TGFBR1 Intralocus Epistatic Interaction as a Risk Factor for Colorectal Cancer

In colorectal cancer (CRC), an inherited susceptibility risk affects about 35% of patients, whereas high-penetrance germline mutations account for <6% of cases. A considerable proportion of sporadic tumors could be explained by the coinheritance of multiple low-penetrance variants, some of which are common. We assessed the susceptibility to CRC conferred by genetic variants at the TGFBR1 locus. We analyzed 14 polymorphisms and the allele-specific expression (ASE) of TGFBR1 in 1025 individuals from the Spanish population. A case-control study was undertaken with 504 controls and 521 patients with sporadic CRC. Fourteen polymorphisms located at the TGFBR1 locus were genotyped with the iPLEX Gold (MassARRAY-Sequenom) technology. Descriptive analyses of the polymorphisms and haplotypes and association studies were performed with the SNPator workpackage. No relevant associations were detected between individual polymorphisms or haplotypes and the risk of CRC. The TGFBR1*9A/6A polymorphism was used for the ASE analysis. Heterozygous individuals were analyzed for ASE by fragment analysis using cDNA from normal tissue. The relative level of allelic expression was extrapolated from a standard curve. The cutoff value was calculated with Youden's index. ASE was found in 25.4% of patients and 16.4% of controls. Considering both bimodal and continuous types of distribution, no significant differences between the ASE values of patients and controls were identified. Interestingly, a combined analysis of the polymorphisms and ASE for the association with CRC occurrence revealed that ASE-positive individuals carrying one of the most common haplotypes (H2: 20.7%) showed remarkable susceptibility to CRC (RR: 5.25; 95% CI: 2.547–5.250; p<0.001) with a synergy factor of 3.7. In our study, 54.1% of sporadic CRC cases were attributable to the coinheritance of the H2 haplotype and TGFBR1 ASE. These results support the hypothesis that the allelic architecture of cancer genes, rather than individual polymorphisms, more accurately defines the CRC risk

Nuove residenze nella città compatta. Progetti per il quartiere San Salvario a Torino

La presente ricerca nasce da una duplice esigenza. La prima, che esprime una necessità contingente, è quella legata ad un caso studio specifico, la riqualificazione e trasformazione del quartiere di San Salvario a Torino. Un settore di ampliamento urbano costituito da una maglia ortogonale di isolati edificati tra la fine dell’Ottocento e la prima metà del Novecento, che presentano una struttura a tratti discontinua a causa di parcelle mai edificate o distrutte durante la seconda guerra mondiale e che per incuria o indecisioni urbanistiche sono rimaste irrisolte. La seconda, che esprime un'idea permanente, è il concetto di continuità della città della storia e costituisce l’occasione per una riflessione sul tema dell'isolato urbano e del quartiere attraverso il progetto contemporaneo. La ricerca ha come obiettivo generale quello di confermare il ruolo della città compatta come principio insediativo di grande valore culturale e sociale e di dimostrarne la validità anche in termini di sostenibilità ambientale attraverso progetti nuovi che si inseriscono nel tessuto costruito a completamento e trasformazione della struttura esistente

Nuove residenze nella città compatta. Progetti per il quartiere San Salvario a Torino

La presente ricerca nasce da una duplice esigenza. La prima, che esprime una necessità contingente, è quella legata ad un caso studio specifico, la riqualificazione e trasformazione del quartiere di San Salvario a Torino. Un settore di ampliamento urbano costituito da una maglia ortogonale di isolati edificati tra la fine dell’Ottocento e la prima metà del Novecento, che presentano una struttura a tratti discontinua a causa di parcelle mai edificate o distrutte durante la seconda guerra mondiale e che per incuria o indecisioni urbanistiche sono rimaste irrisolte. La seconda, che esprime un'idea permanente, è il concetto di continuità della città della storia e costituisce l’occasione per una riflessione sul tema dell'isolato urbano e del quartiere attraverso il progetto contemporaneo. La ricerca ha come obiettivo generale quello di confermare il ruolo della città compatta come principio insediativo di grande valore culturale e sociale e di dimostrarne la validità anche in termini di sostenibilità ambientale attraverso progetti nuovi che si inseriscono nel tessuto costruito a completamento e trasformazione della struttura esistente

Tungsten oxide films by radio-frequency magnetron sputtering for near- infrared photonics

Tungsten oxide WO3-x is a transition metal oxide and a wide bandgap semiconductor, with a wide range of possible optical and photonic applications. In dependence on the fabrication techniques different stoichiometric ratios (x) and crystalline phases are obtained, which end up with an overall polymorph and extremely versatile material, characterized by tailorable dielectric properties. In particular, WO3-x thin film deposition by Radio- Frequency (RF) sputtering techniques provides a precise control of thickness, composition and nanostructure. In this work we introduce and discuss a specific process of deposition, that is magnetron RF-sputtering as a suitable way to grow WO3-x thin films with selected properties. Possibility of integrating WO3-x thin film on to one-dimensional (1D) photonic crystal structures is also explored. Films are transparent in the near and shortwavelength infrared optical spectral range. Their quality is assessed by morphological, structural and compositional characterizations. Dielectric properties are characterized by optical spectroscopy and ellipsometry, the latter also evaluates the degree of optical anisotropy of thin films in their crystalline phase. An 1D photonics bandgap structure is designed, formed by a SiO2–TiO2 multilayer and capped with a 450 nm-thick transparent WO3-x film, so that surface confinement and local enhancement of the optical field at 1416 nm in the topmost WO3-x layer is obtained

Elevated Expression of ADAM10 in Skeletal Muscle of Patients with Idiopathic Inflammatory Myopathies Could Be Responsible for FNDC5/Irisin Unbalance

Dermatomyositis (DM) and immune-mediated necrotizing myopathy (IMNM) are two rare diseases belonging to the group of idiopathic inflammatory myopathies (IIM). Muscle involvement in DM is characterized by perifascicular atrophy and poor myofiber necrosis, while IMNM is characterized by myofiber necrosis with scarce inflammatory infiltrates. Muscle biopsies and laboratory tests are helpful in diagnosis, but currently, few biomarkers of disease activity and progression are available. In this context, we conducted a cohort study of forty-one DM and IMNM patients, aged 40&ndash;70 years. In comparison with control subjects, in the muscle biopsies of these patients, there was a lower expression of FNDC5, the precursor of irisin, a myokine playing a key role in musculoskeletal metabolism. Expectedly, the muscle cross-sectional areas of these patients were reduced, while, surprisingly, serum irisin levels were higher than in CTRL, as were mRNA levels of ADAM10, a metalloproteinase recently shown to be the cleavage agent for FNDC5. We hypothesize that elevated expression of ADAM10 in the skeletal muscle of DM and IMNM patients might be responsible for the discrepancy between irisin levels and FNDC5 expression. Future studies will be needed to understand the mechanisms underlying exacerbated FNDC5 cleavage and muscle irisin resistance in these inflammatory myopathies

Time-dependent unloading effects on muscle and bone and involvement of FNDC5/irisin axis

Abstract The identification of biomarkers and countermeasures to prevent the adverse effects on the musculoskeletal system caused by the absence of mechanical loading is the main goal of space biomedical research studies. In this study, we analyzed over 4 weeks of unloading, the modulation in the expression of key proteins in Vastus lateralis, Gastrocnemius and cortical bone in parallel with the modulation of irisin serum levels and its precursor FNDC5 in skeletal muscle of hind limb unloaded (HU) mice. Here we report that Atrogin-1 was up-regulated as early as 1- and 2-week of unloading, whereas Murf-1 at 2- and 3-weeks, along with a marked modulation in the expression of myosin heavy chain isoforms during unloading. Since HU mice showed reduced irisin serum levels at 4-weeks, as well as FNDC5 decrease at 3- and 4-weeks, we treated HU mice with recombinant irisin for 4 weeks, showing that unloading-dependent decline of myosin heavy chain isoforms, MyHCIIα and MyHCIIx, and the anti-apoptotic factor Bcl2, were prevented. In parallel, irisin treatment inhibited the increase of the senescence marker p53, and the pro-apoptotic factor Bax. Overall, these results suggest that the myokine irisin could be a possible therapy to counteract the musculoskeletal impairment caused by unloading

Irisin Protects against Loss of Trabecular Bone Mass and Strength in Adult Ovariectomized Mice by Stimulating Osteoblast Activity

Irisin is a peptide secreted by skeletal muscle that plays a major role in bone metabolism. Experiments in mouse models have shown that administration of recombinant irisin prevents disuse-induced bone loss. In this study, we aimed to evaluate the effects of irisin treatment for the prevention of bone loss in the ovariectomized (Ovx) mouse, the animal model commonly used to investigate osteoporosis caused by estrogen deficiency. Micro-Ct analysis conducted on Sham mice (Sham-veh) and Ovx mice treated with vehicle (Ovx-veh) or recombinant irisin (Ovx-irisn) showed bone volume fraction (BV/TV) decreases in femurs (Ovx-veh 1.39± 0.71 vs. Sham-veh 2.84 ± 1.23; p = 0.02) and tibia at both proximal condyles (Ovx-veh 1.97 ± 0.68 vs. Sham-veh 3.48 ± 1.26; p = 0.03) and the subchondral plate (Ovx-veh 6.33 ± 0.36 vs. Sham-veh 8.18 ± 0.41; p = 0.01), which were prevented by treatment with a weekly dose of irisin for 4 weeks. Moreover, histological analysis of trabecular bone showed that irisin increased the number of active osteoblasts per bone perimeter (Ovx-irisin 32.3 ± 3.9 vs. Ovx-veh 23.5 ± 3.6; p = 0.01), while decreasing osteoclasts (Ovx-irisin 7.6 ± 2.4 vs. Ovx-veh 12.9 ± 3.04; p = 0.05). The possible mechanism by which irisin enhances osteoblast activity in Ovx mice is upregulation of the transcription factor Atf4, one of the key markers of osteoblast differentiation, and osteoprotegerin, thereby inhibiting osteoclast formation

Once-Daily Subcutaneous Irisin Administration Mitigates Depression- and Anxiety-like Behavior in Young Mice

Major depression is one of the most common psychiatric disorders worldwide, usually associated with anxiety. The multi-etiological nature of depression has increased the search for new antidepressant molecules, including irisin, for which, in a previous study, we tested its effect in young mice when administered intraperitoneally in a long-term intermittent manner. Here, we evaluated the effect of subcutaneous short-term irisin administration (100 µg/Kg/day/5 days) in male and female mice subjected to behavioral paradigms: Tail Suspension Test (TST), Forced Swim Test (FST), Elevated Plus Maze (EPM), and Y Maze (YM). Moreover, a qRT-PCR assay was performed to analyze the impact of irisin treatment on Pgc-1α/FNDC5 expression in the brain. A significant reduction in immobility time in TST and FST was observed in irisin-treated mice. Furthermore, irisin treatment significantly increased the number of entries and time spent in open arms, demonstrating its anxiolytic effect. Memory-enhancing effects were not reported in YM. Interestingly, no gender differences were observed in all behavioral tests. Overall, these results suggest that short-term subcutaneous irisin administration can exert an antidepressant and anxiolytic role, probably due to the activation of the Pgc-1α/FNDC5 system in the brain. Further investigation could lead to the identification of irisin as a new agent for the treatment of psychiatric disorders