Pre- and post-natal exposure of children to organophosphate flame retardants: A nationwide survey in France.

The use of organophosphate flame retardants (OPFRs) has been on the rise ever since many brominated flame retardants were banned, back in the 2000 s. The objectives of this study are to describe the pre- and post-natal exposure of children to OPFRs, and to explore their possible determinants. A total of 259 children aged 3.5 years and 388 mothers from the French ELFE mother-child cohort were included. Both pre- and post-natal exposure to OPFRs were assessed, using OPFR concentrations in the hair of pregnant women (in 2011) and their 3.5-year-old children (in 2014-2015) for 15 OPFRs, of which 9 were detected in > 20 % hair samples. The highest geometric means for pre-natal exposure were 272 ng/g for tris(1-chloro-2-propyl) phosphate (TCPP), 69.7 ng/g for ng/g for triphenyl phosphate (TPP) and 54.4 ng/g for tris(1,3-dichloro-2-propyl) phosphate (TDCPP). The highest geometric means for post-natal exposure were 249.6 ng/g for TCPP, 85.3 ng/g for TDCPP and 83.8 ng/g for 2-ethylhexyl diphenyl phosphate (EHDPP). Correlations were found between both pre-natal exposures, and between pre-and post-natal exposures. No correlation was however found between pre-and post-natal exposures for any given OPFR. Pre-natal exposure to the 9 OPFRs was associated with pre-natal exposure to polybrominated diphenyl ethers 209 (BDE209), and 47 (BDE47). Maternal BMI was associated with pre-natal exposure to OPFRs other than TBEP. Home renovation work prior to birth was also associated with pre-natal exposure to OPFRs, with the exception of EHDPP, tris(2-butoxyethyl) phosphate (TBEP) and triethyl phosphate (TEP). Determinants of post-natal exposure appeared more disparate across OPFRs; although both the type of flooring in children's rooms and pre-natal exposure to polybrominated diphenyl ethers seem to be associated with post-natal exposure. Lastly, higher socioeconomic status appeared to be associated with lower exposure for several (though not all) OPFRs. The high prevalence of exposure to OPFRs suggests the need for studies to assess the health effects of OPFRs exposure, particularly on children.

Identification of insulin domains important for binding to and degradation by endosomal acidic insulinase.

The endosomal compartment of hepatic parenchymal cells contains an acidic endopeptidase, endosomal acidic insulinase (EAI), which hydrolyzes internalized insulin at a limited number of sites. Although the positions of these cleavages are partially known, the residues of insulin important in its binding to and proteolysis by EAI have not been defined. To this end, we have studied the degradation over time of native human insulin and three insulin-analog peptides using a soluble endosomal extract from rat liver parenchyma followed by purification of the products by HPLC and determination of their structure by mass spectrometry. We found variable rates of ligand processing, i.e. high ([Asp(B10)]- and [Glu(A13),Glu(B10)]-insulin), moderate (insulin) and low (the H2-analog). On the basis of IC(50) values, competition studies revealed that human and mutant insulins display nearly equivalent affinity for the EAI. Proteolysis of human and mutant insulins by EAI resulted in eight cleavages in the B-chain which occurred in the central region (Glu(B13)-Leu(B17)) and at the C-terminus (Arg(B22)-Thr(B27)), the latter region comprising the initial cleavages at Phe(B24)-Phe(B25) (major pathway) and Phe(B25)-Tyr(B26) (minor pathway) bonds. Except for the [Glu(A13),Glu(B10)]-insulin mutant, only one cleavage on the A-chain was observed at residues Gln(A15)-Leu(A16). Analysis of the nine cleavage sites showed a preference for hydrophobic and aromatic amino acid residues on both the carboxyl and amino sides of a cleaved peptide bond. Using the B-chain alone as a substrate resulted in a 30-fold increase in affinity for EAI and a 6-fold increase in the rate of hydrolysis compared with native insulin. A similar role for the C-terminal region of the B-chain of insulin in the high-affinity recognition of EAI was supported by the use of the corresponding B(22)-B(30) peptide, which displayed an increase in EAI affinity similar to the entire B-chain vs. wild-type insulin. Thus, we have identified a highly specific molecular interaction of insulin with EAI at the aromatic locus Phe(B24)-Phe(B25)-Tyr(B26). Analytical subfractionation of a postmitochondrial supernatant fraction showed that a pulse of internalized [(125)I]Tyr(A14)-H2-analog, a protease-resistant insulin analog, undergoes a greater lysosomal transfer and lesser degradation than [(125)I]Tyr(A14)-insulin, confirming that endosomal sorting is regulated directly or indirectly by endosomal proteolysis.

In vitro endosome-lysosome transfer of dephosphorylated EGF receptor and Shc in rat liver.

We have studied the endosome-lysosome transfer of internalized epidermal growth factor receptor (EGFR) complexes in a cell-free system from rat liver. Analytical subfractionation of a postmitochondrial supernatant fraction showed that a pulse of internalized [(125)I]EGF was largely associated with a light endosomal fraction devoid of lysosomal markers. After an additional 30 min incubation in vitro in the presence of an ATP-regenerating system, the amount of [(125)I]EGF in this compartment decreased by 39%, with an increase in [(125)I]EGF in lysosomes. No transfer of [(125)I]EGF to the cytosol was detected. To assess the fate of the internalized EGFR protein over the time course of the endo-lysosomal transfer of the ligand, the effect of a saturating dose of native EGF on subsequent lysosomal targeting of the EGFR was evaluated by immunoblotting. A massive translocation of the EGFR to the endosomal compartment was observed in response to ligand injection coincident with its tyrosine phosphorylation and receptor recruitment of the tyrosine-phosphorylated adaptor protein Shc. During cell-free endosome-lysosome fusion, a time-dependent increase in the content of the EGFR and the two 55- and 46-kDa Shc isoforms was observed in lysosomal fractions with a time course superimposable with the lysosomal transfer of the ligand; no transfer of the 66-kDa Shc isoform was detected. The relationship between EGFR tyrosine kinase activity and EGFR sorting in endosomes investigated by immunoblot studies with anti-phosphotyrosine antibodies revealed that endosomal dephosphorylation of EGFR and Shc preceded lysosomal transfer. These results support the view that a lysosomal targeting machinery distinct from the endosomal receptor kinase activity, such as the recruitment of the signaling molecule Shc, may regulate this sorting event in the endosome.

On associative motor learning by the cerebellar cortex: from Purkinje unit to network with variational learning rules.

This paper is an attempt to describe the ability of the cerebellar cortical network to coordinate movement on the basis of the continuous behavior of individual neural networks, the so-called "Purkinje units." The problem is considered from the point of view of a hierarchical network with two levels of organization: the level of Purkinje units including Purkinje, star and basket cells, and the level of granule cells and Golgi cells which is a network with a specific architecture. We suggest that the coordination of movements is based on a new class of learning rules between Purkinje units, called variational learning rules (VLR), which are mathematically deduced from the dynamics of a Purkinje unit. This network is driven by two functions H0 and H, defined for each Purkinje unit, which depend on external signals for this unit. Specifically, the proposed interpretation of the coordination of movement depends on three main features: (i) The definition of a unit of function, the Purkinje unit, made up of a Purkinje cell and closely associated cells and connections; (ii) a new learning rule called the "Variational Learning Rule" (VLR), operating at the level of the Purkinje units; (iii) the interpretation of the coordination of movements in terms of excitatory and inhibitory interactions between Purkinje units. An emergent property of the model is that Purkinje units occur in groups which act in opposition in the sense that when the output of one group increases, that of the other decreases.

Delay equation analysis of human respiratory stability.

A mathematical analysis of the stability in human respiration, based on the tau-decomposition method, is conducted on a simple, but realistic CO2 model of the respiratory system. This model incorporates a two-compartment representation (lungs and tissues) for the plant and a very general class of controller. By deriving an explicit stability criterion, the stability domain of the respiratory system can be characterized. We quantify the influence of four major parameters of respiratory instability, i.e. transport delay, lung volume, and equilibrium values of lung CO2 partial pressure and controller gain. We demonstrate the existence of a bifurcation point and periodic solutions, giving some characteristics of solutions near the bifurcation point.

Mathematical study of periodic breathing as an instability of the respiratory system.

A theoretical study of respiratory stability, based on a simple CO2 model of the respiratory system, investigates each component of respiration: the plant system and the central and peripheral controller systems. Analysis of the dynamic properties of the plant leads to a simplified respiratory model for the study of the influence of the central and peripheral controller components on stability. It is shown that the central component is not involved in respiratory instability phenomena such as periodic breathing whereas the peripheral component plays a major role. The explicit analytical index of stability obtained allows definition of the conditions of occurrence of periodic breathing in terms of the fundamental respiratory parameters. Moreover, this index can be used to evaluate the influence of various respiratory parameters on the stability of respiration.

On the role of anatomy in learning by the cerebellar cortex.

The properties due to the location of neurons, synapses, and possibly even synaptic channels, in neuron networks are still unknown. Our preliminary results suggest that not only the interconnections but also the relative positions of the different elements in the network are of importance in the learning process in the cerebellar cortex. We have used neural field equations to investigate the mechanisms of learning in the hierarchical neural network. The numerical resolution of these equations reveals two important properties: (i) The hierarchical structure of this network has the expected effect on learning because the flow of information at the neuronal level is controlled by the heterosynaptic effect through the synaptic density-connectivity function, i.e. the action potential field variable is controlled by the synaptic efficacy field variable at different points of the neuron. (ii) The geometry of the system involves different velocities of propagation along different fibers, i.e. different delays between cells, and thus has a stabilizing effect on the dynamics, allowing the Purkinje output to reach a given value. The field model proposed should be useful in the study of the spatial properties of hierarchical biological systems.

An algorithmic method for determining the kinetic system of receptor-channel complexes.

The mathematical study of receptor-channel kinetics involving numerous sites and conformations of the channel calls for specific analytic methods generally based on stochastic formulation in terms of Markov processes. These methods allow the determination of the number of states from the experimental data. When the number of states is known, it is necessary to try numerous kinetic diagrams to find the best one. The construction of the kinetic diagram and the corresponding kinetic system are based on physiological hypotheses. When the number of states is large, the kinetic schema becomes difficult to establish. We present a method that uses an algorithmic scheme to deduce a kinetic system directly from physiological hypotheses. This method takes into account any number of ligands and sites. The set of all the states given by the combination of site occupation and channel conformations is reduced by using two types of hypothesis: (1) molecular constraints that specify the transitions physically possible between states and (2) kinetic considerations related to the assumed physiology of the system, which gives the conditions necessary for a transition between two states. These hypotheses are expressed in terms of rules operating on the initial states of transitions. The expression of rules does not ensure their coherence (i.e., the fact that each kinetic transition is defined by one and only one rule). A mathematical condition has been found that ensures the coherence of rules. When coherence has been established, the corresponding dynamic system can be automatically generated. Because the rules are established in a systematic way and their coherence can be mathematically established, the computer implementation of this method makes it easy to test various kinetic hypotheses for problems where the number of states is large.

A mathematical analysis of intestinal peristaltic waves.

Gut motility is usually investigated by introducing probes in the intestinal lumen. Image analysis could be used instead of intraluminal pressure measurements to avoid the inconvenience of this invasive procedure. The present study exposes the theoretical principles of intestinal peristalsis in terms of indirect intraluminal pressure and content velocity measurements. A geometrical model of intestinal contractions is mathematically described by using Stokes' equations in order to evaluate velocities and pressures in the equations established by quantitative analysis of cinematography pictures. The couple velocity-pressure is calculated at each point of the geometrical model for a viscous and non-compressible fluid. This fluid flows in a geometrical structure, the boundaries of which vary with time and behave in a periodic and regular way by simulating the movements of intestinal contractions. A comparison is made between experimental pressure recordings in isolated rat intestines and pressure values calculated by utilizing the geometrical model. Velocity values calculated at every grid node show positive and negative zones in the geometrical model output. The position of these zones vary from one geometrical model to another. Moreover, the calculated pressure and velocity values change according to the applied vector efforts. The similarity of the results obtained shows the efficiency of the finite element technique in the case of Stokes' equations.

[Biological control of vectors of human and tropical diseases. Present means and prospects (author's transl)]. / Lutte biologique contre les vecteurs d'affections humaines et tropicales. Moyens actuels et perspectives.

Biological control is "direct or indirect use of natural enemies of the injurious species to increase its mortality" (W.H.O., 1963). The more and more frequent apparition of resistant insects populations, the fears as regards the environment, the increase cost of hydrocarbur products and also some technic and operational difficulties to stop transmission by the use of only insecticide pulvérisation, impose this process. Nevertheless, practic use of natural enemies of vectors is yet unusual in spite of important research. (Identification problems, dynamic of species, insufficiency of ethology knowledge particulary of the host specificity, difficulties of application on the vectors which are the most usually widely scattered). For control of insects of medical importance (mosquitoes, black flies, tse-tse flies) it has been used either pathogen agents such as virus bacteria, microsporida or parasit agents such as fungi, mermithid nematods or at last, predators, essentially larvivorus fish. Actually, no biological agent is able to take the place of chemical and physical "traditional" means. In case of mosquito control which is more advanced, the only biological mean which is operational is the use of larvivorus fish and specially Gambusia.

Age-related changes in insulin receptor mRNA and protein expression in genetically obese Zucker rats.

AIM: The mechanisms underlying the age-related decrease in insulin-receptor (IR) binding in genetically obese Zucker rats are not well understood. For this reason, the present study analyzed the expression of IR mRNA and protein in selected tissues from 1- to 4-month-old obese (fa/fa) Zucker rats and lean (Fa/-) age-matched controls. METHODS: The following parameters were evaluated: (1) IR mRNA level, and proportion of isotypes A (exon 11-) and B (exon 11+) of IR mRNA in liver, brain and kidney; (2) level, molecular size and tyrosine phosphorylation of IR-beta subunit in liver subcellular fractions; and (3) stability of liver IR based on sensitivity in vivo of insulin-binding activity and IR-beta levels in response to tunicamycin, a glycosylation inhibitor. RESULTS: At one month, IR mRNA level was increased in liver and brain, but decreased in kidneys and, at four months, both mRNA level and isotype B proportion were decreased in liver. From age two months, the following changes in liver IR protein expression were observed: (1) decreased IR-beta level in whole homogenates, but increased IR-beta levels in endosomal fractions; (2) increased IR-beta tyrosine phosphorylation; and (3) at four months, increased levels of both intact IR-beta (95 kDa) and IR-beta fragments (72 and 52 kDa) in lysosomal fractions, along with decreased stability in vivo of the IR. CONCLUSION: These data show that obese Zucker rats display age-related alterations of IR gene expression at both pre- and post-translational stages and, in particular, increased endocytosis and degradation of IR protein.

Habituation rules for a theory of the cerebellar cortex.

A quantitative model of cerebellar cortical function is described with a complete formalization based on (i) the topology of cerebellar cortical neuronal network, (ii) some particular synaptic properties of cell classes in cerebellum cortex, and (iii) the dynamics of excitation in this network. For (i), a construction of functional classes around one Purkinje cell is given and their existence is discussed. For (ii), as in Marr-Albus model, the modifiability of synapses between parallel fibres and Purkinje cell is assumed. But the formalization permits to consider the consequences of such a property at the level of glomerulus (with granule cells) which is known as a complex transformation system. For (iii) habituation rules are assumed. It is shown that this method leads to some interesting properties in the functioning of cerebellar cortex. Particularly, emitting frequency along a Purkinje cell axon results from a discrimination by the system between transformed input signals and an external "noise" due to all other "contexts," and learning could be considered as the result of a conflict between a set of patterns and the transformed input signals. This model could be a basis for future numerical simulations.

Discussion on basic equations for a flow in human air passages and their representation.

Basic equations of time-dependent flow are discussed in the case of rigid or elastic branches and according to the airway representation pattern, both continuous and discontinuous. Two relevant fundamental continuous functions are defined: the 'order of generation' G(x) and the cumulative bronchial diameter D(x). A numerical solution is outlined in the former case, then in the latter case, and the system of equations which completely describes the flow is solved.

An interpretation of asynchronism in non-sequential ventilation (apical and basal regions of the lung).

Non-sequential asynchronous ventilation is interpreted by a variation of velocity of fluid at a given level of bronchial tree based on a physical model already published (Chauvet and Tuchais, 1976). The possible different causes of this variation of velocity are examined. A complete study of apical and basal regions of the lung is made and it shows the influence of some factors (phase difference, amplitude, respiratory frequency) on the regional variations of alveolar pressure.

Non-locality in biological systems results from hierarchy. Application to the nervous system.

The concept of non-locality is deduced from a new concept for biological systems, the "functional interaction." It is shown that a biological system, which is expressed in terms of functional interactions, can be constructed as a hierarchical system, the dynamics of which are represented by a non-local field at each level of organization. The two following constraints: continuous representation of state variables and hierarchy of the system, result in non-locality, i.e., a space property according to which the system depends on mechanisms that are located elsewhere in the space. Concepts and theory are illustrated in the case of the nervous system, where two levels of organization are considered, the level of neurons and the level of synapses. Non-local versus local field operators are discussed, and an interpretation of the field equation terms is proposed. A general formulation of non-local operators for hierarchical systems is given.