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The catalytically inactive caspase-8-homologous protein, c-FLIP, is a potent antiapoptotic protein highly expressed in various types of cancers. c-FLIP competes with caspase-8 for binding to the adaptor protein FADD (Fas-Associated Death Domain) following death receptors’ (DRs) activation via the ligands of the TNF-R family. As a consequence, the extrinsic apoptotic signaling pathway involving DRs is inhibited. The inhibition of c-FLIP activity in tumor cells might enhance DR-mediated apoptosis and overcome immune and anticancer drug resistance. Based on an in silico approach, the aim of this work was to identify new small inhibitory molecules able to bind selectively to c-FLIP and block its anti-apoptotic activity. Using a homology 3D model of c-FLIP, an in silico screening of 1880 compounds from the NCI database (National Cancer Institute) was performed. Nine molecules were selected for in vitro assays, based on their binding affinity to c-FLIP and their high selectivity compared to caspase-8. These molecules selectively bind to the Death Effector Domain 2 (DED2) of c-FLIP. We have tested in vitro the inhibitory effect of these nine molecules using the human lung cancer cell line H1703, overexpressing c-FLIP. Our results showed that six of these newly identified compounds efficiently prevent FADD/c-FLIP interactions in a molecular pull-down assay, as well as in a DISC immunoprecipitation assay. The overexpression of c-FLIP in H1703 prevents TRAIL-mediated apoptosis; however, a combination of TRAIL with these selected molecules significantly restored TRAIL-induced cell death by rescuing caspase cleavage and activation. Altogether, our findings indicate that new inhibitory chemical molecules efficiently prevent c-FLIP recruitment into the DISC complex, thus restoring the caspase-8-dependent apoptotic cascade. These results pave the way to design new c-FLIP inhibitory molecules that may serve as anticancer agents in tumors overexpressing c-FLIP.

Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account. We have established cell lines expressing the luciferase gene from lines with varied genetic backgrounds, commonly encountered in patients with pulmonary adenocarcinoma. We have characterized these lines by testing their response to multiple drugs. Thus, we have developed orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency. These models allow the easy monitoring of tumor growth, particularly in response to treatment, and of tumor cells dissemination in the body. We show that concomitant treatment with osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab (anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFR-mutated tumors. We also show that the addition of afatinib to osimertinib-treated tumors in escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms.

Abstract One of the routine clinical treatments to eliminate ischemic stroke thrombi is injecting a biochemical product into the patient’s bloodstream, which breaks down the thrombi’s fibrin fibers: intravenous or intravascular thrombolysis. However, this procedure is not without risk for the patient; the worst circumstances can cause a brain hemorrhage or embolism that can be fatal. Improvement in patient management drastically reduced these risks, and patients who benefited from thrombolysis soon after the onset of the stroke have a significantly better 3-month prognosis, but treatment success is highly variable. The causes of this variability remain unclear, and it is likely that some fundamental aspects still require thorough investigations. For that reason, we conducted in vitro flow-driven fibrinolysis experiments to study pure fibrin thrombi breakdown in controlled conditions and observed that the lysis front evolved non-linearly in time. To understand these results, we developed an analytical 1D lysis model in which the thrombus is considered a porous medium. The lytic cascade is reduced to a second-order reaction involving fibrin and a surrogate pro-fibrinolytic agent. The model was able to reproduce the observed lysis evolution under the assumptions of constant fluid velocity and lysis occurring only at the front. For adding complexity, such as clot heterogeneity or complex flow conditions, we propose a 3-dimensional mesoscopic numerical model of blood flow and fibrinolysis, which validates the analytical model’s results. Such a numerical model could help us better understand the spatial evolution of the thrombi breakdown, extract the most relevant physiological parameters to lysis efficiency, and possibly explain the failure of the clinical treatment. These findings suggest that even though real-world fibrinolysis is a complex biological process, a simplified model can recover the main features of lysis evolution.

Léon Cordes (1913-1985) est imprégné d’un héritage culturel où se mêlent, de Minerve à Argeliers, le souvenir des cathares, la Croisade menée contre eux au XIIIème siècle, et, tout proche, celui de la révolte vigneronne de 1907. Dès les années 1930, il prend part à l’éclosion d’un occitanisme entièrement renouvelé, aux côtés de Charles Camproux, puis de Robert Lafont et Max Rouquette. Auteur de théâtre et rédacteur de revues, poète sensible, il revendique le profil singulier d’un paysan viscéralement lié à sa terre, mais maîtrisant toutes les disciplines littéraires pour s’engager par la création dans la défense et le développement d’une langue et d’une civilisation occitanes passionnément vécues. Le présent article, né de l’admiration et de l’amitié, s’efforce de restituer les grandes étapes d’un parcours insuffisamment reconnu, celui d’un écrivain-paysan dont le profond enracinement s’est accompagné d’une ouverture délibérée à la modernité. Resumit Léon Còrdas (1913-1985) es impregnat d’un eiretatge cultural ont se mesclan, de Menerba a Argeliers, lo sovenir dels catars, de la Crosada menada contra elis al segle XIIIen, e, tot proche lo de la granda revolta vinhairona de 1907. Tre las annadas 1930, participa a l’espeliment d’un occitanisme completament renovat, amb Carles Camprós, puèi Robert Lafont e Max Roqueta. Autor de teatre e redactor de revistas, poeta sensible, se reclama del perfil singular d’un païsan viscèralament ligat a sa terra, mas mestrejant totas las disciplinas literairas per s’engatjar al mejan de la creacion dins la defensa e lo desvolopament d’una lenga e d’una civilisacion occitans viscudas amb passion. Aquel article, nascut d’admiracion e d’amistat, vòl far reviure las grandas estapas d’un trajecte pas pro reconegut, lo d’un escrivan-païsan que son enrasigament prigond es ligat amb una dobertura volguda a la modernitat.

Abstract Circulating tumor cells (CTC) have been studied in various solid tumors but clinical utility of CTC in small cell lung cancer (SCLC) remains unclear. The aim of the CTC-CPC study was to develop an EpCAM-independent CTC isolation method allowing isolation of a broader range of living CTC from SCLC and decipher their genomic and biological characteristics. CTC-CPC is a monocentric prospective non-interventional study including treatment-naïve newly diagnosed SCLC. CD56+ CTC were isolated from whole blood samples, at diagnosis and relapse after first-line treatment and submitted to whole-exome-sequencing (WES). Phenotypic study confirms tumor lineage and tumorigenic properties of isolated cells for the 4 patients analyzed with WES. WES of CD56+ CTC and matched tumor biopsy reveal genomic alteration frequently impaired in SCLC. At diagnosis CD56+ CTC were characterized by a high mutation load, a distinct mutational profile and a unique genomic signature, compared to match tumors biopsies. In addition to classical pathways altered in SCLC, we found new biological processes specifically affected in CD56+ CTC at diagnosis. High numeration of CD56+ CTC (> 7/ml) at diagnosis was associated with ES-SCLC. Comparing CD56+ CTC isolated at diagnosis and relapse, we identify differentially altered oncogenic pathways (e.g. DLL3 or MAPK pathway). We report a versatile method of CD56+ CTC detection in SCLC. Numeration of CD56+ CTC at diagnosis is correlated with disease extension. Isolated CD56+ CTC are tumorigenic and show a distinct mutational profile. We report a minimal gene set as a unique signature of CD56+ CTC and identify new affected biological pathways enriched in EpCAM-independent isolated CTC in SCLC.

Abstract Global climate changes may cause profound effects on species adaptation, particularly in ectotherms for whom even moderate warmer temperatures can lead to disproportionate heat failure. Still, several organisms evolved to endure high desert temperatures. Here, we describe the thermal tolerance survival and the transcriptomic heat stress response of three genera of desert (Cataglyphis, Melophorus, and Ocymyrmex) and two of temperate ants (Formica and Myrmica) and explore convergent and specific adaptations. We found heat stress led to either a reactive or a constitutive response in desert ants: Cataglyphis holgerseni and Melophorus bagoti differentially regulated very few transcripts in response to heat (0.12% and 0.14%, respectively), while Cataglyphis bombycina and Ocymyrmex robustior responded with greater expression alterations (respectively affecting 0.6% and 1.53% of their transcriptomes). These two responsive mechanisms—reactive and constitutive—were related to individual thermal tolerance survival and convergently evolved in distinct desert ant genera. Moreover, in comparison with desert species, the two temperate ants differentially expressed thousands of transcripts more in response to heat stress (affecting 8% and 12.71% of F. fusca and Myr. sabuleti transcriptomes). In summary, we show that heat adaptation in thermophilic ants involved changes in the expression response. Overall, desert ants show reduced transcriptional alterations even when under high thermal stress, and their expression response may be either constitutive or reactive to temperature increase.

Summary: Antigen selection and prioritization represent crucial determinants of vaccines’ efficacy. Here, we compare two personalized dendritic cell-based vaccination strategies using whole-tumor lysate or neoantigens. Data in mouse and in cancer patients demonstrate that peptide vaccines using neoantigens predicted on the sole basis of in silico peptide-major histocompatibility complex (MHC) binding affinity underperform relative to whole-tumor-lysate vaccines. In contrast, effective in vitro peptide-MHC binding affinity and peptide immunogenicity significantly improve the prioritization of tumor-rejecting neoepitopes and result in more efficacious vaccines.

Abstract Climate change adaptation and mitigation strategies are gaining visibility and support. Decision-makers are defending the extension of large infrastructures that are low greenhouse gas (GHG) emitters, as a way to act quickly and massively without calling into question existing economic models. This situation depoliticizes these projects, masking their other ecological consequences such as their impacts on biodiversity. This article examines how promoters of these projects depoliticized its socio-technical futures while other actors re-politicized them. Using the example of the Seine Nord Europe Canal project, we show a politicization of the territorial future and a depoliticization of the environmental future. This depoliticization is based on the techno-optimist discourse promoting large-scale infrastructures as the only possible solution to the global ecological and climate crisis. It uses a selective framing of the environment that makes some elements visible and others invisible. We conducted semi-structured interviews with biodiversity stakeholders in the territories that would be impacted by the canal. Based on the concepts of environmental forms and motives, we reconstructed the environmental ontologies ignored by the dominant discourse and assembled them into three alternative scenarios. We present the method of investigation and identification of these motives and discuss the likelihood of the constructed scenarios participating in a re-politicization based on the reactions of various actors.

Breast cancer is one of the most prevalent cancers worldwide and pathologists are closely involved in establishing a diagnosis. Tools to assist in making a diagnosis are required to manage the increasing workload. In this context, artificial intelligence (AI) and deep-learning based tools may be used in daily pathology practice. However, it is challenging to develop fast and reliable algorithms that can be trusted by practitioners, whatever the medical center. We describe a patch-based algorithm that incorporates a convolutional neural network to detect and locate invasive carcinoma on breast whole-slide images. The network was trained on a dataset extracted from a reference acquisition center. We then performed a calibration step based on transfer learning to maintain the performance when translating on a new target acquisition center by using a limited amount of additional training data. Performance was evaluated using classical binary measures (accuracy, recall, precision) for both centers (referred to as "test reference dataset" and "test target dataset") and at two levels: patch and slide level. At patch level, accuracy, recall, and precision of the model on the reference and target test sets were 92.1% and 96.3%, 95% and 87.8%, and 73.9% and 70.6%, respectively. At slide level, accuracy, recall, and precision were 97.6% and 92.0%, 90.9% and 100%, and 100% and 70.8% for test sets 1 and 2, respectively. The high performance of the algorithm at both centers shows that the calibration process is efficient. This is performed using limited training data from the new target acquisition center and requires that the model is trained beforehand on a large database from a reference center. This methodology allows the implementation of AI diagnostic tools to help in routine pathology practice.

Abstract Background Osimertinib is a third generation tyrosine kinase inhibitor (TKI) that targets the epidermal growth factor receptor (EGFR) in lung cancer. However, although this molecule is not subject to some of the resistance mechanisms observed in response to first generation TKIs, ultimately, patients relapse because of unknown resistance mechanisms. New relevant non-small cell lung cancer (NSCLC) mice models are therefore required to allow the analysis of these resistance mechanisms and to evaluate the efficacy of new therapeutic strategies. Methods Briefly, PC-9 cells, previously modified for luciferase expression, were injected into the tail vein of mice. Tumor implantation and longitudinal growth, almost exclusively localized in the lung, were evaluated by bioluminescence. Once established, the tumor was treated with osimertinib until tumor escape and development of bone metastases. Results Micro-metastases were detected by bioluminescence and collected for further analysis. Conclusion We describe an orthotopic model of NSCLC protocol that led to lung primary tumor nesting and, after osimertinib treatment, by metastases dissemination, and that allow the isolation of these small osimertinib-resistant micro-metastases. This model provides new biological tools to study tumor progression from the establishment of a lung tumor to the generation of drug-resistant micro-metastases, mimicking the natural course of the disease in human NSCLC patients.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are currently recommended as first-line treatment for advanced non-small-cell lung cancer (NSCLC) with EGFR-activating mutations. Third-generation (3rd G) EGFR-TKIs, including osimertinib, offer an effective treatment option for patients with NSCLC resistant 1st and 2nd EGFR-TKIs. However, the efficacy of 3rd G EGFR-TKIs is limited by acquired resistance that has become a growing clinical challenge. Several clinical and preclinical studies are being carried out to better understand the mechanisms of resistance to 3rd G EGFR-TKIs and have revealed various genetic aberrations associated with molecular heterogeneity of cancer cells. Studies focusing on epigenetic events are limited despite several indications of their involvement in the development of resistance. Preclinical models, established in most cases in a similar manner, have shown different prevalence of resistance mechanisms from clinical samples. Clinically identified mechanisms include EGFR mutations that were not identified in preclinical models. Thus, NRAS genetic alterations were not observed in patients but have been described in cell lines resistant to 3rd G EGFR-TKI. Mainly, resistance to 3rd G EGFR-TKI in preclinical models is related to the activation of alternative signaling pathways through tyrosine kinase receptor (TKR) activation or to histological and phenotypic transformations. Yet, preclinical models have provided some insight into the complex network between dominant drivers and associated events that lead to the emergence of resistance and consequently have identified new therapeutic targets. This review provides an overview of preclinical studies developed to investigate the mechanisms of acquired resistance to 3rd G EGFR-TKIs, including osimertinib and rociletinib, across all lines of therapy. In fact, some of the models described were first generated to be resistant to first- and second-generation EGFR-TKIs and often carried the T790M mutation, while others had never been exposed to TKIs. The review further describes the therapeutic opportunities to overcome resistance, based on preclinical studies.

IRE1α plays a key role in the unfolded protein response (UPR) by promoting the unconventional splicing of the XBP1 and the selective cleavage of RNAs. Here the authors report that IRE1α is activated upon the DNA damage response and selectively controls the stability of mRNAs to maintain genome integrity.

Background: Air pollution in subway environments is a growing concern as it often exceeds WHO recommendations for indoor air quality. Ultrafine particles (UFP), for which there is still no regulation nor a standardized exposure monitoring method, are the strongest contributor to this pollution when the number concentration is used as exposure metric. Objectives: We aimed to assess the real-time UFP number concentration in the personal breathing zone (PBZ) of three types of underground Parisian subway professionals and analyze it using a novel Bayesian spline approach. Consecutively, we investigated the effect of job, week day, subway station, worker location, and some further events on UFP number concentrations. Methods: The data collection procedure originated from a longitudinal study and lasted for a total duration of 6 weeks (from October 7 to November 15, 2019, i.e. two weeks per type of subway professionals). Time-series were built from the real-time particle number concentration (PNC) measured in the PBZ of professionals during their work-shifts. Complementarily, contextual information expressed as Station, Environment, and Event variables were extracted from activity logbooks completed for every work-shift. A Bayesian spline approach was applied to model the PNC within a Bayesian framework as a function of the mentioned contextual information. Results: Overall, the Bayesian spline method suited a real-time personal PNC data modeling approach. The model enabled estimating the differences in UFP exposure between subway professionals, stations, and various locations. Our results suggest a higher PNC closer to the subway tracks, with the highest PNC on subway station platforms. Studied event and week day variables had a lesser influence. Conclusion: It was shown that the Bayesian spline method is suitable to investigate individual exposure to UFP in underground subway settings. This method is informative for better documenting the magnitude and variability of UFP exposure, and for understanding the determinants in view of further regulation and control of this exposure.

Urine cytology is non-invasive, easy to collect, with medium sensitivity and a high specificity. It is an effective way to detect high-grade bladder cancer (BC), but it is less effective on low-grade BC because the rate of equivocal results is much higher. Recently, the fluorescent properties of plasma membranes of urothelial tumor cells (UTC) found in urine cytology have been shown to be useful in improving the early detection of BC. This phenomenon is called peri-membrane fluorescence (PMF). Based on previous studies that have identified the PMF on UTCs, the main objective was to characterize this phenomenon. For this study, a software was specially created to quantify the PMF of all tested cells and different treatments performed. PMF was not found to be a morphological and discriminating feature of UTCs, all cells in shape and not from urine show PMF. We were able to highlight the crucial role of plasma membrane integrity in the maintenance of PMF. Finally, it was found that the induction of a strong cellular stress induced a decrease in PMF, mimicking what was observed in non-tumor cells collected from urine. These results suggest that PMF is found in cells able to resist this stress, such as tumor cells.

Liquid biopsies are increasingly used for the diagnosis and follow-up of cancer patients. Urine is a body fluid that can be used to detect cancers and others diseases. It is noninvasive and easy to collect. To detect Bladder Cancer (BC), cytology is the first assay used. It is an effective way to detect high grade BC but has a high rate of equivocal results, especially for low grade BC. Furthermore, cystoscopy is used to confirm cytology results and to determine cancer status. Cystoscopy is also effective but highly invasive, and not well accepted by patients, especially for BC follow-up. In this review we survey the numerous assays recently developed in order to diagnose BC at an early stage, and to facilitate the follow-up of patients. We discuss their effectiveness, ease of use, and applications. Finally, we discuss assays that, in the future, could improve the diagnosis and management of BC patients.

The ING family of tumor suppressor genes is composed of five members (ING1-5) involved in cell cycle regulation, DNA damage response, apoptosis and senescence. All ING proteins belong to various HAT or HDAC complexes and participate in chromatin remodeling that is essential for genomic stability and signaling pathways. The gatekeeper functions of the INGs are well described by their role in the negative regulation of the cell cycle, notably by modulating the stability of p53 or the p300 HAT activity. However, the caretaker functions are described only for ING1, ING2 and ING3. This is due to their involvement in DNA repair such as ING1 that participates not only in NERs after UV-induced damage, but also in DSB repair in which ING2 and ING3 are required for accumulation of ATM, 53BP1 and BRCA1 near the lesion and for the subsequent repair. This review summarizes evidence of the critical roles of ING proteins in cell cycle regulation and DNA repair to maintain genomic stability.

Non-small cell lung cancer (NSCLC) has been the leading cause of cancer-related death worldwide, over the last few decades. Survival remains extremely poor in the metastatic setting and, consequently, innovative therapeutic strategies are urgently needed. Inhibitor of Growth Gene 2 (ING2) is a core component of the mSin3A/Histone deacetylases complex (HDAC), which controls the chromatin acetylation status and modulates gene transcription. This gene has been characterized as a tumor suppressor gene and its status in cancer has been scarcely explored. In this review, we focused on ING2 and other mSin3A/HDAC member statuses in NSCLC. Taking advantage of existing public databases and known pharmacological properties of HDAC inhibitors, finally, we proposed a therapeutic model based on an ING2 biomarker-guided strategy.

Two compounds (1) and (2) containing tert-butylphenol groups were, for the first time, produced during the culture of Paenibacillus odorifer, a bacterial strain associated with the crustose lichen, Rhizocarpon geographicum. Their entire structures were identified by one-dimensional (1D) and two-dimensional (2D) NMR and high-resolution electrospray ionisation mass spectrometry (HRESIMS) spectroscopic analyses. Among them, Compound 1 exhibited significant cytotoxicity against B16 murine melanoma and HaCaT human keratinocyte cell lines with micromolar half maximal inhibitory concentration (IC50) values. Furthermore, after supplementation studies, a putative biosynthesis pathway was proposed for Compound 1 throughout a bioconversion by this bacterial strain of butylated hydroxyanisole (BHA), an antioxidant polymer additive.

Half a century after the May-June 1968 events, two former key figures of the student movement look back on their experience. These conversations show how the dynamics of challenging the university establishment and the logic of regulation interwove to fuel a deep redefinition of French university, both during and after the days of protest

Public policies have known a new managerial approach growth promoted by the cognitive and practice framework of New Public Management. This development has empowered the institutionalization of efficiency and effectiveness indicators in public sector’s practices. In fact, it seems that ecosystem services and payments for environmental services register in this new philosophy. Drawing on this, this paper proposes to consider the production’s conditions of tools and monetary evaluation procedures in environmental policies. Finally, the article argues that this procedures contains and disseminate a reduction point of view about the biodiversity value.

This text introduces the special section « Biodiversity loss, New Public Management and neoliberalism ». It analyzes the effects and the consequences of neo-managerial management of biodiversity in a context of ecological emergency. This introduction allows to question the policy implementation of biodiversity crisis starting from what the neoliberal rationality makes it possible to apprehend it. The discussion aims at interrogating the framing of the crisis and the instrumentation performed within the administration. It is then the capacity of neoliberal rationality to respond to the biodiversity crisis that is ultimately questioned.

This interview with Gabrielle Bouleau is part of a series of exchanges conducted as part of the anniversary issue of the journal Développement durable & territoires. by drawing up her scientific trajectory and the epistemological challenges of her major contributions to DD&T, Gabrielle Bouleau underlines the pivotal role that the journal has played in structuring a research path which is anchored in interdisciplinarity and in constant iteration with the territories. The interview thus offers a panoramic view of the expectations – in particular the capacity to address emerging issues – with regards to DD&T, which 20 years after its creation, is now well established in the field of French-speaking journals on environmental social sciences applied to territory.

This interview with Lucie Morère is part of a series of exchanges conducted for the anniversary issue of Développement durable & territoires, which aims at retracing the history of the journal and to define some future perspectives. The young researcher, now a practitioner of public action, recalls the added-value of her participation to the editorial committee in the construction of her professional development. The interview highlights the double heuristic and political interest of the action-research agenda, which characterizes the journal.

The 20th anniversary issue of Développement Durable & Territoires (Sustainability & territories) provides an opportunity to highlight the ambitions of the « Point de vue » (Viewpoints) section and to review its history. The section was conceived as an original one, aiming to allow the expression of « points de vue » on subjects or objects related to the editorial line of DD&T, in a freer format than that of standard scientific articles and/or from non-academic actors. This introduction looks back at the highlights of the section and sheds light on the type of publication it contains. The contributions of the section are highlighted, but also the difficulty inherent in the objective : in the end, few publications are by non-academic actors. This is why one of the prospects for the future is to publish more content in the form of interview transcripts, which is undoubtedly more conducive to the circulation of « points de vue ». This approach is initiated in this issue with the publication of three interviews reflecting three different points of view on the history and characteristics of the DD&T journal.

Since the biodiversity law in 2016, biological offsetting, which is traduced by consulting firms, is an adaptation of performance logic induced by New Public Management. Biodiversity offsets are determined by consulting firms. It is based on quantification and substitutability of biodiversity, which contributes to reduce complexity of interdependencies between natural environment and social environment in order to respond to NPM goals of efficiency and results. It aims at promote economical value of biodiversity at the expense of ecosystemic value. In a context of biodiversity crisis, we should emphasize the shifting between biodiversity offsetting tool (in order to contain biodiversity crisis) and their irreversible ecological consequences.

The notion of "strong sustainability" is being reassessed in different disciplines of the humanities and social sciences such as history (Quenet, 2016), geography (Chartier, 2016), but also ethics and political science. It obviously raises important epistemological questions about the integration of environmental issues into social sciences (Blanc et al., 2017). However, the distinction between "weak" and "strong" sustainability first emerged in ecological economics in the mid-1990s. Strong sustainability immediately became part of the interplay of actors and conflicts of legitimacy that still weigh on its heuristic scope, as well as on its ability to nurture the plurality of representations of social relations with the environment.

Since the biodiversity law in 2016, biological offsetting, which is traduced by consulting firms, is an adaptation of performance logic induced by New Public Management. Biodiversity offsets are determined by consulting firms. It is based on quantification and substitutability of biodiversity, which contributes to reduce complexity of interdependencies between natural environment and social environment in order to respond to NPM goals of efficiency and results. It aims at promote economical value of biodiversity at the expense of ecosystemic value. In a context of biodiversity crisis, we should emphasize the shifting between biodiversity offsetting tool (in order to contain biodiversity crisis) and their irreversible ecological consequences.

The notion of "strong sustainability" is being reassessed in different disciplines of the humanities and social sciences such as history (Quenet, 2016), geography (Chartier, 2016), but also ethics and political science. It obviously raises important epistemological questions about the integration of environmental issues into social sciences (Blanc et al., 2017). However, the distinction between "weak" and "strong" sustainability first emerged in ecological economics in the mid-1990s. Strong sustainability immediately became part of the interplay of actors and conflicts of legitimacy that still weigh on its heuristic scope, as well as on its ability to nurture the plurality of representations of social relations with the environment.

Morphological and enzymatic characterization of Phlebotomus perniciosus and Phlebotomus longicuspis in Morocco is reported. Twenty-nine localities in central and southern of Morocco were sampled and compared with three localities from the Rif (northern Morocco). For morphological study, sand flies were collected by sticky-paper traps. For males, the morphology of the copulatory valves (aedeagi) was examined and the number of coxite hairs was recorded. For isoenzyme analyses, specimens were collected in CDC light traps and immediately conserved at -80 degrees C. P. perniciosus samples from the south of Morocco, up to 150 km from Marrakech, showed single-pointed aedeagi curved at their apices, indistinguishable from the atypical morph of P. perniciosus, previously described in northern Morocco. Twelve enzyme systems were tested and the qualitative analysis of zymogram profiles revealed eight polymorphic loci (glucosephosphate isomerase (GPI), phosphoglucomutase (PGM), hexokinase (HK), fumarate hydratase (FUM), malate dehydrogenase 1 (MDH1), malate dehydrogenase 2 (MDH2), 6 phosphogluconate dehydrogenase (6PGD) and aconitase (ACO)). Enzyme loci showed fixed alleles diagnostic for P. perniciosus (aconitase) and P. longicuspis (aconitase and hexokinase).