Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dab1 to the positioning of cortical neurons in the developing mouse brain

Cyclin-dependent kinase (Cdk) 5 is a unique member of the Cdk family, because Cdk5 kinase activity is detected only in the nervous tissue. Two neuron-specific activating subunits of Cdk5, p35 and p39, have been identified. Overlapping expression pattern of these isoforms in the embryonic mouse brain and the significant residual Cdk5 kinase activity in brain homogenate of the p35−/− mice indicate the redundant functions of the Cdk5 activators in vivo. Severe neuronal migration defects in p35−/−Cdk5 +/− mice further support the idea that the redundant expression of the Cdk5 activators may cause a milder phenotype in p35−/− mice compared with Cdk5−/− mice. Mutant mice lacking either Cdk5 or p35 exhibit certain similarities with Reelin/Dab1-mutant mice in the disorganization of cortical laminar structure in the brain. To elucidate the relationship between Cdk5/p35 and Reelin/Dab1 signaling, we generated mouse lines that have combined defects of these genes. The addition of heterozygosity of either Dab1 or Reelin mutation to p35−/− causes the extensive migration defects of cortical neurons in the cerebellum. In the double-null mice of p35 and either Dab1 or Reelin, additional migration defects occur in the Purkinje cells in the cerebellum and in the pyramidal neurons in the hippocampus. These additional defects in neuronal migration in mice lacking both Cdk5/p35 and Reelin/Dab1 indicate that Cdk5/p35 may contribute synergistically to the positioning of the cortical neurons in the developing mouse brain.

Flows of knowledge from universities and federal laboratories: Modeling the flow of patent citations over time and across institutional and geographic boundaries

The extent to which new technological knowledge flows across institutional and national boundaries is a question of great importance for public policy and the modeling of economic growth. In this paper we develop a model of the process generating subsequent citations to patents as a lens for viewing knowledge diffusion. We find that the probability of patent citation over time after a patent is granted fits well to a double-exponential function that can be interpreted as the mixture of diffusion and obsolescense functions. The results indicate that diffusion is geographically localized. Controlling for other factors, within-country citations are more numerous and come more quickly than those that cross country boundaries.

Molecular genetics of pattern formation in the inner ear: Do compartment boundaries play a role?

The membranous labyrinth of the inner ear establishes a precise geometrical topology so that it may subserve the functions of hearing and balance. How this geometry arises from a simple ectodermal placode is under active investigation. The placode invaginates to form the otic cup, which deepens before pinching off to form the otic vesicle. By the vesicle stage many genes expressed in the developing ear have assumed broad, asymmetrical expression domains. We have been exploring the possibility that these domains may reflect developmental compartments that are instrumental in specifying the location and identity of different parts of the ear. The boundaries between compartments are proposed to be the site of inductive interactions required for this specification. Our work has shown that sensory organs and the endolymphatic duct each arise near the boundaries of broader gene expression domains, lending support to this idea. A further prediction of the model, that the compartment boundaries will also represent lineage-restriction compartments, is supported in part by fate mapping the otic cup. Our data suggest that two lineage-restriction boundaries intersect at the dorsal pole of the otocyst, a convergence that may be critical for the specification of endolymphatic duct outgrowth. We speculate that the patterning information necessary to establish these two orthogonal boundaries may emanate, in part, from the hindbrain. The compartment boundary model of ear development now needs to be tested through a variety of experimental perturbations, such as the removal of boundaries, the generation of ectopic boundaries, and/or changes in compartment identity.

Periodicity of strong nucleosome positioning sites around the chicken adult beta-globin gene may encode regularly spaced chromatin.

Positioned nucleosomes contribute to both the structure and the function of the chromatin fiber and can play a decisive role in controlling gene expression. We have mapped, at high resolution, the translational positions adopted by limiting amounts of core histone octamers reconstituted onto 4.4 kb of DNA comprising the entire chicken adult beta-globin gene, its enhancer, and flanking sequences. The octamer displays extensive variation in its affinity for different positioning sites, the range exhibited being about 2 orders of magnitude greater than that of the initial binding of the octamer. Strong positioning sites are located 5' and 3' of the globin gene and in the second intron but are absent from the coding regions. These sites exhibit a periodicity (approximately 200 bp) similar to the average spacing of nucleosomes on the inactive beta-globin gene in vivo, which could indicate their involvement in packaging the gene into higher-order chromatin structure. Overlapping, alternative octamer positioning sites commonly exhibit spacings of 20 and 40 bp, but not of 10 bp. These short-range periodicities could reflect features of the core particle structure contributing to the pronounced sequence-dependent manner in which the core histone octamer interacts with DNA.

Structure of human T-cell receptors specific for an immunodominant myelin basic protein peptide: positioning of T-cell receptors on HLA-DR2/peptide complexes.

T-cell receptors (TCRs) recognize peptide bound within the relatively conserved structural framework of major histocompatibility complex (MHC) class I or class II molecules but can discriminate between closely related MHC molecules. The structural basis for the specificity of ternary complex formation by the TCR and MHC/peptide complexes was examined for myelin basic protein (MBP)-specific T-cell clones restricted by different DR2 subtypes. Conserved features of this system allowed a model for positioning of the TCR on DR2/peptide complexes to be developed: (i) The DR2 subtypes that presented the immunodominant MBP peptide differed only at a few polymorphic positions of the DR beta chain. (ii) TCR recognition of a polymorphic residue on the helical portion of the DR beta chain (position DR beta 67) was important in determining the MHC restriction. (iii) The TCR variable region (V) alpha 3.1 gene segment was used by all of the T-cell clones. TCR V beta usage was more diverse but correlated with the MHC restriction--i.e., with the polymorphic DR beta chains. (iv) Two clones with conserved TCR alpha chains but different TCR beta chains had a different MHC restriction but a similar peptide specificity. The difference in MHC restriction between these T-cell clones appeared due to recognition of a cluster of polymorphic DR beta-chain residues (DR beta 67-71). MBP-(85-99)-specific TCRs therefore appeared to be positioned on the DR2/peptide complex such that the TCR beta chain contacted the polymorphic DR beta-chain helix while the conserved TCR alpha chain contacted the nonpolymorphic DR alpha chain.

Use of binding energy by an RNA enzyme for catalysis by positioning and substrate destabilization.

A fundamental catalytic principle for protein enzymes in the use of binding interactions away from the site of chemical transformation for catalysis. We have compared the binding and reactivity of a series of oligonucleotide substrates and products of the Tetrahymena ribozyme, which catalyzes a site-specific phosphodiester cleavage reaction: CCCUCUpA+G<-->CCCUCU-OH+GpA. The results suggest that this RNA enzyme, like protein enzymes, can utilize binding interactions to achieve substantial catalysis via entropic fixation and substrate destabilization. The stronger binding of the all-ribose oligonucleotide product compared to an analog with a terminal 3' deoxyribose residue gives an effective concentration of 2200 M for the 3' hydroxyl group, a value approaching those obtained with protein enzymes and suggesting the presence of a structurally well defined active site capable of precise positioning. The stabilization from tertiary binding interactions is 40-fold less for the oligonucleotide substrate than the oligonucleotide product, despite the presence of the reactive phosphoryl group in the substrate. This destabilization is accounted for by a model in which tertiary interactions away from the site of bond cleavage position the electron-deficient 3' bridging phosphoryl oxygen of the oligonucleotide substrate next to an electropositive Mg ion. As the phosphodiester bond breaks and this 3' oxygen atom develops a negative charge in the transition state, the weak interaction of the substrate with Mg2+ becomes strong. These strategies of "substrate destabilization" and "transition state stabilization" provide estimated rate enhancements of approximately 280- and approximately 60-fold, respectively. Analogous substrate destabilization by a metal ion or hydrogen bond donor may be used more generally by RNA and protein enzymes catalyzing reactions of phosphate esters.

Crossing Blurred Lines: A Training Program to Train Teachers in Appropriate Sexual Boundaries

Boundaries between students and teachers were once clearly defined. Students only interacted with their teachers at school. Currently, however, boundaries are becoming increasingly unclear. As technology advances, students have more venues to interact with their teachers. In addition, teachers are asked to take on more roles in their students' lives. A significant number of teachers and students engage in inappropriate relationships and the possible damage to students is high. Unfortunately, current training programs do not adequately address how teachers can maintain appropriate boundaries with their charges. This paper outlines a proposal for a new training program to fill this gap. This program utilizes training techniques that have been shown to be useful for adult learners as it helps teachers establish and maintain boundaries as well as incorporating elements of effective prevention programs.

Incorporating global positioning data in real time P2P audio/video streams for mobile devices

We propose an original method to geoposition an audio/video stream with multiple emitters that are at the same time receivers of the mixed signal. The achieved method is suitable for those comes where a list of positions within a designated area is encoded with a degree of precision adjusted to the visualization capabilities; and is also easily extensible to support new requirements. This method extends a previously proposed protocol, without incurring in any performance penalty.

P2P audio/video protocol with global positioning data in real time for mobile devices

In this paper, we propose an original method to geoposition an audio/video stream with multiple emitters that are at the same time receivers of the mixed signal. The obtained method is suitable when a list of positions within a known area is encoded with precision tailored to the visualization capabilities of the target device. Nevertheless, it is easily adaptable to new precision requirements, as well as parameterized data precision. This method extends a previously proposed protocol, without incurring in any performance penalty.

Redrawing Identity Boundaries through Integration Policies: Strategies of Inclusion/Exclusion of Immigrants in Québec and South Tyrol. EDAP Paper 01/2013

Following the research agenda introduced by Will Kymlicka, this qualitative study offers an interpretation of how the sub-national elites of Québec and South Tyrol police the integration of immigrants. For these national minority groups, which are constantly undergoing a process of redefinition of their collective identities by differentiating themselves from the Others who do not belong to the in-group, immigrants have progressively become the most significant Others as they are not part of the original system of compromises. This article questions how sub-national elites are handling this relatively new kind of ethnocultural diversity brought about by large-scale permanent immigration on two levels: first, the political narrative of the ruling sub-national parties, their electoral appeals, manifestos and speeches; second, the policy arrangements for the integration of immigrants in education, language and social policy. The initial approach of the article is pessimistic, as it assumes that sub-national elites will marginalize immigrants to please core nationalist supporters. In fact, the hypotheses to be tested are whether the national minority groups of Québec and South Tyrol engage in a process of reconstruction of their ethnic identity bounded by opposition to real or imagined Others – the newcomers; and whether they adopt practical measures that force newcomers to be assimilated into the group or to be marginalized. The comparison between Québec and South Tyrol provides a basic understanding of the impact of immigration in two sub-national polities that are very different, but still adopt similar political narratives and policy strategies with regard to the integration of newcomers.

50 years of the ‘twin engine’. Franco-German reconciliation, European integration and reflections for Asia. EU Centre Singapore Background Brief No. 8, March 2013

On 22 January 2013, French President François Hollande and German Chancellor Angela Merkel gathered in Berlin to celebrate the 50th anniversary of the signing of the Élysée Treaty, the document that ended centuries of rivalry and warfare between their two countries. It is all too easy to forget the importance of Franco-German reconciliation. The 1950 Schuman Declaration, which led to the creation of the European Union’s (EU) predecessor, the European Coal and Steel Community (ECSC), sought to render the prospect of war between France and Germany ‘not only unthinkable but materially impossible’. Over 60 years later, when the EU was awarded the Nobel Peace Prize, the Norwegian Nobel Committee noted that indeed, ‘war between Germany and France is unthinkable’. Halfway around the world in Asia, the other theatre of World War II, tensions between China and Japan have arisen, with Taiwan and South Korea also in the fray. Nationalist movements in these countries have grown. This background brief lays out the issues for a timely reappraisal of the applicability, or otherwise, of the European integration and reconciliation processes to East Asia. The brief seeks to outline the contours of the historic act of Franco-German reconciliation, and its consequences ever since. Starting from a brief look at the history of rivalry and war between the two countries, the brief examines the events leading to the signing of the Élysée Treaty in 1963, and the development of Franco-German exchanges that have cemented the relationship. Difficulties between the countries are also raised. A timescale analysis of the opinion of the two publics is considered, as a measure of the success of Franco-German reconciliation.

Breaking the boundaries. The transformation of Central European gas markets. OSW Point of View Number 46, December 2014

According to the European Council decision of February 2011, the process of creating the European Union’s internal gas market should be completed by the end of 2014. Therefore, it is worth summarising the changes which have taken place in the gas markets of Central Europe so far. The past few years have seen not only a period of gradual ‘marketisation’ of the national gas sectors, but also the building of new gas infrastructure, a redrawing of the gas flow map, and changes in the ownership of the Central European gas companies. Another change in Central Europe is the fact that individual states and companies are moving away from their traditional focus on their national gas markets; instead, they are beginning to develop a variety of concepts for the regional integration of Central European markets. This publication attempts to grasp the main elements of the ongoing transformation of Central Europe’s gas markets, with particular emphasis on the situation in Poland, the Czech Republic, Slovakia and Hungary.