Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate.

Funder: Intramural Research Programs of the National Human Genome Research InstituteRegulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application

Isolation and characterization of 3-deoxypentulose and its determination in heated milk

The presence of 3-deoxypentulose in heated milk is reported. This compound has been isolated from alkaline solutions of lactose and characterized by spectroscopic and Chromatographie techniques. Gas Chromatographic analysis of free monosaccharides of milk revealed two peaks corresponding to 3-deoxypentulose in commercial sterilized milk samples, in a concentration range of 30–50 mg/1. Its concentration increased with temperature and length of time of processing.This work was supported by Comision Interministerial de Ciencia y Tecnologia (Projects ALI88-0158-C02-02 and ALI91-0540).Peer reviewe

Gas chromatographic analysis of free monosaccharides in milk

Three silylation methods for the gas chromatographic analysis of ketohexoses have been compared for yield and tautomeric composition of trimethylsilyl ethers. One of them has been applied to the analysis of milk monosaccharides and evaluated for precision and accuracy. Of the different stationary phases employed, OV-215 and AT-1000 were the best suited to resolve the TMS ethers of the studied sugars.Peer reviewe

Turbidity in alkali feldspars from granitic pegmatites

Alkali feldspars from pegmatite of Brazil and Spain have microscopic to submicroscopic inclusions giving a >turbid> and >clouded> appearance. Inclusions are isotropic, irregular and spatially associated with patch/vein lamellae in network and/Or isolated masses. Inclusions have no detectable lines in XRD and microprobe analyses show strong variability: Si02 40-46 wt%, Al203 30-40 wt%, Kp up to 5 wt%, Nap up to 0.5 wt%, FeO up to 2.5 wt%, MgO up to 1.3 wt%, CaO up to 0.4 wt%, pps up to 0.35 wt%, F up to 2000 ppm, Cl up to 5500 ppm. Dark coronas around them are richer in Cl, Fe, Mg. Thermal analysis up to 600°C shows a TG curve with multiple steps of water loss up to 11 wt%. A homogeneous matrix with a clot appearance is observed in transmission electron microscopy containing crystals inside. Electron diffraction patterns show an amorphous nature. 29Si-MAS¿NMR spectra show one or two broad lines at approximately -87 and -91.6 ppm from Si in the Q3 environment. TI Al-MAS-NMR spectra show one or two broad lines at approximately -70 and -3 ppm due to Al in IV and VI coordination. Inclusions with a >turbid> appearance are kaolin-like amorphous materials. They may be interpreted as a product of the interaction of early rock with Cl-rich aqueous fluids from the late transformation stage in the pegmatite process. This interaction is associated with Na-feldspar patch/vein-lamellae formation of perthites.Peer Reviewe