Integrin-linked kinase regulates the rate of platelet activation and is essential for the formation of stable thrombi

BACKGROUND: Integrin-linked kinase (ILK) and its associated complex of proteins are involved in many cellular activation processes, including cell adhesion and integrin signaling. We have previously demonstrated that mice with induced platelet ILK deficiency show reduced platelet activation and aggregation, but only a minor bleeding defect. Here, we explore this apparent disparity between the cellular and hemostatic phenotypes. METHODS: The impact of ILK inhibition on integrin αII b β3 activation and degranulation was assessed with the ILK-specific inhibitor QLT0267, and a conditional ILK-deficient mouse model was used to assess the impact of ILK deficiency on in vivo platelet aggregation and thrombus formation. RESULTS: Inhibition of ILK reduced the rate of both fibrinogen binding and α-granule secretion, but was accompanied by only a moderate reduction in the maximum extent of platelet activation or aggregation in vitro. The reduction in the rate of fibrinogen binding occurred prior to degranulation or translocation of αII b β3 to the platelet surface. The change in the rate of platelet activation in the absence of functional ILK led to a reduction in platelet aggregation in vivo, but did not change the size of thrombi formed following laser injury of the cremaster arteriole wall in ILK-deficient mice. It did, however, result in a marked decrease in the stability of thrombi formed in ILK-deficient mice. CONCLUSION: Taken together, the findings of this study indicate that, although ILK is not essential for platelet activation, it plays a critical role in facilitating rapid platelet activation, which is essential for stable thrombus formation.

Societal transformation in response to global environmental change: a review of emerging concepts

The study of societal transformation in response to environmental change has become established, yet little consensus exists regarding the conceptual basis of transformation. This paper aims to provide structure to the dialog on transformation, and to reflect on the challenges of social research in this area. Concepts of transformation are identified through a literature review, and examined using four analytical criteria. It is found that the term ‘transformation’ is frequently used merely as a metaphor. When transformation is not used as a metaphor, eight concepts are most frequently employed. They differ with respect to (i) system conceptualization, (ii) notions of social consciousness (deliberate/emergent), and (iii) outcome (prescriptive/descriptive). Problem-based research tends to adopt concepts of deliberate transformation with prescriptive outcome, while concepts of emergent transformation with no prescriptive outcome tend to inform descriptive-analytical research. Dialog around the complementarities of different concepts and their empirical testing are priorities for future research.

Basic concepts for convection parameterization in weather forecast and climate models: COST Action ES0905 final report

The research network “Basic Concepts for Convection Parameterization in Weather Forecast and Climate Models” was organized with European funding (COST Action ES0905) for the period of 2010–2014. Its extensive brainstorming suggests how the subgrid-scale parameterization problem in atmospheric modeling, especially for convection, can be examined and developed from the point of view of a robust theoretical basis. Our main cautions are current emphasis on massive observational data analyses and process studies. The closure and the entrainment–detrainment problems are identified as the two highest priorities for convection parameterization under the mass–flux formulation. The need for a drastic change of the current European research culture as concerns policies and funding in order not to further deplete the visions of the European researchers focusing on those basic issues is emphasized.

Networks and plant disease management: concepts and applications

A network is a natural structure with which to describe many aspects of a plant pathosystem. The article seeks to set out in a nonmathematical way some of the network concepts that promise to be useful in managing plant disease. The field has been stimulated by developments designed to help understand and manage animal and human disease, as well as by technical infrastructures, such as the internet. It overlaps partly with landscape ecology. The study of networks has helped identify likely ways to reduce flow of disease in traded plants, to find the best sites to monitor as warning sites for annually reinvading disease, and to understand the fundamentals of how a pathogen spreads in different structures. A tension between the free flow of goods or species down communication channels and free flow of pathogens down the same pathways is highlighted.

Death of the high street: identification, prevention, reinvention

Location is of paramount importance within the retail sector, yet defining locational obsolescence remains overlooked, despite significant concerns over the viability of parts of the complex sector. This paper reviews the existing literature and, through this, explores retail locational obsolescence, including the multi-spatial nature of the driving forces that range from the global economy, local markets and submarkets, to individual property-specific factors; and, crucially, the need to disentangle locational obsolescence from other important concepts such as depreciation and functional obsolescence that are often mistakenly used. Through this, a conceptual model, definition and diagnostic criteria are presented to guide future studies, policy development and the allocation of resources. Importantly, three stages are presented to enable the operationalization of the model, essential to future academic and industry studies as well as the ongoing development of policy in this economically important, complex and contentious area.

Nicked-site substrates for a serine recombinase reveal enzyme–DNA communications and an essential tethering role of covalent enzyme–DNA linkages

To analyse the mechanism and kinetics of DNA strand cleavages catalysed by the serine recombinase Tn3 resolvase, we made modified recombination sites with a single-strand nick in one of the two DNA strands. Resolvase acting on these sites cleaves the intact strand very rapidly, giving an abnormal half-site product which accumulates. We propose that these reactions mimic second-strand cleavage of an unmodified site. Cleavage occurs in a synapse of two sites, held together by a resolvase tetramer; cleavage at one site stimulates cleavage at the partner site. After cleavage of a nicked-site substrate, the half-site that is not covalently linked to a resolvase subunit dissociates rapidly from the synapse, destabilizing the entire complex. The covalent resolvase–DNA linkages in the natural reaction intermediate thus perform an essential DNA-tethering function. Chemical modifications of a nicked-site substrate at the positions of the scissile phosphodiesters result in abolition or inhibition of resolvase-mediated cleavage and effects on resolvase binding and synapsis, providing insight into the serine recombinase catalytic mechanism and how resolvase interacts with the substrate DNA.

Enterprise Architecture adoption method for Higher Education Institutions

During the last few years Enterprise Architecture has received increasing attention among industry and academia. Enterprise Architecture (EA) can be defined as (i) a formal description of the current and future state(s) of an organisation, and (ii) a managed change between these states to meet organisation’s stakeholders’ goals and to create value to the organisation. By adopting EA, organisations may gain a number of benefits such as better decision making, increased revenues and cost reductions, and alignment of business and IT. To increase the performance of public sector operations, and to improve public services and their availability, the Finnish Parliament has ratified the Act on Information Management Governance in Public Administration in 2011. The Act mandates public sector organisations to start adopting EA by 2014, including Higher Education Institutions (HEIs). Despite the benefits of EA and the Act, EA adoption level and maturity in Finnish HEIs are low. This is partly caused by the fact that EA adoption has been found to be difficult. Thus there is a need for a solution to help organisations to adopt EA successfully. This thesis follows Design Science (DS) approach to improve traditional EA adoption method in order to increase the likelihood of successful adoption. First a model is developed to explain the change resistance during EA adoption. To find out problems associated with EA adoption, an EA-pilot conducted in 2010 among 12 Finnish HEIs was analysed using the model. It was found that most of the problems were caused by misunderstood EA concepts, attitudes, and lack of skills. The traditional EA adoption method does not pay attention to these. To overcome the limitations of the traditional EA adoption method, an improved EA Adoption Method (EAAM) is introduced. By following EAAM, organisations may increase the likelihood of successful EA adoption. EAAM helps in acquiring the mandate for EA adoption from top-management, which has been found to be crucial to success. It also helps in supporting individual and organisational learning, which has also found to be essential in successful adoption.

Care, disability and HIV in Africa: diverging or interconnected concepts and practices?

Recent research and policy have recognised the central role of unpaid care-givers (often women and girls) in the global South. Disability rights perspectives, however, challenge the language of ‘care’ and ‘dependence’. Drawing on qualitative research with women living with HIV and children caring for them in Tanzania, and on learning from the National Community of Women Living with HIV and AIDS in Uganda (NACWOLA), this paper explores the divergences and interconnections between the concepts and practices of care, disability and HIV in the context of East Africa. Despite the development of interdependent caring relations, both care-givers and people living with HIV in Tanzania experience ‘diminished autonomy’. The participation of people living with HIV, including disabled people, in home-based care and in peer support groups, however, can enhance ‘relational autonomy’ for both care-givers and care-recipients. We reflect on opportunities and challenges for mutual learning and cross-movement advocacy by disabled people, people living with HIV and care-givers.

CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development

The C-type lectin receptor CLEC-2 signals through a pathway that is critically dependent on the tyrosine kinase Syk. We show that homozygous loss of either protein results in defects in brain vascular and lymphatic development, lung inflation, and perinatal lethality. Furthermore, we find that conditional deletion of Syk in the hematopoietic lineage, or conditional deletion of CLEC-2 or Syk in the megakaryocyte/platelet lineage, also causes defects in brain vascular and lymphatic development, although the mice are viable. In contrast, conditional deletion of Syk in other hematopoietic lineages had no effect on viability or brain vasculature and lymphatic development. We show that platelets, but not platelet releasate, modulate the migration and intercellular adhesion of lymphatic endothelial cells through a pathway that depends on CLEC-2 and Syk. These studies found that megakaryocyte/platelet expression of CLEC-2 and Syk is required for normal brain vasculature and lymphatic development and that platelet CLEC-2 and Syk directly modulate lymphatic endothelial cell behavior in vitro.

MiR-375 is essential for human spinal motor neuron development and may be involved in motor neuron degeneration

The transcription factor REST is a key suppressor of neuronal genes in non-neuronal tissues. REST has been shown to suppress pro-neuronal microRNAs in neural progenitors indicating that REST-mediated neurogenic suppression may act in part via microRNAs. We used neural differentiation of Rest-null mouse ESC to identify dozens of microRNAs regulated by REST during neural development. One of the identified microRNAs, miR-375, was upregulated during human spinal motor neuron development. We found that miR-375 facilitates spinal motor neurogenesis by targeting the cyclin kinase CCND2 and the transcription factor PAX6. Additionally, miR-375 inhibits the tumor suppressor p53 and protects neurons from apoptosis in response to DNA damage. Interestingly, motor neurons derived from a spinal muscular atrophy patient displayed depressed miR-375 expression and elevated p53 protein levels. Importantly, SMA motor neurons were significantly more susceptible to DNA damage induced apoptosis suggesting that miR-375 may play a protective role in motor neurons.

Concepts for a geostationary-like polar missions

An evidence-led scientific case for development of a space-based polar remote sensing platform at geostationary-like (GEO-like) altitudes is developed through methods including a data user survey. Whilst a GEO platform provides a nearstatic perspective, multiple platforms are required to provide circumferential coverage. Systems for achieving GEO-like polar observation likewise require multiple platforms however the perspective is non-stationery. A key choice is between designs that provide complete polar view from a single platform at any given instant, and designs where this is obtained by compositing partial views from multiple sensors. Users foresee an increased challenge in extracting geophysical information from composite images and consider the use of non-composited images advantageous. Users also find the placement of apogee over the pole to be preferable to the alternative scenarios. Thus, a clear majority of data users find the “Taranis” orbit concept to be better than a critical inclination orbit, due to the improved perspective offered. The geophysical products that would benefit from a GEO-like polar platform are mainly estimated from radiances in the visible/near infrared and thermal parts of the electromagnetic spectrum, which is consistent with currently proven technologies from GEO. Based on the survey results, needs analysis, and current technology proven from GEO, scientific and observation requirements are developed along with two instrument concepts with eight and four channels, based on Flexible Combined Imager heritage. It is found that an operational system could, mostly likely, be deployed from an Ariane 5 ES to a 16-hour orbit, while a proof-of-concept system could be deployed from a Soyuz launch to the same orbit.