Early urinary biomarkers of diabetic nephropathy in type 1 diabetes mellitus show involvement of kallikrein-kinin system

Abstract Background Additional urinary biomarkers for diabetic nephropathy (DN) are needed, providing early and reliable diagnosis and new insights into its mechanisms. Rigorous selection criteria and homogeneous study population may improve reproducibility of the proteomic approach. Methods Long-term type 1 diabetes patients without metabolic comorbidities were included, 11 with sustained microalbuminuria (MA) and 14 without MA (nMA). Morning urine proteins were precipitated and resolved by 2D electrophoresis. Principal component analysis (PCA) and Projection to latent structures discriminatory analysis (PLS-DA) were adopted to assess general data validity, to pick protein fractions for identification with mass spectrometry (MS), and to test predictive value of the resulting model. Results Proteins (n = 113) detected in more than 90% patients were considered representative. Unsupervised PCA showed excellent natural data clustering without outliers. Protein spots reaching Variable Importance in Projection score above 1 in PLS (n = 42) were subjected to MS, yielding 33 positive identifications. The PLS model rebuilt with these proteins achieved accurate classification of all patients (R2X = 0.553, R2Y = 0.953, Q2 = 0.947). Thus, multiple earlier recognized biomarkers of DN were confirmed and several putative new biomarkers suggested. Among them, the highest significance was met in kininogen-1. Its activation products detected in nMA patients exceeded by an order of magnitude the amount found in MA patients. Conclusions Reducing metabolic complexity of the diseased and control groups by meticulous patients’ selection allows to focus the biomarker search in DN. Suggested new biomarkers, particularly kininogen fragments, exhibit the highest degree of correlation with MA and substantiate validation in larger and more varied cohorts

Mechanochemical action of the dynamin protein

Dynamin is a ubiquitous GTPase that tubulates lipid bilayers and is implicated in many membrane severing processes in eukaryotic cells. Setting the grounds for a better understanding of this biological function, we develop a generalized hydrodynamics description of the conformational change of large dynamin-membrane tubes taking into account GTP consumption as a free energy source. On observable time scales, dissipation is dominated by an effective dynamin/membrane friction and the deformation field of the tube has a simple diffusive behavior, which could be tested experimentally. A more involved, semi-microscopic model yields complete predictions for the dynamics of the tube and possibly accounts for contradictory experimental results concerning its change of conformation as well as for plectonemic supercoiling.Comment: 17 pages, 4 figures; typos corrected, reference adde

Collective Adaptive Systems: Qualitative and Quantitative Modelling and Analysis (Dagstuhl Seminar 14512)

This report documents the program and the outcomes of Dagstuhl Seminar 14512 "Collective Adaptive Systems: Qualitative and Quantitative Modelling and Analysis". Besides presentations on current work in the area, the seminar focused on the following topics: (i) Modelling techniques and languages for collective adaptive systems based on the above formalisms. (ii) Verification of collective adaptive systems. (iii) Humans-in-the-loop in collective adaptive systems

Predicted chance that global warming will temporarily exceed 1.5 °C

The Paris Agreement calls for efforts to limit anthropogenic global warming to less than 1.5 °C above preindustrial levels. However, natural internal variability may exacerbate anthropogenic warming to produce temporary excursions above 1.5 °C. Such excursions would not necessarily exceed the Paris Agreement, but would provide a warning that the threshold is being approached. Here we develop a new capability to predict the probability that global temperature will exceed 1.5 °C above preindustrial levels in the coming 5 years. For the period 2017 to 2021 we predict a 38% and 10% chance, respectively, of monthly or yearly temperatures exceeding 1.5 °C, with virtually no chance of the 5‐year mean being above the threshold. Our forecasts will be updated annually to provide policy makers with advanced warning of the evolving probability and duration of future warming events

Uptake and transport of B12-conjugated nanoparticles in airway epithelium

Non-invasive delivery of biotherapeutics, as an attractive alternative to injections, could potentially be achieved through the mucosal surfaces, utilizing nanoscale therapeutic carriers. However, nanoparticles do not readily cross the mucosal barriers,with the epitheliumpresenting a major barrier to their translocation. The transcytotic pathway of vitamin B12 has previously been shown to ‘ferry’ B12-decorated nanoparticles across intestinal epithelial (Caco-2) cells. However, such studies have not been reported for the airway epithelium. Furthermore, the presence in the airways of the cell machinery responsible for transepithelial trafficking of B12 is not widely reported. Using a combination of molecular biology and immunostaining techniques, our work demonstrates that the bronchial cell line, Calu-3, expresses the B12-intrinsic factor receptor, the transcobalamin II receptor and the transcobalamin II carrier protein. Importantly, the work showed that sub-200 nm model nanoparticles chemically conjugated to B12 were internalised and transported across the Calu-3 cell layers,with B12 conjugation not only enhancing cell uptake and transepithelial transport, but also influencing intracellular trafficking. Our work therefore demonstrates that the B12 endocytotic apparatus is not only present in this airway model, but also transports ligand-conjugated nanoparticles across polarised epithelial cells, indicating potential for B12-mediated delivery of nanoscale carriers of biotherapeutics across the airways

Opposite-polarity motors activate one another to trigger cargo transport in live cells

Mechanical interactions between any two opposite-polarity motors are necessary and sufficient for bidirectional organelle transport in live cells