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Parkinson’s disease (PD) is the second most common neurodegenerative disorder which requires a long-term, interdisciplinary disease management. While there remains no cure for Parkinson’s disease, treatments are available to help reduce the main symptoms and maintain quality of life for as long as possible. Owing to the global burden faced by chronic conditions such as PD, Assistive technologies (AT’s) are becoming an increasingly common prescribed form of treatment. Low adoption is hampering the potential of digital technologies within health and social care. It is then necessary to employ classification algorithms have been developed for differentiating adopters and non-adopters of these technologies; thereby, potential negative effects on people with PD and cost overruns can be further minimized. This paper bridges this gap by extending the Multi-criteria decision-making approach adopted in technology adoption modeling for people with dementia. First, the fuzzy Analytic Hierarchy Process (FAHP) is applied to estimate the initial relative weights of criteria and sub-criteria. Then, the Decision-making Trial and Evaluation Laboratory (DEMATEL) is used for evaluating the interrelations and feedback among criteria and sub-criteria. The Technique for Order of Preferences by Similarity to Ideal Solution (TOPSIS) is finally implemented to rank three classifiers (Lazy IBk – knearest neighbors, Naive bayes, and J48 decision tree) according to their ability to model technology adoption. A real case study considering is presented to validate the proposed approach.

The use of nanometer-sized semiconductor crystals, known as quantum dots, allows us to directly observe individual biomolecular transactions through a fluorescence microscope. Here, we review the evolution of single quantum dot tracking over the past two decades, highlight key biophysical discoveries facilitated by quantum dots, briefly discuss biochemical and optical implementation strategies for a single quantum dot tracking experiment, and report recent accomplishments of our group at the interface of molecular neuroscience and nanoscience.

A subset of pancreatic body and tail cancers present with locally advanced disease due to involvement of the celiac axis. Previously considered unresectable, these T4 tumors may be extirpated with a distal pancreatectomy and en bloc resection of the celiac trunk in carefully selected patients. In the setting of multimodality treatment, these resections can yield survival similar to resectable and borderline resectable lesions. Robotic surgery has been shown to be safe and feasible in complex pancreatic resections. This article summarizes our patient selection criteria and operative approach to robotic distal pancreatectomy with celiac axis resection (DP-CAR) for locally advanced body and tail tumors of the pancreas.

The case presented is that of a man in his late 60s who experienced an acute anterior myocardial infarction. A complete 2D echocardiogram with color flow and Doppler imaging had been performed on the patient's first hospital day. On day 2 of his hospitalization, a follow-up limited study was performed to reevaluate left ventricular function. Cardiac function was essentially unchanged from the prior day's study. However, color flow Doppler was performed, and a distal septal ventricular septal defect was detected incidentally, only in the final apical view while using the full-height color sector box. This study demonstrates the value of using the full-size color sector box as a screening tool when performing color flow Doppler. Current high-capacity (256 channel and above) equipment assists the sonographer with image optimization and decreases the need to use the truncated color flow box.

Here we describe the three-dimensional crystal structures of human glucocorticoid receptor ligand-binding domain (GR-LBD) in complex with the antagonist RU-486 at 2.3 A resolution and with the agonist dexamethasone ligand together with a coactivator peptide at 2.8 A. The RU-486 structure was solved in several different crystal forms, two with helix 12 intact (GR1 and GR3) and one with a protease-digested C terminus (GR2). In GR1, part of helix 12 is in a position that covers the co-activator pocket, whereas in the GR3, domain swapping is seen between the crystallographically identical subunits in the GR dimer. An arm consisting of the end of helix 11 and beyond stretches out from one molecule, and helix 12 binds to the other LBD, partly blocking the coactivator pocket of that molecule. This type of GR-LBD dimer has not been described before but might be an artifact from crystallization. Furthermore, the subunits of the GR3 dimers are covalently connected via a disulfide bond between the Cys-736 residues in the two molecules. All three RU-486 GR-LBD structures show that GR has a very flexible region between the end of helix 11 and the end of helix 12.

Although partnerships are emerging as a central feature in governance arrangements in advanced capitalist societies, much discussion has taken place on the value and effectiveness of the approach. In recent years this debate has come to the fore in Northern Ireland, as a plethora of partnerships have been increasingly applied across a wide range of different government programmes at different levels of governance. Using a map of partnership arrangements in Northern Ireland, the author examines three case studies with a view to analysing the value and importance of partnership and assessing the activities that they do best. From this analysis, the author then discusses the future of partnership governance, outlines a number of areas for new research, and presents an agenda for development. As the case studies suggest that too much emphasis has been placed on developing a ‘process’, to the detriment of product outcomes, it is argued that partnerships need to adopt a dual approach to development by combining an inclusive process with greater strategic focus. At the regional level, however, a partnership framework is needed to facilitate coordination, reduce duplication, and improve understanding between partnerships, and between partnerships, local authorities, and government departments. Moreover, by adopting an inclusive approach, a partnership framework has the potential to provide a voice for the socially and politically excluded and to encourage participative planning and pluralist policymaking.

To increase the efficiency of diffraction data collection for protein crystallographic studies, an automated system designed to store frozen protein crystals, mount them sequentially, align them to the X-ray beam, collect complete data sets, and return the crystals to storage has been developed. Advances in X-ray data collection technology including more brilliant X-ray sources, improved focusing optics, and faster-readout detectors have reduced diffraction data acquisition times from days to hours at a typical protein crystallography laboratory [1, 2]. In addition, the number of high-brilliance synchrotron X-ray beam lines dedicated to macromolecular crystallography has increased significantly, and data collection times at these facilities can be routinely less than an hour per crystal. Because the number of protein crystals that may be collected in a 24 hr period has substantially increased, unattended X-ray data acquisition, including automated crystal mounting and alignment, is a desirable goal for protein crystallography. The ability to complete X-ray data collection more efficiently should impact a number of fields, including the emerging structural genomics field [3], structure-directed drug design, and the newly developed screening by X-ray crystallography [4], as well as small molecule applications.

The need to decrease the time scale for clinical compound discovery has led to innovations at several stages in the process, including genomics/proteomics for target identification, ultrahigh-throughput screening for lead identification, and structure-based drug design and combinatorial chemistry for lead optimization. A critical juncture in the process is the identification of a proper lead compound, because a poor choice may generate costly difficulties at later stages. Lead compounds are commonly identified from high-throughput screens of large compound libraries, derived from known substrates/inhibitors, or identified in computational prescreeusing X-ray crystal structures. Structural information is often consulted to efficiently optimize leads, but under the current paradigm, such data require preidentification and confirmation of compound binding. Here, we describe a new X-ray crystallography-driven screening technique that combines the steps of lead identification, structural assessment, and optimization. The method is rapid, efficient, and high-throughput, and it results in detailed crystallographic structure information. The utility of the method is demonstrated in the discovery and optimization of a new orally available class of urokinase inhibitors for the treatment of cancer.

All reported GnRH receptor mutants (causing human hypogonadotropic hypogonadism) are misfolded proteins that cannot traffic to the plasma membrane. Pharmacoperones correct mis-folding and rescue mutants, routing them to the plasma membrane where they regain function. Because pharmacoperones are often peptidomimetic antagonists, these must be removed for receptor function after rescue; in vivo this necessitates pulsatile pharmacoperone administration. As an antecedent to in vivo studies, we determined whether pharmacoperones need to be present at the time of synthesis or whether previously misfolded proteins could be refolded and rescued. Accordingly, we blocked either protein synthesis or intra-cellular transport. Biochemical and morphological studies using 12 mutants and 10 pharmacoperones representing three different chemical classes show that previously synthesized mutant proteins, retained by the quality control system (QCS), are rescued by pharmacoperones, showing that pharmacoperone administration in vivo likely need not consider whether the target protein is being synthesized at the time of drug administration.

Two-dimensional 1H NMR investigations were used to locate elements of regular secondary structure in the human complement protein C3a (the des-Arg77 derivative) in solution. The results were compared to a refined crystal structure based on the 3.2-A resolution structure of des-Arg77-C3a [Huber, R., Scholze, H., Paques, E. P. & Deisenhofer, J. (1980) Hoppe-Seyler's Z. Physiol. Chem. 361, 1389-1399]. In excellent agreement with the x-ray data, helices occur in the regions of residues 17-28 and 36-43 in solution. In contrast to the x-ray data, where a third long helix was found from residue 47 to residue 73, the solution data show a shorter helix in the region from residue 47 to residue 66, followed by a transition range at positions 67-70, leading into a six-residue carboxyl-terminal peptide in dynamic random coil conformation. At the amino terminus, a well-defined helix is observed in solution for the residues 8-15 region, which, like the carboxyl terminus, gradually changes to dynamic random coil toward the end of the polypeptide chain. This is at variance with the x-ray data as well, in which residues 13-15 are nonhelical and no electron density could be assigned to the first 12 residues due to disorder.

The complement cleavage product C5a is a potent stimulant of inflammatory processes; thus, inhibition of C5a activity is of therapeutic interest. The three-dimensional structure of the major portion of C5a was modeled from the homologous C3a crystal structure by comparative modeling techniques. The model shows that core residues of C5a are completely conserved, while external residues differ from C3a. Even though the amino-terminal 12 residues of C3a are disordered in the crystal, this sequence in C5a may form an amphipathic helix. The distribution of species sequence differences in the complete C5a structure suggests a possible receptor binding site.

A model has been constructed for haptoglobin heavy chain by using the known sequence homology to the mammalian serine proteases. The three-dimensional structures for three serine proteases, chymotrypsin, trypsin, and elastase, were compared and the structural features that are conserved in all three were extracted. The haptoglobin heavy chain sequence was aligned to the sequences of the three serine proteases by maximizing sequence homology in the regions of conserved structure. The resulting alignment shows that haptoglobin heavy chain must be very closely homologous to these proteases in structure as well as in sequence. Coordinates were derived for the heavy chain by using the homologous structures. The problems associated with these coordinates are outlined and methods for solving them are indicated. The features of the haptoglobin heavy chain structure are described. Implications of the structure for the very strong interaction between this subunit and hemoglobin are discussed.

A quantitative function equivalent to the "molecular" surface proposed by F. M. Richards [(1977) Annu. Rev. Biophys. Bioeng. 6, 151--176] is defined by the closest approach of solvent spheres to a macromolecule. The function can be used to visualize surface topography, polarity, and charge either as a three-dimensional net or by mapping onto a plane; to calculate surface areas; and to demarcate complementary sites in contacts between subunits. Applications to shape-specific recognition in protein structure and aggregation are discussed.

Proteins often occur in families whose structure is closely similar, even though the proteins may come from widely different sources and have quite distinct functions. It would be useful to be able to construct the three-dimensional structure of these proteins from the known structure of one or more of them without having to solve the structure of each protein ab initio. We have been using comparative model building to derive the structure of an unusual protein of the trypsin-like serine protease family. We have recently extended this comparison to include other serine protease homologs for which a primary structure is available. To generate structures for the different members of the serine protease family, it is necessary to extract the common structural features of the molecule. Fortunately, three independently determined protein structures are available: schymotrypsin, trypsin, and elastase. These three structures were compared in detail and the structurally conserved regions in all three, mainly the BETA-sheet and the ..cap alpha..-helix, were identified. The variable portions occur in the loops on the surface of the molecule. By using these structures, the primary sequences of these three proteins were aligned. From this alignment, it is clear that sequence homology between the proteins occursmore » mainly in the structurally conserved regions of the molecule, while the variable portions show very little sequence homology.« less