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The impact of modern imaging in uncovering the underlying pathology of PMR cannot be understated. Long dismissed as an inflammatory syndrome with links to the large vessel vasculitis giant cell arteritis (GCA), a pathognomonic pattern of musculotendinous inflammation is now attributed to PMR and may be used to confirm its diagnosis. Among the available modalities, 18F-fluorodeoxyglucose (18F-FDG) PET/CT is increasingly recognized for its high sensitivity and specificity, as well as added ability to detect concomitant large vessel GCA and exclude other relevant differentials like infection and malignancy. This atlas provides a contemporary depiction of PMR's pathology and outlines how this knowledge translates into a pattern of findings on whole body 18F-FDG PET/CT that can reliably confirm its diagnosis. [ABSTRACT FROM AUTHOR]

Saccharomyces cerevisiae remains an ideal organism for studying the cell biological roles of lipids in vivo, as yeast has phospholipid metabolic pathways similar to mammalian cells, is easy and economical to manipulate, and is genetically tractable. The availability of isogenic strains containing specific genetic inactivation of each non-essential gene allowed for the development of a high-throughput method, called synthetic genetic analysis (SGA), to identify and describe precise pathways or functions associated with specific genes. This review describes the use of SGA to aid in elucidating the function of two lipid-binding proteins that regulate vesicular transport, Sec14 and Kes1. Sec14 was first identified as a phosphatidylcholine (PC)--phosphatidylinositol (PI) transfer protein required for viability, with reduced Sec14 function resulting in diminished vesicular transport out of the fraws-Golgi. Although Sec14 is required for cell viability, inactivating the KES1 gene that encodes for a member of the oxysterol binding protein family in cells lacking Sec14 function results in restoration of vesicular transport and cell growth. SGA analysis identified a role for Kes1 and Sec14 in regulating the level and function of Golgi PI-4-phosphate (PI-4-P). SGA also determined that Sec14 not only regulates vesicular transport out of the fraws-Golgi, but also transport from endosomes to the fraws-Golgi. Comparing SGA screens in databases, coupled with genetic and cell biological analyses, further determined that the PI-4-P pool affected by Kes1 is generated by the PI 4-kinase Pik1. An important biological role for Sec14 and Kes1 revealed by SGA is coordinate regulation of the Pik1-generated Golgi PI-4-P pool that in turn is essential for vesicular transport into and out of the fraws-Golgi. Key words: phospholipid, metabolism, sterol, vesicular trafficking, synthetic genetic analysis. Saccharomyces cerevisiae demeure un organisme de choix pour etudier le role des lipides dans la biologie cellulaire in vivo car les voies metaboliques des phospholipides de la levure sont similaires a celles des cellules mammiferes, cette levure est facile et economique a manipuler et elle est genetiquement malleable. La disponibilite de souches isogeniques comportant une inactivation genique de chaque gene non essentiel a permis de developper des methodes a haut debit, appelees SGA (acronyme de << synthetic genetic analysis >>), afin d'identifier et d'attribuer precisement des sentiers ou des fonctions associesa des genes specifiques. Cet article de synthese decrit l'utilisation de la SGA pour aider a elucider la fonction des proteines de liaison des lipides Sec14 et Kes1qui regulent le transport vesiculaire. Sec 14 a ete la premiere a etre identifiee comme proteine de transfert de phosphatidylcholine (PC)--phosphatidylinositol (PI) requise pour la viabilite,la reduction de la fonction de Sec14 resultant en une diminution du transport vesiculaire vers l'exterieur du trans-Golgi. Meme si Sec14 est requise a la viabilite cellulaire, l'inactivation de gene KES1 qui code un membre de la famille de proteines de liaison des oxysterols dans les cellules depourvues des fonctions associees a Sec14 retablit le transport vesiculaire et la croissance cellulaire. L'analyse par SGA a permis d'attribuer un role a Kes1 et Sec14 dans la regulation du niveau et de la fonction du PI-4-phosphate (PI-4-P) du Golgi. La SGA a aussi permis de determiner que Sec l4 regule non seulement le transport vesiculaire vers l'exterieur du fraws-Golgi, mais aussi le transport des endosomes vers le trans-Golgi. La comparaison des criblages par SGA des bases de donnees, conjointement a des analyses genetiques et biologiques, a de plus permis de determiner que le pool de PI-4-P affecte par Kes1 est genere par la PI 4-kinase Pik1. Un role biologique important de Sec14 et Kes1 revele par la SGA consiste en la regulation coordonnee du pool de PI-4-P du Golgi genere par la Pik1 qui, a son tour, est essentiel au transport vesiculaire vers l'interieur et l'exterieur du trans-Golgi. Mots-cles: phospholipides, metabolisme, sterol, trafic vesiculaire, analyse genetique synthetique (GSA). [Traduit par la Redaction], The Golgi apparatus plays a central role in the regulation of vesicular transport pathways. The integrity of cellular membranes and compartments is dependent on the proper trafficking of lipids and [...]

Abstract: Phosphatidylcholine is the major phospholipid in eukaryotic cells and serves as both a permeability barrier as well as a modulator of a plethora of cellular and biological functions. This [...]

Abstract With the advent of next-generation DNA sequencing, the pace of inherited orphan disease gene identification has increased dramatically, a situation that will continue for at least the next several years. At present, the numbers of such identified disease genes significantly outstrips the number of laboratories available to investigate a given disorder, an asymmetry that will only increase over time. The hope for any genetic disorder is, where possible and in addition to accurate diagnostic test formulation, the development of therapeutic approaches. To this end, we propose here the development of a strategic toolbox and preclinical research pathway for inherited orphan disease. Taking much of what has been learned from rare genetic disease research over the past two decades, we propose generalizable methods utilizing transcriptomic, system-wide chemical biology datasets combined with chemical informatics and, where possible, repurposing of FDA approved drugs for pre-clinical orphan disease therapies. It is hoped that this approach may be of utility for the broader orphan disease research community and provide funding organizations and patient advocacy groups with suggestions for the optimal path forward. In addition to enabling academic pre-clinical research, strategies such as this may also aid in seeding startup companies, as well as further engaging the pharmaceutical industry in the treatment of rare genetic disease.