The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons.

The amino acid L-glutamate is a neurotransmitter that mediates fast neuronal excitation in a majority of synapses in the central nervous system. Glutamate stimulates both N-methyl-D-aspartate (NMDA) and non-NMDA receptors. While activation of NMDA receptors has been implicated in a variety of neurophysiologic processes, excessive NMDA receptor stimulation (excitotoxicity) is thought to be primarily responsible for neuronal injury in a wide variety of acute neurological disorders including hypoxia-ischemia, seizures, and trauma. Very little is known about endogenous molecules and mechanisms capable of modulating excitotoxic neuronal death. Saturated N-acylethanolamides like palmitoylethanolamide accumulate in ischemic tissues and are synthesized by neurons upon excitatory amino acid receptor activation. Here we report that palmitoylethanolamide, but not the cognate N-acylamide anandamide (the ethanolamide of arachidonic acid), protects cultured mouse cerebellar granule cells against glutamate toxicity in a delayed postagonist paradigm. Palmitoylethanolamide reduced this injury in a concentration-dependent manner and was maximally effective when added 15-min postglutamate. Cannabinoids, which like palmitoylethanolamide are functionally active at the peripheral cannabinoid receptor CB2 on mast cells, also prevented neuron loss in this delayed postglutamate model. Furthermore, the neuroprotective effects of palmitoylethanolamide, as well as that of the active cannabinoids, were efficiently antagonized by the candidate central cannabinoid receptor (CB1) agonist anandamide. Analogous pharmacological behaviors have been observed for palmitoylethanolamide (ALI-Amides) in downmodulating mast cell activation. Cerebellar granule cells expressed mRNA for CB1 and CB2 by in situ hybridization, while two cannabinoid binding sites were detected in cerebellar membranes. The results suggest that (i) non-CB1 cannabinoid receptors control, upon agonist binding, the downstream consequences of an excitotoxic stimulus; (ii) palmitoylethanolamide, unlike anandamide, behaves as an endogenous agonist for CB2-like receptors on granule cells; and (iii) activation of such receptors may serve to downmodulate deleterious cellular processes following pathological events or noxious stimuli in both the nervous and immune systems.

Pathogenic autoantibodies are routinely generated during the response to foreign antigen: a paradigm for autoimmune disease.

The immune system's ability to distinguish self and nonself is essential for both host defense against foreign agents and protection of self-antigens from autoimmune destruction. Such discrimination is complicated by extensive structural homology shared between foreign and self antigens. One hypothesis to explain the development of an autoimmune response is that some B cells activated by foreign antigen acquire, through somatic mutation, specificity for both the eliciting foreign antigen and self antigen. If such clones arise frequently, there must be a mechanism for their elimination. We have analyzed the extent of autoreactivity arising in a nonautoimmune host during the response to a foreign antigen. To overcome the process of apoptosis in primary B cells that might routinely eliminate autoreactive clones, we generated B-cell hybridomas from spleen cells of immunized mice by using a fusion partner constitutively expressing bcl-2. Multiple lines were obtained that recognize simultaneously the hapten phosphorylcholine and the self antigen double-stranded DNA. This dual specificity was not present early but was detected by day 10 after immunization. Some of these cross-reactive antibodies deposit in kidneys in a pattern similar to what is seen in autoimmune disease. These results demonstrate that autoantibodies arise at a high frequency as part of a response to foreign antigen. It has previously been shown that autoreactivity is regulated by central deletion; these data demonstrate a need for negative selection in peripheral lymphoid organs also, to regulate autoantibodies acquiring their self-specificity by somatic mutation.

Three-dimensional structure of recombinant human osteogenic protein 1: structural paradigm for the transforming growth factor beta superfamily.

We report the three-dimensional structure of osteogenic protein 1 (OP-1, also known as bone morphogenetic protein 7) to 2.8-A resolution. OP-1 is a member of the transforming growth factor beta (TGF-beta) superfamily of proteins and is able to induce new bone formation in vivo. Members of this superfamily share sequence similarity in their C-terminal regions and are implicated in embryonic development and adult tissue repair. Our crystal structure makes possible the structural comparison between two members of the TGF-beta superfamily. We find that although there is limited sequence identity between OP-1 and TGF-beta 2, they share a common polypeptide fold. These results establish a basis for proposing the OP-1/TGF-beta 2 fold as the primary structural motif for the TGF-beta superfamily as a whole. Detailed comparison of the OP-1 and TGF-beta 2 structures has revealed striking differences that provide insights into how these growth factors interact with their receptors.

A paradigm for drug discovery employing encoded combinatorial libraries.

Very large combinatorial libraries of small molecules on solid supports can now be synthesized and each library element can be identified after synthesis by using chemical tags. These tag-encoded libraries are potentially useful in drug discovery, and, to test this utility directly, we have targeted carbonic anhydrase (carbonate dehydratase; carbonate hydro-lyase, EC 4.2.1.1) as a model. Two libraries consisting of a total of 7870 members were synthesized, and structure-activity relationships based on the structures predicted by the tags were derived. Subsequently, an active representative of each library was resynthesized (2-[N-(4-sulfamoylbenzoyl)-4'-aminocyclohexanespiro]-4-oxo-7 -hydroxy- 2,3-dihydrobenzopyran and [N-(4-sulfamoylbenzoyl)-L-leucyl]piperidine-3-carboxylic acid) and these compounds were shown to have nanomolar dissociation constants (15 and 4 nM, respectively). In addition, a focused sublibrary of 217 sulfamoylbenzamides was synthesized and revealed a clear, testable structure-activity relationship describing isozyme-selective carbonic anhydrase inhibitors.

Integrated Solar City: Application of the Ecological Risk Assessment Paradigm to Inform Reclamation

The Integrated Solar City (ISC) is a large solar project that has been proposed for development in the western state of Gujarat, India. The project will be the largest solar project in the world. It will require the use of large land resources to construct. An ecological risk assessment (ERA) is used to assess potential impacts from project construction and operation. Previous research suggests that a solar project of this scale would require the removal of vegetation along with other negative effects on vegetation and soil. The ERA was used to lay out a revegetation plan that would help mitigate the long-term environmental impacts in the Banaskantha and Kachchh regions of Gujarat, India.

A new paradigm: cloud agile manufacturing

Cloud Agile Manufacturing is a new paradigm proposed in this article. The main objective of Cloud Agile Manufacturing is to offer industrial production systems as a service. Thus users can access any functionality available in the cloud of manufacturing (process design, production, management, business integration, factories virtualization, etc.) without knowledge — or at least without having to be experts — in managing the required resources. The proposal takes advantage of many of the benefits that can offer technologies and models like: Business Process Management (BPM), Cloud Computing, Service Oriented Architectures (SOA) and Ontologies. To develop the proposal has been taken as a starting point the Semantic Industrial Machinery as a Service (SIMaaS) proposed in previous work. This proposal facilitates the effective integration of industrial machinery in a computing environment, offering it as a network service. The work also includes an analysis of the benefits and disadvantages of the proposal.

Epistemological Considerations on Systemic Paradigm

This brief study makes some reflections on the systemic paradigm and the claim that Reality is a system advocated by some thinkers. We argue that the General Systems Theory is an abstract theory relating to formal reasons that correspond to real systems scientifically established, and its development can facilitate the task mentioned, which is characteristic of ordinary scientific work.

Flexible Framework for Real-Time Embedded Systems Based on Mobile Cloud Computing Paradigm

The development of applications as well as the services for mobile systems faces a varied range of devices with very heterogeneous capabilities whose response times are difficult to predict. The research described in this work aims to respond to this issue by developing a computational model that formalizes the problem and that defines adjusting computing methods. The described proposal combines imprecise computing strategies with cloud computing paradigms in order to provide flexible implementation frameworks for embedded or mobile devices. As a result, the imprecise computation scheduling method on the workload of the embedded system is the solution to move computing to the cloud according to the priority and response time of the tasks to be executed and hereby be able to meet productivity and quality of desired services. A technique to estimate network delays and to schedule more accurately tasks is illustrated in this paper. An application example in which this technique is experimented in running contexts with heterogeneous work loading for checking the validity of the proposed model is described.

The world innovation landscape: Asia rising? Bruegel Policy Contribution 2013/02, February 2013

Highlights • Research and development spending has risen rapidly in Asia, particularly in China, which is now the world’s second R&D spender behind the United States.The increase in Korean and Chinese patent applications has been even more rapid, but Chinese patenting for exploitation on the main markets for innovation(the European Union, Japan and the US) is still marginal. • Asia's increased innovation spending is most prominently related to information and communication technologies. Overall, the Chinese and Korean economies are still not specialised in knowledge-intensive goods and services.Furthermore, China in particular is not (so far) capturing much value from its role as a manufacturer and exporter of high-tech goods; China remains mostly an assembler of goods, the value of which is created elsewhere. • It would be wrong to ignore China's innovation potential on the basis of its current performance. Its clear innovation ambitions are likely to drive its future growth. • Europe is struggling much more than the US to retain its place at the global innovation table. The EU should use Asia’s capacity building in innovation as an opportunity for value capture.

The New Financial Regulatory Paradigm: A transatlantic perspective. CEPS Policy Brief No. 287, 21 March 2013

This CEPS Policy Brief reviews key aspects of the new financial paradigm in a transatlantic perspective, focusing on the general approach in EU and US legislation in response to the financial crisis and the G-20 commitments and specifically as regards the extraterritorial implications. Following discussion of the institutional setting, conclusions are offered on what these changes mean in the context of the recently proposed Transatlantic Trade and Investment Partnership. In comparing the EU and the US efforts in re-engineering their regulatory regimes in response to the financial crisis, the paper finds, with the notable exception of the banking union, serious grounds for concern that the outcome may be an even more fragmented European financial market, access to which for third-country institutions is highly problematic.

The Portuguese Version of the Placental Paradigm Questionnaire at the Third Trimester of Pregnancy

The purpose of this article is to present the adaptation and factorial validation of the Placental Paradigm Questionnaire (PPQ) for the Portuguese population. Method: The original PPQ was translated into Portuguese (designated as ‘Questionário do Paradigma Placentário’, QPP) and then back-translated into English; the Portuguese and the back-translated versions were evaluated by a panel of experts. The participants were 189 pregnant Portuguese women, interviewed twice while waiting for sonogram examinations. At first, between 20 and 24 weeks of gestation, an Informed Consent was obtained as well as sociodemographic information. Between 28 and 36 weeks of gestation, participants answered the QPP. Results: The principal components analysis showed items to load mainly on two factors: in factor one, loads ranged between .778 and .522, while in factor 2, loads ranged between .658 and .421. Accordingly, two subscales of prenatal maternal orientation to motherhood were considered: (1) Facilitator Factor (α = .815) and Regulator Factor (α = .770). Conclusion: Overall, these data suggest that the Portuguese version of the QPP is a reliable and valid measure for the assessment of prenatal orientation for motherhood. In the future, QPP measurements will allow to relate maternal orientation to motherhood with other variables of psychic organisation in pregnancy and after birth.

The Visegrad group and Germany: towards a new paradigm. CEPS Commentary, 28 November 2013

In surveying the strategic realignment now underway in Central Europe among the four members of the Visegrad Group, Michal Simecka observes in a new CEPS Commentary that it is hard to think of another point in modern history that permitted a scenario of Germany and its eastern neighbours working together to constructively shape Europe.

The EU and ASEAN – In Search of a New Regional Paradigm? EU Centre Singapore Working Paper No. 15, August 2013

The European Union (EU) has been hailed as the most successful model of regional integration thus far, while the Association of Southeast Asian Nations (ASEAN), despite its fair share of critics and doomsayers, has been seen as a relatively successful regional organisation in the developing world. However, both seemed to have arrived at a critical juncture in their respective regional projects. Challenged by recent events, internal and external, and faced with increasing uncertainties and complexities, the EU and ASEAN are forced to re-examine the journey they have taken so far and ponder the road ahead. This paper seeks first to provide an overview of the two parallel processes of regionalism in Europe and Southeast Asia by focusing on the developments of the EU and ASEAN, and dissecting both the external forces and internal dynamics that shape the respective regional processes. It then sketches out some of the global trends likely to impact regional developments in Europe and Asia, and questions if the EU and ASEAN would need a new regional approach or paradigm if they are to maintain their salience and relevance as regional actors.

Regulation of European Banks and Business Models: Towards a new paradigm? CEPS Paperbacks. June 2012

Amidst talks of establishing an EU-wide banking union, the recent changes in the regulatory framework and the rethinking of the future of European banking structure, the future of EU bank regulation is inextricably linked to banks’ business models. Using a sample of over 70 banks, which overlaps with those subjected to the EBA’s 2011 stress tests, this report emphasizes the key regulatory gaps that emerge from a comprehensive analysis of the soundness and performance of bank business models and provides policy-makers with guidance to reinforce the evolving regulatory framework in European banking.