linking of 3D models with excavation data, and the use of 3D models as a scientific tool demonstrate the huge potential of 3D data for archaeological research