Free-energy landscape of enzyme catalysis

The concept is developed that enzyme mechanisms should be viewed as "catalytic networks" with multiple conformations that occur serially and in parallel in the mechanism. These coupled ensembles of conformations require a multi-dimensional standard free-energy surface that is very "rugged", containing multiple minima and transition states. Experimental and theoretical evidence is presented to support this concept.     

Host-limited dynamics of autoparasitoids

Patrick Suppes' slogan that "to axiomatize a theory is to present a set-theoretical predicate" was used in the synthetic theory of evolution. The system presented here extends the axiomatics of the evolutionary theory presented by M. Williams to encompass aspects of genetics. Some biological implications of the system are discussed, including the relationship between the Darwinian concept of fitness, as applied to organisms, and the concept of fitness as applied to genotypes, as it is normally used in population genetics. This paper should be viewed as an adjunct to the speculations on the logical-mathematical foundations of biological sciences.     

The "protein-machine" concept and its consequences

Analysis is presented of the concept "protein-machine" and implying consequences, both of theoretical and experimental character. The approach "protein-machine" is compared with other approaches--"coherent excitation", "molecular dynamics" and "limited diffusion". In terms of the approach "protein-machine" valuable information inserted in the biological macromolecule and determining its functions is taken into account. It reflects the biological specificity and at the same time removes mystic shadow from this concept.     

On the concept of effective number.

A generalized conceptual basis for Wright's notion of effective size is presented. The concept is applied to the calculation of effective numbers based on the rate of change of genetic variability. With particular reference to the inbreeding, the eigen value, and the newly introduced "diversity" effective size, the use of the concept as a means for discrimination between and identification of various effective sizes is demonstrated.     

Behaviour and the concept of “Heritability” axioms of an ethological refutation

This paper discusses the widespread use of heritability calculations in recent behaviour research including behaviour genetics. In the sequel, a radical criticism concerning the basic axioms of the underlying, more general concept itself is presented. The starting point for testing the proclaimed universal validity of this concept stems from a fictitious yet realistic example taken from learning research. The theoretical result, based on the application of the conventional reasoning in this field, states that developmental processes — and learning is only one specific case out of an immense number of similar behavioural mechanisms — can neither be adequately described nor causally explained with sufficient reliability within the context of the heredity paradigm. On the contrary, an inherent inconsistency of the concept itself when applied to behaviour processes is demonstrated. Finally, a conceptual alternative involving a systems-theoretical approach to the problem is presented: In such a perspective it is the concept of cognition which represents the adequate explanatory theorem - a theorem in which quantitative processing of information from the environment is clearly revealed to belong to a subordinate level of living organization.     

The Psychology of Human Existence and the Subject's Self-Understanding

The author compares understandings of the concept of "subject" in Russian and Western (existential and cognitive) psychology. Psychological reality is presented as a value-oriented phenomenon and as the reason that the main method of studying psychological reality is the "narrative principle," which unifies the cognitive and existential approaches.     

Cirrhosis with atypia. A potential pitfall in the interpretation of liver aspirates

Needle aspirations of the liver yielding highly atypical hepatocytes present a diagnostic challenge, with the differential diagnosis lying between hepatocellular carcinoma and benign reactive atypia. A case of a healing liver abscess in a patient with cirrhosis, mistakenly diagnosed as an hepatocellular carcinoma, is presented. Criteria for the avoidance of false-positive diagnoses of hepatocellular carcinoma on needle aspirates are presented, and the concept of "liver cell dysplasia" as a cytodiagnostic entity is discussed.     

Regulation of IgE antibody production by serum molecules. V. Evidence that coincidental sensitization and imbalance in the normal damping mechanism results in "allergic breakthrough".

Experiments presented in this paper were designed to test a new concept concerning the possible pathogenesis of the allergic phenotype. This concept, termed "allergic breakthrough" considers that one of the avenues toward the allergic phenotype involves coincidental sensitization combined with an imbalance in the normal damping mechanism that serves to limit IgE antibody production. The three predictions of this concept that can be tested experimentally are: 1) manipulations that are effective in heightening or re-establishing the damping mechanism should manifest persistence insofar as IgE antibody synthesis to the relevant allergen is concerned; 2) once allergic breakthrough has occurred, the height of production of IgE antibodies specific for the sensitizing agent should remain elevated at levels characteristic of the allergic phenotype, even after the threshold of damping activity has returned to a normal level; and 3) allergic breakthrough should display specificity in that breakthrough would occur in response to subsequent exposure to the specific antigen to which coincidental sensitization initially occurred, but not for other unrelated antigens. The studies presented herein confirm each one of these predictions, thereby providing substantial support for the validity of this concept as one possible distinguishing feature between individuals manifesting the nonallergic and allergic phenotypes, respectively.     

Role of microvillar cell surfaces in the regulation of glucose uptake and organization of energy metabolism

Experimental evidencesuggesting a type of glucose uptake regulation prevailing inresting and differentiated cells was surveyed. This type of regulationis characterized by transport-limited glucose metabolism and depends onsegregation of glucose transporters on microvilli of differentiated orresting cells. Earlier studies on glucose transport regulation and arecently presented general concept of influx regulation for ions andmetabolic substrates via microvillar structures provide the basicframework for this theory. According to this concept, glucose uptakevia transporters on microvilli is regulated by changes in thestructural organization of the microfilament bundle, which is acting asa diffusion barrier between the microvillar tip compartment and thecytoplasm. Both microvilli formation and the switch of glucosemetabolism from "metabolic regulation" to "transportlimitation" occur during differentiation. The formation ofmicrovillar cell surfaces creates the essential preconditions toestablish the characteristic functions of specialized tissue cellsincluding the coordination between glycolysis and oxidativephosphorylation, regulation of cellular functions by external signals,and Ca²⁺ signaling. The proposed concept integrates variousaspects of glucose uptake regulation into a ubiquitous cellularmechanism involved in regulation of transmembrane ion and substrate fluxes.

     

Chemosensory cross-modal stroop effects: congruent odors facilitate taste identification

In order to explore the cross-modal cognitive associations between smell and taste, a chemosensory analogue of the Stroop task (Stroop 1935) was developed. Fourteen participants were presented with an odorant and a tastant and asked to identify the tastant as "sweet" or "sour" by pressing 1 of 2 buttons as quickly as possible. Participants were faster to name the taste when it was presented with an odor that was congruent (e.g., strawberry/sweet) than with an incongruent odor (e.g., strawberry/sour). These results support the concept of a high level of cognitive integration between the senses of smell and taste and illustrates occasions of interference between information arising from different sensory systems.     

森林公园在我国自然保护区系统中的地位

本文针对我国森林公园建设发展迅速的现状,阐述了“森林公园”的自然保护性质和作用,提出“国家自然保护区系统”的概念,将森林公园与自然保护区、风景名胜区三个体系同视为“国家自然保护区系统”中的三个组成部分,并阐述了这三个体系各自的特点、地位及其相互关系。同时,还提出进一步加强森林公园管理的建议。     

Metabolic “In VivoDesigning” of Tumors at the Levels of an Organism and Population under Conditions of Individual Genetic Predisposition: Communication I

The concept of a metabolic in vivodesigning of tumors at the levels of an organism and population (metabolic ethnic oncopathology) is presented. According to this concept, the beginning and growth of tumors in various populations (ethnic groups), the inherited predisposition of such groups to tumors, and the incidence of cancer are determined by group-specific differences in the starting conditions of enzyme systems responsible for the metabolism of chemical carcinogens. Therefore, the in vivodesigning of tumors, the predisposition to cancer, and the cancer morbidity should be ethnically dependent. Genetically homogeneous populations should be either predisposed to a certain type of cancer or less sensitive to chemical carcinogenesis than heterogeneous populations. Based on this concept, the idea of metabolic ethnic oncological data register of a population is suggested. The purpose of such a data register would be to assess the genetical predisposition to tumors in various ethnic groups by determining the starting conditions of enzyme systems responsible for the metabolism of chemical carcinogens. Two phases and main pathways of metabolism (activation and detoxification) of chemical carcinogens are characterized briefly, and the role of certain enzymes in these processes is also described. The literature data are presented on the correlations between the enzyme activity and cancer morbidity in various ethnic groups.     

A general model for the propagation of uncertainty in measurements into heat transfer simulations and its application to cryosurgery

This report presents a technique for estimating the propagation of uncertainty in measurements into mathematical simulations of heat transfer. The motivation for this report is to show the dramatic uncertainty associated with estimating the value of the so-called "lethal temperature," even in a case where a perfect correlation appears to exist between histo-pathologic observations and a corresponding heat transfer simulation. Although the example presented in this report relates to cryosurgery, the technique proposed in this report is rather general and can be applied to any heat transfer problem. The uncertainty analysis presented in this report can be considered as an extension of the well-known concept of the rule of the square root of the sum of the square errors. A comparison of the new technique with the worst case scenario concept is also presented. In conclusion, it is recommended that the proposed technique be routinely applied when presenting simulated results, whether as a part of a theoretical study, or in comparison with experimental data.     

Self-organization and emergence are some irrelevant concepts without their association with the concepts of hetero-organization and immergence

There are many reasons for questioning the relevance of the concepts of self-organization (SO) and emergence. By studying three types of SO, respectively related to ontogeny, phylogeny and formalized models, we show that we always have to suppose an associated hetero-organization and preconceived immergence, unconsciously present in the authors mind. In order to understand how these unusual couples are working, they must be considered as agonistic antagonistic couples. Heteroorganization and immergence put constraints on the system so that SO and emergence will produce new patterns and forms, depending on these constraints. Besides, such couples (SO and heteroorganization, emergence and immergence) seem to belong to a series of couples of the same type, allowing us to define a kind of model of life.The concept of self-organization has been presented as the main concept defining systemics, and second order cybernetics. This concept has been accepted also in general Biological Theory (BT) where authors endowed the key to many phenomena until then poorly understood.Nevertheless, we question the validity of this concept, or more precisely point out that the concept contains non explicit elements which were neglected. We propose a frame in which this concept-and the associated concept of emergence-remains available, but can no longer claim to give an account for the features they are said to explain by themselves alone.     

5-diacetoxymethyl-cycloSal-d4TMP - A prototype of enzymatically activated cycloSal-pronucleotides

A new class of "lock-in"-modified cycloSal-pronucleotides has been synthesized. On the example of 5-diacetoxymethyl-cycloSal-d4T-monophosphate (5-di-AM-cycloSal-d4TMP), the concept of enzymatically activated cycloSal-pronucleotides is elucidated. Synthesis, hydrolysis studies, and antiviral activities against HIV are presented.     

The ribbon structure of the mitochondrial inner membrane

Electron microscopic evidence is presented for the extensive association of protein subunits into ribbons within the mitochondrial inner membrane. The mitochondrial cristae can be rearranged to a narrow tubular form which exhibits ribbon structure and is fully functional; the morphology of particles derived from submitochondrial electron transport particles by treatment with lysolecithin suggests that the backbone of the ribbon is provided by the cytochrome-free tripartite unit (headpiece, stalk, basepiece) in linear repeat. These results are inconsistent with any single model of the inner membrane previously proposed, but are best understood in terms of a model which combines the concept of an ordered protein continuum with the concept of a fluid lipid bilayer. Further, it is concluded that the headpiece out morphology of the tripartite unit represents a viable conformation of the endergonic transducing unit.     

Transmembrane electron transport and the neutral theory of evolution

Based on the concept of "pairs of basic functional states" the evolution of the first chemiosmotic mechanism of energy conversion is discussed in terms of point mutations, gene duplications and of the neutral theory of evolution. A model for estimating the overall probability of the evolutionary step in question is presented, both for the "selectionist" and "neutralist" position. It is concluded that, concerning the present stage of knowledge, the evolution of transmembrane electron transport is an unsolved problem in evolutionary biology.     

The quantitation of buffering action II. Applications of the formal &; general approach

Background  

The paradigm of "buffering" originated in acid-base physiology, but was subsequently extended to other fields and is now used for a wide and diverse set of phenomena. In the preceding article, we have presented a formal and general approach to the quantitation of buffering action. Here, we use that buffering concept for a systematic treatment of selected classical and other buffering phenomena.     

The iliac passion.

"The Iliac Passion" traces a return from the new but busy and rapidly growing discipline of "bioethics" to its source in "fundamental philosophical inquiry." The dilemma between bioethics and medicine is examined in two ways. First, the philosophical concept of the "big question" is presented. If we ask of life or of human experience "What does it all mean?", the "it" needs to be defined, and what I propose to do is to "take on" the "it." In Part Two, the task of combining the medical-technical objectifying mode of thinking about patients, necessary to treat them effectively, with the ability to understand and sympathize with their pain and distress, is illustrated by means of a personal story or parable.     

Teaching calcium-induced calcium release in cardiomyocytes using a classic paper by Fabiato

This teaching paper utilizes the materials presented by Dr. Fabiato in his review article entitled "Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum." In the review, supporting evidence of calcium-induced calcium release (CICR) is presented. Data concerning potential objections to the CICR theory are discussed as well. In closing, technical issues associated with the skinned cell model are mentioned. Based on this review article, teaching and learning points are put forth in this article to highlight two concepts: 1) the regulatory mechanisms of CICR in cardiomyocytes and 2) the recognition of contradicting hypotheses and limitations in experimental design. The first concept is certainly an important one for physiology students. The second concept is universally applicable to researchers in all fields of science. It is thus the aim of this article to cultivate a rewarding teaching and learning experience for both instructors and students.