STRUCTURAL INSIGHTS INTO INHIBITOR OF APOPTOSIS PROTEINS RECOGNITION BY PRO-APOPTOTIC COMPOUNDS

Inhibitor of Apoptosis Proteins (IAPs) are negative regulators of apoptosis and their overexpression is observed in many cancer cells, correlating with the inhibition of caspases. IAPs inhibitory function is exploited by the BIR domains, which were firstly identified in baculovirus. Among the IAP family, XIAP (X chromosome-linked IAP) directly inhibits caspases preventing proteolytic cleavage through its BIR2 and BIR3 domains; furthermore, XIAP-BIR1 in a dimeric form recognizes TAB1, a kinase activator, regulating pro-survival pathways. In the last years, cIAPs have become crucial players of the extrinsic pathway; in fact, through the recognition of TRAFs (TNF Receptor Associated Factors) by the cIAP2-BIR1 domain, they are recruited to the TNF-\uf061 Receptor Signaling Complex and act as E3 ubiquitin ligases. One of the most promising approaches that have been proposed to inhibit these proteins is represented by the structure-based design of small molecules, named Smac-mimetics, that mimic Smac/DIABLO (Second mitochondria-derived activator of caspases/Direct IAp Binding protein with Low pI), an endogenous antagonist of IAPs. Initially designed in 2001 against the BIR3 domain of XIAP, Smac-mimetics have shown to prevent the inhibitory action of XIAP on initiator and executioner caspases, but also to bind to the BIR3 of cIAPs, inducing their autoubiquitylation and degradation. This work focuses on the cloning, expression and purification of the IAPs constructs of interest and their biochemical and biophysical characterization alone and in the presence of some of the Smac-mimetics from our library. The X-ray technique on crystals and protein solutions allowed a structural study of the protein-ligand complexes at atomic level, favoring the process of drug lead optimization. Furthermore, the screening of libraries of pharmacologically active compounds through in silico docking searches on new targets, such as XIAP- and cIAP2-BIR1, resulted in the discovery of potential new pro-apoptotic leads, whose clinical properties are known. Since in the last months new macromolecular protein complexes have been identified as involved in apoptosis and pro-survival pathways, novel protocols for the expression and purification of cIAP1 and TRAFs full length constructs have been optimized to obtain pure and homogeneous samples ready for the structural characterization

Omental well-differentiated liposarcoma: US, CT and MR findings

Liposarcomas are the most common of sarcoma tumours, they are usually located in the lower limbs, retroperitoneum, or abdominal cavity; up to date, only a few cases of omental liposarcoma with different histotype have been described. We present a case of omental well-differentiated liposarcoma and discuss imaging findings on ultrasound, computed tomography, and magnetic resonance to differentiate omental liposarcomas from other abdominal tumour entities

Dissipative effects on the sustainment of a magnetorotational dynamo in Keplerian shear flow

The magnetorotational (MRI) dynamo has long been considered one of the possible drivers of turbulent angular momentum transport in astrophysical accretion disks. However, various numerical results suggest that this dynamo may be difficult to excite in the astrophysically relevant regime of magnetic Prandtl number (Pm) significantly smaller than unity, for reasons currently not well understood. The aim of this article is to present the first results of an ongoing numerical investigation of the role of both linear and nonlinear dissipative effects in this problem. Combining a parametric exploration and an energy analysis of incompressible nonlinear MRI dynamo cycles representative of the transitional dynamics in large aspect ratio shearing boxes, we find that turbulent magnetic diffusion makes the excitation and sustainment of this dynamo at moderate magnetic Reynolds number (Rm) increasingly difficult for decreasing Pm. This results in an increase in the critical Rm of the dynamo for increasing kinematic Reynolds number (Re), in agreement with earlier numerical results. Given its very generic nature, we argue that turbulent magnetic diffusion could be an important determinant of MRI dynamo excitation in disks, and may also limit the efficiency of angular momentum transport by MRI turbulence in low Pm regimes.Comment: 7 pages, 6 figure

On a self-sustained process at large scale in the turbulent channel flow

Large-scale motions, important in turbulent shear flows, are frequently attributed to the interaction of structures at smaller scale. Here we show that, in a turbulent channel at Re_{\tau} \approx 550, large-scale motions can self-sustain even when smaller-scale structures populating the near-wall and logarithmic regions are artificially quenched. This large-scale self-sustained mechanism is not active in periodic boxes of width smaller than Lz ~ 1.5h or length shorter than Lx ~ 3h which correspond well to the most energetic large scales observed in the turbulent channel

Magnetorotational dynamo chimeras. The missing link to turbulent accretion disk dynamo models?

In Keplerian accretion disks, turbulence and magnetic fields may be jointly excited through a subcritical dynamo process involving the magnetorotational instability (MRI). High-resolution simulations exhibit a tendency towards statistical self-organization of MRI dynamo turbulence into large-scale cyclic dynamics. Understanding the physical origin of these structures, and whether they can be sustained and transport angular momentum efficiently in astrophysical conditions, represents a significant theoretical challenge. The discovery of simple periodic nonlinear MRI dynamo solutions has recently proven useful in this respect, and has notably served to highlight the role of turbulent magnetic diffusion in the seeming decay of the dynamics at low magnetic Prandtl number Pm (magnetic diffusivity larger than viscosity), a common regime in accretion disks. The connection between these simple structures and the statistical organization reported in turbulent simulations remained elusive, though. Here, we report the numerical discovery in moderate aspect ratio Keplerian shearing boxes of new periodic, incompressible, three-dimensional nonlinear MRI dynamo solutions with a larger dynamical complexity reminiscent of such simulations. These "chimera" cycles are characterized by multiple MRI-unstable dynamical stages, but their basic physical principles of self-sustainment are nevertheless identical to those of simpler cycles found in azimuthally elongated boxes. In particular, we find that they are not sustained at low Pm either due to subcritical turbulent magnetic diffusion. These solutions offer a new perspective into the transition from laminar to turbulent instability-driven dynamos, and may prove useful to devise improved statistical models of turbulent accretion disk dynamos.Comment: 12 pages, 8 figures, submitted to A&

The multidimensional prognostic index (MPI) predicts long-term mortality in old type 2 diabetes mellitus patients: a 13-year follow-up study

Purpose: The Multidimensional Prognostic Index (MPI) is a tool capable of holistically frame older patients in different settings and affected by different pathologies, establishing a risk of adverse events. Among them, type 2 diabetes mellitus (T2DM), a common metabolic disease in the elderly, is responsible for complications and deaths. Few previous works have focused specifically on MPI and DM, and none have followed up the patients for more than 3 years. The aim of the present study is to analyze MPI accuracy in predicting mortality in a cohort of T2DM patients followed-up for 13 years. Methods: The enrolled subjects were evaluated with MPI, identifying three levels of risk: MPI1 (low risk, 0.0-0.33), MPI2 (moderate risk, 0.34-0.66), and MPI3 (severe risk, 0.67-1.0), and with glycated hemoglobin, and years since T2DM diagnosis. Results: One hundred and seven patients met the inclusion criteria. MPI3 was excluded by further analysis since it was made up of only three patients. Overall, cognitive performances, autonomies in daily living, nutritional status, risk of pressure injuries, comorbidities, and taken drugs were better (p ≤ 0.0077) in MPI1 than MPI2; moreover, the story of T2DM was shorter (p = 0.0026). Cox model showed an overall 13-year survival of 51.9%, and survival rates were significantly smaller in MPI2 (HR: 4.71, p = 0.0007). Finally, increased age (HR: 1.15), poorer cognitive abilities (HR: 1.26), vascular (HR: 2.15), and kidney (HR: 2.17) diseases were independently associated with death. Conclusion: Our results prove that MPI predicts short-, mid-, and even long-term mortality in T2DM patients, whose death seems to be related to age and cognitive status, and even more to vascular and kidney diseases

Diverse Linguistic Development in Prelingually Deaf Children with Cochlear Implants

The advent of cochlear implants has enormously improved the quality of sensory perception in deaf children. Notwithstanding these advantages, the current literature shows a substantial variability in language proficiency among implanted children. This case series explores the variability of language acquisition in congenitally deaf children with cochlear implants. We report 4 prelingually deaf children (mean age=10.5; SD=1.08), affected by a genetically determined bilateral deafness, due to GJB2 gene mutation Cx26. Each implanted child underwent a systematic assessment of speech perception and production, as well as of lexical, morphologic, and syntactic skills in both comprehension and production. Notwithstanding similar clinical histories and similarly good postimplant pure-tone audiometry, two of the four children fared very poorly in speech audiometry, whereas the other two children gained very good results. We suggest that the language impairment detected in (some) implanted children may not be fully accounted for by pure auditory thresholds and that may be the outcome of concomitant damage to core components of the child's linguistic brain

A study of the influence of the gauge group on the Dyson-Schwinger equations for scalar-Yang-Mills systems

The particular choice of the gauge group for Yang-Mills theory plays an important role when it comes to the influence of matter fields. In particular, both the chosen gauge group and the representation of the matter fields yield structural differences in the quenched case. Especially, the qualitative behavior of the Wilson potential is strongly dependent on this selection. Though the algebraic reasons for this observation is clear, it is far from obvious how this behavior can be described besides using numerical simulations. Herein, it is investigated how the group structure appears in the Dyson-Schwinger equations, which as a hierarchy of equations for the correlation functions have to be satisfied. It is found that there are differences depending on both the gauge group and the representation of the matter fields. This provides insight into possible truncation schemes for practical calculations using these equations.Comment: 47 page

UHPLC-MS/MS Method for the Analysis of 2,6 Toluene Diisocyanate and 2,4 Toluene Diisocyanate Released from Microa-gglomerated Corks in Wine

Micro-agglomerate corks, made by agglutination of cork granulate through the addition of different adhesives, represent an important slice of the market of cork stoppers. Binder glues which are polyurethane- or butadiene-based have been used since they have strong agglomerating effect. Unfortunately, polyurethane-based glues can have isocyanide end group compounds which can migrate into the wine. 2,4-toluene diisocyanate (2,4-TDI) and 2,6 toluene diisocyanate (2,6-TDI), can be found in adhesive and could migrate into wine. A simple ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) method for the determination of these active ingredients (a.is.) in wine has been developed. The method has been validated under Eurachem CITAC guidelines (Cooperation on International Traceability in Analytical Chemistry). Instrument limit of detection (LOD) and to a limit of quantification (LOQ) for 2,6 TDI and 2,4 TDI were 0.42 and 0.39 μg/L, and 1.72 and 1.57 μg/L, respectively. Four different solvents applied for recoveries showed quite different rates ranging for 2,6 TDI and 2,4 TDI from 17.96 to 88.53 %, and 40.08 to 99.18 %, respectively. Real sample analysis showed low residue levels, especially of 2,6 TDI, with values always below the LOQ. The data reported on real samples allowed to establish that from a risk management purpose, no toxicology risk can be accomplished