Mathematical modeling of gonadotropin-releasing hormone signaling

Gonadotropin-releasing hormone (GnRH) acts via G-protein coupled receptors on pituitary gonadotropes to control reproduction. These are Gq-coupled receptors that mediate acute effects of GnRH on the exocytotic secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as the chronic regulation of their synthesis. GnRH is secreted in short pulses and GnRH effects on its target cells are dependent upon the dynamics of these pulses. Here we overview GnRH receptors and their signaling network, placing emphasis on pulsatile signaling, and how mechanistic mathematical models and an information theoretic approach have helped further this field

A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X

Background:Activated factor X (FXa) is a vitamin K-dependent serine protease that plays a pivotal role in blood coagulation by converting prothrombin to thrombin. There are no reports of humans with complete deficiency of FX, and knockout of murine F10 is embryonic or perinatal lethal. Objective:We sought to generate a viable mouse model of FX deficiency. Methods:We used a socket-targeting construct to generate F10-knockout mice by eliminating F10 exon 8 (knockout allele termed F10tm1Ccmt, abbreviated as ‘−’; wild-type ‘+’), and a plug-targeting construct to generate mice expressing a FX variant with normal antigen levels but low levels of FX activity [4–9% normal in humans carrying the defect, Pro343→Ser, termed FX Friuli (mutant allele termed F10tm2Ccmt, abbreviated as F)]. Results:F10 knockout mice exhibited embryonic or perinatal lethality. In contrast, homozygous Friuli mice [F10 (F/F)] had FX activity levels of ∼5.5% (sufficient to rescue both embryonic and perinatal lethality), but developed age-dependent iron deposition and cardiac fibrosis. Interestingly, F10 (−/F) mice with FX activity levels of 1–3% also showed complete rescue of lethality. Further study of this model provides evidence supporting a role of maternal FX transfer in the embryonic survival. Conclusions:We demonstrate that, while complete absence of FX is incompatible with murine survival, minimal FX activity as low as 1–3% is sufficient to rescue the lethal phenotype. This viable low-FX mouse model will facilitate the development of FX-directed therapies as well as investigation of the FX role in embryonic development

Quantum and Thermal Fluctuations in Field Theory

Blocking transformation is performed in quantum field theory at finite temperature. It is found that the manner temperature deforms the renormalized trajectories can be used to understand better the role played by the quantum fluctuations. In particular, it is conjectured that domain formation and mass parameter generation can be observed in theories without spontaneous symmetry breaking.Comment: 27pp+7 figures, MIT-CTP-214

Information Transfer in Gonadotropin-Releasing Hormone (GnRH) Signaling:Extracellular Signal-Regulated Kinase (ERK)-Mediated Feedback Loops Control Hormone Sensing

Cell signaling pathways are noisy communication channels, and statistical measures derived from information theory can be used to quantify the information they transfer. Here we use single cell signaling measures to calculate mutual information as a measure of information transfer via gonadotropin-releasing hormone (GnRH) receptors (GnRHR) to extracellular signal-regulated kinase (ERK) or nuclear factor of activated T-cells (NFAT). This revealed mutual information values <1 bit, implying that individual GnRH-responsive cells cannot unambiguously differentiate even two equally probable input concentrations. Addressing possible mechanisms for mitigation of information loss, we focused on the ERK pathway and developed a stochastic activation model incorporating negative feedback and constitutive activity. Model simulations revealed interplay between fast (min) and slow (min-h) negative feedback loops with maximal information transfer at intermediate feedback levels. Consistent with this, experiments revealed that reducing negative feedback (by expressing catalytically inactive ERK2) and increasing negative feedback (by Egr1-driven expression of dual-specificity phosphatase 5 (DUSP5)) both reduced information transfer from GnRHR to ERK. It was also reduced by blocking protein synthesis (to prevent GnRH from increasing DUSP expression) but did not differ for different GnRHRs that do or do not undergo rapid homologous desensitization. Thus, the first statistical measures of information transfer via these receptors reveals that individual cells are unreliable sensors of GnRH concentration and that this reliability is maximal at intermediate levels of ERK-mediated negative feedback but is not influenced by receptor desensitization

Physicochemical and rheological properties of a transparent asphalt binder modified with Nano-TiO2

Transparent binder is used to substitute conventional black asphalt binder and to provide light-colored pavements, whereas nano-TiO2 has the potential to promote photocatalytic and self-cleaning properties. Together, these materials provide multifunction effects and benefits when the pavement is submitted to high solar irradiation. This paper analyzes the physicochemical and rheological properties of a transparent binder modified with 0.5%, 3.0%, 6.0%, and 10.0% nano-TiO2 and compares it to the transparent base binder and conventional and polymer modified binders (PMB) without nano-TiO2. Their penetration, softening point, dynamic viscosity, master curve, black diagram, Linear Amplitude Sweep (LAS), Multiple Stress Creep Recovery (MSCR), and Fourier Transform Infrared Spectroscopy (FTIR) were obtained. The transparent binders (base and modified) seem to be workable considering their viscosity, and exhibited values between the conventional binder and PMB with respect to rutting resistance, penetration, and softening point. They showed similar behavior to the PMB, demonstrating signs of polymer modification. The addition of TiO2 seemed to reduce fatigue life, except for the 0.5% content. Nevertheless, its addition in high contents increased the rutting resistance. The TiO2 modification seems to have little effect on the chemical functional indices. The best percentage of TiO2 was 0.5%, with respect to fatigue, and 10.0% with respect to permanent deformation.Fundação para a Ciência e a Tecnologia—under the projects for Strategic Funding UIDB/04650/2020 and UIDB/04029/2020, and Nanobased concepts for Innovative and Eco-sustainable constructive material surfaces PTDC/FIS/120412/2010. Furthermore, we would like to thank the Industrial Research Fund (IOF) of the University of Antwerp for funding the PAPPoA project (IOF/SBO/41859/2020). Lastly, the first author would like to acknowledge FCT for the PhD scholarship (SFRH/BD/137421/2018

The fidelity of dynamic signaling by noisy biomolecular networks

This is the final version of the article. Available from Public Library of Science via the DOI in this record.Cells live in changing, dynamic environments. To understand cellular decision-making, we must therefore understand how fluctuating inputs are processed by noisy biomolecular networks. Here we present a general methodology for analyzing the fidelity with which different statistics of a fluctuating input are represented, or encoded, in the output of a signaling system over time. We identify two orthogonal sources of error that corrupt perfect representation of the signal: dynamical error, which occurs when the network responds on average to other features of the input trajectory as well as to the signal of interest, and mechanistic error, which occurs because biochemical reactions comprising the signaling mechanism are stochastic. Trade-offs between these two errors can determine the system's fidelity. By developing mathematical approaches to derive dynamics conditional on input trajectories we can show, for example, that increased biochemical noise (mechanistic error) can improve fidelity and that both negative and positive feedback degrade fidelity, for standard models of genetic autoregulation. For a group of cells, the fidelity of the collective output exceeds that of an individual cell and negative feedback then typically becomes beneficial. We can also predict the dynamic signal for which a given system has highest fidelity and, conversely, how to modify the network design to maximize fidelity for a given dynamic signal. Our approach is general, has applications to both systems and synthetic biology, and will help underpin studies of cellular behavior in natural, dynamic environments.We acknowledge support from a Medical Research Council and Engineering and Physical Sciences Council funded Fellowship in Biomedical Informatics (CGB) and a Scottish Universities Life Sciences Alliance chair in Systems Biology (PSS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Modification of a transparent binder for road pavements using TiO2 nanoparticles

Light and heat are relevant factors for road pavements since they promote the aging of the asphalt surfaces [1], and a large amount of heating can intensify the Urban Heat Island (UHI) effect [2]. Contrariwise, the lack of light strongly affects visibility conditions, reducing safety [3]. The conventional black color of asphalt pavements absorbs light and stores a large amount of thermal energy, which can be reduced opting by the application of light-colored pavements using, for example, a transparent binder [3]. Industrial activities and road traffic are the main sources of pollutant emissions, mostly SO2 and NOx, which are hazardous atmospheric pollutants. There are several consequences at different scales caused by these harmful gases, such as intensification of the greenhouse effect, acid rain, and public health problems. With the use of nano-TiO2 into/over asphalt mixtures, and consequently with the functionalization process considering the photocatalytic and self-cleaning properties, road pavements become the ideal places to mitigate environmental pollution due to proximity to the emissions [4]. If a transparent binder modified with nanoparticles of TiO2 is used, pavements will present multifunction effects and benefits when submitted to high solar irradiation. The production at laboratory-scale of such pavements is presented in Figure 1. First, the transparent binder was modified with nano-TiO2 (0, 0.5%, 3.0%, 6.0% and 10.0%). Binder's workability was confirmed. It presented similar behavior as a polymer modified binder. In these binder samples, the addition of high contents of nano-TiO2 increased the rutting resistance, but it seemed to reduce fatigue life, except for the 0.5%. Also, the nano-TiO2 modification had a slight effect on the chemical functional indices. The best percentage of TiO2 was 10.0% considering rutting resistance and 0.5% concerning fatigue life