Hybrid Control of a Bioreactor with Quantized Measurements: Extended Version

We consider the problem of global stabilization of an unstable bioreactor model (e.g. for anaerobic digestion), when the measurements are discrete and in finite number ("quantized"), with control of the dilution rate. The model is a differential system with two variables, and the output is the biomass growth. The measurements define regions in the state space, and they can be perfect or uncertain (i.e. without or with overlaps). We show that, under appropriate assumptions, a quantized control may lead to global stabilization: trajectories have to follow some transitions between the regions, until the final region where they converge toward the reference equilibrium. On the boundary between regions, the solutions are defined as a Filippov differential inclusion. If the assumptions are not fulfilled, sliding modes may appear, and the transition graphs are not deterministic

Modeling and Estimation of Biological Plants

Estimating the state of a dynamic system is an essential task for achieving important objectives such as process monitoring, identification, and control. Unlike linear systems, no systematic method exists for the design of observers for nonlinear systems. Although many researchers have devoted their attention to these issues for more than 30 years, there are still many open questions. We envisage that estimation plays a crucial role in biology because of the possibility of creating new avenues for biological studies and for the development of diagnostic, management, and treatment tools. To this end, this thesis aims to address two types of nonlinear estimation techniques, namely, the high-gain observer and the moving-horizon estimator with application to three different biological plants. After recalling basic definitions of stability and observability of dynamical systems and giving a bird's-eye survey of the available state estimation techniques, we are interested in the high-gain observers. These observers may be used when the system dynamics can be expressed in specific a coordinate under the so-called observability canonical form with the possibility to assign the rate of convergence arbitrarily by acting on a single parameter called the high-gain parameter. Despite the evident benefits of this class of observers, their use in real applications is questionable due to some drawbacks: numerical problems, the peaking phenomenon, and high sensitivity to measurement noise. The first part of the thesis aims to enrich the theory of high-gain observers with novel techniques to overcome or attenuate these challenging performance issues that arise when implementing such observers. The validity and applicability of our proposed techniques have been shown firstly on a simple one-gene regulatory network, and secondly on an SI epidemic model. The second part of the thesis studies the problem of state estimation using the moving horizon approach. The main advantage of MHE is that information about the system can be explicitly considered in the form of constraints and hence improve the estimates. In this work, we focus on estimation for nonlinear plants that can be rewritten in the form of quasi-linear parameter-varying systems with bounded unknown parameters. Moving-horizon estimators are proposed to estimate the state of such systems according to two different formulations, i.e., "optimistic" and "pessimistic". In the former case, we perform estimation by minimizing the least-squares moving-horizon cost with respect to both state variables and parameters simultaneously. In the latter, we minimize such a cost with respect to the state variables after picking up the maximum of the parameters. Under suitable assumptions, the stability of the estimation error given by the exponential boundedness is proved in both scenarios. Finally, the validity of our obtained results has been demonstrated through three different examples from biological and biomedical fields, namely, an example of one gene regulatory network, a two-stage SI epidemic model, and Amnioserosa cell's mechanical behavior during Dorsal closure

Quantitative and systems pathology for therapeutic response prediction

The measurement of tissue biomarkers for therapeutic response prediction in cancer patients has become standard pathological practice, but only for a very limited number of targets. This is in spite of massive intellectual and financial investment in molecular pathology for translational cancer research. A re-evaluation of current approaches, and the testing of new ones, is required in order to meet the challenges of predicting responses to existing and novel therapeutics, and individualising therapy.Herein I critique the current state of tissue biomarker analysis and quantification in cancer pathology and the reasons why so few novel biomarkers have entered the clinic. In particular, we examine the central role of signalling pathway biology in sensitivity and resistance to targeted therapy. I discuss how accurate quantification, and the ability to simulate biological responses over time and space, may lead to more accurate prediction of therapeutic response. I propose that different mathematical techniques used in the nascent field of systems biology (ordinary differential equation-based, S-systems, and Bayesian approaches) may provide promising new avenues to improve prediction in clinical and pathological practice. I also discuss the challenges and opportunities for quantification in pathological research and practice.I have examined the role of cellular signalling pathways in therapeutic sensitivity and resistance in three different ways. Firstly, I have taken a hypothesis-driven and reductionist approach and shown that decreased Sprouty 2, a feedback inhibitor of MAPK and PI3K signalling, is associated with trastuzumab-resistance in vitro and in a cohort of breast cancer patients treated with trastuzumab. Secondly, I have characterised the activation state of ten growth and survival pathways across different histological subtypes of ovarian cancer using quantitative fluorescence microscopy. I have shown that unsupervised clustering of phosphoprotein expression profiles results in new subgroups with distinct biological properties (in terms of proliferation and apoptosis), and which predict therapeutic response to chemotherapy. Thirdly, I have developed a new mathematical model of PI3K signalling, parameterised using quantitative phosphoprotein expression data from cancer cell lines using reverse-phase protein microarrays, and shown that quantitative PTEN protein expression is the key determinant of resistance to anti-HER2 therapy in silico. Furthermore, the quantitative measurement of PTEN is more predictive of response than other pathway components taken in isolation and when tested by multivariate analysis in a cohort of breast cancers treated with trastuzumab. For the first time, a systems biology approach has successfully been used to stratify patients for personalised therapy in cancer, and is further compelling evidence that PTEN, appropriately measured in the clinical setting, refines clinical decision-making in patients treated with anti-HER2 therapies

Harnessing Openness to Transform American Health Care

The Digital Connections Council (DCC) of the Committee for Economic Development (CED) has been developing the concept of openness in a series of reports. It has analyzed information and processes to determine their openness based on qualities of "accessibility" and "responsiveness." If information is not available or available only under restrictive conditions it is less accessible and therefore less "open." If information can be modified, repurposed, and redistributed freely it is more responsive, and therefore more "open." This report looks at how "openness" is being or might usefully be employed in the healthcare arena. This area, which now constitutes approximately 16-17 percent of GDP, has long frustrated policymakers, practitioners, and patients. Bringing greater openness to different parts of the healthcare production chain can lead to substantial benefits by stimulating innovation, lowering costs, reducing errors, and closing the gap between discovery and treatment delivery. The report is not exhaustive; it focuses on biomedical research and the disclosure of research findings, processes of evaluating drugs and devices, the emergence of electronic health records, the development and implementation of treatment regimes by caregivers and patients, and the interdependence of the global public health system and data sharing and worldwide collaboration

India and the multilateral trading system after Seattle - toward a proactive role

The authors argue that India should engage more actively in the multilateral trading system for four reasons: First, such engagement could facilitate domestic reform, and improve access to export markets. If the government could show that domestic reform would pay off with increased access to markets abroad, those who gain from such access - whether they export textiles, software, professional services, or other products - could represent a countervailing voice to reform's opponents. In turn, the need for this external payoff to secure domestic reform makes India a credible bargainer, which could induce trading partners, to open their markets to India. Second, external commitments can foster good domestic policies, by providing guarantees against the reversal of current policies, or lending credibility to promises of future reform. Such pre-commitments could help strike a balance between the reluctance to unleash competition immediately, and the desire not to be held perpetual hostage to vested interests, or weak domestic industries. Third, engagement can help enforce India's market access rights. If other countries do not eliminate quotas on textiles, and clothing as scheduled, India can credibly threaten to withdraw its obligations under the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPs). Fourth, multilateral tariff reduction could reduce the disadvantage (to India) of not being part of regional agreements. The value of multilateral engagement might be limited, if the prospects for securing increased market access are dim, as the failed Seattle negotiations might appear to suggest. India must credibly test negotiating pessimism by showing its willingness to open its markets in return for improved access to foreign markets. Success is not certain, but India's chances are improved if aligns itself with countries pressing for sound policies of open trade.Environmental Economics&Policies,Labor Policies,Economic Theory&Research,Rules of Origin,ICT Policy and Strategies,TF054105-DONOR FUNDED OPERATION ADMINISTRATION FEE INCOME AND EXPENSE ACCOUNT,Environmental Economics&Policies,Economic Theory&Research,Trade and Regional Integration,ICT Policy and Strategies

A robust LMI approach on nonlinear feedback stabilization of continuous state-delay systems with Lipschitzian nonlinearities : experimental validation

This paper suggests a novel nonlinear state-fe edback stabilization control law using linear matrix inequalities for a class oftime-delayed nonlinear dynamic systems with Lipschitz nonlinearity conditions. Based on the Lyapunov–Krasovskiistability theory, the asymptotic stabilization criterion is derived in the linear matrix inequality form and the coef¿cients ofthe nonlinear state-feedback controller are determined. Meanwhile, an appropriate criterion to ¿nd the proper feedbackgain matrix F is also provided. The robustness purpose against nonlinear functions and time delays is guaranteed in thisscheme. Moreover , the problem of robust H!performance analysis for a class of nonlinear time-delayed system s withexternal disturbance is studied in this paper. Simulations are presented to demonstrate the pro¿ciency of the offeredtechnique. For this purpos e, an unstable nonlinear numerical system and a rotary inverted pendulum system have beenstudied in the simulation section. Moreover, an experimental study of the practical rotary inverted pendul um system isprovided. These results con¿rm the expected satisfactory performance of the suggested method.Peer ReviewedPostprint (author's final draft

The prodrome of autism: early behavioral and biological signs, regression, peri- and post-natal development and genetics

Autism is one of the most heritable neurodevelopmental conditions and has an early onset, with symptoms being required to be present in the first 3 years of life in order to meet criteria for the ‘core’ disorder in the classification systems. As such, the focus on identifying a prodrome over the past 20 years has been on pre-clinical signs or indicators that will be present very early in life, certainly in infancy. A number of novel lines of investigation have been used to this end, including retrospective coding of home videos, prospective population screening and ‘high risk’ sibling studies; as well as the investigation of pre- and peri-natal, brain developmental and other biological factors. Whilst no single prodromal sign is expected to be present in all cases, a picture is emerging of indicative prodromal signs in infancy and initial studies are being undertaken to attempt to ameliorate the early presentation and even ‘prevent’ emergence of the full syndrome

Administrative Performance of “No-Fault” Compensation for Medical Injury

No-fault is the leading alternative to traditional liability systems for resolving medically caused injuries, and policy interest in such reform reflects numerous concerns with the traditional tort system as it operates in the medical field through malpractice insurance. The administrative experience of the Florida and Virginia no-fault programs is examined

Acute pyelonephritis and renal scarring are caused by dysfunctional innate immunity in mCxcr2 heterozygous mice

The CXCR1 receptor and chemokine CXCL8 (IL-8) support neutrophil-dependent clearance of uropathogenic Escherichia coli from the urinary tract. CXCR1 is reduced in children prone to pyelonephritis, and heterozygous hCXCR1 polymorphisms are more common in this patient group than in healthy individuals, strongly suggesting a disease association. Since murine CXCR2 (mCXCR2) is functionally similar to human CXCR1, we determined effects of gene heterozygosity on the susceptibility to urinary tract infection by infecting heterozygous (mCxcr2+/−) mice with uropathogenic Escherichia coli. Clearance of infection and tissue damage were assessed as a function of innate immunity in comparison to that in knockout (mCxcr2−/−) and wild-type (mCxcr2+/+) mice. Acute sepsis-associated mortality was increased and bacterial clearance drastically impaired in heterozygous compared to wild-type mice. Chemokine and neutrophil responses were delayed along with evidence of neutrophil retention and unresolved kidney inflammation 1 month after infection. This was accompanied by epithelial proliferation and subepithelial fibrosis. The heterozygous phenotype was intermediate, between knockout and wild-type mice, but specific immune cell infiltrates that accompany chronic infection in knockout mice were not found. Hence, the known heterozygous CXCR1 polymorphisms may predispose patients to acute pyelonephritis and urosepsis