Optimal design of phosphorylation-based insulation devices

We seek to minimize both the retroactivity to the output and the retroactivity to the input of a phosphorylation-based insulation device by finding an optimal substrate concentration. Characterizing and improving the performance of insulation devices brings us a step closer to their successful implementation in biological circuits, and thus to modularity. Previous works have mainly focused on attenuating retroactivity effects to the output using high substrate concentrations. This, however, worsens the retroactivity to the input, creating an error that propagates back to the output. Employing singular perturbation and contraction theory tools, this work provides a framework to determine an optimal substrate concentration to reach a tradeoff between the retroactivity to the input and the retroactivity to the output.Grant FA9550-12-1-021

Retroactivity attenuation through signal transduction cascades

This paper considers the problem of attenuating retroactivity, that is, the effect of loads in biological networks and demonstrates that signal transduction cascades incorporating phosphotransfer modules have remarkable retroactivity attenuation ability. Uncovering the biological mechanisms for retroactivity attenuation is relevant in synthetic biology to enable bottom-up modular composition of complex circuits. It is also important in systems biology for deepening our current understanding of natural principles of modular organization. In this paper, we perform a combined theoretical and computational study of a cascade system comprising two phosphotransfer modules, ubiquitous in eukaryotic signal transduction, when subject to load from downstream targets. Employing singular perturbation on the finite time interval, we demonstrate that this system implements retroactivity attenuation when the input signal is sufficiently slow. Employing trajectory sensitivity analysis about nominal parameters that we have identified from in vivo data, we further demonstrate that the key parameters for retroactivity attenuation are those controlling the timescale of the system.Grant FA9550-12-1-0219National Science Foundation (U.S.). Division of Computing and Communication Foundations (1058127

Existence of Cascade Discrete-Continuous State Estimators for Systems on a Partial Order

In this paper, a cascade discrete-continuous state estimator on a partial order is proposed and its existence investigated. The continuous state estimation error is bounded by a monotonically nonincreasing function of the discrete state estimation error, with both the estimation errors converging to zero. This work shows that the lattice approach to estimation is general as the proposed estimator can be constructed for any observable and discrete state observable system. The main advantage of using the lattice approach for estimation becomes clear when the system has monotone properties that can be exploited in the estimator design. In such a case, the computational complexity of the estimator can be drastically reduced and tractability can be achieved. Some examples are proposed to illustrate these ideas

Recognizable neonatal clinical features of aplasia cutis congenita

Background: Aplasia cutis congenita (ACC), classified in nine groups, is likely to be underreported, since milder isolated lesions in wellbeing newborns could often be undetected, and solitary lesions in the context of polymalformative syndromes could not always be reported. Regardless of form and cause, therapeutic options have in common the aim to restore the deficient mechanical and immunological cutaneous protection and to limit the risk of fluid leakage or rupture of the exposed organs. We aimed to review our institutional prevalence, comorbidities, treatment and outcome of newborns with ACC. Methods: We conducted a retrospective study including all newborns affected by ACC and admitted at the University Mother-Child Department from October 2010 to October 2019. Anthropometric and clinical characteristics of ACC1 versus a non-isolated ACC group were analyzed. Results: We encountered 37 newborns, 16 with ACC1 versus 21 with non-isolated ACC. The incidence rate of 0.1% in ACC1 was higher than expected, while 19% of cases showed intrafamilial autosomal dominant transmission. Higher birth weight centile, though lower than reference population, being adequate for gestational age, normal Apgar score and euglycemia characterizing ACC1 resulted associated to a rapid tissue regeneration. Non-isolated ACC, in relation to concomitant congenital anomalies and higher prematurity rate, showed more surgical and medical complications along with the risk of neonatal death. Specifically, newborns with ACC4 were characterized by the frequent necessity of abdominal wall defect repair, responsible for the occurrence of an abdominal compartment syndrome. Conclusion: Prompt carefully assessment of the newborn with ACC in order to exclude concomitant other congenital malformations, provides clues to the underlying pathophysiology, and to the short-term prognosis. Family should be oriented toward identification of other family members affected by similar pathology, while obstetric history should exclude initial multiple pregnancy with death of a co-twin, placental anomalies and drug assumption. Molecular-genetic diagnosis and genetic counseling are integrative in individualized disease approach

Classification of human actions into dynamics based primitives with application to drawing tasks

We develop the study of primitives of human motion, which we refer to as movemes. The idea is to understand human motion by decomposing it into a sequence of elementary building blocks that belong to a known alphabet of dynamical systems. How can we construct an alphabet of movemes from human data? In this paper we address this issue by introducing the notion of well-posednes. Using examples from human drawing data, we show that the well-posedness notion can be applied in practice so to establish if sets of actions, viewed as signals in time, can define movemes

A dynamical model for the low efficiency of induced pluripotent stem cell reprogramming

In the past decade, researchers have been able to obtain pluripotent stem cells directly from an organism's differentiated cells through a process called cell reprogramming. This opens the way to potentially groundbreaking applications in regenerative and personalized medicine, in which ill patients could use self-derived induced pluripotent stem (iPS) cells where needed. While the process of reprogramming has been shown to be possible, its efficiency remains so low after almost ten years since its conception as to render its applicability limited to laboratory research. In this paper, we study a mathematical model of the core transcriptional circuitry among a set of key transcription factors, which is thought to determine the switch among pluripotent and early differentiated cell types. By employing standard tools from dynamical systems theory, we analyze the effects on the system's dynamics of overexpressing the core factors, which is what is performed during the reprogramming process. We demonstrate that the structure of the system is such that it can render the switch from an initial stable steady state (differentiated cell type) to the desired stable steady state (pluripotent cell type) highly unlikely. This finding provides insights into a possible reason for the low efficiency of current reprogramming approaches. We also suggest a strategy for improving the reprogramming process that employs simultaneous overexpression of one transcription factor along with enhanced degradation of another.Massachusetts Institute of Technology. Undergraduate Research Opportunities Program (Paul E. Gray Fund)United States. Air Force Office of Scientific Research (BRI Grant FA9550-14-1-0060

Infinite index extensions of local nets and defects

Subfactor theory provides a tool to analyze and construct extensions of Quantum Field Theories, once the latter are formulated as local nets of von Neumann algebras. We generalize some of the results of [LR95] to the case of extensions with infinite Jones index. This case naturally arises in physics, the canonical examples are given by global gauge theories with respect to a compact (non-finite) group of internal symmetries. Building on the works of Izumi, Longo, Popa [ILP98] and Fidaleo, Isola [FI99], we consider generalized Q-systems (of intertwiners) for a semidiscrete inclusion of properly infinite von Neumann algebras, which generalize ordinary Q-systems introduced by Longo [Lon94] to the infinite index case. We characterize inclusions which admit generalized Q-systems of intertwiners and define a braided product among the latter, hence we construct examples of QFTs with defects (phase boundaries) of infinite index, extending the family of boundaries in the grasp of [BKLR16].Comment: 50 page

Design of insulating devices for in vitro synthetic circuits

This paper describes a synthetic in vitro genetic circuit programmed to work as an insulating device. This circuit is composed of nucleic acids, which can be designed to interact according to user defined rules, and of few proteins that perform catalytic functions. A model of the circuit is derived from first principle biochemical laws. This model is shown to exhibit time-scale separation that makes its output insensitive to downstream time varying loads. Simulation results show the circuit effectiveness and represent the starting point for future experimental testing of the device