Contribution of polymorphic variation of inositol hexakisphosphate kinase 3 (IP6K3) gene promoter to the susceptibility to late onset Alzheimer's disease

Maintenance of electric potential and synaptic transmission are energetically demanding tasks that neuronal metabolism must continually satisfy. Inability to fulfil these energy requirements leads to the development of neurodegenerative disorders, including Alzheimer's disease. A prominent feature of Alzheimer's disease is in fact neuronal glucose hypometabolism. Thus understanding the fine control of energetic metabolism might help to understand neurodegenerative disorders. Recent research has indicated that a novel class of signalling molecules, the inositol pyrophosphates, act as energy sensors. They are able to alter the balance between mitochondrial oxidative phosphorylation and glycolytic flux, ultimately affecting the cellular level of ATP. The neuronal inositol pyrophosphate synthesis relies on the activity of the neuron enriched inositol hexakisphosphate kinase 3 (IP6K3) enzyme. To verify an involvement of inositol pyrophosphate signalling in neurodegenerative disorders, we performed tagging single nucleotide polymorphism (SNP) analysis of the IP6K3 gene in patients with familial and sporadic late onset Alzheimer's disease (LOAD). Two SNPs in the 5'-flanking promoter region of the IP6K3 gene were found to be associated with sporadic LOAD. Characterizing the functionality of the two polymorphisms by luciferase assay revealed that one of them (rs28607030) affects IP6K3 promoter activity, with the G allele showing an increased activity. As the same allele has a beneficial effect on disease risk, this may be related to upregulation of IP6K3 expression, with a consequent increase in inositol pyrophosphate synthesis. In conclusion, we provide the first evidence for a contribution of genetic variability in the IP6K3 gene to LOAD pathogenesis

Multi-Objective Optimization of a Vehicle Body by Combining Gradient-based Methods and Vehicle Concept Modelling

Abstract In the automotive field, size optimization procedures can be combined with concept modelling approaches, in order to design a vehicle Body-In-White (BIW) model with optimal static and dynamic performances already in the early design stages. However, this specific optimization problem, with hundreds of design variables, limited design space and often conflicting objectives, makes the choice of the appropriate optimization method really difficult. The aim of this paper is to show an industrial case study, where two different implementations of the classical gradient-based (GB) method are used in combination with a technique for vehicle body concept modelling to achieve a multi-objective BIW optimization of a passenger car

Fatigue assessment of Ti-6Al-4V titanium alloy laser welded joints in absence of filler material by means of full-field techniques

The aim of this research activity was to study the fatigue behavior of laser welded joints of titanium alloy, in which the welding was performed using a laser source and in the absence of filler material, by means of unconventional full field techniques: Digital Image Correlation (DIC), and Infrared Thermography (IRT). The DIC technique allowed evaluating the strain gradients around the welded zone. The IRT technique allowed analyzing the thermal evolution of the welded surface during all the fatigue tests. The fatigue limit estimated using the Thermographic Method corresponds with good approximation to the value obtained from the experimental fatigue tests. The obtained results provided useful information for the development of methods and models to predict the fatigue behavior of welded T-joints in titanium alloy

Numerical modeling of fluid flow, heat, and mass transfer for similar and dissimilar laser welding of Ti-6Al-4V and Inconel 718

AbstractMost of the researches published on the numerical modeling of laser welding are looking at similar welding, mainly due to the difficulty of simulating the mixing phenomenon that occurs in dissimilar welding. Furthermore, numerical modeling of dissimilar laser welding of titanium and nickel alloys has been rarely reported in the literature. In this study, a 3D finite volume numerical model is proposed to simulate fluid flow, heat, and mass transfer for similar and dissimilar laser welding of Ti-6Al-4V and Inconel 718. The laser source was simulated by volumetric heat distribution, which considers the effects of keyhole and heat transfer on the workpiece. The heat source parameters were calibrated through preliminary experiments, by comparing the simulated and experimental weld pool shapes and dimensions. The model was used to simulate both homogenous and dissimilar laser weldings of Ti-6Al-4V and Inconel 718, and a systematic comparison was carried out through a number of selected experiments. The effects of three distinct levels of laser power (1.25 kW, 1.5 kW, 2.5 kW) on temperature distribution and velocity field in the welds pool were analyzed. Results highlighted the effects of Marangoni forces in the weld pool formation. Furthermore, in order to analyze the mass transfer phenomenon in dissimilar welding, species transfer equations were considered, demonstrating the important role played by the mass mixture in the weld pool formation. Finally, a high level of agreement between simulations and experiments—in terms of weld pool shape and dimensions—was observed in all cases analyzed. This proves the ability of the proposed numerical model to properly simulate both the similar and dissimilar welding of Ti-6Al-4V and Inconel 718 alloys

IP6K3 and IPMK variations in LOAD and longevity: evidence for a multifaceted signaling network at the crossroad between neurodegeneration and survival

Several studies reported that genetic variants predisposing to neurodegeneration were at higher frequencies in centenarians than in younger controls, suggesting they might favor also longevity. IP6K3 and IPMK regulate many crucial biological functions by mediating synthesis of inositol poly- and pyrophosphates and by acting non-enzymatically via protein–protein interactions. Our previous studies suggested they affect Late Onset Alzheimer Disease (LOAD) and longevity, respectively. Here, in the same sample groups, we investigated whether variants of IP6K3 also affect longevity, and variants of IPMK also influence LOAD susceptibility. We found that: i) a SNP of IP6K3 previously associated with increased risk of LOAD increased the chance to become long-lived, ii) SNPs of IPMK, previously associated with decreased longevity, were protective factors for LOAD, as previously observed for UCP4. SNP-SNP interaction analysis, including our previous data, highlighted phenotype-specific interactions between sets of alleles. Moreover, linkage disequilibrium and eQTL data associated to analyzed variants suggested mitochondria as crossroad of interconnected pathways crucial for susceptibility to neurodegeneration and/or longevity. Overall, data support the view that in these traits interactions may be more important than single polymorphisms. This phenomenon may contribute to the non-additive heritability of neurodegeneration and longevity and be part of the missing heritability of these traits

Absence of Phase Stiffness in the Quantum Rotor Phase Glass

We analyze here the consequence of local rotational-symmetry breaking in the quantum spin (or phase) glass state of the quantum random rotor model. By coupling the spin glass order parameter directly to a vector potential, we are able to compute whether the system is resilient (that is, possesses a phase stiffness) to a uniform rotation in the presence of random anisotropy. We show explicitly that the O(2) vector spin glass has no electromagnetic response indicative of a superconductor at mean-field and beyond, suggesting the absence of phase stiffness. This result confirms our earlier finding (PRL, {\bf 89}, 27001 (2002)) that the phase glass is metallic, due to the main contribution to the conductivity arising from fluctuations of the superconducting order parameter. In addition, our finding that the spin stiffness vanishes in the quantum rotor glass is consistent with the absence of a transverse stiffness in the Heisenberg spin glass found by Feigelman and Tsvelik (Sov. Phys. JETP, {\bf 50}, 1222 (1979).Comment: 8 pages, revised version with added references on the vanishing of the stiffness constant in the Heisenberg spin glas

Reentrant Spin-Peierls Transition in Mg-Doped CuGeO_3

We report a synchrotron x-ray scattering study of the diluted spin-Peierls (SP) material Cu_{1-x}Mg_xGeO_3. In a recent paper we have shown that the SP dimerization attains long-range order only for x < x_c = 0.022(0.001). Here we report that the SP transition is reentrant in the vicinity of the critical concentration x_c. This is manifested by broadening of the SP dimerization superlattice peaks below the reentrance temperature, T_r, which may mean either the complete loss of the long-range SP order or the development of a short-range ordered component within the long-range ordered SP state. Marked hysteresis and very large relaxation times are found in the samples with Mg concentrations in the vicinity of x_c. The reentrant transition is likely related to the competing Neel transition which occurs at a temperature similar to T_r. We argue that impurity-induced competing interchain interactions play an essential role in these phenomena.Comment: 5 pages, 4 embedded eps figure

Predictor Analysis in Radiofrequency Ablation of Benign Thyroid Nodules: A Single Center Experience

PURPOSE: To confirm the efficacy of ultrasound (US) guided radiofrequency ablation (RFA) in the treatment of benign thyroid nodules, we evaluated as primary outcome the technical efficacy and clinical success in a single center dataset. The secondary outcome was to find a correlation between nodules’ pre-treatment features and volume reduction rate (VRR) ≥75% at 12 months after RFA and during follow-up period. METHODS: This retrospective study included 119 consecutive patients (99 females, 20 males, 51.5 ± 14.4 years) with benign thyroid nodules treated in our hospital between October 2014 and December 2018 with a mean follow-up of 26.8 months (range 3–48). Clinical and US features before and after RFA were evaluated by a US examination at 1, 3, 6, 12 months and annually thereafter up to 48 months. RESULTS: The median pre-treatment volume was 22.4 ml; after RFA we observed a statistically significant volume reduction from the first month (11.7 ml) to the last follow-up (p 22.4 ml (HR 0.54, p 0.036) were found to be independent positive and negative predictors of VRR ≥75% respectively. One-month post RFA VRR ≥50% represented the best positive predictor of technical success. CONCLUSIONS: This study confirmed the efficacy of RFA in the treatment of benign thyroid nodules. In particular we show that by selecting macrocystic nodules smaller than 22.4 ml better long-term response can be achieved, which is predicted by an early shrinkage of the nodule

Nonlinear magnetic susceptibility and aging phenomena in reentrant ferromagnet: Cu0.2_{0.2}Co0.8_{0.8}Cl2_{2}-FeCl3_{3} graphite bi-intercalation compound

Linear and nonlinear dynamic properties of a reentrant ferromagnet Cu$_{0.2}$Co$_{0.8}$Cl$_{2}$-FeCl$_{3}$ graphite bi-intercalation compound are studied using AC and DC magnetic susceptibility. This compound undergoes successive phase transitions at the transition temperatures $T_{h}$ (= 16 K), $T_{c}$ (= 9.7 K), and $T_{RSG}$ (= 3.5 K). The static and dynamic behaviors of the reentrant spin glass phase below $T_{RSG}$ are characterized by those of normal spin glass phase with critical exponent $\beta$ = 0.57 $\pm$ 0.10, a dynamic critical exponent $x$ = 8.5 $\pm$ 1.8, and an exponent $p$ (= 1.55 $\pm$ 0.13) for the de Almeida -Thouless line. A prominent nonlinear susceptibility is observed between $T_{RSG}$ and $T_{c}$ and around $T_{h}$, suggesting a chaotic nature of the ferromagnetic phase ($T_{RSG} \leq T \leq T_{c}$) and the helical spin ordered phase ($T_{c} \leq T \leq T_{h}$). The aging phenomena are observed both in the RSG and FM phases, with the same qualitative features as in normal spin glasses. The aging of zero-field cooled magnetization indicates a drastic change of relaxation mechanism below and above $T_{RSG}$. The time dependence of the absorption $\chi^{\prime \prime}$ is described by a power law form ($\approx t^{-b^{\prime \prime}}$) in the ferromagnetic phase, where $b^{\prime \prime} \approx 0.074 \pm 0.016$ at $f$ = 0.05 Hz and $T$ = 7 K. No $\omega t$-scaling law for $\chi^{\prime \prime}$ [$\approx (\omega t)^{-b^{\prime \prime}}$] is observed.Comment: 14 pages, 16 figures, and 2 table