Robustness and autonomy in biological systems: how regulatory mechanisms enable functional integration, complexity and minimal cognition through the action of second-order control constraints

Living systems employ several mechanisms and behaviors to achieve robustness and maintain themselves under changing internal and external conditions. Regulation stands out from them as a specific form of higher-order control, exerted over the basic regime responsible for the production and maintenance of the organism, and provides the system with the capacity to act on its own constitutive dynamics. It consists in the capability to selectively shift between different available regimes of self-production and self-maintenance in response to specific signals and perturbations, due to the action of a dedicated subsystem which is operationally distinct from the regulated ones. The role of regulation, however, is not exhausted by its contribution to maintain a living system’s viability. While enhancing robustness, regulatory mechanisms play a fundamental role in the realization of an autonomous biological organization. Specifically, they are at the basis of the remarkable integration of biological systems, insofar as they coordinate and modulate the activity of distinct functional subsystems. Moreover, by implementing complex and hierarchically organized control architectures, they allow for an increase in structural and organizational complexity while minimizing fragility. Finally, they endow living systems, from their most basic unicellular instances, with the capability to control their own internal dynamics to adaptively respond to specific features of their interaction with the environment, thus providing the basis for the emergence of minimal forms of cognition

MTHFR polymorphisms in childhood acute lymphoblastic leukemia: influence on methotrexate therapy

Maitane Umerez,1 Ángela Gutierrez-Camino,1 Carmen Muñoz-Maldonado,1 Idoia Martin-Guerrero,1 Africa Garcia-Orad1,2 1Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Medicine and Nursery, University of the Basque Country, UPV/EHU, Leioa, 2BioCruces Health Research Institute, Barakaldo, Spain Abstract: Methotrexate (MTX) is an important component in the therapy used to treat childhood acute lymphoblastic leukemia (ALL). Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme for MTX pharmacokinetics. Two single-nucleotide polymorphisms in MTHFR gene, C677T and A1298C, affecting MTHFR activity, have been widely studied as potential markers of MTX toxicity and/or outcome in pediatric ALL. In this review, we show that the majority of published reports do not find association or present opposite effect. Therefore, MTHFR C677T and A1298C polymorphisms do not seem to be good markers of MTX-related toxicity and/or outcome in pediatric ALL. The efforts should be focused on other genes, such as transporter genes or microRNA-related genes. Keywords: MTHFR, methotrexate, toxicity, outcome, C677T, A1298

Systems and organizations: Theoretical tools, conceptual distinctions and epistemological implications.

The aim of this paper is to present some system-theoretical notions ─ such as constraint, closure, integration, coordination, etc. ─ which have recently raised a renovated interest and have undergone a deep development, especially in those branches of philosophy of biology characterized by a systemic approach. The im- plications of these notions for the analysis and characterization of self-maintaining organizations will be discussed with the aid of examples taken from models of minimal living systems, and some conceptual distinctions will be provided. In the last part of the paper the epistemic implications of these ideas will be presented