Podocyte-Related Mechanisms Underlying Survival Benefit of Long-Term Angiotensin Receptor Blocker

We previously found that short-term treatment (week 8 to 12 after injury) with high-dose angiotensin receptor blocker (ARB) induced the regression of existing glomerulosclerosis in 5/6 nephrectomy rats. We therefore assessed the effects of long-term intervention with ARB vs. nonspecific antihypertensives in this study. Adult rats underwent 5/6 nephrectomy and renal biopsy 8 weeks later. The rats were then divided into three groups with equivalent renal function and glomerular sclerosis and treated with high-dose losartan (ARB), nonspecific antihypertensive triple-therapy (TRX), or left untreated (Control) until week 30. We found that blood pressure, serum creatinine levels, and glomerulosclerosis were lower at sacrifice in ARB and TRX vs. Control. Only ARB reduced proteinuria and maintained the density of WT-1-positive podocytes. Glomerular tufts showed more double-positive cells for CD44, a marker of activated parietal epithelial cells, and synaptopodin after ARB vs. TRX or Control. ARB treatment reduced aldosterone levels. ARB-treated rats had significantly improved survival when compared with TRX or Control. We conclude that both long-term ARB and triple-therapy ameliorate progression, but do not sustain the regression of glomerulosclerosis. ARB resulted in the superior preservation of podocyte integrity and decreased proteinuria and aldosterone, linked to increased survival in the uremic environment.     

Potential of the Stromal Matricellular Protein Periostin as a Biomarker to Improve Risk Assessment in Prostate Cancer

Prostate cancer (PCa) ranges from indolent to aggressive tumors that may rapidly progress and metastasize. The switch to aggressive PCa is fostered by reactive stroma infiltrating tumor foci. Therefore, reactive stroma-based biomarkers may potentially improve the early detection of aggressive PCa, ameliorating disease classification. Gene expression profiles of PCa reactive fibroblasts highlighted the up-regulation of genes related to stroma deposition, including periostin and sparc. Here, the potential of periostin as a stromal biomarker has been investigated on PCa prostatectomies by immunohistochemistry. Moreover, circulating levels of periostin and sparc have been assessed in a low-risk PCa patient cohort enrolled in active surveillance (AS) by ELISA. We found that periostin is mainly expressed in the peritumoral stroma of prostatectomies, and its stromal expression correlates with PCa grade and aggressive disease features, such as the cribriform growth. Moreover, stromal periostin staining is associated with a shorter biochemical recurrence-free survival of PCa patients. Interestingly, the integration of periostin and sparc circulating levels into a model based on standard clinico-pathological variables improves its performance in predicting disease reclassification of AS patients. In this study, we provide the first evidence that circulating molecular biomarkers of PCa stroma may refine risk assessment and predict the reclassification of AS patients.     

Adipose Tissue Dysfunction and Obesity-Related Male Hypogonadism

Obesity is a chronic illness associated with several metabolic derangements and comorbidities (i.e., insulin resistance, leptin resistance, diabetes, etc.) and often leads to impaired testicular function and male subfertility. Several mechanisms may indeed negatively affect the hypothalamic–pituitary–gonadal health, such as higher testosterone conversion to estradiol by aromatase activity in the adipose tissue, increased ROS production, and the release of several endocrine molecules affecting the hypothalamus–pituitary–testis axis by both direct and indirect mechanisms. In addition, androgen deficiency could further accelerate adipose tissue expansion and therefore exacerbate obesity, which in turn enhances hypogonadism, thus inducing a vicious cycle. Based on these considerations, we propose an overview on the relationship of adipose tissue dysfunction and male hypogonadism, highlighting the main biological pathways involved and the current therapeutic options to counteract this condition.     

NGF Modulates Cholesterol Metabolism and Stimulates ApoE Secretion in Glial Cells Conferring Neuroprotection against Oxidative Stress

Cholesterol plays a crucial role in the brain, where its metabolism is particularly regulated by astrocytic activity. Indeed, adult neurons suppress their own cholesterol biosynthesis and import this sterol through ApoE-rich particles secreted from astrocytes. Recent evidence suggests that nerve growth factor (NGF) may exert neurotrophic activity by influencing cell metabolism. Nevertheless, the effect of NGF on glial cholesterol homeostasis has still not been elucidated. Thus, the aim of this project is to assess whether NGF could influence cholesterol metabolism in glial cells. To reach this objective, the U373 astrocyte-derived cell line was used as an experimental model. Immunoblot and ELISA analysis showed that proteins and enzymes belonging to the cholesterol metabolism network were increased upon NGF treatment in glial cells. Furthermore, NGF significantly increased ApoE secretion and the amount of extracellular cholesterol in the culture medium. Co-culture and U373-conditioned medium experiments demonstrated that NGF treatment efficiently counteracted rotenone-mediated cytotoxicity in N1E-115 neuronal cells. Conversely, neuroprotection mediated by NGF treatment was suppressed when N1E-115 were co-cultured with ApoE-silenced U373 cells. Taken together, these data suggest that NGF controls cholesterol homeostasis in glial cells. More importantly, NGF exerts neuroprotection against oxidative stress, which is likely associated with the induction of glial ApoE secretion.     

Fibrosis of Peritoneal Membrane as Target of New Therapies in Peritoneal Dialysis

Peritoneal dialysis (PD) is an efficient renal replacement therapy for patients with end-stage renal disease. Even if it ensures an outcome equivalent to hemodialysis and a better quality of life, in the long-term, PD is associated with the development of peritoneal fibrosis and the consequents patient morbidity and PD technique failure. This unfavorable effect is mostly due to the bio-incompatibility of PD solution (mainly based on high glucose concentration). In the present review, we described the mechanisms and the signaling pathway that governs peritoneal fibrosis, epithelial to mesenchymal transition of mesothelial cells, and angiogenesis. Lastly, we summarize the present and future strategies for developing more biocompatible PD solutions.     

Modeling the leadership – project performance relation: radial basis function,Gaussian and Kriging methods as alternatives to linear regression

The purpose of this paper is to analyze alternative forecasting methods that produce results at least similar to or better than linear regression (MLR) that can be used in the modeling of social systems. While organizations may be considered as typically non-linear systems, the common feature of most models found in literature continues to be the use of linear regression techniques. From a case study, advanced statistical methods of Gaussian and Kriging are evaluated, as well as an artificial intelligence (AI) tool, the radial basis function (RBF). The results show the best performance of the suggested methods compared to MLR, especially RBF, because of its uniform prediction behavior throughout all ranges of evaluation. These techniques, although somewhat unconventional in social systems modeling, present a potential contribution in increasing the accuracy and precision of the predictions allowing a more accurate assessment of the impact of certain strategies on the project performance to be made before the allocation of material, human and financial resources.     

Compact DSOP and Partial DSOP Forms

Given a Boolean function f on n variables, a Disjoint Sum-of-Products (DSOP) of f is a set of products (ANDs) of subsets of literals whose sum (OR) equals f, such that no two products cover the same minterm of f. DSOP forms are a special instance of partial DSOPs, i.e. the general case where a subset of minterms must be covered exactly once and the other minterms (typically corresponding to don’t care conditions of f) can be covered any number of times. We discuss finding DSOPs and partial DSOPs with a minimal number of products, a problem theoretically connected with various properties of Boolean functions and practically relevant in the synthesis of digital circuits. Finding an absolute minimum is hard, in fact we prove that the problem of absolute minimization of partial DSOPs is NP-hard. Therefore it is crucial to devise a polynomial time heuristic that compares favorably with the known minimization tools. To this end we develop a further piece of theory starting from the definition of the weight of a cube c as a functions of the number of fragments induced on other cubes by the selection of c, and show how cube weights can be exploited for building a class of minimization heuristics for DSOP and partial DSOP synthesis. A set of experiments conducted on major benchmark functions show that our method, with a family of variants, always generates better results than the ones of previous heuristics, including the method based on a BDD representation of f.     

Mechanical squeezing of an elastomeric nanochannel device: numerical simulations and ionic current characterization

Peculiar transport phenomena appear at nanoscale, since surface effects strongly affect the behaviour of fluids. Electrostatic and steric interactions, capillary forces and entropic effects play a key role in the behaviour of fluids and biomolecules. Since these effects strongly depend on the size of the nanofluidic system, a careful characterization of the fluidic environment is necessary. Moreover, the possibility to dynamically modulate the size of nanochannels is very appealing in the field of biomolecule manipulation. Recently, we have developed a lab-on-chip made of poly(dimethylsiloxane) (PDMS). This polymeric device is based on a tuneable nanochannel able to dynamically change its dimension in order to fit the application of interest. In fact, a mechanical compression applied on the top of the elastomeric device squeezes the nanochannel, reducing the channel cross section and allowing a dynamical optimization of the nanostructures. In this paper, this squeezing process is fully characterized both numerically and experimentally. This analysis provides information on the reduction of the nanochannel dimensions induced by compression as a function of the work of adhesion and of the stiffness of the materials composing the device. Moreover, calculations demonstrate the possibility to predict the change of the nanochannel size and shape induced by the compression. The possibility to dynamically tune the channel size opens up new opportunities in biomolecular sensing or sieving and in the study of new hydrodynamics effects.     

Supercritical Flow over a Dentated Sill

Experimental analysis concerning supercritical flow over a dentated sill in nonsubmerged conditions and the local scour downstream of this sill is presented. In this case, the energy dissipation is incomplete so that a scour control downstream of the hydraulic structure could be required. The use of this type of dissipation device could be needed in cases where the maximum flow depth upstream of the sill must be limited to satisfy physical or structural conditions. This could happen, for instance, in the restoration of stilling basin in gravity dams and at the outlet of diversion systems. Experimental and theoretical results, useful in the design of this type of stilling basin and scour control, are presented in the paper, with an application to the case of the Molato Dam in Italy.     

Model-Supported Impact Assessment for the Water Sector in Central Germany Under Climate Change—A Case Study

Climate change challenges water managers and researchers to find sustainable management solutions, in order to avoid undesirable impacts on water resources, environment and water-dependent sectors. Needed are projections into the future for the main driving forces, the resulting pressures on water resources, and quantification of the impacts. Modeling studies can play an important role in investigating, quantifying, and communicating possible impacts of climate change, with account of uncertainty of the results. However, climate change related impacts and a need for adaptation still play a minor role in current river basin management plans that have to comply e.g. with the EU Water Framework Directive (WFD). One important reason is that climate impact assessment is generally done in research institutes, while management plans are designed by practitioners working in national and regional environmental agencies and water supply companies. Knowledge transfer from science to practice and visa versa is often missing. In the present study, we propose a methodology and a case study for model-supported decision making in the water sector applicable to a participatory water resources planning process. The methodology is applied in a case study investigating climate change impacts on water resources. The case study area is the German State of Saxony-Anhalt, where the task was to develop a climate change impact assessment including possible adaptation measures as basis for a federal adaptation directive.