Sustained High Rates Of Job Creation And Destruction In Substate Economies

Widely utilized net employment change statistics actually mask an extremely volatile process of job creation and destruction.  In the past decade economists have addressed this problem by exploiting newly available longitudinal data series to estimate these job flows and the subsequent amount of job churning at the national, state and MSA level.  This study is unique in that it uses an innovative technique to capture job flows within and between industries at the local area level where longitudinal BLS data series are not available.  The geographic unit of analysis in this paper is a Cohesive Commercial Statistical Area™ (CCSA), a substate aggregate of cities and towns sharing common economic interests but not a Metropolitan Statistical Area.  The paper examines job flows in two very different Massachusetts substate economies: the MetroWest CCSA, a technology sensitive research and development economy, and the South Shore CCSA, a mature economy with a competitive edge in financial services. This study establishes that a sizable portion of disaggregated job flows can be captured at a substate level using available employment data. Building upon techniques used in earlier studies, the authors confirmed very high levels of employment volatility, “job churning”, in both substate regions.  The authors found that over two decades, job reallocation rates in MetroWest averaged 9%, affecting one out of 11 jobs annually. The study traced the pattern of job creation and destruction over the course of local business cycles and found that both job creation and destruction existed during all phases of the business cycle. Although, as expected, job creation dominated the expansion phase and destruction dominated the contraction phase, the total amount of job reallocation (creation plus destruction) remained relatively stable through all stages of the business cycle.   However, the composition of the job reallocation varied dramatically by stage of business cycle.  A Job Replacement Ratio has been developed as a quick test to confirm economic expansion or contraction and to focus economic development efforts

Beyond Committees: Parliamentary Oversight of Coalition Government in Britain

A legislature's ability to engage in oversight of the executive is believed to derive largely from its committee system. For example, powerful parliamentary committees are considered a necessary condition for the legislature to help police policy compromises between parties in multiparty government. But can other parliamentary instruments perform this role? This paper suggests parliamentary questions as an alternative parliamentary vehicle for coalition parties to monitor their partners. Questions force ministers to reveal information concerning their legislative and extra-legislative activities, providing coalition members unique insights into their partners’ behaviour. To test our argument, we build and analyse a new dataset of parliamentary questions in the British House of Commons covering the 2010-15 coalition. As expected, government MPs ask more questions as the divisiveness of a policy area increases. Legislatures conventionally considered weak due to the lack of strong committees may nevertheless play an important oversight role through other parliamentary devices, including helping to police the implementation of coalition agreements

Political Institutions and Public Policy: The Co-Decision Procedure in the European Union and the Reform of the Common Agricultural Policy

In this paper we study the implications of the introduction of the co-decision procedure for the European Union's Common Agricultural Policy and its refirm. We use a game-theoretical model of the legislative procedures in the European Union and show that the move from consultation to co-decision implies a shift of power from the Commission to the European Parliament. The implications for the Common Agricultural Policy depend on the configuration of preferences, the location of the status quo, and the bargaining powers in the Conciliation Committee. If the member states and the European Parliament are more opposed to refirm than is the Commission, the introduction of co-decision reduces the prospects for refirm of the European Union's Common Agricultural Policy

Volkskrankheit Alzheimer: Handlungsbedarf und mögliche Lösungsansätze für die Zukunft

Die Gesellschaft wird immer älter - und damit nehmen auch Krankheiten wie zb Alzheimer zu. In Österreich leben derzeit rund 139.000 Menschen mit einer Demenz und etwa zwei Drittel davon, sind von der Alzheimer-Erkrankung betroffen. Nach aktuellen Schätzungen wird die Gesamtzahl der Betroffenen bis zum Jahr 2050 dramatisch ansteigen. Alzheimer ist damit eine der größten Herausforderungen für unser Gesundheitswesen und Gegenstand intensiver Forschungen. Die Krankheit stellt dabei nicht nur die Betroffenen selbst, sondern auch die Angehörigen, das soziale Umfeld und die gesamte Gesellschaft vor enorme Aufgaben

Dictyostelium possesses highly diverged presenilin/γ-secretase that regulates growth and cell-fate specification and can accurately process human APP: a system for functional studies of the presenilin/γ-secretase complex

Presenilin (PS) is the catalytic moiety of the γ-secretase complex. PS and other γ-secretase components are well conserved among metazoa, but their presence and function in more-distant species are not resolved. Because inappropriate γ-secretase processing of amyloid precursor protein (APP) in humans is associated with familial Alzheimer’s disease, understanding essential elements within each γ-secretase component is crucial to functional studies. Diverged proteins have been identified in primitive plants but experiments have failed to demonstrate γ-secretase activity. We have identified highly diverged orthologs for each γ-secretase component in the ancient eukaryote Dictyostelium, which lacks equivalents of APP, Notch and other characterized PS/γ-secretase substrates. We show that wild-type (WT) Dictyostelium is capable of amyloidogenic processing of ectopically expressed human APP to generate amyloid-β peptides Aβ40 and Aβ42; strains deficient in γ-secretase cannot produce Aβ peptides but accumulate processed intermediates of APP that co-migrate with the C-terminal fragments α- and β-CTF of APP that are found in mammalian cells. We further demonstrate that Dictyostelium requires PS for phagocytosis and cell-fate specification in a cell-autonomous manner, and show that regulation of phagocytosis requires an active γ-secretase, a pathway suggested, but not proven, to occur in mammalian and Drosophila cells. Our results indicate that PS signaling is an ancient process that arose prior to metazoan radiation, perhaps independently of Notch. Dictyostelium might serve to identify novel PS/γ-secretase signaling targets and provide a unique system for high-throughput screening of small-molecule libraries to select new therapeutic targets for diseases associated with this pathway

Oxidative Ring Contraction of Cyclobutenes: General Approach to Cyclopropylketones including Mechanistic Insights

An original oxidative ring contraction of easily accessible cyclobutene derivatives for the selective formation of cyclopropylketones (CPKs) under atmospheric conditions is reported. Comprehensive mechanistic studies are proposed to support this novel, yet unusual, rearrangement. Insights into the mechanism ultimately led to simplification and generalization of the ring contraction of cyclobutenes using <i>m</i>CPBA as an oxidant. This unique and functional group tolerant transformation proceeds under mild conditions at room temperature, providing access to a new library of polyfunctionalized motifs. With CPKs being attractive and privileged pharmacophores, the elaboration of such a simple and straightforward strategy represents a highly valuable tool for drug discovery and medicinal chemistry. Additionally, the described method was employed to generate a pool of bioactive substances and key precursors in a minimum number of steps

Modifications of Adenovirus Hexon Allow for Either Hepatocyte Detargeting or Targeting With Potential Evasion From Kupffer Cells

In vivo gene transfer with adenovirus vectors would significantly benefit from a tight control of the adenovirus-inherent liver tropism. For efficient hepatocyte transduction, adenovirus vectors need to evade from Kupffer cell scavenging while delivery to peripheral tissues or tumors could be improved if both scavenging by Kupffer cells and uptake by hepatocytes were blocked. Here, we provide evidence that a single point mutation in the hexon capsomere designed to enable defined chemical capsid modifications may permit both detargeting from and targeting to hepatocytes with evasion from Kupffer cell scavenging. Vector particles modified with small polyethylene glycol (PEG) moieties specifically on hexon exhibited decreased transduction of hepatocytes by shielding from blood coagulation factor binding. Vector particles modified with transferrin or, surprisingly, 5,000 Da PEG or dextran increased hepatocyte transduction up to 18-fold independent of the presence of Kupffer cells. We further show that our strategy can be used to target high-capacity adenovirus vectors to hepatocytes emphasizing the potential for therapeutic liver-directed gene transfer. Our approach may lead to a detailed understanding of the interactions between adenovirus vectors and Kupffer cells, one of the most important barriers for adenovirus-mediated gene delivery

Traceless Bioresponsive Shielding of Adenovirus Hexon with HPMA Copolymers Maintains Transduction Capacity In Vitro and In Vivo

<div><p>Capsid surface shielding of adenovirus vectors with synthetic polymers is an emerging technology to reduce unwanted interactions of the vector particles with cellular and non-cellular host components. While it has been shown that attachment of shielding polymers allows prevention of undesired interactions, it has become evident that a shield which is covalently attached to the vector surface can negatively affect gene transfer efficiency. Reasons are not only a limited receptor-binding ability of the shielded vectors but also a disturbance of intracellular trafficking processes, the latter depending on the interaction of the vector surface with the cellular transport machinery. A solution might be the development of bioresponsive shields that are stably maintained outside the host cell but released upon cell entry to allow for efficient gene delivery to the nucleus. Here we provide a systematic comparison of irreversible versus bioresponsive shields based on synthetic <i>N</i>-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. In addition, the chemical strategy used for generation of the shield allowed for a traceless bioresponsive shielding, i.e., polymers could be released from the vector particles without leaving residual linker residues. Our data demonstrated that only a bioresponsive shield maintained the high gene transfer efficiency of adenovirus vectors both in vitro and in vivo. As an example for bioresponsive HPMA copolymer release, we analyzed the in vivo gene transfer in the liver. We demonstrated that both the copolymer's charge and the mode of shielding (irreversible versus traceless bioresponsive) profoundly affected liver gene transfer and that traceless bioresponsive shielding with positively charged HPMA copolymers mediated FX independent transduction of hepatocytes. In addition, we demonstrated that shielding with HPMA copolymers can mediate a prolonged blood circulation of vector particles in mice. Our results have significant implications for the future design of polymer-shielded Ad and provide a deeper insight into the interaction of shielded adenovirus vector particles with the host after systemic delivery.</p></div

Oxidative Ring Contraction of Cyclobutenes: General Approach to Cyclopropylketones including Mechanistic Insights

An original oxidative ring contraction of easily accessible cyclobutene derivatives for the selective formation of cyclopropylketones (CPKs) under atmospheric conditions is reported. Comprehensive mechanistic studies are proposed to support this novel, yet unusual, rearrangement. Insights into the mechanism ultimately led to simplification and generalization of the ring contraction of cyclobutenes using <i>m</i>CPBA as an oxidant. This unique and functional group tolerant transformation proceeds under mild conditions at room temperature, providing access to a new library of polyfunctionalized motifs. With CPKs being attractive and privileged pharmacophores, the elaboration of such a simple and straightforward strategy represents a highly valuable tool for drug discovery and medicinal chemistry. Additionally, the described method was employed to generate a pool of bioactive substances and key precursors in a minimum number of steps