Concept of the "physiological age" of animals and its application to ixodid ticks

The definition "physiological age" of animals has been revised. A new definition has been formulated on the basis of V. N. Beklemishev's (1962) and Ju. S. Balashov's (1962) theses as follows: physiological age of animals (= biological) is an extent of general irreversible morphophysiological change of organism during its whole life and determined by the accumulation of irreversible changes as a result of its normal vital activity. This definition is equivalent to that of "biological ages" of man. The contents of this definition is enlarged and the possibility of its use for different animals including their males is unified. On the basis of the general concept this definition is specified in regard to ixodid ticks: physiological age of hungry ixodid tick is an extent of general irreversible morpholophysiological change of its organism during the whole life and determined by the state of reserve nutrient and excretory substances. According to the amount of reserve and excretory substances in the organism of ixodid tick we distinguish 4 main physiological ages: new-born, young, mature and old which reflect general biological regularity of age development of animals.     

The growth and maturation of the "tarantula", Avicularia avicularia L.

The growth of the theraphosid spider, Avicularia avicularia L. was studied principally by taking measurements of the fang length of exuviae and dead specimens. The relatic ships between fang length and increment at ecdysis and fang length and instar duration were investigated and used to construct a projected growth curve for the species. This suggests that males reach sexual maturity in approximately 13 instars and at a minimum age of about two and a half years. In males the adult instar is terminal and rarely lasts more than three months. Reproductive maturity in females is probably not reached earlier than the XIVth instar or three years from birth. The females continue to moult annually after maturity and have a longevity in excess of seven years. The pattern of colouration shows characteristic changes in early immature life and develops a slight sexual dimorphism in adults. Type II urticating hairs are present throughout life and occur in light and dark forms in the IInd instar. The mean length of the urticating hairs increases during the life cycle and a sexual dimorphism develops in the XIIth or XIIth instar. In adult males the urticating hairs are uniformly barbed whereas in the adult females the barbs are restricted to the proximal end.     

The early life environment and the epigenome

Several lines of evidence point to the early origin of adult onset disease. A key question is: what are the mechanisms that mediate the effects of the early environment on our health? Another important question is: what is the impact of the environment during adulthood and how reversible are the effects of early life later in life? The genome is programmed by the epigenome, which is comprised of chromatin, a covalent modification of DNA by methylation and noncoding RNAs. The epigenome is sculpted during gestation, resulting in the diversity of gene expression programs in the distinct cell types of the organism. Recent data suggest that epigenetic programming of gene expression profiles is sensitive to the early-life environment and that both the chemical and social environment early in life could affect the manner by which the genome is programmed by the epigenome. We propose that epigenetic alterations early in life can have a life-long lasting impact on gene expression and thus on the phenotype, including susceptibility to disease. We will discuss data from animal models as well as recent data from human studies supporting the hypothesis that early life social-adversity leaves its marks on our epigenome and affects stress responsivity, health, and mental health later in life.     

How the genome got a life span

In the space of little more than a decade, ideas of the human genome have shifted significantly, with the emergence of the notion that the genome of an individual changes with development, age, disease, environmental inputs, and time. This paper examines the emergence of the genome with a life span, one that experiences drift, instability, and mutability, and a host of other temporal changes. We argue that developments in chromatin biology have provided the basis for this genomic embodiment of experience and exposure. We analyze how time has come to matter for the genome through chromatin, providing analysis of examples in which the human life course is being explored as a set of material changes to chromatin. A genome with a life span aligns the molecular and the experiential in new ways, shifting ideas of life stages, their interrelation, and the temporality of health and disease.     

Inheritance of polymorphic metabolizing genes on environmental disease and quality of life.

From investigations based on the human genome and the environmental genome programs, genetic basis for individual differences in response to environmental mutagens is being characterized. Inheritance of variant versions of certain polymorphic genes is frequently associated with the development of environmental disease, such as lung cancer from cigarette smoking. Inheritance of these alleles may also affect the quality of life such as longevity. Evidence in support of these possibilities is presented. It is obvious that through the understanding of susceptibility, more precise disease prevention strategies can be implemented which will not only reduce the disease burden but also improve the quality of life.     

"Vulnerable plaques"--ticking of the time bomb

Atherosclerosis and its sequelae are one of the leading causes of morbidity and mortality, especially in the developed nations. Over the years, treatment protocols have changed with the changing understanding of the disease process. Inflammatory mechanisms have emerged as key players in the formation of the atherosclerotic plaque. For the majority of its life span, the plaque develops silently and only some exhibit overt clinical manifestations. The purpose of this review is to examine the inherent properties of some of these "vulnerable" or symptomatic plaques. Rupture of the plaque is related to the thickness of the fibrous cap overlying the necrotic lipid core. A thin cap is more likely to lead to rupture. Multiple factors broadly grouped as the "determinants of vulnerability" are responsible for directly or indirectly influencing the plaque dynamics. Apoptosis is considered an important underlying mechanism that contributes to plaque instability. Inflammatory reactions within the plaque trigger apoptosis by cell-cell contact and intra cellular death signaling. Once started, the apoptotic process affects all of the components that make up the plaque, including vascular smooth muscle cells, endothelial cells, and macrophages. Extensive research has identified many of the key cellular and molecular regulators that play a part in apoptosis within the atherosclerotic lesion. This information will help us to gain a better understanding of the underlying mechanisms at the cellular and molecular level and enable us to formulate better therapeutic strategies to combat this disease.     

Setting a standard for a "silent" disease: defining osteoporosis in the 1980s and 1990s

Osteoporosis, a disease of bone loss associated with aging and estrogen loss, can be crippling but is 'silent' (symptomless) prior to bone fracture. Despite its disastrous health effects, high prevalence, and enormous associated health care costs, osteoporosis lacked a universally accepted definition until 1992. In the 1980s, the development of more accurate medical imaging technologies to measure bone density spurred the medical community's need and demand for a common definition. The medical community tried, and failed, to resolve these differing definitions several times at consensus conferences and through published articles. These experts finally accepted a standard definition at an international consensus conference convened by the World Health Organization in 1992. The construction of osteoporosis as a disease of quantifiable risk diagnosed by medical imaging machines reflects contemporary trends in medicine, including the quantification of disease, the risk factor model, medical disciplinary boundaries, and global standardization of medical knowledge.     

Determination of the processes driving the acquisition of immunity to malaria using a mathematical transmission model

Acquisition of partially protective immunity is a dominant feature of the epidemiology of malaria among exposed individuals. The processes that determine the acquisition of immunity to clinical disease and to asymptomatic carriage of malaria parasites are poorly understood, in part because of a lack of validated immunological markers of protection. Using mathematical models, we seek to better understand the processes that determine observed epidemiological patterns. We have developed an age-structured mathematical model of malaria transmission in which acquired immunity can act in three ways (“immunity functions”): reducing the probability of clinical disease, speeding the clearance of parasites, and increasing tolerance to subpatent infections. Each immunity function was allowed to vary in efficacy depending on both age and malaria transmission intensity. The results were compared to age patterns of parasite prevalence and clinical disease in endemic settings in northeastern Tanzania and The Gambia. Two types of immune function were required to reproduce the epidemiological age-prevalence curves seen in the empirical data; a form of clinical immunity that reduces susceptibility to clinical disease and develops with age and exposure (with half-life of the order of five years or more) and a form of anti-parasite immunity which results in more rapid clearance of parasitaemia, is acquired later in life and is longer lasting (half-life of >20 y). The development of anti-parasite immunity better reproduced observed epidemiological patterns if it was dominated by age-dependent physiological processes rather than by the magnitude of exposure (provided some exposure occurs). Tolerance to subpatent infections was not required to explain the empirical data. The model comprising immunity to clinical disease which develops early in life and is exposure-dependent, and anti-parasite immunity which develops later in life and is not dependent on the magnitude of exposure, appears to best reproduce the pattern of parasite prevalence and clinical disease by age in different malaria transmission settings. Understanding the effector mechanisms underlying these two immune functions will assist in the design of transmission-reducing interventions against malaria.     

The microbiota,a necessary element of immunity

The intestinal microbiota is essential for digestion, the production of physiological metabolites, and defense. More than 10¹³ bacteria are present in the intestine, inspiring awe as well as fear of potential infections. By definition, the immune system protects us from infection, and is given the task to recognize dangerous pathogens from useful mutualists. Nevertheless, the definition of pathogens and mutualists is often contextual, and the immune system reacts to all types of microbes. In fact, immune reactivity to microbiota is necessary for the development of the immune system. If the host-microbe cross-talk is perturbed before birth or weaning, the immune system develops “pathological imprinting” and increased susceptibility to inflammatory pathology later in life. Reactivity to microbiota is also important in adulthood to regulate immune responses and maintain homeostasis.     

Cell defense systems against oxidative stress and endoplasmic reticulum stress: Mechanisms of regulation and the effect of hepatitis C virus

Hepatitis C virus (HCV) is one of the most widespread and dangerous human pathogens. In most cases, hepatitis C develops into chronic conditions, which often escape antiviral therapy and cause damage to various organs and systems. The conditions include liver fibrosis, steatosis, and hepatocellular carcinoma. These diseases are currently linked to oxidative stress and endoplasmic reticulum (ER) stress, which are induced by virus proteins. At the same time, HCV disturbs the systems that protect cells from these stresses, thus avoiding their effect on the virus life cycle. The review analyzes recent data on the function of the cell defense system in HCV-infected and uninfected cells. In addition, the structure of the HCV genome and the main functions of virus proteins are summarized in brief.     

Reflections on the problem of "discreteness" and "steady state" in living processes

A survey is given over the different meaning of the dialectic pair of terms continuity and discontinuity in philosophy contrasting with sciences. In mathematics, the term continuum is defined by Cantor in set theory as the innumerable multitude of the real numbers especially in the interval [0, 1]. The discontinuum means in Cantor's definition the rational fractions in [0, 1] which in triadic development do not contain the figure 1 [written I). In a more general sense, continuum is used in the mechanics of continuous fluids and gases in physics as well as in physiology. Here, the use of this term neglects the reality of intermolecular spaces intentionally. To employ in the life sciences, the pair of terms steady state and discreteness is clearer. Processes of life mostly are steady in the sense of balanced proceedings but numbers of individuals, cells, molecules, sexes etc, are discrete only. For example, the difference or the dimorphism between males and females is a distinct one between two different conditions but cannot be projected on "discontinuity". Discreteness as a term comprehends Boole an variables as are male-female, living-dead, as well as crowds of measure points.     

Toxicology and genetic toxicology in the new era of "toxicogenomics": impact of "-omics" technologies.

The unprecedented advances in molecular biology during the last two decades have resulted in a dramatic increase in knowledge about gene structure and function, an immense database of genetic sequence information, and an impressive set of efficient new technologies for monitoring genetic sequences, genetic variation, and global functional gene expression. These advances have led to a new sub-discipline of toxicology: "toxicogenomics". We define toxicogenomics as "the study of the relationship between the structure and activity of the genome (the cellular complement of genes) and the adverse biological effects of exogenous agents". This broad definition encompasses most of the variations in the current usage of this term, and in its broadest sense includes studies of the cellular products controlled by the genome (messenger RNAs, proteins, metabolites, etc.). The new "global" methods of measuring families of cellular molecules, such as RNA, proteins, and intermediary metabolites have been termed "-omic" technologies, based on their ability to characterize all, or most, members of a family of molecules in a single analysis. With these new tools, we can now obtain complete assessments of the functional activity of biochemical pathways, and of the structural genetic (sequence) differences among individuals and species, that were previously unattainable. These powerful new methods of high-throughput and multi-endpoint analysis include gene expression arrays that will soon permit the simultaneous measurement of the expression of all human genes on a single "chip". Likewise, there are powerful new methods for protein analysis (proteomics: the study of the complement of proteins in the cell) and for analysis of cellular small molecules (metabonomics: the study of the cellular metabolites formed and degraded under genetic control). This will likely be extended in the near future to other important classes of biomolecules such as lipids, carbohydrates, etc. These assays provide a general capability for global assessment of many classes of cellular molecules, providing new approaches to assessing functional cellular alterations. These new methods have already facilitated significant advances in our understanding of the molecular responses to cell and tissue damage, and of perturbations in functional cellular systems.As a result of this rapidly changing scientific environment, regulatory and industrial toxicology practice is poised to undergo dramatic change during the next decade. These advances present exciting opportunities for improved methods of identifying and evaluating potential human and environmental toxicants, and of monitoring the effects of exposures to these toxicants. These advances also present distinct challenges. For example, the significance of specific changes and the performance characteristics of new methods must be fully understood to avoid misinterpretation of data that could lead to inappropriate conclusions about the toxicity of a chemical or a mechanism of action. We discuss the likely impact of these advances on the fields of general and genetic toxicology, and risk assessment. We anticipate that these new technologies will (1) lead to new families of biomarkers that permit characterization and efficient monitoring of cellular perturbations, (2) provide an increased understanding of the influence of genetic variation on toxicological outcomes, and (3) allow definition of environmental causes of genetic alterations and their relationship to human disease. The broad application of these new approaches will likely erase the current distinctions among the fields of toxicology, pathology, genetic toxicology, and molecular genetics. Instead, a new integrated approach will likely emerge that involves a comprehensive understanding of genetic control of cellular functions, and of cellular responses to alterations in normal molecular structure and function.     

The effect of haplotype-block definitions on inference of haplotype-block structure and htSNPs selection

It has been recently suggested that the human genome is organized as a series of haplotype blocks, and efforts to create a genome-wide haplotype map are already underway. Several computational algorithms have been proposed to partition the genome. However, little is known about their behaviors in relation to the haplotype-block partitioning and haplotype-tagging SNPs selection. Here, we present a systematic comparison of three classes of haplotype-block partition definitions, a diversity-based method, a linkage-disequilibrium (LD)-based method, and a recombination-based method. The data used were derived from a coalescent simulation under both a uniform recombination model and one that assumes recombination hotspots. There were considerable differences in haplotype information loss in the measure of entropy when the partition methods were compared under different population-genetics scenarios. Under both recombination models, the results from the LD-based definition and the recombination-based definition were more similar to each other than were the results from the diversity-based definition. This work demonstrates that when undertaking haplotype-based association mapping, the choice of haplotype-block definition and SNP selection requires careful consideration.     

Ontogenetic variation of the human genome

The human genome demonstrates variable levels of instability during ontogeny. Achieving the highest rate during early prenatal development, it decreases significantly throughout following ontogenetic stages. A failure to decrease or a spontaneous increase of genomic instability can promote infertility, pregnancy losses, chromosomal and genomic diseases, cancer, immunodeficiency, or brain diseases depending on developmental stage at which it occurs. Paradoxically, late ontogeny is associated with increase of genomic instability that is considered a probable mechanism for human aging. The latter is even more appreciable in human diseases associated with pathological or accelerated aging (i.e. Alzheimer's disease and ataxia-telangiectasia). These observations resulted in a hypothesis suggesting that somatic genomic variations throughout ontogeny are determinants of cellular vitality in health and disease including intrauterine development, postnatal life and aging. The most devastative effect of somatic genome variations is observed when it manifests as chromosome instability or aneuploidy, which has been repeatedly noted to produce pathologic conditions and to mediate developmental regulatory and aging processes. However, no commonly accepted concepts on the role of chromosome/genome instability in determination of human health span and life span are available. Here, a review of these ontogenetic variations is given to propose a new "dynamic genome" model for pathological and natural genomic changes throughout life that mimic those of phylogenetic diversity.     

Cybernetic formulation of the definition of life

A definition of life (a living individual) in cybernetic terms is proposed. In this formulation, life (a living individual) is defined as a network of inferior negative feedbacks (regulatory mechanisms) subordinated to (being at service of) a superior positive feedback (potential of expansion). It is suggested that this definition is the minimal definition, necessary and sufficient, for life to be distinguished from inanimate phenomena and, as such, it describes the essence of life. Subsequently, a quantitative expression for the amount of the biologically relevant ("purposeful") information (as opposed to the amount of information in the thermodynamic sense) is proposed. This is followed by the application of the formulated approach to different phenomena of a dubious status existing presently on the Earth as well as to the process of origination of life on our planet.     

Analysis of correlation between some parameters depending on cell proliferation and life span of "stationary phase aging" cultures and maximum life span of mammals

Earlier we developed a "stationary phase aging" model and introduced a definition of life span of "stationary phase aging" cell cultures. In this model the cells grow after seeding in flasks without subcultivation and medium change. They reach cell saturation density, stop dividing, gradually degrade ("stationary phase aging") and perish. By the term "culture life span" we designate the time from cell seeding until culture death. We designate the culture as dead when the number of living cells is less than 10 per cent of their number at saturation density of cell culture. The life span of transformed Chinese hamster cells was found to be proportional to the duration of their growth from cell seeding up to saturation density, as well as to the number of cell culture doublings and to be inversely proportional to the velocity of cell culture doubling for the same growth period. Maximum life span of mammals is known to be proportional to pregnancy duration and to the age at puberty. We found that maximal life span of mammals was proportional to the number of cell population doublings and inversely proportional to the velocity of cell population doubling during embryonal period or for the time from zygote to growth termination. The dependences for cell cultures and for mammals are analogous to each other.     

Proceedings of the SMBE Tri-National Young Investigators' Workshop 2005. Investigating the intron recognition mechanism in eukaryotes

Recent studies indicate that many introns, as well as the complex spliceosomal mechanism to remove them, were present early in eukaryotic evolution. This study examines intron and exon characteristics from annotations of whole genomes to investigate the intron recognition mechanism. Exon definition uses the exon as the unit of recognition, placing length constraints on the exon but not on the intron (allowing it a greater range of lengths). In contrast, intron definition uses the intron itself as the unit of recognition and thus removes constraints on internal exon length forced by the use of an exon definition mechanism. Thus, intron and exon lengths within a genome can reflect the constraints imposed by its splicing. This study shows that it is possible firstly to recover valid intron and exon information from genome annotation. We then compare internal intron and exon information from a range of eukaryotic genomes and investigate possible evolutionary length constraints on introns and exons and how they can impact on the intron recognition mechanism. Results indicate that exon definition-based mechanisms may predominate in vertebrates although the exact system in fish is expected to show some differences with the better characterized system from mammals. We also raise the possibility that the last common ancestor of plants and animals contained some type of exon definition and that this mechanism was replaced in some genes and lineages by intron definition, possibly as a result of intron loss and/or intron shortening.     

Towards a General Definition of Life

A new definition of life is proposed and discussed in the present article. It is formulated by modifying and extending NASA’s working definition of life, which postulates that life is a “self-sustaining chemical system capable of Darwinian evolution”. The new definition includes a thermodynamical aspect of life as a far from equilibrium system and considers the flow of information from the environment to the living system. In our derivation of the definition of life we have assumed the hypothesis, that during the emergence of life evolution had to first involve autocatalytic systems that only subsequently acquired the capacity of genetic heredity. The new proposed definition of life is independent of the mode of evolution, regardless of whether Lamarckian or Darwinian evolution operated at the origins of life and throughout evolutionary history. The new definition of life presented herein is formulated in a minimal manner and it is general enough that it does not distinguish between individual (metabolic) network and the collective (ecological) one. The newly proposed definition of life may be of interest for astrobiology, research into the origins of life or for efforts to produce synthetic or artificial life, and it furthermore may also have implications in the cognitive and computer sciences.