Computational modelling of placental amino acid transfer as an integrated system

AbstractPlacental amino acid transfer is essential for fetal development and its impairment is associated with poor fetal growth. Amino acid transfer is mediated by a broad array of specific plasma membrane transporters with overlapping substrate specificity. However, it is not fully understood how these different transporters work together to mediate net flux across the placenta. Therefore the aim of this study was to develop a new computational model to describe how human placental amino acid transfer functions as an integrated system. Amino acid transfer from mother to fetus requires transport across the two plasma membranes of the placental syncytiotrophoblast, each of which contains a distinct complement of transporter proteins. A compartmental modelling approach was combined with a carrier based modelling framework to represent the kinetics of the individual accumulative, exchange and facilitative classes of transporters on each plasma membrane. The model successfully captured the principal features of transplacental transfer. Modelling results clearly demonstrate how modulating transporter activity and conditions such as phenylketonuria, can increase the transfer of certain groups of amino acids, but that this comes at the cost of decreasing the transfer of others, which has implications for developing clinical treatment options in the placenta and other transporting epithelia

Computational modelling of amino acid exchange and facilitated transport in placental membrane vesicles

AbstractPlacental amino acid transport is required for fetal development and impaired transport has been associated with poor fetal growth. It is well known that placental amino acid transport is mediated by a broad array of specific membrane transporters with overlapping substrate specificity. However, it is not fully understood how these transporters function, both individually and as an integrated system. We propose that mathematical modelling could help in further elucidating the underlying mechanisms of how these transporters mediate placental amino acid transport.The aim of this work is to model the sodium independent transport of serine, which has been assumed to follow an obligatory exchange mechanism. However, previous amino acid uptake experiments in human placental microvillous plasma membrane vesicles have persistently produced results that are seemingly incompatible with such a mechanism; i.e. transport has been observed under zero-trans conditions, in the absence of internal substrates inside the vesicles to drive exchange. This observation raises two alternative hypotheses; (i) either exchange is not fully obligatory, or (ii) exchange is indeed obligatory, but an unforeseen initial concentration of amino acid substrate is present within the vesicle which could drive exchange.To investigate these possibilities, a mathematical model for tracer uptake was developed based on carrier mediated transport, which can represent either facilitated diffusion or obligatory exchange (also referred to as uniport and antiport mechanisms, respectively). In vitro measurements of serine uptake by placental microvillous membrane vesicles were carried out and the model applied to interpret the results based on the measured apparent Michaelis–Menten parameters Km and Vmax. In addition, based on model predictions, a new time series experiment was implemented to distinguish the hypothesised transporter mechanisms. Analysis of the results indicated the presence of a facilitated transport component, while based on the model no evidence for substantial levels of endogenous amino acids within the vesicle was found

Model Analysis of Time Reversal Symmetry Test in the Caltech Fe-57 Gamma-Transition Experiment

The CALTECH gamma-transition experiment testing time reversal symmetry via the E2/M1 mulipole mixing ratio of the 122 keV gamma-line in Fe-57 has already been performed in 1977. Extending an earlier analysis in terms of an effective one-body potential, this experiment is now analyzed in terms of effective one boson exchange T-odd P-even nucleon nucleon potentials. Within the model space considered for the Fe-57 nucleus no contribution from isovector rho-type exchange is possible. The bound on the coupling strength phi_A from effective short range axial-vector type exchange induced by the experimental bound on sin(eta) leads to phi_A < 10^{-2}.Comment: 5 pages, RevTex 3.

Effective magnetic dipole operators for 88^{\bf 88}Sr and 90^{\bf 90}Zr closed-shell cores

Core-polarisation and meson-exchange current calculations have been performed at $^{88}$Sr and $^{90}$Zr closed-shell cores to determine the effective magnetic dipole operator for valence orbitals. The values obtained show considerable core- and orbit-dependency. The results are tested in shell-model calculations for magnetic moments in $N$=50 and $N$=51 nuclides and the comparison with experiment is satisfactory

Effective charges for 88^{88}Sr and 90^{90}Zr closed-shell cores

Effective charges are calculated for protons and neutrons in the region of mass 90. It is found that their magnitudes differ appreciably depending on whether the proton $p_{1/2}$ shell is empty or full. The calculated values are compared with values deduced from nuclei with simple configurations, and from a fit to N=50 data. The empirical values are used in shell-model calculations of quadrupole moments of N=50-58 nuclei

Charge-independent effective interactions for shell-model studies in the 0g9/2−1p1/2{0g_{9/2}{-}1p_{1/2}} space

The matrix elements of the effective Hamiltonian in the $0g_{9/2}{-}1p_{1/2}$ space are determined by a least-square fit to the energies of 477 levels of nuclei with $38\le Z \le 50$ and $47 \le N \le 50$. The results of the calculation are found to be in better agreement with experiment than those obtained with previously determined interactions

Testosterone and androstenedione profiles in the blood of domestic tom-cats

Testosterone and androstenedione were measured in the blood of four mature, intact tom-cats. Samples were collected from an indwelling jugular catheter once an hour for 24 h, and at more frequent intervals after a number of experimental procedures. Testosterone and androstenedione concentrations have a pattern of episodic release over a 24-h period but no diurnal rhythm was evident. The range of testosterone concentration was 0-23.5 ng/ml and androstenedione concentration 0-35.7 ng/ml. There was evidence of some seasonal influence on testosterone concentration, it being low in the period of reduced sexual activity (Jan-March) and high in the period of peak sexual activity (Aug). Sexual stimulation did not cause a rise in testosterone concentration as it was already high, but androstenedione concentration was significantly increased. Castration produced an immediate decrease in testosterone to baseline concentrations of 0-0.5 ng/ml but the concentration of androstenedione was variable and it is probable that a substantial amount of androstenedione is contributed from another source (possibly from the adrenals)

DNS of aircraft wake vortices: the effect of stable stratification on the development of the Crow instability

A numerical experiment is performed to determine the likelihood that the Crow instability will mitigate the potentially hazardous effects of the buoyancy-induced rebound of initially parallel line vortices. Parameters are chosen to correspond to wake vortices downstream of an elliptically loaded wing with large span (typical of the A380) landing in very stable conditions. The DNS is initiated by perturbing the vortex pair into the shape of the linearly most unstable Crow eigenmode, with a maximum displacement of 1% of the initial distance between the pair. Under these conditions, the Crow instability progresses fast enough to break the two dimensionality of the vortex system before it returns to its original elevation. This suggests that in many cases the Crow instability will prevent the rebounding vorticity from being a serious danger to following aircraft. Whether or not this will always happen in practice is an open question, requiring further investigatio

Computational modelling of placental amino acid transfer as an integrated system

Placental amino acid transfer is essential for fetal development and its impairment is associated with poor fetal growth. Amino acid transfer is mediated by a broad array of specific plasma membrane transporters with overlapping substrate specificity. However, it is not fully understood how these different transporters work together to mediate net flux across the placenta. Therefore the aim of this study was to develop a new computational model to describe how human placental amino acid transfer functions as an integrated system. Amino acid transfer from mother to fetus requires transport across the two plasma membranes of the placental syncytiotrophoblast, each of which contains a distinct complement of transporter proteins. A compartmental modelling approach was combined with a carrier based modelling framework to represent the kinetics of the individual accumulative, exchange and facilitative classes of transporters on each plasma membrane. The model successfully captured the principal features of transplacental transfer. Modelling results clearly demonstrate how modulating transporter activity and conditions such as phenylketonuria, can increase the transfer of certain groups of amino acids, but that this comes at the cost of decreasing the transfer of others, which has implications for developing clinical treatment options in the placenta and other transporting epithelia