Autopoiesis: The organization of living systems,its characterization and a model

We formulate the organization of living organisms through the characterization of the class of autopoietic systems to which living things belong. This general characterization is seen at work in a computer simulated model of a minimal case satisfying the conditions for autopoietic organization.     

The logic of kinetic regulation in the thioredoxin system

Background  

The thioredoxin system consisting of NADP(H), thioredoxin reductase and thioredoxin provides reducing equivalents to a large and diverse array of cellular processes. Despite a great deal of information on the kinetics of individual thioredoxin-dependent reactions, the kinetic regulation of this system as an integrated whole is not known. We address this by using kinetic modeling to identify and describe kinetic behavioral motifs found within the system.     

A biochemical logic gate using an enzyme and its inhibitor. Part II: The logic gate

Enzyme-Based Logic Gates (ENLOGs) are key components in bio-molecular systems for information processing. This report and the previous one in this series address the characterization of two bio-molecular switching elements, namely the alpha-chymotrypsin (alphaCT) derivative p-phenylazobenzoyl-alpha-chymotrypsin (PABalphaCT) and its inhibitor (proflavine), as well as their assembly into a logic gate.The experimental output of the proposed system is expressed in terms of enzymic activity and this was translated into logic output (i.e. "1" or "0") relative to a predetermined threshold value. We have found that an univalent link exists between the dominant isomers of PABalphaCT (cis or trans), the dominant form of either acridine (proflavine) or acridan and the logic output of the system. Thus, of all possible combinations, only the trans-PABalphaCT and the acridan lead to an enzymic activity that can be defined as logic output "1". The system operates under the rules of Boolean algebra and performs as an "AND" logic gate.     

Autopoiesis, Life, Mind and Cognition: Bases for a Proper Naturalistic Continuity

The strong version of the life-mind continuity thesis claims that mind can be understood as an enriched version of the same functional and organizational properties of life. Contrary to this view, in this paper I argue that mental phenomena offer distinctive properties, such as intentionality or representational content, that have no counterpart in the phenomenon of life, and that must be explained by appealing to a different level of functional and organizational principles. As a strategy, and following Maturana’s autopoietic theory of cognition, I introduce a conceptual distinction between mind and cognition. I argue that cognition corresponds to the natural behaviour that every living being exhibits in the realization of its existence, and that, viewed in that way, cognition is a dynamic process of structural coupling that, unlike mental phenomena, involves no representational contents. On the basis of this distinction, I try to show that while life suffices for cognition, it does not suffice for mind. That is, that the strong continuity is not between life and mind but between life and cognition.     

Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis

The general utility of the maximum tolerated dose (MTD) paradigm, a strategy aimed at optimizing the chance of total tumor cell eradication, is here questioned. Evidence to date suggests that for many tumors the potential for eradication is in fact remote, with patients consistently demonstrating tumor cell presence subsequent to MTD treatments having eradicative intent. The failure to eradicate is attributed largely to the heterogeneous nature of the tumor. Heterogeneous cell populations demonstrate short-term refractoriness to up-front dose delivery, but "resensitize" as part of dose recovery, showing increased overall susceptibility to a given series of doses when delivered more evenly spaced. It is demonstrated: (1) that the minimization of total tumor burden, rather than complete eradication, may often be the more practical objective; and (2) that regularly spaced, "metronomic" dosing is the best way to achieve it. As a corollary, it is found that the more efficient ability of the tumor endothelial cells to resensitize following dosing predicts a targeting bias towards the endothelial compartment of a tumor when metronomic dosing is employed. This lends theoretical support to recent empirical studies showing that regularly spaced dosing schedules with no extended rest periods act more antiangiogenically, thereby delaying or avoiding the onset of acquired resistance.     

Laboratory diagnosis of the status of the hemostasis system

Activators of fibrinogen, prothrombin and protein C isolated from venoms of Agkistrodon halys halys and Echis multisquamatus may be used as a tool both for thrombosis investigations in the model systems and for diagnostic in the clinical practice. The complex of diagnostic tests developed on the base of these activators allows to characterize the haemostatic system at different pathologies and as well as to determine the unbalance between separate components of haemostasis. The tests are approved on plasma of patients with heart diseases, ulcers, nephrites, hestoses etc. The tests are sensitive, informative, easy to use and do not require an additional equipment. They have no analogues in Ukraine.     

Haemophilus influenzae: the current status of its in vitro susceptibility to antimicrobials

Continuous surveillance of the antimicrobial susceptibility patterns of strains of Haemophilus influenzae (H. i.) is part of a routine surveillance of bacterial sensitivity to antibiotics. In this study a major attention was given to the clinically important antimicrobials used in the treatments of H. i. infections, namely ampicillin, chloramphenicol and some cephalosporin preparations. Antimicrobial susceptibility determinations carried out in 1983 and before on H.i. strains isolated in different Czech regions show a clear-cut tendency towards the higher incidence of strains resistant to ampicillin and its derivative amoxycillin. The rise in resistance to erythromycin was also observed. Susceptibility to chloramphenicol continues to remain unchanged. Of the cephalosporin antimicrobials tested (cephalothin, ceftriaxone, cefaperazone, cefsulodine and cefadroxil) the most active were ceftriaxone and cefaperazone. The need of a further continuation of surveillance of H.i. drug susceptibility patterns is strongly emphasized; to ensure effective treatment results antibiograms should be done in each case of H.i. infection.     

Current status of the anticoagulant hirudin: its biotechnological production and clinical practice

Hirudin is a potent thrombin inhibitor originally derived from the medicinal leech, Hirudo medicinalis. Owing to its high affinity and specificity for thrombin, hirudin has been intensively investigated for research and therapeutic purposes. The investigation of hirudin has contributed greatly to the understanding of the mode of action of thrombin and the clotting system. Hirudin and several hirudin analogues have also been demonstrated to have several advantages as a highly specific anticoagulant over the most widely used drug, heparin. Due to the great demand for hirudin in physicochemical and clinical studies, various recombinant systems have been developed, using bacteria, yeasts, and higher eukaryotes, to obtain the biologically active hirudin in significant quantities. After 10 years of clinical applications, two recombinant hirudins and a hirudin analogue have gained marketing approval from the United States Food and Drug Administration, for several applications. Clinical trials are currently ongoing for other treatments for thrombotic disease. As a consequence, it is conceivable that hirudin may expand its therapeutic utility over heparin in the near future.     

Leptin and the immune system: how nutritional status influences the immune response

Several observations suggest the presence of an interaction between immune and the endocrine systems. Leptin is an adipocyte-derived hormone, that belongs structurally to the long-chain helical cytokine family such as interleukin-2 (IL-2), interleukin-12 (IL-12), growth hormone (GH), and signals by a class I cytokine receptor (Ob-R). This cytokine represents an important link between fat mass on the one side and the regulation of energy balance and reproductive function on the other. Indeed, obese leptin-deficient ob/ob mice display low body temperature, hyperphagia, infertility and evidence of immune defects with lymphoid organ atrophy, mainly affecting thymic size and cellularity. Acute starvation, associated with decreased leptin levels, causes thymic atrophy and reduces the delayed type hypersensitivity (DTH) reaction to antigens in normal mice, resembling that observed in ob/ob mice. Leptin replacement reverses the immunosuppressive effects of acute starvation in mice. Leptin differentially affects the in vitro proliferation and cytokine production by naive and memory T cells, increasing IL-2 secretion and proliferation of naive T cells, while inducing IFN-g production in memory T cells with little effect on their proliferation. Presence of leptin seems to be necessary for the induction and maintenance of the pro-inflammatory Th1 immune response. These findings support the hypothesis that leptin plays a key role in linking nutritional state to the T cell function. According to this view, leptin might represent an important target for immune intervention in a variety of pathophysiological conditions.     

Alternative pre-mRNA splicing: the logic of combinatorial control

Alternative splicing of mRNA precursors is a versatile mechanism of gene expression regulation that accounts for a considerable proportion of proteomic complexity in higher eukaryotes. Its modulation is achieved through the combinatorial interplay of positive and negative regulatory signals present in the RNA, which are recognized by complexes composed of members of the hnRNP and SR protein families.