A Statistical Approach Reveals Designs for the Most Robust Stochastic Gene Oscillators

The engineering of transcriptional networks presents many challenges due to the inherent uncertainty in the system structure, changing cellular context, and stochasticity in the governing dynamics. One approach to address these problems is to design and build systems that can function across a range of conditions; that is they are robust to uncertainty in their constituent components. Here we examine the parametric robustness landscape of transcriptional oscillators, which underlie many important processes such as circadian rhythms and the cell cycle, plus also serve as a model for the engineering of complex and emergent phenomena. The central questions that we address are: Can we build genetic oscillators that are more robust than those already constructed? Can we make genetic oscillators arbitrarily robust? These questions are technically challenging due to the large model and parameter spaces that must be efficiently explored. Here we use a measure of robustness that coincides with the Bayesian model evidence, combined with an efficient Monte Carlo method to traverse model space and concentrate on regions of high robustness, which enables the accurate evaluation of the relative robustness of gene network models governed by stochastic dynamics. We report the most robust two and three gene oscillator systems, plus examine how the number of interactions, the presence of autoregulation, and degradation of mRNA and protein affects the frequency, amplitude, and robustness of transcriptional oscillators. We also find that there is a limit to parametric robustness, beyond which there is nothing to be gained by adding additional feedback. Importantly, we provide predictions on new oscillator systems that can be constructed to verify the theory and advance design and modeling approaches to systems and synthetic biology

Automated design of gene circuits with optimal mushroom-bifurcation behavior

Recent advances in synthetic biology are enabling exciting technologies, including the next generation of biosensors, the rational design of cell memory, modulated synthetic cell differentiation, and generic multifunctional biocircuits. These novel applications require the design of gene circuits leading to sophisticated behaviors and functionalities. At the same time, designs need to be kept minimal to avoid compromising cell viability. Bifurcation theory addresses such challenges by associating circuit dynamical properties with molecular details of its design. Nevertheless, incorporating bifurcation analysis into automated design processes has not been accomplished yet. This work presents an optimization-based method for the automated design of synthetic gene circuits with specified bifurcation diagrams that employ minimal network topologies. Using this approach, we designed circuits exhibiting the mushroom bifurcation, distilled the most robust topologies, and explored its multifunctional behavior. We then outline potential applications in biosensors, memory devices, and synthetic cell differentiation

The morbidity of urethral stricture disease among male Medicare beneficiaries

<p>Abstract</p> <p>Background</p> <p>To date, the morbidity of urethral stricture disease among American men has not been analyzed using national datasets. We sought to analyze the morbidity of urethral stricture disease by measuring the rates of urinary tract infections and urinary incontinence among men with a diagnosis of urethral stricture.</p> <p>Methods</p> <p>We analyzed Medicare claims data for 1992, 1995, 1998, and 2001 to estimate the rate of dual diagnoses of urethral stricture with urinary tract infection and with urinary incontinence occurring in the same year among a 5% sample of beneficiaries. Male Medicare beneficiaries receiving co-incident ICD-9 codes indicating diagnoses of urethral stricture and either urinary tract infection or urinary incontinence within the same year were counted.</p> <p>Results</p> <p>The percentage of male patients with a diagnosis of urethral stricture who also were diagnosed with a urinary tract infection was 42% in 2001, an increase from 35% in 1992. Eleven percent of male Medicare beneficiaries with urethral stricture disease in 2001 were diagnosed with urinary incontinence in the same year. This represents an increase from 8% in 1992.</p> <p>Conclusions</p> <p>Among male Medicare beneficiaries diagnosed with urethral stricture disease in 2001, 42% were also diagnosed with a urinary tract infection, and 11% with incontinence. Although the overall incidence of stricture disease decreased over this time period, these rates of dual diagnoses increased from 1992 to 2001. Our findings shed light into the health burden of stricture disease on American men. In order to decrease the morbidity of stricture disease, early definitive management of strictures is warranted.</p

A theoretical framework for the regulation of Shh morphogen-controlled gene expression.

How morphogen gradients govern the pattern of gene expression in developing tissues is not well understood. Here, we describe a statistical thermodynamic model of gene regulation that combines the activity of a morphogen with the transcriptional network it controls. Using Sonic hedgehog (Shh) patterning of the ventral neural tube as an example, we show that the framework can be used together with the principled parameter selection technique of approximate Bayesian computation to obtain a dynamical model that accurately predicts tissue patterning. The analysis indicates that, for each target gene regulated by Gli, which is the transcriptional effector of Shh signalling, there is a neutral point in the gradient, either side of which altering the Gli binding affinity has opposite effects on gene expression. This explains recent counterintuitive experimental observations. The approach is broadly applicable and provides a unifying framework to explain the temporospatial pattern of morphogen-regulated gene expression

The estrogenicity of bisphenol A-related diphenylalkanes with various substituents at the central carbon and the hydroxy groups

This work was reported in part at the meeting Estrogens in the Environment IV: Linking Fundamental Knowledge, Risk Assessment, and Public Policy held in Washington, DC, 19-21 July 1997.The chemical structure of hydroxylated diphenylalkanes or bisphenols consists of two phenolic rings joined together through a bridging carbon. This class of endocrine disruptors that mimic estrogens is widely used in industry, particularly in plastics. Bisphenol F, bisphenol A, fluorine-containing bisphenol A (bisphenol AF), and other diphenylalkanes were found to be estrogenic in a bioassay with MCF7 human breast cancer cells in culture (E-SCREEN assay). Bisphenols promoted cell proliferation and increased the synthesis and secretion of cell type-specific proteins. When ranked by proliferative potency, the longer the alkyl substituent at the bridging carbon, the lower the concentration needed for maximal cell yield; the most active compound contained two propyl chains at the bridging carbon. Bisphenols with two hydroxyl groups in the para position and an angular configuration are suitable for appropriate hydrogen bonding to the acceptor site of the estrogen receptor. Our data suggest that estrogenicity is influenced not only by the length of the substituents at the bridging carbon but also by their nature. Because diphenylalkane derivatives are widespread and their production and use are increasing, potential exposure of humans to estrogenic bisphenols is becoming a significant issue. The hazardous effects of inadvertent exposure to bisphenol-releasing chemicals in professional workers and the general populations therefore deserve investigation.This research was supported by grants from the Spanish Ministry of Health (FIS, 95/1959) and the Andalusian Regional Government Department of Health (Consejerla de Salud, 96/159)

Vacuum Stability, Perturbativity, and Scalar Singlet Dark Matter

We analyze the one-loop vacuum stability and perturbativity bounds on a singlet extension of the Standard Model (SM) scalar sector containing a scalar dark matter candidate. We show that the presence of the singlet-doublet quartic interaction relaxes the vacuum stability lower bound on the SM Higgs mass as a function of the cutoff and lowers the corresponding upper bound based on perturbativity considerations. We also find that vacuum stability requirements may place a lower bound on the singlet dark matter mass for given singlet quartic self coupling, leading to restrictions on the parameter space consistent with the observed relic density. We argue that discovery of a light singlet scalar dark matter particle could provide indirect information on the singlet quartic self-coupling.Comment: 25 pages, 10 figures; v2 - fixed minor typos; v3 - added to text discussions of other references, changed coloring of figures for easier black and white viewin

The SPHERE view of three interacting twin disc systems in polarized light

Dense stellar environments as hosts of ongoing star formation increase the probability of gravitational encounters among stellar systems during the early stages of evolution. Stellar interaction may occur through non-recurring, hyperbolic, or parabolic passages (a so-called 'fly-by'), through secular binary evolution, or through binary capture. In all three scenarios, the strong gravitational perturbation is expected to manifest itself in the disc structures around the individual stars. Here, we present near-infrared polarized light observations that were taken with the SPHERE/IRDIS instrument of three known interacting twin-disc systems: AS 205, EM∗ SR 24, and FU Orionis. The scattered light exposes spirals likely caused by the gravitational interaction. On a larger scale, we observe connecting filaments between the stars. We analyse their very complex polarized intensity and put particular attention to the presence of multiple light sources in these systems. The local angle of linear polarization indicates the source whose light dominates the scattering process from the bridging region between the two stars. Further, we show that the polarized intensity from scattering with multiple relevant light sources results from an incoherent summation of the individuals' contribution. This can produce nulls of polarized intensity in an image, as potentially observed in AS 205. We discuss the geometry and content of the systems by comparing the polarized light observations with other data at similar resolution, namely with ALMA continuum and gas emission. Collective observational data can constrain the systems' geometry and stellar trajectories, with the important potential to differentiate between dynamical scenarios of stellar interaction

Mapping and assessment of ecosystems and their services. Urban ecosystems

Action 5 of the EU Biodiversity Strategy to 2020 requires member states to Map and Assess the state of Ecosystems and their Services (MAES). This report provides guidance for mapping and assessment of urban ecosystems. The MAES urban pilot is a collaboration between the European Commission, the European Environment Agency, volunteering Member States and cities, and stakeholders. Its ultimate goal is to deliver a knowledge base for policy and management of urban ecosystems by analysing urban green infrastructure, condition of urban ecosystems and ecosystem services. This report presents guidance for mapping urban ecosystems and includes an indicator framework to assess the condition of urban ecosystems and urban ecosystem services. The scientific framework of mapping and assessment is designed to support in particular urban planning policy and policy on green infrastructure at urban, metropolitan and regional scales. The results are based on the following different sources of information: a literature survey of 54 scientific articles, an online-survey (on urban ecosystems, related policies and planning instruments and with participation of 42 cities), ten case studies (Portugal: Cascais, Oeiras, Lisbon; Italy: Padua, Trento, Rome; The Netherlands: Utrecht; Poland: Poznań; Spain: Barcelona; Norway: Oslo), and a two-day expert workshop. The case studies constituted the core of the MAES urban pilot. They provided real examples and applications of how mapping and assessment can be organized to support policy; on top, they provided the necessary expertise to select a set of final indicators for condition and ecosystem services. Urban ecosystems or cities are defined here as socio-ecological systems which are composed of green infrastructure and built infrastructure. Urban green infrastructure (GI) is understood in this report as the multi-functional network of urban green spaces situated within the boundary of the urban ecosystem. Urban green spaces are the structural components of urban GI. This study has shown that there is a large scope for urban ecosystem assessments. Firstly, urban policies increasingly use urban green infrastructure and nature-based solutions in their planning process. Secondly, an increasing amount of data at multiple spatial scales is becoming available to support these policies, to provide a baseline, and to compare or benchmark cities with respect to the extent and management of the urban ecosystem. Concrete examples are given on how to delineate urban ecosystems, how to choose an appropriate spatial scale, and how to map urban ecosystems based on a combination of national or European datasets (including Urban Atlas) and locally collected information (e.g., location of trees). Also examples of typologies for urban green spaces are presented. This report presents an indicator framework which is composed of indicators to assess for urban ecosystem condition and for urban ecosystem services. These are the result of a rigorous selection process and ensure consistent mapping and assessment across Europe. The MAES urban pilot will continue with work on the interface between research and policy. The framework presented in this report needs to be tested and validated across Europe, e.g. on its applicability at city scale, on how far the methodology for measuring ecosystem condition and ecosystem service delivery in urban areas can be used to assess urban green infrastructure and nature-based solutions