Influence of zinc on glycosaminoglycan neutralisation during coagulation

This work was supported by the British Heart Foundation (grant codes: PG/15/9/31270 and FS/15/42/31556). SJP is supported by a Royal Society of Edinburgh Biomedical Fellowship.Heparan sulfate (HS), dermatan sulfate (DS) and heparin are glycosaminoglycans (GAGs) that serve as key natural and pharmacological anticoagulants. During normal clotting such agents require to be inactivated or neutralised. Several proteins have been reported to facilitate their neutralisation, which reside in platelet α-granules and are released following platelet activation. These include histidine-rich-glycoprotein (HRG), fibrinogen and high-molecular-weight kininogen (HMWK). Zinc ions (Zn2+) are also present in α-granules at a high concentration and participate in the propagation of coagulation by influencing the binding of neutralising proteins to GAGs. Zn2+ in many cases increases the affinity of these proteins to GAGs, and is thus an important regulator of GAG neutralisation and haemostasis. Binding of Zn2+ to HRG, HMWK and fibrinogen is mediated predominantly through coordination to histidine residues but the mechanisms by which Zn2+ increases the affinity of the proteins for GAGs are not yet completely clear. Here we will review current knowledge of how Zn2+ binds to and influences the neutralisation of GAGs and describe the importance of this process in both normal and pathogenic clotting.Publisher PDFPeer reviewe

Dual diagnosis clients' treatment satisfaction - a systematic review

Background: The aim of this systematic review is to synthesize existing evidence about treatment satisfaction among clients with substance misuse and mental health co-morbidity (dual diagnoses, DD). Methods: We examined satisfaction with treatment received, variations in satisfaction levels by type of treatment intervention and by diagnosis (i.e. DD clients vs. single diagnosis clients), and the influence of factors other than treatment type on satisfaction. Peer-reviewed studies published in English since 1970 were identified by searching electronic databases using pre-defined search strings. Results: Across the 27 studies that met inclusion criteria, high average satisfaction scores were found. In most studies, integrated DD treatment yielded greater client satisfaction than standard treatment without explicit DD focus. In standard treatment without DD focus, DD clients tended to be less satisfied than single diagnosis clients. Whilst the evidence base on client and treatment variables related to satisfaction is small, it suggested client demographics and symptom severity to be unrelated to treatment satisfaction. However, satisfaction tended to be linked to other treatment process and outcome variables. Findings are limited in that many studies had very small sample sizes, did not use validated satisfaction instruments and may not have controlled for potential confounders. A framework for further research in this important area is discussed. Conclusions: High satisfaction levels with current treatment provision, especially among those in integrated treatment, should enhance therapeutic optimism among practitioners dealing with DD clients

Automatic abstraction in symbolic trajectory evaluation

Symbolic trajectory evaluation (STE) is a model checking technology based on symbolic simulation over a lattice of abstract state sets. The STE algorithm operates over families of these abstractions encoded by Boolean formulas, enabling verification with many different abstraction cases in a single modelchecking run. This provides a flexible way to achieve partitioned data abstraction. It is usually called "symbolic indexing' and is widely used in memory verification, but has seen relatively limited adoption elsewhere, primarily because users typically have to create the right indexed family of abstractions manually. This work provides the first known algorithm that automatically computes these partitioned abstractions given a reference-model specification. Our experimental results show that this approach not only simplifies memory verification, but also enables handling completely different designs fully automatically

Aggregation and Contingent Metal/Surface Reactivity of 1,3,8,10-Tetraazaperopyrene (TAPP) on Cu(111)

13 páginas, 12 figuras, 2 tablas.-- et al.The structural chemistry and reactivity of 1,3,8,10-tetraazaperopyrene (TAPP) on Cu(111) under ultra-high-vacuum (UHV) conditions has been studied by a combination of experimental techniques (scanning tunneling microscopy (STM) and X-ray photoelectron spectroscopy, XPS) and DFT calculations. Depending on the deposition conditions, TAPP forms three main assemblies, which result from initial submonolayer coverages based on different intermolecular interactions: a close-packed assembly similar to a projection of the bulk structure of TAPP, in which the molecules interact mainly through van der Waals (vDW) forces and weak hydrogen bonds; a porous copper surface coordination network; and covalently linked molecular chains. The Cu substrate is of crucial importance in determining the structures of the aggregates and available reaction channels on the surface, both in the formation of the porous network for which it provides the Cu atoms for surface metal coordination and in the covalent coupling of the TAPP molecules at elevated temperature. Apart from their role in the kinetics of surface transformations, the available metal adatoms may also profoundly influence the thermodynamics of transformations by coordination to the reaction product, as shown in this work for the case of the Cu-decorated covalent poly(TAPP--Cu) chains.We thank the Swiss National Science Foundation, the European Union through the Marie Curie Research Training Network PRAIRIES (MRTN-CT-2006-035810) and the University of Heidelberg for funding, and acknowledge the award of a predoctoral fellowship to S.M. by the Landesgraduiertenfçrderung Baden-Württemberg (Promotionskolleg “Molekulare Sonden”).Peer reviewe