Marcelo T Okano

Fernando A S Marins

Oduvaldo Vendrametto

Selecting theoretical models for IT and supply chain through a bibliometric research

Keywords: IT, SCM, SCOR, GSCF

The objective of this research is to identify the major works in IT and supply chain and selecting the main theoretical models for analysis. A literature search was performed on the major knowledge bases to determine and select the conceptual models being used. This resulted in the choice of Gunasekaran et al model. SCOR (https://supply-chain.org) and GSCF (http://www.gsb.stanford.edu/scforum).

As a result, we analyze these three mentioned models. The research is important because it provided a bibliographical study on the use of information technology in managing supply chain by means of theoretical models.

Introduction

Most companies are more and more applying IT (Information technology) systems, especially in Supply Chain Management (Supply Chain Management -SCM) to enhance their performance in competitive global markets [START_REF] Kuo-Jui | Information technology in supply chain management: a case study[END_REF].

According to Prajogo & Olhager [START_REF] Prajogo | Supply chain integration and performance: The effects of long-term relationships, information technology and sharing, and logistics integration[END_REF], Information (and communication) technology plays a central role in supply chain management in the following aspects. First, IT allows firms to increase the volume and complexity of informations which needs to be communicated with their trading partners. Second, IT allows firms to provide real-time supply chain information, including inventory level, delivery status, and production planning and scheduling which enables firms to manage and control its supply chain activities. Third, IT also facilitates the alignment of forecasting and scheduling of operations between firms and suppliers, allowing better inter-firms coordination There are several conceptual models and many discussions on measures of supply chain performance in the literature, however, there is a lack of empirical analysis and case studies on performance metrics and measurements in an environment of supply chain [START_REF] Gunasekaran | A framework for supply chain performance measurement[END_REF], impacted by the use of information technology.

The objective of this research project is to identify the main works on IT and supply chain and selecting the main theoretical models for analysis. We performed a literature search in major knowledge bases to determine and select the conceptual models being used. This resulted in the choice of models Gunasekaran et al. [START_REF] Gunasekaran | A framework for supply chain performance measurement[END_REF], SCOR (https://supply-chain.org) and GSCF (http://www.gsb.stanford.edu/scforum). As a result we have the analysis of these three models mentioned. The research is important because it provided a detailed study on the use of information technology in managing supply chain by means of theoretical models.

Material and methods

A broad survey of a relevant theoretical framework was done to investigate the IT applied to SCM from a literature survey conducted in major databases in the area of Information Technology, Logistics and Supply Chain Management. A bibliometric survey, or bibliometrics was performed for a quantitative analysis of the written communication of journal articles. Citations and cocitations were analyzed. The citation analysis is based on the premise that authors cite articles that are important in the development of their research.

Tarapanoff et al [START_REF] Tarapanoff | Técnicas para tomada de decisão nos sistemas de informação[END_REF] defines bibliometrics as the study of quantitative aspects of production, distribution and use of recorded information from mathematical models for the process of decision making .

Some researchers observed that the frequency distribution of the data in a text or a set of references follows certain standards. These observations led to the bibliometric laws: Lotka's law that determines the contribution of each author to the advancement of science; Bradford's Law which is a method to select the most representative journals for an area of science; and Zipf's Law which found that words that occur in a text are counted and sorted in descending order of number of occurrences, the multiplication of the number of occurrences by the ranking position for each word is a constant [START_REF] Amaral | Uma visão da produção científica nos Anais do Encontro Nacional de Engenharia de Produção através da Bibliometria[END_REF].

Among the various bibliometric indicators formed from citation data, stands out even though the identification of the number of references to a specific set of work you want to qualify is possibly as important evaluation process of research activity, and operationally difficult to be applied to the funding agencies. These difficulties are mainly due to the large amount of documents involved in these situations and the known inconsistencies in the rates of citations and bibliographies.

Given these limitations, the data categorized quote by periodical and published in the form of indicators in the Journal Citation Reports (JCR) of the Institute for Scientific Information (ISI) began to be used as an evaluation parameter of researchers and institutions. Are published annually in the JCR three indicators, by journal title: the immediate index citation (immediacy index), the half-life of citations (cited HalfLife) and finally the bibliometric index most known and used, the impact factor (impact Factor) [START_REF] Strehl | O fator de impacto do ISI e a avaliação da produção científica: aspectos conceituais e metodológicos[END_REF].

For international journals the research was conducted through the site ISI Web of Science (http://apps.webofknowledge.com), using the advanced search terms for IT or Information Technology and SCM or Supply Chain Management in the titles of articles . For Brazilian publications, we used the site SciELO (http://www.scielo.org) through the advanced search with the terms of Information Technology and Management of the supply chain. 36 articles, 27 of which were international and national 9 were found.

The publications are from the period 1999-2013, distributed according to Figure 1, and the relation of this periodic consulted in Table 1.

TRENDS IN SUPPLY CHAIN DESIGN AND MANAGEMENT: TECHNOLOGIES AND METHODOLOGIES 1

There are several conceptual models and many discussions on measures of supply chain performance in the literature, however, there is a lack of empirical analysis and case studies on performance metrics and measurements in an environment of supply chain [START_REF] Gunasekaran | A framework for supply chain performance measurement[END_REF], impacted by the use of information technology.

The criteria used to select the models were originally cited in the articles studied. Thereafter, which related to IT and supply chain and covering at least the areas of customers, suppliers, delivery and production After reading the articles, the articles selected from table 2 and their major contributions to the research. Proposes the benefits of the use of IT in supply chain

Analysis of results

A) Model proposed by Gunasekaran et al. [START_REF] Gunasekaran | A framework for supply chain performance measurement[END_REF], a framework for performance measures and metrics is presented (see Table 3), considering the four major supply chain activities/ processes (plan, source, make/assemble, and deliver). These metrics were classified at strategic, tactical and operational to clarify the appropriate level of management authority and responsibility for performance.

According to Rushton & Oxley [START_REF] Rushton | Handbook of Logistics and Distribution Management[END_REF], this hierarchy is based on the time horizon for activities and the relevance of the decisions and the influence of different levels of management.

Measures to influence the strategic decisions manages high level, often reflecting the broad based policy research, corporate financial planning , competitiveness and the level of adherence to organizational goals .

The tactical level deals with the allocation of resources and measure performance against targets to be met in order to achieve specified outcomes at the strategic level. The measure of performance at this level provides valuable feedback on decisions mid-level management.

Measurements and metrics for operational level require accurate data and evaluate the results of management decisions at the operational level. Supervisors and workers must adjust the operational objectives that, if achieved , result in the achievement of tactical objectives [START_REF] Gunasekaran | A framework for supply chain performance measurement[END_REF]. It is a reference model of supply chain operations, coordinated by the Supply Chain Council -SCC (http://supply-chain.org/), analyzing their structure, composition and its performance indicators [START_REF] Rodrigues | O modelo de referência das operações na cadeia de suprimentos -(SCOR-model)[END_REF].

It was designed to assist in learning companies in relation to internal and external processes to their field of expertise [START_REF] Rodrigues | O modelo de referência das operações na cadeia de suprimentos -(SCOR-model)[END_REF].

The SCOR Framework is the basis for all supply chain management. It helps companies describe how a supply chain is organized, how well it performs and capabilities it possesses. The metrics in SCOR provide a solid foundation for measuring performance and identifying priorities, the processes are the common language in your supply chain operations.. The model allows companies the following advantages:

-Evaluation of effective processes themselves; -Compare your performance with other companies; -Looking specify the competitive advantage; -Uses benchmarking information and best practices to improve their activities; -Quantify the benefits in implementing change; -Identifies the best software tools to meet their specific needs.

The SCOR ® is version 10.0, and is based on five core management processes -planning, supply, produce, deliver and return, as illustrated in Figure 2. The description of the five processes: a) Plan -the scope of the planning process and management of supply and demand as a reference model has been the definition of resources and demand planning inventory, distribution, production and capacity planning; b) Supply -acquisition of raw materials, qualification and certification of suppliers, quality monitoring, negotiating contracts with vendors and receiving materials; c) Manufacturing -manufacturing of the final product, testing, packing, process changes, product launch and ownership; d) Deliver -order management and credit, warehouse management, transportation, shipping and customer service. Create database of consumers, products and prices; e) Return -the raw material, finished product, maintenance, repairs and inspection. These processes extend to the supporting post sale to the consumer.

C) SCM Model -GSCF -Global Supply Chain Forum

This model GSCF was developed at Ohio State University in 1994 by Professor Douglas Lambert (http://fisher.osu.edu/research/facultyexpertise/marketing-logistics/lambert). He describes three levels (strategic, tactical and operational) and highlights the links between the process and structure of the supply chain. It focuses on eight processes: customer relationship management, customer service management, demand management, order fulfillment, manufacturing flow management, relationship management vendor, product development and marketing and management of return [START_REF] Estampe | A framework for analysing supply chain performance evaluation models[END_REF].

Figure 3 illustrates the eight business processes along the supply chain and presents the network structure of the supply chain, flow of products and materials, and key business processes interrelated, and borders intra-company involved in a chain supplies [START_REF] Santos | Modelo de referência para o processo de desenvolvimento de produtos em um ambiente de scm[END_REF]. The GSCF suggests the classification of the processes of supply chain management for the four types of business, according to Santos [START_REF] Santos | Modelo de referência para o processo de desenvolvimento de produtos em um ambiente de scm[END_REF]: 1. Managed processes: business processes conducted with a set of key companies along the supply chain will be treated and managed in an integrated manner.

2. processes: are not as critical to the company focus as managed processes, but it is important that they are integrated and constantly monitored.

3. Unmanaged processes: unmanaged processes are those that focus the company decides not to get involved in their management that considers not to be critical or monitored. 4. Processes of non-members: those involving members of the supply chain of the company focus and not members of the supply chain. These metrics and models will be the basis for the development of performance indicators of the supply chain impacted by the use of IT.

Final Considerations

The survey reached a view to identifying the main models for IT systems used in the supply chain.

The research objective was achieved because we can identify the major works in IT and Supply Chain using bibliometrics and selected the main theoretical models for analysis. As a result we get three Gunasekaran, Scor and GSCF models. Based on the conceptual framework in three related models verified that the six key areas are engineering, manufacturing, delivery, return, suppliers and customers.

Despite the lack of literature found in the survey, we perceive its importance for the occurrence of the continuity of the articles, which began early in this century and remain to the present day, presenting an increase in cocitações the last five years.

The literature is using bibliometrics is important to check what is being written on the subject in the major countries and academic centers tool.

One sees a lot of interest from various authors on the subject and the relevance of academic articles written on various research bases.

As a future project, is expected to use these this search to reassessment and development of indicators in order to measure the level of impact in different areas of the company, as well as contribute to improving the analysis of information technology systems in supply chain management supplies.

Figure 1 -

 1 Figure 1 -Publications per yearTable1-List of publications by periodicals

Figure 2 -

 2 Figure 2-SCOR Model-version 10.0 Source: Supply Chain Council

Figure 3 -

 3 Figure3-Supply Chain Management: integration and management of business processes through the supply chain[START_REF] Santos | Modelo de referência para o processo de desenvolvimento de produtos em um ambiente de scm[END_REF]

Table 1 -

 1 List of publications by periodicals

	Periodic

Table 2 -

 2 Periodics used in research

	Títle							Author	Contribution to research
	Information technology, operational,	Definitions of terms Competence of IT, IT Flexibility
	and management competencies for	Ngai, Eric W. T.;	and Integration of IT.
	supply chain agility: Findings from	Chau, Dorothy C.
	case studies						K.; Chan, T. L. A.
	A framework for analysing supply	Indicators Model SCM GSCF -Global Supply Chain
	chain	performance	evaluation	ESTAMPE,	D.,	Forum
	models.						LAMOURI, S.
								Model proposed by Gunasekaran et al. (2004) -
	A framework for supply chain performance measurement,	GUNASEKARAN, A.; PATEL, C.; MCGAUGHEY,	strategic, operational and tactical levels are hierarchies in the function, where policies and compensation can be distinguished and proper
								R.E.	control exercised (Ballou, 1992).
	Better	supply	chains	through	Proposes the benefits of the use of IT in supply
	information technology.				LEVARY, R.R.,	chain
	The	performance	prism:	The	NEELY,	A.;	define performance appraisal
	scorecard	for	measuring and	ADAMS,	C.;
	managing business success.			KENNERLEY, M.
	Use of information technology in managing supply chain in São Luís, Maranhão, and opportunities for the	Morais, Káty Maria Nogueira; Tavares, Elaine.
	development of local suppliers

Table 3 -

 3 Supply Chain Performance Metrics Framework

B) SCOR® -Supply Chain Operations Reference Model


Laure Guenin-Macé

Reid Oldenburg

Fabrice Chrétien

Caroline Demangel
email: demangel@pasteur.fr

Pathogenesis of skin ulcers: lessons from the Mycobacterium ulcerans and Leishmania spp pathogens

Keywords: Skin, infection, cutaneous Leishmaniasis, Leishmania spp, Buruli ulcer, Mycobacterium ulcerans, mycolactone

Skin ulcers are most commonly due to circulatory or metabolic disorders and are a major public health concern. In developed countries, chronic wounds affect more than 1% of the population and their incidence is expected to follow those observed for diabetes and obesity. In tropical and subtropical countries, an additional issue is the occurrence of ulcers of infectious origins with diverse aetiologies. While the severity of cutaneous Leishmaniasis correlates with protective immune responses, Buruli ulcers caused by Mycobacterium ulcerans develop in the absence of inflammation. Based on these two examples, this review aims to demonstrate how studies on microorganism-provoked wounds can provide insight into the molecular mechanisms controlling skin integrity. We highlight the potential interest of a mouse model of non-inflammatory skin ulceration caused by intradermal injection of mycolactone, an unusual lipid toxin with ulcerative and immunosuppressive properties produced by M. ulcerans.

Introduction

Chronic wounds can result from a variety of causes, such as venous stasis, arterial insufficiency, diabetes, inflammation and cancer. A common complication of their treatment is bacterial colonization, which causes significant morbidity and elevates considerably health care costs. The expenditures for wound care are estimated $15 billion per year today, and they are expected to rise with the globalization of diabetes [START_REF] Hu | Globalization of diabetes: the role of diet, lifestyle, and genes[END_REF] . Diabetes affects 285 million patients worldwide, two-thirds of which occur in low-to middle-income countries. It is estimated that 15% of diabetic patients will develop a diabetic foot ulcer, of which 50% (21 million patients) will become infected. In addition to this modern crisis, subtropical and tropical countries have to face the burden imposed by ulcerative pathogens. Both primarily and secondarily infected wounds often result in failure to heal, by mechanisms that are diverse and highly dependent on the infectious agent [START_REF] Frank | Approach to infected skin ulcers[END_REF] . Based on the description of the pathogenic processes employed by M. ulcerans and Leishmania spp, this paper aims to describe the contribution of infective ulcers to our general understanding of wound formation and repair.

Structure and functions of the skin

Before we review the various conditions leading to skin ulceration, it is important to describe the architecture and functions of this organ. As illustrated (Figure 1), human skin is composed of two superposed layers, the epidermis and the dermis. The epidermis is a stratified squamous epithelium composed of a first layer of proliferating basal keratinocytes attached to a basement membrane (referred to as stratum basale) covered with suprabasal keratinocyte layers at various stages of differentiation (spinosum, granulosum, lucidum and corneum from deep to superficial). This external layer of the skin is not vascularised and keratinocytes receive oxygen and nutriments by diffusion from the underlying tissues. The dermis is a connective tissue that is essentially composed of an extracellular matrix (ECM) produced by dermal fibroblasts. The ECM is made of fibrous structural proteins including collagen, elastin and laminin, which are embedded in highly hydrated proteoglycans (such as dermatan sulfate and hyaluronan). In contrast to the epidermis, the dermis harbours nerves and sensory organs, hair follicles and various glands (sweat, sebaceous and apocrine). It is perfused by a dense anastomotic network of blood vessels and by draining lymphatics coming from the hypodermis. The hypodermis (also called subcutis) is primarily composed of connective and adipose tissues (accounting for 50% of the body fat) linking the dermis to bone and muscles. The different structure, physico-chemical properties and cellular composition of the tissues composing the skin allow this largest organ of the body to perform numerous functions such as protection against mechanical injuries, thermoregulation, immune surveillance and sensation.

Non-infectious causes of skin ulceration

Acute wounds, due to surgical incision or traumatic injury, typically proceed into a timely reparative process that results in the restoration of anatomic and functional integrity.

However in a number of conditions this process is abnormally slow, or interrupted, and wounds become chronic. Venous ulcers are the most common type of chronic wounds, accounting for up to 80% of all leg ulcers [START_REF] Lawall | Treatment of chronic wounds[END_REF] . Diabetic ulcers represent a growing challenge, as the burden of diabetes mellitus increases and patients continue to age [START_REF] Wild | Global prevalence of diabetes: estimates for the year 2000 and projections for 2030[END_REF] . Less common than venous and diabetic ulcers, ulcers of arterial aetiology are found in older patients who have risk factors of peripheral arterial disease. Pressure ulcers, also known as decubitus ulcers or bedsores, occur when mobility is limited in patients who are post-operative, paralysed or taking sedative medication. They can lead to severe pain, are prone to infection, and associated with high mortality in elderly individuals. Skin ulceration can also result from immune dysfunction. For example Pyoderma gangrenosum is thought to result from a neutrophil-instigated destruction of the skin that is frequently associated with other immune-mediated diseases, such as inflammatory bowel disease or rheumatoid arthritis [START_REF] Powell | Pyoderma gangrenosum: a review of 86 patients[END_REF] .

Finally, malignancies can ulcerate with squamous cell carcinoma commonly having central ulceration at presentation [START_REF] Firnhaber | Diagnosis and treatment of Basal cell and squamous cell carcinoma[END_REF] .

Chronic wounds are commonly associated with defective blood flow (ischemia) [START_REF] Cornwall | Leg ulcers: epidemiology and aetiology[END_REF] .

Venous insufficiency causes a local rise in blood pressure within superficial venous structures, leading to blood leakage into the interstitial space. Arterial ulcers occur after occlusion of an artery or arteriole, which in the vast majority of cases is a consequence of atherosclerosis or material deposition in small or medium sized arteries. Diabetic ulcers occur in patients with peripheral neuropathy and often-concurrent peripheral vascular diseases. Pressure ulcers usually occur at the muscle-bone interface in patients remaining in the same position for a prolonged period of time. In that case, pathogenesis is believed to result from cycles of ischemia and reperfusion, generating inflammation and necrosis. How defective blood flow leads to skin ulceration nevertheless remains largely unknown, due to the difficulty in establishing satisfactory in vitro systems and animal models to study cutaneous ischemia [START_REF] Salcido | Animal models in pressure ulcer research[END_REF] . In contrast, the comparison of acute versus chronic wounds in human patients, and the development of surgical mouse models of wound healing [START_REF] Wong | Surgical approaches to create murine models of human wound healing[END_REF] , have helped improve our understanding of the cellular and molecular mechanisms underpinning skin repair.

Mechanisms governing wound healing

Acute skin wounds typically heal by progressing through four consecutive yet overlapping phases: (i) haemostasis, (ii) inflammation (with an initial wave of neutrophils that are later replaced by macrophages), (iii) a proliferative phase during which the synthesis of new ECM results in scar formation then epithelialisation, and finally (iv) a remodelling of the ECM (Figure 1). Although haemostasis and inflammation proceed normally in chronic wounds, they do not translate into the proliferative and remodelling phases of healing. The comparison of acute versus chronic wounds has shown that production of new, fibrin/fibrinogen-rich ECM following clotting is essential in providing a scaffold for cell migration into the wound. Venous hypertension and blood stasis reduces vascular shear stress, resulting in a pro-inflammatory state that promotes leukocyte adhesion and migration [START_REF] Bergan | Chronic venous disease[END_REF] . The production of pro-inflammatory cytokines such as TNF and IL-1b by macrophages signal fibroblasts to secrete matrix metalloproteinases (MMPs) that degrade the ECM [START_REF] Mast | Interactions of cytokines, growth factors, and proteases in acute and chronic wounds[END_REF] . By producing reactive oxygen species (ROS), infiltrating inflammatory cells also generate a pro-oxidant microenvironment in the ulcers [START_REF] James | Evidence of oxidative stress in chronic venous ulcers[END_REF][START_REF] Moseley | Comparison of oxidative stress biomarker profiles between acute and chronic wound environments[END_REF] . ROS contribute to ECM proteolysis directly by degrading components of the matrix, and by stimulating the synthesis and activity of MMPs. In addition, the attack of ROS on extravasated erythrocytes results in iron deposition, which in combination with hydrogen peroxide released by activated neutrophils generate highly toxic radicals, further damaging skin tissues and fuelling inflammation [START_REF] Wenk | Selective pick-up of increased iron by deferoxamine-coupled cellulose abrogates the iron-driven induction of matrix-degrading metalloproteinase 1 and lipid peroxidation in human dermal fibroblasts in vitro: a new dressing concept[END_REF] .

While uncontrolled inflammation impairs wound healing, it may not be an absolute requirement for the initial steps of skin ulceration. By studying chronically ischemic but uninjured skin, Dalton et al. demonstrated that ECM homeostasis, which relies on the balance between collagen synthesis and degradation by MMPs, is profoundly impacted by defective blood circulation in the absence of inflammation [START_REF] Dalton | Abnormal extracellular matrix metabolism in chronically ischemic skin: a mechanism for dermal failure in leg ulcers[END_REF][START_REF] Dalton | Mechanisms of chronic skin ulceration linking lactate, transforming growth factor-beta, vascular endothelial growth factor, collagen remodeling, collagen stability, and defective angiogenesis[END_REF] . Compared to controls, ischemic skin tissue samples showed a decreased mechanical resistance. At the molecular level, they were marked by increased expression of the vascular endothelial growth factor VEGF and lactate, indicative of hypoxia. Hypoxic conditions are known to stimulate the production of TGF-b by fibroblasts that in turn promotes fibroblastic collagen synthesis [START_REF] Falanga | Low oxygen tension stimulates collagen synthesis and COL1A1 transcription through the action of TGF-beta1[END_REF] and the concurrent expression of MMP-2 by keratinocytes [START_REF] Salo | Transforming growth factor-beta 1 up-regulates type IV collagenase expression in cultured human keratinocytes[END_REF] . The increased synthesis of both collagen and MMP-2 collagenase results in an elevated matrix turnover. The hypoxiainducible factor (HIF)-1a and TGF-b also stimulate angiogenesis via the production of VEGF [START_REF] Detmar | Hypoxia regulates the expression of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) and its receptors in human skin[END_REF][START_REF] Berse | Hypoxia augments cytokine (transforming growth factor-beta (TGFbeta) and IL-1)-induced vascular endothelial growth factor secretion by human synovial fibroblasts[END_REF] . Together, these observations suggested that hypoxia might be sufficient to explain the remodelling of ECM and vessels, weakening the skin and facilitating ulceration.

Infective ulcers

Chronic wounds are always contaminated by microorganisms originating from the surrounding skin (such as Corynebacteria and Propionibacteria spp) and other endogenous sources or the external environment (including multi-resistant organisms such as methicillinresistant Staphylococcus aureus). However, wound healing is not compromised unless bacterial proliferation occurs, with generation of host immune responses and tissue injury 2 .

The initial bacterial burden, virulence and capacity of invading pathogens to grow within biofilms, combined with the ability of the host to mount protective immune responses both determine the transition to this infectious state. Other risk factors include malnutrition or obesity, diabetes and advanced age.

Chronic wounds can also occur as a result of a primary infection with microorganisms.

Amongst the most common ulcerative pathogens are mycobacterium species such as M. marinum, M. tuberculosis and the causative agent of Buruli ulcer (BU) M. ulcerans [START_REF] Johnson | Buruli ulcer (M. ulcerans infection): new insights, new hope for disease control[END_REF][START_REF] Silva | Pathogenetic mechanisms of the intracellular parasite Mycobacterium ulcerans leading to Buruli ulcer[END_REF][START_REF] Van Der Werf | Mycolactones and Mycobacterium ulcerans disease[END_REF][START_REF] Wansbrough-Jones | Buruli ulcer: emerging from obscurity[END_REF] . BU has been reported in more than 33 countries with tropical, subtropical and temperate climates and has become a major public health problem in sub-Saharan Africa. In Ghana, the point prevalence of BU can reach 150.8 per 100,000 individuals [START_REF] Amofah | Buruli ulcer in Ghana: results of a national case search[END_REF] . The protozoan parasite Leishmania is another major cause of infectious skin ulcers, with an estimated worldwide occurrence of cutaneous leishmaniasis of 1.5 million cases per year [START_REF] Khan | Cutaneous leishmaniasis in Pakistan[END_REF]

Mycobacterium ulcerans and Buruli ulcer disease

M. ulcerans is a mycobacterium causing BU in communities associated with an aquatic environment. Outbreaks are commonly associated with changes involving river areas [START_REF] Ross | Detection of Mycobacterium ulcerans in environmental samples during an outbreak of ulcerative disease[END_REF] .

Human to human transmission is rare [START_REF] Debacker | First case of Mycobacterium ulcerans disease (Buruli ulcer) following a human bite[END_REF] . Infection may occur by exposure of injured skin to contaminated water, although there is evidence for a role of biting insects as vectors of M. ulcerans, and aquatic snails and fish as intermediate hosts (reviewed in [START_REF] Merritt | Ecology and transmission of Buruli ulcer disease: a systematic review[END_REF] ). BU lesions typically start as a non-characteristic, pre-ulcerative stage (nodule, papule, plaque or oedema). After weeks to months, the skin covering the pre-ulcerative lesion eventually opens to form a characteristic ulcer with undermined edges. Histopathological hallmarks of BU are defective inflammatory responses in the presence of acid-fast bacilli, and extensive necrosis of dermal and adipose tissues. Common features also include epidermal hyperplasia in the regions flanking the ulcer, collagen destruction and vascular damage in the underlying dermis and subcutis [START_REF] Guarner | Histopathologic features of Mycobacterium ulcerans infection[END_REF][START_REF] Hayman | Mycobacterium ulcerans infection[END_REF][START_REF] Hayman | The pathology of Mycobacterium ulcerans infection[END_REF] . In addition, patients with BU display a distinctive profile of immune suppression, marked by the defective capacity of T cells to produce cytokines upon stimulation ex vivo [START_REF] Yeboah-Manu | Systemic suppression of interferon-gamma responses in Buruli ulcer patients resolves after surgical excision of the lesions caused by the extracellular pathogen Mycobacterium ulcerans[END_REF][START_REF] Phillips | Immunosuppressive Signature of Cutaneous Mycobacterium ulcerans Infection in the Peripheral Blood of Patients with Buruli Ulcer Disease[END_REF] .

Mycolactone, a diffusible cytotoxin uniquely produced by this pathogen, is believed to cause this intriguing combination of necrosis and immune suppression. In vitro experiments have shown that mycolactone is cytotoxic to epithelial cells and fibroblasts [START_REF] George | Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence[END_REF][START_REF] Hong | Mycolactones: immunosuppressive and cytotoxic polyketides produced by aquatic mycobacteria[END_REF] , and blocks the expression of homing receptors and production of cytokines by monocytes, dendritic and T cells at non-cytotoxic concentrations [START_REF] Coutanceau | Selective suppression of dendritic cell functions by Mycobacterium ulcerans toxin mycolactone[END_REF][START_REF] Coutanceau | Modulation of the host immune response by a transient intracellular stage of Mycobacterium ulcerans: the contribution of endogenous mycolactone toxin[END_REF][START_REF] Demangel | Buruli ulcer: reductive evolution enhances pathogenicity of Mycobacterium ulcerans[END_REF][START_REF] Guenin-Mace | Mycolactone impairs T cell homing by suppressing microRNA control of L-selectin expression[END_REF][START_REF] Pahlevan | The inhibitory action of Mycobacterium ulcerans soluble factor on monocyte/T cell cytokine production and NF-kappa B function[END_REF][START_REF] Simmonds | Mycolactone inhibits monocyte cytokine production by a posttranscriptional mechanism[END_REF] . Notably, bacterial killing in BU patients or experimentally infected animals undergoing antibiotic therapy is followed by a massive infiltration of necrotic material with leukocytes and the phagocytosis of dead mycobacterium [START_REF] Ruf | Secondary Buruli ulcer skin lesions emerging several months after completion of chemotherapy: paradoxical reaction or evidence for immune protection?[END_REF][START_REF] Ruf | Chemotherapy-associated changes of histopathological features of Mycobacterium ulcerans lesions in a Buruli ulcer mouse model[END_REF][START_REF] Schutte | Immunosuppression and treatment-associated inflammatory response in patients with Mycobacterium ulcerans infection (Buruli ulcer)[END_REF][START_REF] Schutte | Development of highly organized lymphoid structures in Buruli ulcer lesions after treatment with rifampicin and streptomycin[END_REF][START_REF] Schutte | Phagocytosis of Mycobacterium ulcerans in the course of rifampicin and streptomycin chemotherapy in Buruli ulcer lesions[END_REF] , showing that local and systemic cellular immune responses are suppressed by M. ulcerans during ulcer formation.

We reported recently that mycolactone targets and hyper-activates the Neural Wiskott-Aldrich syndrome protein (N-WASP) in epithelial cells [START_REF] Guenin-Mace | Mycolactone activation of Wiskott-Aldrich syndrome proteins underpins Buruli ulcer formation[END_REF] . N-WASP is particularly abundant in neurons, but is ubiquitously expressed by mammalian cells [START_REF] Snapper | N-WASP deficiency reveals distinct pathways for cell surface projections and microbial actin-based motility[END_REF] . Its best-known function is to regulate actin dynamics by transducing multiple endogenous signals into actin nucleation, via the Arp2/3 complex [START_REF] Machesky | Scar, a WASp-related protein, activates nucleation of actin filaments by the Arp2/3 complex[END_REF][START_REF] Rohatgi | The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly[END_REF][START_REF] Thrasher | WASP: a key immunological multitasker[END_REF] . By supporting the assembly and homeostasis of Ecadherin junctions [START_REF] Kovacs | N-WASP regulates the epithelial junctional actin cytoskeleton through a non-canonical post-nucleation pathway[END_REF] , N-WASP is critical for the maintenance of epithelial cell contacts in vitro. In vivo, conditional knockdown of N-WASP expression in mouse skin epithelium results in profound defects in hair follicle cycling [START_REF] Lefever | N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGF{beta} pathways[END_REF][START_REF] Lyubimova | Neural Wiskott-Aldrich syndrome protein modulates Wnt signaling and is required for hair follicle cycling in mice[END_REF] . It has a more variable impact on skin ulceration and no effect on wound healing. We demonstrated that hyper-activation of N-WASP by mycolactone is also dramatic for the maintenance of skin integrity and functions (Figure 2). In vitro, mycolactone-induced activation of N-WASP inhibited the maintenance of cell-cell and cell-matrix adhesive contacts, leading to detachment and death of epithelial cells. In addition, mycolactone triggered N-WASP-dependent defects in cell migration reflected by increased velocity and impaired directionality. Epidermal homeostasis is controlled by the maintenance of such cell-cell contacts and the coordinated migration of keratinocytes (reviewed in [START_REF] Etienne-Manneville | Polarity proteins in migration and invasion[END_REF] ). Injection of mycolactone into mouse ears altered the junctional organization and stratification of keratinocytes, leading to a progressive thinning of the external layers with concurrent loss of E-cadherin contacts. This process was efficiently counteracted by co-administration of wiskostatin, a specific inhibitor of N-WASP stabilizing its auto-inhibited conformation [START_REF] Peterson | Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation[END_REF] . Our study thus suggested that mycolactoneinduced activation of N-WASP in epithelial cells and the consequent dynamic rearrangements of the actin cytoskeleton are the primary cause of epidermal rupture in BU formation.

Leishmania spp and cutaneous Leishmaniasis

A total of about 21 Leishmania spp have been identified that are pathogenic to humans.

Leishmania parasites exist as promastigotes in the sand fly vector and as amastigotes in human hosts. They have developed multiple strategies to survive and multiply within phagolysosomal vacuoles in human phagocytes (macrophages, dendritic cells and neutrophils). The clinical presentation of Leishmaniasis varies significantly according to the species of infection and location [START_REF] Ridley | The evolution of the lesion in cutaneous leishmaniasis[END_REF] . It manifests predominantly as visceral (VL) or cutaneous (CL), with VL being the most severe form and lethal if untreated. CL typically starts as red patches progressing into crusted ulcers with hypertrophied borders that are painless unless there is secondary bacterial infection. Cutaneous lesions are usually solitary and heal spontaneously within a year. However, depending on the infecting species and hostassociated risk factors, they may evolve into more generalized forms, like diffuse CL or muco-CL 59 .

Protective immunity against Leishmaniasis is mediated by Th1-oriented cellular immune responses, while in contrast Th2 cytokines promote disease progression [START_REF] Sharma | Immunobiology of leishmaniasis[END_REF] . Mouse studies using L. major have shown that production of IFN-g by Th1 cells is key to the resolution of CL. Activation of infected macrophages by IFN-g triggers the production of nitric oxide (NO), resulting in the efficient killing of intracellular parasites. While the targeted disruption of cytokines promoting the development of Th1/IFN-g responses (IL-12, TNF) augment mouse susceptibility to leishmanial infection, deficiency for the Th2 cytokines IL-4 and IL-10 leads on the contrary to a better control of the disease. Humans with CL display mixed Th1/Th2 types of immune responses, however the production of IFN-g is consistently associated with resolution of the disease and treatments based on IFN-g have a positive impact on wound healing [START_REF] Kolde | Successful treatment of cutaneous leishmaniasis using systemic interferon-gamma[END_REF] . The variability in the intensity of humoral and cellular immune responses in patients with CL is reflected by the diverse pathological presentations.

Histological analysis of skin biopsies reveals a wide range of immune profiles, from almost normal to highly inflammatory, with infiltration of macrophages, presence of granulomas and extensive necrosis of dermal tissues [START_REF] Saab | Cutaneous leishmaniasis mimicking inflammatory and neoplastic processes: a clinical, histopathological and molecular study of 57 cases[END_REF] . Fas ligand (FasL) and Tumour necrosis factorrelated apoptosis-inducing ligand (TRAIL) have been reported to contribute to CL pathology by inducing keratinocyte killing and promoting neutrophilic infiltration [START_REF] Tasew | Systemic FasL and TRAIL neutralisation reduce leishmaniasis induced skin ulceration[END_REF][START_REF] Rethi | FasL and TRAIL signaling in the skin during cutaneous leishmaniasis -implications for tissue immunopathology and infectious control[END_REF] . Accordingly, the size of CL lesions and healing time correlate with TNF levels in patients with CL [START_REF] Oliveira | Lesion size correlates with Leishmania antigen-stimulated TNF-levels in human cutaneous leishmaniasis[END_REF] . Together, these data thus suggest that skin ulceration in CL results primarily from the Th1 immune responses mounted by the host in response to infection.

Mycolactone injection in mice: a useful model to study skin ulcer pathogenesis?

The examples of CL and BU illustrate the complexity and the diversity of infective ulcer pathogenesis. Exacerbated inflammation is critical in the pathogenesis of CL and in the defective healing of secondarily colonised wounds. In contrast, M. ulcerans uses an original mechanism to destroy the skin in the absence of local and systemic inflammation.

Mycolactone is a diffusible lipid of 740 Da gaining access to its molecular targets in remote tissues by passive diffusion [START_REF] Snyder | Uptake and cellular actions of mycolactone, a virulence determinant for Mycobacterium ulcerans[END_REF] . This property, combined with a potent immunosuppressive activity, makes mycolactone a potentially useful tool to study the non-inflammatory components of skin ulceration. Guinea pig and mouse models of infection with M. ulcerans have been developed that are based on intradermal, or subcutaneous injection of bacilli [START_REF] Silva | Pathogenetic mechanisms of the intracellular parasite Mycobacterium ulcerans leading to Buruli ulcer[END_REF][START_REF] George | Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence[END_REF][START_REF] George | A Mycobacterium ulcerans toxin, mycolactone, causes apoptosis in guinea pig ulcers and tissue culture cells[END_REF][START_REF] Huygen | Prospects for vaccine development against Buruli disease[END_REF][START_REF] Ji | Orally administered combined regimens for treatment of Mycobacterium ulcerans infection in mice[END_REF] . The resulting ulcers resemble human lesions in many aspects, with comparable epidermal hyperplasia, coagulative necrosis, oedema and vasculopathy. Interestingly, intradermal injection of 5 µg purified mycolactone into mouse ears generates in less than two weeks lesions that are comparable to those observed by infection with M. ulcerans in the footpad model [START_REF] Ruf | Chemotherapy-associated changes of histopathological features of Mycobacterium ulcerans lesions in a Buruli ulcer mouse model[END_REF] (Figure 3). Furthermore, the histopathological changes occurring upon mycolactone injection mimic the different stages of BU formation. In particular, the epidermal rupture, dermal elastolysis and subcutaneous necrosis that characterizes the transition from pre-ulcerative to ulcerative stage in BU, are adequately reproduced within a ten day period.

We have shown previously that mycolactone mediates epidermal rupture by hyperactivating N-WASP, however the molecular mechanisms leading to the necrosis of the underlying dermis and hypodermis remain to be elucidated. Based on the vascular damages observed in mycolactone-injected or M. ulcerans-infected tissues, we can propose that mycolactone also impairs endothelial integrity via the activation of N-WASP, leading to vascular leakage and oedema that pre-dispose skin to ulceration. Recent findings showing that N-WASP regulates endothelial permeability by maintaining adherens junctions [START_REF] Rajput | Neural Wiskott-Aldrich syndrome protein (N-WASP)-mediated p120catenin interaction with Arp2-Actin complex stabilizes endothelial adherens junctions[END_REF] strongly support our hypothesis.

Conclusions

To prevent ulcer formation and improve current wound management practices, it is important to progress in the identification of the different pathways controlling skin integrity. The study of infective ulcers provides important insights into these mechanisms, and in particular into the double-edged contribution of inflammation. The generation of inflammatory responses at the site of infection promotes skin ulceration in CL and delays the healing of secondarily contaminated wounds. Paradoxical reactions with aggravation of the ulcers have been reported in 2-10% of BU patients initiating antibiotic therapy [START_REF] Nienhuis | Paradoxical responses after start of antimicrobial treatment in Mycobacterium ulcerans infection[END_REF] . In these patients, clinical deterioration is efficiently stopped by adjunctive steroid therapies [START_REF] Friedman | Corticosteroid use for paradoxical reactions during antibiotic treatment for Mycobacterium ulcerans[END_REF][START_REF] Trevillyan | Steroids control paradoxical worsening of Mycobacterium ulcerans infection following initiation of antibiotic therapy[END_REF] , suggesting that in case of severe inflammation, immune suppression may improve the treatment of infected ulcers. In spite of the potent immunostimulatory activity and adjuvant potential of mycobacterial cell wall components, M. ulcerans induces the formation of BU without triggering inflammation. This original pathogenic process, based on the unique ulcerative and immunosuppressive properties of mycolactone, highlights the importance of epidermal and vascular cell-cell contacts in ulcer pathogenesis. It may provide researchers with a good model to investigate the non-inflammatory processes mediating skin ulceration.

Healing

  . So-called "tropical" ulcers are common infectious lesions caused by associations of Fusobacterium ulcerans and Borrelia vincenti, although the role of these bacteria in skin destruction remains poorly understood. Other ulcers of infectious origin include yaws caused by Treponema pertenue, cutaneous diphteria caused by toxigenic strains of Corynebacterium diphtheriae and occasionally by C. ulcerans, and mycoses such as sporotrichosis, chromoblastomycosis or eumycetoma. The following paragraphs further describe our current knowledge of the pathogenic processes employed by M. ulcerans and Leishmania spp.

Fig. 1 Fig. 2 :Fig. 3

 123 Fig. 1 Structure of human skin. The different tissues and cell layers composing this organ are depicted, together with the physiological mechanisms and molecular species varying during skin ulceration and healing.

  ë N


Romain Franceschini
email: r.franceschini@univ-corse.fr

Paul-Antoine Antoine Bisgambiglia
email: bisgambiglia@univ-corse.fr

DECENTRALIZED APPROACH FOR EFFICIENT SIMULATION OF DEVS MODELS

This paper proposes to improve simulation efficiency of DEVS models based on the classical Discrete Event system Specification (DEVS) formalism by reducing the number of messages exchanged between simulators. We propose three changes: hierarchical modeling tree flattening based on closure under coupling, direct coupling and decentralized scheduling. The main idea is to relieve coordinators by giving to simulators more tasks to process.

INTRODUCTION

The study of production systems necessitates the development of specific tools. Discrete EVent system Specification formalism [START_REF] Zeigler | Theory of Modeling and Simulation[END_REF]] is an expressive, open and flexible formalism that can be extended. Recent studies [Vangheluwe, 2000, Zeigler, 2003], have shown that DEVS formalism may be called multi-formalism because, due to its open nature, it allows the encapsulation of other modeling formalisms to meet specific applications requirements. From a performance perspective, the formalism can be improved as it does not scale well with a large number of models to simulate. At hardware level, it is possible to scale vertically by increasing power of machines, and horizontally by parallelizing [Chow and Zeigler, 1994] simulations, with a cost [START_REF] Balakrishnan | A framework for performance analysis of parallel discrete event simulators[END_REF], Chow et al., 1994, Glinsky and Wainer, 2006]. At software level, we can work on algorithms efficiency by reducing their complexity.

In the DEVS formalism, the model hierarchy suggests that each evolution of a model state can produce a message, which traverse all the hierarchy up to the root of the tree. The number of messages is therefore proportional to the output of the models, the number of models, and the level of the hierarchy. In certain cases, this can affect and raise simulation execution time. Previous works already proposed different approaches to improves simulation efficiency. We can cite: parallelization approach [Chow et al., 1994, Balakrishnan et al., 1997, Kim et al., 2000, Glinsky and Wainer, 2006, Zacharewicz and Hamri, 2007, Jafer and Wainer, 2009]; distribution [START_REF] Kim | Efficient distributed simulation of hierarchical DEVS models: transforming model structure into a non-hierarchical one[END_REF], Liu, 2006, Zacharewicz and Hamri, 2007]; and software approaches. These last approaches improve simulation time by getting rid of the hierarchical structure [START_REF] Jafer | Global lookahead management (GLM) protocol for conservative DEVS simulation[END_REF], Jafer and Wainer, 2009, Lowry et al., 2000, Zacharewicz and Hamri, 2007], and suggests to use direct coupling between models [START_REF] Chen | [END_REF]Vangheluwe, 2010, Muzy and[START_REF] Muzy | [END_REF]. The purpose of this article is to propose modifications to the simulation algorithms to reduce significantly the number of exchanged messages between components.

Currently, our approach is based on the classical DEVS formalism. The rest of the paper is organized as follows: first part, we present the DEVS formalism. In the second part, we detail the modifications we introduce to the classical DEVS formalism. In the last part, we present simulation results using our "decentralized" simulation approach.

BACKGROUND

DEVS [Zeigler, 2003] allows representing any system whose input/output behavior can be described with a sequence of events. It allows defining hierarchical modular models with two distinct types: atomic (behavioral) and coupled (structural) models. The first describes the autonomous behavior of a discrete-event system; the last one is composed of sub-models, each of them being an atomic or a coupled model. Formally, an atomic model is described by: X, Y, S, δ int , δ ext , λ, ta , and a DEVS coupled model is described by X, Y, D, {M d | d ∈ D}, EIC, EOC, IC, Select .

We use the DEVS formalism because of its openness and extensibility. It offers both a formal framework to define models and a flexible implementation in object-oriented programming. It allows modeling all types of systems. In some cases, depending on the system, the simulation can be very time consuming. To explain the excess messages must detail the simulation part [START_REF] Jafer | Flattened conservative parallel simulator for DEVS and CELL-DEVS[END_REF]. There are many works that aim to accelerate the simulation. We can cite [START_REF] Glinsky | New parallel simulation techniques of DEVS and cell-DEVS in CD++[END_REF][START_REF] Hu | A high performance simulation engine for large-scale cellular DEVS models[END_REF], Jafer and Wainer, 2009, Jafer et al., 2013, Lee and Kim, 2003[START_REF] Liu | Multicore acceleration of discrete event system specification systems[END_REF], Muzy and Nutaro, 2005, Wainer and Giambiasi, 2001, Zacharewicz et al., 2010]. Some of these solutions propose to flatten the hierarchy of models in order to reduce communication overhead between models. This is achieved by simplifying the underlying simulator structure, while keeping the same model definition and preserving the separation between model and simulator. There are two advantages to using a so-called flat structure: reduce exchanges of messages and simplify the simulation tree. This simplification is often used to allow parallelize or distributed simulations. These many works have shown that flat simulators outperform hierarchical ones significantly. They have also showed that although the hierarchical simulator presented in [START_REF] Glinsky | [END_REF]Wainer, 2006, Zacharewicz et al., 2010] reduced the number of messages by introducing two specialized DEVS coordinators, the communication overhead was still high in some cases. Others propose modifications simulation algorithms to parallelize and/or distribute computations (outsource). We propose to improve the simulator structure to accelerate simulation time. Our approach to accelerate simulations is not based on outsourcing the computations, but on three items: flat structure, direct coupling and decentralized scheduling.

OUR APPROACH

The objective of this work is not to provide a comparison with other approaches that are based on parallelization or distribution; we propose algorithms to improve the classical DEVS formalism. The aim of our modifications is to simplify the DEVS formalism, in order to make it more effective and faster. To reduce the number of exchanged messages between DEVS components, we propose three changes while remaining in compliance with the universal properties of DEVS, such as closure under coupling.

Local schedule

In order to avoid message overhead, we propose to avoid dispatching *-messages when possible, which we will call local or decentralized schedule. The purpose of this modification is to make the simulator more autonomous and to simplify the task of flat coordinator. Right after processing an *-message, a simulator checks if it is the next scheduled simulator by its parent and if there is no other simulator scheduled at the same time. If so, then the simulator will keep control and process the new fictive *-message at its tn.

Direct coupling

Message generation in the DEVS formalism is caused by message routing, specifically routing induced by the hierarchical structure of the formalism. For example, a component C1 of level H2 cannot communicate directly with a component C2 of the same level (H2). This is the case for all components. Messages must always be propagated to the parent, in H1 or H0 level. This hierarchy is a source of communication too. The fact of not being able to communicate directly with a component of the same level is a problem. We propose to add a list of couplings in simulators as a state variable. The simulators know their coupling, that is to say, the components to which they are connected, and with whom they should communicate. This list of decentralized coupling has been added to simulators.

Flattening architecture and direct connection

The hierarchy flattening, also called direct connection by [START_REF] Chen | Symbolic flattening of DEVS models[END_REF], is not new and has become a key to improve simulation time. The property of closure under coupling demonstrated in [START_REF] Zeigler | Theory of Modeling and Simulation[END_REF] implies that any coupled DEVS model offers the same behavior as a resultant atomic model, which allows to delete all coupled models in the hierarchy. In the hierarchical structure proposed in the DEVS formalism, a root coordinator is placed on top with a coordinator just below (H0 level). To flatten the simulation architecture, all the coordinators below the H0 level are deleted. Other works already offer this mechanism [Jafer andWainer, 2009, Zacharewicz andHamri, 2007], usually in order to parallelize and distribute the simulation. Our goal is to make the simulator standalone by removing redundant communications. We still keep the top-most coordinator, positioned just below the root. It gives an execution order to simulators. It has a schedule with an event number equal to the number of simulators. Now that we flattened the hierarchy, the top-most coordinator still coordinates its components. A component that generates an y-message still pass by its parent, which could be avoided with direct coupling.

Algorithms

We are now going to present algorithms for the modifications we propose, based on the classical DEVS simulation algorithms defined in [START_REF] Zeigler | Theory of Modeling and Simulation[END_REF].

Decentralized simulator tend to reduce the number of messages generated during a simulation in two different ways: (1) by allowing a simulator to communicate directly another component of its parent whenever possible and (2) by keeping control of *messages whenever possible. We achieve direct coupling by introducing indirect couplings to the simulator variables. Indirect couplings represent the direct route to another component of the parent. They are all IC of the parent involving one of the output port of the simulator model, excluding output ports involved in a EOC of the parent coordinator. As Listing 1.1 shows, when an output is generated by the model, an y-message has to be dispatched to the parent coordinator only if no indirect coupling exists and that the port is not involved in a EOC. If that is not the case, an x-message is directly sent to each indirect coupling recipient.

To avoid to return control from *-message, a simulator checks at the end of *message processing if it is the next scheduled message by its parent. Then, if it is the only scheduled model at that time, it is not necessary to the parent to call the Select method. In that case, the message time is set to the simulator tn and the *-message processing starts again unless we reached the end of the simulation.

RESULTS

The suggested approach allows to reduce the complexity of the simulation algorithms. We still have to demonstrate through some examples that this is expressed by a major reduction of the number of messages exchanged. We propose to present the results obtained with a [START_REF] Wainer | Studying performance of DEVS modeling and simulation environments using the DEVStone benchmark[END_REF] benchmark. DEVStone allows to evaluate the performance of DEVS-based simulators. It generates a suite of model with varied structure and behavior automatically. The test environment is based on a Intel(R) Core(TM) i5-3210M CPU @ 2.50GHz, 8 GB (2 x DDR3 -1600 MHz) of RAM, APPLE SSD SM128E hard drive, running on OSX 10.9.3. Software used for the benchmarking is DEVS-Ruby [START_REF] Franceschini | DEVS-Ruby: a Domain Specific Language for DEVS Modeling and Simulation (WIP)[END_REF] (without C extensions enabled) running on the Ruby 2.1.2 VM. DEVS-Ruby is a DEVS-based simulation framework implemented with the Ruby language.

Simulation results

Table 1 shows the total number of exchanged messages along with the CPU time of a simulation for each of the three approaches. The DEVstone model is parameterized with a depth between 3 and 9, a width from 5 to 15, with HO models type, a δ int transition time of 1ms, and a δ ext transition time of 0.1ms. Results show a major drop of scheduled messages between flat simulations and classic simulations. This is predictable because of all messages no longer sent to sub coupled models since they have been deleted from the hierarchy. Those results are very interesting but were already obtained by previous works on hierarchy flattening. However, decentralized simulation offers very encouraging results since we can observe an additional message drop. We obtain this by reducing the number of scheduled *messages and by avoiding to each atomic model that produces an y-message to pass by its parent coordinator by dispatching directly an x-message to the recipient.

Although we significantly reduce the number of messages and that CPU times shows slightly better results with our approach, the difference is not as impressive as the number of messages. In our case, this is due to the naiveness of the sorted listbased scheduler which is used for now in DEVS-Ruby. Indeed, the hierarchy flattening increase the number of atomic models to handle by the scheduler of the last present coordinator. Moreover, the HO type of coupling in DEVStone involves many collisions, which is a stress condition for the scheduler.

CONCLUSIONS

In this article, we presented an approach that aims to reduce the number of exchanged messages in the classic DEVS formalism. To reduce the number of messages exchanged, we propose to expand the role of simulators. Indeed, we propose three major changes compared to classical DEVS formalism: direct coupling, flat structure and local schedule. The goal is the decentralization of a number of tasks in order to make the simulators more autonomous, and relieve coordinators. Through these modifications the universal property of DEVS are preserved, and it is possible to couple a classical model with a decentralized model.

The results obtained with our framework are good; the number of exchanged messages is reduced by a factor of two. For complex systems with many components such as production systems, this method seems very interesting. As a future work, we plan to work on the PDEVS formalism.

Table 1 .

 1 Number of exchanged messages and CPU time for each approach using DEVStone

					Approach
	Depth Width		Classic		Flat	Decentralized
			Messages CPU time(s) Messages CPU time(s) Messages CPU time(s)
		5	132	0.027517	90	0.027047	61	0.027517
	3	10	359	0.07453 260	0.072432 161	0.071881
		15	722	0.172698 530	0.170959 311	0.148885
		5	333	0.060773 195	0.058662 133	0.0571
	6	10	1043	0.177945 620	0.173918 383	0.198214
		15	2183	0.4381 1295	0.375843 758	0.370906
		5	588	0.09689 300	0.093082 205	0.091734
	9	10	1952	0.285154 980	0.296403 605	0.276397
		15	4148	0.648915 2060	0.709434 1205	0.609233

ACKNOWLEDGEMENTS

The present work was supported in part by the French Ministry of Research, the Corsican Region and the CNRS.


Thècle Alix

Youssef Benama

Nicolas Perry

Reconfigurable Manufacturing System Design

Keywords: Mobility, RMS, manufacturing system design

de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

It is becoming increasingly obvious that the era of mass production is being replaced by the era of high value added and specific market niches. The key to create products that can meet the demands of a diversified customer panel is a short development cycle yielding low cost and high quality goods in sufficient quantity. This makes flexibility an increasingly important attribute to manufacturing [START_REF] Chryssolouris | Manufacturing systems theory and practice[END_REF]. Manufacturing system must have the ability to be rapidly transformed due to new technologies and demand changes, and also the ability to change their facilities and even their locations. In addition, they are expected to produce instantly high quality while coping with these changes [START_REF] Elmaraghy | Flexible and reconfigurable manufacturing systems paradigms[END_REF].

In the following sections we first discuss the concept of mobile manufacturing. Secondly, we address issues about reconfigurable manufacturing system and present a case study where this type of systems can be justified. Finally we present a design framework for mobile and reconfigurable manufacturing systems.

2

The concept of mobile manufacturing system 2.1

A specific need for mobility Due to excessive production capability and economic globalization, the manufacturing environment becomes turbulent and uncertain. Manufacturing enterprises must reassess their production paradigms, so that a manufacturing system can be designed and operated efficiently in the ever-changing environment [START_REF] Bi | Reconfigurable manufacturing systems: the state of the art[END_REF]. In some cases where customer's order books are deterministic, distributed in a unique place per customer and performed sequentially, a mobile manufacturing system can be a solution. That kind of system has to enable the changes i.e. the adaptation to altering needs, whatever the location. In each case, product specifications should be revised and adapted to cope with each country constraints (political, geographical, social, etc. constraints), supply chain can be modified and even the local workers knowledge can differ.

The purpose of the mobile manufacturing concept is to move manufacturing equipment from a stationary location (the site where the actor that controls and manages the capacity is) to a temporary location (the site where the capacity is used in operation) [START_REF] Stillström | The concept of mobile manufacturing[END_REF]. Reasons for introducing mobile manufacturing systems are fourfold:  Mobility is needed to increase flexibility: Upton considered mobility as an operational form of flexibility: "the ability to change product being manufactured quickly, on an on-going basis is the capability which most frequently supports the ability to provide quick response" [START_REF] Upton | Flexibility as process mobility: The management of plant capabilities for quick response manufacturing[END_REF].  Mobility is needed to improve efficiency: Mobile manufacturing capacity can be used to adjust the manufacturing system to an inconsistent workload. By implementing mobile manufacturing modules that quickly and easily can be used on different production sites, fewer investments are needed in manufacturing equipment. The effectiveness and the quality of the performed work are improved and the overall equipment efficiency is maximized.  Mobility is needed to reach new markets: Mobility is used as a characteristic in strategic domain to describe manufacturing in a long-term perspective. "By using mobile manufacturing capacity, it is possible to enter geographically new markets while maintaining control of the business. The company could win a new order and produce part of the order in a local country, while a large part of the order could still be manufactured at the company's manufacturing site in [home country]" [START_REF] Stillström | The concept of mobile manufacturing[END_REF].  Mobility is needed to reduce the manufacturing cost of the end product: In the case of products with important volume dimensions that are produced in important quantities and should be livered to different geographical locations, shipping costs can dramatically raise the final cost. In this case, Producing close to the client site could be an alternative to reduce the global manufacturing cost. Thereby economy of scale may be considered to split the investment on mobile manufacturing unit.

Several dimensions can affect mobility and consequently the way the manufacturing system can be designed.

2.2

Dimensions affecting mobility

Mobility refers to the movement of physical manufacturing resources [START_REF] Stillström | The concept of mobile manufacturing[END_REF]. It exists at the same time a geographical distance between the temporary and the stationary location in mobile manufacturing, and a technological, organizational, and social distances as well as cultural differences. Those distances and differences are not totally separated from each other, but rather connected. Ask and Stillström have highlighted two forms of distances through case studies [START_REF] Stillström | The concept of mobile manufacturing[END_REF]: the geographical distance defined as the distance that can be measured between the stationary and temporary location, in kilometers or yard for example, and the organizational distance corresponding to the distance between departments, functions, or levels. The organizational distance is not as easy to determine as the geographical distance, but it is of huge importance in information handling for example. Once the distances are determined it is possible to manage the mobility of the system.

Managing the mobility of manufacturing systems

Stillström describes the main lifecycle of the system for one rotation, i.e operating cycle for one temporary location [START_REF] Stillström | The concept of mobile manufacturing[END_REF]: "the life cycle starts with configuration of the manufacturing modules to a specific order. Thereafter, the modules are transported to the location where they will be used in production. When the order is finished, the manufacturing modules are transported to home site, or to another location, where they are reconfigured and reused". In addition, we should consider other necessary stages detailed below (Figure 1):  Factory set up: the plant is built on the end-user site. Before this stage, site preparation operations are already carried out. The manufacturing system is set up and commissioning operations are performed.  Diagnosis control: at the end of the production campaign, all resources are controlled and reconfigured to prepare the next production campaign.  Disassembly: the manufacturing system is disassembled, conditioned, and ready to be shipped to next end user location or to home location.

When considering operating cycle of mobile manufacturing unit between two rotations, we must consider the commercial order book of the firm. Indeed, in the case of several rotations, there are two possible scenarios:

 After the first rotation, the mobile manufacturing system is already reserved to produce on a determined location. In this case, maintenance operations and necessary modules replacement could be operated at: [START_REF] Chryssolouris | Manufacturing systems theory and practice[END_REF] the end of the first rotation, (2) before producing on the next location or (3) during the transportation stage. For each case, required components supplying, availability of the required operators qualification and delay constraints should be taken into account when deciding or choosing solution.  The second scenario corresponds to the case when there is no immediate command after the first rotation. In this case, modules of the mobile manufacturing system should be stored for a period.

Furthermore, a specific stage corresponding to periodic inspection may be required. The need to consider this stage depends strongly on the technical solutions adopted to allow modules mobility. For example, to allow the mobility of machinery, it is possible to embed the machinery into a container. Due to regulation constraints on marine container shipment, resources must be inspected periodically.

Reconfigurable manufacturing systems as a basis to design mobile manufacturing systems

Reconfigurable Manufacturing Systems (RMS) are able to cope with changes rapidly and cost effectively. In the context of a dynamic market demand with volume demand fluctuation and product mix variability, the manufacturing system adaptability is obviously valuable [START_REF] Wiendahl | Changeable Manufacturing -Classification, Design and Operation[END_REF].

RMSs features

RMSs allow changeable functionality and scalable capacity by physically changing the components of the system, by adding, removing or modifying machine modules, machines, manufacturing cells, material handling and/or complete lines". For Koren and Shpitalni, RMSs are designed "at the outset for rapid change in structure, as well as in hardware and software components, in order to quickly adjust production capacity and functionality within a part family in response to sudden changes in market or regulatory requirements" [START_REF] Koren | Design of reconfigurable manufacturing systems[END_REF]. The authors conduct a comparison between Dedicated manufacturing lines (DML), Flexible Manufacturing System (FMS) and RMS based on several features (Table 1). Regarding the context described previously RMS are the most convenient system to consider reaching mobility.

Design framework for RMS

Manufacturing systems engineering frameworks can be classified into 3 families:

 frameworks that address the manufacturing system selection process [START_REF] Chryssolouris | Manufacturing systems theory and practice[END_REF],  manufacturing system design [START_REF] Cochran | A decomposition approach for manufacturing system design[END_REF],

 manufacturing system control [START_REF] Chen | GRAI integrated methodology and its mapping onto generic enterprise reference architecture and methodology[END_REF].

Deif proposed a systematic design approach for reconfigurable manufacturing system [START_REF] Deif | A Systematic Design Approach for Reconfigurable Manufacturing Systems[END_REF]. The architecture is composed of two modules. The first one describes the design process of the reconfigurable manufacturing systems while. The second one describes the control of the design process at each level. The control module is based on performance measurements that reflect the strategic objectives of the RMS. The architecture of the design process is made of 3 layers: (1) market-capture layer, (2) system-level reconfiguration layer and (3) component-level reconfiguration layer. Determination of the decisions that drive the design of the manufacturing system is necessary. These decisions impact both the nature and the number of resources needed to satisfy the demand. We propose a design framework allowing to take into account and to structure the main decisions driving generation of manufacturing system configurations. This framework, adapted from Deif [START_REF] Deif | A Systematic Design Approach for Reconfigurable Manufacturing Systems[END_REF], is based on 3 layers :

Strategic Level: The objective of this level is to capture the market demand to generate the required capacity and functionality that will be used as inputs to the tactical level. Control module is based on performance measurements: cost, quality and responsiveness time.

Tactical level: The objective of this level is to select the best configuration that will enable the satisfaction of the market demand. Figure 2 shows some examples of decisions that will impact the design of the manufacturing system. Generation of multiple configurations is enabled by the modular design of the manufacturing system components. Modeling and evaluation are based on a genetic algorithm. The selection of the best solution uses an evaluation module and a simulation tool.

The generation of reconfigurable manufacturing system configurations is controlled by constraints (cost, space, demand satisfaction...). Best feasible configuration among the generated ones is then selected using predetermined performance measurements: Time, Quality, Reconfiguration smoothness index.

Operational level: Operational level deals with the physical implementation of a selected configuration. The implementation affects physical, logical and human components. Integrability and machine open control architecture are the major enabling technologies for the successful of the real physical implementation of the reconfigurable manufacturing system [START_REF] Deif | A Systematic Design Approach for Reconfigurable Manufacturing Systems[END_REF]. This level is controlled by performance measurements like cost, quality, time and reconfigurability.

RMS in the Solar Energy field: case study

In the Solar Energy Field, shipping costs drive the global manufacturing cost of solar collectors. Currently, shipping costs are expensive due to the wide surface of solar collectors, light and uncompact structures. A solution to reduce the global manufacturing cost is to produce close to the end-user installation site. Moreover, in order to make the production system investment more profitable, it would be wise if the same production system can serve producing many solar fields i.e. if the manufacturing system can move between different production sites. Furthermore, as the market demand forecast fluctuates between two orders, the product volume and duration to satisfy this demand may vary. The manufacturing system may cope with this variability. Demand variation results in a necessary, cost effectively, up gradation or down gradation of the manufacturing system capacity. Solar fields are installed in desert environment, with high temperatures and rough climatic conditions the functionality of the manufacturing system must be adapted to the specifications of each site. Finally, the manufacturing system is operated by technical and human resources. The need to employ local labor requires adapting the mobile manufacturing system. Available qualification and socio-cultural background should be taken into account when reconfiguring the manufacturing system. For economic and feasibility reasons, the production system must be moveable to various end-user sites. The main idea is to easily reuse manufacturing capacity between different orders or projects. Manufacturing system must be prepared for reconfiguration according to market and order situation. System reconfigurability is driven by external change triggers such as:  Variable volume demand: the demand profile is characterized by mass production, and high volume variability due to market uncertainties. Scalable capacity is needed to handle volume demand variability.  Geographical location change: to be able to move to each final location, manufacturing system and all its components should be mobile.  Location specifications: production system must be operational in various final locations with specific constraints (e.g. temperature, climate conditions).To cope with these changes, scalability, mobility and convertibility are considered as necessary characteristics and must be embedded into the manufacturing system. Figure 2

Conclusion

The concept of mobile manufacturing system has been presented, and the reasons why this solution could be needed were identified. Factors impacting mobility have been described. Special issues about the management of the mobility between the stationary and temporary location have been addressed. Furthermore, questions related to the interaction of the manufacturing system with its environment have been addressed as well as reflections induced by mobility constraints.

In addition to the need for mobility, the manufacturing system must cope with variability in demand volume and product mix. Reconfigurable manufacturing system paradigm has been analyzed. In this connection a design framework for RMS has been presented. Finally, the make or buy problem for RMS operation in multi-site context has been addressed, the reader is encouraged to consult [START_REF] Benama | Supporting make or buy decision for reconfigurable manufacturing system, in multi-site context[END_REF] for in-depth analysis of this question.

Fig. 1 .

 1 Fig. 1. Exploitation stages of a mobile production system, for one rotation

Table 1 .

 1 Comparison of RMS features with dedicated and flexible systems[START_REF] Koren | Design of reconfigurable manufacturing systems[END_REF]

		DML	RMS	FMS
	System structure	Fixed	Changeable	Changeable
	Machine structure	Fixed	Changeable	Fixed
	System FocusPart	Part	Part Family	Machine
	Scalability	No	Yes	Yes
	Flexibility	No	Customized	General
	Simultaneously	Yes	Possible	No
	operating tools
	Productivity	Very High	High	Low
	Cost per part	Low	Medium	Reasonable

the RMS configuration design RMS configuration design Generation of RMS configurations Evaluation of RMS configurations

							Strategic level
					Capture market demand	Performance
							Measurements
							Cost
			Capacity level		Functionality level	Quality
							Time (Respon-
							siveness
							Reconfiguration
							delay)
							Tactical level
	Soft Config Production planning SI	Human Config Operators Managers Driving Configuration 1 Machinery selection or Hard Config design Material handling system Structures and building Driving Logi-cal Config Planning control level Make or buy Driving Hard Config Job configura-tion (2x8;3x8) Hard config Soft config Human config Configuration n Hard config Soft config Human config	Driving Human Config Required qualifi-cation level Formation plan-ning	Driving Reconfigurability Critical characteris-tics Supporting charac-teristics	Constraints Cost Demand satisfac-tion (capacity, capa-bility) Space Performance measurements Time Quality Reconfigurability (Reconfigurations smoothness index)
		adfa, p. 7, 2011. © Springer-Verlag Berlin Heidelberg 2011	Component level configuration	Operational level
			Soft system installation grams control changes pro-scheduling	Hard system M/C installation Parts installation Tools installation Material handling	Human system Tasks allocation Work sheets Training	Performance measurements Cost Time Quality
							Reconfigurabilit
				Fig. 2. : Reconfigurable manufacturing system design framework	y Level
				shows the RMS design framework we propose
		dedicated	to	the		solar	energy	field.
	adfa, p. 8, 2011.
	© Springer-Verlag Berlin Heidelberg 2011