Raphaël Oger
email: raphael.oger@mines-albi.fr

Frédérick Bénaben

Matthieu Lauras

Benoit Montreuil

Towards Decision Support Automation for Supply Chain Risk Management among Logistics Network Stakeholders

Keywords: Supply Chain, Supply Chain Risk Management, Decision Support, Logistics Network, Strategic Business Planning, Supply Chain Design, Risk Management, Opportunity Management. 

This paper is one pillar of a research project aimed to design a decision support system supporting collaborative Supply Chain Risk Management among logistics network stakeholders. It presents the motivation behind this objective, and the contribution towards this objective: a methodology to automatically deduce all the supply chain options enabled by a logistics network to fulfil the demand. This methodology is introduced as part of a decision support automation framework for Supply Chain Risk and Opportunity Management among logistics network stakeholders. The methodology focuses on strategic and tactical supply chain decisions, and on manufacturing stakeholders.

INTRODUCTION

There was a time when businesses were designing their supply chains almost only when a product was added to their portfolio, without reconsidering their structure over time if no major issues were encountered. The supply chain community observed and analyzed over the past decades the evolution of how businesses are designing and challenging their supply chains [START_REF] Abadi | Supply Chain Evolution and key elements of progress[END_REF][START_REF] Mehmeti | A Literature Review on Supply Chain Management Evolution[END_REF][START_REF] Rasool | SUPPLY CHAIN EVOLUTION AND GREEN SUPPLY CHAIN PERSPECTIVE[END_REF]. The supply chain environment progressively evolved from a stable ecosystem to a very dynamic, complex and competitive ecosystem nowadays [START_REF] Ballou | The evolution and future of logistics and supply chain management[END_REF][START_REF] Christopher | The agile supply chain: competing in volatile markets[END_REF].

For businesses, evolutions in their supply chain environment (evolution of stakeholders, services, products, market demand, policies, etc.) mean the potential appearance of new risks and opportunities about their performance and ability to reach their objectives. To be competitive, businesses try to identify and assess risks and opportunities, so as to identify and make decisions to mitigate the risks taking advantage of the opportunities. As an example, risks can correspond to the inability to fulfil the demand, as well as the inability to reach competitive prices, and an opportunity could be a new equipment bought by a stakeholder that enable cost efficiency improvements and production capacity increase. So, one factor of success for businesses is their ability to keep a complete, accurate and up-to-date vision of their supply chain environment, and the risks and opportunities related to their supply chains [START_REF] Bartlett | Improving supply chain performance through improved visibility[END_REF][START_REF] Joshi | Information visibility and its effect on supply chain dynamics[END_REF]. This paper, starts with a literature review on Supply Chain Risk Management (SCRM) that highlights the need for additional research about collaborative SCRM, dynamic SCRM, and SCRM information systems. Then, it introduces a framework outline for designing a decision support system supporting collaborative SCRM among logistics network stakeholders. Based on this introduction, a proposal is made to implement a part of this framework: a methodology and associated algorithm to automatically deduce all supply chain options enabled by manufacturing stakeholders of a logistics network to produce a set of products. This proposal can be used either for designing a more complete SCRM decisionsupport system, or untouched to simply automatically discover all the possible supply chains made available by a set of manufacturing stakeholders to make a set of products. Finally, the paper concludes with the proposal limitations and avenues for future research.

SUPPLY CHAIN RISK MANAGEMENT LITERATURE REVIEW: RESEARCH AVENUES FOR SUPPORTING COLLABORATIVE SCRM AMONG LOGISTICS NETWORK STAKEHOLDERS

The supply chain community did a lot of research on SCRM during the past decades and the interest is still growing, as it is shown by the number of papers and by literature reviews.

Some simple examples shown this trend: 650 papers containing "supply chain risk management" in their title were found on September 2017 using the Google Scholar search engine with the request "allintitle: "supply chain risk management"" (citations not included). 411 papers containing "supply chain risk management" in their title, abstract or keywords were found on September 2017 using the Web of Science search engine and database with the request "TOPIC: ("supply chain risk management")".35 surveys were found on September 2017 using the Google Scholar search engine with the request "allintitle: ("supply chain risk management" OR SCRM) (review OR art)".11 surveys were found using the Web of Science search engine and database with the request "TITLE: (("supply chain risk management" OR SCRM) (review OR art))".

Over the past few years, several surveys have pointed out the lack of research efforts about collaboration among supply chain stakeholders for managing risks [START_REF] Colicchia | Supply chain risk management: a new methodology for a systematic literature review[END_REF][START_REF] Prakash | A critical analysis of supply chain risk management content: a structured literature review[END_REF]Vanany et al., 2009). Their reviews clearly express the need for future research exploring collaborative risk management among supply chain players. [START_REF] Colicchia | Supply chain risk management: a new methodology for a systematic literature review[END_REF] also insist on the importance of dynamicity of risk management to always stay up-to-date with the business context.

In addition of highlighting the need for collaboration and dynamicity, some reviews insist on the need for the prescription of practical information system solutions to be implemented within the industry [START_REF] Chen | Agent-based modeling and simulation for supply chain risk management-a survey of the state-of-the-art[END_REF][START_REF] Prakash | A critical analysis of supply chain risk management content: a structured literature review[END_REF][START_REF] Singhal | Supply chain risk management: review, classification and future research directions[END_REF]. [START_REF] Singhal | Supply chain risk management: review, classification and future research directions[END_REF] recommend that research be extended on more focused prescriptive studies applicable to industry. [START_REF] Chen | Agent-based modeling and simulation for supply chain risk management-a survey of the state-of-the-art[END_REF] focused on the Agent-Based Modeling and Simulation approach, they identified the development of decision support systems for SCRM that sit on the top of ERPs as a promising research directions. [START_REF] Prakash | A critical analysis of supply chain risk management content: a structured literature review[END_REF] found a lack of research on information system implementation for managing risks in supply chains.

These gaps identified within the SCRM literature correspond to the origin of the research objective presented in this paper: designing a decision support system supporting collaborative Supply Chain Risk Management among logistics network stakeholders.

A DECISION SUPPORT AUTOMATION FRAMEWORK FOR SUPPLY CHAIN RISK MANAGEMENT AMONG LOGISTICS NETWORK STAKEHOLDERS

Previous research works have considered different options to decompose SCRM into several activity domains [START_REF] Chen | Agent-based modeling and simulation for supply chain risk management-a survey of the state-of-the-art[END_REF][START_REF] Cruz | SUPPLY CHAIN RISK MANAGEMENT AND DECISION SUPPORT TOOLS: A SYSTEMATIC LITERATURE REVIEW[END_REF][START_REF] Ho | Supply chain risk management: a literature review[END_REF]. This paper refers to the SCRM activity domains synthetized by [START_REF] Ho | Supply chain risk management: a literature review[END_REF] and named by the authors "SCRM processes":

-Risk Identification, defined as the process to identify risk types and factors.

-Risk Assessment, defined as the process to evaluate probability of an event occurring and the significance of the consequences.

-Risk Mitigation, defined as the process to mitigate either the probability of an event occurring or the significance of the consequences.

-Risk Monitoring, defined as the process to detect a disruption occurrence.

-Risk Recovery, defined as the process to enable the supply chain to quickly return to its original state during the occurrence of a disruption. [START_REF] Ho | Supply chain risk management: a literature review[END_REF] have shown that most SCRM frameworks have been focusing on two of these SCRM processes, and say that the next focus should be to integrate more than two processes.

The following lines will introduce the framework suggested to enable decision support automation for SCRM among stakeholders of a logistics network. It describes the scope of the framework ambitions and position the main components. As the framework is not the main focus of this paper, only a high-level description is presented.

Framework scope

The framework focuses on stakeholders of a logistics network and their knowhows, including manufacturing, transportation and distribution. The ambition of the decision support system framework is to support strategic and tactical business planning decisions.

According to the SCRM processes previously identified by [START_REF] Ho | Supply chain risk management: a literature review[END_REF], the ambition is to cover the 5 highlighted SCRM processes, including the automation of the 4 following ones: "Risk Assessment", "Risk Mitigation", "Risk Monitoring", and "Risk Recovery". The "Risk identification" process would be part of the initial configuration of the decision support system.

However, potential evolutions in the logistics network environment imply the potential appearance of new risks that SCRM approaches try to manage. But a change is not necessarily negative and can also lead to opportunities [START_REF] Olsson | In search of opportunity management: Is the risk management process enough?[END_REF]. It is important to highlight the fact that these potential evolutions also imply the potential appearance of new opportunities. The framework also aims to cover the opportunities in addition of the risks, so the processes covered are renamed as following: "Risk and Opportunities Assessment", "Risk Mitigation and Opportunities Readying", "Risk and Opportunities Monitoring", and "Risk Recovery and Opportunities Exploitation". The "Risk Identification" process becomes "Risk and Opportunities Identification", part of the decision support system initial configuration.

These processes could extend the usual SCRM approach to a Supply Chain Risk and Opportunities Management (SCROM) approach integrating the five previously suggested processes.

Framework processes

The suggested decision support system framework is structured according to the suggested SCROM processes, with an additional step for information system automation purpose: "Data Gathering and Consolidation".

The "Risk and Opportunities Identification" process would take part during the configuration phase of the decisionsupport system. Then, during the run-time, there is the "Data Gathering and Consolidation" step that continuously feeds the four SCROM processes (Figure 1) with information that enable their automation.

Figure 1: Processes of the framework suggested to enable decision support automation for SCRM among stakeholders of a logistics network

The next section of the paper focuses on this "Data Gathering and Consolidation" step, so more details about it are given hereinafter. This process is aimed to automatically collect data from the logistics network stakeholders and their environment, and transform and structure these data into relevant information for the four SCROM processes it feeds.

It especially implies to have an interconnexion between stakeholders' information systems thought information sharing infrastructure, policies and protocols.

This paper proposes a first contribution to the "Data Gathering and Consolidation" step towards providing information that enable the automation of the four SCROM processes. The proposal corresponds to a methodology to automatically deduce all the supply chain options enabled by the logistics network to fulfil the demand, using the logistics network stakeholders' data. The deduction of these available supply chains would be the starting point enabling to manage risk and opportunities thought the four SCROM processes.

The next section of this paper focusses on this available supply chains deduction step.

A PROPOSAL TO AUTOMATICALLY IDENTIFY ALL SUPPLY CHAIN OPTIONS ENABLED BY MANUFACTURING STAKEHOLDERS OF A LOGISTICS NETWORK

This section presents a methodology to structure data gathered from logistics network manufacturing stakeholders so as to be able to use this structured data to deduce all the supply chain options enabled by these manufacturing stakeholders to fulfil the market demand. A supply chain option corresponds to a possible supply chain configuration among all possibilities. It is important to note that in this study, we only consider manufacturing stakeholders and not the transportation and distribution ones.

To structure the data gathered from logistics network manufacturing stakeholders, a metamodel has been developed. A metamodel corresponds to a model describing the structure and behavior of models, all models following a metamodel will have to respect the structure defined by the metamodel [START_REF] Ramu | Metamodel based analysis and its applications: A review[END_REF][START_REF] Wu | Metamodel instance generation: A systematic literature review[END_REF]. The design of the metamodel is know-how oriented to make the logistics network stakeholders' know-hows the cornerstone of this methodology. The metamodel is based on the CORE metamodel created by [START_REF] Bénaben | A Metamodel for Knowledge Management in Crisis Management[END_REF] to support collaborative situations. To make the logistics network metamodel as clear as possible, it has been simplified in Figure 2 keeping only the relevant elements for this paper. It originally contained packages specific for the logistics network around the CORE metamodel, as described by [START_REF] Bénaben | A Metamodel for Knowledge Management in Crisis Management[END_REF] in the context of the crisis management, but they are not presented in this paper.

As described by Figure 2, the metamodel contains concepts and links between concepts that will both be used by the deduction algorithm. The concepts are: "Collaborative Network" that corresponds to the logistics network, "Stakeholders" that corresponds to logistics network stakeholders, "Know-How" that corresponds to the manufacturing services provided by the logistics network stakeholders, "Resource Category" that can correspond to products or equipment, and "Objective" that corresponds to the logistics network sales plan. The links between concepts are described as the following: A collaborative network "contains" stakeholders and "aims" to fulfil objectives, a stakeholder "provides" know-hows, a know-how "consumes", "creates" and "requires" resource categories, and an objective "consumes" resource categories. 2016))

The data from the logistics network manufacturing stakeholders are collected and consolidated within a model that follows the structure of the previously presented metamodel. This model structure makes possible for the deduction algorithm presented below to automatically deduce all the possible supply chains options enabled by the logistics network to fulfil the objective (sales plan). To be more precise, the algorithm deduces the, defined right after, Available Supply Chain Processes (ASCP) on the base of the model of the logistics network. For each product that the logistics network plans to sell to end consumers (i.e. each "Resource Category" having at least one link "consumes" from an "Objective"), we define the corresponding ASCP as the succession of all possible activities, instances of the logistics network stakeholders' know-hows, which enable to realize the product. In other words, it corresponds to a unique supply chain process containing all the possible ways (all the supply chain options) making possible the considered product production. An ASCP gives the vision, to the logistics network stakeholders, of all the supply chain options, however it doesn't imply that all must be implemented.

The ASCP are represented using a process modeling language inspired from the Business Process Model and Notation (BPMN) (Object Management Group, 2011;[START_REF] White | Introduction to BPMN[END_REF], with some specificities. The deduction algorithm uses the following BPMN elements to represent the ASCPs: start event, end event, activity, parallel gateway (named in the algorithm "AND Opening gateway" or "AND Closing gateway"), and inclusive OR gateway (named in the algorithm "OR Opening gateway" or "OR Closing gateway"). The distinction between opening and closing gateway is one specificity of the process modeling language used to represent the ASCPs, it is an enabler of the deduction automation used within the deduction algorithm.

To make the ASCP deductions, we propose the following algorithm taking advantage of the logistics network model to create ASCP models using the BPMN language. This algorithm has been initially designed to answer one of the business needs identified during interviews with a pharmaceutical company: to automatically discover all supply chain options enabled by a set of manufacturing stakeholders to fulfil a sales objective.

Algorithm to deduce Available Supply Chain Processes:

Find all objectives within the logistics network model.

Find all resource categories concerned by the objective.

For each resource category concerned by at least one objective, create an ASCP model: Create the "end event" of the ASCP model (according to the BPMN language).

[Line A] Find all know-hows able to create the resource category.

If there are two or more know-hows able to create the resource category, then: Create an "OR Closing Gateway" and create a link oriented from this gateway to the last created element ("end event", "activity", or "AND Closing gateway").

For each know-how able to create the resource category:

[Line B] Create an "activity" being an instance of this know-how, and create a link oriented from this "activity" to the "OR Closing Gateway" previously created.

Find the resource categories consumed by this "activity" (according to the know-how).

If there are at least two different resource categories consumed by this "activity", then: Create a "AND Closing gateway" and create a link oriented from this gateway to the last "activity" created (line B).

For each resource category consumed by this know-how:

Continue going back to "line A" considering this resource category and the "activity" which needs it.

If there is one resource category consumed by this "activity", then: Continue going back to "line A" considering this resource category and the "activity" which needs it.

If there is no resource category indicated as consumed by this "activity", then: Following the created process, starting from the current considered "activity", find the closest closing gateway ("OR Closing gateway" or "AND Closing gateway").

If a closing gateway was found and does not already has its corresponding opening gateway, then:

Create the corresponding opening gateway ("OR Opening gateway" or "AND Opening gateway") and create a link oriented from this gateway to the considered "activity".

[Line C] Following the created process, starting from the current considered closing gateway, find the next closest closing gateway ("OR Closing gateway" or "AND Closing gateway").

If a closing gateway was found and does not already has its corresponding opening gateway, then:

Create the corresponding opening gateway ("OR Opening gateway" or "AND Opening gateway") and create a link oriented from this gateway to the previously considered opening gateway.

Continue going back to line C considering this new closing and opening gateways.

If no closing gateway was found, then: Create the "start event" and a link oriented from this "start event" to the lastly created opening gateway.

If a closing gateway was found and already has its corresponding opening gateway, then: Create a link oriented from this gateway to the considered "activity".

If no closing gateway was found, then: Create the "start event" and a link oriented from this "start event" to the current considered "activity".

If there is only one know-how able to create the resource category, then:

Continue going to line B considering this know-how.

A software has been developed to demonstrate the proper functioning of the deduction algorithm. From modeling the logistics network to visualizing all the supply chain options made possible by the logistics network manufacturing stakeholders. The main technologies used are the programming language Java and the databases MongoDB and GraphDB. It is composed of the following 3 major elements:

-Web-based user interfaces ("Stakeholders & Knowhows", "Resource Categories", and "Objectives") to manually model the logistics network (step needed because the data gathering automation isn't part of the scientific contribution of this paper) (Figure 3).

-The implementation of the deduction algorithm to automatically deduce the ASCPs from the logistics network modeled by the user.

-A graphical interface to visualize the ASCPs and so all the supply chain options (Figure 4).

The effectiveness of the algorithm has been confirmed checking the validity of the deduced ASCPs in one real and one fictive use cases. The real case has been done considering a network of existing and potential suppliers of a pharmaceutical company according to one of their product category. The fictive case has been realized considering a network of manufacturing stakeholders enabling the production of bread (Figure 3 and Figure 4). So, a business can use this approach to automatically deduce all possible supply chain options (ASCPs), enabled by a set of manufacturing stakeholders, to fulfil a production or sales objective. It must be noted that the efficiency, in terms of speed performance, of the algorithm has not been a point of interest in this research work.

CONCLUSION, LIMITATIONS AND AVENUES FOR FUTURE RESEARCH

In this paper, a methodology has been suggested to automatically deduce all the supply chain options enabled by manufacturing stakeholders of a logistics network to fulfil the demand. This methodology has been introduced as part of a decision support automation framework for Supply Chain Risk and Opportunity Management (SCROM) among logistics network stakeholders. And more precisely as a proposal for the consolidation part of the suggested "Data gathering and consolidation" step, towards providing information that enable the automation of the SCROM processes. The methodology includes a metamodel and a deduction algorithm proposal that only consider manufacturing stakeholders, so, future research work will have to extend it to transportation and distribution. In addition, the framework needs to be consolidated with more details about its practical implementation. From another perspective, risks and opportunities regarding human factors and data integrity have not been considered in this paper, so it would be relevant to supplement these results with additional research on these aspects. Finally, from an information system perspective, the five considered SCROM processes still need to be designed and developed to really provide businesses with a complete and practical decision-support system.

Figure 2 :

 2 Figure 2: A metamodel to structure the data gathered from logistics network manufacturing stakeholders (showing only the elements being relevant for supply chain deduction)(inspired by Bénaben et al. (2016))

Figure 3 :

 3 Figure 3: Web-based user interfaces to manually model the logistics network information according to the metamodel presented in Figure 2

Figure 4 :

 4 Figure 4: Graphical interface to visualize ASCPs: An example of a deduced ASCP enabling to visualize all the supply chain options enabled by the set of manufacturing stakeholders to fulfil the production objective (modelled in Figure 3)


Angélique Vétillard
email: angéliquevétillard@univ-jfc.fr

Wafa Bouzid

Fourmis : une chimiothèque de nouveaux anticancéreux

accepté le 7 juin 2016

Résumé -La composition des venins est très compliquée à déterminer à cause de leur complexité et de leur diversité moléculaire, cependant l'étude transcriptomique des glandes à venin de la fourmi Tetramorium bicarinatum révèle une grande diversité fonctionnelle des peptides/protéines qui pourraient être produits par ces glandes. Ces molécules peptidiques correspondent pour partie à des toxines connues mais de nombreuses séquences ne sont répertoriées dans aucune base de données et pourraient correspondre à des peptides de venins originaux non décrits auparavant. Nos travaux étaient les premiers à rapporter le séquençage du transcriptome de la glande à venin chez une fourmi, d'abord par la technique de la SSH (Suppression Subtractive Hybridization), puis par une technique de séquençage profond permettant de progresser dans le degré d'informations que renferme le transcriptome (Illumina). Nos expériences montrent clairement que l'extrait de venin brut induit l'apoptose de certaines lignées de cellules tumorales résistantes à tous les traitements actuels et l'analyse en spectrométrie de masse nous a orientés vers une molécule dont la structure nous est encore inconnue. L'identification et la caractérisation du mécanisme d'action de la molécule responsable de cette cytotoxicité constituent donc un espoir de découvrir de nouvelles stratégies thérapeutiques dans la lutte contre cette pathologie encore aujourd'hui incurable. D'une manière générale, l'extraordinaire diversité taxonomique des fourmis laisse présager d'une grande diversité de leurs toxines [START_REF] Hoffman | Ant venoms[END_REF]. La probabilité de découvrir de nouvelles molécules d'intérêt pour l'homme n'en est que renforcée.

Mots clés : Fourmi Tetramorium bicarinatum / toxines de venin / allergènes d'hyménoptères / Séquençage EST / séquençage de novo Illumina Abstract -Ants: a chemical library of anticancer molecules.

Animal venoms are complex mixtures containing simple organic molecules, proteins, peptides, and other bioactive elements with extraordinary biological properties associated with their ability to act on a number of molecular receptors in the process of incapacitating their target organisms. In such a context, arthropod venoms are invaluable sources of bioactive substances with therapeutic interest but the limited availability of some venom such as those from ants, has restricted the potential that these biomolecules could represent. We investigated for the first time transcriptomic expression from the ant species Tetramorium bicarinatum. Four hundred randomly selected clones from cDNA libraries were sequenced and a total of 374 expressed sequence tags (ESTs) were generated. Based on the results of BLAST searches, these sequences were clustered and assembled into 269 contigs.About 72% (269) of these matched BLASTx hits with an interesting diversity and unusual abundance of cellular transcripts (48%) related to gene and protein expression reflecting the specialization of this tissue. In addition, transcripts encoding transposases were relatively highly expressed (14%). It may be that transposable elements are present and that their presence accounts for some of the variation in venom toxins. About twenty per cent of the ESTs were categorized as putative toxins, the major part represented by allergens (48% of the total venom toxins) such as pilosulin 5, sol i 3 and Myp p I and II. Several contigs encoding enzymes, including zinc-metalloproteases (17%) that are likely involved in the processing and activation of venom proteins/peptides, were also identified from the library. In addition, a number of sequences (8%) had no significant similarity to any known sequence which indicates a potential source of for the discovery of new toxins. In order to provide a global insight on the transcripts expressed in the venom gland of the Brazilian ant species Tetramorium bicarinatum and to unveil the potential of their products, high-throughput expressed sequence tags were generated using Illumina paired-end sequencing technology. A total of 212 371 758 pairs of quality-filtered, 100-base-pair Illumina reads were obtained. The de novo assemblies yielded 36 042 contigs for which 27 873 have at least one predicted ORF among which 59.77% produce significant hits in the available databases. The investigation of the read mapping toxin class revealed and confirmed a high diversification with the major part consistent with the classical hymenopteran venom protein signature represented by venom allergen (33.3%) followed by a diverse toxin-expression profile including several distinct isoforms of phospholipase A1 and A2, venom serine protease, hyaluronidase, protease inhibitor and secapin. Moreover, our results revealed for the first time the presence of toxin-like peptides that have been previously identified from unrelated venomous animals such as waprin-like (snakes) and agatoxins (spiders and conus). These studies provide a first insight of the gene expression scenario of the venom gland of T. bicarinatum which might contribute to acquiring a more comprehensive view about the origin and functional diversity of venom proteins of this ant.

Based on such results, we conducted cytotoxic tests from the crude venom of T. bicarinatum ant and reported toxic effect on tumoral cells lines from one of the fifth of the most frequently occurring cancers with a 3-year survival rate of only 30%. In such a context, new therapeutic strategies are essential and the discovery of new molecules in ant venom could be one possible avenue. Thus our project aims to characterize, from the crude venom of T. bicarinatum, the molecule(s) which have potential anti-cancerous toxicity as well as their mechanisms of action. Aujourd'hui, seul le venin de quelques espèces a été exploré, avec à chaque fois la mise en évidence de toxines originales [START_REF] Davies | Characterisation of major peptides in "jack jumper" ant venom by mass spectrometry[END_REF]. Pourtant, les fourmis (Formicidae) sont ubiquistes et quantitativement dominantes au sein des milieux colonisés [START_REF] Floren | Arboreal ants as key predators in tropical lowland rainforest trees[END_REF][START_REF] Moreau | Phylogeny of the ants: diversifica-44 tion in the age of Angiosperms[END_REF]. La myrmécofaune renferme ainsi la plus importante richesse spécifique parmi les insectes sociaux avec plus de 15 000 espèces recensées dans la base de données AntWeb. L'une des premières expressions de cette richesse est l'existence de différences importantes dans leur écologie, et notamment selon leur mode de vie. Les fourmis sont ainsi présentes sur tous les territoires et au regard de la grande diversité dans leur écologie, leurs sécrétions chimiques, adaptées notamment pour attaquer, se défendre et communiquer chimiquement, représentent une richesse de diversification offrant des perspectives de nouvelles découvertes très importantes dans ce groupe zoologique. Les investigations déjà menées sur le venin des fourmis ont d'ailleurs révélé un mélange de molécules d'une grande complexité et

33

D'une manière générale, la plupart des études sur les venins correspondent à une caractérisation directe biochimique/protéique plutôt qu'à des études de génomique ou de transcriptomique. Pourtant, les quelques études de transcriptomique se sont avérées très utiles pour révéler la complexité des composants des venins et des processus cellulaires sous-jacents [START_REF] Liang | Proteome and peptidome profiling of spider venoms[END_REF][START_REF] Ruiming | Comparative 55 venom gland transcriptome analysis of the scor-56 pion Lychas mucronatus reveals intraspecific toxic 57 gene diversity and new venomous components[END_REF]. Ces approches ont aussi montré leur efficacité dans la découverte de nouvelles toxines jusqu'alors non révélées par des méthodes directes. Les résultats générés sont révélateurs des processus biologiques mis en oeuvre dans les cellules de la glande à venin, mais apportent également une vue générale, jamais investiguée par ailleurs, sur la dynamique moléculaire au niveau de la glande à venin.

Nos travaux consistaient à répertorier des gènes qui s'exprimaient différentiellement dans les glandes à venin et pour la première fois chez une espèce de fourmi exotique, Tetramorium bicarinatum, fourmi sélectionnée eu égard à sa diversité biologique et à la puissance de son venin contre l'homme et les vertébrés en général. L'intérêt d'identifier les molécules qui composent ce venin réside notamment dans leurs éventuelles vertus thérapeutiques. Dans le domaine de lutte contre le cancer, un article a d'ailleurs montré que le venin d'une espèce de fourmis du genre Samsum induit l'apoptose d'une lignée cellulaire de cancer mammaire [START_REF] Badr | Human breast carcinoma cells are induced to apoptosis by samsum ant venom through an IHF-1-dependant pathway, PI3K/AKT and ERK signaling[END_REF].

Les collections de marqueurs de séquences exprimées représentent ainsi un point de départ indéniable pour l'identification de gènes et donc de nouvelles molécules médicamenteuses, notamment chez les organismes n'ayant pas de génome de référence. 4).

36

Enfin, une proportion non négligeable de nos 37 séquences (26 %) (Figure 2) n'a pas été identifiée, et 38 ce malgré plusieurs bases de données sollicitées. Ces 39 séquences, dotées pour la plupart de séquences signal 40 et de pattern cystéine, correspondraient par hypothèse 41 à des peptides de venins originaux n'ayant pas été 42

  Key words: Tetramorium bicarinatum ant / venom toxins / hymenopteran allergens / ESTs library / Illumina technology Les venins de fourmis, une richesse 1 chimique encore inexplorée 2 Les venins animaux, par leur richesse biochimique 3 et la diversité de leurs cibles moléculaires, sont une 4 source très importante de nouvelles molécules dont 5 les applications potentielles sont nombreuses, en par-6 ticulier dans le domaine médical (Lewis & Garcia, 7 2003 ; King, 2011). Même si la recherche sur le 8 développement d'anti-venins reste une préoccupation 9 majeure, depuis plusieurs années la communauté 10 scientifique s'intéresse, en effet, à identifier, dans les 11 venins, de nouvelles molécules bioactives susceptibles 12 d'intéresser le domaine médical mais aussi pharma-13 cologique et agronomique. La recherche de molécules 14 bioactives d'intérêt sociétal s'est d'abord orientée 15 vers les venins de serpents, en raison de leur ac-16 tion foudroyante et des dommages corporels que peut 17 engendrer une morsure, mais également en raison 18 de l'abondance du venin chez ces animaux. Depuis 19 une trentaine d'années, de nombreux travaux sont 20 développés sur les venins d'insectes, ce que l'on peut 21 en partie expliquer par les avancées technologiques 22 rendant accessible l'étude de très petites quantités 23 de venins et la caractérisation de molécules à l'état 24 de traces. Si parmi les études portant sur les venins d'hyménoptères, les abeilles et les guêpes sont des modèles récurrents dans la littérature, les études sur les venins de fourmis sont encore rares.

  "jbio160021" -2016/8/16 -15:51 -page 3 -#3

Fig. 1 .

 1 Fig. 1. Appareil vulnérant de la fourmi Tetramorium bicarinatum.

Fig. 2 .

 2 Fig. 2. Répartition des transcrits identifiés dans la glande à venin de Tetramorium bicarinatum.

Fig. 5 .

 5 Fig. 5. Alignement de séquences d'acides aminés de l'agatoxine-like de Tetramorium bicarinatum (contig 37 135 et 25 047) avec des agatoxines d'autres Hyménoptères. Le degré de conservation des acides aminés est indiqué par un dégradé de bleu. Les cystéines conservées sont surlignées en rouge et la séquence signal en vert.

Fig. 6 .

 6 Fig.6. Alignement de séquences d'acides aminés de la phospholipase A2-like de Tetramorium bicarinatum avec des phospholipases A2 d'autres Hyménoptères, de scorpion et de lézard indiqués par leur code d'accès dans GenBank. Le degré de conservation des acides aminés est indiqué par un dégradé de bleu. La séquence signal prédite est surlignée en rouge. Les régions soulignées indiquent le site de fixation de la boucle calcium-dépendante et le site actif de l'enzyme en accord avec la numérotation des acides aminés de la PLA2 de pancréas bovin[START_REF] White | Crystal structure of cobra-venom 71 phospholipase A2 in a complex with a transition-state 72 analogue[END_REF].

43

  Ces données serviront de base et seront croisées 44 avec des données générées par des études de 45 protéomique et confirmeront ainsi les séquences 46 prédites par les techniques de séquençage transcrip-47 tomiques. Malgré la difficulté de réaliser cette tech-48 nique, tributaire de la quantité du venin et sa qualité 49 d'extraction, une première analyse a été réalisée et a 50 permis de dégager un nombre de peptides ✭✭ nouveaux ✮✮ 51 non révélés jusque-là. Le premier séquençage du transcriptome de la 53 glande à venin d'une fourmi a été réalisé dans notre 54 équipe, chez l'espèce exotique Tetramorium bicarina-55 tum et a révélé de nouvelles molécules potentielle-56 ment à l'origine de la bioactivité anticancéreuse de 57 son venin. 58 L'intérêt d'identifier les molécules du venin 59 réside notamment dans leurs éventuelles vertus 60 thérapeutiques. Dans ce sens, ce séquençage a, en 61 effet, été très informatif puisque l'identification des 62 séquences transcrites dans les cellules des glandes à ve-63 nin a été utilisée notamment comme base décisionnelle 64 pour le ciblage des tests de bioactivité, et nous a 65 orientés sur la piste d'une lignée cancéreuse qui s'est 66 avérée très sensible au venin.Si l'application clinique de certaines toxines a 72 été possible pour certaines pathologies telles que 73 l'hypertension, la douleur chronique, le diabète et 74 la thrombose[START_REF] King | Venoms as a platform for human drugs: translating toxins into therapeutics[END_REF], aucune molécule obte-75 nue à partir de venins d'animaux n'est utilisée au-76 jourd'hui en thérapie anticancéreuse. Néanmoins, cer-77 taines études rapportent des effets antiprolifératifs de 78 certains venins in vitro mais également in vivo chez la 79 souris. Le venin de scorpion est capable d'inhiber la 80 prolifération in vitro de cellules de gliome ainsi que la 81

		67
	Bioactivité anticancéreuse du venin de	68
	Tetramorium bicarinatum et identification 69
	de nouvelles cibles thérapeutiques	70
	dans la lutte contre le cancer	71

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