A convergent decomposition method for box-constrained optimization problems.

In this work we consider the problem of minimizing a continuously differentiable function over a feasible set defined by box constraints. We present a decomposition method based on the solution of a sequence of subproblems. In particular, we state conditions on the rule for selecting the subproblem variables sufficient to ensure the global convergence of the generated sequence without convexity assumptions. The conditions require to select suitable variables (related to the violation of the optimality conditions) to guarantee theoretical convergence properties, and leave the degree of freedom of selecting any other group of variables to accelerate the convergence. © 2009 Springer-Verlag

A Ciliary View of the Immunological Synapse

The primary cilium has gone from being a vestigial organelle to a crucial signaling hub of growing interest given the association between a group of human disorders, collectively known as ciliopathies, and defects in its structure or function. In recent years many ciliogenesis proteins have been observed at extraciliary sites in cells and likely perform cilium-independent functions ranging from regulation of the cytoskeleton to vesicular trafficking. Perhaps the most striking example is the non-ciliated T lymphocyte, in which components of the ciliary machinery are repurposed for the assembly and function of the immunological synapse even in the absence of a primary cilium. Furthermore, the specialization traits described at the immunological synapse are similar to those seen in the primary cilium. Here, we review common regulators and features shared by the immunological synapse and the primary cilium that document the remarkable homology between these structures

Une guerre oubliée

L’article reconstitue les temps et les modalités à travers lesquels la Provence angevine définit, contrôla et défendit sa frontière orientale avec la seigneurie de Dolceacqua, dans la Ligurie du Ponant. Ces confins se caractérisaient par des limites instables, où la défense n’était que très partiellement confiée aux officiers du roi et où le contrôle du territoire était surtout exercé par les communautés villageoises. La compréhension des rapports difficiles entre les deux puissances a été facilitée par la découverte d’un document de 1381, qui atteste l’existence d’une guerre jusqu’à maintenant oubliée. Elle fut menée entre la maison d’Anjou et la seigneurie de Dolceacqua pour la possession du Monte Comune, un vaste territoire alpin qui possédait une importance économique et stratégique considérable.This paper reconstructs the timeline and the modalities through which Angevin Provence defined, controlled and defended its eastern borders with the Dolceacqua seigneurie in the Ligurian west. The frontier, which was characterized by unstable borders, was defended only partially by the king’s officials while the control of the territory was largely exercised by the communities. The understanding of the difficult relations between the two potentates has been made easier by the discovery of a 1381 document which attests a war which until now had been forgotten. The bone of contention in this war fought between the House of Anjou and the Dolceacqua seigneurie was the Monte Comune, a vast alpine territory of considerable strategic and economic importance.L’articolo ricostruisce i tempi e le modalità attraverso i quali la Provenza angioina definì, controllò e difese la frontiera orientale con la signoria di Dolceacqua, nella Liguria di Ponente. Una frontiera caratterizzata da confini instabili, dove la difesa era affidata solo parzialmente agli ufficiali del re e dove il controllo del territorio era esercitato soprattutto dalle comunità. La comprensione dei rapporti difficili fra i due potentati è stata agevolata dalla scoperta di un documento del 1381 che attesta l’esistenza di una guerra finora dimenticata. Essa fu combattuta fra la Casa d’Angiò e la signoria di Dolceacqua per il possesso del Monte Comune, un vasto territorio alpino dall’importanza economica e strategica considerevole

Cooperative leadership in hyperscanning. Brain and body synchrony during manager-employee interactions

Recent advances in neurosciences permitted to extend the knowledge about brain functioning to the organizational field with a specific interest to leadership, with the extent to explore more proficient ways of managing. In the present research, through a hyperscanning paradigm, EEG and autonomic synchrony was explored during performance reviews to investigate if different leadership styles (partecipative vs. authoritative), could be associated with different dyadic engagement. Analysis involved coherence computation assessing the strenght of inter-brain and body synchrony, which revealed the presence of a higher emotional synchronization for both neural and bodily reactions mainly for partecipative style

Exploiting flexible functional split in converged software defined access networks

5G targets to offer a huge network capacity to support the expected unprecedented traffic growth due mainly to mobile and machine-type services. Thus, the 5G access network has to comply with very challenging architectural requirements. Mobile network scalability is achieved by playing appropriately with the centralization of network functions and by applying the functional split introducing the fronthaul. Although more advantageous in terms of network management and performance optimization, low-layer functional split options require larger bandwidth and lower latency to be guaranteed by the fronthaul in the access network, while preserving other concurrent fiber-to-the-x services. Thus, advanced mechanisms for the efficient management of available resources in the access network are required to control jointly both radio and optical domains. Softwarized mobile and optical segments facilitate the introduction of dedicated protocols to enable the inter-working of the two control planes. This paper proposes a new cooperation scheme to manage the adaptive flexible functional split in 5G networks conditioned to the resource availability in the optical access network. Techniques for the accurate estimation of available bandwidth and the associated real-time selection of the best suitable functional split option are investigated. Results show that the proposed software defined converged approach to wavelength and bandwidth management guarantees the optimal allocation of optical resources. The triple exponential smoothing forecasting technique enables efficient coexistence of mobile fronthaul and fixed connectivity traffic in the network, reducing traffic impairments with respect to other well-known forecasting techniques, while keeping the same level of centralization.This work was partially supported by the Italian Government under CIPE resolution no. 135 (December 21, 2012), project INnovating City Planning through Information and Communication Technologies (INCIPICT) and by the EC through the H2020 5G-TRANSFORMER project (Project ID 761536)

Efficient Management of Flexible Functional Split through Software Defined 5G Converged Access

Softwarization of mobile and optical networks facilitates the inter-working between control planes of the two domains, allowing a more efficient management of available resources. Radio resource utilization benefits from the centralization of mobile network functionalities with the application of high-order functional split options by fronthauling. However, higher-order options require larger bandwidth and lower latency in the fronthaul. Advanced mechanisms for the joint control of the access network represent the sole solution to support such fronthaul requirements. This paper proposes a new cooperation scheme to manage the adaptive flexible functional split in 5G networks conditioned to the resource availability in the optical access network. Results show that the proposed converged approach guarantees the optimal allocation of optical resources through a software defined wavelength and bandwidth allocation. The proposed scheme adapts to current traffic demand and simultaneously allows the mobile network to take advantage of the highest possible centralization of mobile network functions by leveraging flexible functional split adaptively compliant to the current optical traffic demand.This work was partially supported by the Italian Government under CIPE resolution no. 135 (December 21, 2012), project INnovating City Planning through Information and Communication Technologies (INCIPICT) and by the EC through the H2020 5G-TRANSFORMER project (Project ID 761536

Encapsulation of metal complex into apoferritin for drug delivery and prodrug activation

Cancer is one of the principal causes of mortality and the onset of new cases is estimated to increase from 19.3 million new cases in 2020 to 28.4 million by 2040 worldwide. Brain tumours represent a group of diseases characterised by high aggressiveness and poor prognosis. Glioblastoma represents 47% of cases and is currently treated with the anticancer agent temozolomide. This agent can induce tumour regression and promote patients’ survival but is characterised by low specificity and premature conversion into its metabolites causing severe side effects. Recent research has focused on the improvement of the tumour-targeted delivery of drugs such as temozolomide for anticancer chemotherapy exploiting nanocapsules. The protein shell apoferritin is biocompatible, biodegradable, non-immunogenic and pH-responsive and can be preferentially internalised by tumour cells. These features make apoferritin an ideal nanocarrier. However, when small molecules like temozolomide are encapsulated within apoferritin, they can easily leak through the interprotein channels that connect the core of the nanocage with the external environment. This problem can lead to reduced nanoparticle uptake into the brain, consequent decrease in drug efficacy and higher probability of undesired toxicity. This work aims to exploit the natural affinity of apoferritin for transition metals and their complexes, to improve the retention of temozolomide inside apoferritin when exposed to physiological environments. It was hypothesised that the loading of apoferritin with both Cu2+-phenanthroline complex and temozolomide could promote the coordination of the metal and prevent the escape of the anticancer agent. Furthermore, Cu2+-phenanthroline itself is the precursor of a family of anticancer compounds currently under clinical evaluation. Therefore, Cu2+-phenanthroline has the potential to both prevent temozolomide leakage from apoferritin and contribute to the anticancer activity of the formulation. The work presented in this thesis evaluates the viability of this dual-drug delivery approach by using either horse spleen or human heavy chain apoferritin to achieve temozolomide delivery only in cancer cells and achieve enhanced anticancer activity. The metal affinity of the Apoferritin cage is essential to this approach. Horse spleen apoferritin is employed to evaluate the encapsulation of Cu2+-phenanthroline using the nanoreactor method and its effect on temozolomide loading and retention. With human heavy chain apoferritin, site-specific covalent conjugation of the Cu2+-phenanthroline complex has been undertaken before temozolomide encapsulation given the lower metal accumulation capacity of this apoferritin variant. The nano-formulations are characterised by UV-vis, high resolution transmission electron microscopy (HRTEM), inductively coupled plasma mass spectrometry (ICP-MS), Ellman’s assay, Matrix-assisted Laser Desorption/ionization Time of Flight (MALDI-TOF MS) and tested for in vitro anticancer activity by cell viability 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and clonogenic assays. The encapsulation of Cu2+-phenanthroline into horse spleen apoferritin led to the formation of different copper(II) species some of them organised into crystal patterns visible by HRTEM and stable for up to 4 months. Upon loading of 339 temozolomide molecules per cage by nanoreactor route, the nano-formulation was able to protect the drug from degradation but the introduction of the metal complex had no effect on drug retention. In vitro results reported enhanced cytotoxicity of the apoferritin encapsulated agents with a 30-fold decrease in GI50 for glioblastoma cell lines compared to temozolomide treatment. The covalent conjugation of Cu2+-phenanthroline to human heavy chain apoferritin was challenging and robust confirmation of bioconjugation could not be achieved due the heterogeneity of the purified reaction mixtures. Consequently, no significant metal accumulation was observed even when 1,10-phenanthroline was detected. Temozolomide was entrapped within human apoferritin with encapsulation efficiency of 43 % of the total temozolomide added (moles) and drug loading of 12.9 % of the total nano-formulation weight (encapsulated drug and protein). This work illustrates the potential of horse spleen apoferritin as an efficient drug delivery vehicle for the anticancer agent temozolomide, able to protect it from premature degradation and favour intracellular delivery. The anticancer activity of the metallodrug Cu2+-phenanthroline showed promising results for the treatment of glioblastoma multiforme alone and in combination with temozolomide. However, this application would require functionalisation of the apoferritin cage for precise tumour targeting, given the in vitro toxicity caused by the metallodrug to non-tumour cells. In summary, although none of the nano-formulations studied resulted in improved temozolomide retention into apoferritin, this work provided additional evidence to support the use of this protein nanocage as a valuable drug delivery tool

MaxHadoop: An Efficient Scalable Emulation Tool to Test SDN Protocols in Emulated Hadoop Environments

AbstractThis paper presents MaxHadoop, a flexible and scalable emulation tool, which allows the efficient and accurate emulation of Hadoop environments over Software Defined Networks (SDNs). Hadoop has been designed to manage endless data-streams over networks, making it a tailored candidate to support the new class of network services belonging to Big Data. The development of Hadoop is contemporary with the evolution of networks towards the new architectures "Software Defined." To create our emulation environment, tailored to SDNs, we employ MaxiNet, given its capability of emulating large-scale SDNs. We make it possible to emulate realistic Hadoop scenarios on large-scale SDNs using low-cost commodity hardware, by resolving a few key limitations of MaxiNet through appropriate configuration settings. We validate the MaxHadoop emulator by executing two benchmarks, namely WordCount and TeraSort, to evaluate a set of Key Performance Indicators. The tests' outcomes evidence that MaxHadoop outperforms other existing emulation tools running over commodity hardware. Finally, we show the potentiality of MaxHadoop by utilizing it to perform a comparison of SDN-based network protocols

Learning from TCR Signaling and Immunological Synapse Assembly to Build New Chimeric Antigen Receptors (CARs).

Chimeric antigen receptor (CAR) T cell immunotherapy is a revolutionary pillar in cancer treatment. Clinical experience has shown remarkable successes in the treatment of certain hematological malignancies but only limited efficacy against B cell chronic lymphocytic leukemia (CLL) and other cancer types, especially solid tumors. A wide range of engineering strategies have been employed to overcome the limitations of CAR T cell therapy. However, it has become increasingly clear that CARs have unique, unexpected features; hence, a deep understanding of how CARs signal and trigger the formation of a non-conventional immunological synapse (IS), the signaling platform required for T cell activation and execution of effector functions, would lead a shift from empirical testing to the rational design of new CAR constructs. Here, we review current knowledge of CARs, focusing on their structure, signaling and role in CAR T cell IS assembly. We, moreover, discuss the molecular features accounting for poor responses in CLL patients treated with anti-CD19 CAR T cells and propose CLL as a paradigm for diseases connected to IS dysfunctions that could significantly benefit from the development of novel CARs to generate a productive anti-tumor response