Optimal Regulation of Blood Glucose Level in Type I Diabetes using Insulin and Glucagon

The Glucose-Insulin-Glucagon nonlinear model [1-4] accurately describes how the body responds to exogenously supplied insulin and glucagon in patients affected by Type I diabetes. Based on this model, we design infusion rates of either insulin (monotherapy) or insulin and glucagon (dual therapy) that can optimally maintain the blood glucose level within desired limits after consumption of a meal and prevent the onset of both hypoglycemia and hyperglycemia. This problem is formulated as a nonlinear optimal control problem, which we solve using the numerical optimal control package PSOPT. Interestingly, in the case of monotherapy, we find the optimal solution is close to the standard method of insulin based glucose regulation, which is to assume a variable amount of insulin half an hour before each meal. We also find that the optimal dual therapy (that uses both insulin and glucagon) is better able to regulate glucose as compared to using insulin alone. We also propose an ad-hoc rule for both the dosage and the time of delivery of insulin and glucagon.Comment: Accepted for publication in PLOS ON

Artificial intelligence in cancer target identification and drug discovery

Artificial intelligence is an advanced method to identify novel anticancer targets and discover novel drugs from biology networks because the networks can effectively preserve and quantify the interaction between components of cell systems underlying human diseases such as cancer. Here, we review and discuss how to employ artificial intelligence approaches to identify novel anticancer targets and discover drugs. First, we describe the scope of artificial intelligence biology analysis for novel anticancer target investigations. Second, we review and discuss the basic principles and theory of commonly used network-based and machine learning-based artificial intelligence algorithms. Finally, we showcase the applications of artificial intelligence approaches in cancer target identification and drug discovery. Taken together, the artificial intelligence models have provided us with a quantitative framework to study the relationship between network characteristics and cancer, thereby leading to the identification of potential anticancer targets and the discovery of novel drug candidates

Network controllability solutions for computational drug repurposing using genetic algorithms

Control theory has seen recently impactful applications in network science, especially in connections with applications in network medicine. A key topic of research is that of finding minimal external interventions that offer control over the dynamics of a given network, a problem known as network controllability. We propose in this article a new solution for this problem based on genetic algorithms. We tailor our solution for applications in computational drug repurposing, seeking to maximize its use of FDA-approved drug targets in a given disease-specific protein-protein interaction network. We demonstrate our algorithm on several cancer networks and on several random networks with their edges distributed according to the Erdos-Renyi, the Scale-Free, and the Small World properties. Overall, we show that our new algorithm is more efficient in identifying relevant drug targets in a disease network, advancing the computational solutions needed for new therapeutic and drug repurposing approaches

Optimal Control Strategies for Complex Biological Systems

To better understand and to improve therapies for complex diseases such as cancer or diabetes, it is not sufficient to identify and characterize the interactions between molecules and pathways in complex biological systems, such as cells, tissues, and the human body. It also is necessary to characterize the response of a biological system to externally supplied agents (e.g., drugs, insulin), including a proper scheduling of these drugs, and drug combinations in multi drugs therapies. This obviously becomes important in applications which involve control of physiological processes, such as controlling the number of autophagosome vesicles in a cell, or regulating the blood glucose level in patients affected by diabetes. A critical consideration when controlling physiological processes in biological systems is to reduce the amount of drugs used, as in some therapies drugs may become toxic when they are overused. All of the above aspects can be addressed by using tools provided by the theory of optimal control, where the externally supplied drugs or hormones are the inputs to the system. Another important aspect of using optimal control theory in biological systems is to identify the drug or the combination of drugs that are effective in regulating a given therapeutic target, i.e., a biological target of the externally supplied stimuli. The dynamics of the key features of a biological system can be modeled and described as a set of nonlinear differential equations. For the implementation of optimal control theory in complex biological systems, in what follows we extract \textit{a network} from the dynamics. Namely, to each state variable $x_i$ we will assign a network node $v_i$ ($i=1,...,N$) and a network directed edge from node $v_i$ to another node $v_j$ will be assigned every time $x_j$ is present in the time derivative of $x_i$. The node which directly receives an external stimulus is called a \emph{driver nodes} in a network. The node which directly connected to an output sensor is called a \emph{target node}. %, and it has a prescribed final state that we wish to achieve in finite time. From the control point of view, the idea of controllability of a system describes the ability to steer the system in a certain time interval towards thea desired state with a suitable choice of control inputs. However, defining controllability of large complex networks is quite challenging, primarily because of the large size of the network, its complex structure, and poor knowledge of the precise network dynamics. A network can be controllable in theory but not in practice when a very large control effort is required to steer the system in the desired direction. This thesis considers several approaches to address some of these challenges. Our first approach is to reduce the control effort is to reduce the number of target nodes. We see that by controlling the states of a subset of the network nodes, rather than the state of every node, while holding the number of control signals constant, the required energy to control a portion of the network can be reduced substantially. The energy requirements exponentially decay with the number of target nodes, suggesting that large networks can be controlled by a relatively small number of inputs as long as the target set is appropriately sized. We call this strategy \emph{target control}. As our second approach is based on reducing the control efforts by allowing the prescribed final states are satisfied approximately rather than strictly. We introduce a new control strategy called \textit{balanced control} for which we set our objective function as a convex combination of two competitive terms: (i) the distance between the output final states at a given final time and given prescribed states and (ii) the total control efforts expenditure over the given time period. Based on the above two approaches, we propose an algorithm which provides a locally optimal control technique for a network with nonlinear dynamics. We also apply pseudo-spectral optimal control, together with the target and balance control strategies previously described, to complex networks with nonlinear dynamics. These optimal control techniques empower us to implement the theoretical control techniques to biological systems evolving with very large, complex and nonlinear dynamics. We use these techniques to derive the optimal amounts of several drugs in a combination and their optimal dosages. First, we provide a prediction of optimal drug schedules and combined drug therapies for controlling the cell signaling network that regulates autophagy in a cell. Second, we compute an optimal dual drug therapy based on administration of both insulin and glucagon to control the blood glucose level in type I diabetes. Finally, we also implement the combined control strategies to investigate the emergence of cascading failures in the power grid networks

Model reduction in mathematical pharmacology: integration, reduction and linking of PBPK and systems biology models

In this paper we present a framework for the reduction and linking of physiologically based pharmacokinetic (PBPK) models with models of systems biology to describe the effects of drug administration across multiple scales. To address the issue of model complexity, we propose the reduction of each type of model separately prior to being linked. We highlight the use of balanced truncation in reducing the linear components of PBPK models, whilst proper lumping is shown to be efficient in reducing typically nonlinear systems biology type models. The overall methodology is demonstrated via two example systems; a model of bacterial chemotactic signalling in Escherichia coli and a model of extracellular regulatory kinase activation mediated via the extracellular growth factor and nerve growth factor receptor pathways. Each system is tested under the simulated administration of three hypothetical compounds; a strong base, a weak base, and an acid, mirroring the parameterisation of pindolol, midazolam, and thiopental, respectively. Our method can produce up to an 80% decrease in simulation time, allowing substantial speed-up for computationally intensive applications including parameter fitting or agent based modelling. The approach provides a straightforward means to construct simplified Quantitative Systems Pharmacology models that still provide significant insight into the mechanisms of drug action. Such a framework can potentially bridge pre-clinical and clinical modelling - providing an intermediate level of model granularity between classical, empirical approaches and mechanistic systems describing the molecular scale

Interictal Network Dynamics in Paediatric Epilepsy Surgery

Epilepsy is an archetypal brain network disorder. Despite two decades of research elucidating network mechanisms of disease and correlating these with outcomes, the clinical management of children with epilepsy does not readily integrate network concepts. For example, network measures are not used in presurgical evaluation to guide decision making or surgical management plans. The aim of this thesis was to investigate novel network frameworks from the perspective of a clinician, with the explicit aim of finding measures that may be clinically useful and translatable to directly benefit patient care. We examined networks at three different scales, namely macro (whole brain diffusion MRI), meso (subnetworks from SEEG recordings) and micro (single unit networks) scales, consistently finding network abnormalities in children being evaluated for or undergoing epilepsy surgery. This work also provides a path to clinical translation, using frameworks such as IDEAL to robustly assess the impact of these new technologies on management and outcomes. The thesis sets up a platform from which promising computational technology, that utilises brain network analyses, can be readily translated to benefit patient care

Role of brain imaging in disorders of brain-gut interaction: a Rome Working Team Report.

Imaging of the living human brain is a powerful tool to probe the interactions between brain, gut and microbiome in health and in disorders of brain-gut interactions, in particular IBS. While altered signals from the viscera contribute to clinical symptoms, the brain integrates these interoceptive signals with emotional, cognitive and memory related inputs in a non-linear fashion to produce symptoms. Tremendous progress has occurred in the development of new imaging techniques that look at structural, functional and metabolic properties of brain regions and networks. Standardisation in image acquisition and advances in computational approaches has made it possible to study large data sets of imaging studies, identify network properties and integrate them with non-imaging data. These approaches are beginning to generate brain signatures in IBS that share some features with those obtained in other often overlapping chronic pain disorders such as urological pelvic pain syndromes and vulvodynia, suggesting shared mechanisms. Despite this progress, the identification of preclinical vulnerability factors and outcome predictors has been slow. To overcome current obstacles, the creation of consortia and the generation of standardised multisite repositories for brain imaging and metadata from multisite studies are required

Time-Delay Systems: Analysis and Control using the Lambert W Function.

Time-delay systems can arise due to inherent time-delays in the system or a deliberate introduction of time-delays into the system for control purposes. Such systems frequently occur in engineering and science. Time-delays can cause significant problems (e.g., instability and inaccuracy) and, thus, limit and degrade achievable performance. Time-delay terms lead to an infinite number of roots of the characteristic equation, and make analysis difficult using classical methods, especially, in determining stability and designing stabilizing controllers. Thus, such problems have been addressed mainly by using approximate, numerical, and graphical methods. However, such approaches constitute limitations, for example, on accuracy and robustness. The objective of this research is to develop an effective approach to analyze and control time-delay systems. Using the LambertWfunction, free and forced analytical solutions to delay differential equations are derived. The main advantage of this solution approach lies in the fact that the solution has an analytical form expressed in terms of system parameters and, thus, one can explicitly determine how each parameter affects each eigenvalue and the solution. Also, each eigenvalue in the infinite eigenspectrum is associated individually with a branch of the LambertWfunction. Solutions are obtained, for the first time, for systems of delay differential equations using the matrix Lambert W function. The obtained solutions are used to analyze essential system properties, such as stability, controllability and observability, and to design controllers for stabilizing systems, improving robustness and/or meeting time-domain specifications. Then, these methods are applied to biological systems to analyze the immune system via eigenvalue sensitivity analysis, to automotive powertrain systems to design feedback control with observers for improvements in fuel economy and emissions, and to manufacturing processes to improve productivity via stability analysis. The newly developed approach based on the matrix Lambert W function provides a tool for analysis and control, which is accurate (i.e., no approximation of timedelay terms), robust (i.e., no prediction of responses from models), and easy to implement (i.e., no need for complex nonlinear controllers).Ph.D.Mechanical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/64756/1/syjo_1.pd

Monoclonal Antibodies

Monoclonal antibodies are established in clinical practice for the treatment of cancer, and autoimmune and infectious diseases. The first generation of antibodies has been dominated by classical IgG antibodies, however, in the last decade, the field has advanced, and, nowadays, a large proportion of antibodies in development have been engineered. This Special Issue on "Monoclonal Antibodies" includes original manuscripts and reviews covering various aspects related to the discovery, analytical characterization, manufacturing and development of therapeutic and engineered antibodies