Impact of late-onset Alzheimer’s genetic risk factors on beta-amyloid endocytic production

The increased production of the 42 aminoacids long beta-amyloid (Aβ42) peptide has been established as a causal mechanism of the familial early onset Alzheimer’s disease (AD). In contrast, the causal mechanisms of the late-onset AD (LOAD), that affects most AD patients, remain to be established. Indeed, Aβ42 accumulation has been detected more than 30 years before diagnosis. Thus, the mechanisms that control Aβ accumulation in LOAD likely go awry long before pathogenesis becomes detectable. Early on, APOE4 was identified as the biggest genetic risk factor for LOAD. However, since APOE4 is not present in all LOAD patients, genome-wide association studies of thousands of LOAD patients were undertaken to identify other genetic variants that could explain the development of LOAD. PICALM, BIN1, CD2AP, SORL1, and PLD3 are now with APOE4 among the identified genes at highest risk in LOAD that have been implicated in Aβ42 production. Recent evidence indicates that the regulation of the endocytic trafficking of the amyloid precursor protein (APP) and/or its secretases to and from sorting endosomes is determinant for Aβ42 production. Thus, here, we will review the described mechanisms, whereby these genetic risk factors can contribute to the enhanced endocytic production of Aβ42. Dissecting causal LOAD mechanisms of Aβ42 accumulation, underlying the contribution of each genetic risk factor, will be required to identify therapeutic targets for novel personalized preventive strategies.     

LIVESTOCK PRODUCTION PLANNING UNDER ENVIRONMENTAL RISKS AND UNCERTAINTIES

1. Introduction The world food economy is increasingly being driven by a shift of diets towards livestock products. In the developing countries, consumption of meat has been growing at 5-6 percent p.a., and that of milk and dairy products at 3.3-3.5 percent p.a. in the last few decades. Much of the growth is taking place in China (Huang and Zhang et al. 2003a, Huang and Liu 2003b, Keyzer and van Veen 2004, Ma and Huang et al. 2004, Simpson and Cheng et al.1994, USDA Economic Research Se…     

Developing an Innovative Style of Thinking and Innovative Behavior

Russia is currently attempting to create a modern, innovative economy, which requires a new type of worker and a new, more cooperative style of management. Twenty years of Russian market reforms have clearly shown that one of the most serious obstacles to creating an innovative economy in Russia is to change the totalitarian style of thinking. A person needs to be considered as more than a means to achieve economic goals. This paper aims to describe some aspects of the social, economic and organizational changes occurring in Russia and one way out of the current predicament: using a constructivist approach to education in order to develop the innovative competencies of people. In this action research a presumption is made that changes in mentality and patterns of behavior are required for both managers and workers. Style of management in organizations should change in a manner that would support the creation of an innovative society.     

Stability of trajectories from Poincaré to Birkhoff: approaching a qualitative definition

The article investigates the different conceptions of stability found in qualitative studies on the solutions of differential equations. We start from the definitions proposed by Poincaré and criticized by Birkhoff for not being fully qualitative, and show that the clarification of the criterion for stating that a property is qualitative comes precisely with Birkhoff. In addition, we note that the stability conceptions of Lyapunov and Levi-Civita are also important in this transition from the appearance of the first qualitative tools in the study of differential equations to the definition of stability in use in dynamical systems theory. The history of stability can help to explain the meaning of the word “qualitative” in this context.     

Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution

Influenza viruses are remarkably adept at surviving in the human population over a long timescale. The human influenza A virus continues to thrive even among populations with widespread access to vaccines, and continues to be a major cause of morbidity and mortality. The virus mutates from year to year, making the existing vaccines ineffective on a regular basis, and requiring that new strains be chosen for a new vaccine. Less-frequent major changes, known as antigenic shift, create new strains against which the human population has little protective immunity, thereby causing worldwide pandemics. The most recent pandemics include the 1918 'Spanish' flu, one of the most deadly outbreaks in recorded history, which killed 30-50 million people worldwide, the 1957 'Asian' flu, and the 1968 'Hong Kong' flu. Motivated by the need for a better understanding of influenza evolution, we have developed flexible protocols that make it possible to apply large-scale sequencing techniques to the highly variable influenza genome. Here we report the results of sequencing 209 complete genomes of the human influenza A virus, encompassing a total of 2,821,103 nucleotides. In addition to increasing markedly the number of publicly available, complete influenza virus genomes, we have discovered several anomalies in these first 209 genomes that demonstrate the dynamic nature of influenza transmission and evolution. This new, large-scale sequencing effort promises to provide a more comprehensive picture of the evolution of influenza viruses and of their pattern of transmission through human and animal populations. All data from this project are being deposited, without delay, in public archives.     

The DIX domain targets dishevelled to actin stress fibres and vesicular membranes

Colorectal cancer results from mutations in components of the Wnt pathway that regulate beta-catenin levels. Dishevelled (Dvl or Dsh) signals downstream of Wnt receptors and stabilizes beta-catenin during cell proliferation and embryonic axis formation. Moreover, Dvl contributes to cytoskeletal reorganization during gastrulation and mitotic spindle orientation during asymmetric cell division. Dvl belongs to a family of eukaryotic signalling proteins that contain a conserved 85-residue module of unknown structure and biological function called the DIX domain. Here we show that the DIX domain mediates targeting to actin stress fibres and cytoplasmic vesicles in vivo. Neighbouring interaction sites for actin and phospholipid are identified between two helices by nuclear magnetic resonance spectroscopy (NMR). Mutation of the actin-binding motif abolishes the cytoskeletal localization of Dvl, but enhances Wnt/beta-catenin signalling and axis induction in Xenopus. By contrast, mutation of the phospholipid interaction site disrupts vesicular association of Dvl, Dvl phosphorylation, and Wnt/beta-catenin pathway activation. We propose that partitioning of Dvl into cytoskeletal and vesicular pools by the DIX domain represents a point of divergence in Wnt signalling.     

DETERMINATION OF AN ANALYTICAL DEPENDENCE DESCRIBING THE PROCESS OF TENSION OSCILLATION DURING THE WORK OF A WARP KNITTING MACHINE

The analytanl repnsedtfon of the osciliation of tension in the proass of fabric meking on a warp knitting machine is ddsiled, basis on funCtion approxfortion by Fourie row.