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Introduction Several circulating markers, including autoantibodies to erythropoietin receptor (anti-EPOR antibodies), have been identified as useful biomarkers in predicting diabetic kidney disease progression. However, a direct comparison of their utility is lacking. We aimed to validate and to compare the prognostic value of anti-EPOR antibodies with that of other known biomarkers, using the ADVANCE trial and its long-term follow-up, ADVANCE-ON, cohorts. Methods In this nested case-control study from the ADVANCE trial cohort, we included 165 case participants who had the composite kidney outcome (renal replacement therapy, renal death, or doubling of serum creatinine to ≥200 μmol/l) and 330 matched controls. We compared the associations of baseline plasma levels of anti-EPOR antibodies, tumor necrosis factor receptor (TNFR)-1 and -2, and bone morphogenetic protein (BMP)-7 with kidney outcomes. Results Cases had higher baseline plasma levels of anti-EPOR antibodies than controls (median 1.7 vs. 0.6 enzyme-linked immunosorbent assay unit, P < 0.001). Higher levels of anti-EPOR antibodies were associated with an increased risk of kidney outcome (odds ratio 2.16 [95% confidence interval 1.51, 3.08], per 1 SD of log-transformed levels) after adjusting for conventional markers. Elevated circulating TNFR1 and TNFR2 levels, and lower BMP-7 levels at baseline, were associated with poor kidney outcome (odds ratios 2.06 [1.29, 3.30], 1.66 [1.13, 2.43], and 0.45 [0.32, 0.65], respectively). The addition of anti-EPOR antibodies into the model improved the prediction of kidney outcome, regardless of other biomarkers. Conclusion Anti-EPOR antibodies provide a promising biomarker, as with TNFR1, TNFR2, and BMP-7, in predicting kidney disease progression in people with type 2 diabetes mellitus., Graphical abstract

The semantic umbrella term nanotechnology covers every branch of science pursuing controlled manipulation of matter at the nanoscale, at which point a discrete set of atoms constitute a functional object. At these scales, proximal surface effects, such as, quantum coherence completely redefine the physical properties of nanostructures. Insulating polymeric materials, if properly engineered, are transformed into electrical conductors resulting in the flexible light-emitting materials such as organic LEDs or OLEDs now found in modern consumer electronics. Such novel material classes have been accompanied by major technological advances in high-throughput manufacture, measurement, and characterization. We now are able to engineer complex systems based on nanostructured materials that interact at the molecular scale. The ability to interrogate single molecules with techniques, such as, scanning tunneling microscopy (STM) and atomic force microscopy (AFM), has opened a whole new chapter in life sciences, where biomolecules could be manipulated and analyzed directly, paving the way for nanobiotechnology and personalized nanomedicine. This chapter details the major classes of nanomaterials and highlights their translation into modern technologies and products that now affect our daily life.

Interleukin-1β (IL-1β) is a cytokine whose bioactivity is controlled by activation of the inflammasome. However, in response to lipopolysaccharide, human monocytes secrete IL-1β independently of classical inflammasome stimuli. Here, we report that this constituted a species-specific response that is not observed in the murine system. Indeed, in human monocytes, lipopolysaccharide triggered an “alternative inflammasome” that relied on NLRP3-ASC-caspase-1 signaling, yet was devoid of any classical inflammasome characteristics including pyroptosome formation, pyroptosis induction, and K+ efflux dependency. Genetic dissection of the underlying signaling pathway in a monocyte transdifferentiation system revealed that alternative inflammasome activation was propagated by TLR4-TRIF-RIPK1-FADD-CASP8 signaling upstream of NLRP3. Importantly, involvement of this signaling cascade was limited to alternative inflammasome activation and did not extend to classical NLRP3 activation. Because alternative inflammasome activation embraces both sensitivity and promiscuity of TLR4, we propose a pivotal role for this signaling cascade in TLR4-driven, IL-1β-mediated immune responses and immunopathology in humans. This work was supported by grants from the German Research Foundation (SFB704 and SFB670) to V.H. V.H. is a member of the Excellence cluster ImmunoSensation.

This chapter introduces fundamental concepts of modeling natural systems using a G×E×M framework and discusses the prospects for an integrated approach for improving crop performance that tackles the G×E×M interactions holistically. It outlines general principles of modeling biophysical systems, including a description of fundamental components of crop models. It describes G×E×M systems and introduces gene-to-phenotype (GP) models and concepts of adaptation landscapes as applied to plant breeding. The chapter discusses the application of the framework by studying genetic improvement of maize in the US Corn Belt. It reviews and summarizes theoretical developments toward a framework that integrates quantitative genetics, breeding simulation, and modeling of physiological traits and dynamic GP relations. Such a framework is intended to enable breeders and agronomists to project trajectories in the G×E×M space into the future and gain insights on the consequences of manipulating genomes to the creation of improved crops for target management and environments.

Summary Recently, we demonstrated that nitric oxide synthase immunoreactive (NOS-IR) neurons are closely associated with the retinal vasculature and have proposed that these neurons are the mechanism by which retinal blood flow and metabolism are linked. This study examined the effect of diabetes on the population of NADPH diaphorase (NADPHd)-positive (equivalent to NOS-IR) neurons in the retina. Aminoguanidine (AG), an inhibitor of advanced glycation, has been shown to attenuate AGE accumulation as well as the progression of retinal disease in experimental diabetes. It is known that aminoguanidine also inhibits NOS in vitro. This study investigated the effect of diabetes and aminoguanidine (an inhibitor of advanced glycation) or NG-monomethyl-L-arginine (L-NAME) (an inhibitor of NOS), treatment on the population of NAPDHd-positive amacrine cells in the rat retina. Diabetic and control rats were randomized and received no treatment, aminoguanidine or L-NAME for 32 weeks. Diabetic rats had increased serum glucose levels and blood pressure, but lower body weight compared with controls. The number of NADPHd-positive neurons per retina was significantly reduced (−26%) in diabetic rats compared with control rats. Aminoguanidine treatment of diabetic rats restored the number of NADPHd-positive neurons to normal levels at 32 weeks. L-NAME treatment of diabetic animals had no effect on the number of NADPHd-positive neurons. Since the retinoprotective effect of aminoguanidine cannot be reproduced by L-NAME, it is likely to be mediated by a decrease in advanced glycation rather than by inhibition of NOS.

Over the last 10 years, the process of advanced glycation endproduct (AGE) formation has been implicated in the pathogenesis of many of the longterm complications of diabetes. Since the restoration of blood glucose levels to normal remains difficult, any treatment which can modify the effects of longterm hyperglycemia represents an attractive option for the prevention of diabetic complications. This report describes the effects of aminoguanidine on micro- and macroangiopathy in experimental diabetes. Acute effects of aminoguanidine in the diabetic state have included prevention of the increase in blood flow and permeability in a number of tissues including the eye and kidney. Aminoguanidine has also largely prevented the reduction in motor and sensory nerve conduction velocity and the increased arterial wall protein cross-linking that is observed in diabetes. Several studies have shown that aminoguanidine prevents the accumulation of AGEs in the kidney, with a concomitant reduction in albuminuria and renal structural changes. With respect to retinopathy, it has been shown that aminoguanidine prevents the diabetes-induced increase in number of acellular capillaries and reduces the magnitude of pericyte loss. Studies on experimental diabetic neuropathy have demonstrated that aminoguanidine prevents axonal atrophy and a decrease in nerve conduction velocity. Recently it has also been shown that aminoguanidine may prevent atherosclerosis in a non-diabetic model of atherosclerosis.