Molecular recognition in helix-loop-helix and helix-loop-helix-leucine zipper domains: Design of repertoires and selection of high affinity ligands for natural proteins

Helix-loop-helix (HLH) and helix-loop-helix-leucine zipper (HLHZip) are dimerization domains that mediate selective pairing among members of a large transcription factor family involved in cell fate determination. To investigate the molecular rules underlying recognition specificity and to isolate molecules interfering with cell proliferation and differentiation control, we assembled two molecular repertoires obtained by directed randomization of the binding surface in these two domains. For this strategy we selected the Heb HLH and Max Zip regions as molecular scaffolds for the randomization process and displayed the two resulting molecular repertoires on lambda phage capsids. By affinity selection, many domains were isolated that bound to the proteins Mad, Rox, MyoD, and Id2 with different levels of affinity. Although several residues along an extended surface within each domain appeared to contribute to dimerization, some key residues critically involved in molecular recognition could be identified. Furthermore, a number of charged residues appeared to act as switch points facilitating partner exchange. By successfully selecting ligands for four of four HLH or HLHZip proteins, we have shown that the repertoires assembled are rather general and possibly contain elements that bind with sufficient affinity to any natural HLH or HLHZip molecule. Thus they represent a valuable source of ligands that could be used as reagents for molecular dissection of functional regulatory pathways

Lean practices implementation, their criticalities and their relationships with operational responsiveness and firm performance

In the last few years, at European Union level, companies are facing many obstacles due to macroeconomic instability. In order to stay competitive and survive in the present world turmoil, companies must seek to new ways of reducing costs, increase the quality of the products and meet the ongoing changes in the market. Driven by the success performed by Toyota and several other organizations worldwide, a growing number of firms have been adopting Lean manufacturing practices to fulfill market needs, reduce costs, and gain competitive advantages over competitors. But, although many firms report large benefits from Lean implementation, Lean is not a panacea. Through an overview of Lean strategy implementation in Italian manufacturing industries, and a classification in "low"/"medium" and "high lean performers" we are able to see whether lean thinking could be a way for improving operational performance. Moreover, combining field interviews with the literature review, theoretical connections have been developed among Lean manufacturing techniques, operational responsiveness and firm growth performances. A conceptual model has been proposed and represented. The aim is investigating the network of influences among lean best practices (supplier practices, workforce practices, production efficiency practices and quality practices), operational responsiveness (Product mix variety, Product innovation and Time effectiveness) and firm growth performances

Enhancer of zeste homolog 2 (EZH2) in pediatric soft tissue sarcomas: first implications.

Soft tissue sarcomas of childhood are a group of heterogeneous tumors thought to be derived from mesenchymal stem cells. Surgical resection is effective only in about 50% of cases and resistance to conventional chemotherapy is often responsible for treatment failure. Therefore, investigations on novel therapeutic targets are of fundamental importance. Deregulation of epigenetic mechanisms underlying chromatin modifications during stem cell differentiation has been suggested to contribute to soft tissue sarcoma pathogenesis. One of the main elements in this scenario is enhancer of zeste homolog 2 (EZH2), a methyltransferase belonging to the Polycomb group proteins. EZH2 catalyzes histone H3 methylation on gene promoters, thus repressing genes that induce stem cell differentiation to maintain an embryonic stem cell signature. EZH2 deregulated expression/function in soft tissue sarcomas has been recently reported. In this review, an overview of the recently reported functions of EZH2 in soft tissue sarcomas is given and the hypothesis that its expression might be involved in soft tissue sarcomagenesis is discussed. Finally, the therapeutic potential of epigenetic therapies modulating EZH2-mediated gene repression is considered

MicroRNAs in rhabdomyosarcoma: pathogenetic implications and translational potentiality

There is growing evidence that interconnections among molecular pathways governing tissue differentiation are nodal points for malignant transformation. In this scenario, microRNAs appear as crucial players. This class of non-coding small regulatory RNA molecules controls developmental programs by modulating gene expression through post-transcriptional silencing of target mRNAs. During myogenesis, muscle-specific and ubiquitously-expressed microRNAs tightly control muscle tissue differentiation. In recent years, microRNAs have emerged as prominent players in cancer as well. Rhabdomyosarcoma is a pediatric skeletal muscle-derived soft-tissue sarcoma that originates from myogenic precursors arrested at different stages of differentiation and that continue to proliferate indefinitely. MicroRNAs involved in muscle cell fate determination appear down-regulated in rhabdomyosarcoma primary tumors and cell lines compared to their normal counterparts. More importantly, they behave as tumor suppressors in this malignancy, as their re-expression is sufficient to restore the differentiation capability of tumor cells and to prevent tumor growth in vivo. In addition, up-regulation of pro-oncogenic microRNAs has also been recently detected in rhabdomyosarcoma

Relation of project managers' personality and project performance: an approach based on value stream mapping

Purpose: This work investigates the influence of project managers’ personality on the success of a project in a Multinational Corporation. The methodology proposed for analyzing the project managers’ personality is based on the Myers-Briggs Type Indicator. Design/methodology/approach: Forty projects carried out in 2012 by multinational corporation, concerning new product development (NPD), have been analyzed, comparing the profile of project managers with results obtained in terms of traditional performance indexes (time delay and over-budget of projects) and performance indexes usually used in “Lean Production” sector (waste time and type of “wastes”). A detailed analysis of the most important “wastes” during the project development is carried out using the Value Stream Mapping (VSM) technique. Findings and Originality/value: Relying on the Myers–Briggs personality instrument, results show that extroverted managers (as opposed to introverted managers) carry out projects that show lower delay and lower waste time. Introverted managers often make “Over-processing” and “Defect” types of waste. Moreover, lower delay and over-budget have been shown by perceiving managers. Research limitations: Regarding the limitations of this work it is necessary to highlight that we collected data from project managers in a retrospective way. While we believe that several aspects of our data collection effort helped enhance the accuracy of the results, future research could conduct real-time case study research to get more detailed insights into the proposed relationships and avoid retrospective bias. Moreover we focused on a single respondent, the project manager. This helped us ensure that their interpretations played an important role in product development. But, we cannot examined the opinion of team members that could be different from project managers opinion regarding some questions. Originality/value: This research provides insight useful to develop proactive approaches to prevent project failures, including the creation of more effective messages and methods to help companies to make the best choices during managers´ hiring. Moreover this research would allow organizations to better match the short-term organizational needs with appropriate personality types.Peer Reviewe

Improved Decision-Making through a DEMATEL and Fuzzy Cognitive Maps-Based Framework

The decision-making process is highly demanding. There has been an increasing tendency to incorporate human thinking, individual experience about a problem, and pure mathematical approaches. Here, a novel integrated approach is investigated and proposed to develop an advanced hybrid decision-support system based on the decision-making trial and evaluation laboratory (DEMATEL) and fuzzy cognitive maps (FCMs). Indeed, knowledge acquisition and elicitation may present distortions and difficulties finding a consensus and an interpretation. Thus, the proposed combined approach aims to examine in depth the potential to improve FCMs' outcomes by integrating FCM with the DEMATEL approach. The combined methodology achieves at avoiding some of the drawbacks, such as the lack of a standardized FCM theoretical model. Thus, it provides advanced comparative analysis and results in better interpretation of the decision-making process. It is highlighted that the traditional FCM approach does not allow distinguishing the whole number of defined scenarios, in contrast to the hybrid one presented here, which increases the ability of users to make correct decisions. Combining the two approaches provides new capabilities to FCMs in grouping experts' knowledge, while the DEMATEL approach contributes to refining the strength of concepts' connections

Enhancer of zeste homolog 2 (EZH2) in pediatric soft tissue sarcomas: first implications

Soft tissue sarcomas of childhood are a group of heterogeneous tumors thought to be derived from mesenchymal stem cells. Surgical resection is effective only in about 50% of cases and resistance to conventional chemotherapy is often responsible for treatment failure. Therefore, investigations on novel therapeutic targets are of fundamental importance. Deregulation of epigenetic mechanisms underlying chromatin modifications during stem cell differentiation has been suggested to contribute to soft tissue sarcoma pathogenesis. One of the main elements in this scenario is enhancer of zeste homolog 2 (EZH2), a methyltransferase belonging to the Polycomb group proteins. EZH2 catalyzes histone H3 methylation on gene promoters, thus repressing genes that induce stem cell differentiation to maintain an embryonic stem cell signature. EZH2 deregulated expression/function in soft tissue sarcomas has been recently reported. In this review, an overview of the recently reported functions of EZH2 in soft tissue sarcomas is given and the hypothesis that its expression might be involved in soft tissue sarcomagenesis is discussed. Finally, the therapeutic potential of epigenetic therapies modulating EZH2-mediated gene repression is considered

A design method for improving assembly and environmental sustainability in packaging solutions: a case study in household appliances

By using a functional requirement analysis, through Design for Manufacture and Assembly and Design for Environment principles, this paper aims at showing a new design method to improve the overall assembly features and environmental sustainability of a packaging solution. This method provides to rank functional requirements according to three different design specifications and also to the number of relationships they have with each other. At the same time, a ranked order of importance for the packaging parts has been realised, considering the number of performed functions. The purpose of this method is to support the designers in focusing their attention on the most important packaging parts and, at the same time, giving them a clear idea of which are the most important functional requirements to be satisfied. This study has been focused on domestic household packaging, but the provided method can be extended to any particular packaging solution and its findings are still valid. According to the Design for Environmental perspective, the actual and the new resulting packaging solutions have been then compared through Life Cycle Assessment method. The results have shown the new packaging solution being able to cut down the environmental impacts, on average, of approximately 30%

sustainability analysis of friction stir welding of aa5754 sheets

Abstract The environmental impact of friction stir welding process vs. welding parameters was evaluated and analysed in detail. To this purpose, butt joints in AA5754 aluminum alloy sheets were obtained at different rotational and welding speeds. All input and output data, in terms of materials, energies and emissions, were collected and analyzed using a life cycle assessment software in order to evaluate the environmental impact index. Sound weld was used as functional unit and all energy and material flows were based on it. The results given by the life cycle assessment analysis has shown that the environmental impact of friction stir welding is strongly affected by rotational and welding speeds. The environmental impact was also related to the mechanical properties of joints, expressed as ultimate tensile strength and ultimate elongation