Integrated simulation–optimisation of pull control systems

Pull policies are considered to be among the most efficient control strategy. Setting the correct parameters to maximise their efficiency is, however, not a trivial task. Simulation–optimisation techniques have received particular attention as a means to solve this problem. Nevertheless, they require the iterative solution of an optimisation model to generate the parameter values and a discrete event simulator to evaluate the resulting system performance. In the framework of simulation-optimisation, this paper proposes a combined solution of the optimisation and simulation problems for the optimal operation of pull control systems under several control strategies. Numerical experiments were performed to evaluate the performance of the proposed technique.     

3D flow around a rectangular cylinder: A computational study

The aim of this paper is to provide a contribution to the analysis of the 3D, high Reynolds number, turbulent, separated and reattached flow around a fixed sharp-edged rectangular cylinder with a chord-to-depth ratio equal to 5. The work is developed in the perspective of the benchmark on the aerodynamics of a rectangular cylinder (BARC), in terms of an exploratory computational study. First, the adopted flow modelling and computational approach are shortly described. Second, the obtained main aerodynamic integral parameters are compared with other results proposed in the literature. Hence, the 3D flow features around the nominally 2D cylinder are investigated by means of both proper orthogonal decomposition and coherence function of the side-surface fluctuating pressure field. Once the main 2D nature of the flow has been pointed out, some of the 2D mechanisms that are responsible for the variation of the fluctuating aerodynamic forces are scrutinised: the computational approach post-processing facilities are employed to look for significant relationships between the flow structures, the pressure field and the aerodynamic force components.     

A two-stage stochastic programming project scheduling approach to production planning

In engineering-to-order (ETO) or manufacturing-to-order (MTO) systems producing highly customized items, the high level of customization, together with long flow times, forces the production plan to be defined before information on items customization, and details on the manufacturing activities are completely disclosed. Due to the partial available information, the production plan must provide a robust schedule of the activities and of the resources utilization, trying to incorporate a certain degree of anticipation of uncertainty. This paper proposes a two-stage stochastic programming project scheduling approach to support production planning in ETO/MTO system. The approach provides a baseline production plan together with a set of revisions of the plan to react to the occurrence of uncertain events. A scenario-based approach is used to model the changes affecting the characteristics of the activities to be processed. The proposed approach is tested on random-generated instances and on a real manufacturing system producing machining centers.     

Hematite nucleation and growth in the firing of carbonate-rich clay for pottery production

Here we describe the evolution of iron-bearing phases in the firing of carbonate-rich illite and chlorite clay. Breakdown of chlorite forms an amorphous phase, which continues to retain iron in a (distorted) paramagnetic octahedral site, until carbonates start to decompose and react at 750 °C, forming Ca-silicates. Only at this temperature can hematite nucleate and grow in specific micro-domains located in former chlorite flakes. At 950 °C, decomposition of illite in the presence of an amorphous phase and CaO produces a melt in which nano-sized hematite may nucleate, although its growth is inhibited due to low diffusion with respect to soaking time.     

Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment

Deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be overcome with small molecules termed correctors. We investigated the efficacy and properties of VX-445, a newly developed corrector, which is one of the three active principles present in a drug (Trikafta^®/Kaftrio^®) recently approved for the treatment of CF patients with F508del mutation. We found that VX-445, particularly in combination with type I (VX-809, VX-661) and type II (corr-4a) correctors, elicits a large rescue of F508del-CFTR function. In particular, in primary bronchial epithelial cells of CF patients, the maximal rescue obtained with corrector combinations including VX-445 was close to 60–70% of CFTR function in non-CF cells. Despite this high efficacy, analysis of ubiquitylation, resistance to thermoaggregation, protein half-life, and subcellular localization revealed that corrector combinations did not fully normalize F508del-CFTR behavior. Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties.     

Cobalt‐Catalyzed Cross‐Coupling Reaction between Functionalized Primary and Secondary Alkyl Halides and Aliphatic Grignard Reagents

The coupling of primary and secondary unactivated alkyl bromides with alkyl‐Grignard reagents was performed in good yields under mild conditions by using a new catalytic system: consisting of cobalt chloride and tetramethylethylenediamine (CoCl₂⋅2 LiI, 4 TMEDA). The reaction is very chemoselective since ketone, ester and nitrile functions are tolerated.     

The Association between α-Synuclein and α-Tubulin in Brain Synapses

α-synuclein is a small protein that is mainly expressed in the synaptic terminals of nervous tissue. Although its implication in neurodegeneration is well established, the physiological role of α-synuclein remains elusive. Given its involvement in the modulation of synaptic transmission and the emerging role of microtubules at the synapse, the current study aimed at investigating whether α-synuclein becomes involved with this cytoskeletal component at the presynapse. We first analyzed the expression of α-synuclein and its colocalization with α-tubulin in murine brain. Differences were found between cortical and striatal/midbrain areas, with substantia nigra pars compacta and corpus striatum showing the lowest levels of colocalization. Using a proximity ligation assay, we revealed the direct interaction of α-synuclein with α-tubulin in murine and in human brain. Finally, the previously unexplored interaction of the two proteins in vivo at the synapse was disclosed in murine striatal presynaptic boutons through multiple approaches, from confocal spinning disk to electron microscopy. Collectively, our data strongly suggest that the association with tubulin/microtubules might actually be an important physiological function for α-synuclein in the synapse, thus suggesting its potential role in a neuropathological context.