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In recent years manufacturing companies have been faced with various challenges related to volatile demand and changing requirements from customer as well as suppliers. This trend is now even accelerating with a direct impact on the value chain. New technological roadmaps and suggested interventions in manufacturing systems try to solve these challenges and solutions such as the German high tech strategy “Industrie 4.0” or the Italian cluster “Fabbrica Intelligente” which often aimed at enhancing the flexibility of manufacturing systems among many other competitive dimensions. However, these approaches often do not provide a detailed definition of flexibility and its different manifestations. Therefore, the question rises if different types of flexibility, that have an impact on the complete manufacturing system, can be better identified with the existing Manufacturing Value Modeling Methodology (MVMM). This question becomes even more important when considering the potential that smart machines interacting with humans, such as cyber-physical systems (CPS), and the possibility to increase connectivity and data access through technologies, such as the internet of things (IoT), offer for increasing flexibility. Especially due to the various possibilities it becomes even more important to understand, which kind of flexibility is needed for a given problem. Implementing flexibility into the MVMM requires a ‘catalog’ that makes use of the MVMM framework presenting an overview of internal and external influence factors in order to support the identification of correct solutions and improvements related to functional areas in the manufacturing environment. Starting from a qualitative literature review on manufacturing flexibility, a ‘flexibility catalog’ is designed, which provides a structural definition of existing flexibility types and their composition as well as providing decision support. In conclusion, the scope of the ‘flexibility catalog’ is to verify that the flexibility demand fits into the market trends and is aligned to the manufacturing and company strategy, in order to help firms to take decisions and delivering value.

In recent years there has been appreciable academic activity in manufacturing value creation resulting in that the ability to create value is based on the competence to make decisions and implement strategies; even though this evidence it is still difficult to understand where the company's weak points are located so value modeling approaching is arising. In this study Authors first report a qualitative review on value creation and modeling based on the identification, selection and analysis of about 100 papers, then specify the value concept within manufacturing companies. Within this context the Authors describe a novel methodology for manufacturing value modeling from strategic level down to operational improvements. The methodology and the related mapping and analysis tools have been co-developed with Siemens MES division within Industry 4.0 context. The Manufacturing Value Modeling Methodology (MVMM) is based on 5 steps: Value Map, Maturity Model, Gap and Process Analysis, Validation and Improvement Areas Definition. Through this methodological approach, a series of structured interviews allowing to construct the value map accordingly to the current company maturity model and the relationships between the strategic objectives and operational practices, capabilities, and methods. Combining the assessments interview with the Company’ resources, infrastructure and IT structures, it is possible to establish a current level of the company. The mapping step is followed by a gap and process analysis, assessing most relevant areas for the creation of value aiming at constructing an interventions roadmap, setting out priorities and activities to be improved. The selection of the improvement areas defines process initiatives, KPIs and interventions to improve business alignment. To provide a practical view of the methodology a sample of the Value Modeler tool is presented and discussed.

The long-lasting impetus to design novel modes of macrocyclization, and their implementation into a wide range of bioactive peptides, originates from their contributions to the restriction of conformational space and the stabilization of preferential bioactive conformations that support higher efficacy and binding affinity to cognate macromolecular targets, improved specificity and lowering susceptibility to enzymatic degradation processes. Introducing CuI-catalyzed azide-alkyne cycloaddition (CuAAC), a prototypical click reaction, to the field of peptide sciences as a bio-orthogonal reaction that generates a disubstituted-[1,2,3]triazol-1-yl moiety as a pseudopeptidic bond that is peptidomimetic in nature, paved the way to its widespread application as a new and promising mode of macrocyclization. This review presents the state-of-art of CuAAC-mediated macrocyclization as it applies to an expansive range of bioactive peptides and explores the relationship among the structural diversity of CuAACmediated cyclizations, biological activities and conformations.

Over the last years, manufacturing companies have to face several challenges, mainly related to the volatility of the demand and to the continuously changing requirements, both from the customers and suppliers. In the meantime, new technological roadmaps and suggested interventions in manufacturing systems have been implemented. These solutions aim to exploit the high innovation and economic potential resulting from the continuing impact of rapidly advancing information and communication technology (ICT) in industry. This paper explores these topics focusing on the food sector. Indeed, companies belonging to this industry are facing global challenges, which can be met with the support of the information technologies (IT). The overall goal of this study is to help food companies toward digitalization, with a particular focus on the design and manufacturing processes. From the methodological point of view, Case Study has been used as research method. Furthermore, a questionnaire characterized by the different elements of the Manufacturing Value Modelling Methodology (MVMM) has been developed and used to gather information from companies. A framework for the digitalization process in the food industry has been developed basing on the results of a preliminary literature review and of different focus groups. On completion of the aforementioned framework, a list of enabling technologies has been discussed. These represent the technological solutions for the specific food issues highlighted by the framework. Finally, a case study has been accomplished in order to test and validate the contents’ framework.

Scientific Reports 6: Article number: 39430; published online: 23 December 2016; updated: 22 March 2017. The original version of this Article contained typographical errors in the Abstract. ‘In autoimmune diseases, there have been proposals that exogenous “molecular triggers”, i.e., specific this should be ‘non-self antigens’ accompanying infectious agents, might disrupt control of the adaptive immune system resulting in serious pathologies’.

Human Work Interaction Design (HWID) studies the integration of work analysis and interaction design methods to foster new strategies aimed at designing systems that may effectively and efficiently change the way people work. Pervasive technologies and smart places deeply influence traditional physical boundaries and operational modes, leading to important changes in work practice. The goal of this paper is to provide the basis for an improved co-operation and mutual inspiration among public employees by using End-User Development (EUD). EUD in the e-Government context provides non-professional software developers with methods, techniques, and tools for configuring services that citizens can use to interact with public offices. The paper describes how, by using EUD-enabled tools, the work practice of the public staff changes, and how this transformation allows public employees with limited technical background to create services according to their expertise and expectations, and to share them.

In autoimmune diseases, there have been proposals that exogenous “molecular triggers”, i.e., specific ‘non-self antigens’ accompanying infectious agents, might disrupt control of the adaptive immune system resulting in serious pathologies. The etiology of multiple sclerosis (MS) remains unclear. However, epidemiologic data suggest that exposure to infectious agents may be associated with increased MS risk and progression may be linked to exogenous, bacterially-derived, antigenic molecules, mimicking mammalian cell surface glycoconjugates triggering autoimmune responses. Previously, antibodies specific to a gluco-asparagine (N-Glc) glycopeptide, CSF114(N-Glc), were identified in sera of an MS patient subpopulation. Since the human glycoproteome repertoire lacks this uniquely modified amino acid, we turned our attention to bacteria, i.e., Haemophilus influenzae, expressing cell-surface adhesins including N-Glc, to establish a connection between H. influenzae infection and MS. We exploited the biosynthetic machinery from the opportunistic pathogen H. influenzae (and the homologous enzymes from A. pleuropneumoniae) to produce a unique set of defined glucosylated adhesin proteins. Interestingly we revealed that a hyperglucosylated protein domain, based on the cell-surface adhesin HMW1A, is preferentially recognized by antibodies from sera of an MS patient subpopulation. In conclusion the hyperglucosylated adhesin is the first example of an N-glucosylated native antigen that can be considered a relevant candidate for triggering pathogenic antibodies in MS., Massachusetts Institute of Technology (Class of 1922 Professorship)

The recently introduced Cu(I)-catalyzed azide-alkyne 1,3-dipolar Huisgen cycloaddition as a prototypic "click chemistry reaction" presented an opportunity for introducing the 1,4-disubstituted-[1,2,3]triazolyl moiety as a new isostere for peptide bonds in the backbone. Previous study in our lab focused on the synthesis of a model i-to-i+4 side chain-to-side chain 1,4- and 4,1-disubstituted-[1,2,3]triazolyl-bridged cyclo-nonapeptide I (Scheme 1) as analogues of its structurally related helical i-to-i+4 lactam-bridged cyclo-nonapeptide [Lys¹³ (&¹), Asp¹⁷ (&²)]parathyroid hormone related peptide (PTHrP)(11-19)NH₂ (1) a truncated version of the α-helical and potent parathyroid hormone receptor 1 agonist [Lys¹³ (&¹), Asp¹⁷ (&²)]PTHrP(1-34)NH₂, (2,3) N(α) -Ac-Lys-Gly-Lys(&¹)-Ser-Ile-Gln-Asp(&²)-Leu-Arg-NH₂]. Systematic [1,2,3]triazolyl-containing bridge structure-conformation relationship studies in hexafluoroacetone/water mixture included incorporation of bridges varied in size and position and orientation of the triazolyl ring within the bridge. These studies revealed that the size of methylene bridge flanking triazolyl moiety is critical to reproduce in the heterodetic cyclo-nonapeptides. The conformational features of the analogues cyclo-nonapeptide in which Lys¹³ and Asp¹⁷ are bridged by the isosteric lactam. Here, we extend our conformational analysis to dimethyl sulfoxide/water mixture in an effort to characterize inherent conformational properties of the heterodetic cyclopeptides that are solvent independent. Our present study shows that the physicochemical properties of the structure-supporting solvent cannot override the effect of the size of methylene bridge to form helical mimetic structures. Moreover, we prove that [1,2,3]triazolyl ring is not a simple bioisostere of lactam bond, but it affects the secondary structure of the peptide, in relation to its positioning orientation.

Attracted by the possibility to optimize time and yield of the synthesis of difficult peptide sequences by MW irradiation, we compared Fmoc/tBu MW-assisted SPPS of 1-34 N-terminal fragment of parathyroid hormone-related peptide (PTHrP) with its conventional SPPS carried out at RT. MWs were applied in both coupling and deprotection steps of SPPS protocol. During the stepwise elongation of the resin-bound peptide, monitoring was conducted by performing MW-assisted mini-cleavages and analyzing them by UPLC-ESI-MS. Identification of some deletion sequences was helpful to recognize critical couplings and as such helped to guide the introduction of MW irradiations to these stages.

Objectives Phthalates might be implicated with obesity and insulin sensitivity. We evaluated the levels of primary and secondary metabolites of Di-(2-ethylhexyl) phthalate (DEHP) in urine in obese and normal-weight subjects both before and during puberty, and investigated their relationships with auxological parameters and indexes of insulin sensitivity. Design and Methods DEHP metabolites (MEHP, 6-OH-MEHP, 5-oxo-MEHP, 5-OH-MEHP, and 5-CX-MEHP), were measured in urine by RP-HPLC-ESI-MS. Traditional statistical analysis and a data mining analysis using the Auto-CM analysis were able to offer an insight into the complex biological connections between the studied variables. Results The data showed changes in DEHP metabolites in urine related with obesity, puberty, and presence of insulin resistance. Changes in urine metabolites were related with age, height and weight, waist circumference and waist to height ratio, thus to fat distribution. In addition, clear relationships in both obese and normal-weight subjects were detected among MEHP, its products of oxidation and measurements of insulin sensitivity. Conclusion It remains to be elucidated whether exposure to phthalates per se is actually the risk factor or if the ability of the body to metabolize phthalates is actually the key point. Further studies that span from conception to elderly subjects besides further understanding of DEHP metabolism are warranted to clarify these aspects.

Side chain-to-side chain cyclizations represent a strategy to select a family of bioactive conformations by reducing the entropy and enhancing the stabilization of functional ligand-induced receptor conformations. This structural manipulation contributes to increased target specificity, enhanced biological potency, improved pharmacokinetic properties, increased functional potency, and lowered metabolic susceptibility. The Cu(I)-catalyzed azide-alkyne 1,3-dipolar Huisgen's cycloaddition, the prototypic click reaction, presents a promising opportunity to develop a new paradigm for an orthogonal bioorganic and intramolecular side chain-to-side chain cyclization. In fact, the proteolytic stable 1,4- or 4,1-disubstituted [1,2,3]triazolyl moiety is isosteric with the peptide bond and can function as a surrogate of the classical side chain-to-side chain lactam forming bridge. Herein we report the design, synthesis, conformational analysis, and functional biological activity of a series of i-to-i+5 1,4- and 4,1-disubstituted [1,2,3]triazole-bridged cyclopeptides derived from MT-II, the homodetic Asp(5) to Lys(10) side chain-to-side chain bridged heptapeptide, an extensively studied agonist of melanocortin receptors.

ASDs (autism spectrum disorders) are a complex group of neurodevelopment disorders, still poorly understood, steadily rising in frequency and treatment refractory. Extensive research has been so far unable to explain the aetiology of this condition, whereas a growing body of evidence suggests the involvement of environmental factors. Phthalates, given their extensive use and their persistence, are ubiquitous environmental contaminants. They are EDs (endocrine disruptors) suspected to interfere with neurodevelopment. Therefore they represent interesting candidate risk factors for ASD pathogenesis. The aim of this study was to evaluate the levels of the primary and secondary metabolites of DEHP [di-(2-ethylhexyl) phthalate] in children with ASD. A total of 48 children with ASD (male: 36, female: 12; mean age: 11 ± 5 years) and age- and sex-comparable 45 HCs (healthy controls; male: 25, female: 20; mean age: 12 ± 5 years) were enrolled. A diagnostic methodology, based on the determination of urinary concentrations of DEHP metabolites by HPLC-ESI-MS (HPLC electrospray ionization MS), was applied to urine spot samples. MEHP [mono-(2-ethylhexenyl) 1,2-benzenedicarboxylate], 6-OH-MEHP [mono-(2-ethyl-6-hydroxyhexyl) 1,2-benzenedicarboxylate], 5-OH-MEHP [mono-(2-ethyl-5-hydroxyhexyl) 1,2-benzenedicarboxylate] and 5-oxo-MEHP [mono-(2-ethyl-5-oxohexyl) 1,2-benzenedicarboxylate] were measured and compared with unequivocally characterized, pure synthetic compounds (>98%) taken as standard. In ASD patients, significant increase in 5-OH-MEHP (52.1%, median 0.18) and 5-oxo-MEHP (46.0%, median 0.096) urinary concentrations were detected, with a significant positive correlation between 5-OH-MEHP and 5-oxo-MEHP ( rs=0.668, P