From Environment to Genome and Back : a Lesson from HFE Mutations

The environment and the human genome are closely entangled and many genetic variations that occur in human populations are the result of adaptive selection to ancestral environmental (mainly dietary) conditions. However, the selected mutations may become maladaptive when environmental conditions change, thus becoming candidates for diseases. Hereditary hemochromatosis (HH) is a potentially lethal disease leading to iron accumulation mostly due to mutations in the HFE gene. Indeed, homozygosity for the C282Y HFE mutation is associated with the primary iron overload phenotype. However, both penetrance of the C282Y variant and the clinical manifestation of the disease are extremely variable, suggesting that other genetic, epigenetic and environmental factors play a role in the development of HH, as well as, and in its progression to end-stage liver diseases. Alcohol consumption and dietary habits may impact on the phenotypic expression of HFE-related hemochromatosis. Indeed, dietary components and bioactive molecules can affect iron status both directly by modulating its absorption during digestion and indirectly by the epigenetic modification of genes involved in its uptake, storage and recycling. Thus, the premise of this review is to discuss how environmental pressures led to the selection of HFE mutations and whether nutritional and lifestyle interventions may exert beneficial effects on HH outcomes and comorbidities

Performance of a large limited streamer tube cell in drift mode

The performance of a large (3x3 $cm^2$) streamer tube cell in drift mode is shown. The detector space resolution has been studied using cosmic muons crossing an high precision silicon telescope. The experimental results are compared with a GARFIELD simulation.Comment: 18 pages, 7 figures. Accepted by Nucl. Instr. and Methods

Nutrition and genetics in NAFLD : The perfect binomium

Nonalcoholic fatty liver disease (NAFLD) represents a global healthcare burden since it is epidemiologically related to obesity, type 2 diabetes (T2D) and Metabolic Syndrome (MetS). It embraces a wide spectrum of hepatic injuries, which include simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The susceptibility to develop NAFLD is highly variable and it is influenced by several cues including environmental (i.e., dietary habits and physical activity) and inherited (i.e., genetic/epigenetic) risk factors. Nonetheless, even intestinal microbiota and its by-products play a crucial role in NAFLD pathophysiology. The interaction of dietary exposure with the genome is referred to as \u2018nutritional genomics,\u2019 which encompasses both \u2018nutrigenetics\u2019 and \u2018nutriepigenomics.\u2019 It is focused on revealing the biological mechanisms that entail both the acute and persistent genome-nutrient interactions that influence health and it may represent a promising field of study to improve both clinical and health nutrition practices. Thus, the premise of this review is to discuss the relevance of personalized nutritional advices as a novel therapeutic approach in NAFLD tailored management

MOLECULAR MECHANISMS AND THERAPEUTIC APPROACHES IN MN DISEASES

Chapter 1 Spinal and Bulbar Muscular Atrophy (SBMA or Kennedy disease) is an inherited X-linked motor neuron disease characterized by loss of lower motor neurons located in the spinal cord and brain stem resulting in bulbar and limb muscle atrophy. SBMA is due to an expansion of a CAG triplet repeat sequence in the androgen receptor (AR) gene, which codes for an elongated polyglutamine (polyQ) tract of AR protein. Sequence longer than 38Q are present in SBMA patients. It is known that the elongated polyQ tract confers a neurotoxic gain-of-function to AR, probably causing aberrant conformations of the protein, leading to protein aggregation and cell toxicity. ARpolyQ toxicity is exerted only after the interaction with androgens which induce conformational changes and AR nuclear translocation. In fact, several evidences shows that misfolded ARpolyQ exerts most of its toxicity in the nucleus. Our previous in vitro works indicate that prevention of ARpolyQ nuclear translocation and enhancement of the autophagic process could be possible approaches to counteract ARpolyQ neurotoxicity. Here, we tested in vivo a combined treatment with: a) bicalutamide, an FDA-approved antiandrogen that reduces the rate of ARpolyQ nuclear translocation, and b) trehalose, a disaccharide able to enhance ARpolyQ degradation stimulating autophagy. We took advantage of a knock in mouse model of the Kennedy disease expressing an AR with 113Q, and showing many features of the pathology. Single treatment with bicalutamide or trehalose increased AR113Q mouse survival, and the combined treatment had a synergic activity leading to a further increase in survival. Oral trehalose treatment improved mouse motor behavior measured by rotarod, without affecting the hind limb muscle force. Furthermore, bicalutamide or the combined treatment improved both muscle force and motor coordination behavior. Molecular analyses of gastrocnemius muscle indicated an increased expression of PGC1alpha mRNA, a critical regulator of mitochondrial biogenesis. Our results indicate that the combined bicalutamide and trehalose treatment could be a novel approach to counteract ARpolyQ toxicity in vivo. Chapter 2 Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease caused by the dysfunction and loss of upper and lower motor neurons and of their target muscle cells. There is evidence showing age related gender differences in human patients and mouse models. ALS is more common in male than female, and gender influences the clinical features of the disease. Patients suffering from ALS show increased levels of transforming growth factor beta 1 (TGF\u3b21) in the serum and cerebrospinal \ufb02uid. Here, we tested whether altered TGF\u3b21 levels in ALS are associated with aberrant expression of TGF\u3b21 and its related signaling molecules, i.e. TGF\u3b2-Receptor type II (TGF\u3b2-RII) and Smads, in the spinal cord and skeletal muscle of a transgenic ALS mouse model, considering gender and disease progression. At pre-symptomatic (PS) stage TGF\u3b21 expression was reduced in the spinal cord of both male and female mice, while it was induced selectively in males in the skeletal muscle. At symptomatic (S) stage TGF\u3b21 was robustly induced both in the spinal cord and muscle of male and female mice. Similar findings were obtained in muscle biopsies derived from sporadic ALS patients. Tgf\u3b2-RII mRNA levels were induced only in the spinal cord without gender differences. Smad2 and Smad4 gene expression were decreased in spinal cord and muscle both in male and female mice, while Smad2 protein levels were increased selectively in male muscle. SMAD3 expression was increased only in muscle. Expression of genes controlled by TGF\u3b21 in muscle, such as Pax7, Collagen1\u3b21 and Fibronectin, was reduced both in male and female ALS mice at S stage independently of denervation. Our results suggest that, the expression of TGF\u3b21 is increased in ALS tissues, but its signaling pathway regulating the expression of downstream target genes is altered. These observations highlight TGF\u3b21 and its signaling as a novel therapeutic target for ALS. Furthermore, they strengthen the idea that skeletal muscle has a key role in ALS

High resolution pixel detectors for e+e- linear colliders

The physics goals at the future e+e- linear collider require high performance vertexing and impact parameter resolution. Two possible technologies for the vertex detector of an experimental apparatus are outlined in the paper: an evolution of the Hybrid Pixel Sensors already used in high energy physics experiments and a new detector concept based on the monolithic CMOS sensors.Comment: 8 pages, to appear on the Proceedings of the International Workshop on Linear Colliders LCWS99, Sitges (Spain), April 28 - May 5, 199

Endocytoscopic imaging and tattooing: a caveat

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Synthesis of 2-substituted-6-hydroxy and 6-methoxy benzothiazoles from 1,4-benzoquinone

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Application of a prioritisation scheme for seismic intervention in schools buildings in Italy

A risk management framework has recently been developed to assign priorities for the rehabilitation of school buildings in Italy, and to give timescales within which retrofit or demolition must take place. Since it is not practical to carry out a detailed assessment of the 60,000 Italian state and public schools, the framework is a multiple-level procedure which aims to identify the highest-risk buildings based on filters of increasing detail, and reduces the size of the building inventory at each step. The first risk ranking is based on a strength deficit, which measures the difference between the current design forces defined for the building site and an estimation of the level of seismic resistance which was required at the time of design. The second ranking is based on lateral strength calculations that are already available for a large portion of the Italian masonry building stock, and that are obtained from a survey form that is familiar to Italian engineers. Finally, a simplified displacement-based methodology is used to give a more accurate assessment of seismic risk based on a limited amount of geometrical and material data. The final assessment leads to a capacity ratio and a risk rating, which are used within a transparent procedure to assign priorities for seismic intervention, and timescales within which detailed assessment leading to retrofit or demolition must take place. The first step of the methodology has been applied herein to the school building stock within two Regions in Italy and preliminary results are presented

Infinite compressibility states in the Hierarchical Reference Theory of fluids. II. Numerical evidence

Continuing our investigation into the Hierarchical Reference Theory of fluids for thermodynamic states of infinite isothermal compressibility kappa[T] we now turn to the available numerical evidence to elucidate the character of the partial differential equation: Of the three scenarios identified previously, only the assumption of the equations turning stiff when building up the divergence of kappa[T] allows for a satisfactory interpretation of the data. In addition to the asymptotic regime where the arguments of part I (cond-mat/0308467) directly apply, a similar mechanism is identified that gives rise to transient stiffness at intermediate cutoff for low enough temperature. Heuristic arguments point to a connection between the form of the Fourier transform of the perturbational part of the interaction potential and the cutoff where finite difference approximations of the differential equation cease to be applicable, and they highlight the rather special standing of the hard-core Yukawa potential as regards the severity of the computational difficulties.Comment: J. Stat. Phys., in press. Minor changes to match published versio

Mir-101-3p downregulation promotes fibrogenesis by facilitating hepatic stellate cell transdifferentiation during insulin resistance

Insulin resistance (IR) and microRNAs (miRNAs), which regulate cell-to-cell communication between hepatocytes and hepatic stellate cells (HSCs), may intertwine in nonalcoholic fatty liver disease (NAFLD) pathogenesis. The aim of this study was to evaluate whether epigenetics and environmental factors interact to promote progressive NAFLD during IR. We examined the miRNA signature in insulin receptor haploinsufficient (InsR+/ 12) and wild-type (wt) HSCs by RNAseq (n = 4 per group). Then, we evaluated their impact in an IR-NASH (nonalcoholic steatohepatitis) model (InsR+/ 12 mice fed standard or methionine choline deficient (MCD) diet, n = 10 per group) and in vitro. InsR+/ 12 HSCs displayed 36 differentially expressed miRNAs (p < 0.05 vs. wt), whose expression was then analyzed in the liver of InsR+/ 12 mice fed an MCD diet. We found that miR-101-3p negatively associated with both InsR+/ 12 genotype and MCD (p < 0.05) and the histological spectrum of liver damage (p < 0.01). miR-101-3p was reduced in InsR+/ 12 hepatocytes and HSCs and even more in InsR+/ 12 cells exposed to insulin (0.33 \ub5M) and fatty acids (0.25 mM), resembling the IR-NASH model. Conversely, insulin induced miR-101-3p expression in wt cells but not in InsR+/ 12 ones (p < 0.05). In conclusion, IR combined with diet-induced liver injury favors miR-101-3p downregulation, which may promote progressive NAFLD through HSC and hepatocyte transdifferentiation and proliferation