Bio-analog dissipative structures and principles of biological behavior.

The place of living organisms in the natural world is a nearly perennial question in philosophy and the sciences; how can inanimate matter yield animate beings? A dominant answer for several centuries has been to treat organisms as sophisticated machines, studying them with the mechanistic physics and chemistry that have given rise to technology and complex machines. Since the early 20th century, many scholars have sought instead to naturalize biology through thermodynamics, recognizing the precarious far-from-equilibrium state of organisms. Erwin Bauer was an early progenitor of this perspective with ambitions of "general laws for the movement of living matter". In addition to taking a thermodynamic perspective, Bauer recognized that organisms are fundamentally behaving systems, and that explaining the physics of life requires explaining the origins of intentionality, adaptability, and self-regulation. Bauer, like some later scholars, seems to advocate for a "new physics", one that extends beyond mechanics and classical thermodynamic, one that would be inclusive of living systems. In this historical review piece, we explore some of Bauer's ideas and explain how similar concepts have been explored in modern non-equilibrium thermodynamics and dissipative structure theory. Non-living dissipative structures display end-directedness, self-maintenance, and adaptability analogous to organisms. These findings also point to an alternative framework for the life sciences, that treats organisms not as machines but as sophisticated dissipative structures. We evaluate the differences between mechanistic and thermodynamic perspectives on life, and what each theory entails for understanding the behavior of organisms.

Thermodynamics, organisms and behaviour.

The physical origin of behaviour in biological organisms is distinct from those of non-living systems in one significant way: organisms exhibit intentionality or goal-directed behaviour. How may we understand and explain this important aspect in physical terms, grounded in laws of physics and chemistry? In this article, we discuss recent experimental and theoretical progress in this area and future prospects of this line of thought. The physical basis for our investigation is thermodynamics, though other branches of physics and chemistry have an important role. This article is part of the theme issue 'Thermodynamics 2.0: Bridging the natural and social sciences (Part 1)'.

Unveiling the masked native blood group following thalidomide therapy in a thalassemia patient: A 5 WHY analysis approach.

Blood grouping discrepancy in patients with hematological disorders can occur due to red cell sensitization following transfusion, transplantation, and pregnancy or pre-analytical errors. Prompt initiation of root cause analysis is vital to avoid complications of wrong blood transfusion. We present an unusual case of Rh mismatched grouping report of 24 year old female thalassemia patient being managed in our hospital since 2015. Her current type and screen were observed as O Rh D negative with negative antibody screen while the historical blood group was O Rh D positive. The pre-analytical errors were ruled out and blood grouping performed from fresh sample also demonstrated as O Rh D negative despite antigen enhancement techniques and had no recent transfusion history. We sought to reason out the possibilities for discordant Rh grouping report, historical and present group through "Funnel based problem solving 5 WHY analysis" approach. The review of the past clinical history revealed that the patient had undergone Rh mismatch bone marrow transplant (Rh D positive donor and Rh D negative recipient) at 5 years of age which soon resulted in graft failure. Yet, she continued to receive Rh D positive blood thereafter with no development of anti-D which explains the historical blood group. Recently the patient was started on thalidomide, the Hb F inducer drug, which helped in maintaining her hemoglobin level between 9 and 10 g/dl without transfusion support for two months. This allowed unmasking of native Rh D negative blood and the review of clinical history played a significant role in resolution of grouping discrepancy.

A Network Theory Approach to Curriculum Design.

In this paper we hypothesize that education, especially at the scale of curriculum, should be treated as a complex system composed of different ideas and concepts which are inherently connected. Therefore, the task of a good teacher lies in elucidating these connections and helping students make their own connections. Such a pedagogy allows students to personalize learning and strive to be 'creative' and make meaning out of old ideas. The novel contribution of this work lies in the mathematical approach we undertake to verify our hypothesis. We take the example of a precalculus course curriculum to make our case. We treat textbooks as exemplars of a specific pedagogy and map several texts into networks of isolated (nodes) and interconnected concepts (edges) thereby permitting computations of metrics which have much relevance to the education theorists, teachers and all others involved in the field of education. We contend that network metrics such as average path length, clustering coefficient and degree distribution provide valuable insights to teachers and students about the kind of pedagogy which encourages good teaching and learning.

A game-theoretic approach to deciphering the dynamics of amyloid-ß aggregation along competing pathways.

Aggregation of amyloid-ß (Aß) peptides is a significant event that underpins Alzheimer's disease (AD). Aß aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD pathogenesis. Therefore, there is increasing interest in understanding their formation and behaviour. In this paper, we use our previously established results on heterotypic interactions between Aß and fatty acids (FAs) to investigate off-pathway aggregation under the control of FA concentrations to develop a mathematical framework that captures the mechanism. Our framework to define and simulate the competing on- and off-pathways of Aß aggregation is based on the principles of game theory. Together with detailed simulations and biophysical experiments, our models describe the dynamics involved in the mechanisms of Aß aggregation in the presence of FAs to adopt multiple pathways. Specifically, our reduced-order computations indicate that the emergence of off- or on-pathway aggregates are tightly controlled by a narrow set of rate constants, and one could alter such parameters to populate a particular oligomeric species. These models agree with the detailed simulations and experimental data on using FA as a heterotypic partner to modulate the temporal parameters. Predicting spatio-temporal landscape along competing pathways for a given heterotypic partner such as lipids is a first step towards simulating scenarios in which the generation of specific 'conformer strains' of Aß could be predicted. This approach could be significant in deciphering the mechanisms of amyloid aggregation and strain generation, which are ubiquitously observed in many neurodegenerative diseases.

Cause and consequence of Aß - Lipid interactions in Alzheimer disease pathogenesis.

Self-templating propagation of protein aggregate conformations is increasingly becoming a significant factor in many neurological diseases. In Alzheimer disease (AD), intrinsically disordered amyloid-ß (Aß) peptides undergo aggregation that is sensitive to environmental conditions. High-molecular weight aggregates of Aß that form insoluble fibrils are deposited as senile plaques in AD brains. However, low-molecular weight aggregates called soluble oligomers are known to be the primary toxic agents responsible for neuronal dysfunction. The aggregation process is highly stochastic involving both homotypic (Aß-Aß) and heterotypic (Aß with interacting partners) interactions. Two of the important members of interacting partners are membrane lipids and surfactants, to which Aß shows a perpetual association. Aß-membrane interactions have been widely investigated for more than two decades, and this research has provided a wealth of information. Although this has greatly enriched our understanding, the objective of this review is to consolidate the information from the literature that collectively showcases the unique phenomenon of lipid-mediated Aß oligomer generation, which has largely remained inconspicuous. This is especially important because Aß aggregate "strains" are increasingly becoming relevant in light of the correlations between the structure of aggregates and AD phenotypes. Here, we will focus on aspects of Aß-lipid interactions specifically from the context of how lipid modulation generates a wide variety of biophysically and biochemically distinct oligomer sub-types. This, we believe, will refocus our thinking on the influence of lipids and open new approaches in delineating the mechanisms of AD pathogenesis. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.

Entropy production in a fluid-solid system far from thermodynamic equilibrium.

The terminal orientation of a rigid body in a moving fluid is an example of a dissipative system, out of thermodynamic equilibrium and therefore a perfect testing ground for the validity of the maximum entropy production principle (MaxEP). Thus far, dynamical equations alone have been employed in studying the equilibrium states in fluid-solid interactions, but these are far too complex and become analytically intractable when inertial effects come into play. At that stage, our only recourse is to rely on numerical techniques which can be computationally expensive. In our past work, we have shown that the MaxEP is a reliable tool to help predict orientational equilibrium states of highly symmetric bodies such as cylinders, spheroids and toroidal bodies. The MaxEP correctly helps choose the stable equilibrium in these cases when the system is slightly out of thermodynamic equilibrium. In the current paper, we expand our analysis to examine i) bodies with fewer symmetries than previously reported, for instance, a half-ellipse and ii) when the system is far from thermodynamic equilibrium. Using two-dimensional numerical studies at Reynolds numbers ranging between 0 and 14, we examine the validity of the MaxEP. Our analysis of flow past a half-ellipse shows that overall the MaxEP is a good predictor of the equilibrium states but, in the special case of the half-ellipse with aspect ratio much greater than unity, the MaxEP is replaced by the Min-MaxEP, at higher Reynolds numbers when inertial effects come into play. Experiments in sedimentation tanks and with hinged bodies in a flow tank confirm these calculations.

Fatty Acid Concentration and Phase Transitions Modulate Aß Aggregation Pathways.

Aggregation of amyloid ß (Aß) peptides is a significant event that underpins Alzheimer disease (AD) pathology. Aß aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD and hence, there is increasing interest in understanding their formation and behavior. Aggregation is a nucleation-dependent process in which the pre-nucleation events are dominated by Aß homotypic interactions. Dynamic flux and stochasticity during pre-nucleation renders the reactions susceptible to perturbations by other molecules. In this context, we investigate the heterotypic interactions between Aß and fatty acids (FAs) by two independent tool-sets such as reduced order modelling (ROM) and ensemble kinetic simulation (EKS). We observe that FAs influence Aß dynamics distinctively in three broadly-defined FA concentration regimes containing non-micellar, pseudo-micellar or micellar phases. While the non-micellar phase promotes on-pathway fibrils, pseudo-micellar and micellar phases promote predominantly off-pathway oligomers, albeit via subtly different mechanisms. Importantly off-pathway oligomers saturate within a limited molecular size, and likely with a different overall conformation than those formed along the on-pathway, suggesting the generation of distinct conformeric strains of Aß, which may have profound phenotypic outcomes. Our results validate previous experimental observations and provide insights into potential influence of biological interfaces in modulating Aß aggregation pathways.

Determination of critical nucleation number for a single nucleation amyloid-ß aggregation model.

Aggregates of amyloid-ß (Aß) peptide are known to be the key pathological agents in Alzheimer disease (AD). Aß aggregates to form large, insoluble fibrils that deposit as senile plaques in AD brains. The process of aggregation is nucleation-dependent in which the formation of a nucleus is the rate-limiting step, and controls the physiochemical fate of the aggregates formed. Therefore, understanding the properties of nucleus and pre-nucleation events will be significant in reducing the existing knowledge-gap in AD pathogenesis. In this report, we have determined the plausible range of critical nucleation number (n(*)), the number of monomers associated within the nucleus for a homogenous aggregation model with single unique nucleation event, by two independent methods: A reduced-order stability analysis and ordinary differential equation based numerical analysis, supported by experimental biophysics. The results establish that the most likely range of n(*) is between 7 and 14 and within, this range, n(*) = 12 closely supports the experimental data. These numbers are in agreement with those previously reported, and importantly, the report establishes a new modeling framework using two independent approaches towards a convergent solution in modeling complex aggregation reactions. Our model also suggests that the formation of large protofibrils is dependent on the nature of n(*), further supporting the idea that pre-nucleation events are significant in controlling the fate of larger aggregates formed. This report has re-opened an old problem with a new perspective and holds promise towards revealing the molecular events in amyloid pathologies in the future.

A modified Stokes-Einstein equation for Aß aggregation.

BACKGROUND: In all amyloid diseases, protein aggregates have been implicated fully or partly, in the etiology of the disease. Due to their significance in human pathologies, there have been unprecedented efforts towards physiochemical understanding of aggregation and amyloid formation over the last two decades. An important relation from which hydrodynamic radii of the aggregate is routinely measured is the classic Stokes-Einstein equation. Here, we report a modification in the classical Stokes-Einstein equation using a mixture theory approach, in order to accommodate the changes in viscosity of the solvent due to the changes in solute size and shape, to implement a more realistic model for Aß aggregation involved in Alzheimer's disease. Specifically, we have focused on validating this model in protofibrill lateral association reactions along the aggregation pathway, which has been experimentally well characterized. RESULTS: The modified Stokes-Einstein equation incorporates an effective viscosity for the mixture consisting of the macromolecules and solvent where the lateral association reaction occurs. This effective viscosity is modeled as a function of the volume fractions of the different species of molecules. The novelty of our model is that in addition to the volume fractions, it incorporates previously published reports on the dimensions of the protofibrils and their aggregates to formulate a more appropriate shape rather than mere spheres. The net result is that the diffusion coefficient which is inversely proportional to the viscosity of the system is now dependent on the concentration of the different molecules as well as their proper shapes. Comparison with experiments for variations in diffusion coefficients over time reveals very similar trends. CONCLUSIONS: We argue that the standard Stokes-Einstein's equation is insufficient to understand the temporal variations in diffusion when trying to understand the aggregation behavior of Aß42 proteins. Our modifications also involve inclusion of improved shape factors of molecules and more appropriate viscosities. The modification we are reporting is not only useful in Aß aggregation but also will be important for accurate measurements in all protein aggregation systems.