Macroscopic nucleation phenomena in continuum media with long-range interactions

Nucleation, commonly associated with discontinuous transformations between metastable and stable phases, is crucial in fields as diverse as atmospheric science and nanoscale electronics. Traditionally, it is considered a microscopic process (at most nano-meter), implying the formation of a microscopic nucleus of the stable phase. Here we show for the first time, that considering long-range interactions mediated by elastic distortions, nucleation can be a macroscopic process, with the size of the critical nucleus proportional to the total system size. This provides a new concept of "macroscopic barrier-crossing nucleation". We demonstrate the effect in molecular dynamics simulations of a model spin-crossover system with two molecular states of different sizes, causing elastic distortions.Comment: 12 pages, 4 figures. Supplementary information accompanies this paper at http://www.nature.com/scientificreport

HIV-1 Promotes Renal Tubular Epithelial Cell Protein Synthesis: Role of mTOR Pathway

Tubular cell HIV-infection has been reported to manifest in the form of cellular hypertrophy and apoptosis. In the present study, we evaluated the role of mammalian target of rapamycin (mTOR) pathway in the HIV induction of tubular cell protein synthesis. Mouse proximal tubular epithelial cells (MPTECs) were transduced with either gag/pol-deleted NL4-3 (HIV/MPTEC) or empty vector (Vector/MPTEC). HIV/MPTEC showed enhanced DNA synthesis when compared with Vector/MPTECs by BRDU labeling studies. HIV/MPTECs also showed enhanced production of β-laminin and fibronection in addition to increased protein content per cell. In in vivo studies, renal cortical sections from HIV transgenic mice and HIVAN patients showed enhanced tubular cell phosphorylation of mTOR. Analysis of mTOR revealed increased expression of phospho (p)-mTOR in HIV/MPTECs when compared to vector/MPTECs. Further downstream analysis of mTOR pathway revealed enhanced phosphorylation of p70S6 kinase and associated diminished phosphorylation of eEF2 (eukaryotic translation elongation factor 2) in HIV/MPTECs; moreover, HIV/MPTECs displayed enhanced phosphorylation of eIF4B (eukaryotic translation initiation factor 4B) and 4EBP-1 (eukaryotic 4E binding protein). To confirm our hypothesis, we evaluated the effect of rapamycin on HIV-induced tubular cell downstream signaling. Rapamycin not only attenuated phosphorylation of p70S6 kinase and associated down stream signaling in HIV/MPTECs but also inhibited HIV-1 induced tubular cell protein synthesis. These findings suggest that mTOR pathway is activated in HIV-induced enhanced tubular cell protein synthesis and contributes to tubular cell hypertrophy

Individualised variable-interval risk-based screening for sight-threatening diabetic retinopathy: the Liverpool Risk Calculation Engine

Aims/hypothesis Individualised variable-interval risk-based screening offers better targeting and improved cost-effectiveness in screening for diabetic retinopathy. We developed a generalisable risk calculation engine (RCE) to assign personalised intervals linked to local population characteristics, and explored differences in assignment compared with current practice. Methods Data from 5 years of photographic screening and primary care for people with diabetes, screen negative at the first of > 1 episode, were combined in a purpose-built near-real-time warehouse. Covariates were selected from a dataset created using mixed qualitative/quantitative methods. Markov modelling predicted progression to screen-positive (referable diabetic retinopathy) against the local cohort history. Retinopathy grade informed baseline risk and multiple imputation dealt with missing data. Acceptable intervals (6, 12, 24 months) and risk threshold (2.5%) were established with patients and professional end users. Results Data were from 11,806 people with diabetes (46,525 episodes, 388 screen-positive). Covariates with sufficient predictive value were: duration of known disease, HbA1c, age, systolic BP and total cholesterol. Corrected AUC (95% CIs) were: 6 months 0.88 (0.83, 0.93), 12 months 0.90 (0.87, 0.93) and 24 months 0.91 (0.87, 0.94). Sensitivities/specificities for a 2.5% risk were: 6 months 0.61, 0.93, 12 months 0.67, 0.90 and 24 months 0.82, 0.81. Implementing individualised RCE-based intervals would reduce the proportion of people becoming screen-positive before the allocated screening date by > 50% and the number of episodes by 30%. Conclusions/interpretation The Liverpool RCE shows sufficient performance for a local introduction into practice before wider implementation, subject to external validation. This approach offers potential enhancements of screening in improved local applicability, targeting and cost-effectiveness

The Renal Endothelium in Diabetic Nephropathy

Diabetic nephropathy is the leading cause of end-stage renal disease. Diabetes mellitus is characterized by generalized endothelial dysfunction. However, recent data also emphasizes the role of local renal endothelium dysfunction in the pathogenesis of diabetic nephropathy. Hyperglycemia triggers a complex network of signal-transduction molecules, transcription factors, and mediators that culminate in endothelial dysfunction. In the glomerulus, vascular endothelial growth factor-A (VEGF)-induced neoangiogenesis may contribute to the initial hyperfiltration and microalbuminuria due to increased filtration area and immaturity of the neovessels, respectively. However, subsequent decrease in podocytes number decreases VEGF production resulting in capillary rarefaction and decreased glomerular filtration rate (GFR). Decreased nitric oxide availability also plays a significant role in the development of advanced lesions of diabetic nephropathy through disruption of glomerular autoregulation, uncontrolled VEGF action, release of prothrombotic substances by endothelial cells and angiotensin-II-independent aldosterone production. In addition, disturbances in endothelial glycocalyx contribute to decreased permselectivity and microalbuminuria; whereas there are recent evidences that reduced glomerular fenestral endothelium leads to decreased GFR levels. Endothelial repair mechanisms are also impaired in diabetes, since circulating endothelial progenitor cells number is decreased in diabetic patients with microalbuminuria. Finally, in the context of elevated profibrotic cytokine transforming growth factor-beta levels, endothelial cells also confer to the deteriorating process of fibrosis in advanced diabetic nephropathy through endothelial to mesenchymal transition