APP controls the formation of PI(3,5)P2 vesicles through its binding of the PIKfyve complex

Phosphoinositides are signalling lipids that are crucial for major signalling events as well as established regulators of membrane trafficking. Control of endosomal sorting and endosomal homeostasis requires phosphatidylinositol-3-phosphate (PI(3)P) and phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2), the latter a lipid of low abundance but significant physiological relevance. PI(3,5)P2 is formed by phosphorylation of PI(3)P by the PIKfyve complex which is crucial for maintaining endosomal homeostasis. Interestingly, loss of PIKfyve function results in dramatic neurodegeneration. Despite the significance of PIKfyve, its regulation is still poorly understood. Here we show that the Amyloid Precursor Protein (APP), a central molecule in Alzheimer’s disease, associates with the PIKfyve complex (consisting of Vac14, PIKfyve and Fig4) and that the APP intracellular domain directly binds purified Vac14. We also show that the closely related APP paralogues, APLP1 and 2 associate with the PIKfyve complex. Whether APP family proteins can additionally form direct protein–protein interaction with PIKfyve or Fig4 remains to be explored. We show that APP binding to the PIKfyve complex drives formation of PI(3,5)P2 positive vesicles and that APP gene family members are required for supporting PIKfyve function. Interestingly, the PIKfyve complex is required for APP trafficking, suggesting a feedback loop in which APP, by binding to and stimulating PI(3,5)P2 vesicle formation may control its own trafficking. These data suggest that altered APP processing, as observed in Alzheimer’s disease, may disrupt PI(3,5)P2 metabolism, endosomal sorting and homeostasis with important implications for our understanding of the mechanism of neurodegeneration in Alzheimer’s disease.

Delay of light in an optical bottle resonator with nanoscale radius variation : dispersionless, broadband, and low-loss

It is shown theoretically that an optical bottle resonator with a nanoscale radius variation can perform a multinanosecond long dispersionless delay of light in a nanometer-order bandwidth with minimal losses. Experimentally, a 3 mm long resonator with a 2.8 nm deep semiparabolic radius variation is fabricated from a 19??µm radius silica fiber with a subangstrom precision. In excellent agreement with theory, the resonator exhibits the impedance-matched 2.58 ns (3 bytes) delay of 100 ps pulses with 0.44??dB/ns intrinsic loss. This is a miniature slow light delay line with the record large delay time, record small transmission loss, dispersion, and effective speed of light.

Delay of light in an optical bottle resonator with nanoscale radius variation:dispersionless, broadband, and low-loss

It is shown theoretically that an optical bottle resonator with a nanoscale radius variation can perform a multinanosecond long dispersionless delay of light in a nanometer-order bandwidth with minimal losses. Experimentally, a 3 mm long resonator with a 2.8 nm deep semiparabolic radius variation is fabricated from a 19??µm radius silica fiber with a subangstrom precision. In excellent agreement with theory, the resonator exhibits the impedance-matched 2.58 ns (3 bytes) delay of 100 ps pulses with 0.44??dB/ns intrinsic loss. This is a miniature slow light delay line with the record large delay time, record small transmission loss, dispersion, and effective speed of light.

Probing three-way interactions in moderated multiple regression:Development and application of a slope difference test

Researchers often use 3-way interactions in moderated multiple regression analysis to test the joint effect of 3 independent variables on a dependent variable. However, further probing of significant interaction terms varies considerably and is sometimes error prone. The authors developed a significance test for slope differences in 3-way interactions and illustrate its importance for testing psychological hypotheses. Monte Carlo simulations revealed that sample size, magnitude of the slope difference, and data reliability affected test power. Application of the test to published data yielded detection of some slope differences that were undetected by alternative probing techniques and led to changes of results and conclusions. The authors conclude by discussing the test's applicability for psychological research. Copyright 2006 by the American Psychological Association.

Identification, mutagenesis, and transcriptional analysis of the methanesulfonate transport operon of methylosulfonomonas methylovora

Recently identified genes located downstream (3') of the msmEF (transport encoding) gene cluster, msmGH, and located 5' of the structural genes for methanesulfonate monooxygenase (MSAMO) are described from Methylosulfonomonas methylovora. Sequence analysis of the derived polypeptide sequences encoded by these genes revealed a high degree of identity to ABC-type transporters. MsmE showed similarity to a putative periplasmic substrate binding protein, MsmF resembled an integral membraneassociated protein, and MsmG was a putative ATP-binding enzyme. MsmH was thought to be the cognate permease component of the sulfonate transport system. The close association of these putative transport genes to the MSAMO structural genes msmABCD suggested a role for these genes in transport of methanesulfonic acid (MSA) into M. methylovora. msmEFGH and msmABCD constituted two operons for the coordinated expression of MSAMO and the MSA transporter systems. Reverse-transcription-PCR analysis of msmABCD and msmEFGH revealed differential expression of these genes during growth on MSA and methanol. The msmEFGH operon was constitutively expressed, whereas MSA induced expression of msmABCD. A mutant defective in msmE had considerably slower growth rates than the wild type, thus supporting the proposed role of MsmE in the transport of MSA into M. methylovora.

State intervention in technology in the post war years: case studies in technology policy

This thesis is concerned with the means by which the state in Britain has attempted to influence the technological development of private industry in the period 1945-1979. Particular emphasis is laid on assessing the abilities of technology policy measures to promote innovation. With that objective, the innovation literature is selectively reviewed to draw up an analytical framework to evaluate the innovation content of policy (Chapter 2). Technology policy is taken to consist of the specific measures utilised by government and its agents that affect the technological behaviour of firms. The broad sweep of policy during the period under consideration is described in Chapter 3 which concentrates on elucidating its institutional structure and the activities of the bodies involved. The empirical core of the thesis consists of three parallel case studies of policy toward the computer, machine tool and textile machinery industries (Chapters 4-6). The studies provide detailed historical accounts of the development and composition of policy, relating it to its specific institutional and industrial contexts. Each reveals a different pattern and level of state intervention. The thesis concludes with a comparative review of the findings of the case studies within a discussion centred on the arguments presented in Chapter 2. Topics arising include the state's differential support for the range of activities involved in innovation, the location of state-funded R&D, the encouragement of supplier-user contact, and the difficulties raised in adoption and diffusion.

Empirical studies of corporate governance in China

The thesis aims to provide empirical studies towards Chinese corporate governance. Since China initially established its stock exchange system in the 1990s, it has gone through different stages of changes to become a more market-oriented system. Extensive studies have been conducted in Chinese corporate governance, however, many were theoretical discussion focusing on the early stages and there‘s a general lack of empirical analysis. This paper provides three empirical analysis of the Chinese corporate governance: the overall market discipline efficiency, the impact of capital structure on agency costs, the status of 2005- 2006 reform that substantially modified ownership structure of Chinese listed firms and separated ownership and control of listed firms. The three empirical studies were selected to reflect four key issues that need answering: the first empirical study, using event study to detect market discipline on a collective level. This study filled a gap in the Chinese stock market literature for being the first one ever using cross-market data to test market discipline. The second empirical study endeavoured to contribute to the existing corporate governance literature regarding capital structure and agency costs. Two conclusions can be made through this study: 1) for Chinese listed firms, higher gearing means higher asset turnover ratios and ROE, i.e. more debts seem to reduce agency costs; 2) concentration level of shares appears to be irrelevant with company performance, controlling shareholders didn‘t seem to commit to the improvement of corporate assets utilization or contribute to reducing agency costs. This study addressed a key issue in Chinese corporate governance since the state has significant shareholding in most big listed companies. The discussion of corporate governance in the Chinese context would be completely meaningless without discussing the state‘s role in corporate governance, given that about 2/3 of the almost all shares were non-circulating shares controlled by the state before the 2005-2006 overhaul ownership reform. The third study focused on the 2005-2006 reform of ownership of Chinese listed firms. By collecting large-scale data covering all 64 groups of Chinese listed companies went through the reform by the end of 2006 (accounting for about 97.86% and 96.76% of the total market value of Shanghai (SSE) and Shenzhen Stock Exchange (SZSE) respectively), a comprehensive study about the ownership reform was conducted. This would be first and most comprehensive empirical study in this area. The study of separated ownership and control of listed firm is the first study conducted using the ultimate ownership concept in Chinese context.