Permanent Bilateral Carotid Filters for Stroke Prevention in Atrial Fibrillation.

PURPOSE OF REVIEW: A novel permanent carotid filter device for percutaneous implantation was developed for the purpose of stroke prevention. In this review, we cover rationale, existing preclinical and clinical data, and potential future directions for research using such a device. RECENT FINDINGS: The Vine™ filter was assessed for safety in sheep and in 2 observational human studies, the completed CAPTURE 1 (n = 25) and the ongoing CAPTURE 2 (planned n = 100). CAPTURE 1 has shown high procedural and long-term implant safety. A control group was not available for comparison. A mechanical filter for permanent stroke prevention can be implanted bilaterally in the common carotid artery safely and efficiently. A randomized trial is planned for 2021 (n = 3500, INTERCEPT) to demonstrate superiority of a filter + anticoagulation strategy over anticoagulation alone in patients at high risk for ischemic stroke.

Constraints on reciprocal flux sensitivities in biochemical reaction networks.

We identify a connection between the structural features of mass-action networks and the robustness of their steady-state fluxes against rate constant variations. We find that in all positive steady states of so-called injective networks-networks that arise, for example, in metabolic and gene regulation contexts-there are certain firm bounds on the flux control coefficients. In particular, the control coefficient of the flux of a reaction, with respect to variation in its own rate constant, is delimited in a precise way. Moreover, for each pair of reactions, the flux of at least one of them must have a precisely delimited control coefficient with respect to variation in the rate constant of the other. The derived bounds can, however, be violated in noninjective networks, so for them a more pronounced lack of robustness could be exhibited. These results, which indicate a mechanism by which some degree of robustness is induced in the injective setting, also shed light on how robustness might evolve.

Evolutionary balancing of fitness-limiting factors.

Debates concerning the roles of different factors that may limit an organism's reproductive success pervade evolutionary ecology. We suggest that a broad class of limiting-factors problems involving essential resources or essential components of reproductive effort can be analyzed with an evolutionary application of Liebig's law of the minimum. We explore life-history evolution using the metaphor of an organism that must harvest two essential resources (resources 1 and 2) from a stochastically varying environment. Our models make three predictions. First, organisms should overinvest, relative to the deterministic case, in harvesting the resource whose per-offspring harvest cost is smaller. Second, at the optimum, organisms balance multiple fitness-limiting factors rather than being consistently limited by one factor. Third, the optimal investment in harvesting a resource is directly linked to the probability that the organism's fitness will be limited by that resource. Under temporal variation, the optimal proportional investment in harvesting resource 1 is equal to the probability that resource 1 will limit fitness. Our results help to explain why the responses of populations to environmental perturbations are hard to predict: as an organism transitions between different limiting factors, its responses to perturbations of those factors will likewise change.

Robustness in glyoxylate bypass regulation.

The glyoxylate bypass allows Escherichia coli to grow on carbon sources with only two carbons by bypassing the loss of carbons as CO(2) in the tricarboxylic acid cycle. The flux toward this bypass is regulated by the phosphorylation of the enzyme isocitrate dehydrogenase (IDH) by a bifunctional kinase-phosphatase called IDHKP. In this system, IDH activity has been found to be remarkably robust with respect to wide variations in the total IDH protein concentration. Here, we examine possible mechanisms to explain this robustness. Explanations in which IDHKP works simultaneously as a first-order kinase and as a zero-order phosphatase with a single IDH binding site are found to be inconsistent with robustness. Instead, we suggest a robust mechanism where both substrates bind the bifunctional enzyme to form a ternary complex.

Input output robustness in simple bacterial signaling systems.

Biological signaling systems produce an output, such as the level of a phosphorylated protein, in response to defined input signals. The output level as a function of the input level is called the system's input-output relation. One may ask whether this input-output relation is sensitive to changes in the concentrations of the system's components, such as proteins and ATP. Because component concentrations often vary from cell to cell, it might be expected that the input-output relation will likewise vary. If this is the case, different cells exposed to the same input signal will display different outputs. Such variability can be deleterious in systems where survival depends on accurate match of output to input. Here we suggest a mechanism that can provide input-output robustness, that is, an input-output relation that does not depend on variations in the concentrations of any of the system's components. The mechanism is based on certain bacterial signaling systems. It explains how specific molecular details can work together to provide robustness. Moreover, it suggests an approach that can help identify a wide family of nonequilibrium mechanisms that potentially have robust input-output relations.

A Permanent Common Carotid Filter for Stroke Prevention in Atrial Fibrillation: Ex Vivo and In Vivo Pre-Clinical Testing.

BACKGROUND AND PURPOSE: A novel, permanent, bilateral, common carotid artery (CCA) coil filter implant was designed to capture stroke-producing emboli in atrial fibrillation patients. Under ultrasound guidance, it is automatically deployed through a 24-guage needle and is retrievable up to 4 h post-procedure. We assessed the feasibility, safety, and effectiveness of the CCA filter in pre-clinical testing. METHODS: In a pulsatile flow simulator, the filter's embolic capture efficiency and integrity of simulated (1.2 mm diameter nylon balls) and actual thromboemboli were tested. Implant insertion, retrieval, and chronic safety were tested in sheep by ultrasound and X-ray. At termination, the CCAs were explanted and examined by pathology, histopathology and scanning electron microscopy. The fate of captured emboli was evaluated in sheep 3 weeks after upstream injection of autologous thromboemboli. RESULTS: In the flow simulator, 10 filters captured 29 of 29 (100%) 1.2 mm diameter nylon balls. In the thromboemboli integrity test, all captured thromboemboli (99 of 99) were adherent to the filter, without fragmentation. All sheep (n = 30/60 implants) underwent successful CCA filter implantation. During follow-ups at 4, 12, 13, 23, and 31 weeks (6 sheep/12 implants at each follow-up), there were no (0%) major bleeds, CCA damage/stenosis, implant migration, flow obstruction, or thrombi detected by ultrasound. Two organized microthrombi (<100 µm) were observed by histopathology at the puncture site. After 3 weeks, autologous captured thromboemboli (n = 10) either completely regressed (5 of 5) or did not progress (5 of 5). CONCLUSION: These favorable pre-clinical results prompt clinical testing of the CCA filter in stroke prevention clinical trials.

Sharper graph-theoretical conditions for the stabilization of complex reaction networks.

Across the landscape of all possible chemical reaction networks there is a surprising degree of stable behavior, despite what might be substantial complexity and nonlinearity in the governing differential equations. At the same time there are reaction networks, in particular those that arise in biology, for which richer behavior is exhibited. Thus, it is of interest to understand network-structural features whose presence enforces dull, stable behavior and whose absence permits the dynamical richness that might be necessary for life. We present conditions on a network's Species-Reaction Graph that ensure a high degree of stable behavior, so long as the kinetic rate functions satisfy certain weak and natural constraints. These graph-theoretical conditions are considerably more incisive than those reported earlier.

Concordant chemical reaction networks and the Species-Reaction Graph.

In a recent paper it was shown that, for chemical reaction networks possessing a subtle structural property called concordance, dynamical behavior of a very circumscribed (and largely stable) kind is enforced, so long as the kinetics lies within the very broad and natural weakly monotonic class. In particular, multiple equilibria are precluded, as are degenerate positive equilibria. Moreover, under certain circumstances, also related to concordance, all real eigenvalues associated with a positive equilibrium are negative. Although concordance of a reaction network can be decided by readily available computational means, we show here that, when a nondegenerate network's Species-Reaction Graph satisfies certain mild conditions, concordance and its dynamical consequences are ensured. These conditions are weaker than earlier ones invoked to establish kinetic system injectivity, which, in turn, is just one ramification of network concordance. Because the Species-Reaction Graph resembles pathway depictions often drawn by biochemists, results here expand the possibility of inferring significant dynamical information directly from standard biochemical reaction diagrams.

Response to comment on "Evolutionary trade-offs, Pareto optimality, and the geometry of phenotype space".

Edelaar raises concerns about the way we tested our theory. Our mathematical theorem predicts that despite the high dimensionality of trait space, trade-offs between tasks leads to phenotypes in low-dimensional regions in trait space, such as lines and triangles. We address Edelaar's questions with statistical tests that eliminate pseudoreplication concerns, finding that our predictions remain convincingly supported.

Concordant chemical reaction networks.

We describe a large class of chemical reaction networks, those endowed with a subtle structural property called concordance. We show that the class of concordant networks coincides precisely with the class of networks which, when taken with any weakly monotonic kinetics, invariably give rise to kinetic systems that are injective - a quality that, among other things, precludes the possibility of switch-like transitions between distinct positive steady states. We also provide persistence characteristics of concordant networks, instability implications of discordance, and consequences of stronger variants of concordance. Some of our results are in the spirit of recent ones by Banaji and Craciun, but here we do not require that every species suffer a degradation reaction. This is especially important in studying biochemical networks, for which it is rare to have all species degrade.

Design principles for robust biochemical reaction networks: what works, what cannot work, and what might almost work.

We bring together recent results that connect the structure of a mass-action reaction network to its capacity for concentration robustness - that is, its capacity to keep the concentration of a critical bio-active species within narrow limits, even against large fluctuations in the overall supply of the network's constituents.

Structural sources of robustness in biochemical reaction networks.

In vivo variations in the concentrations of biomolecular species are inevitable. These variations in turn propagate along networks of chemical reactions and modify the concentrations of still other species, which influence biological activity. Because excessive variations in the amounts of certain active species might hamper cell function, regulation systems have evolved that act to maintain concentrations within tight bounds. We identify simple yet subtle structural attributes that impart concentration robustness to any mass-action network possessing them. We thereby describe a large class of robustness-inducing networks that already embraces two quite different biochemical modules for which concentration robustness has been observed experimentally: the Escherichia coli osmoregulation system EnvZ-OmpR and the glyoxylate bypass control system isocitrate dehydrogenase kinase-phosphatase-isocitrate dehydrogenase. The structural attributes identified here might confer robustness far more broadly.

Rules for biological regulation based on error minimization.

The control of gene expression involves complex mechanisms that show large variation in design. For example, genes can be turned on either by the binding of an activator (positive control) or the unbinding of a repressor (negative control). What determines the choice of mode of control for each gene? This study proposes rules for gene regulation based on the assumption that free regulatory sites are exposed to nonspecific binding errors, whereas sites bound to their cognate regulators are protected from errors. Hence, the selected mechanisms keep the sites bound to their designated regulators for most of the time, thus minimizing fitness-reducing errors. This offers an explanation of the empirically demonstrated Savageau demand rule: Genes that are needed often in the natural environment tend to be regulated by activators, and rarely needed genes tend to be regulated by repressors; in both cases, sites are bound for most of the time, and errors are minimized. The fitness advantage of error minimization appears to be readily selectable. The present approach can also generate rules for multi-regulator systems. The error-minimization framework raises several experimentally testable hypotheses. It may also apply to other biological regulation systems, such as those involving protein-protein interactions.