ATP-binding cassette (ABC) transporters in normal and pathological lung

ATP-binding cassette (ABC) transporters are a family of transmembrane proteins that can transport a wide variety of substrates across biological membranes in an energy-dependent manner. Many ABC transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) are highly expressed in bronchial epithelium. This review aims to give new insights in the possible functions of ABC molecules in the lung in view of their expression in different cell types. Furthermore, their role in protection against noxious compounds, e.g. air pollutants and cigarette smoke components, will be discussed as well as the (mal)function in normal and pathological lung. Several pulmonary drugs are substrates for ABC transporters and therefore, the delivery of these drugs to the site of action may be highly dependent on the presence and activity of many ABC transporters in several cell types. Three ABC transporters are known to play an important role in lung functioning. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene can cause cystic fibrosis, and mutations in ABCA1 and ABCA3 are responsible for respectively Tangier disease and fatal surfactant deficiency. The role of altered function of ABC transporters in highly prevalent pulmonary diseases such as asthma or chronic obstructive pulmonary disease (COPD) have hardly been investigated so far. We especially focused on polymorphisms, knock-out mice models and in vitro results of pulmonary research. Insight in the function of ABC transporters in the lung may open new ways to facilitate treatment of lung diseases

Keratan sulphate in the tumour environment

Keratan sulphate (KS) is a bioactive glycosaminoglycan (GAG) of some complexity composed of the repeat disaccharide D-galactose β1→4 glycosidically linked to N-acetyl glucosamine. During the biosynthesis of KS, a family of glycosyltransferase and sulphotransferase enzymes act sequentially and in a coordinated fashion to add D-galactose (D-Gal) then N-acetyl glucosamine (GlcNAc) to a GlcNAc acceptor residue at the reducing terminus of a nascent KS chain to effect chain elongation. D-Gal and GlcNAc can both undergo sulphation at C6 but this occurs more frequently on GlcNAc than D-Gal. Sulphation along the developing KS chain is not uniform and contains regions of variable length where no sulphation occurs, regions which are monosulphated mainly on GlcNAc and further regions of high sulphation where both of the repeat disaccharides are sulphated. Each of these respective regions in the KS chain can be of variable length leading to KS complexity in terms of chain length and charge localization along the KS chain. Like other GAGs, it is these variably sulphated regions in KS which define its interactive properties with ligands such as growth factors, morphogens and cytokines and which determine the functional properties of tissues containing KS. Further adding to KS complexity is the identification of three different linkage structures in KS to asparagine (N-linked) or to threonine or serine residues (O-linked) in proteoglycan core proteins which has allowed the categorization of KS into three types, namely KS-I (corneal KS, N-linked), KS-II (skeletal KS, O-linked) or KS-III (brain KS, O-linked). KS-I to -III are also subject to variable addition of L-fucose and sialic acid groups. Furthermore, the GlcNAc residues of some members of the mucin-like glycoprotein family can also act as acceptor molecules for the addition of D-Gal and GlcNAc residues which can also be sulphated leading to small low sulphation glycoforms of KS. These differ from the more heavily sulphated KS chains found on proteoglycans. Like other GAGs, KS has evolved molecular recognition and information transfer properties over hundreds of millions of years of vertebrate and invertebrate evolution which equips them with cell mediatory properties in normal cellular processes and in aberrant pathological situations such as in tumourogenesis. Two KS-proteoglycans in particular, podocalyxin and lumican, are cell membrane, intracellular or stromal tissue–associated components with roles in the promotion or regulation of tumour development, mucin-like KS glycoproteins may also contribute to tumourogenesis. A greater understanding of the biology of KS may allow better methodology to be developed to more effectively combat tumourogenic processes

Cell therapy for the diseased liver: from stem cell biology to novel models for hepatotropic human pathogens

It has long been known that hepatocytes possess the potential to replicate through many cell generations because regeneration can be achieved in rodents after serial two-thirds hepatectomy. It has taken considerable time and effort to harness this potential, with liver regeneration models involving hepatocyte transplantation developing over the past 15 years. This review will describe the experiments that have established the models and methodology for liver repopulation, and the use of cells other than adult hepatocytes in liver repopulation, including hepatic cell lines and hematopoietic, cord blood, hepatic and embryonic stem cells. Emphasis will be placed on the characteristics of the models and how they can influence the outcome of the experiments. Finally, an account of the development of murine models that are competent to accept human hepatocytes is provided. In these models, liver deficiencies are induced in immunodeficient mice, where healthy human cells have a selective advantage. These mice with humanized livers provide a powerful new experimental tool for the study of human hepatotropic pathogens

Multidisciplinary Optimization of a Generic 2D High-Lift Configuration Regarding Kinematics, Aerodynamics and Flight Mechanics

This work deals with the multidisciplinary optimization of a generic two dimensional three element high-lift configuration. The objective of this work is to conduct a proof-of concept optimization and to find an optimized high-lift system with a feasible flap mechanism and enhanced aerodynamic performance which is reflected in a decreased take-off and landing distance. During the multidisciplinary optimization following disciplines are analyzed: Kinematics, Aerodynamics and Flight Mechanics. The proof-of-concept optimization is performed successfully and reveals a configuration with improved aerodynamic performance, reduced take-off and landing distance while the kinematic and aerodynamic constraints are satisfied. The overall take-off distance is reduced due to the augmentation of the maximum lift coefficient for the take-off configuration which leads to a significant shorter ground roll distance. At landing the moderate reduction in the overall landing distance is related to the enhanced maximum lift coefficient, which lowers the approach and touch-down speed. According to the data sets of the optimization it seems that the take-off and landing distance that form the objective function are not in conflict in this scenario. The optimization results indicate that the aerodynamic performance is more sensitive to parameters that define the slat setting and the magnitude of the flap deployment than to parameters that define the geometry of the flap mechanism

A Knowledge Preservation And Re-Use Tool Based On Context-Driven Reasoning

This article describes a knowledge preservation and re-use tool designed to capture the knowledge of a specific individual at the US National Science Foundation, for later retrieval by successors after his retirement. The system is designed in a Q&A format, where it is sufficiently intelligent to ask for clarifying questions. The primary objective was to create a system that would result in acceptance of the system by the users. The domain of interest to be preserved and re-used was programmatic knowledge about the NSF Industry/University Collaborative Research Centers (I/UCRC) Program, and more specifically, the knowledge of its long-time director, Dr. Alex Schwarzkopf. The system is called AskAlex and it uses a trio of techniques to accomplish its objectives. Contextual graphs (CxG) are used as the basic knowledge representation structure. CxG\u27s are assisted by a search engine and an ontology of terms to help find the proper contextual graph that can best answer the question being asked. Evaluations with users and potential users generally confirm our selection and provided some guidance for improvements in the system