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

Addendum to "Superimposed Oscillations in the WMAP Data?"

We elaborate further on the possibility that the inflationary primordial power spectrum contains superimposed oscillations. We study various effects which could influence the calculation of the multipole moments in this case. We also present the theoretical predictions for two other cosmological observables, the matter power spectrum and the EE polarization channel.Comment: 4 pages, 3 figures, uses RevTex4, matches published versio

Tuning out vibrational levels in molecular electron energy-loss spectra

The phenomenon whereby features associated with certain vibrational levels in molecular states of mixed electronic character disappear under specific scattering conditions in electron energy-loss spectra is investigated. In particular, using a combination of experimental measurements and coupled-channel calculations, anomalous vibrational intensities in the mixed valence-Rydberg 1Π u←X1Σg+ transition of N 2 are explained. A single parameter, i.e., the ratio of the generalized electronic transition moments to the diabatic valence and Rydberg components of the mixed states, dependent on the experimental scattering conditions, is found to be essentially capable of describing all observed relative vibrational intensities, including the near disappearance of the b1Π u(v=5) feature for momentum-transfer-squared values K2 ≈ 0.3 a.u. This result highlights the interesting possibility of experimental control of molecular quantum-interference effects in electron energy-loss spectra, something that is not possible in optical spectra

The effect of oxygenate fuels on PN emissions from a highly boosted GDI engine

Gasoline Direct Injection (GDI) engines are increasingly available in the market. Such engines are known to emit more Particulate Matter (PM) than their port-fuel injected predecessors. There is also a widespread use of oxygenate fuels in the market, up to blends of E85, and their impact on PN emissions is widely studied. However the impact of oxygenate fuels on PN emissions from downsized, and hence highly-boosted engines is not known. In this work, PN emissions from a highly boosted engine capable of running at up to 35 bar Brake Mean Effective Pressure (BMEP) have been measured from a baseline gasoline and three different oxygenate fuels (E20, E85, and GEM – a blend of gasoline, ethanol, and methanol) using a DMS500. The engine has been run at four different operating points, and a number of engine parameters relevant to highly-boosted engines (such as EGR, exhaust back pressure, and lambda) have been tested – the PN emissions and size distributions have been measured from all of these. The results show that the oxygenate content of the fuel has a very large impact on its PN emissions, with E85 giving low levels of PN emissions across the operating range, and GEM giving very low and extremely high levels of PN emissions depending on operating point. These results have been analysed and related back to key fuel properties

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

Strong Gravitational Lensing and Dark Energy Complementarity

In the search for the nature of dark energy most cosmological probes measure simple functions of the expansion rate. While powerful, these all involve roughly the same dependence on the dark energy equation of state parameters, with anticorrelation between its present value w_0 and time variation w_a. Quantities that have instead positive correlation and so a sensitivity direction largely orthogonal to, e.g., distance probes offer the hope of achieving tight constraints through complementarity. Such quantities are found in strong gravitational lensing observations of image separations and time delays. While degeneracy between cosmological parameters prevents full complementarity, strong lensing measurements to 1% accuracy can improve equation of state characterization by 15-50%. Next generation surveys should provide data on roughly 10^5 lens systems, though systematic errors will remain challenging.Comment: 7 pages, 5 figure

Integration of computational modeling with membrane transport studies reveals new insights into amino acid exchange transport mechanisms

Uptake of system L amino acid substrates into isolated placental plasma membrane vesicles in the absence of opposing side amino acid (zero-trans uptake) is incompatible with the concept of obligatory exchange, where influx of amino acid is coupled to efflux. We therefore hypothesized that system L amino acid exchange transporters are not fully obligatory and/or that amino acids are initially present inside the vesicles. To address this, we combined computational modeling with vesicle transport assays and transporter localization studies to investigate the mechanism(s) mediating [14C]L-serine (a system L substrate) transport into human placental microvillous plasma membrane (MVM) vesicles. The carrier model provided a quantitative framework to test the 2 hypotheses that L-serine transport occurs by either obligate exchange or nonobligate exchange coupled with facilitated transport (mixed transport model). The computational model could only account for experimental [14C]L-serine uptake data when the transporter was not exclusively in exchange mode, best described by the mixed transport model. MVM vesicle isolates contained endogenous amino acids allowing for potential contribution to zero-trans uptake. Both L-type amino acid transporter (LAT)1 and LAT2 subtypes of system L were distributed to MVM, with L-serine transport attributed to LAT2. These findings suggest that exchange transporters do not function exclusively as obligate exchangers.—Widdows, K. L., Panitchob, N., Crocker, I. P., Please, C. P., Hanson, M. A., Sibley, C. P., Johnstone, E. D., Sengers, B. G., Lewis, R. M., Glazier, J. D. Integration of computational modeling with membrane transport studies reveals new insights into amino acid exchange transport mechanisms

Spatial Periodicity of Galaxy Number Counts, CMB Anisotropy, and SNIa Hubble Diagram Based on the Universe Accompanied by a Non-Minimally Coupled Scalar Field

We have succeeded in establishing a cosmological model with a non-minimally coupled scalar field $\phi$ that can account not only for the spatial periodicity or the {\it picket-fence structure} exhibited by the galaxy $N$-$z$ relation of the 2dF survey but also for the spatial power spectrum of the cosmic microwave background radiation (CMB) temperature anisotropy observed by the WMAP satellite. The Hubble diagram of our model also compares well with the observation of Type Ia supernovae. The scalar field of our model universe starts from an extremely small value at around the nucleosynthesis epoch, remains in that state for sufficiently long periods, allowing sufficient time for the CMB temperature anisotropy to form, and then starts to grow in magnitude at the redshift $z$ of $\sim 1$, followed by a damping oscillation which is required to reproduce the observed picket-fence structure of the $N$-$z$ relation. To realize such behavior of the scalar field, we have found it necessary to introduce a new form of potential $V(\phi)\propto \phi^2\exp(-q\phi^2)$, with $q$ being a constant. Through this parameter $q$, we can control the epoch at which the scalar field starts growing.Comment: 19 pages, 18 figures, Accepted for publication in Astrophysics & Space Scienc

A framework for assessing clinical trial site readiness

Clinical trial processes are unnecessarily inefficient and costly, slowing the translation of medical discoveries into treatments for people living with disease. To reduce redundancies and inefficiencies, a group of clinical trial experts developed a framework for clinical trial site readiness based on existing trial site qualifications from sponsors. The site readiness practices are encompassed within six domains: research team, infrastructure, study management, data collection and management, quality oversight, and ethics and safety. Implementation of this framework for clinical trial sites would reduce inefficiencies in trial conduct and help prepare new sites to enter the clinical trials enterprise, with the potential to improve the reach of clinical trials to underserved communities. Moreover, the framework holds benefits for trial sponsors, contract research organizations, trade associations, trial participants, and the public. For novice sites considering future trials, we provide a framework for site preparation and the engagement of stakeholders. For experienced sites, the framework can be used to assess current practices and inform and engage sponsors, staff, and participants. Details in the supplementary materials provide easy access to key regulatory documents and resources. Invited perspective articles provide greater depth from a systems, DEIA (diversity, equity, inclusion, and accessibility) and decentralized trials perspective