Gennady Bocharov

Anas Bouchnita

Jean Clairambault

Vitaly Volpert

Mathematics of Pharmacokinetics and Pharmacodynamics: Diversity of Topics, Models and Methods

Keywords: pharmacokinetics-pharmacodynamics, mathematical models, model analysis, parameter estimation, computer simulation Mathematics Subject Classification: 92C30, 92C45

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"Spatial dimension" of PK-PD problems in immunology

The classical modelling approach in PK-PD is based on mathematical models representing a compartmental view of the organism [START_REF] Macheras | Modeling in Biopharmaceutics, Pharmacokinetics and Pharmacodynamics, Homogeneous and Heterogeneous Approaches[END_REF]. The models consider organs and cells as compartments in which the concentration of a drug is spatially uniform or homogeneous. However, recent clinical and experimental studies of infections such as human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) clearly indicate that the view has to be extended to consider a genuine spatial dimension of the tissues and organs in which the infection and drug distribution processes take place.

One of the first evidences of the key role of spatial distribution of drugs in the efficacy of antiretroviral (ART) HIV treatment was presented in [START_REF] Fletcher | Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues[END_REF]. It was shown that HIV continues to replicate in lymphatic tissues of some inc EDP Sciences, 2016 i i "preface2-2" -2016/12/9 -12:16 -page 1 -#2 i i i i i i G. Bocharov, A. Bouchnita, J. Clairambault, V. Volpert Diversity of mathematics of PK-PD dividuals under taking ART regimens considered fully suppressive, based on undetectable viral loads in peripheral blood. One mechanism proposed to explain the persistent replication of HIV in lymphatic tissues was lower concentrations of the ART drugs in those tissues compared with peripheral blood. Overall, a clear association between low drug concentrations in tissues and persistent viral replication was documented. The evidence has been further corroborated in recent studies of the persistent productive HIV infection during therapy [START_REF] Lorenzo-Redondo | Persistent HIV-1 replication maintains the tissue reservoir during therapy[END_REF] and SIV infections in elite controllers [START_REF] Fukazawa | B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers[END_REF]. The existence of the drug-free zones in lymphoid tissues is broadly discussed in [START_REF] Licht | A drug-free zone-lymph nodes as a safe haven for HIV[END_REF]. It is a remarkable finding that multiple drug concentrations in lymph nodes can be about 100-times lower than those in blood for the same patient [START_REF] Fletcher | Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues[END_REF].

To analyse the novel aspects of the drug dynamics and effect in organs spatially extended models of drug transport in tissues are needed. For example, the drug concentration field can be studied using the reaction-diffusion equation:

-div(D∇c(x)) + αc(x) = M ∑ k=1 ρδ (x -x k ), (1.1)
where D is a tensor diffusion coefficient, D = D (i) in domains Ω i , i = 1, ..., N, specifying various structures of the organs under investigation. The equation is understood in a weak sense. Although the above model is rather simple, it can be used in conjunction with the anatomical description of the tissue structure to provide novel insights into the spatial patterns of drug distribution in complex organ environments. Instructive example is provided by studies of type I interferon (IFN) distribution in lymph nodes (LNs) [START_REF] Bocharov | Reaction-diffusion modelling of interferon distribution in secondary lymphoid organs[END_REF][START_REF] Bocharov | Simulation of the interferon-mediated protective field in lymphoid organs with their spatial and functional organization taken into consideration[END_REF]. The structural organisation of LNs is quite elaborate [START_REF] Junt | Form follows function: lymphoid tissue microarchitecture in antimicrobial immune defence[END_REF] and a paradigmatic view gives a simplified but still a representative geometry of the LN. The 3D geometry of a paradigmatic LN approximated with a tetrahedral mesh is shown in Figure 1, left. The elements considered include subcapsular sinus (SCS), trabecular sinuses, B-cell follicles,T cell zone, conduits. This geometry requires a multiple length scale resolution for the representation of the conduits and other major domains. The above reaction-diffusion partial differential equation governing the interferon dynamics was used to analyse the steady-state distribution of IFN across the subdomains of the 3D lymph node. The LN domain Ω consists of subdomains represesnting SCS Ω 1 , trabecular sinuses Ω 2 , conduit "network" Ω 3 , B cell follicle Ω 4 , T cell zone Ω 5 . Obviously, the penetration of the cytokine to various parts of the LN is governed by the relative balance of convection, diffusion and degradation/absorption of the IFN molecules. Under these settings, M is the number of cell producing IFN, x k denotes the cell location, ρ is the production rate, α the degradation/absorbtion rate of IFN. There is a non-homogeneity in diffusion coefficients D (1,2,3) = D * , D (4) = 0.1D * , D (5) = 0.01D * as suggested by experimentally observed differences of small molecular tracers distribution in LN domains [START_REF] Lammermann | The microanatomy of T-cell responses[END_REF]. The regions of LNs that contain T lymphocytes (the cortical and para-cortical zones or the Ω 5 region) are characterised by weak molecular diffusion, which is associated with poor hydraulic conductivity [START_REF] Lammermann | The microanatomy of T-cell responses[END_REF]. Calibrating the model parameters using the estimates from [START_REF] Bocharov | A systems immunology approach to plasmacytoid dendritic cell function in cytopathic virus infections[END_REF][START_REF] Keener | Mathematical Physiology[END_REF]] D * = dI, d = 0.16 mm 2 /hr, ρ = 4.4 • 10 -4 pg/hr, α = 0.012/hr allows one to examine the extent of non-homogeneity of the IFN field in LN as shown in Figure 1, centre. The numerical solution for the model predicts that a substantial variation of IFN concentration takes place within the LN, i.e. by two orders of magnitude. Therefore the compartmentalisation of the cytokine can occur due to the diffusion process. The conclusion is robust with respect to variations in geometrical structure of LN and justified variations in the model parameter values. Type I interferon is generally considered as an antiviral drug for HIV infection. In a broader context, it can be hypothesised that when the drug distributions is concerned the morphology and biophysical properties of secondary lymphoid organs can lead to the formation of poorly protected areas. In these areas, localization of the cells infected by viruses, such as CD4+ T lymphocytes or macrophages in the case of HIV infection provides the conditions for the continuation of active infectious processes.

The effect of spatial compartmentalisation of this important cytokine in lymphoid tissue is predicted based on embedding a reaction-diffusion model into a spatial 3D context of the LN and some basic information about the hydraulic conductivity taken into account. Deeper insights into the spatial patterns of cytokine and drug penetration into LN will require a finer approximation of the LN structures, e.g., such as the conduit network and the blood microvascular system as well as studies of the molecular transport in domains densely packed with cells. Figure 1, right shows a 3D model of the LN with geometrically and topologically consistent representation of fibroblastic reticular cell network. Some elements necessary to move in this direction has already been elaborated in recent studies of fluid flow through LNs [START_REF] Savinkov | Data-driven modelling of the FRC network for studying the fluid flow in the conduit system[END_REF][START_REF] Jafarnejad | Modeling lymph flow and fluid exchange with blood vessels in lymph nodes[END_REF][START_REF] Kislitsyn | Computational approach to 3D modeling of the lymph node geometry[END_REF][START_REF] Cooper | An image-based model of fluid flow through lymph nodes[END_REF].

Non-spatial models in oncology

Representing healthy and cancer proliferating cell populations, the targets of anticancer drugs, may involve space, but most often the spatial structure of the cell populations is not known. Tumours are far from presenting themselves as spatially well-organised tissues; furthermore anticancer drugs act on molecular or functional targets in cell populations, that are by nature highly heterogeneous in physiology as well in pathology. Space is thus not necessarily relevant to describe their action, whose result is seen on cell population numbers or growth rates. Much more relevant than space-structured models are physiologically structured models, that are amenable to account for the relevant biological variability (=heterogeneity) of the cell population under study. In this special issue, an age-structured transport model of the cell division cycle in healthy and cancer cell populations is presented, following previous ones [START_REF] Billy | Designing proliferating cell population models with functional targets for control by anti-cancer drugs[END_REF][START_REF] Billy | Age-structured cell population model to study the influence of growth factors on cell cycle dynamics[END_REF][START_REF] Billy | Optimisation of cancer drug treatments using cell population dynamics[END_REF][START_REF] Billy | Synchronisation and control of proliferation in cycling cell population models with age structure[END_REF]. Its originality is that it is coupled with an ODE model for the PK-PD of the two main drugs used in colorectal cancer: 5-fluorouracil and oxaliplatin. It has been originally designed in the framework of chronotherapeutics (chrono-PK-PD) [START_REF] Clairambault | Deterministic mathematical modelling for cancer chronotherapeutics: cell population dynamics and treatment optimisation[END_REF], but it can also be used outside of this framework, provided that the time differences in gating at the cell cycle checkpoints between healthy and cancer cell populations are preserved.

Given such fundamental differences, one can, as shown in the article of the present issue, design optimised strategies for the delivery of anticancer drugs. The optimisation method proposed operates under the constraint of preserving the healthy cell population. Another crucial aspect of theoretical therapeutic optimisation consists in avoiding the emergence of resistant cell subpopulations, which is the other major pitfall of therapeutics in oncology. It is only alluded at in this article, but it is studied in detail in [START_REF] Lorz | Populational adaptive evolution, chemotherapeutic resistance and multiple anti-cancer therapies[END_REF][START_REF] Lorz | Modeling the effects of space structure and combination therapies on phenotypic heterogeneity and drug resistance in solid tumors[END_REF]. In the models used, cell populations are structured in a phenotype representing the expression of drug resistance in the cells. They are basically nonspatial, but space can be introduced as complementary structure variable when it is relevant to the description of the heterogeneity under study, for instance if the tumour is assumed to be spheroid-shaped [START_REF] Lorz | Modeling the effects of space structure and combination therapies on phenotypic heterogeneity and drug resistance in solid tumors[END_REF]. Then PK-PD ODE models for the drug considered (a cytotoxic and a cytostatic) could be coupled to the phenotype-structured models as it has been done in age-structured models of the cell cycle, but this remains to be done.

PK-PD and systems pharmacology in blood clotting pathologies

Developing mathematical models of blood coagulation is essential in understanding the pathogenesis of blood clotting abnormalities such as thrombosis and hemophilia. Usually, the developed models are firstly built in order to describe the dynamics of healthy blood coagulation. However, it is sufficient to change some parameters associated with a coagulation disorder to describe pathological blood coagulation. The ultimate goal of these models is to study the action of treatments on the coagulation process. Despite the wide range of mathematical methods used in the development of PK-PD hemostasis models, the modellers are faced with numerous challenges due to the complexity of the blood clotting system. Below, we present a state of the art of the approaches used in the mathematical modelling of blood clotting disorders and their treatment.

Venous thrombosis is a blood clotting disorder characterized by the formation of excessive blood clots within a vein resulting in the perturbation of blood flow. Warfarin and heparin are two anticoagulant drugs that are usually prescribed to prevent venous thrombosis [START_REF] Dahlback | Haematology: blood coagulation[END_REF]. In a recent model [START_REF] De Pillis | Injury-initiated clot formation under flow: a mathematical model with warfarin treatment[END_REF], the effect of warfarin on clot growth in flow was studied. Warfarin is an anti-vitamin K drug which downregulates the synthesis of some clotting factors in the liver. Its action is monitored by an in vitro assay called INR (international normalized ratio) which is based on the necessary time for prothrombin conversion into thrombin. In order to prevent thrombosis, the INR should be maintained between 2.0 and 3.0 during warfarin treatment. The authors used previously developed models for both in vivo clot formation and in vitro PT and INR assays, and then compared the action of warfarin on individual patients under these two conditions. They conducted numerical simulation describing growth during warfarin treatment under various flow conditions. They concluded that the in vitro assays do not represent a reliable tool for monitoring warfarin treatment due to the absence of blood flow in in vitro tests. This explains the persistence of thrombosis for some patients even when their INR is in the targeted range.

In addition to warfarin, heparin is one of the commonly used venous thrombosis treatments. Heparin upregulates the activity of antithrombin which reduces blood coagulability. In a recent work [START_REF] Dydek | Simulated thrombin generation in the presence of surface-bound heparin and circulating tissue factor[END_REF], Dydek and Chaikof equipped a previously developed model for in situ clot growth with the action of heparin. The resulting model is detailed and focuses on the spatio-temporal dynamics of clot growth during heparin treatment. The authors evaluated the effects of different doses and types of heparin under venous and arterial flows and included the effect of circulating tissue factor. In the future, this work can be combined with pharmacokinetics models of heparin treatments to assess the efficacy and safety of various protocols.

A comprehensive model which encompasses both the PK-PD and the in vitro assays aspects of venous thrombosis was developed using systems pharmacology [START_REF] Wajima | A comprehensive model for the humoral coagulation network in humans[END_REF]. It uses ODEs to describe the concentrations of drugs, proteins, and clotting factors in different time scales which affect each other. In this work, the authors compared the results of different in vitro tests and clotting times such as PT and aPTT during anticoagulant treatment. They studied the action of different drugs such as warfarin and heparin and simulated the pathogenesis of blood clotting disorders such as thrombosis, hemophilia A and B. To the best of our knowledge, this is one of the few complex models that were validated by experimental data in the literature. The model can serve as an in silico predicting tool in drug development and clinical trials.

Although most of the PK-PD models of thrombosis study the action of warfarin and heparin, some of the recent works are devoted to the action of new oral anticoagulants such as rivaroxaban. It is a direct factor Xa inhibitor which is commonly used to prevent strokes and thrombo-embolic events in adult patients. An important PK-PD model which assesses the efficacy and safety rivaroxaban treatments was developed by Burghaus et al. [START_REF] Burghaus | Evaluation of the efficacy and safety of rivaroxaban using a computer model for blood coagulation[END_REF]. This work is of practical interest because it is based on previously validated models [START_REF] Bungay | A mathematical model of lipid-mediated thrombin generation[END_REF][START_REF] Hockin | A model for the stoichiometric regulation of blood coagulation[END_REF]. Furthermore, it encompasses both the extrinsic and intrinsic pathways as well as the effects of blood flow on clot growth. All of these factors make the model appropriate for clinical studies. Recently, the model was used in order to study the optimal dosing schedule for switching from warfarin to rivaroxaban treatment (Burghaus et al. 2014). Another systems pharmacology model of rivaroxaban action was developed by Zhou et al. [START_REF] Zhou | A systems pharmacology model for predicting effects of factor Xa inhibitors in healthy subjects: assessment of pharmacokinetics and binding kinetics[END_REF]. It contains one of the most complete descriptions of the blood coagulation cascade and accurately predicts clotting times during anticoagulant treatment. Direct thrombin inhibitors are another class of new oral anticoagulant drugs which are used in the prevention of thromboembolic events. Dabigatran etexilate is one of the commonly used direct thrombin inhibitors as it can replace warfarin but does not require monitoring by the INR test. The only in vitro assay which can potentially assess the efficacy and safety of such treatments is the thrombin generation test. In a recent study [START_REF] Gribkova | The modification of the thrombin generation test for the clinical assessment of dabigatran etexilate efficiency[END_REF], the authors used a calibrated version of this test to assess the efficacy of dabigatran. Although the study does not directly provide a mathematical model which can be used in in silico dabigatran treatments assessment, it presents valuable experimental data which can help the future developments of PK-PD models describing the action of dabigatran on the coagulation process.

There are many other systems pharmacology models which describe blood coagulation pathologies and the action of treatments ( [START_REF] Cromme | Computer-aided dosage in oral anticoagulation therapy using phenprocoumon[END_REF][START_REF] Gulati | Scale reduction of a systems coagulation model with an application to modeling pharmacokineticpharmacodynamic data[END_REF][START_REF] Luan | Computational modeling and simulation of thrombus formation[END_REF][START_REF] Lynd | Advances in risk-benefit evaluation using probabilistic simulation methods: an application to the prophylaxis of deep vein thrombosis[END_REF][START_REF] Parunov | Improvement of spatial fibrin formation by the anti-TFPI aptamer BAX499: changing clot size by targeting extrinsic pathway initiation[END_REF]). While most of these models are more appropriate for an accurate multi-scale description of the coagulation process during treatment, they are usually built in complex and sophisticated ways that incorporate many details. As a result, it becomes difficult to interpret the obtained results and to derive simple relations between the parameters of interest. To encourage the use of multi-scale models in clinical studies, Gulati et al. showed how to reduce a 62-state model to 5-state model [START_REF] Gulati | Scale reduction of a systems coagulation model with an application to modeling pharmacokineticpharmacodynamic data[END_REF]. They also derived mechanistic relationships between coagulation parameters that agree with experimental data.

Developing PK-PD models of blood coagulation pathologies requires an appropriate characterization of individual patientsṕrofiles. Brummel-Ziedins [START_REF] Brummel-Ziedins | Models for thrombin generation and risk of disease[END_REF] addressed this point by developing and validating computational approaches which capture the dynamics of thrombin generation in individual patients depending on plasma composition. Such approaches can be used in identifying thrombosis risk during anticoagulant treatments. Other models study the hemostatic response in individuals with pre-existing health conditions associated with clotting disorders including rheumatoid arthritis [START_REF] Undas | Thrombin generation in rheumatoid arthritis: dependence on plasma factor composition[END_REF], cancer [START_REF] Clegg | Systems biology of the microvasculature[END_REF], and deep venous thrombosis [START_REF] Brummel-Ziedins | Thrombin generation profiles in deep venous thrombosis[END_REF]. PK-PD models of thrombosis and other blood coagulation disorders represent a promising tool that can potentially predict individual haemostatic responses. However, for these models to be incorporated in clinical studies, it is crucial to them with in vitro and in vivo blood clotting experimental data. Ultimately, we can expect that accurate computer models of blood coagulation will replace in vitro diagnostic assays. Until then, a significant effort should be made in order to develop more accurate and experimentally validated models that capture all the pathophysiological aspects of blood coagulation.

Future developments 4.1. Whole-body and multi-scale modelling

The development of patient-specific drug therapies requires high-resolution mathematical models for assimilating of the vast amount of data including -omics, sequencing, flow cytometry, imaging, immune profiling characterizing the organism response to drug intervention at various levels of resolution. Therapies of some complex pathologies also include adoptive immune cell transfer in addition to drug injections. This combination of therapeutic agents of different nature call for the models considering the spatial distribution of target cells (e.g., CD4 T cells in follicles in HIV infection) and the migration of immune cells in various parts of the LN (e.g., CTL destroying infected cells). Overall, a shift from a compartmental consideration of the PK-PD processes to multi-physics and multiscale framework (see, e.g. [START_REF] Bouchnita | Hybrid approach to model the spatial regulation of T cell responses[END_REF]) in active and soft tissues and organs in a 3D setting environment suggests the following agenda for research:

1. Parameterised computational 3D models of the organs and tissues viewed as idealised 3D structures complementing the reconstruction based approaches from imaging data; 2. Anatomically based mathematical models of processes dynamics; 3. Systemic cell recirculation in the host in conjunction with local migration within organs and tissues; 4. Biophysical properties of tissues, e.g., hydraulic conductivity, porosity; 5. Blood and lymph flow patterns in lymphoid organs; 6. Transport and distribution governing equations (e.g., sub-, normal or super-diffusion) of cytokines, chemokines, drugs; 7. Fluid-tissue interactions; 8. Regulation of structural homeostasis in health and disease (e.g., the role of FRCs in immune responses).

As space becomes the current frontier in systems immunology [START_REF] Ludewig | A global "imaging" view on systems approaches in immunology[END_REF], technologies to observe and analyze cells and drugs distributions in tissues are developing. Implementation of a systems approach to PK-PD problems requires looking at the structure, dynamics, regulation and design principles of specific organs. Whereas the dynamics have been extensively studied within the compartmental framework, the last three topics require further investigation. This should help to overcome the concern existing in PK-PD community about the impact of mathematical modelling and simulation [START_REF] Allerheiligen | Impact of modeling and simulation: myth or fact?[END_REF][START_REF] Bonate | What happened to the modeling and simulation revolution?[END_REF]. Linking the structure of organs to well established PK-PD modelling methodologies in a computationally tractable and physiologically relevant manner will require cross-disciplinary research teams. "This is not the end, it is not even the beginning of the end, but it is perhaps the end of the beginning." (Sir Winston Churchill Speech "The End Of The Beginning", 20th November 1942).

Drug resistance, or how to deal with the failure of targeted therapies in cancer

Targeted therapies in cancer aim at controlling known hubs in intracellular signalling pathways. The cases of imatinib in Chronic Myelogenous Leukaemia (CML) [START_REF] Druker | Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia[END_REF] and of All-transretinoic acid in Acute Promyelocytic Leukaemia [START_REF] Haferlach | Molecular genetic pathways as therapeutic targets in AML[END_REF] are known success stories in targeted therapies, however such cases remain rare because most often when a hub is blocked in a cancer cell, other hubs may take over, and one such cell is enough to thrive into an emergent drug-resistant subpopulation. The fundamental heterogeneity in phenotype of cancer cell populations [START_REF] Chisholm | Cell population heterogeneity and evolution towards drug resistance in cancer: biological and mathematical assessment, theoretical treatment optimisation[END_REF], that has been proposed to be the result of some sort of bet hedging [START_REF] Brutovsky | Structure of intratumor heterogeneity: Is cancer hedging its bets?[END_REF] and that can be accurately represented in phenotype-structured models [START_REF] Chisholm | Emergence of drug tolerance in cancer cell populations: an evolutionary outcome of selection, nongenetic instability, and stress-induced adaptation[END_REF], may thus explain the evolution towards drug resistance in tumour cell populations. To document such mechanisms, PK-PD models to describe the fate of drugs in healthy and cancer cells are not enough. Indeed, one must consider the levels of expression of all concerned genes, as has been recently described for instance in [START_REF] Wu | Ancient hot and cold genes and chemotherapy resistance emergence[END_REF] for resistance to doxorubicin in Mutiple Myeloma. In this way, the future prospects that are open to model such phenomena in cancer go far beyond PK-PD and offer an immense challenge to mathematicians: how to model and analyse the action of drugs in cancer, considering issues of both toxicity in healthy tissues and of emergence of drug resistance in tumour cell populations? This will involve designing relevant functional phenotypes from whole genome dynamic data processing. Some bioinformatic methods are already available for this, but the relevant corresponding mathematical models are still to be designed, and new and advanced statistical methods to process biological data will also be needed. When one considers the necessity to design on the basis of such models optimal control algorithms for therapeutic strategies to be clinically efficient, the challenge appears even more tremendous. But it has to be met.

FIGURE 1 .

 1 FIGURE 1. Spatial organisation of lymph node (LN). Left: Finite-element based approximation of major structural elements of a paradigmatic LN. Centre: 3D reaction-diffusion model predictions of the spatial distribution of type I interferon in LN. Color bar reflects the relative concentration of the molecules. Right: Geometric model of LN with anatomically consistent representation of the B-cell follicles and Fibroblastic Reticular Cell network.

  , A. Bouchnita, J. Clairambault, V. Volpert Diversity of mathematics of PK-PD

  , A. Bouchnita, J. Clairambault, V. Volpert Diversity of mathematics of PK-PD

  , A. Bouchnita, J. Clairambault, V. Volpert Diversity of mathematics of PK-PD

Acknowledgements. The research of GB was funded by the Russian Science Foundation (Grant 15-11-00029).


Sébastien Dominiak

Pascal Terray
email: terray@lodyc.jussieu.fr

Improvement of ENSO prediction using a linear regression model with a southern Indian Ocean sea surface temperature predictor

This study presents a detailed comparison between three ENSO precursors which can predict across the spring persistence barrier: the anomalous equatorial Pacific upper ocean heat content, the zonal equatorial wind stress anomaly in the far-western Pacific and SST anomalies in the South-East Indian Ocean (SEIO) during the late boreal winter. A new correlation analysis confirms that El Niño (La Niña) onsets are preceded by significant cold (warm) SST anomalies in the SEIO during the late boreal winter after the 1976-77 climate regime shift. Thus, the objective is to examine the respective potential of these three ENSO precursors to predict ENSO events across the boreal spring barrier during recent decades. Surprisingly, in this focus, cross-validated hindcasts of the linear regression models based on the lagged relationship between Niño3.4 SST and the predictors suggest that SEIO SST anomalies during the late boreal winter is the more robust ENSO predictor.

1.

Introduction [2] Predicting the occurrence the El Niño-Southern Oscillation (ENSO) phenomenon several months in advance is a major goal of climate research. During recent years, dynamical models have been used to this end, but despite great efforts and significant progress, they encounter many difficulties to forecast the timing, structure and amplitude of ENSO events [START_REF] Landsea | How much skill was there in forecasting the very strong 1997-98 El Niño?[END_REF]. On the other hand, statistical models show modest, but still significant skill in forecasting various ENSO indices such as Niño3.4 Sea Surface Temperature (SST) [START_REF] Clarke | Improving El Niño prediction using a space-time integration of Indo-Pacific winds and equatorial Pacific upper ocean heat content[END_REF]. In this study, we discuss a new ENSO precursor, SEIO SSTs during late boreal winter, and demonstrate through various linear regression exercices that this new parameter leads to a significant improvement in ENSO statistical prediction across the socalled boreal spring persistence barrier during recent decades [START_REF] Torrence | Comments on "The Connection between the Boreal Spring Southern Oscillation Persistence Barrier and Biennial Variability[END_REF].

2.

A selection of robust ENSO precursors.

[3] Two critical factors have been identified to have a close relationship with the onset of El Niño events and are pivotal in many ENSO prediction exercises [START_REF] Clarke | Improving El Niño prediction using a space-time integration of Indo-Pacific winds and equatorial Pacific upper ocean heat content[END_REF]. First, the equatorial Pacific upper ocean heat content anomaly during the boreal winter preceding El Niño onset plays an important role in ENSO evolution [START_REF] Meinen | Observations of warm water volume changes in the Equatorial Pacific and their relationship to El Niño and La Niña[END_REF]. Second, the local wind anomalies over the western Pacific and Indian Ocean warm pool region have also been considered as a cause for ENSO variability [START_REF] Mcphaden | The tropical ocean global atmosphere observing system : A decade of progress[END_REF]]. Both are two excellent ENSO predictors that can predict across the boreal spring [START_REF] Clarke | Improving El Niño prediction using a space-time integration of Indo-Pacific winds and equatorial Pacific upper ocean heat content[END_REF]. Drawing on the experience of two very recent studies [Terray et al., 2005, Terray andDominiak, 2005], a further predictor is introduced here, SEIO SSTs during boreal winter. The two aforementioned studies suggest that SEIO SST anomalies have a delayed and/or prolonged impact on ENSO variability through two mechanisms: an external forcing of local wind anomalies over the Pacific warm pool and a modulation of the regional Hadley cell in the southwest Pacific [Terray and Dominiak, 2005]. Several other very recent studies have also confirmed that SST and convective anomalies over the eastern Indian Ocean are physically linked to the wind anomalies over the western Pacific [START_REF] Kug | Preconditions for El Niño and La Niña onsets and their relation to the Indian Ocean[END_REF]. These findings suggest that the Indian Ocean could be one more important factor in contributing to ENSO evolution during the recent decades.

[4] Figure 1 shows the lag correlations between December-January Niño3.4 SSTs and the previous February-March surface zonal wind [from NCEP/NCAR reanalysis, [START_REF] Kalnay | The NCEP-NCAR 40-year reanalysis project[END_REF], 20°C isotherm depth [from the SODA data, [START_REF] Carton | A simple ocean data assimilation analysis of the global upper ocean 1950-95-Part I: Methodology[END_REF] and SST [from the Extended Reconstruction of global SST, [START_REF] Smith | Improved extended reconstruction of SST (1854-1997)[END_REF] over the Indo-Pacific area. Computations are made for the 1977-2001 period, to avoid possible effects due to the socalled 1976-77 climate regime shift [START_REF] Nitta | Recent warming of tropical sea surface temperature and its relationship to the Northern Hemisphere[END_REF]], as it is known that ENSO precursors changed significantly around this date [START_REF] Wang | Interdecadal changes in El Niño onset in the last four decades[END_REF]. This correlation analysis illustrates the significance of the two ENSO precusors introduced by [START_REF] Clarke | Improving El Niño prediction using a space-time integration of Indo-Pacific winds and equatorial Pacific upper ocean heat content[END_REF], the western equatorial Pacific zonal wind (130°E-160°E, 5°S-5°N, black frame in Figure 1a, UWPAC hereafter) and the equatorial Pacific upper ocean heat content (130°E-80°W, 5°S-5°N, black frame in Figure 1b, hereafter Z20). Consistent with the ENSO recharge-oscillator paradigm [START_REF] Jin | An equatorial ocean recharge paradigm fo ENSO. Part I: conceptual model[END_REF], the mean depth of the February-March 20°C isotherm over the equatorial Pacific is positively and significantly correlated (0.72) with

Niño3.4 SSTs ten months after. This suggests that the amount of warm water in the tropical Pacific builds up prior to El Niño onset. Thus, a substantial heat content anomaly in the Pacific Ocean mixed layer seems to be a necessary contition for El Niño growth. The significant positive correlation (0.75) between February-March surface zonal wind over the western Pacific Ocean warm pool region and December-January Niño3.4 SSTs also confirms that the wind anomalies in this area is an important factor for ENSO variability (Figure 1a).

These westerly wind anomalies can induce eastward propagating equatorial Kelvin waves and have also been proposed to be a trigger for some El Niño events. Finally, the highest correlations with the SST fields are found in the Indian Ocean (-0.77). The SEIO area (90°E-122°E, 5°S-45°S, black frame in Figure 1c) seems to be another strategic factor for determining of developing El Niño or not before the onset [Terray and Dominiak, 2005].

Thus, this precursor is also a good candidate for ENSO prediction across the boreal spring barrier.

Linear prediction results

[5] We assess now the usefulness of SEIO SSTs to improve the limited amount of skill of

PP = 1 -(RMSE/SD) 2 (1)
where SD is the standard-deviation of Niño3.4 SST for the respective season. When PP is greater (lower) than zero the forecast is better (worse) than a climatological forecast.

[6] We start by discussing the three simple linear regression models where each predictor serves as sole imput (Table 1). For the October-December season, the SEIO and UWPAC models yield virtually the same RMSE and correlation coefficient between predicted and observed Niño3.4 SSTs, with correlation coefficients of 0.7 and RMSE of 0.68, while the forecast performance of Z20 is inferior using this cross-validated method. For longer time leads, SEIO exhibits consistently higher correlations and lower RMSEs than Z20 and UWPAC. Surprisingly, the predictive skills for SEIO precursor are also better when the time lead between the predictor and predictand is increased. Finally it is interesting to note that all of these univariate models perform better than a climatological forecast since PP is always greater than zero.

[7] Figure 2 shows the observed and forecast October-December Niño3.4 SST for all the univariate models. Each predictor exhibits successful forecasts, but also major failures. The Z20 model has a high predictive skill for La Niña events, but this model has major failures for predicting El Niño events, excepted the 1997-98 El Niño. Interestingly, this latter event is very well-captured by the UWPAC model. This is consistent with results stressing the crucial importance of the March 1997 westerly wind burst over the Pacific warm pool for the onset of the 1997-98 El Niño [START_REF] Wang | The 1997-98 El Niño Evolution Relative to Previous El Niño Events[END_REF]. However, the performance of this last model for other ENSO events is rather poor. The SEIO model has a high predictive skill in the first half of the record, while this model has a substantially degraded performance for the more recent period. Finally, all three univariate models have major difficulties in the 1990s when ENSO events are known to be particularly unusual. During the 1991-94 time interval, a substantial warming is observed in the central Pacific and even if these years correspond to one or several events is a controversial matter [START_REF] Trenberth | The 1990-1995 El Niño-Southern Oscillation event: longest on record[END_REF][START_REF] Van Loon | The Southern Oscillation in the early 1990s[END_REF]. These results serve to emphasize that a complicated combination of atmospheric and oceanic conditions are necessary for El Niño to occur [START_REF] Mcphaden | The tropical ocean global atmosphere observing system : A decade of progress[END_REF]].

[8] A natural way of improving the univariate models is to add new variables (table 2).

Comparison of Table 2 with Table 1 bears out the overall remarkably superior performance of the updated models. Note that SEIO remains the most important predictor since the models have a higher predictive skill over nearly all the forecast lead times when SEIO is included in the model. Nevertheless, the other two elements add useful information which always improve the performance skill of the univariate SEIO model (cf. Table 1). It appears clearly that the most efficient model is built using SEIO and UWPAC. Regardless of which lead time is chosen, the same hierarchy is found with this model performing somewhat better than the others, followed by Z20-SEIO model and afterwards Z20-UWPAC. This result confirms that SEIO SSTs are not only a precursor of Niño 3.4 SSTs via the zonal wind anomalies over the far western equatorial Pacific, but also via a modulation of the regional Hadley cell in the Southwest Pacific ocean [Terray and Dominiak, 2005]. Moreover, this regression exercise also suggests that the Z20 precursor is of subordinate importance in predicting ENSO variability from the late boreal winter setting.

[9] Figure 3 shows cross-validated Niño3.4 SST time series forecast for November-December for the "two predictors" models. Considering the UWPAC-SEIO model, we observe that many El Niño or La Niña events are correctly identified, especially in the 1980s when this model predicts the occurrence and amplitude of ENSO events. The very strong 1997-98 El Niño is also identified, but with a weaker amplitude. Discrepancies between the forecast and observed values for the UWPAC-SEIO model correspond to some consecutive years of anomalously warm or cold Niño3.4 SSTs, such as 1986-87 or 1991-94. For this last time interval, Goddard and [START_REF] Graham | El Niño in the 1990s[END_REF] suggest that the 1993-94 event is partly due to the persistence of warm SSTs in the central equatorial Pacific, these features being not linked to the selected precursors. Now considering the Z20-SEIO model, we observe a high predictive skill of La Niña events. This is consistent with the behaviour of these two predictors in an univariate setting, as seen on Figure 2. On the other hand, this model performs poorly on El Niño events. Consistent with the work of [START_REF] Wang | The 1997-98 El Niño Evolution Relative to Previous El Niño Events[END_REF], the Z20-UWPAC model predicts the very strong 1997-98 El Niño with the highest predictive skill in all the models presented in this study. However, the performance of this model is largely degraded for the rest of the record. In synthesis, it appears that UWPAC-SEIO model is surely the best one in predicting ENSO variability. But other models are able to lead to better predictions on specific occasions, again illustrating the complexity of the Pacific climate system.

[10] Surprisingly, the Z20-UWPAC-SEIO model does not lead to any significant improvement in predictive skill whatever the time lead may be (Table 3). This model exhibits a similar efficiency as the UWPAC-SEIO model. This raises again the question of the importance of the Z20 precursor during recent decades. Does one need to consider that Z20 is a crucial parameter for ENSO prediction because of its physical relevance [Jin, 1987;[START_REF] Meinen | Observations of warm water volume changes in the Equatorial Pacific and their relationship to El Niño and La Niña[END_REF]] ? This question needs further exploration. First, the weakness of the SODA data is a possible factor for explaining the present results. In order to check the reliability of the SODA reanalysis, the Z20 time series has been recomputed from the BMRC ocean thermal analysis [START_REF] Smith | An improved system for tropical ocean subsurface temperature analysis[END_REF] which covers the period 1980-2001. The correlation coefficient between the SODA and BMRC February-March Z20 time series is as high as 0.93 during the 1980-2001 time span and is significant at the 99% confidence level. The possibility that the results may improve with the BMRC analysis has been further examined by performing additional cross-validated regression experiments where the Z20 time series is computed from the BMRC data. The statistics for these experiments are reported in Table 4. It is noteworthy that the predictive skills of the experiments using the BMRC index are not significantly better than the skills obtained from the models using the SODA reanalysis with similar correlation coefficients, but higher RMSEs. This suggests that the poor performance of the Z20 parameter is not due to a deficiency of the SODA data. Thus, according to the principle of parsimony which requires that a statistical model should employ a number of predictors as small as possible, the multiple linear regression model with all three precursors as input offers no advantage. Of course, this conclusion is only valid for the specific time leads examined here. For longer time leads (eg for more than one year), Z20 remains a highly significant precursor (not shown) since the transition for SEIO SST anomalies occurs in early boreal winter when the seasonal wind over the eastern Indian Ocean turns from southeasterly to northwesterly (Terray et al., 2005).

Concluding remarks.

[11] This study explores the robustness of ENSO precursors which have not been previously considered. In addition to well-recognized precursors of El Niño onsets, such the Z20 and UWPAC parameters during the late boreal winter, a further predictor is examined here, namely SST anomalies in the SEIO. Various statistical prediction models for predicting Niño3.4 SST were constructed based on the lag relationship between Niño3.4 SST and these three predictors observed during the late boreal winter. Surprisingly, the most prominent precursor is SEIO SSTs, whereas the much less powerful precursor is the Z20 parameter. The forecast skill is considerably better for the models which use SEIO SST as a predictor over different lead times during the 1977-2001 period.

[12] Considering the best model, the UWPAC-SEIO model, the highly significant correlations and PP scores between the forecast and observed Niño3.4 SST index indicate that about half of the interannual variability of Niño3.4 SST can be predicted from antecedent circulation and (Indian) oceanic departures during the late boreal winter, ten months before the peak phase of ENSO events. It is conjectured, that the regression models would yield a substantially inferior performance for prediction proper-that is, for years beyond the last year on which the regression model is based due to the large body of analyses already conducted on the selected precursors. However, this contention could not be verified from the short database used here.

Nevertheless, the limited experiments conducted here do support the proposition that the Indian Ocean is now a crucial parameter in ENSO evolution. Thus, the inclusion of SEIO SSTs as a predictor may further improve the predictive skill of the current dynamical or statistical models which are currently used to forecast equatorial Pacific SST. 1, but for the two-predictors regression models using two elements as input from the set of UWPAC, Z20, SEIO precursors.

Figure captions

Table 3 : Same as Table 1, but for the three-predictors regression model using all the UWPAC, Z20, SEIO precursors.

  current statistical models in predicting ENSO from the late boreal winter season (February-March) before the El Niño onset. To this end, we developed various regression models for forecasting Niño3.4 SST anomalies for different time averages (October-December, November-January, December-February) around the ENSO peak season, using only February-March anomalies of the predictors. As a measure of the predictive skill, we compare the observed Niño3.4 SST with the values calculated from regression equations based successively on all years with the 1977-2001 time span, except the forecast year. To assess the forecast potential, three statistics have been used: the correlation coefficient (COR) between the observed and forecast Niño3.4 SST, the Root-Mean-Square-Error (RMSE) and the socalled Performance Parameter (PP):

Figure 1 :

 1 Figure 1: a) Correlation analysis of December-January Niño3.4 (5°S-5°N/190°E-240°E) SST

Figure 2 :

 2 Figure 2: October-December Niño3.4 SST, observed (solid line and closed squares) and

Figure 3 :

 3 Figure 3: Same as figure 2) but for UWPAC-SEIO, Z20-SEIO and Z20-UWPAC bivariate

Table Captions Table 1 :

 Captions1 Appraisal of Niño3.4 SST predictions from the February-March season for different

	lead times (10-12, 11-01, 12-02) around the peak phase of ENSO events by simple linear
	regression models using one predictor (UWPAC, Z20 or SEIO) as sole imput. The forecast
	skill of the models is assessed by cross-validated RMSE, COR and PP statistics calculated
	from the observed and forecast Niño3.4 SST by each model without involving data of the
	forecast year. Correlation coefficients significant at the 10%, 1%, 0.01% levels are indicated
	by one (*), two (**) and three stars (***), respectively.

Table 2 :

 2 Same as Table

Table 4 :

 4 Same as Table1, but for the one and three-predictors regression models using the Z20 precursor computed from the BMRC reanalysis during the 1980-2001 period.

	10S 0 10N 20N a)	. 0 -		0 -	2				10S 0 10N 20N b)		. 0 2 6 . 0	0	2 .		. 0 2 . 0 6	20S 0 20N c)	. 2 . 0 6	-	0	2	-	0	2 .	. 0 2	. 0 2	. 0 -	2
	20S		2 . 0		0	.	2 . 0 -		20S	6 . 0	0.2 .					40S		6 . 0 -
	30S	50E	100E	150E		160W	110W	30S	50E	100E	150E	160W	110W		50E	100E		150E	160W	110W

Acknowledgements: The BMRC upper Pacific Ocean 20°C isothern depth was kindly provided by Neville Smith. We thank Keith A. J. Rodgers for comments and careful re-reading of the manuscript.


Civil Societies based on Clientship:

A Challenge to Democracy?

BERNARD FORMOSO

Social Anthropology, Université Paris Ouest -IRASEC (Bangkok)

According to Kevin Hewison and Garry Rodan 1 , a Tocquevillean view of civil society dominates analyses of Southeast Asian public spheres. In these analyses civil society is frequently seen as the natural and functional domain of individual and group freedom, contrasted with the state"s coercive institutions and relationships. For Tocqueville associational life fuses order and liberty, as well as private interest and the common good. He envisages a civil society consisting of an array of organizations that hem in the state on every side, mobilizing distinct constituencies and lobbying in favor of diverse and particularistic interests. However, this liberal definition of civil society based on the assumption that individuals freely bond for limiting absolute rule cannot be exported to non-western contexts, despite the claim of its universality by western policy makers.

Civil society doesn"t represent separate systems of independent logics 2 .

From an historical and cultural context to another the norms determining the ability of people to relate to one another may change. The distinction between public and private spheres may not always apply to Southeast Asian societies where kinship remains the cultural core of a wide range of institutions and voluntary associations. Moreover, "the liberal notion that political authority should respect the autonomy of civil society from which its legitimacy derives may also require qualification for some Southeast Asian societies, just as it may be a mistake to assume that civil society must be oppositional" 3 . Thus, authoritarian Asian regimes have for more than three decades encouraged the creation of what Michael Frolic has called state-led civil societies 4 , that is, social organizations and quasi-administrative unites created as an adjunct to state power and designed for managing and monitoring the rapid evolution of economy and society. The prevalence of these social organizations in authoritarian regimes challenges the Western-centric approaches to the relationship between civil society and democracy. Hence the rejection by national leaders such as Lee Kuan Yew and Dr. Mahathir Mohammad of the Western-style model of democracy and their strong ideological advocacy in the 1990s for the concept of "Asian democratic systems ", whose main characteristics are communitarianism, authority, strong states, and longevity of ruling parties 5 , as well as personalism and patronage 6 . In the same vein, Thai intellectuals, such as Chai-Anan Samudavanija and Prawase Wasi have coined the concept of elite civil society which emphasizes partnership between social organizations and the state under the patronage of the elite 7 .

Significantly, most of Southeast Asia has no language equivalent of "public interest", "civil" or "pluralism". For instance, in the Thai recently forged compound for civil society, prachaa sangkhom, prachaa may be alternatively translated by "subjects" of a kingdom, "populace", "people", or "citizens". It also appears that sangkhum, the Khmer equivalent to Thai sangkhom, only entered the Khmer language in the 1930s, via Pāli and Thai languages 8 . From this statement it can be inferred that the notion of civil society in Southeast Asia is not only new but can be interpreted in various and discordant ways.

Although the concept of civil society is a generic label that lumps together disparate and contradictory forms of organization and action, it remains however useful in helping to explore the social and political relations and configurations in national societies of the non-western world 9 . To preserve its analytical potential there is however the need to overstep the basic tension "Catching Up Southeast Asian New Body: States, Markets and Public Spheres" between universalist and relativist approaches. As noted by Chris Hann, the "choice between universalism and relativism needs to be posed starkly and anthropologists can negotiate an intermediary path" 10 . This intermediary path implies to unravel the interplay of social structures and power, both being partly informed by the historical complexity of external factors and the socioeconomic dynamics of the national society as a whole. Rather than stasis cultures are to be considered as "landscapes of struggle in which certain historical features are embedded" [START_REF] Hughes | Reassessing Tradition Times of Political Change : Post-War Cambodia Reconsidered[END_REF] .

Here I want to briefly argue in favor of this approach by challenging some preconceptions about clientship as a normative pattern which prompt individuals to build vertical relationships in Buddhist societies of Southeast Asia. I shall compare two national contexts, namely Thailand and Cambodia.

Their respective cultures share basically the same concepts and values concerning the regime of obligations that the patron and his clients should respect. However, the sharply contrastive evolution of these countries regarding the configuration of their civil society and the state management of popular contestation reveals that patron-clientelism as a basic bond system may accommodate a wide range of political forms and civic spaces. Against a current opinion, it is not an impediment to civic struggles and to local claim for an original path to democratization.

Patron-client relationships

In both Thai and Cambodian societies clientship cannot be interpreted separately from the senior -junior dyadic relationship whose codification it extends outside the family. The metaphorical use of basic kinship terms coupled with the tacit behavioral norms it triggers are the main linguistic and social idioms for building ties which are both integrative and hierarchical. The phinong compound, whose equivalent in Cambodian language is bang-b'on, is systematically resolved into reciprocal terms of address in situations when the interlocutors want to launch or to maintain an enduring, friendly and faithful relationship. Ideally, the phi-nong/bang-b'on are tied by mutual obligations. On the one hand, the junior by age or inferior by status should display marks of respect toward the senior/superior (khaorop in Thai ; khorob in Khmer). The junior should not act against the interests of the superior as a token of obedience (Thai : chuafang ; Khmer : kasdap bangkoap), of faithfulness and of tact for fear to hurting him (Thai : krengcai, Khmer : klach) [START_REF]Alliance et séniorité, le cas des Lao du nord-est de la Thaïlande[END_REF] . In return, the senior or patron should protect the junior or client (Thai : saksit ; Khmer : kapie). His duty is also to contribute to his social promotion and to help him financially (Thai: chuailua ; Khmer : chumruny). In both cultural contexts the ideological cement of the relationship rest on the Buddhist concept of katanyu-katawethi which means to remember and to return the service provided or the merits received as a token of gratitude [START_REF]For more details see Akin Rabhibadana[END_REF] . Keystone of the prime-education and normative bedrock of the relationships within the nuclear family, the kindred, the neighborhood or the village, the elderyounger relational pattern becomes a habitus, all the more powerfully incorporated by the individuals and generative of social practice that everybody is at the same time younger and older than others. Irreducible to a specific cultural institution but structuring them all, it extends far beyond the notion of fait social total conceptualized by Marcel Mauss, but should be more properly considered as a global social mechanism. Concerning the indigenous conception of what his own relation to the world should be, it leads to the common belief that without « string » or « connection » (Thai: phueng ; Khmer : khsaer), the individual is nobody and his/her life will be a failure.

However, from a context of interaction to another this global social mechanism varies in emotional intensity and its regime of mutual obligations may also fluctuate. The expectations and moral duties of the patrons and clients are adjusted to their social and spatial distance as well as to the economic gap "Catching Up Southeast Asian New Body: States, Markets and Public Spheres" separating them. The more important is the difference of status, the less personal ties account in the relation and higher are the respect, the admiration and the fear of the patron"s authority (Thai : amnat ; Khmer : omnaich), and of his coercive power (Thai : kamlang ; Khmer : komlang). In return, the less the relationship is strengthened by personal links and the more volatile are the individual and collective allegiances. In the literature clientship is often considered as an unbalanced relationship mainly benefiting the patron at the expense of clients entirely subjected to his rule. However, faithfulness doesn"t necessarily means unwavering loyalty, even when the patron is believed to be a man of "great virtue" (Thai: barami ; Khmer : boromei) or is much-dreaded for his influence and coercive power. In many cases the Thai and Khmer, men and women, pull several "threads" at the same time. They are multi-connected to different alternative and sometimes concurrent networks for securing several sources of income, reducing unforeseen turns of events, and preventing the danger of tyranny. For example, in the present day Cambodia a large proportion of civil servants are officially adherents to the ruling Cambodian People Party (CPP), while being simultaneously and more discretely supporters of the main opposition party, the Cambodia National Rescue Party. In the same vein, many young Cambodian women working in the garment sector are at the same time affiliated to pro-and anti-CPP trade unions. In short, the individuals positioned as clients may be as much puppeteer as puppet, even though their latitude depends on their level of education, their economic situation and their ability to handle people. The more precarious their economic and social condition is, the more they are facing indebtedness and the more restricted is their latitude in the context of clientship, thus opening the door to human-trafficking, hyperdependence and over-exploitation.

Clientship and the pattern of civil society

What lessons can be drawn from these observations? First, as a global social mechanism, patron-clientelism is the backbone of the whole range of organizations and informal forms of contracts in the Buddhist societies taken into consideration. In those contexts, the political system, the market and the civil society as a third sector are dominated by networks and complex patronclient ties. These ties entail a more or less powerful sense of obligation, reciprocity and moral indebtedness. In many respects, they are the functional equivalents of the values that form the backdrop to voluntary associations in the West. Second, patron-clientelism, individual freedom, critical reflection and civic consciousness are not mutually exclusive. All depends on the economic, social and political latitude let to individuals. In this respect, one helpful definition of civil society which has been used in Asian contexts [START_REF] Chong | Civil Society Organizations: Definitions and Concepts[END_REF] is that "civil society is a mature form of critical reflection, which marks the transition from a "conventional orientation" to fixed rules, unreflective duty and respect for authority to a "post conventional" critical attitude towards identity construction" [START_REF] Fine | Civil Society, Theory, Enlightenment and Critique[END_REF] . This definition may take explicit account of the current processes of democratization for both Thailand and Cambodia. However, the civil societies of these two countries sharply differ because of historical contingencies and political factors. From the late 1960s to the early 1990s Thailand experienced some major economic and social transformations which led to a more classstratified and urban society. During this period the country opened to the inflow of foreign capital and transformed progressively from an agriculture-oriented economy to one dominated by industrial and service activities. According to Kevin Hewison, "As the economic base expanded, a more complex division of labor demanded a greater range of human resource skills. This resulted in a Thai society that was far more diverse, and where economic power was firmly in the urbanized and increasingly internationalized private sector" 16 . During this "Catching Up Southeast Asian New Body: States, Markets and Public Spheres" period the educated middle class enlarged widely its social basis. It also became more receptive to cosmopolitan values and more sensitive to social injustice. Such conditions were fertile ground for the emergence of social movements promoting human, women and worker rights. The political system changed consequently as well as the criteria defining legitimate power and good governance. Pasuk Phongpaichit and Chris Baker [START_REF] Phongpaichit | Thailand's Boom[END_REF] or Kevin Hewison [START_REF] Hewison | Political Space in Southeast Sia: "Asian-Style" and other Democracies[END_REF] have pointed out that the military leaders lost rapidly their dominant role in politics when the big business, becoming more confident in its own strength, considered less necessary to share its profit with the generals. An important step in this process was the Chatichai civilian government. From 1988 to 1992, it promoted the parliamentary system and challenged the holistic notions of hierarchy, stability, unity, and statutory subordination promoted by the conservative state.

The point of no return was reached in 1992 when, following a military takeover, a wide range of Bangkok"s population massively rejected the return to the semidemocratic regime of the late 1970s and advocated for values such as competence, integrity, and honesty in government [START_REF]Sleeping Giants Awakens? The Middle Class in Thai Politics[END_REF] . From then on, the tensions resulting from an increasing gap between small farmers facing impoverishment and urban white collars have partly overlapped the political divide between parliamentary and conservative forces, with the future of kingship and the megalomaniac ambition of Thaksin as backdrop stakes. In this context, political clientship ties reflect the general evolution of the society. The allegiances are more diversified, conditional and volatile. Moreover, grassroot social movements, forums or networks, united by the convergent interests of their adherents and which emphasize horizontal ties have emerged during the last three decades. Some of them rushed the government and gained a large audience through national protest by challenging development and environmental policies in Thailand, at the example of the Assembly of the Poor [START_REF] Baker | Thailand"s Assembly of the Poor: Background, Drama, Reaction[END_REF] .

Whereas the 1970s-1990s were for Thailand a period of peace and rapid economic growth, they were for Cambodia one of the most chaotic phase of its modern political history. The country was torn apart by tragic years of civil war punctuated by the murderous rule of the Khmer Rouges. After centuries of precarious condition as a buffer state between its more powerful neighbours, namely Siam and Vietnam, it became the sacrificial victim of the bloody confrontation between the Western and the Communist blocs. After centuries of vassalage, Cambodia shifted after the peace-agreement of 1991 and the brief UNTAC period toward international aid-dependence which weakened its institutional capacity, undermined accountability and encouraged rentseeking and corruption among the political elite [START_REF] Ear | Aid Dependence in Cambodia. How Foreign Assistance Undermines Democracy[END_REF] . Following its triple transition from war to peace, from communism to electoral democracy, and from command economy to free market, the results of political and economic development have been mixed in the case of Cambodia 22 . At the political level "while democratic participation has been expanded widely, democracy has failed to "consolidate" as a result of underdeveloped political institutions, rentseeking in government, a lack of free and fair competition among political parties, and the underdevelopment of civil society to act as a check against government abuse" 23 . Concerning the economy, Cambodia is ranked among the "Least Developed Countries". Although the country has sustained remarkable economic growth over the past two decades, development is uneven. About 80% of the population continue to live poorly in rural villages and the levels of education and of qualification are low. In these conditions the middle-class remains embryonic. It cannot challenge overtly the CPP regime, which has steadily consolidated control over the country for more than two decades by cultivating symbiotic relations with big tycoons and by building an encompassing system of clientship from the top of the state to the local through the channel of commune or village councils and CPP-led organizations.

"Catching Up Southeast Asian New Body: States, Markets and Public Spheres"

In recent years, officials who occupy government positions and their cronies have been able to block economic reform processes at either the policymaking or implementation stages, leading to the perseverance of oligarchic systems of capitalism in which political authority remains concentrated in the hands of the elite [START_REF] Rosser | Donors, Neo-Liberalism and Country Ownership in Southeast Asia[END_REF] . Cambodia can thus be characterised as being in a stage of "primitive accumulation", whose key features are violence, the crude imposition of state authority and early stages of state-building [START_REF]For more details see Richard Robison[END_REF] . Moreover, the ability of many Cambodian people to empathise with each other has been severely compromised by years of civil war and the paranoia of the Khmer Rouges who pitted neighbour against neighbour and kin against kin. A profound collective trauma ensued. It still undermines the prospects of creating effective organisations and networks. Therefore, there are obvious difficulties for Cambodian civil society actors in building an empowered constituency.

Conclusion

Finally, the comparison of the contemporary Thai and Cambodian civic spaces reveals that clientship needs to be understood in dynamic terms as a structure of social ties in process. Its pattern varies with the different level of authoritarianism as opposed to democratization in the societies considered. In Thailand, the degree of clients" faithfulness in that structure still depends on the dialogism of individual advantages. However, it increasingly correlates in with political consciousness, critical reflection, the challenge of conservative values, the demand for social justice from the poor, and the advocacy by segments of

  the middle class for honesty, competence and dedication in politics. During the last two decades these new claims and more demanding allegiances served as a fertile ground for the creation of pluralist networks of support and collective advocacy. They opened the door to what Robert Fine calls "the postconventional critical attitude towards [national] identity construction".Cambodia, for its part, remains at a stage of "conventional orientation". It is a country where the CPP propaganda delights in trotting out a conservative view of clientship that emphasize deference and unquestioning obedience of the peasantry to elicit popular consent. This political use of patron-clientelism awards residual power to the poor and to the embryonic middle class. It interferes with a constructive process to achieve popular claims which could efficiently challenge the authoritarian state.

Democracy and Capitalism: Asian and American Perspectives, eds

  Notes 1 Kevin Hewison and Garry Rodan, "Southeast Asia : the Left and the Rise of Bourgeois Opposition", in Routledge Handbook of Southeast Asian Politics 2012, ed. R. Robison (London: Routledge, 2012), pp. 25-39. David Schack and Wayne Hudson, "Civil Society in Asia", in Civil Society in Asia, eds. D. Schack & W. Hudson (Aldershot: Ashgate Publishing Ltd, 2003), p.2. 4 For more details see Michael Frolic, "State-led civil society", in Civil Society in China, eds. T. Brook and M. Frolic (New York: East Gate, 1997), p. 48. 5 Heng-Chee Chang, "Democracy: Evolution and Implementation. An Asian Perspective » in . R. Bartley et al. (Singapore: Institute of Southeast Asian Studies, 1993), pp. 1-26.

2 David Studdert, Conceptualizing Community: Beyond the State and Individual (Basingstoke: Palgrave MacMillan, 2005), p.56. 3 6 Clarck Neher and Marlay Ross, Democracy

and Development in Southeast Asia. The Winds of Change

  (Boulder: Westview press, 1995).7 For more details see Somchai Phatharathananunth, Civil

Society and Democratization. Social Movements in Northeast Thailand

  (Copenhagen: NIAS Press, 2006), p. 7. 8 See David Chandler, A History of Cambodia (Boulder,Colorado: Westview Point, 2008) [4th edition]. 9 Hock-Guan Lee, "Introduction in Southeast Asia", in Civil Society in Southeast Asia, ed. Hock-Guan Lee (Singapore: Institute of Southeast Asian Studies, 2004), p. 8.