87 research outputs found
A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover.
Mutations in LRRK2 are a common cause of genetic Parkinson's disease (PD). LRRK2 is a multi-domain Roco protein, harbouring kinase and GTPase activity. In analogy with a bacterial homologue, LRRK2 was proposed to act as a GTPase activated by dimerization (GAD), while recent reports suggest LRRK2 to exist under a monomeric and dimeric form in vivo. It is however unknown how LRRK2 oligomerization is regulated. Here, we show that oligomerization of a homologous bacterial Roco protein depends on the nucleotide load. The protein is mainly dimeric in the nucleotide-free and GDP-bound states, while it forms monomers upon GTP binding, leading to a monomer-dimer cycle during GTP hydrolysis. An analogue of a PD-associated mutation stabilizes the dimer and decreases the GTPase activity. This work thus provides insights into the conformational cycle of Roco proteins and suggests a link between oligomerization and disease-associated mutations in LRRK2
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Systematic review of the effects of the intestinal microbiota on selected nutrients and non-nutrients
The systematic review demonstrates that the IM plays a major role in the breakdown and transformation of the dietary substrates examined. However, recent human data are limited with the exception of data from studies examining fibres and polyphenols. Results observed in relation with dietary substrates were not always consistent or coherent across studies and methodological limitations and differences in IM analyses made comparisons difficult. Moreover, non-digestible components likely to reach the colon are often not well defined or characterised in studies making comparisons between studies difficult if not impossible. Going forward, further rigorously controlled randomised human trials with well-defined dietary substrates and utilizing omic-based technologies to characterise and measure the IM and their functional activities will advance the field. Current evidence suggests that more detailed knowledge of the metabolic activities and interactions of the IM hold considerable promise in relation with host health
PATHOPHYSIOLOGY, DIAGNOSIS AND TREATMENTOF DUMPING SYNDROME AND ITS RELATION TO BARIATRIC SURGERY
Stripping the Boss : The Powerful Role of Humor in the Egyptian Revolution 2011
The Egyptian Revolution 2011 has shaken the Arab world and stirred up Middle-East politics. Moreover, it caused a rush in political science and the neighboring disciplines, which had not predicted an event like this and now have troubles explaining it. While many things can be learned from the popular uprising, and from the limitations of previous scholarship, our focus will be on a moral resource, which has occasionally been noticed, but not sufficiently explored: the role of humor in keeping up the spirit of the Revolution. For eighteen days, protestors persevered at Liberation Square in Central Cairo, the epicenter of resistance; at times a few dozens, at times hundreds of thousands. What they did was to fight the terror of the regime, which reached absurd peaks during those days, with humor â successfully. We offer a social-functionalist account of the uprising, which includes behavioral as well as cultural levels of analysis, and illuminates how humorous means helped to achieve deadly serious goals. By reconstructing how Egyptians laughed themselves into democracy, we outline a social psychology of resistance, which uses humor both as a sword and a shield.Peer reviewe
LRRK2 Biology from structure to dysfunction: research progresses, but the themes remain the same
Since the discovery of leucine-rich repeat kinase 2 (LRRK2) as a protein that is likely central to the aetiology of Parkinson's disease, a considerable amount of work has gone into uncovering its basic cellular function. This effort has led to the implication of LRRK2 in a bewildering range of cell biological processes and pathways, and probable roles in a number of seemingly unrelated medical conditions. In this review we summarise current knowledge of the basic biochemistry and cellular function of LRRK2. Topics covered include the identification of phosphorylation substrates of LRRK2 kinase activity, in particular Rab proteins, and advances in understanding the activation of LRRK2 kinase activity via dimerisation and association with membranes, especially via interaction with Rab29. We also discuss biochemical studies that shed light on the complex LRRK2 GTPase activity, evidence of roles for LRRK2 in a range of cell signalling pathways that are likely cell type specific, and studies linking LRRK2 to the cell biology of organelles. The latter includes the involvement of LRRK2 in autophagy, endocytosis, and processes at the trans-Golgi network, the endoplasmic reticulum and also key microtubule-based cellular structures. We further propose a mechanism linking LRRK2 dimerisation, GTPase function and membrane recruitment with LRRK2 kinase activation by Rab29. Together these data paint a picture of a research field that in many ways is moving forward with great momentum, but in other ways has not changed fundamentally. Many key advances have been made, but very often they seem to lead back to the same places
Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.
Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.JS, DES and ARB thank the Wellcome Trust for funding.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nrd.2016.2
Viral, bacterial, and fungal infections of the oral mucosa:Types, incidence, predisposing factors, diagnostic algorithms, and management
Virtual Reality Social Cognition Training for Young Adults with High-Functioning Autism
Improvement compressive strength of cementitious composites in different curing media by incorporating ZrO2 nanoparticles
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