Cyclin-dependent kinase 5 has been implicated in Alzheimer's disease pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with a (...) targeted mutation in the STAT3 cdk5 responsive site had lower levels of BACE1. Increased BACE levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor. These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis. (shrink)

In recent years important contributions to the interpretation of the eighth book of Lucan have been made by Professor Postgate , and by Mr.J.D.Duff .The following notes make a further attempt to solve some of the many problems presented by the book.

In recent years important contributions to the interpretation of the eighth book of Lucan have been made by Professor Postgate, and by Mr.J.D.Duff.The following notes make a further attempt to solve some of the many problems presented by the book.

Isolation in the back-country: George Chamier, G.B. Lancaster, Katherine Mansfield, John Mulgan, and Graham Billing -- Outsiders and misfits in fragmented social milieux: William Satchell, Vincent Pyke, John A. Lee, Robin Hyde, Frank Sargeson, and others -- The lonely and the alone in the fiction of Janet Frame -- Maurice Gee and postmodern isolation -- Women, isolation, and history: Fiona Kidman, Noel Hilliard, and Patricia Grace -- Cultural deracination and isolation : Witi Ihimaera, Keri Hulme, and Alan Duff.

In addition to facing the known competitors in the formal economy, entrepreneurs must also be concerned with rivalry emanating from the informal economy. The informal economy is characterized by actions outside the normal scope of commerce, such as unsanctioned payments and gift-giving, as means of influencing competition. Scholars and policy makers alike have an interest in mitigating the impacts of such informal activity in that it might present an obstacle for legitimate commerce. Received theory suggests that country institutions can enable (...) and constrain productive activity, and, in doing so, influence competitive obstacles in a country. Leveraging 13,670 responses from entrepreneurs distributed across 59 countries, we provide evidence that two particular types of enabling institutions, countries’ property rights regulations and cooperative actions, are useful for lowering the obstacles presented by informal activity. We also find evidence that two constraining institutions, economic and financial regulations lead to more obstacles presented by informal activity. We describe implications for entrepreneurs, policy makers, and future researchers stemming from these findings. (shrink)

Rome and Carthage had established peaceful diplomatic relations before 300 b.c. — as early as the close of the sixth century according to Polybius, whose dating there no longer seems good cause to doubt. A second treaty was struck probably in 348. Both dealt essentially with traders' and travellers' obligations and entitlements, so any military or political terms sprang from that context. In both, the Carthaginians agreed to hand over any independent town they captured in Latium. In the first treaty (...) they were not to establish a fort in Latium either; in the second, the Romans were not to found a city in Carthaginian Africa, Spain or Sardinia. But independent military considerations are the stuff of a third treaty concluded during Rome's war with Pyrrhus. Rome and Carthage now pledged each other military aid in certain circumstances, as we shall see. And ‘geopolitical’ concerns of a very broad kind imbued a treaty which was reported by the third-century historian Philinus of Agrigentum. By this, he stated, ‘the Romans must keep out of the whole of Sicily, the Carthaginians out of Italy’ . This is Polybius' citation of Philinus' allegation; Polybius himself then roundly rejects the very existence of such a pact and declares himself at a loss to understand how his predecessor could record it, but modern scholarship is no longer all that ready to accept his view. A strong majority of historians prefer to follow the Agrigentine, and many see 306 b.c. as the likely year for the agreement because Livy records a ‘renewal’ then of a foedus with Carthage. (shrink)

In my first study of the borrowings from Athenian sacred treasure to finance the Archidamian War I assumed, in common with others, certain irregularities in the stoichedon order of IG. i. 324. The text has subsequently been amplified and improved by Tod, notably with the addition of one amount of interest due to Athena and of the total amounts of principal credited to the Other Gods and to all the gods . This further expansion, however, has introduced additional irregularities, the (...) restoration [τάδε τος λλοις θεος έλοσι τόκο ]ν νδεκα τεα[ιν:…] being too long by one letter in line 120 and the restoration [τάδε πασι τος θεος έλοσι τόκο ν] νδεκα τεσ[ιν:…] being likewise too long in line 123. (shrink)

The two epigraphical monuments which have preserved parts of the treaties of alliance between Athens, on the one hand, and Rhegion and Leontinoi, respectively, on the other, must be studied together, for both treaties had their old preambles erased in 433/2 and their validity reaffirmed as of that year. The new preambles, both dating from the same day, were inscribed in the erasures and juxtaposed, somewhat awkwardly, before the body of the old texts thatstill remained.

Summary A study of the metallurgy and manufacturing techniques of a group of eight astrolabes (seven from Lahore, one attributed to India) using non-destructive methods has produced the earliest evidence for systematic use of high-zinc (α?+??) brass. To produce this alloy, the brass industry supplying the Lahore instrument makers must have co-melted metallic copper and zinc. This brass-making technology was previously believed to have been developed on an industrial scale in the nineteenth century in Europe. This work hypothesizes that this (...) technology was used in Lahore on an industrial scale as early as ad 1601. In addition, this work hypothesizes that the α?+?? brass alloy was used specifically for its ease in manufacturing the thin sheet brass required for astrolabe-component manufacture. (shrink)

Successful behavior requires actively acquiring and representing information about the environment and people, and manipulating and using those acquired representations flexibly to optimally act in and on the world. The frontal lobes have figured prominently in most accounts of flexible or goal-directed behavior, as evidenced by often-reported behavioral inflexibility in individuals with frontal lobe dysfunction. Here, we propose that the hippocampus also plays a critical role by forming and reconstructing relational memory representations that underlie flexible cognition and social behavior. There (...) is mounting evidence that damage to the hippocampus can produce inflexible and maladaptive behavior when such behavior places high demands on the generation, recombination, and flexible use of information. This is seen in abilities as diverse as memory, navigation, exploration, imagination, creativity, decision-making, character judgments, establishing and maintaining social bonds, empathy, social discourse, and language use. Thus, the hippocampus, together with its extensive interconnections with other neural systems, supports the flexible use of information in general. Further, we suggest that this understanding has important clinical implications. Hippocampal abnormalities can produce profound deficits in real-world situations, which typically place high demands on the flexible use of information, but are not always obvious on diagnostic tools tuned to frontal lobe function. This review documents the role of the hippocampus in supporting flexible representations and aims to expand our understanding of the dynamic networks that operate as we move through and create meaning of our world. (shrink)

Sutton ( 2010 ) claims that on our analysis (2007), the problem in the two-envelope paradox is an error in counterfactual reasoning. In fact, we distinguish two formulations of the paradox, only one of which, on our account, involves an error in conditional reasoning. According to Sutton, it is conditional probabilities rather than subjunctive conditionals that are essential to the problem. We argue, however, that his strategy for assigning utilities on the basis of conditional probabilities leads to absurdity. In addition, (...) we show that a crucial presupposition of Sutton’s argument — namely, that one can know that envelope A contains n simply on the basis of a stipulation — is mistaken. (shrink)

This first article is intended as a brief introduction to the general philosophical assumptions of Newton: namely, his mathematicism, empiricism, positivism, reductionism, and dualism. These five "isms" provide an important background to the main articles that are also briefly described.

Newton's conception of time has had a profound influence upon science, particularly psychology. Five characteristics of explanation have devolved from Newton's temporal framework: objectivity, continuity, linearity, universality, and reductivity. These characteristics are outlined in the present essay and shown to be central to psychological theories and methods. Indeed, Newton's temporal framework is so central that it often goes unexamined in psychology. Examination is important, however, because recent critics of Newton's framework - including both scientists and philosophers - have questioned its (...) validity and usefulness. (shrink)

Summary A study of the metallurgy and manufacturing techniques of a group of eight astrolabes using non-destructive methods has produced the earliest evidence for systematic use of high-zinc brass. To produce this alloy, the brass industry supplying the Lahore instrument makers must have co-melted metallic copper and zinc. This brass-making technology was previously believed to have been developed on an industrial scale in the nineteenth century in Europe. This work hypothesizes that this technology was used in Lahore on an industrial (...) scale as early as ad 1601. In addition, this work hypothesizes that the α + β brass alloy was used specifically for its ease in manufacturing the thin sheet brass required for astrolabe-component manufacture. (shrink)

Early versions of satellite and radiosonde datasets suggested that the tropical surface had warmed more than the troposphere, while climate models consistently showed tropospheric amplification of surface warming in response to human-caused increases in greenhouse gases. We revisit such comparisons here using new observational estimates of surface and tropospheric temperature changes. We find that there is no longer a serious discrepancy between modeled and observed trends in the tropics. Our results contradict a recent claim that all simulated temperature trends in (...) the tropical troposphere are inconsistent with observations. This claim was based on the use of older radiosonde and satellite datasets and on two methodological errors: the neglect of observational trend uncertainties introduced by interannual climate variability and application of an inappropriate statistical “consistency test”.This emerging reconciliation of models and observations has two primary explanations. First, because of changes in the treatment of buoy and satellite information, new surface temperature datasets yield slightly reduced tropical warming relative to earlier versions. Second, recently developed satellite and radiosonde datasets now show larger warming of the tropical lower troposphere. In the case of a new satellite dataset from remote sensing systems, enhancedRSS warming is due to an improved procedure of adjusting for inter-satellite biases. When the RSS-derived tropospheric temperature trend is compared with four different observed estimates of surface temperature change, the surface warming is invariably amplified in the tropical troposphere, consistent with model results. Even if we use data from a second satellite dataset with smaller tropospheric warming than in remote sensing systems RSS, observed tropical lapse rates are not significantly different from those in all model simulations.Our results contradict a recent claim that all simulated temperature trends in the tropical troposphere and in tropical lapse rates are inconsistent with observations. This claim was based on the use of older radiosonde and satellite datasets and on two methodological errors: the neglect of observational trend uncertainties introduced by interannual climate variability and application of an inappropriate statistical “consistency test”. (shrink)

Using the principles and sometimes the conclusions of his teacher Adolf Stöhr, Cleve insists that he is giving a philosophical interpretation and not simply a philological reconstruction of these Pre-Socratics. The philosophers have been divided into 1) "Religious Reformers", 2) "Philosophers of Nature", 3) "Champions of Culture Politics"—"The Glossomorphics". There will certainly be disagreement on some of Cleve's interpretations but it must be said that Cleve carries through his philosophical reconstruction with admirable lucidity and consistency though, occasionally, some of his (...) criticisms of the "philologists" are rather waspish. Nevertheless, this is a splendid and important study which is a tribute to the author's erudition and insight.—D. J. B. (shrink)