Clément Moulin-Frier

Jean-Luc Schwartz

Julien Diard

Pierre Bessière

A Unified Theoretical Bayesian Model of Speech Communication

Keywords: Speech Communication, Cognitive Bayesian Modeling, Sensory-Motor interaction

Based on a review of models and theories in speech communication, this paper proposes an original Bayesian framework able to express each of them in a unified way. This framework allows to selectively incorporate motor processes in perception or auditory representations in production, thus implementing components of a perceptuo-motor link in speech communication processes. This provides a basis for future computational works on the joint study of perception, production and their coupling in speech communication.

INTRODUCTION:MODELSANDTHEORIESINSPEECH COMMUNICATION

Speech communication involves a set of actuators for producing speech stimuli (enabling to control the orofacial system: lungs, glottis, jaw, tongue, lips, velum) and a set of sensors for perceiving them (audition of course, but also vision for lipreading, and haptics and proprioception for sensing the state of the vocal tract). This enables the speaker to control the task in speech production that is achieving the correct gestures for uttering the adequate sounds. Hence, speech production can be conceived as a typical robotics problem, involving proximal control in reference to given distal objectives, together with learning, adaptability, or any other problem related to cognitive robotics. But the special issue in speech communication is that the task IS communicative. The speaker is also a listener, and has probably a model of the listener incorporated in the production task itself. Production and perception are closely related in communication and probably also in the human's brain. This intimate link between production and perception in speech communication has been largely discussed by phoneticians and cognitive (neuro)psychology, but seldom addressed from a modeling perspective. This is the focus of the present paper.

A key question in speech science concerns the nature of the content of communication, with three major frameworks that are motor, auditory, and sensorymotor theories of speech communication. We shall describe here how each of these theories considers both the speech production and perception processes. Then we will propose a Bayesian formal framework able to express each of them in a unified way, and discuss the possible interpretations of this model. Finally, we will conclude on the possible functional roles for the perceptuo-motor link in speech communication.

M OTOR T HEORIES

Motor theories consider the reference frames of speech communication as gestures. In the Articulatory Phonology framework [START_REF] Browman | Articulatory Gestures as Phonological Units[END_REF], production is modeled as scores of overlapping gestures (Fig. 1.1), able to express the context-dependent variability of speech, without taking explicitly into account the auditory consequence of a motor event. In line with the idea that the frames of speech communication are motor events, the Motor Theory of Speech Perception [START_REF] Liberman | The Motor Theory of Speech Perception Revised[END_REF] proposes that perceiving speech amounts to perceiving gestures. A main argument is coarticulation-driven signal variability, which makes the auditory content of a given phoneme dependent on the phonetic context (e.g. /d/ does not produce the same sound in /da/ vs. /du/, see Fig. 1.2), whereas the intended gesture is invariant. The interest for the Motor Theory of Speech Perception was recently renewed by the discovery of mirror neurons (located in the premotor cortex of the macaque, active both when the macaque performs a transitive action or observes another individual performing the same action, [START_REF] Rizzolatti | Language within our grasp[END_REF].

A UDITORY T HEORIES

Auditory Theories consider that the reference frame for speech is auditory. In the case of speech production, the target would be a region in the auditory space [START_REF] Guenther | A Theoretical Investigation of Reference Frames for the Planning of Speech Movements[END_REF]. The main argument is motor equivalence, showing that various articulatory configurations are used for achieving the same auditory goal, as shown in perturbation experiments: if the articulatory apparatus is constrained, e.g. by inserting a tube between the lips [START_REF] Savariaux | Compensation strategies for the perturbation of French [u] using lip-tube. II. Perceptual analysis[END_REF], speakers reorganize their motor configuration to achieve the same auditory region.

FIGURE1.3.Motorequivalencefor/r/inEnglishintheDIVAmodel (fromGuentheret al., 1998). Relationship between a simple convex region corresponding to /r/ in the acoustic space (left) and the corresponding regions in the articulatory space (right).

Arrows indicate model trajectories when producing /r/ starting from a /d/ configuration(solidlines)andfroma/g/configuration(dashedlines).

d

Speech production would exploit this adaptability, as in the case of /r/ in English, pronounced in the DIVA articulatory model [START_REF] Guenther | A Theoretical Investigation of Reference Frames for the Planning of Speech Movements[END_REF] with different configurations (bunched vs. retroflex) depending on the previous consonant (Fig. 1.3).

In the case of speech perception, proponents of auditory theories consider that speech perception involves auditory or multisensory representations and processing, with no reference to speech production [START_REF] Diehl | Speech Perception[END_REF].

S ENSORY M OTOR T HEORIES

Sensory-motor theories have recently emerged for both speech perception and production. They generally consider auditory frames as the core for communication, but they include the sensory-motor link inside the global architecture. They claim that in normal conditions, production involves cortical motor (frontal) areas and perception involves cortical (temporal) auditory ones, but that the perceptuo-motor link, necessary for speech acquisition, could also play a role in adverse conditions.

Regarding speech production, the DIVA model [START_REF] Guenther | Cortical interactions underlying the production of speech sounds[END_REF] combines a feedforward control sub-system for on-line production, and a feedback control subsystem when the auditory consequence of a gesture is not congruent (Fig. 1.4). In a similar way, sensory-motor theories of speech perception argue for a core auditory (or audio-visual) system for speech perception, enhanced by motor processes in complex conditions such as noise, through "binding" (Schwartz et al., 2010, see Fig. 1.5) or "prediction" [START_REF] Skipper | Hearing lips and seeing voices: how cortical areas supporting speech production mediate audiovisual speech perception[END_REF].

T AXONOMY

This review of speech production and perception theories and models shows that both fields share the same debates about the nature of the reference frame and the functionality of the perceptuo-motor link. Table 1.1 thus proposes an original classification of all these theories in a unified way. The next section will formalize this classification in a Bayesian framework. In other words, we aim at filling Table 1.1 with probabilistic expressions.

Table1.1Taxonomyofspeechproductionandperceptiontheoriesandmodels

Task

Theory Production Perception

Motor Articulatory Phonology [START_REF] Browman | Articulatory Gestures as Phonological Units[END_REF] Motor Theory [START_REF] Liberman | The Motor Theory of Speech Perception Revised[END_REF] Auditory Auditory reference frames for speech planning [START_REF] Guenther | A Theoretical Investigation of Reference Frames for the Planning of Speech Movements[END_REF] Auditory theories [START_REF] Diehl | Speech Perception[END_REF] Sensory-motor DIVA model [START_REF] Guenther | Cortical interactions underlying the production of speech sounds[END_REF] Perception for Action Control Theory [START_REF] Schwartz | The Perception-for-Action-Control Theory (PACT): A perceptuo-motor theory of speech perception[END_REF]

AUNIFIEDBAYESIANFRAMEWORK

In this section, we define in probabilistic terms what are a motor subsystem, a sensory subsystem, and a sensory-motor link, and how they can be combined in a general system for communication. We then show how selectively disabling subsystems leads to a unified expression of the six categories of Table 1.1 in probabilistic terms. We limit our analysis to an abstract model from which we extract possible interpretations. The reliability of this model in realistic simulations of language emergence has been studied in [START_REF] Moulin-Frier | Emergence of a language through deictic games within a society of sensori-motor agents in interaction[END_REF], 2010).

B AYESIAN M ODELING

Bayesian Robot Programming (BRP, [START_REF] Lebeltel | Bayesian Robot Programming[END_REF] specifies the knowledge of a sensory-motor agent as a joint probability distribution over variables of interest (typically motor, sensory and internal variables). This joint distribution is generally expressed as a product of simpler distributions, using Bayes rule and conditional independence hypotheses. Using this knowledge, a sensory-motor behavior is then defined as a conditional probability distribution computed from the joint distribution (for example: "given the values of some sensory variables, what is the probability distribution over the motor variables"), called a question to the model. Our modeling of a general communication system is based on four variables (but we will discuss in more details the possible interpretations):

• M: the speaker's motor gesture,

• S: the listener's sensory percept,

• O S , O L : the object of communication (in a very general sense, hereafter the object), respectively from the speaker and the listener point of view. We then define the three subsystems as follow:

• The motor subsystem is defined as a conditional probability distribution P(M|O S ): given an object to communicate, what is the probability distribution over the speaker's motor gesture? • The sensory subsystem is defined as a conditional probability distribution P(O L |S): given a sensory percept, what is the probability distribution over the objects that can be inferred by the listener by the listener? • The sensory-motor subsystem is defined as a conditional probability distribution P(S|M): given a motor gesture, what is the probability distribution over the sensory percepts?

FIGURE2.1.Modelstructure.

Finally, considering the a priori knowledge on the speaker's object P(O S ) as uniform, the general communication system is a joint probability distribution:

M S OL OS

P(M|O S ) P(S|M) P(O L |S)

In this framework, a successful communication corresponds to equality between O S and O L (the object inferred by the listener must be the same as the object intended by the speaker). Therefore, each question asked to the model will be under the constraint O S =O L .

Speech production and perception are defined as the following probabilistic questions to the general model P(O S ^M^S^O L ):

• Production: P(M|O S =O L ). For a given object in the speaker's mind, and knowing that O L is equal to O S to evoke the same object in the listener's mind, what is the probability distribution over motor gestures? • Perception: P(O S =O L |S). Knowing the sensory input perceived by the listener, what is the probability distribution over objects, inferred by the listener and likely to have been in the speaker's head at the input?

In probabilistic terms, motor and sensory subsystems can be deactivated by setting the corresponding distribution as uniform (that is, without explicit knowledge about the corresponding link). Motor, auditory and sensory-motor theories of speech communication will thus be expressed as the following:

• Motor theories correspond to a deactivation of the sensory subsystem, defining P(O L |S) as a uniform distribution, • Auditory theories correspond to a deactivation of the motor subsystem, defining P(M|O S ) as a uniform distribution, • Sensory-motor theories let both the motor and sensory subsystem active, each distribution being considered as informative. Finally, using these definitions and rules of Bayesian inference (typically Bayes and normalization rules), we can now assign a probabilistic expression to each type of theory (Table 2.1).

Table2.1ModelTaxonomy

I NTERPRETATIONS

GeneralModel

The general model in Figure 2.1 can be interpreted from different points of view:

• As an objective model of communication, where the motor model is a model of the speaker, the sensory one a model of the listener, and the perceptuo-motor link is a model of the environment. • As a subjective neurolinguistic model, where the motor and sensory models would correspond respectively to the motor and auditory cortices, and the perceptuo-motor link as the neural connections between them. • As a subjective model of the Theory of Mind, where the motor model (resp. the sensory model) would be an internal representation of the speaker (resp. the listener) in the brain of the listener (resp. the speaker).

Let us focus on the computational interpretation of the behaviors defined by the probabilistic questions in Table 2.1.

Behaviors:Motortheories

In our Bayesian framework, motor theories of speech communication correspond to a deactivation of the sensory subsystem, setting P(O L |S) as uniform. Speech production thus leads to select a motor gesture M for a given object to communicate O S according to the distribution P(M|O S ), considering that the sensory subsystem does not provide any information. This is in line with Articulatory Phonology [START_REF] Browman | Articulatory Gestures as Phonological Units[END_REF], which considers speech production as motor gestures scores, not influenced by the auditory consequence of those gestures.

Conversely, motor theories of speech perception are defined by the probabilistic question:

For a given auditory percept S heard by the listener, the inferred object thus corresponds to an object for which the speaker would have produced a gesture with the same auditory consequence. This is in line with the Motor Theory of speech perception [START_REF] Liberman | The Motor Theory of Speech Perception Revised[END_REF], which considers that perceiving speech actually amounts to perceiving the intended gestures of the speaker.

Behaviors:Auditorytheories

Auditory theories of speech communication correspond in our framework to a deactivation of the motor subsystem, setting P(M|O S ) as uniform. Speech production is then defined by the probabilistic question:

For a given object to communicate by the speaker, the selected motor gesture thus corresponds to a gesture for which the auditory consequence would allow the speaker to correctly infer the object using his/her sensory subsystem. This is in line with models considering that speech production targets are defined by regions in the acoustic/auditory space [START_REF] Guenther | A Theoretical Investigation of Reference Frames for the Planning of Speech Movements[END_REF].

Regarding speech perception, the probabilistic question is simply P(O L |S), without any information from the motor subsystem. This is in line with the claim that speech perception does not incorporate any input from speech production mechanisms [START_REF] Diehl | Speech Perception[END_REF].

Behaviors:Sensorymotortheories

Finally, sensory-motor theories correspond in our framework to activating both the motor and the sensory subsystems, leading to distributions which are the products of those for motor and auditory theories. Speech production is thus defined by the probabilistic question:

For a given object to communicate, the selected motor gesture is then a compromise between an often-used gesture, and a gesture for which the auditory consequence would allow the speaker to correctly infer the object. This is in line with models like DIVA [START_REF] Guenther | Cortical interactions underlying the production of speech sounds[END_REF] with its two components, feedforward for on-line production (the first factor) and feedback for correction (the second factor).

Regarding speech perception, the corresponding probabilistic question is:

For a given sound heard by the listener, the inferred object has both to satisfy the sensory subsystem and to correspond to an object for which the listener would have produced a motor gesture with the same auditory consequence. This is in line with the Perception for Action Control Theory [START_REF] Schwartz | The Perception-for-Action-Control Theory (PACT): A perceptuo-motor theory of speech perception[END_REF], which considers the cues of speech perception as essentially auditory (the first factor), but possibly helped by access to motor knowledge (the second factor).

ConclusionandPerspectives

In this paper, we proposed a unified formal framework for speech production and perception, based on a Bayesian model able to express the major theories in the field.

In further works, our aim is to computationally study the possible functional role of the perceptuo-motor link in speech communication. Previous works [START_REF] Moulin-Frier | Emergence of a language through deictic games within a society of sensori-motor agents in interaction[END_REF], 2010) already showed that this link is necessary in production for realistic simulations of language emergence (backed by data showing that human phonological systems are optimized for perceptual distinctiveness).

Regarding speech perception, we are planning simulations showing that in simple cases like vowel categorization, the sensory subsystem is better than the motor one to infer the corresponding object (in favor of auditory theories of speech perception) but, in more complex cases like syllable categorizations, the motor subsystem can add reliable information (in favor of sensory-motor theories).

  FIGURE1.1ArticulatoryPhonology(fromBrowmanandGoldstein,1989).a)Gestural computationalmodel.b)Gesturalscorefortheutterance'pan'.

  FIGURE 1.2. Illustration of the core argument for the Motor Theory of Speech Perception,regardingthephoneme/d/in/di/vs/du/:a)thegestureisthesame,that is closing the front of the vocal tract by putting the tongue against the teeth, b) the signalisdifferentandc)theperceptisthesame.Therefore,theinvariantwouldbethe gesture.

FIGURE1. 4 .

 4 FIGURE1.4.TheDIVAmodel(fromGuenther,2006):afeedforwardcontrolsubsystem located in the motor cortex is coupled to a parieto-temporal feedback control subsystem.

  FIGURE1.5.PerceptionforActionControlTheory(PACT):motorschemasareinvolved both in extracting relevant auditory information through binding, and in improving categorizationthroughsensory-motormaps.


Jérôme Nika
email: jerome.nika@telecom-paristech.fr

Marc Chemillier
email: chemilli@ehess.fr

_180 IMPROTEK, INTEGRATING HARMONIC CONTROLS INTO IMPROVISATION IN THE FILIATION OF OMAX

. Moreover, it can adapt to a regular beat and produce improvisations following a given chord progression. ImproteK is conceived as an interactive instrument dedicated to performance: its improvisations are based on the style modeling performed on live playing or on an offline corpus. Combined with pattern reuse techniques, this modeling expands on harmonization and arrangement in a harmonic interaction module.

INTRODUCTION

The aim of ImproteK is to combine style modeling and interaction to install an original dialogue between musicians and a virtual improviser feeding its inspiration on their playing. Both these paradigms and the automaton structure at the heart of its implementation (section 2) make this system a cousin of the improvisation software OMax [START_REF] Assayag | Omax brothers: a dynamic topology of agents for improvization learning[END_REF][START_REF] Assayag | Omaxofon[END_REF][START_REF] Lévy | Visualising omax[END_REF] conceived and developed at Ircam.

Following previous works on musical style modeling by G. Assayag et. al [START_REF] Assayag | Guessing the composers mind: Applying universal prediction to musical style[END_REF], OMax is capable of learning the style of a human improviser thanks to a representation based on the oracle structure introduced by C. Allauzen et. al [START_REF] Allauzen | Factor oracle: A new structure for pattern matching[END_REF] extended to a musical context [START_REF] Assayag | Using factor oracles for machine improvisation[END_REF]. The software builds a model of a musician's playing in real-time, and is then able to navigate through this representation by following different paths from that taken by the musician. This leads to generate original improvisations with a common aesthetics.

With the same intention, ImproteK focuses on measured music supported by an underlying harmonic structure. It provides an enriched interaction by taking the beat into account in the framework of a given chord progression (section 3). This conception of improvisation is made concrete by an architecture enabling its integration in a musical band whose tempo can be extracted and followed (section 4). Finally, it introduces harmonic interaction by extending style modeling to the scope of harmonization and arrangement (section 5).

The purpose of this paper is first to recall some general principles underlying both ImproteK and OMax approaches, and then to describe the specific developments of the ImproteK software.

MUSICAL STYLE MODELING AND ORACLE STRUCTURE

Style modeling in improvisation and harmonization

Since M&Jam Factory [START_REF] Zicarelli | M and jam factory[END_REF], R. Rowe's Cypher [START_REF] Rowe | Interactive music systems: machine listening and composing[END_REF], or G. Lewis' Voyager [START_REF] Lewis | Too many notes: Computers, complexity and culture in voyager[END_REF], often considered as the first realtime interactive systems, many "virtual improvisation partners" have been conceived. Most of them benefited from the development of machine learning techniques with the growing idea to get always closer to the interacting human performer's discourse. Among them, the Continuator [START_REF] Pachet | The continuator: Musical interaction with style[END_REF] conceived by F. Pachet models the musical input using an extended Markovian model to create new phrases from this learning. As in OMax free mode, there is no rhythmic perception to enable a synchronization with the musician. On the other hand, GenJam [START_REF] Biles | Genjam: Evolutionary computation gets a gig[END_REF] developed by J. Biles is closer to the previous experiments of OMax with a beat mode: the software provides an accompaniment with a given tempo to support a musician's improvisation. After listening, it repeats some sequences modified through a genetic algorithm. B. Thom's Band Out of a Box [START_REF] Thom | BoB : an interactive improvisational music companion[END_REF] also involves a non-interactive computer accompanist with a fixed tempo in a trading fours interaction scheme where a human improviser and a virtual partner repeatedly call and respond in four-bar chunks. Each bar of the human improvisation is assigned to a cluster called playing mode, and the computer response is constituted by 4 bars belonging to the same sequence of modes.

This last example introduces the recurring issue of segmenting and representing the musical inputs. This point is particularly crucial in the corpus-based systems dealing with harmonization, arrangement or accompaniment such as ImproteK. Whether they are interactive and dedicated to performance or conceived to be used offline, these systems can basically be classified according to two characteristics: the exclusive use of formalized musical rules and the use of a musical corpus (see [START_REF] Nika | Intégrer l'harmonie dans un processus informatique d'improvisation musicale[END_REF] for the positioning of ImproteK within a more exhaustive classification system).

In this last category, the corpus can be considered as a training environment to create generative models (among them C. Chuan and E. Chew [START_REF] Chuan | A hybrid system for automatic generation of style-specific accompaniment[END_REF], Microsoft Mysong-Songsmith software [START_REF] Simon | MySong: automatic accompaniment generation for vocal melodies[END_REF]) and/or as a musical memory in which fragments are retrieved and combined to create the new material (G. Ramalho's jazz bass player ImPact [START_REF] Ramalho | An artificially intelligent jazz performer[END_REF]).

The definition of the segmentation unit in the corpus processing is one of the key differences: the grain can be key notes of a reduced melody in C. Chuan and E. Chew's system, a single chord in Songsmith and the software Band in a Box (PG Music), or particular chord chunks in G. Ramalho's ImPact. The idea is to find the right balance between long enough slices to provide plausibility and coherence in the returned accompaniment, and fine enough slices to avoid recopying too long and identifiable segments from the corpus. In the case of Improtek, the chosen unit is the beat. Indeed, the oracle structure prevents from choosing between musical smoothness and innovation by providing continuity by construction, and enables to work with such a fine grain.

Oracle and pattern recognition

The oracle was initially conceived for optimal string matching, and was extended for computing repeated factors in a word and for data compression. This acyclic automaton represents at least all the factors in a word, and the incremental construction algorithm is time and space linear in its length (for the details of the construction algorithm, see [START_REF] Allauzen | Factor oracle: A new structure for pattern matching[END_REF]).

The formal properties of the oracle structure are detailed in the founding articles, and fully applied to the issue of stylistic reinjection [START_REF] Assayag | Omax brothers: a dynamic topology of agents for improvization learning[END_REF] in several OMax papers. We briefly summarize here the tools providing the continuity and coherence of the sequences generated through an oracle: the forward transitions and the suffix links.

The forward transitions (forward links, plain lines) enable to reach every sub-pattern in the original sequence starting from the initial state. In this way, every progression between consecutive states of the original sequence can be generated. Fig. 1 shows the oracle for the sequence abcadbcd and illustrates this point by displaying a path using forward transitions to generate the sub-sequence bcd (0, 2, 3, 8), originally occurring between the states 5 and 8.

The oracle also locates the repeated sub-pattern in the original sequence with the suffix links (backward links, dashed lines). They point at the final state of the previously encountered occurrences of a pattern. In the example of fig. 2, a suffix link connects the states 7 and 3. 3 is indeed the leftmost position where a longest repeated suffix of the sequence ending in 7 (abcadbc) is recognized: bc.

The oracle structure can be used as a tool to create new sequences by a non-linear navigation following the previously introduced links thanks to its understanding of the logic in the progressions present in the strings. In a musical application, its ability to preserve the discourse of the original material enables to develop an aesthetics close to that of the musicians in interaction.

IMPROVISING WITHIN A METRIC AND HARMONIC FRAMEWORK

The beat hypothesis

The philosophy of the current version of OMax is to turn every single musical event into a state in an oracle object.

The free real-time navigation [START_REF] Assayag | Navigating the oracle: A heuristic approach[END_REF] through a thus structured memory makes it an interactive instrument dedicated to improvisation in a free musical context. The approach of the ImproteK project differs by the integration of two paradigms. First, its improvisations take place in an underlying harmonic structure represented by a chord progression we will refer to as grid. In this way, it makes the system able to expand its modeling on harmonization and arrangement. Then, it takes a metric framework into account by setting the beat as the elementary unit in its acquisitions, restitutions, and generations. The only musical hypothesis is therefore the existence of a regular beat in the material listened and produced by ImproteK. The tendancy to the synchronization with a periodic beat being a deep universal of the human music perception [START_REF] Patel | Investigating the human-specificity of synchronization to music[END_REF], this sole assumption does not make the system oriented towards a restricted musical field. Starting from this point, we add a notion of labels making some musical slices separated by beats, making them equivalent (see section 5.1.2). This process enriches the set of possible combinations, but does not carry any harmonic hypothesis. Indeed, as discussed in the last section, the references to the jazz idiom through this article come from the context in which ImproteK has been used so far.

Mode beat oracles

The improvisation module is built on a previous version of OMax (OMax 2.0, 2004) conceived as a Lisp library under the OpenMusic environment [START_REF] Bresson | Openmusic 5: A cross-platform release of the computer-assisted composition environment[END_REF]. This version implemented the oracle structure both in a free improvisation context (mode free, direction adopted by the current version of OMax) and with a regular beat (mode beat, starting point of ImproteK).

In this view, each state of the oracles represents a musical slice whose duration is given by the current tempo and which contains differents types of events happening between two beats. These events can be musical MIDI sequences -melody or accompaniment fragments -or symbolic information such as chord labels. During the generation steps, these different features constituting the states will sometimes be considered as elementary outputs concatenated in a fragment reuse process, and sometimes seen as labels to compare with the given path to follow in the navigation through the oracle.

Learning and improvising with the live oracle

ImproteK improvises by retrieving and combining preexistant elementary units: the new phrases are built by concatenating "beat slices" coming from its musical memory. These fragments are not independently and randomly drawn but continuously collected by following the chosen harmonic grid supporting the musical session as a guideline.

This process involves a first instance of the oracle structure: the live oracle, which carries its learning process out on the phrases played by the musicians (fig. 3). These MIDI inputs are indeed indexed beat by beat in real-time by the chord labels of the current harmonic grid (see section 4.2) and are therefore formated for the building of this object. What we call "improvise" is the generation of new musical phrases using the memory stored in this live oracle. To do so, the chord labels in the oracle are considered as indexes in the context of a constrained navigation, a heuristic designed by G. Assayag. This mechanism amounts to searching sub-patterns of an input se-quence (here the harmonic grid) in a different sequence (here the oracle's harmonic labels). When a label matches, the melodic beat slice present in the state is returned to be added to the the sequence constituted by the results of the previous steps.

Constrained Navigation and continuity

To "improvize following a grid" means here to follow a path in the automaton using transitions indexed by labels coming from that grid. At each step, if no matching label is found from the current state, the navigation tries to follow a suffix link pointing on an other state where the required label could be read. The suffix links provide the existence of a common context between both concatenated fragments in the orignal sequence used to build the oracle. In this way, the navigation first looks for continuity by trying to stick to the previously learned progressions. Then, it searches for the labels independently of the local context if they do not appear, even after transposition, in the chosen oracle.

A continuity parameter is tested at each step of the calculation. It counts the number of successive forward transitions followed during the navigation, and then gives the length of the duplicated segments from the sequence in the oracle. By imposing a maximum continuity parameter, one can therefore quantify the wished balance between fidelity to the original sequence and originality in the generated improvisation: a high value will lead to a high ressemblance whereas a low value will bring more surprises.

The constrained navigation process consists in reading the successive labels of the input grid to look for beats indexed by these same labels in the oracle. If the current continuity parameter does not exceed the imposed maximum continuity, the search is operated following graded modes:

• Continuity mode: If its label matches, follow a forward transition, update the current beat position in the oracle, and output the associated melody fragment. If not, switch to Suffix mode if operating suffix links are found, otherwise switch to Nothing mode.

• Suffix mode: Follow the suffix link pointing on the longest repeated suffix to reach a matching label (see fig. 4) , update the current beat position in the oracle, and output the associated melody fragment.

Otherwise switch to Nothing mode.

• Nothing mode: The pattern matching is performed independently of the context and the label is searched in the whole oracle. A transposition can be used if necessary. The notion of common context is crucial because it ensures coherence and smooth musical transitions in the generated sequences even if the navigation involves jumps between different zones of the oracle. Indeed, in the case of this exemple, neither the input chord labels sequence nor the output musical segment can be found on their own in the memory of the live oracle.

TOWARDS AN INTERACTIVE INSTRUMENT

Architecture

The live performance from the musicians is received, segmented, formatted and saved in real-time via an interface developed under Max/MSP. Through this same interface, the ImproteK user selects a symbolic harmonic grid which constitutes the spinal column of the improvisation. Then, he has access to control parameters to guide the calculation of different kinds of musical phrases: new improvisations accompanied or not (see section 5) or live arrangements of the grid (see paragraph 4.5).

These processing instructions are sent via OSC protocol to the OpenMusic improvisation module introduced in the previous section (fig. 5), following therefore the global architecture of OMax 2.0 who worked in live interaction with Max/MSP through a basic interface who did not deal with the tempo management exposed in the following paragraph.

Under this version, a metronymic beat was imposed by the computer. This condition necessarily implied the loss of a part of the musical richness, and constrained the

Get rhythm

During the performance, an external source of beat is required to segment the inputs from the musician in the listening process, and to play phrases rhythmically fitting the current improvisation. To do so, ImproteK integrates the association of a beat tracker and a score follower acting as a sequencer by emitting in real-time the current position in the harmonic grid. First, it marks every beat of the listened live improvisations with the current chord label.

Then, the phrases returned by the improvisation module being labelized sequences, it triggers the playing of the corresponding beat slices. The aim of the ImproteK project is to be a proper interactive instrument finding its place within a band. It was therefore fundamental that its use did not limit creativity and expressivity by subordinating the musicians to a metronomic tempo dictated by its outputs. The Max/MSP beat tracker object [START_REF] Bonnasse-Gahot | Donner à omax le sens du rythme: vers une improvisation plus riche avec la machine[END_REF] was especially developed to be integrated into an environment related to OMax to result in a richer musicality, the previous applications of the mode beat oracles involving a fixed tempo imposed by the system.

This module processes MIDI or audio streams (for example the rhythm section of the band) and continually estimates the local tempo to be used to generate and play improvisations adjusted to the necessarily variable human beat. During an initialization phase, the user provides a tempo indication with a manual time beating whose goal is also to give the initial phase by indicating the absolute dates of the beats in order to avoid an offbeat synchronization. Following this stage, the tempo variations are calculated throughout the whole performance (the description of the beat tracker is not the subject of the present paper, more details can be found in [START_REF] Bonnasse-Gahot | Donner à omax le sens du rythme: vers une improvisation plus riche avec la machine[END_REF]). This signal is then used as a clock to trigger the different elements constituting the sequences loaded in Antescofo.

Using a score follower as a sequencer

Antescofo [START_REF] Cont | Antescofo: Anticipatory synchronization and control of interactive parameters in computer music[END_REF] is a polyphonic score following system and a synchronous programming language for musical composition conceived by A. Cont. This object, developed as an external module for Max/MSP and PureData programming environments, conducts an automatic recognition of music score position from a real-time audio stream. It enables the synchronization of an instrumental performance with the computer realized elements of an electronic score.

The sequences calculated by the Lisp/OpenMusic module are written and saved as Anstescofo scores. The phrases thus generated broaden the improvisations collection and are available to be loaded by the performer during the improvisation: in our use of Antescofo, the beats provided by the beat tracker object act as the "notes" in the electronic score, and the contents to be triggered are the beat slices. Finally, an improvisation generated from an acquisition performed at a given tempo can be played with a different one since the time notation under the Antescofo format is relative.

Segmenting and indexing the inputs

This couple of objects in charge of the beat management is found downstream to play the generated sequences, and equally upstream in the live acquisition process. The improvisation session takes place in the scope of a known harmonic grid, and this last is written as a progression of chord labels, each of them being associated to a numbered beat under the Antescofo format. In this way, a live indexing of the MIDI inputs can be performed with these harmonic labels.

We use a particular encoding to mark the MIDI streams: the channel 16 is dedicated to the grid representation with conventions to notify the root and the type of the chords which are received from Antescofo. In this way, the MIDI buffers used by the improvisation module contains all the required information of segmentation and indexing to build new oracles or musical phrases.

A source of proposals

ImproteK is conceived as an instrument played by a fulltime performer interacting with the rest of the band. He pilots the system through a graphical interface and controls in real-time the parameters of both steps of learning and generation which are initiated on demand. During the performance, he selects the musical phrases given as inputs for the style modeling, determines the current oracles (the live oracle as well as the instances involved in the harmonization and arrangement module introduced in section 5) and sets technical parameters such as the maximum continuity parameter in the navigation for every oracle. Among other characteristics, the learning material, the length, or even the "boldness" of the improvisations are therefore left to his discretion.

The performer is not only in charge of the listening and learning but he also fully leads the playing via keyboard controls. He has access to phrases generated from the last musical events as well as the ones from the previous sessions. Different forms of improvisation are available: they can be for instance melodic or accompanied sequences, or live arrangements of the grid, and he can easily and immediately switch phrases in real-time in a continuous musical discourse.

Finally, the part played by ImproteK can evolve during an improvisation session: it is actually able to be soloist and/or accompanist depending on the nature of the sequences chosen by the performer to fill the live oracle. Indeed, making this oracle listen to an accompanist's playing will lead to perform real-time arrangement of the harmonic grid. The second way to deal with accompaniment is the harmonization and arrangement module introduced in the following section.

HARMONIZED AND ARRANGED IMPROVISATIONS

The harmonization and arrangement module can be used in an autonomous way as an independent block producing an accompaniment for a melody without interacting in real-time. Yet, it was conceived to be integrated in the wider environment of ImproteK to compose new accompanied improvisations. It does not use any musical rule and is exclusively based on a corpus which is simultaneously seen as a learning ground to extract empirical harmonization mechanisms, and as a musical memory in the framework of a pattern reuse technique to make the accompaniment concrete once it has been calculated.

Learning step

The corpus

The learning of the corpus is performed on three features: the melodic track (theme, solo improvisation, etc.), the accompaniment track, and the associated harmonic grid. It is carried out on live performances by musicians and consists for the moment in jazz standards and pieces by Bernard Lubat.

We refer to "corpus" to designate the set of models extracted from an offline learning as well as those created during the current performance which are immediately available for generation: once again, the system listens to the musicians, segments the inputs by beat, and learns these sequences as well as the associations between the three features by building oracle objects. The learning step is actually double. A couple of oracles is built for every element of the corpus: an harmonization oracle, and an arrangement oracle (fig. 6).

The harmonization oracle records the sequence of associations between the melodic fragments and the chord labels of the beats it covers. In the case of the arrangement oracle, the concerned associations involve the chord labels and the fragments of accompaniment. As their names suggest, they will be used to associate a symbolic chord progression with a melodic track, and a accompaniment track with a symbolic chord progression, respectively.

Equivalence

This incremental building, as wells as the pattern matching described in the next paragraph (5.2.1), is actually performed on equivalence classes.

In the case of a harmonization oracle, two states are considered as equivalent if they are indexed by the same notes without taking into consideration their duration, order, or repetition in the beat slice. In the same way, two states of an arrangement oracle are equivalent if they are indexed by the same chord label whatever the associated fragment of accompaniment is.

These equivalences have been introduced to avoid the unproductive rigidity which could have been brought by a strict equality criterion. The consequence regarding the oracles' structure impacts the number of operating suffix links as illustrates the simplified example in fig 7, applied to a character string: an oracle built on the word oracle.

In the first example, every suffix link points on the initial state because no repeated sub-pattern has been found (every letter only appears once). In the second example using the equivalence classes vowels and consonants, we observe repeated sub-patterns and the structure is much more complex.

Generation step

Harmonizing and arranging in a cascade

The whole harmonization and arrangement process amounts to repeating the mechanism of constrained navigation in a cascade, first with a chosen harmonization oracle then with a chosen arrangement oracle (fig. 8). The harmonization outputs a chord labels progression, and this symbolic sequence therefore becomes the path to follow for the navigation in the chosen arrangement oracle (filled by sequences of associations between melodic fragments and chord label sliced by beat). The pattern matching is this time performed on chord labels to output a sequence formed by the concatenation of the accompaniment fragments found in every stage of the research.

Formal intermediary

It is important to note that, even if an intermediate step involves symbolic data such as chord labels, no harmonic rule is used to perform harmonization and arrangement. The denomination of this formal intermediary is only useroriented to make performance more intuitive: the system itself is unaware of the musical meaning of this labeling and only considers two chord labels as two indexes to compare.

The insertion of this formal language at an intermediate level separating the process in two different steps is motivated by three reasons. First, it naturally comes from the usual notation in jazz scores as we found in the Realbooks where a melody is facing a corresponding chords label progression. Then, it enables to multiply the bilities: a phrase can indeed be harmonized with a given oracle and then arranged using an arrangement oracle learned on a completely different corpus. Finally, it will allow to implement in a future development an optional level of chord substitutions based on a grammar [START_REF] Chemillier | Toward a formal study of jazz chord sequences generated by steedman´s grammar[END_REF].

Furthermore, the terms "harmonization" and "arrangement" come from the fact that ImproteK has been used so far in tonal jazz sessions. In other musical contexts, its genericity enables an understanding of other forms of vertical associations that can be indexed in an agnostic way with an other grammar.

EXPERIMENTS AND RESULTS

ImproteK has been used as a virtual partner by professional musicians, in particular French jazz musician Bernard Lubat during improvisation sessions conducted in Uzeste in 2011. Video and audio examples can be found at http://ehess.modelisationsavoirs.fr/improtech/improtek. Some of them show the real-time control of the software through the Max/MSP interface (see for instance the improvisation based on Erroll Garner's mambo style transcriptions). The direct interaction of the computer with a live musician is illustrated by improvisation sessions where Bernard Lubat and ImproteK alternately play as soloist and accompanist, or trade choruses.

Other series illustrate the wide variety of results for a same input in the harmonization and arrangement module depending on the user's choice to use different parts of the corpus for both steps, and on the continuity he imposed. It goes from "imitation" by choosing a same part of the corpus for the live, harmonization, and arrangement oracles, to originality or even extravagance when completely unrelated oracles are used.

CONCLUSION

We described a music generation system which is able to understand the logic of the horizontal and vertical associations in a live musical improvisation performance to become itself a source of proposals by developing its own aesthetics close to that of its partners. Its prime material is indeed their playing. It is used at the same time as a learning ground for the style and as a musical memory to develop its own improvisations.

The properties of the oracle structuring this memory enable to get over the dilemma "innovation vs. coherence" by ensuring continuity by construction, and therefore giving the possibility to work with a fine grain: the beat is set as the elementary unit in the calculation, and its restitution is made possible by following a beat tracker to reach a better interaction.

ImproteK is indeed conceived as a proper instrument and requires a full-time performer to manage the learning, the generation, and the playing in real-time. It can alternately be soloist or accompanist and is even capable of creating accompanied improvisations via the harmonization and arrangement module.

Current work is devoted to the evaluation of the compatibility between the harmonic progression of the current session and that of the accompaniment returned by this module. For the moment, the performer is given the comparison between both grids through the interface which displays the respective chord labels. This study will lead to a better integration of the "harmonic interaction" in the instrument, and will make its use more intuitive.

Figure 1 .

 1 Figure 1. Oracle for the sequence abcadbcd: generation of a sub-pattern starting from the initial state.

Figure 2 .

 2 Figure 2. Oracle for the sequence abcadbcd: repeated sub-pattern.

Figure 3 .

 3 Figure 3. Learning the live oracle

Fig. 4 Figure 4 .

 44 Fig. 4 shows an example of generation step. At the current stage, the chord labels d, b and c have been searched and found in the live oracle, and the concatenation of the associated musical fragments D, B´and C´forms the

Figure 5 .

 5 Figure 5. Architecure

Figure 6 .

 6 Figure 6. Learning the harmonization and arrangement oracles.

Figure 7 .

 7 Figure 7. Suffix links and equivalence classes.

Figure 8 .

 8 Figure 8. Harmonization and arrangement process.

Acknowledgment

This work is realised with the support of the French National Research Agency, in the framework of the project "IMPROTECH", ANR-09-SSOC-068.

We wish to thank the OMax family Gérard Assayag, Georges Bloch, and Benjamin Lévy for the fruitful exchange of experiences and ideas regarding the conception and implementation of ImproteK. We thank Laurent Bonnasse-Gahot who made it get rhythm with the beat tracker, Carlos Agon and Jean Bresson for their advice concerning OpenMusic, and Arshia Cont for the custommade Antescofos. Finally, we want to express special thanks to La Compagnie Lubat for the always enriching sessions.


Djillali Sahali
email: dil.sahali@inserm.fr

Kelhia Sendeyo

Mélanie Mangier

Vincent Audard

Yu Shao

Philippe Zhang

Mario Lang

Andre Ollero

Pawlak

Melanie Mangier

Immunopathogenesis of idiopathic nephrotic syndrome with relapse

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

Introduction

Idiopathic nephrotic syndrome (INS) is a primary glomerular disease, which mainly includes two histological variants, minimal change nephrotic syndrome (MCNS) and focal and segmental glomerulosclerosis (FSGS).

MCNS is a primary glomerular disease defined by massive proteinuria and hypoalbuminemia without inflammatory lesions or immune complex deposits. Glomerular changes consist mainly of podocyte foot-process effacement, assuming a flattened rather than a foot-like morphology. This aspect is non-specific since it is commonly observed in glomerular diseases with nephrotic proteinuria. MCNS is recognized as a chronic illness in childhood, accounting for 70% of idiopathic nephrotic syndrome (INS) in children and 25% of INS in adults [1,2].

Focal and segmental glomerulosclerosis (FSGS), which is less frequent in young children (20%), is a distinct glomerular disease characterized by a nephrotic syndrome associated with histological lesions including segmental hyalinosis and sclerosis of the glomeruli [3]. Whereas MCNS seems to be a single entity, FSGS appears as a heterogeneous disease, with both immune and non-immune causes. Recent genetic approaches have elucidated some pathogenic aspects of FSGS by identifying several genes that play a critical role in podocyte function and glomerular filtration barrier [4][5][6][7][8][9][10]. However, a mechanistic explanation of the glomerular abnormalities in MCNS and idiopathic FSGS with relapse remains elusive. In this review, we will discuss the results of recent investigations that may contribute to our understanding of the pathophysiology of these glomerular diseases. Proteinuria in membranous nephropathy results also from podocyte dysfunction but this distinct glomerular disease deserves separate consideration.

The molecular relationship between MCNS and FSGS with relapse is unclear. Nearly 50% of patients with FSGS are steroid-sensitive but relapse. Given the infrequency of kidney biopsies in children with nephrotic syndromes, the relative prevalence of MCNS and FSGS at the time of presentation is unknown. The most critical parameter of prognosis is the response to steroid therapy: steroid-sensitive FSGS shares the same benign course as MCNS. Of those children with nephrotic syndromes, 80-90%, presumably MCNS, are steroid-responsive.

Overall, 60-80% of steroid-responsive nephrotic children will relapse and about 60% of those will have five or more relapses [11]. Around 60% of MCNS children show steroid dependence. In these patients, anti-CD20 therapy by Rituximab has demonstrated its efficiency by inducing sustained remission even after switching off other immunosuppressive medications, while very rare side effects have been observed [12][13][14]. Thus, Rituximab becomes an invaluable alternative therapy in patients with steroid and/or anti-calcineurin dependent nephrotic syndrome.

Over the past four decades, extensive research aiming to elucidate the pathogenesis of MCNS and FSGS with relapse yielded significant insight regarding both immune and podocyte disorders, although the exact origin of molecular mechanisms remain unclear.

Various alterations in cytokine production during MCNS have been described by a large number of studies, which, unfortunately, are not all in agreement [15]. This variation might result from the different immunogenetic backgrounds of the patients, or from the heterogeneity of studies on stimulated cells in environments that are far from physiological. It might also be due to the diversity of the dosage techniques, which do not always take relapse [16]. IL13 was found to increase transcellular ion transport in podocytes, which express IL13 receptor.

IL13 transgenic rats develop nephrotic proteinuria and display a MCNS-like phenotype [17]. However, in many pathological conditions in which IL-13 is increased, such as asthma, psoriasis, and allergic dermatitis, proteinuria does not occur. Moreover, IL13 does not affect permeability to macromolecules [18]. These observations suggest that besides IL13, additional events are required to develop nephrosis in the human disease.

Angiopoietin-like 4 as potential soluble proteinuric factor in MCNS

Angiopoietin-like 4 (Angptl4) is a secreted glycoprotein, which was classified as an adipokine due to its predominant expression in adipose tissues and liver. Although it is involved in many functions including energy homoeostasis, wound repair, tumorigenesis, angiogenesis and redox regulation [19], its crucial role seems to be related to the regulation of lipid metabolism during fasting, in which Angptl4 induces hypertriglyceridemia through inhibition of lipoprotein lipase and stimulates intracellular adipocyte lipolysis [20]. The expression of which are potent inducers of Angptl4 [21]. Transgenic mice overexpressing Angptl4 in liver did not exhibit overt phenotype or significant abnormalities but displayed high triglyceride serum levels [22].

Angptl4 has recently been reported as a possible mediator of MCNS, based on the finding that transgenic rats overproducing Angptl4 specifically in the podocyte, but not in adipose tissue, display heavy proteinuria with pathological features of MCNS [23]. The mechanism of proteinuria in this model was attributed to podocyte release of hyposialylated Angptl4, which interacts with negatively charged glycosaminoglycan chains, and promotes the loss of GBM charges, commonly observed in nephrotic proteinuria. Unfortunately, the serum and urinary levels of Angptl4 and its derivatives in MCNS patients and related controls have not been reported.

CD80 and podocyte diseases

CD80, also named B7.1, is a transmembrane protein commonly expressed by antigen presenting cells (APC) and B cells, but not by normal podocyte. However, CD80 is induced in the latter by LPS and puromycin administration, as well as in human lupus nephritis, including proliferative and non-proliferative forms [24].

Further studies have shown that urinary CD80 levels are increased in MCNS but also in other glomerular diseases, suggesting that this phenomenon is common to proteinuric states [25][26][27]. In the absence of quantitative evaluation of podocyte CD80 abundance, the measurement of urinary CD80 deserves some caution because its podocyte origin is not ascertained.

The finding that LPS triggers a signaling pathway in podocyte miming APC through toll-like receptor 4 (TLR-4) is interesting in that it supports the role of podocyte not only as a target but also as an actor in the pathogenesis of glomerular diseases. The induction of CD80 by LPS trough TLR-4 signaling pathway is associated with cytoskeleton disorganization and foot process effacement, leading to proteinuria in wild-type but not in CD80deficient podocytes [24]. Therefore, inhibition of CD80 could be of therapeutic interest in experimental models of nephrotic syndromes and in human glomerular diseases. This step has recently been achieved with success [28]. In this study, five patients with B7 positive podocyte biopsy-proven, four with FSGS recurrence and one with primary FSGS, were treated by Abatacept, a CD80 inhibitor (single dose, 10 mg/kg). Nephrotic syndrome was resolved in all patients with a sustained remission between 12 and 48 months. This study refines the mechanism of CD80-induced proteinuria. Using different in vitro and in vivo approaches, it was demonstrated [29,30]. The natural isoform of c-mip encodes an 86-kDa protein that does not belong to any known family. Its predicted structure includes an N-terminal region containing a pleckstrin homology domain (PH), a middle region characterized by the presence of several interacting docking sites including a 14-3-3 module, a PKC domain, an Erk domain, an SH3 domain similar to the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), and a C-terminal region containing a leucine-rich repeat (LRR) domain (fig1). C-mip contains a nuclear localization site (NLS) near the C-terminus of the PH domain. Depending on physiological or pathological situations, c-mip can move to the nucleus but its localization is not restricted to a particular subcompartment. In basal conditions, c-mip abundance is very low in most tissues examined, as well as in cell lines like Jurkat T or M15 ([31] The expression of c-mip has been analyzed by both in situ hybridization, quantitative PCR on lasermicrodissected glomeruli and Western-blots on glomerular protein lysates [32,35]. Its basal expression is low or undetectable in humans, rats and mice, whereas in primary INS, as well as in mouse and rat models of adriamycin-induced nephrotic syndrome, c-mip is strongly increased ([32, 35] and unpublished data). By contrast, immunohistochemical studies show that c-mip is not expressed in glomerular proliferative diseases such as mesangiocapillary or extracapillary glomerulopathy [36], albeit low levels of transcript are identified by quantitative PCR. These observations suggest that c-mip is a marker of primary podocyte diseases without inflammatory proliferative lesions.

Expression of c-mip in glomerular diseases

C-mip was initially identified from MCNS T-cells by subtractive and differential cloning

Functional consequences of c-mip induction in podocytes.

To clarify the potential effects of c-mip in podocytes, we generated transgenic mice in which a single copy of human c-mip is inserted in the HPRT locus by homologous recombination. The expression of c-mip is driven by the nephrin promoter, allowing selective expression in podocytes. Transgenic mice develop proreinuria a few days after birth and progress to nephrotic range in a few weeks. Morphological analysis shows only minimal glomerular lesions in the form of podocyte effacement and fusion of foot processes, while FSGS lesions occur lastly [36]. To investigate the mechanisms by which c-mip alters podocyte function and induces proteinuria, we used several approaches including the identification of c-mip partners by yeast-two hybrid screening and generation of inducible and stable c-mip transfectant podocyte cell lines. Among the partners, we found that Fyn, a major podocyte Src kinase, interacts in vitro and in vivo with c-mip through its PH domain [35]. In physiological conditions, Fyn binds and activates nephrin and N-WASP (Wiskott Aldrich syndrome protein), thus playing a key role in proximal signaling and cytoskeleton remodeling. It was recently shown that Nck interacts with and promotes Fyn-mediated phosphorylation of nephrin, a central component of the slit diaphragm playing a crucial role in signal transduction and podocyte integrity [37,38]. It is likely that phosphorylation of Fyn at Tyr 417 is required for Nck-Fyn interaction. Nephrin phosphorylation induces the recruitment of p85/p110 heterodimer of PI3 kinase (PI3K), through the interaction of nephrin SH2 domain with p85, the regulatory subunit of PI3K, leading to activation of the p110 catalytic subunit and generation of phosphoinositides [39]. This step initiates a signaling cascade including the activation of serine threonine kinase Akt and the recruitment of podocin and CD2-associated protein (CD2AP). The c-mip-Fyn interaction is merely negative, c-mip preventing Fyn phosphorylation at Tyr 417, which is required for its interaction with nephrin and N-WASP [32]. This results in inactivation of key proximal signaling events, including nephrin, PI3K, Akt and N-WASP phosphorylation, which is demonstrated both in stably transfected podocytes and in vivo in transgenic mice (Fig 2). Interestingly, inactivation of nephrin and Akt is confirmed in kidney biopsies from patients with INS, highlighting the role of proximal signaling alterations in the pathophysiology of podocyte disorders [32].

-arrestin2 and its subsequent endocytosis and degradation [40]. Indeed, nephrin expression is commonly decreased in c-mip transgenic mice as well as in INS [32]. However, its downregulation is not only observed in MCNS/FSGS but also in other primary nephrotic syndromes such as membranous nephropathy [41]. The mechanism by which c-mip expression is increased in podocytes of patients with INS relapse is unclear.

C-mip displays pro-apoptotic functions by p53-independent mechanisms

Although c-mip interferes with RelA stability and may contribute to NF-kB downregulation, the initiating event leading to c-mip induction is unknown. Whether this mechanism involves NF-amplified by c-mip as suggested by VEGFR TKI, or another podocyte signaling disorder induced by a circulating factor remains to be clarified.

Research on permeability factors

Resistance to therapy occurs in 50% of FSGS and 10% of MCNS patients despite various immunosuppressive treatments (cyclosporine, cyclophosphamide, high-dose steroids) [60,61]. Such patients often progress to renal failure, requiring dialysis and transplantation. Recurrent disease in the transplant accounts in 30-50% of patients with FSGS, often within the first hours or days following engraftment [60]. This percentage is as high as 80% for the second graft if recurrence caused the loss of the first one [62,63]. The number of years to achieve end-stage renal failure predicts the risk of recurrence after transplantation: 50% if end-stage renal failure is attained in less than 3 years and 10-20% if this period is longer [64,65].

Given the short time between engraftment and disease recurrence, one may exclude the generation of an immune response against any component of the allogeneic glomerular filtration barrier, but a circulating factor endowed with pathogenic properties across the glomerular structure has been postulated [66]. The absence of inflammatory lesions and immune complex deposits within the glomeruli, as well as the rapid relapses following of a permeability factor remains a serious challenge although there is little doubt about its immune origin.

Several candidates, such as cardiotrophin-like cytokine-1 (CLC-1) and soluble urokinase-type plasminogen activator receptor (suPAR), have been proposed and some of them are yet being discussed [65,78,79]. For now, few data related to CLC-1 are available.

SuPAR is released from cleavage of the urokinase-type plasminogen activator receptor (uPAR). High suPAR serum levels have been initially reported in most patients with primary FSGS, the highest concentrations found in FSGS patients who recur after renal transplantation. The pathophysiological relevance of these findings anchors podocyte to the glomerular basement membrane, resulting in foot process effacement and nephrotic inhibitor. These clinical and experimental data have been recently challenged by several reports, which make highly questionable the use of this molecule as a biomarker for FSGS recurrence. First, suPAR is highly secreted in broad conditions such as infections, inflammation, cancers, cardiovascular diseases and diabetes and is not correlated with proteinuria [80]. In a large survey in children, suPAR levels were found not significantly different between FSGS, non-FSGS glomerular diseases and healthy controls, whereas higher levels were rather found in non-glomerular diseases (hypoplasia, obstructive nephropathy or cortical necrosis) versus FSGS [81].

Interestingly, serum suPAR levels were found inversely correlated with glomerular filtration rate but no correlation with the degree of proteinuria was found [81][82][83]. In another recent study, it was found that serum suPAR levels do not differentiate between FSGS (with or without recurrence), membranous nephropathy, diabetic nephropathy and IgA nephropathy, among others, but a negative correlation with GFR has also been noticed [84]. By contrast, it seems that urinary suPAR excretion could predict the risk of recurrence [84].

Nonetheless, given the low number of patients analyzed (five patients), this data requires to be confirmed.

Although the role of suPAR and its derivative forms in FSGS remains to be clarified, compelling evidence suggests that high serum suPAR levels are significantly correlated with systemic inflammation and renal failure, so that suPAR cannot be used presently as a biomarker of FSGS recurrence. Lastly, it has been demonstrated that suPAR does not bind in vitro and in vivo to protein-A column, which is successfully used to deplete the putative circulating factor from patients with FSGS recurrence [85].

The mechanisms by which Rituximab, an anti-CD20 monoclonal antibody usually used for the treatment of lymphoma, induces remission in post-transplant recurrence has been recently revisited [86]. The efficacy of Rituximab was initially attributed to interference with B cell function and/or T cell-B cell cooperation. However, it has been reported that Rituximab, besides its original target, also binds to sphingomyelin phosphodiesterase acid-like 3 (SMPDL-3b), which was found basally expressed in the podocytes [86]. Incubation of podocytes with serum from recurrent FSGS patients induces SMPDL-3b downregulation, as well as loss of stress fibers, which is prevented by Rituximab.

The presence of permeability factors in circulation, the beneficial role of Rituximab, and the expression of c-mip by the lymphocyte-podocyte axis in pathologic conditions, might constitute different sides of the same conundrum. The current state of investigations is nonetheless far from establishing a mechanistic connexion between these three elements.

Conclusion and perspectives

Our understanding of pathophysiology of podocyte disorders in INS has considerably evolved during this last decade. The cytokine era has given way to some unknown molecules discovered by several groups using distinct approaches. It is likely that new genes relevant to INS disease will be identified in the future. For now, CD80

and Angptl4 define two different mechanisms of proteinuria. Regardless of initial event, both proteins are produced by the podocytes, which currently may be considered as an actor and not only as target of the disease.

Consistent data derived from animal models, human diseases, as well as experimental investigations support a role of c-mip in lymphocyte and podocyte disorders occurring in INS relapse. These data suggest that c-mip is at the crossroads of proximal signaling events and cytoskeletal organization, ultimately leading to regulation of cell

  and unpublished data). Unexpectedly, we found c-mip overproduced in the podocytes of patients with INS, including MCNS and FSGS with relapse [32]. A relevant argument supporting the implication of c-mip in INS comes from the observation that occurrence of INS in Hodgkin disease is closely associated with overproduction of c-mip in both Reed-Sternberg cells and podocytes [33, 34]. Several works summarized below point out a role of c-mip in the pathophysiology of immune and podocyte disturbances occurring in INS.

  Podocyte survival is regulated by extracellular and intracellular signals. Nephrin and vascular endothelial growth factor (VEGF) recruit the PI3K-Akt signaling pathway, activating NFfactors, which are potent inhibitors of podocyte apoptosis[42]. Mutation of nephrin abrogates the antiapoptotic effect of VEGF, suggesting that nephrin is required for VEGF signaling[42]. CD2AP is an adapter protein anchoring nephrin to actin cytoskeleton and inhibits p38 mitogen-activated protein kinase (p38 MAPK) through PI3K-mediatedAkt activation[43, 44]. CD2AP-deficient mice develop nephrotic syndrome and renal failure caused by glomerulosclerosis[45]. Inhibition of PI3K pathway plays a determinant role in apoptosis occurring in CD2AP-deficient podocytes[39]. Although p38 MAPK is activated in glomeruli in many proteinuric renal diseases and in diabetic nephropathy, a greater increase is observed in inflammatory, proliferative forms such as severe lupus nephritis and vasculitis[46][47][48][49]. The increased p38 MAPK activation in glomeruli may be related to local cytokine production. In the podocyte, p38 MAPK can promote apoptosis by several mechanisms including increased production of reactive oxygen species and activation of Src homology-2 domain-containing phosphatase-1 (SHP-1) [49]. SHP--3 [50]. Likewise, TNF--induced podocyte apoptosis has been associated in vitro with p38 MAPK activation [43]. Apoptosis induction by c-mip could be the result of several non-exclusive mechanisms. Firstly, we found that c-mip upregulation induces in vitro and in vivo downregulation of Akt, an upstream activator of NF-[32]. Inactivation of Akt is at least partly due to downregulation of PI3K, since c-mip interacts with the p85 regulatory subunit and inhibits the release of the p110 catalytic subunit that is required for PI3K activation ([51] and unpublished data). Secondly, c-mip activates p38 MAPK and increases the abundance of death-associated protein kinase (DAPK) [35, 51]. DAPK promotes apoptosis by disrupting integrin-mediated cell adhesion, altering cytoskeleton, which ultimately results in loss of extracellular matrix-dependent survival signals [52]. Alteration of the actin network induces the production of reactive oxygen species from mitochondria, leading to apoptosis [53]. Thirdly, It has been shown that c-mip binds RelA through its leucinerich repeat-containing C-terminal domain and may target the latter to proteasome-dependent degradation [31], [36]. Altogether, in vitro and in vivo data suggest that c-mip is a multifunctional protein and may promote apoptosis through different mechanisms.NF--mip cross-talk influences the pathophysiology of podocyte diseasesInhibition of angiogenesis by anti-VEGF and VEGF-receptor tyrosine kinase inhibitors (VEGFR TKIs) is believed as a major axis of oncology therapy. Because this ligand-receptor system is fully expressed and plays a prominent functional role in glomeruli, some on-target side effects are expected[54][55][56]. Data derived from several thousands of patients treated with anti-VEGF therapy show that anti-VEGF ligands (Bevacizumab and VEGF trap) may induce thrombotic microangiopathy (TMA), whereas VEGFR TKIs, such as sorafenib and sunitinib, are more frequently associated with heavy proteinuria[57, 58]. Histological analysis of renal biopsies of patients with nephrotic syndrome occurring under VEGFR TKI therapy shows minimal change and /or focal segmental sclerosis lesions (MC/FSG) without TMA-like lesions[58]. We found that c-mip abundance is highly increased in the podocytes of MC/FSG biopsies, whereas its expression is undetectable in TMA glomeruli[58].On the other hand, RelA is upregulated in TMA glomeruli both in podocytes and endothelial cells, while it is dramatically reduced in MC/FSG lesions. These observations suggest that c-mip and RelA are mutually antagonistic (Fig 3). Indeed, we provide evidence that RelA binds to the c-mip promoter in vivo and represses its transcription, whereas RelA knockdown releases this inhibition [58]. Downregulation of RelA by VEGFR TKI such as sorafenib, also reported by other authors [59] may release the transcriptional activation of c-mip as observed in sorafenib-treated podocytes [58]. Altogether, these results may account for c-mip downregulation in the podocytes of patients with TMA. Conversely, RTKI-mediated NF--mip expressionand reproduces an experimental human model of MCNS/FSGS-like lesions. Inasmuch that NF-kB is constitutively active in the podocyte, it is not surprising that c-mip expression is much lower in physiological conditions.

  renal transplantation, support the extra-renal origin of a circulating factor. This concept is also supported by the transmission of transient nephrotic syndrome in a new born from a mother exhibiting INS relapse [67]. Indirect evidence comes from observations showing that nephrotic syndrome disappears when an MCNS or an FSGS kidney is transplanted into an INS-free patient [68, 69]. In addition to clinical observations, plasma replacement performed in patients with FSGS who escape drug therapy has been successful [70, 71]. Moreover, immediate recurrence after transplantation has been successfully treated by plasma exchange or plasma immunoadsorption techniques [72-74]. Another line of evidence suggesting secretion of a permeability factor comes from experiments showing that systemic infusion of supernatants of cultured PBMC or T cells from MCNS relapse induces proteinuria in rats [75-77]. Immunochemical analysis of affinity column eluate fractions inducing proteinuria suggested that the molecular weight of the permeability factor is below 150 kDa [72]. Identification

LegendsFigure 1 .

 1 Figure 1. Structure organization of c-mip. The gene c-mip contains 22 exons spanning 270 Kb. It encodes a messenger RNA of 4.2kb consisting of 434 bp-5'UTR, 2,200 bp-coding sequence and 1600 bp-3'UTR. The protein c-mip is original in that it contains two domains usually not found within the same protein, the Pleckstrin-homogy domain (PH) and LRR domain, as well as an SH3-like domain and many docking sites for signaling molecules.

Figure 2 .

 2 Figure 2. Current understanding of nephrin signaling. In basal conditions, clustering of nephrin in lipid rafts induces Fyn phosphorylation at tyrosine 417, leading to its conformational change in active form. The amount of active Fyn is amplified upon its interaction with Nck. Then, Fyn phosphorylates nephrin at multiple residues within the cytoplasmic domain, which subsequently recruits several proteins including podocin, CD2AP and synaptopodin. Fyn binds to and phosphorylates N-Wasp. These diverse interactions initiated by Fyn preserve cytoskeleton organization. Phosphorylation of nephrin induces the recruitment of PI3 kinase, which then activates Akt and promotes podocyte survival through activation of NF--mip is barely detected in physiological conditions. However, in some pathological situations, c-mip abundance is increased and interferes with Fyn activity and nephrin (and likely other podocyte receptors) signaling.

Figure 3 .

 3 Figure 3. Cross-talk c-mip/NF--VEGF-mediated glomerular diseases. Thrombotic microangiopathy (TMA) is a frequent complication of anti-VEGF ligand therapy (Bevacizumab and VEGF trap), whereas minimal change nephropathy/focal segmental glomerulosclerosis (MCN/FSG) are mostly observed following receptor tyrosine kinase inhibitor (RTKI) treatment. Glomerular TMA is associated with an upregulation of NF--mip. By contrast, RTKI such as Sorafenib inhibits NFleading to increased c-mip abundance and cytoskeleton disorganization, which subsequently induces nephrotic proteinuria with MCN/FSG-like histological lesions.

Acknowledgement

We would like to thank Pr Pierre Ronco for his helpful comments and supports during the progression of this work.

Activation of Prosurvival factors

Dear Sirs,

We have completed the revision of the manuscript. We would like to thank you for the helpful comments. As underlined in your letter, we deleted some paragraphs related to c-mip studies and included new sections on CD80, suPAR and angiopoietin-like 4.

We hope that this revision will meet the expectations of the editorial Board and the referees.

Sincerely yours, D Sahali, M.D., Ph.D.

INSERM U 955