Computer-aided set-up planning for machining centres configuration

One of the key issues in defining the optimal configuration of a machining centre is the problem of determining the minimal number of set-ups for the part types to be machined. This paper proposes a method to define near-optimal set-up plans for prismatic workpieces when multiple parts can be mounted on the same pallet. Set-ups are determined taking into account the accessibility of the machining directions of the workpiece and the technological constraints among the required operations. The technological constraints are divided into three types: constraints that force the operations to share the same set-up, precedence constraints that cannot be violated in the sequence of set-ups, and constraints that translate technological preferences and that might be sacrificed to optimize the set-up plan. The technological constraints are analysed with a graph-based approach. The method proposes a solution for three-, four- and five-axis machines. The set-up plan for three axes is the starting point to determine the solutions for four- and five-axis machines: the set-up plan for four and five axes results from the combination of set-ups of the three-axis machine. Alternative solutions with the minimal number of set-ups are determined. Each solution specifies the orientation of the workpiece on the pallet fixture in each set-up, the operations to be executed in each set-up and the precedence relations among set-ups. Starting from the results of the set-up planning, the configuration of the pallet can be defined and taking into account the pallet configuration, the optimal machining centre for specific manufacturing needs is selected.     

On the Dynamic Semantics and the Timing Behavior of Ravenscar Kernels

Mature research advances in scheduling theory show that carefully-crafted concurrent computational models permit static analysis of real-time behavior. This evidence enables designers to consider using suitable forms of explicit concurrency to model the inherent concurrency of real-time systems. The Ravenscar Profile, a specifically tailored subset of the Ada 95 tasking model, defines a compact and efficient concurrent computational model, especially suited for the development of high integrity, high efficiency real-time systems.Ravenscar runtimes can be implemented by small, efficient, reliable and certifiable kernels. At least two such implementations already exist and are being industrially deployed. The simplicity and intrinsic determinism of Ravenscar kernels facilitate the definition of metrics that cater for very accurate characterization of the dynamic behavior of the runtime and of the execution time of its primitives. Accurate runtime metrics enable forms of response time analysis that minimize the pessimism in the prediction of the runtime influence on the application. This is especially useful for concurrent systems that exhibit significant dependency on runtime support services. This paper recalls the motivations of the Ravenscar Profile, outlines the definition of it and formulates a precise characterisation of the associated runtime metrics.     

ADP ribosylation factor regulates spectrin binding to the Golgi complex

Homologues of two major components of the well-characterized erythrocyte plasma-membrane-skeleton, spectrin (a not-yet-cloned isoform, betaI Sigma* spectrin) and ankyrin (AnkG119 and an approximately 195-kDa ankyrin), associate with the Golgi complex. ADP ribosylation factor (ARF) is a small G protein that controls the architecture and dynamics of the Golgi by mechanisms that remain incompletely understood. We find that activated ARF stimulates the in vitro association of betaI Sigma* spectrin with a Golgi fraction, that the Golgi-associated betaI Sigma* spectrin contains epitopes characteristic of the betaI Sigma2 spectrin pleckstrin homology (PH) domain known to bind phosphatidylinositol 4,5-bisphosphate (PtdInsP2), and that ARF recruits betaI Sigma* spectrin by inducing increased PtdInsP2 levels in the Golgi. The stimulation of spectrin binding by ARF is independent of its ability to stimulate phospholipase D or to recruit coat proteins (COP)-I and can be blocked by agents that sequester PtdInsP2. We postulate that a PH domain within betaI Sigma* Golgi spectrin binds PtdInsP2 and acts as a regulated docking site for spectrin on the Golgi. Agents that block the binding of spectrin to the Golgi, either by blocking the PH domain interaction or a constitutive Golgi binding site within spectrin's membrane association domain I, inhibit the transport of vesicular stomatitis virus G protein from endoplasmic reticulum to the medial compartment of the Golgi complex. Collectively, these results suggest that the Golgi-spectrin skeleton plays a central role in regulating the structure and function of this organelle.     

Role of prion protein aggregation in neurotoxicity

In several neurodegenerative diseases, such as Parkinson, Alzheimer's, Huntington, and prion diseases, the deposition of aggregated misfolded proteins is believed to be responsible for the neurotoxicity that characterizes these diseases. Prion protein (PrP), the protein responsible of prion diseases, has been deeply studied for the peculiar feature of its misfolded oligomers that are able to propagate within affected brains, inducing the conversion of the natively folded PrP into the pathological conformation. In this review, we summarize the available experimental evidence concerning the relationship between aggregation status of misfolded PrP and neuronal death in the course of prion diseases. In particular, we describe the main findings resulting from the use of different synthetic (mainly PrP106-126) and recombinant PrP-derived peptides, as far as mechanisms of aggregation and amyloid formation, and how these different spatial conformations can affect neuronal death. In particular, most data support the involvement of non-fibrillar oligomers rather than actual amyloid fibers as the determinant of neuronal death.     

Efficacy of a Three Drug-Based Therapy for Neuroblastoma in Mice

High-risk neuroblastoma (HR-NB) still remains the most dangerous tumor in early childhood. For this reason, the identification of new therapeutic approaches is of fundamental importance. Recently, we combined the conventional pharmacological approach to NB, represented by cisplatin, with fendiline hydrochloride, an inhibitor of several transporters involved in multidrug resistance of cancer cells, which demonstrated an enhancement of the ability of cisplatin to induce apoptosis. In this work, we co-administrated acetazolamide, a carbonic anhydrase isoform IX (CAIX) inhibitor which was reported to increase chemotherapy efficacy in various cancer types, to the cisplatin/fendiline approach in SKNBE2 xenografts in NOD-SCID mice with the aim of identifying a novel and more effective treatment. We observed that the combination of the three drugs increases more than twelvefold the differences in the cytotoxic activity of cisplatin alone, leading to a remarkable decrease of the expression of malignancy markers. Our conclusion is that this approach, based on three FDA-approved drugs, may constitute an appropriate improvement of the pharmacological approach to HR-NB.     

N6-Isopentenyladenosine Hinders the Vasculogenic Mimicry in Human Glioblastoma Cells through Src-120 Catenin Pathway Modulation and RhoA Activity Inhibition

Background: Vasculogenic mimicry (VM) is a functional microcirculation pattern formed by aggressive tumor cells. Thus far, no effective drugs have been developed to target VM. Glioblastoma (GBM) is the most malignant form of brain cancer and is a highly vascularized tumor. Vasculogenic mimicry represents a means whereby GBM can escape anti-angiogenic therapies. Methods: Here, using an in vitro tube formation assay on Matrigel, we evaluated the ability of N6-isopentenyladenosine (iPA) to interfere with vasculogenic mimicry (VM). RhoA activity was assessed using a pull-down assay, while the modulation of the adherens junctions proteins was analyzed by Western blot analysis. Results: We found that iPA at sublethal doses inhibited the formation of capillary-like structures suppressing cell migration and invasion of U87MG, U343MG, and U251MG cells, of patient-derived human GBM cells and GBM stem cells. iPA reduces the vascular endothelial cadherin (VE-cadherin) expression levels in a dose-dependent manner, impairs the vasculogenic mimicry network by modulation of the Src/p120-catenin pathway and inhibition of RhoA-GTPase activity. Conclusions: Taken together, our results revealed iPA as a promising novel anti-VM drug in GBM clinical therapeutics.     

Regional development and construction in Italy: an input-output analysis, 1959-1992

Using two sets of input-output tables, this paper analyses the role of the construction sector in the North and South regions of Italy, from 1959 to 1992. As expected, the sector has had differing impacts on the two regional economies over the years. In the highly developed North its importance has been declining, similarly to the case of other highly developed countries. In the less developed South, instead, construction has a relatively higher propulsive role in the creation of goods and income. This role is significantly diminished since most of the construction inputs are imported. Some differences are reported in the sector's input and output profiles of the two regions. From the technological and organizational points of view, in the South construction projects appear to be less complex than those in the North.     

A model-based Digital Twin to support responsive manufacturing systems

Manufacturing systems are subject to continuous changing conditions, which are due both to external reasons (e.g. changing demand) and to the natural system evolution, (e.g. machine degradation, operators’ upskilling). At tactical level, production engineers are challenged to continuously improve the system performance. At strategical level, the manufacturing company must monitor the system status and proactively identify reconfiguration actions to ensure system fitness to the evolving competitive scenario. A novel Digital Twin based on an analytical model for performance evaluation of manufacturing system embedding evaluation of joint parameter variations is introduced. In particular this work concentrates on how tactical decision makers can benefit from an integrated system model. The method is proved in a real industrial case in the railway sector.     

Predicting different adhesive regimens of circulating particles at blood capillary walls

A fundamental step in the rational design of vascular targeted particles is the firm adhesion at the blood vessel walls. Here, a combined lattice Boltzmann–immersed boundary model is presented for predicting the near-wall dynamics of circulating particles. A moving least squares algorithm is used to reconstruct the forcing term accounting for the immersed particle, whereas ligand-receptor binding at the particle–wall interface is described via forward and reverse probability distributions. First, it is demonstrated that the model predicts with good accuracy the rolling velocity of tumor cells over an endothelial layer in a microfluidic channel. Then, particle–wall interactions are systematically analyzed in terms of particle geometries (circular, elliptical with aspect ratios 2 and 3), surface ligand densities (0.3, 0.5, 0.7 and 0.9), ligand-receptor bond strengths (1 and 2) and Reynolds numbers (Re = 0.01, 0.1 and 1.0). Depending on these conditions, four different particle–wall interaction regimens are identified, namely not adhering, rolling, sliding and firmly adhering particles. The proposed computational strategy can be efficiently used for predicting the near-wall dynamics of particles with arbitrary geometries and surface properties and represents a fundamental tool in the rational design of particles for the specific delivery of therapeutic and imaging agents.