Free Fatty Acids and Their Metabolism Affect Function and Survival of Podocytes

Podocyte injury and loss critically contribute to the pathogenesis of proteinuric kidney diseases including diabetic nephropathy. Deregulated lipid metabolism with disturbed free fatty acid (FFA) metabolism is a characteristic of metabolically unhealthy obesity and type 2 diabetes and likely contributes to end-stage kidney disease irrespective of the underlying kidney disease. In the current review, we summarize recent findings related to FFAs and altered renal FFA metabolism with a special focus on podocytes. We will outline the opposing effects of saturated and monounsaturated FFAs and a particular emphasis will be given to the underlying molecular mechanisms involving insulin resistance and endoplasmic reticulum homeostasis. Finally, recent data suggesting a critical role of renal FFA metabolism to adapt to an altered lipid environment will be discussed

Transverse Magnetic Anisotropy in Mn12-acetate: Direct Determination by Inelastic Neutron Scattering

A high resolution inelastic neutron scattering (INS) study of fully deuterated Mn$_{12}$-acetate provides the most accurate spin Hamiltonian parameters for this prototype single molecule magnet so far. The Mn$_{12}$-clusters deviate from axial symmetry, a non-zero rhombic term in the model Hamiltonian leading to excellent agreement with observed positions and intensities of the INS peaks. The following parameter set provides the best agreement with the experimental data: $D=-0.0570(1)$ meV, $B_{4}^0=-2.78(7)\cdot 10^{-6}$ meV, $B_{4}^4=-3.2(6)\cdot 10^{-6}$ meV and $\mid$\textit{E}$\mid =6.8(15)\cdot 10^{-4}$ meV. Crystal dislocations are not the likely cause of the symmetry lowering. Rather, this study lends strong support to a recently proposed model, which is based on the presence of several molecular isomers with distinct spin Hamiltonian parameters.Comment: 4 pages, 4 figure

On the Form Factor for the Unitary Group

We study the combinatorics of the contributions to the form factor of the group U(N) in the large $N$ limit. This relates to questions about semiclassical contributions to the form factor of quantum systems described by the unitary ensemble.Comment: 35 page

Pressure Dependence of the Magnetic Anisotropy in the "Single-Molecule Magnet" [Mn4O3Br(OAc)3(dbm)3]

The anisotropy splitting in the ground state of the single-molecule magnet [Mn4O3Br(OAc)3(dbm)3] is studied by inelastic neutron scattering as a function of hydrostatic pressure. This allows a tuning of the anisotropy and thus the energy barrier for slow magnetisation relaxation at low temperatures. The value of the negative axial anisotropy parameter $D_{\rm cluster}$ changes from -0.0627(1) meV at ambient to -0.0603(3) meV at 12 kbar pressure, and in the same pressure range the height of the energy barrier between up and down spins is reduced from 1.260(5) meV to 1.213(9) meV. Since the $\rm Mn-Br$ bond is significantly softer and thus more compressible than the $\rm Mn-O$ bonds, pressure induces a tilt of the single ion Mn$^{3+}$ anisotropy axes, resulting in the net reduction of the axial cluster anisotropy.Comment: 4 pages, 3 figure

Short-term effect of whole milk and milk fermented by Pseudomonas fluorescens on plasma lipids in adult boars

The short-term effects of whole milk and milk fermented by Pseudomonas fluorescens, of the amino acid composition of the diet and of feeding frequency on the level of plasma lipids, were investigated in six 1-year-old adult boars. The experimental diets contained equal amounts of protein, carbohydrates, fat and cholesterol. After an adaptation period of 5 d for each experimental treatment, blood was collected at regular intervals during 48 h and plasma levels of cholesterol, triacylglycerol, high-density-lipoprotein (HDL)-cholesterol and low-density-lipoprotein (LDL-cholesterol were examined). All variables except HDL-cholesterol showed distinct diurnal fluctuations, which were substantially influenced by feeding frequency. Variations in the amino acid composition of the experimental diets, which were within a physiological range, had no effect on the level of plasma lipids. Plasma lipid levels were significantly lower when the animals received the diets containing milk instead of the diet without milk: cholesterol, triacylglycerol, and LDL-cholesterol were reduced by 5.6, 5.8 and 10% respectively (pondered means) while HDL-cholesterol remained unaffected. Fermentation of whole milk by P. fluorescens reduced the lipid-lowering effect. Our findings suggest that the intake of diets containing milk results in a lower plasma cholesterol and LDL-cholesterol level than the intake of diets with a similar nutrient content which do not contain mil

Colorimetric Measurement of Triglycerides Cannot Provide an Accurate Measure of Stored Fat Content in Drosophila

Drosophila melanogaster has recently emerged as a useful model system in which to study the genetic basis of regulation of fat storage. One of the most frequently used methods for evaluating the levels of stored fat (triglycerides) in flies is a coupled colorimetric assay available as a kit from several manufacturers. This is an aqueous-based enzymatic assay that is normally used for measurement of mammalian serum triglycerides, which are present in soluble lipoprotein complexes. In this short communication, we show that coupled colorimetric assay kits cannot accurately measure stored triglycerides in Drosophila. First, they fail to give accurate readings when tested on insoluble triglyceride mixtures with compositions like that of stored fat, or on fat extracted from flies with organic solvents. This is probably due to an inability of the lipase used in the kits to efficiently cleave off the glycerol head group from fat molecules in insoluble samples. Second, the measured final products of the kits are quinoneimines, which absorb visible light in the same wavelength range as Drosophila eye pigments. Thus, when extracts from crushed flies are assayed, much of the measured signal is actually due to eye pigments. Finally, the lipoprotein lipases used in colorimetric assays also cleave non-fat glycerides. The glycerol backbones liberated from all classes of glycerides are measured through the remaining reactions in the assay. As a consequence, when these assay kits are used to evaluate tissue extracts, the observed signal actually represents the amount of free glycerols together with all types of glycerides. For these reasons, findings obtained through use of coupled colorimetric assays on Drosophila samples must be interpreted with caution. We also show here that using thin-layer chromatography to measure stored triglycerides in flies eliminates all of these problems

Life-course socioeconomic conditions, multimorbidity and polypharmacy in older adults: A retrospective cohort study.

Socioeconomic conditions across the life course may contribute to differences in multimorbidity and polypharmacy in old age. However, whether the risk of multimorbidity changes during ageing and whether life-course socioeconomic conditions are associated with polypharmacy remain unclear. We investigated whether disadvantaged childhood socioeconomic conditions (CSCs) predict increased odds of multimorbidity and polypharmacy in older adults, whether CSCs remain associated when adjusting for adulthood socioeconomic conditions (ACSs), and whether CSCs and ACSs are associated cumulatively over the life course. We used data for 31,432 participants (multimorbidity cohort, mean [SD] age 66·2[9] years), and 21,794 participants (polypharmacy cohort, mean age 69·0[8.9] years) from the Survey of Health, Ageing, and Retirement in Europe (age range 50-96 years). We used mixed-effects logistic regression to assess the associations of CSCs, ASCs, and a life-course socioeconomic conditions score (0-8; 8, most advantaged) with multimorbidity (≥2 chronic conditions) and polypharmacy (≥5 drugs taken daily). We found an association between CSCs and multimorbidity (reference: most disadvantaged; disadvantaged: odds ratio (OR) = 0·79, 95% confidence interval (CI) 0·70-0·90; middle: OR = 0·60; 95%CI 0·53-0·68; advantaged: OR = 0·52, 95%CI 0·45-0·60, most advantaged: OR = 0·40, 95%CI 0·34-0·48) but not polypharmacy. This multimorbidity association was attenuated but remained significant after adjusting for ASCs. The life-course socioeconomic conditions score was associated with multimorbidity and polypharmacy. We did not find an association between CSCs, life-course socioeconomic conditions, and change in odds of multimorbidity and polypharmacy with ageing. Exposure to disadvantaged socioeconomic conditions in childhood or over the entire life-course could predict multimorbidity in older age

Fetuin‐A aggravates lipotoxicity in podocytes via interleukin‐1 signaling

Abstract Sterile inflammation is considered critical in the pathogenesis of diabetic nephropathy (DN). Here we show that Fetuin‐A (FetA) or lipopolysaccharide (LPS) exacerbate palmitic acid‐induced podocyte death, which is associated with a strong induction of monocyte chemoattractant protein‐1 (MCP‐1) and keratinocyte chemoattractant (KC). Moreover, blockage of TLR4 prevents MCP‐1 and KC secretion and attenuates podocyte death induced by palmitic acid alone or combined with FetA. In addition, inhibition of interleukin‐1 (IL‐1) signaling by anakinra, a recombinant human IL‐1Ra, or a murinized anti‐IL‐1β antibody attenuates the inflammatory and ultimate cell death response elicited by FetA alone or combined with palmitic acid. In vivo short‐term therapy of diabetic DBA/2J mice with an anti‐IL1‐β antibody for 4 weeks prevented an increase in serum FetA and considerably decreased urinary tumor necrosis alpha (TNF‐α), a known risk factor for DN progression. In summary, our results suggest that FetA similarly to LPS leads to an inflammatory response in podocytes, which exacerbates palmitic acid‐induced podocyte death and our data imply a critical role for IL‐1β signaling in this process. The study offers the rational for prolonged in vivo studies aimed at testing anti‐IL‐1β therapy for prevention and treatment of DN

Recognizing the Importance of Dysphagia: Stumbling Blocks and Stepping Stones in the Twenty-First Century

Altres ajuts: This paper results from an international interdisciplinary and interprofessional expert meeting generously supported by the BANSS-Foundation, Biedenkopf an der Lahn, Germany