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Dynamic and real‐time adaptive configuration of Cyber‐Physical Systems (CPSs) results in increased complexity due to a variety of heterogeneous and interdependent variables and creates unique challenges. For example, (a) Emergent Behavior: How do we ensure that system constituents dynamically and adaptively collaborate to produce a consistent repeatable functionality while supporting the capability to upgrade the individual entities through technology infusion; (b) Scale: How do we ensure scalability of these systems by managing complexity; and (c) Risk Management: How do we evaluate and manage the risks associated with the connection and interdependencies of heterogenous systems. Design and development of this new generation of CPSs can be viewed through the lens of System‐of‐Systems (SoS) methodology which is designed to analyze and assess the evolving topologies created by interactions within a large complex system operating in dynamic and uncertain environment. In this paper, we propose the use of several SoS tools and techniques for the analysis and design of next‐generation CPSs. Our SoS methodologies address features such as diversity of component systems, complex hierarchical structures, dynamic and emergent behavior, and interactions between components. Therefore, they are suitable to treat some of the challenging features of CPSs. However, it is necessary to modify these methodologies to address specific aspects of CPSs. Constraints and metrics from SoS methodology, applied to the design space, will support decision on component systems and the topology of their connections, and provide a set of "good designs," with desired characteristics. [ABSTRACT FROM AUTHOR]

In this paper, we introduce the system operational dependency analysis methodology. Its purpose is to assess the effect of dependencies between components in a monolithic complex system, or between systems in a system-of-systems, and to support design decision making. We propose a parametric model of the behavior of the system. This approach results in a simple, intuitive model, whose parameters give a direct insight into the causes of observed, and possibly emergent, behavior. Using the proposed method, designers, and decision makers can quickly analyze and explore the behavior of complex systems and evaluate different architecture under various working conditions. Thus, the system operational dependency analysis method supports educated decision making both in the design and in the update process of systems architecture, without the need to execute extensive simulations. In particular, in the phase of concept generation and selection, the information given by the method can be used to identify promising architectures to be further tested and improved, while discarding architectures that do not show the required level of global features. Application of the proposed method to a small example is used to demonstrate both the validation of the parametric model, and the capabilities of the method for system analysis, design and architecture. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor A (VEGFA) has different biological activities and plays a central role in tumor proliferation, angiogenesis and metastasis. Different VEGFA isoforms are generated by alternative splice site selection of exons 6, 7 and 8. In this paper, we analyzed the physical and chemical properties of the VEGFA exon 6 sequence, and modeled the three-dimensional structures of the regions corresponding to exons 6, 7 and 8 of six different pro-angiogenic isoforms of VEGFA in comparison to the experimental structure of VEGFA_165 by a combined approach of fold recognition and comparative modeling strategies and molecular dynamics simulations. Our results showed that i) exon 6 is a very flexible polycation with high disordered propensity, features well conserved in all mammals, ii) the structures of all the isoforms are stabilized by H-bond sub-networks organized around HUB residues and, iii) the charge content of exon 6 modulates the intrinsic structural preference of its flexible backbone, which can be described as an ensemble of conformations. Moreover, complexes between NRP-1 and VEGFA isoforms were modeled by molecular docking to study what isoforms are able to bind NRP-1. The analysis of complexes evidenced that VEGFA_121, VEGFA_145, VEGFA_183, VEGFA_189 and VEGFA_206, containing exons 7 and 8a, are able to interact with NRP-1 because they have the key regions of exons 7b and/or 8a. An overview of the isoforms shows how the fluctuations are the main guidance of their biological function. MD simulations also provide insights into factors that stabilize the binding regions of isoforms. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is themost common type of liver cancer and is still one of the most fatal cancers. Hence, it needs to identify always newputative markers to improve its diagnosis and prognosis. Since the seleniumis able to fight the oxidative damage which is one of the major origins of cell damage as well as cancer, we have recently focused our attention on selenoprotein family and their involvement in HCC. In the present paper we have carried out a global analysis of the selenotranscriptome expression in HepG2 and Huh7 cells compared to the normal human hepatocytes by reverse transcription-qPCR (RT-qPCR). Our data showed that in both cells there are three downregulated (DIO1, DIO2, and SELO) and ten upregulated (GPX4, GPX7, SELK, SELM, SELN, SELT, SELV, SEP15, SEPW1, and TrxR1) genes. Additionally, interactomic studies were carried out to evaluate the ability of these down- and upregulated genes to interact between them as well as to identify putative HUB nodes representing the centers of correlation able to exercise a direct control over the coordinated genes. [ABSTRACT FROM AUTHOR]

Abstract: In humans we know 25 selenoproteins that play important roles in redox regulation, detoxification, immune-system protection and viral suppression. In particular, selenoprotein M (SelM) may function as thiol disulfide oxidoreductase that participates in the formation of disulfide bonds, and can be implicated in calcium responses. However, it presents a redox motif (CXXU), where U is a selenocysteine, and may also function as redox regulator because its decreased or increased expression regulated by dietary selenium alters redox homeostasis. No data are reported in literature about its involvement in cancer but only in neurodegenerative diseases. In this paper we evaluated the SelM expression in two hepatoma cell lines, HepG2 and Huh7, compared to normal hepatocytes. The results suggested its involvement in hepatocellular carcinoma (HCC) as well as its possible use to follow the progression of this cancer as putative marker. The aim of this study has been to analyze the structure–function relationships of SelM. Hence, firstly we studied the evolutionary history of this protein by phylogenetic analysis and GC content of genes from various species. So, we modeled the three-dimensional structure of the human SelM evaluating its energetic stability by molecular dynamics simulations. Moreover, we modeled some of its mutants to obtain structural information helpful for structure-based drug design. [Copyright &y& Elsevier]

Sleep deficit and related disorders are becoming increasingly prevalent in modern life and an extensive literature has documented that acute or chronic sleep deprivation can lead to several physiological consequences. Here, we evaluated the effects of sleep deprivation on hematopoietic composition of either bone marrow or peripheral blood. Mice were subjected to paradoxical sleep deprivation (PSD) for 72 h by modified multiple platform method, with or without an additional sleep recovery (SR) period of 10 days. PSD decreased total cellularity of the bone marrow and peripheral blood concomitantly. Subsequent analysis of cell composition showed that absolute number of hematopoietic stem/progenitor cells and colony-forming units was decreased. Moreover, the absolute number of granulocytes and monocytes in bone marrow was reduced in PSD group. These alterations were paralleled by an accumulation of neutrophils and monocytes in peripheral blood. PSD also induced lymphopenia in the circulation. To the best of our knowledge, this is the first study that demonstrates the importance of sleep on the hematopoietic microenvironment and provides new insights into the relationship between sleep and the immune system. J. Cell. Physiol. 227: 361-366, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Alterations in transforming growth factor (TGF)-β signalling have been frequently implicated in human cancer, and an important mechanism underlying its pro-oncogenic nature is suppression of the host antitumour immune response. Considering the immunosuppressive effect of TGF-β, we asked whether human tumour cells, known to secrete TGF-β in culture, would survive and grow when implanted into the peritoneal cavity of immunocompetent mice. Therefore, we developed a xenogeneic model where mice were intraperitoneally (i.p.) injected with a TGF-β-secreting human colorectal adenocarcinoma cell line, LISP-A10. Although animals did not develop macroscopic tumours, the recovery and isolation of human tumour cells was achieved when an inflammatory environment was locally induced by the administration of complete Freund's adjuvant (CFA). This procedure significantly increased TGF-β concentrations in the peritoneal fluid and was accompanied by impaired activation of the host-specific immune response against LISP-A10 cells. Furthermore, inflammatory lesions resembling human inflammatory pseudotumours (IPTs) were observed on the surface of i.p. organs. These lesions could be induced by either injection of LISP-A10 cells, cells-conditioned medium or recombinant TGF-β but only after administration of CFA. In addition, host cyclooxygenase-2 and kinin receptors played an important role in the induction of TGF-β-mediated IPT-like lesions in our experimental model. [ABSTRACT FROM AUTHOR]

• Polyploidization enables plants to occupy, conquer different habitats and, from an evolutionary standpoint, achieve success. • In recent years, polyploidization has become a powerful tool for the improvement of medicinal and aromatic species. • There is a lack of linearity between the increase in genetic material and secondary metabolite production. • A good experimental design is relevant to differentiate the "polyploid effect" from the ones derived from tissue culture conditions. • The constitution of a consortium or a network of laboratories to amplify our knowledge about the "polyploid effect" is essential. The secondary metabolism of plants delivers a wide range of chemical structures with application for a vast array of activities, thus offering opportunities for social and economic development. Polyploidy is the possession of three or more complete sets of chromosomes. The duplication of the genome, and its possible adaptive advantages, has been an important factor in the speciation and evolution of eukaryotes. The generation of synthetic polyploids as a plant breeding strategy has enabled the development of new and improved cultivars. The aim of this paper is to examine the state-of-the-art concerning the application of polyploidization techniques as a breeding tool and its effects on the phenotypical, biochemical and genetic characteristics in some medicinal aromatic plant (MAP) species to explore our current knowledge of the possible mechanisms involved. Over the last years, new studies have demonstrated that autopolyploidization can remodel the transcriptome and the metabolome generating genomic stress. Consequently, polyploidism can also result in a wide spectrum of modifications, both molecular and physiological, with non-linear results and consequences that also depend on the experimental conditions. Likewise, concepts such as genomic shock and genome fluidity are also involved in this phenomenon, which further increase the complexity of the process. [ABSTRACT FROM AUTHOR]

Carbohydrates, also called saccharides, are molecules composed of carbon, hydrogen, and oxygen. They are the most abundant biomolecules and essential components of many natural products and have attracted the attention of researchers because of their numerous human health benefits. Among carbohydrates the polysaccharides represent some of the most abundant bioactive substances in marine organisms. In fact, many marine macro- and microorganisms are good resources of carbohydrates with diverse applications due to their biofunctional properties. By acting on cell proliferation and cycle, and by modulating different metabolic pathways, marine polysaccharides (including mainly chitin, chitosan, fucoidan, carrageenan and alginate) also have numerous pharmaceutical activities, such as antioxidative, antibacterial, antiviral, immuno-stimulatory, anticoagulant and anticancer effects. Moreover, these polysaccharides have many general beneficial effects for human health, and have therefore been developed into potential cosmeceuticals and nutraceuticals. In this reviewwe describe current advances in the development ofmarine polysaccharides for nutraceutical, cosmeceutical and pharmacological applications. Research in this field is opening new doors for harnessing the potential of marine natural products. [ABSTRACT FROM AUTHOR]

A new reality is being observed around the world as the population ages: family caregivers, who are themselves older adults helping their ill older relatives. The aim of this study is to assess the burden of the older family caregiver assisting older patients in his or her end-of-life who are suffering from dementia or cancer. In this context, the elderly person is involved in the dual role of patient and caregiver. In this comparative study, a total of 87 older family caregivers (age ≥ 65 years) completed the Caregiver Burden Inventory (CBI) measurement. The sample was divided into 2 subgroups based on the individuals' advanced disease: Alzheimer's disease (AD) or cancer. Compared to cancer caregivers, the AD subgroup reported significantly higher scores in the CBI-emotional subscale (P = 0.006), confirmed by the evaluation of the generalized linear model (multivariate). There were no significant differences in the other CBI subscales and overall scores. According to the findings of this study, elderly who help elderly with AD are at a higher risk of experiencing an emotional burden than cancer caregivers. This data could be considered in designing interventions to reduce the caregiver burden of older family caregivers as they provide informal end-of-life care. [ABSTRACT FROM AUTHOR]

Ephrin A2 receptor (EphA2) plays a key role in cancer, it is up-regulated in several types of tumors and the process of ligand-induced receptor endocytosis, followed by degradation, is considered as a potential path to diminish tumor malignancy. Protein modulators of this mechanism are recruited at the cytosolic Sterile alpha motif (Sam) domain of EphA2 (EphA2-Sam) through heterotypic Sam-Sam associations. These interactions engage the C-terminal helix of EphA2 and close loop regions (the so called End Helix side). In addition, several studies report on destabilizing mutations in EphA2 related to cataract formation and located in/or close to the Sam domain. Herein, we analyzed from a structural point of view, one of these mutants characterized by the insertion of a novel 39 residue long polypeptide at the C-terminus of EphA2-Sam. A 3D structural model was built by computational methods and revealed partial disorder in the acquired C-terminal tail and a few residues participating in an α-helix and two short β-strands. We investigated by CD and NMR studies the conformational properties in solution of two peptides encompassing the whole C-terminal tail and its predicted helical region, respectively. NMR binding experiments demonstrated that these peptides do not interact relevantly with either EphA2-Sam or its interactor Ship2-Sam. Molecular dynamics (MD) simulations further indicated that the EphA2 mutant could be represented only through a conformational ensemble and that the C-terminal tail should not largely wrap the EphA2-Sam End-Helix interface and affect binding to other Sam domains. An EphA2 receptor mutant linked to cataracts was analyzed by experimental (SDS-PAGE, mass spectrometry, NMR spectroscopy) and computational (ab initio modelling and MD simulations) methods. Image 3 • An EphA2 mutant (= Sam domain plus C-terminal tail) linked to cataracts was analyzed. • A 3D model was built by molecular modelling and revealed a partially disordered C-terminal tail. • Peptide conformational studies highlighted the disorder in the C-terminal tail. • The mutant could be represented only by a conformational ensemble in MD simulations. • Binding to other Sam domains should not be directly affected by the C-terminal tail. [ABSTRACT FROM AUTHOR]

Background: Total pancreatectomy is actually considered a viable option in selected patients even if large comparative studies between partial versus total pancreatectomy are not currently available. Our aim was to evaluate whether total pancreatectomy can be considered as feasible, safe, efficacious, and cost-effective as pancreaticoduodenectomy.Methods: A single center, prospective, observational trial, regarding postoperative outcomes, long-term results, and cost-effectiveness, in a tertiary referral center was conducted, comparing consecutive patients who underwent elective total pancreatectomy and/or pancreaticoduodenectomy.Results: Seventy-three consecutive elective total pancreatectomies and 184 pancreaticoduodenectomies were compared. There were no significant differences regarding postoperative outcomes and overall survival. The quality of life, evaluated in 119 patients according to the EQ-5D-5L questionnaire, showed that there were no significant differences regarding the five items considered. The mean EQ-5D-5L score was similar in the two procedures (total pancreatectomy = 0.872, range 0.345-1.000; pancreaticoduodenectomy = 0.832, range 0.393-1.000; P = 0.320). The impact of diabetes according to the Problem Areas in Diabetes (PAID) questionnaire did not show any significant differences except for question 13 (total pancreatectomy = 0.60; pancreaticoduodenectomy = 0.19; P = 0.022). The cost-effectiveness analysis suggested that the quality-adjusted life year was not significantly different between the two procedures (total pancreatectomy = 0.910, range 0.345-1.000; pancreaticoduodenectomy = 0.910, range -0.393-1.000; P = 0.320).Conclusions: From this study, it seems reasonable to suggest that total pancreatectomy can be considered as safe, feasible, and efficacious as PD and acceptable in terms of cost-effectiveness. [ABSTRACT FROM AUTHOR]