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The neuronal adaptor protein Fe65 is involved in brain development, Alzheimer disease amyloid precursor protein (APP) signaling, and proteolytic processing of APP. It contains three protein-protein interaction domains, one WW domain, and a unique tandem array of phosphotyrosine-binding (PTB) domains. The N-terminal PTB domain (Fe65-PTB1) was shown to interact with a variety of proteins, including the low density lipoprotein receptor-related protein (LRP-1), the ApoEr2 receptor, and the histone acetyltransferase Tip60. We have determined the crystal structures of human Fe65-PTB1 in its apo- and in a phosphate-bound form at 2.2 and 2.7A resolution, respectively. The overall fold shows a PTB-typical pleckstrin homology domain superfold. Although Fe65-PTB1 has been classified on an evolutionary basis as a Dab-like PTB domain, it contains attributes of other PTB domain subfamilies. The phosphotyrosine-binding pocket resembles IRS-like PTB domains, and the bound phosphate occupies the binding site of the phosphotyrosine (Tyr(P)) within the canonical NPXpY recognition motif. In addition Fe65-PTB1 contains a loop insertion between helix alpha2 and strand beta2(alpha2/beta2 loop) similar to members of the Shc-like PTB domain subfamily. The structural comparison with the Dab1-PTB domain reveals a putative phospholipid-binding site opposite the peptide binding pocket. We suggest Fe65-PTB1 to interact with its target proteins involved in translocation and signaling of APP in a phosphorylation-dependent manner.
Cry My Beloved Africa is a compendium of essays having as locus the continent of Africa. It comprises insightful observations on the politics, governmental systems, political economy, cultural practices, educational systems and natural phenomena that impact on the lives of Africans. True to the tradition of French novelist Stendhal, the author intends this work to serve as a mirror that reflects the day-to-day living of the different peoples that inhabit the fifty-three nation-states in Africa. It is directed to contemporary Africa and to the relationship between Africa and the rest of the globe. The didactic value of the book resides in its suitability to the young and the old. The language is clear and free of sophistry.
We highlight the implications of combining underwriting services and lending for the choice of underwriters and for competition in the underwriting business. We show that cross-selling can increase underwriters’ incentives, and we explain three phenomena: first, that cross-selling is important for universal banks to enter the investment banking business; second, that cross-selling is particularly attractive for highly leveraged borrowers; third, that less-than-market rates are no prerequisite for cross-selling to benefit a bank’s clients. In our model, cross-selling reduces rents in the underwriting business.
Num tempo em que Lewis Hamilton é o primeiro negro a ganhar o compeonato do Mundo de Fórmula 1, sendo também o primeiro a participar; tempo em que Barack Obama se torna Presidente dos Estados Unidos da America, lembro-me novamente do meu avó, do meu pai, das lutas que eles tiveram que travar e deparo-me subitamente com a voz da esperança. Os tempos estão a mudar! É verdade. Não basta apenas falar em mudar as mentalidades, é preciso, isso sim, trabalhar nas mentalidades. E tal é impossivel sem saber de onde vimos. É preciso criar um novo grupo de jovens angolanos que, como um vírus, possam contagiar os demais. É preciso buscar as origens étnicas e culturais. Não quero com isso dizer que se deve criar seres independentes de Angola, mas homens e mulheres capazes de entender que Angola é um estado multi-cultural e multi-étnico; que a sua etnia é a xx, a sua língua a yy, e, deste modo, compreender comportamentos sociais que só se pautam sabendo de onde se vem.
The mechanism by which the enzyme pyruvate decarboxylase from yeast is activated allosterically has been elucidated. A total of seven three-dimensional structures of the enzyme, of enzyme variants or of enzyme complexes from two yeast species (three of them reported here for the first time) provide detailed atomic resolution snapshots along the activation coordinate. The prime event is the covalent binding of the substrate pyruvate to the side chain of cysteine 221, thus forming a thiohemiketal. This reaction causes the shift of a neighbouring amino acid, which eventually leads to the rigidification of two otherwise flexible loops, where one of the loops provides two histidine residues necessary to complete the enzymatically competent active site architecture. The structural data are complemented and supported by kinetic investigations and binding studies and provide a consistent picture of the structural changes, which occur upon enzyme activation.
In the course of the ME period, HAVE began to encroach on territory previously held by BE. According to Rydén and Brorström (1987); Kytö (1997), this occurred especially in iterative and durational contexts, in the perfect infinitive and modal constructions. In Early Modern English (henceforth EModE), BE was increasingly restricted to the most common intransitives come and go, before disappearing entirely in the 18th and 19th centuries. This development raises a number of questions, both historical and theoretical. First, why did HAVE start spreading at the expense of BE in the first place? Second, why was the change conditioned by the factors mentioned by Rydén and Brorström (1987) and Kytö (1997)? Third, why did the change take on the order of 800 years to go to completion? Fourth, what implications does the change have for general theories of auxiliary selection? In this paper we’ll try to answer the first question by focusing on one the earliest clearly identifiable advance of HAVE onto BE territory – its first appearance with the verb come, which for a number of reasons is an ideal verb to focus on. First, come is by far the most common intransitive verb, so we get large enough numbers for statistical analysis. Second, clauses containing the past participle of come with a form of BE are unambiguous perfects: they cannot be passives, and they did not continue into modern English with a stative reading like he is gone. Third, and perhaps most importantly, come selected BE categorically in the early stages of English, so the first examples we find with HAVE are clear evidence for innovation. We will present evidence from a corpus study showing that the first spread of HAVE was due to a ban on auxiliary BE in certain types of counterfactual perfects, and will propose an account for that ban in terms of Iatridou’s (2000) Exclusion theory of counterfactuals.
Every day thousands of people die from poverty-related causes. Many of these deaths could be avoided if appropriate medical treatments were available to the world’s poor. Due to the current structure of the international patent regime, they are not. Since the risks and costs associated with pharmaceutical innovation are extremely high, to incentivise research, inventor firms are granted a temporary monopoly over newly invented drugs. While allowing firms to make up for the costs of research, this has the morally perverse effect of raising the prices of pharmaceuticals to a level where they become unaffordable to the world's poor. To correct this grievous flaw, the paper proposes a concrete and realistic alternative scheme which, by rewarding medical innovators in proportion to the impact of their drugs on the global disease burden, would incentivise the production and selling of crucial drugs for the world’s poor at prices accessible to them.
Several regions in human temporal and frontal cortex are known to integrate visual and auditory object features. The processing of audio–visual (AV) associations in these regions has been found to be modulated by object familiarity. The aim of the present study was to explore training-induced plasticity in human cortical AV integration. We used functional magnetic resonance imaging to analyze the neural correlates of AV integration for unfamiliar artificial object sounds and images in naïve subjects (PRE training) and after a behavioral training session in which subjects acquired associations between some of these sounds and images (POST-training). In the PRE-training session, unfamiliar artificial object sounds and images were mainly integrated in right inferior frontal cortex (IFC). The POST-training results showed extended integration-related IFC activations bilaterally, and a recruitment of additional regions in bilateral superior temporal gyrus/sulcus and intraparietal sulcus. Furthermore, training-induced differential response patterns to mismatching compared with matching (i.e., associated) artificial AV stimuli were most pronounced in left IFC. These effects were accompanied by complementary training-induced congruency effects in right posterior middle temporal gyrus and fusiform gyrus. Together, these findings demonstrate that short-term cross-modal association learning was sufficient to induce plastic changes of both AV integration of object stimuli and mechanisms of AV congruency processing.
The paper provides novel insights on the effect of a firm’s risk management objective on the optimal design of risk transfer instruments. I analyze the interrelation between the structure of the optimal insurance contract and the firm’s objective to minimize the required equity it has to hold to accommodate losses in the presence of multiple risks and moral hazard. In contrast to the case of risk aversion and moral hazard, the optimal insurance contract involves a joint deductible on aggregate losses in the present setting.