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  • The identification of CCR B cells within

    2020-02-11

    The identification of CCR6+ Pam3CSK4 Biotin within the LZ as direct progenitors of MBCs provides a new window into the evolution of immune responses. In practical terms, flow-cytometric detection of CCR6+ GC B cells could provide a means of rapidly assessing vaccine efficacy when applied to fine needle aspirates or core biopsies from local lymph nodes in vaccinated subjects and could provide an additional means of investigating patients with primary immuno-deficiencies. More fundamentally, the finding that both high- and low-affinity GC B cells contribute to the MBC pool suggests the evolution of basis for both eliciting rapid recall responses against the original infectious agent (via high-affinity MBCs) and providing broader coverage against related or mutated pathogens (via low-affinity MBCs).
    STAR★Methods
    Acknowledgments
    Oxysterols as Key Players in Metabolic Syndrome? Obesity and sedentary lifestyle are on the rise and pose serious threats to people\'s health and wellbeing. Obesity is often associated with other pathologies and is one of the criteria included in the definition of metabolic syndrome (MetS) (see Glossary). This syndrome regroups a cluster of metabolic disorders such as hyperglycemia, dyslipidemia, obesity, insulin resistance, or hypertension. MetS also increases the incidence of pathologies such as atherosclerosis, type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), stroke, or cancer. Over the years, numerous endogenous mediators have been investigated to better understand and treat this syndrome. Among these, bioactive lipids such as bile acids, endocannabinoids, ceramides, and oxysterols are clearly of interest. Oxysterols were long considered as mere byproducts of cholesterol metabolism, generated as simple intermediates in the synthesis of the more-studied bile acids. The discovery of their affinity for specific receptors, such as liver X receptors (LXRs), and, more recently, EBI2 and CXCR2, favors their study as endogenous mediators. These molecules are now fully considered bioactive lipids that exert their pleiotropic effects through multiple receptors.
    Oxysterol Metabolism and Molecular Targets
    Oxysterols in Metabolic Syndrome
    The Oxysterol System: A Potential Target to Tackle MetS
    Concluding Remarks The question of ⿿is it possible to interfere with the ⿿oxysterome⿿ in order to treat MetS?⿿ is complex. Pharmacologically modulating the levels of a single oxysterol in vivo seems currently out of reach attributable to the rather poor substrate selectivity of most CYP enzymes and of the redundant pathways in oxysterol metabolism. An alternative could be to directly administer an oxysterol of interest, as reported in several studies. Another avenue to explore is the possibility of directly acting on the molecular targets of oxysterols. This is being explored with synthetic LXR ligands and could certainly be tested for other receptors such as EBI2 and ROR. In conclusion, although several questions remain to be answered (see Outstanding Questions), the evidence discussed places a spotlight on oxysterols as important bioactive lipids in metabolism and energy homeostasis.
    Acknowledgments
    Introduction Gas chromatography – mass spectrometry (GC-MS) with the utilisation of stable-isotope labelled standards is the gold standard methodology for the analysis of neutral cholesterol metabolites [1], [2], [3]. Acidic metabolites are efficiently analysed by liquid chromatography (LC)-MS, where optimal analysis is similarly performed with the use of isotope labelled standards [4], [5]. GC-MS with appropriate derivatisation is also suitable for analysis of acidic metabolites [6], while LC-MS can also be used for the analysis of neutrals with appropriate ionisation additives or derivatisation methods [7], [8], [9], [10], [11], [12]. GC-MS methods tend to incorporate a saponification step and measure a combination of both esterified and non-esterified sterols, while LC-MS methods may or may not include base hydrolysis. Using MS methods, a number of exciting discoveries have recently been made. In this short review we will cover the discoveries of most interest to the authors and discuss analytical improvements since our review of analytical methods in 2011 [7].