Time-scale separation based design of biomolecular feedback controllers (extended version)

Time-scale separation is a powerful property that can be used to simplify control systems design. In this work, we consider the problem of designing biomolecular feedback controllers that provide tracking of slowly varying references and rejection of slowly varying disturbances for nonlinear systems. We propose a design methodology that uses time-scale separation to accommodate physical constraints on the implementation of integral control in cellular systems. The main result of this paper gives sufficient conditions under which controllers designed using our time-scale separation methodology have desired asymptotic performance when the reference and disturbance are constant or slowly varying. Our analysis is based on construction of Lyapunov functions for a class of singularly perturbed systems that are dependent on an additional parameter that perturbs the system regularly. When the exogenous inputs are slowly varying, this approach allows us to bound the system trajectories by a function of the regularly perturbing parameter. This bound decays to zero as the parameter's value increases, while an inner-estimate of the region of attraction stays unchanged as this parameter is varied. These results cannot be derived using standard singular perturbation results. We apply our results to an application demonstrating a physically realizable parameter tuning that controls performance.This work was supported in part by the National Science Foundation through grant NSF-CMMI 1727189

Identifiability of Chemical Reaction Networks with Intrinsic and Extrinsic Noise from Stationary Distributions

Many biological systems can be modeled as a chemical reaction network with unknown parameters. Data available to identify these parameters are often in the form of a stationary distribution, such as that obtained from measurements of a cell population. In this work, we introduce a framework for analyzing the identifiability of the reaction rate coefficients of chemical reaction networks from stationary distribution data. Working with the linear noise approximation, which is a diffusive approximation to the chemical master equation, we give a computational procedure to certify global identifiability based on Hilbert's Nullstellensatz. We present a variety of examples that show the applicability of our method to chemical reaction networks of interest in systems and synthetic biology, including discrimination between possible molecular mechanisms for the interaction between biochemical species.Comment: 27 pages, 1 figure, 1 table. The extrinsic noise section is revised, and minor edits have been made throughou

A Stein's Method Approach to the Linear Noise Approximation for Stationary Distributions of Chemical Reaction Networks

Stochastic Chemical Reaction Networks are continuous time Markov chain models that describe the time evolution of the molecular counts of species interacting stochastically via discrete reactions. Such models are ubiquitous in systems and synthetic biology, but often have a large or infinite number of states, and thus are not amenable to computation and analysis. Due to this, approximations that rely on the molecular counts and the volume being large are commonly used, with the most common being the Reaction Rate Equations and the Linear Noise Approximation. For finite time intervals, Kurtz established the validity of the Reaction Rate Equations and Linear Noise Approximation, by proving law of large numbers and central limit theorem results respectively. However, the analogous question for the stationary distribution of the Markov chain model has remained mostly unanswered, except for chemical reaction networks with special structures or bounded molecular counts. In this work, we use Stein's Method to obtain sufficient conditions for the stationary distribution of an appropriately scaled Stochastic Chemical Reaction Network to converge to the Linear Noise Approximation as the system size goes to infinity. Our results give non asymptotic bounds on the error in the Reaction Rate Equations and in the Linear Noise Approximation as applied to the stationary distribution. As a special case, we give conditions under which the global exponential stability of an equilibrium point of the Reaction Rate Equations is sufficient to obtain our error bounds, thus permitting one to obtain conclusions about the Markov chain by analyzing the deterministic Reaction Rate Equations.Comment: 24 pages, 0 figure

A rapid assay for tyrosinase activity

A rapid assay for tyrosinase activit

Determinants of low measles vaccination coverage in children living in an endemic area

Measles outbreaks were recently reported in Europe due to low immunization rates. In this scenario, identifying the reasons of no vaccination is crucial to set up strategies to improve immunization rate. A cross-sectional study was conducted to investigate the determinants of missed vaccination in children living in Southern Italy, during the 2016 outbreak. A standardized face-to-face questionnaire was used to record demographic data, immunization status, and reasons for missed vaccination. A total of 1141 children (median age 86 months, male 47.2%) was enrolled, 77.8% of the children were adequately vaccinated for age, 6.3% were incompletely vaccinated for age, and 15.9% did not receive any vaccine dose. Vaccination rate and reasons for not vaccinating significantly varied according to age, with children ≤ 24 months showing the lowest rate (67.8%). Reasons for not vaccinating included fear for side effects (51%), presence of underlying chronic conditions (12.2%), skip scheduled appointment (12.2%), refusal of vaccination (10.3%), acute illnesses (7.2%), and allergy to eggs (4.6%). The presence of underlying condition was a risk factor for inadequate immunization (p < 0.0001). Only 4.7% of conditions were true contraindications to vaccine administration. Conclusion: We reported inadequate measles immunization rate in Southern Italy, with lowest rates in children ≤ 2 years or with underlying conditions. Only a minority had true contraindications to vaccine uptake. Implementation strategies addressed to health-care professionals and families should focus on the reported determinants to increase measles vaccination coverage.What is Known:• Measles is a viral, highly communicable disease, preventable by vaccine.• Measles elimination in Europe failed as demonstrated by outbreaks in several countries, due to low immunization rates.What is New:• Inadequate measles immunization rate due to false contraindications in Southern Italy, with lowest rates in children ≤ 2 years.• The presence of underlying disease is a risk factor for inadequate immunization

Modularity in signaling systems

Modularity is a property by which the behavior of a system does not change upon interconnection. It is crucial for understanding the behavior of a complex system from the behavior of the composing subsystems. Whether modularity holds in biology is an intriguing and largely debated question. In this paper, we discuss this question taking a control system theory view and focusing on signaling systems. In particular, we argue that, despite signaling systems being constituted of structural modules, such as covalent modification cycles, modularity does not hold in general. As in any engineering system, impedance-like effects, called retroactivity, appear at interconnections and alter the behavior of connected modules. We further argue that while signaling systems have evolved sophisticated ways to counter-act retroactivity and enforce modularity, retroactivity may also be exploited to finely control the information processing of signaling pathways. Testable predictions and experimental evidence are discussed with their implications

Stigma in the context of schools: analysis of the phenomenon of stigma in a population of university students

Background Students have stereotyped views about people with mental illness. In particular, they believe that these persons are incurable, dangerous, unpredictable and responsible for their condition. This study aims to investigate the levels of public stigma in an Italian university population. Methods The Attribution Questionnaire 27 - Italian Version (AQ-27-I) was administered to a sample of students from the Faculty of Medicine and Surgery of the University of Modena and Reggio Emilia. After examining the psychometric characteristics of the AQ-27-I (Cronbach’s Alpha and Confirmatory Factor Analysis), multiple linear regression analyses were carried out to identify the predictors of stigmatizing attitudes in this population. Results Three hundred and eleven students completed the questionnaire, with a response rate of 32.81 % (out of the 948 contacted by email). The AQ-27-I showed good psychometric properties with an α = .68, and the fit indices of the models that partially supported the factor structure and paths. The two variables identified as possible predictors of stigmatizing attitudes (total score of AQ-27-I) were age and time spent reading newspapers. Conclusions Antistigma campaigns are needed in university contexts, targeted in particular to students in health professions

Skull Base Fungal Osteomyelitis: A Case Report and Review of the Literature

Skull base osteomyelitis (SBO) is an invasive infection refractory to therapy, closely linked with malignant otitis externa (MOE). It is characterized by a mild clinical presentation that can delay cross-sectional imaging considered as the key to revealing it. Skull base osteomyelitis typically affects elderly diabetics and immunocompromised patients (>70 years). It most commonly has an otogenic origin due to an extension of MOE. The prognosis can be very poor without the administration of adequate and timely therapy at an early disease stage. Nowadays, Pseudomonas aeruginosa remains the most common pathogen associated with SBO. Fungi are a rare cause of MOE. This report documents a rare case of otogenic SBO caused by Candida parapsilosis in a diabetic patient, with persistent otologic symptoms as clinical onset and resistance to medical treatment. Fungal MOE has more subtle symptoms and is more aggressive than its bacterial counterpart. When MOE is resistant to antibacterial drugs, this should raise the suspicion of a fungal etiology of MOE. The current guidelines do not exhaustively describe the diagnosis, antifungal drugs of choice, and optimum duration of treatment. The description of these rare clinical cases should help with the multidisciplinary management of this disease in order to optimize the diagnosis and therapeutic protocol

Empowerment and satisfaction in a multinational study of routine clinical practice

Objective: Decision-making between mental health clinicians and patients is under-researched. We tested whether mental health patients are more satisfied with a decision made (i) using their preferred decision-making style and (ii) with a clinician with the same decision-making style preference. Method: As part of the CEDAR Study (ISRCTN75841675), a convenience sample of 445 patients with severe mental illness from six European countries were assessed for desired clinical decision-making style (rated by patients and paired clinicians), decision-specific experienced style and satisfaction. Results: Patients who experienced more involvement in decision-making than they desired rated higher satisfaction (OR = 2.47, P = 0.005, 95% CI 1.32–4.63). Decisions made with clinicians whose decision-making style preference was for more active involvement than the patient preference were rated with higher satisfaction (OR = 3.17, P = 0.003, 95% CI 1.48–6.82). Conclusion: More active involvement in decision-making than the patient stated as desired was associated with higher satisfaction. A clinical orientation towards empowering, rather than shared, decision-making may maximise satisfaction

Triple Michelson Interferometer for a Third-Generation Gravitational Wave Detector

The upcoming European design study `Einstein gravitational-wave Telescope' represents the first step towards a substantial, international effort for the design of a third-generation interferometric gravitational wave detector. It is generally believed that third-generation instruments might not be installed into existing infrastructures but will provoke a new search for optimal detector sites. Consequently, the detector design could be subject to fewer constraints than the on-going design of the second generation instruments. In particular, it will be prudent to investigate alternatives to the traditional L-shaped Michelson interferometer. In this article, we review an old proposal to use three Michelson interferometers in a triangular configuration. We use this example of a triple Michelson interferometer to clarify the terminology and will put this idea into the context of more recent research on interferometer technologies. Furthermore the benefits of a triangular detector will be used to motivate this design as a good starting point for a more detailed research effort towards a third-generation gravitational wave detector.Comment: Minor corrections to the main text and two additional appendices. 14 pages, 6 figure