In silico clinical trials through AI and statistical model checking

A Virtual Patient (VP) is a computational model accounting for individualised (patho-) physiology and Pharmaco-Kinetics/Dynamics of relevant drugs. Availability of VPs is among the enabling technology for In Silico Clinical Trials. Here we shortly outline the state of the art as for VP generation and summarise our recent work on Artificial Intelligence (AI) and Statistical Model Checking based generation of VPs

Going Conservative or Conventional? Investigating Farm Management Strategies in between Economic and Environmental Sustainability in Southern Italy

The European “Green Deal” strategy is aimed at making Europe the first climate-neutral continent by 2050 through integrated actions relying on healthier agricultural systems grounded in (environmental and economic) sustainable practices, including soil carbon management and biodiversity enhancement. In this vein, the present study contrasts the economic-environmental performances of conventional (deep tillage) and conservative (no-tillage and soil ripping) practices for two varieties of durum wheat (Triticum turgidum spp. durum), namely a modern (Anco Marzio) and an ancient landrace (Saragolla Lucana) variety in the Basilicata region (Southern Italy). Field and laboratory analysis (granulometry, mineralogy, and geochemistry) as well as satellite data (RapidEye) were used to characterize the soil and vegetation patterns. The empirical results indicate a higher biomass production and vegetative potential together with higher grain yields in soils managed with conventional deep tillage compared with soil managed with conservative practices. Similarly, the modern wheat variety exhibited better performance with respect to the old landrace. The soils managed with conventional practices had a distribution of exchangeable macro-nutrients characterized by a reduction in Ca+ and an increase in Mg2+ and K+ between pre-sowing and post-harvesting. Such a distribution was also genotype-dependent, with a higher variability for Saragolla Lucana than Anco Marzio, showing a diverging adsorption of macro-elements between the modern and ancient landrace varieties

Brain Changes in Kallmann Syndrome

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Identification of Isoform 2 Acid-Sensing Ion Channel Inhibitors as Tool Compounds for Target Validation Studies in CNS

Acid-sensing ion channels (ASICs) are a family of ion channels permeable to cations and largely responsible for the onset of acid-evoked ion currents both in neurons and in different types of cancer cells, thus representing a potential target for drug discovery. Owing to the limited attention ASIC2 has received so far, an exploratory program was initiated to identify ASIC2 inhibitors using diminazene, a known pan-ASIC inhibitor, as a chemical starting point for structural elaboration. The performed exploration enabled the identification of a novel series of ASIC2 inhibitors. In particular, compound 2u is a brain penetrant ASIC2 inhibitor endowed with an optimal pharmacokinetic profile. This compound may represent a useful tool to validate in animal models in vivo the role of ASIC2 in different neurodegenerative central nervous system pathologies

Temporal and Spatial Patterns of Ambient Endotoxin Concentrations in Fresno, California

BackgroundEndotoxins are found in indoor dust generated by human activity and pets, in soil, and adsorbed onto the surfaces of ambient combustion particles. Endotoxin concentrations have been associated with respiratory symptoms and the risk of atopy and asthma in children.ObjectiveWe characterized the temporal and spatial variability of ambient endotoxin in Fresno/Clovis, California, located in California's Central Valley, to identify correlates and potential predictors of ambient endotoxin concentrations in a cohort of children with asthma [Fresno Asthmatic Children's Environment Study (FACES)].MethodsBetween May 2001 and October 2004, daily ambient endotoxin and air pollutants were collected at the central ambient monitoring site of the California Air Resources Board in Fresno and, for shorter time periods, at 10 schools and indoors and outdoors at 84 residences in the community. Analyses were restricted to May-October, the dry months during which endotoxin concentrations are highest.ResultsDaily endotoxin concentration patterns were determined mainly by meteorologic factors, particularly the degree of air stagnation. Overall concentrations were lowest in areas distant from agricultural activities. Highest concentrations were found in areas immediately downwind from agricultural/pasture land. Among three other measured air pollutants [fine particulate matter, elemental carbon (a marker of traffic in Fresno), and coarse particulate matter (PMc)], PMc was the only pollutant correlated with endotoxin. Endotoxin, however, was the most spatially variable.ConclusionsOur data support the need to evaluate the spatial/temporal variability of endotoxin concentrations, rather than relying on a few measurements made at one location, in studies of exposure and and respiratory health effects, particularly in children with asthma and other chronic respiratory diseases

New understandings of the genetic basis of isolated idiopathic central hypogonadism

Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network