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)

The US neutrino community gathered at the Workshop on the Intermediate Neutrino Program at Brookhaven National Laboratory February 4-6, 2015 to explore opportunities in neutrino physics over the next five to ten years. Scientists from particle, astroparticle and nuclear physics participated in the workshop. The workshop examined promising opportunities for neutrino physics in the intermediate term, including possible new small to mid-scale experiments, US contributions to large experiments, upgrades to existing experiments, R&D plans and theory. The workshop was organized into (...) two sets of parallel working group sessions, divided by physics topics and technology. Physics working groups covered topics on Sterile Neutrinos, Neutrino Mixing, Neutrino Interactions, Neutrino Properties and Astrophysical Neutrinos. Technology sessions were organized into Theory, Short-Baseline Accelerator Neutrinos, Reactor Neutrinos, Detector R&D and Source, Cyclotron and Meson Decay at Rest sessions.This report summarizes discussion and conclusions from the workshop. (shrink)

Accounting for the Commandments in Medieval Judaism explores the discursive formation of the commandments as a generative matrix of Jewish thought and life in the posttalmudic period. Each study sheds light on how medieval Jews crafted the commandments out of theretofore underdetermined material. By systematizing, representing, or interrogating the amorphous category of commandment, medieval Jewish authors across both the Islamic and Christian spheres of influence sought to explain, justify, and characterize Israel's legal system, divine revelation, the cosmos, and even the (...) divine order. This volume correlates bodies of knowledge-such as jurisprudence, philosophy, ethics, pietism, and kabbalah-that are normally treated in isolation into a single conversation about a shared constitutional concern. (shrink)

The survival of the personal copy of Commentary on the Mishnah by Maimonides, which he revised throughout his life, provides an unparalleled window into the ways he continually reconsidered legal and conceptual questions. This manuscript covers five of the six orders of the Mishnah and contains countless corrections and emendations, the vast majority in the author’s own hand. This article argues that Maimonides’s intense interest in solving problems related to the enumeration of the commandments, which he addresses at length in (...) Book of the Commandments and, to a lesser extent, Mishneh Torah, led him to make a number of emendations to his Commentary and to rethink other aspects of his work. That is, when writing Book of the Commandments and Mishneh Torah in the decade after completing his Commentary, Maimonides tackled, and sometimes even concocted, questions that he had no reason to consider in the latter work. This study traces two ways that Maimonides’s later works diverge from his earlier ones, in the meaning of Hebrew and Arabic technical terms and in increased attention to scripture in determing Jewish law, revealing a great medieval mind “in perpetual motion.”. (shrink)

Cognitive heuristics, as proffered by Daniel Kahneman and Amos Tversky, are reasoning shortcuts that are useful but flawed. For example, the availability heuristic “infers” an event’s probability, not by performing laborious, ideally rational calculations, but by simply assessing the ease with which similar events can be recalled. Cognitive psychologists presume that cognitive heuristics should be identified with a distinct cognitive mechanism. I argue that this is a mistake ultimately stemming from descriptive rational choice theory’s entangling of descriptive and normative theorizing. (...) Such mechanism-identification is a desideratum for kinds used in answering, “How—in a causal-mechanical sense—do we reason?” However, cognitive heuristics befit a different question, namely, “How—in a contrastive sense—do we reason vis-à-vis ideal rationality?” Clarifying cognitive heuristics’ nature and appropriate explanatory expectations can enhance understanding, provide lessons applicable elsewhere, and illuminate an important episode in the history of cognitive psychological science. (shrink)

Genesis – known by many, understood by few. After reading his lectures, there is no doubt that Viktor von Weizsäcker falls under the second category. Weizsäcker was not a philosopher by profession,...

Controverting Kierkegaard is the fourth and final volume in the series Selected Works of K. E. Løgstrup. The other books are Kierkegaard’s and Heidegger’s Analysis of Existence and Its Relation to...