A Drosophila Model of ALS: Human ALS-Associated Mutation in VAP33A Suggests a Dominant Negative Mechanism

ALS8 is caused by a dominant mutation in an evolutionarily conserved protein, VAPB (vesicle-associated membrane protein (VAMP)-associated membrane protein B)/ALS8). We have established a fly model of ALS8 using the corresponding mutation in Drosophila VAPB (dVAP33A) and examined the effects of this mutation on VAP function using genetic and morphological analyses. By simultaneously assessing the effects of VAPwt and VAPP58S on synaptic morphology and structure, we demonstrate that the phenotypes produced by neuronal expression of VAPP58S resemble VAP loss of function mutants and are opposite those of VAP overexpression, suggesting that VAPP58S may function as a dominant negative. This is brought about by aggregation of VAPP58S and recruitment of wild type VAP into these aggregates. Importantly, we also demonstrate that the ALS8 mutation in dVAP33A interferes with BMP signaling pathways at the neuromuscular junction, identifying a new mechanism underlying pathogenesis of ALS8. Furthermore, we show that mutant dVAP33A can serve as a powerful tool to identify genetic modifiers of VAPB. This new fly model of ALS, with its robust pathological phenotypes, should for the first time allow the power of unbiased screens in Drosophila to be applied to study of motor neuron diseases

Targeting Huntington’s disease through histone deacetylases

Huntington’s disease (HD) is a debilitating neurodegenerative condition with significant burdens on both patient and healthcare costs. Despite extensive research, treatment options for patients with this condition remain limited. Aberrant post-translational modification (PTM) of proteins is emerging as an important element in the pathogenesis of HD. These PTMs include acetylation, phosphorylation, methylation, sumoylation and ubiquitination. Several families of proteins are involved with the regulation of these PTMs. In this review, I discuss the current evidence linking aberrant PTMs and/or aberrant regulation of the cellular machinery regulating these PTMs to HD pathogenesis. Finally, I discuss the evidence suggesting that pharmacologically targeting one of these protein families the histone deacetylases may be of potential therapeutic benefit in the treatment of HD

Genetic Basis of Myocarditis: Myth or Reality?

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International SMEs from emerging markets-Insights from the Colombian textile and apparel industry

The internationalization of firms from emerging markets has been studied mainly from the perspective of large firms. Smaller and younger international firms based in emerging markets suffer from underrepresentation in the literature. This study sheds light on the internationalization of emerging market SMEs, focusing on Colombian textile and apparel exporters. Using mixed research methods, it illustrates the role of firm age in influencing internationalization strategy. It examines 1165 export contracts by 50 SMEs, discussing export intensity, speed, and geographic scope using recurrence analysis and cluster analysis. It contributes to international entrepreneurship by exploring new empirical evidence and examining it using a novel methodological approach

The organizational environment with its measures, antecedents, and consequences: A review and research agenda

The organizational environment is a focal element of multifaceted managerial decisions. Consequently, research has shown a long lasting and still growing interest in investigating the organizational environment and understanding its impact on a firm. Because it is widely assumed that the business environment will become more dynamic, changes in the organizational environment have drawn the particular attention of many scholars. While the extant research has established valuable knowledge, its fragmentation due to differing definitions and contradictory findings calls for a broad review to establish a foundation for future research. By analyzing 279 studies that have investigated different aspects of the organizational environment between 1958 and mid-2017, we contribute to various research streams that involve this environmental factor. We use a comprehensive research framework to categorize and review the previous work. In particular, we distinguish between studies that define or measure the organizational environment, as well as studies that investigate antecedents, outcomes, and moderating effects of the organizational environments. Among those categories, we discuss our findings, before subsequently synthesizing existing works and deriving an agenda for future research