Identification and Modeling of Sensory Feedback Processing in a Brain System for Voluntary Movement Control

The body shows impressive control capabilities in terms of the speed and the precision with which movements can be carried out under a wide variety of circumstances. The cerebellum and brainstem nuclei, including the cuneate nucleus, are believed to play a crucial role in this control. If these control mechanisms can be unveiled, this could yield important insights in not only medicine and neurophysiology, but could also control theory in general, which could then potentially be applied in a variety of industry-based control applications. In this thesis system identification and modeling of one subsystem is considered: the cuneate nucleus. The aim of this project is to create a quantitative model for control of a network of neurons in this structure and to create a detailed single-cell model of the cuneate neuron. A two-pronged approach is used to study the function of this structure. First a black-box like system identification using Matlab with experimental data as in- and output signals is considered. Then, building on a previously developed Scicos neuron model, a detailed neuron model of one cuneate neuron is developed, incorporating many aspects of recently described cellular neurophysiology. Our findings suggest that the cuneate nucleus acts as filter for its input sensory signal, applying a differentiating and phase-lead effect on the transmitted signal. These are interesting features of a control system, and could help understand how the body can attain such a high degree of precision in its movements

Design, modeling and synthesis of an in vitro transcription rate regulatory circuit

This paper describes the design, modeling and realization of a synthetic in vitro circuit that aims at regulating the rate of mRNA transcription. Two DNA templates are designed to interact through their transcripts, creating negative feedback loops that will equate their transcription rates at steady state. A mathematical model is developed for this circuit, consisting of a set of ODEs derived from the mass action laws and Michaelis-Menten kinetics involving all the present chemical species. The DNA strands were accordingly designed, following thermodynamics principles and minimizing unwanted interactions. Preliminary experimental results show that the circuit is performing the expected task, by matching at steady state the transcription rates of the two DNA templates

Design, modeling and synthesis of an in vitro transcription rate regulatory circuit

Abstract-This paper describes the design, modeling and realization of a synthetic in vitro circuit that aims at regulating the rate of mRNA transcription. Two DNA templates are designed to interact through their transcripts, creating negative feedback loops that will equate their transcription rates at steady state. A mathematical model is developed for this circuit, consisting of a set of ODEs derived from the mass action laws and Michaelis-Menten kinetics involving all the present chemical species. The DNA strands were accordingly designed, following thermodynamics principles and minimizing unwanted interactions. Preliminary experimental results show that the circuit is performing the expected task, by matching at steady state the transcription rates of the two DNA templates

Negative autoregulation matches production and demand in synthetic transcriptional networks

We propose a negative feedback architecture that regulates activity of artificial genes, or “genelets”, to meet their output downstream demand, achieving robustness with respect to uncertain open-loop output production rates. In particular, we consider the case where the outputs of two genelets interact to form a single assembled product. We show with analysis and experiments that negative autoregulation matches the production and demand of the outputs: the magnitude of the regulatory signal is proportional to the “error” between the circuit output concentration and its actual demand. This two-device system is experimentally implemented using in vitro transcriptional networks, where reactions are systematically designed by optimizing nucleic acid sequences with publicly available software packages. We build a predictive ordinary differential equation (ODE) model that captures the dynamics of the system and can be used to numerically assess the scalability of this architecture to larger sets of interconnected genes. Finally, with numerical simulations we contrast our negative autoregulation scheme with a cross-activation architecture, which is less scalable and results in slower response times

Causal nature of neighborhood deprivation on individual risk of coronary heart disease or ischemic stroke : A prospective national Swedish co-relative control study in men and women

We studied the association between neighborhood socioeconomic status (SES) and incidence of coronary heart disease (CHD) or ischemic stroke in the total population and in full- and half-siblings to determine whether these associations are causal or a result from familial confounding. Data were retrieved from nationwide Swedish registers containing individual clinical data linked to neighborhood of residence. After adjustment for individual SES, the association between neighborhood SES and CHD showed no decrease with increasing genetic resemblance, particularly in women. This indicates that the association between neighborhood SES and CHD incidence is partially causal among women, which represents a novel finding

Workplace socioeconomic characteristics and coronary heart disease: a nationwide follow-up study

Objectives Important gaps in previous research include a lack of studies on the association between socioeconomic characteristics of the workplace and coronary heart disease (CHD).We aimed to examine two contextual factors in association with individuals’ risk of CHD: the mean educational level of all employees at each individual’s workplace (educationwork) and the neighbourhood socioeconomic characteristics of each individual’s workplace (neighbourhood SESwork).Design Nationwide follow-up/cohort study.Setting Nationwide data from Sweden.Participants All individuals born in Sweden from 1943 to 1957 were included (n=1 547 818). We excluded individuals with a CHD diagnosis prior to 2008 (n=67 619), individuals without workplace information (n=576 663), individuals lacking residential address (n=4139) and individuals who had unknown parents (n=7076). A total of 892 321 individuals were thus included in the study (426 440 men and 465 881 women).Primary and secondary outcome measures The outcome variable was incident CHD during follow-up between 2008 and 2012. The association between educationwork and neighbourhood SESwork and the outcome was explored using multilevel and cross-classified logistic regression models to determine ORs and 95% CIs, with individuals nested within workplaces and neighbourhoods. All models were conducted in both men and women and were adjusted for age, income, marital status, educational attainment and neighbourhood SESresidence.Results Low (vs high) educationwork was significantly associated with increased CHD incidence for both men (OR 1.29, 95% CI 1.23 to 1.34) and women (OR 1.38, 95% CI 1.29 to 1.47) and remained significant after adjusting for potential confounders. These findings were not replicable for the variable neighbourhood SESwork.Conclusions Workplace socioeconomic characteristics, that is, the educational attainment of an individual’s colleagues, may influence CHD risk, which represents new knowledge relevant to occupational health management at workplaces

Neighborhood socioeconomic characteristics and statin medication in patients with myocardial infarction : A Swedish nationwide follow-up study

Background: Coronary heart disease (CHD) and myocardial infarction (MI) are associated with neighborhood-level socioeconomic status (SES). Statins are important drugs for secondary prevention of MI. However, no study has determined whether neighborhood-level SES is associated with statin medication in MI patients. We aimed to determine whether there is a difference in statin medication rate in MI patients across different levels of neighborhood SES. Methods: All patients in Sweden, diagnosed with incident MI from January 1st, 2000 until December 31st 2010, were followed (n = 116,840). Of these, 89.7 % received statin medication. Data were analyzed by multilevel logistic regression, with individual-level characteristics (age, marital status, family income, educational attainment, country of origin, urban/rural status and comorbidities/chronic conditions related to MI) as covariates. Results: Low neighborhood-level SES was significantly associated with low statin medication rate (Odds Ratio 0.80). In the full model, which took into account individual-level socioeconomic characteristics and MI comorbidities, the odds no longer remained significant. Conclusions: Individual-level approaches may be most important in health care policies regarding statin medication in MI patients

Design, modeling and synthesis of an in vitro transcription rate regulatory circuit

Abstract-This paper describes the design, modeling and realization of a synthetic in vitro circuit that aims at regulating the rate of mRNA transcription. Two DNA templates are designed to interact through their transcripts, creating negative feedback loops that will equate their transcription rates at steady state. A mathematical model is developed for this circuit, consisting of a set of ODEs derived from the mass action laws and Michaelis-Menten kinetics involving all the present chemical species. The DNA strands were accordingly designed, following thermodynamics principles and minimizing unwanted interactions. Preliminary experimental results show that the circuit is performing the expected task, by matching at steady state the transcription rates of the two DNA templates