Barriers to cross-region research and development collaborations in Europe. Evidence from the fifth European Framework Programme

The focus of this paper is on cross-region R&D collaboration funded by the 5th EU Framework Programme (FP5). The objective is to measure distance, institutional, language and technological barrier effects that may hamper collaborative activities between European regions. Particular emphasis is laid on measuring discrepancies between two types of collaborative R&D activities, those generating output in terms of scientific publications and those that do not. The study area is composed of 255 NUTS-2 regions that cover the pre-2007 member states of the European Union (excluding Malta and Cyprus) as well as Norway and Switzerland. We employ a negative binomial spatial interaction model specification to address the research question, along with an eigenvector spatial filtering technique suggested by Fischer and Griffith (2008) to account for the presence of network autocorrelation in the origin-destination cooperation data. The study provides evidence that the role of geographic distance as collaborative deterrent is significantly lower if collaborations generate scientific output. Institutional barriers do not play a significant role for collaborations with scientific output. Language and technological barriers are smaller but the estimates indicate no significant discrepancies between the two types of collaborative R&D activities that are in focus of this study.Series: Working Papers in Regional Scienc

L-type calcium channel blockers and substance P induce angiogenesis of cortical vessels associated with beta-amyloid plaques in an Alzheimer mouse model

AbstractIt is well established that L-type calcium channels (LTCCs) are expressed in astroglia. However, their functional role is still speculative, especially under pathologic conditions. We recently showed that the α1 subunit-like immunoreactivity of the CaV1.2 channel is strongly expressed in reactive astrocytes around beta-amyloid plaques in 11-month-old Alzheimer transgenic (tg) mice with the amyloid precursor protein London and Swedish mutations. The aim of the present study was to examine the cellular expression of all LTCC subunits around beta-amyloid plaques by in situ hybridization using 35S-labeled oligonucleotides. Our data show that messenger RNAs (mRNAs) of the LTCC CaV1.2 α1 subunit as well as all auxiliary β and α2δ subunits, except α2δ-4, were expressed in the hippocampus of age-matched wild-type mice. It was unexpected to see, that cells directly located in the plaque core in the cortex expressed mRNAs for CaV1.2 α1, β2, β4, and α2δ-1, whereas no expression was detected in the halo. Furthermore, cells in the plaque core also expressed preprotachykinin-A mRNA, the precursor for substance P. By means of confocal microscopy, we demonstrated that collagen-IV-stained brain vessels in the cortex were associated with the plaque core and were immunoreactive for substance P. In cortical organotypic brain slices of adult Alzheimer mice, we could demonstrate that LTCC blockers increased angiogenesis, which was further potentiated by substance P. In conclusion, our data show that brain vessels associated with beta-amyloid plaques express substance P and an LTCC and may play a role in angiogenesis

Alzheimer\u27s Therapeutics Targeting Amyloid Beta 1-42 Oligomers I: Abeta 42 Oligomer Binding to Specific Neuronal Receptors is Displaced by Drug Candidates That Improve Cognitive Deficits

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer\u27s disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer\u27s disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer\u27s therapeutics

FAIR Metadata Standards for Low Carbon Energy Research—A Review of Practices and How to Advance

The principles of Findability, Accessibility, Interoperability, and Reusability (FAIR) have been put forward to guide optimal sharing of data. The potential for industrial and social innovation is vast. Domain-specific metadata standards are crucial in this context, but are widely missing in the energy sector. This report provides a collaborative response from the low carbon energy research community for addressing the necessity of advancing FAIR metadata standards. We review and test existing metadata practices in the domain based on a series of community workshops. We reflect the perspectives of energy data stakeholders. The outcome is reported in terms of challenges and elicits recommendations for advancing FAIR metadata standards in the energy domain across a broad spectrum of stakeholders

BACE1-cleavage of Sez6 and Sez6L is elevated in Niemann-Pick type C disease mouse brains

It is intriguing that a rare, inherited lysosomal storage disorder Niemann-Pick type C (NPC) shares similarities with Alzheimer’s disease (AD). We have previously reported an enhanced processing of β-amyloid precursor protein (APP) by β-secretase (BACE1), a key enzyme in the pathogenesis of AD, in NPC1-null cells. In this work, we characterized regional and temporal expression and processing of the recently identified BACE1 substrates seizure protein 6 (Sez6) and seizure 6-like protein (Sez6L), and APP, in NPC1-/- (NPC1) and NPC1+/+ (wt) mouse brains. We analysed 4-weeks old brains to detect the earliest changes associated with NPC, and 10-weeks of age to identify changes at terminal disease stage. Sez6 and Sez6L were selected due to their predominant cleavage by BACE1, and their potential role in synaptic function that may contribute to presentation of seizures and/or motor impairments in NPC patients. While an enhanced BACE1-cleavage of all three substrates was detected in NPC1 vs. wt-mouse brains at 4- weeks of age, at 10-weeks increased proteolysis by BACE1 was observed for Sez6L in the cortex, hippocampus and cerebellum of NPC1-mice. Interestingly, both APP and Sez6L were found to be expressed in Purkinje neurons and their immunostaining was lost upon Purkinje cell neurodegeneration in 10-weeks old NPC1 mice. Furthermore, in NPC1- vs. wt-mouse primary cortical neurons, both Sez6 and Sez6L showed increased punctuate staining within the endolysosomal pathway as well as increased Sez6L and BACE1-positive puncta. This indicates that a trafficking defect within the endolysosomal pathway may play a key role in enhanced BACE1-proteolysis in NPC disease. Overall, our findings suggest that enhanced proteolysis by BACE1 could be a part of NPC disease pathogenesis. Understanding the basic biology of BACE1 and the functional impact of cleavage of its substrates is important to better evaluate the therapeutic potential of BACE1 against AD and, possibly, NPC disease

Comparison of Pharmacological Modulation of APP Metabolism in Primary Chicken Telencephalic Neurons and in a Human Neuroglioma Cell Line

Sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases and the formation of Aβ peptides are pivotal for Alzheimer's disease. Therefore, a large number of drugs has been developed targeting APP metabolism. However, many pharmacological compounds have been identified in vitro in immortalized APP overexpressing cell lines rather than in primary neurons. Here, we compared the effect of already characterized secretase inhibitors and modulators on Aβ formation in primary chicken telencephalic neurons and in a human neuroglioma cell line (H4) ectopically expressing human APP with the Swedish double mutation. Primary chicken neurons replicated the effects of a β-secretase inhibitor (β-secretase inhibitor IV), two γ-secretase inhibitors (DAPM, DAPT), two non-steroidal-anti-inflammatory drugs (sulindac sulfide, CW), and of the calpain inhibitor calpeptin. With the exception of the two γ-secretase inhibitors, all tested compounds were more efficacious in primary chicken telencephalic neurons than in the immortalized H4 cell line. Moreover, H4 cells failed to reproduce the effect of calpeptin. Hence, primary chicken telencephalic neurons represent a suitable cell culture model for testing drugs interfering with APP processing and are overall more sensitive to pharmacological interference than immortalized H4 cells ectopically expressing mutant human APP

Stable Mutated tau441 Transfected SH-SY5Y Cells as Screening Tool for Alzheimer’s Disease Drug Candidates

The role of hyperphosphorylation of the microtubule-associated protein tau in the pathological processes of several neurodegenerative diseases is becoming better understood. Consequently, development of new compounds capable of preventing tau hyperphosphorylation is an increasingly hot topic. For this reason, dependable in vitro and in vivo models that reflect tau hyperphosphorylation in human diseases are needed. In this study, we generated and validated an in vitro model appropriate to test potential curative and preventive compound effects on tau phosphorylation. For this purpose, a stably transfected SH-SY5Y cell line was constructed over-expressing mutant human tau441 (SH-SY5Y-TMHT441). Analyses of expression levels and tau phosphorylation status in untreated cells confirmed relevance to human diseases. Subsequently, the effect of different established kinase inhibitors on tau phosphorylation (e.g., residues Thr231, Thr181, and Ser396) was examined. It was shown with several methods including immunosorbent assays and mass spectrometry that the phosphorylation pattern of tau in SH-SY5Y-TMHT441 cells can be reliably modulated by these compounds, specifically targeting JNK, GSK-3, CDK1/5, and CK1. These four protein kinases are known to be involved in in vivo tau phosphorylation and are therefore authentic indicators for the suitability of this new cell culture model for tauopathies

R&D networks and regional knowledge production: an agent-based simulation of the Austrian competence centres programme

Publicly funded competence centres have gained high recognition for improving science-industry collaboration. With the requirement for long-term and geographically concentrated R&D, competence centres provide an environment for joint learning and transfer of “sticky” knowledge. The objective of this paper is to investigate how a competence centres programme affects knowledge production in the regional innovation system. In order to address this issue, we draw on a simulation approach and develop an agent-based model of the Vienna Life Sciences innovation system. Companies, research organisations and universities are heterogeneous agents that create scientific publications, patents, as well as high-tech jobs. Simulation runs refer to long-term scenarios regarding the level and duration of public funding. By addressing the complexities of knowledge interaction in the context of the “local buzz” versus “global pipelines” discussion, the results show the potential of empirically calibrated simulation models for ex-ante impact assessment in R&D policy

Determinants of Collaboration in European R&D Networks: Empirical Evidence from a Discrete Choice Model

This paper focuses on inter-organizational R&D collaborations as captured by joint research projects funded within the European Framework Programmes for Research and Technological Development (EU-FPs). We identify determinants of collaboration, including actor characteristics, relational and network effects as well as geographical effects by means of a discrete choice model. Using data on EU-FP projects from the EUPRO database and from a representative survey of participants, we produce statistically significant evidence that collaboration choices in EU-FPs are primarily facilitated by prior acquaintance, thematic proximity and geographical proximity. Also, network effects are significantly related to collaboration choice. Moreover, the study shows that the impact of geographical effects increases for more intensive collaboration. The results are promising since a deeper understanding of these collaboration processes is needed for future governance of research policies in the EU.R&D collaboration, network formation, EU Framework Programmes, discrete choice model, ordered logistic regression,

Ranking lists and European Framework Programmes: Does university status matter for performance in Framework Programmes?

The operational context for higher education institutions has become increasingly competitive: universities have to compete on national and international markets for students, staff, funding and prestige. In this context, universities have increasingly become to think of themselves as actors who are in direct competition with others, and adapt their strategies to increase their status and survive in the new environment. The possibly best-known approach to measuring the status of universities is through the various ranking lists. Though focusing on different indicators like scientific performance or reputation, ranking lists can be considered as a mechanism for highlighting and even creating status hierarchies and providing information about the “market value” of universities. They have also contributed to the proliferation of various national policy schemes fostering elite universities, which aim to redress the dominance of US universities in the ranking lists. An increasingly important funding source for universities is the EU Framework Programmes, where the European Commission funds basic and applied research with industrial and societal relevance. The aim of our chapter is to explore whether established university rankings in their current form are appropriate instruments for predicting the performance of universities in the EU Framework Programmes and whether university’s status has an influence on its access to FP funding. To address this question, we analyse the relative influence of two different university rankings on the performance in the EU Framework Programmes, while controlling for other factors like previous experience, availability of national funding sources, university size, relational capital, and institutional factors (EU membership age and English language).peerReviewe