The most important physical quantity used to define the deposition of energy in organs and tissues from ionizing radiation is the absorbed dose, but this measure does not characterize the fluctuation of energy absorption resulting from the stochastic nature of the energy deposition events in individual cells. The fluctuation in the energy deposition between cells in a tissue is generally disregarded, but can be significant when the possible effects of ionizing radiation on cells at low doses are considered. Current models of radiation effects in cellular systems are based on direct damage to nuclear DNA being an initiating event in the carcinogenic process. For a given type of radiation, DNA damage is induced in proportion to dose, which implies a linear relationship between cancer induction and dose in the low-dose region. These models have been challenged with a range of studies showing effects in the absence of direct DNA damage due to energy deposition. A range of new observed non-targeted effects of biological responses to radiation shows other mechanisms of action: genomic instability, low dose hypersensitivity, adaptive responses, inverse dose-rate and bystander effects. They are important in determining the biological responses at low doses of radiation and have the potential to influence the shape of the dose-effect relationship by a saturating response above a threshold dose. There is convincing epidemiological evidence that doses of ionizing radiation above about a few tens of mGy cause a small but significant increase in cancer risk.
The history of plant virology has given much space to viruses, especially to Tobacco mosaic virus, but very little space to virus diseases. Still, viruses were clearly characterised only more than fifty years after the first observations and descriptions of diseases appearing infected with ineffable agents and, until the 1950s, most of the plant virologists spent a lot of time to study the disease as the preliminary but absolutely necessity in order to identify the virus. The first virus diseases to be investigated were the "tobacco mosaic" in Europe and "rice stunt" in Far East Asia, and both represented useful models for performing a great number of similar researches. The study of virus diseases made necessary the employment of several strategies, and the introduction of new techniques of research. The simple observation of external symptoms, not too selective and requiring broad experience, was followed by histological and cytological analyses which, in the period herein considered, were carried out by light microscopic methodologies. These analyses helped the research of the physiological causes of symptom formation, which, unfortunately, did not always profit from the interest of plant physiologists and biochemists. This schematic series of efforts was not always followed, since research often proceeded in an erratic way, according to the interest or the possibility of single virologists. However, the comprehensive view emerging from the historical analysis of results (for example, from the first textbook of this discipline) allows us to outline that logical sequence of events we have mentioned above. Obviously, the diffusion of viruses in field was one of most investigated line of research, as well as the individuation of the losses produced by virus diseases. From these fields of research (epidemiology and control), it was possible to enter the war to the most pathogenetic viruses by obtaining the first positive successes: this war became more and more pressing and is still current by the use of a very high technology. The work performed during seventy years at first by beginner virologists and afterwards by mature virologists, amounts to a splendid page of history of virology: This page has been written by hundreds and hundreds researchers, most of them quite neglected by the new generation of plant virologists. This history also represents a grateful homage to those researchers.
Thermostability of proteins in general and especially thermophilic proteins has been subject of a wide variety of studies based on theoretical and experimental investigation. Thermostability seems to be a property obtained through many minor structural modifications. In order to gain better understanding of the thermostability mechanisms of proteins, molecular dynamics simulations of the thermal unfolding reaction of Cyclodextrin glycosyltransferase (EC 2.4.1.19, CGTase) from Bacillus macerans has been carried out for 1.5 ns each at five different temperatures. Distortion of the enzyme is initiated simultaneously in the N- terminal and domain D, while the thermal unfolding of the outer domains of CGTase is faster than that of the catalytic core domain. The catalytic center was well protected by the (a/b)8 TIM-barrel at simulation temperatures up to 600 K. In addition, the unfolding of the 8 b-sheets obeyed the random ordered mechanism, in which the b-sheets 8, 1 and 6 unfolded more rapidly than the others. At the same time, the influences of non-bonded interactions, such as hydrogen bonds and salt bridges, to protein stabilities were also analyzed in detail. The results show clearly that the stability of the protein is not evenly distributed over the whole structure. Our study provides insight into the structure-stability relationship of CGTase, which may help to enlighten our knowledge of protein structural properties, non-bonded interactions that stabilize secondary peptide structures or promote folding and also to better understand their action.
In this article, I critically analyze the impact of the new biology and the biological revolution. I argue that indiscriminate use of the words such as 'interdisciplinary,' 'integrative,' and 'revolution' has caused only confusion when applied to biology. The recent debate, especially after the exploding field of systems biology, has brought back the controversy whether molecular biology is reductionist or holistic. I look at the issues involved critically. I discuss the problem of defining the word 'gene' and argue that recent attempts to redefine the central dogma of molecular biology about the information flow from DNA to RNA to protein are not justified. I support my view with comments from the scientist who discovered RNA splicing. Several aspects of evo-devo, a new branch of biology, are discussed. I give examples from this evolution-developmental biology to show how some of Darwin's inspired guesses have had resounding victory when it was found that specific genes during embryonic development of the Galapagos finches decided the size and shape of their beaks. I discuss the recent publications which show that the conditions in the island, such as wet to dry to wet season, can bring about evolutionary changes from year to year. Thus it is essential to monitor both short and long-term evolutionary changes to get the full picture of evolution.
This short history relates the main events of a phenomenon called "recovery", characterised by the disappearance of symptoms from leaves of plant affected with an initially severe virus disease and by immunity to reinoculation with the same virus. It is a subject first disclosed in 1916 from a rather strange disease of tomato but that was confirmed for a certainty between the 1920s and 1930s in most suitable virus-host combinations. Several authoritative virologists gave different interpretations of this phenomenon so that, for at least two decades, there was on this subject some confusion. The work of Conway Price and Carlyle Bennett directed the problems towards a right understanding of the phenomenon, that had its final legitimation in the 1960s. The mechanism of recovery was long matter of hypotheses, which, however, did not gave solving responses as for neither the disappearance of symptoms nor the presence of virus in recovered tissues. Only in the 1990s, owing to the discovery of the "gene silencing system" some molecular virologists proved that recovery is a consequence of a mechanism operating at the transcript level due to RNA silencing. Today, recovery appears to be an occasional phenomenon shown by a little number of virus-host combinations, but it is not possible to rule out that in the ancient past it was a rather diffuse phenomenon allowing virus to colonise plant without damage.
According to neo-Darwinian theory, biological evolution is produced by natural selection of random hereditary variations. This assumption stems from the idea of a mechanical and deterministic world based on the laws of classic physics. However, the increased knowledge of relationships between metabolism, epigenetic systems, and editing of nucleic acids suggests the existence of self-organized processes of adaptive evolution in response to environmental stresses. Living organisms are open thermodynamic systems which use entropic decay of external source of electromagnetic energy to increase their internal dynamic order and to generate new genetic and epigenetic information with a high degree of coherency and teleonomic creativity. Sensing, information processing, and decision making of biological systems might be mainly quantum phenomena. Amplification of microscopic quantum events using the long-range correlation of fractal structures, at the borderline between deterministic order and unpredictable chaos, may be used to direct a reproducible transition of the biological systems towards a defined macroscopic state. The discoveries of many natural genetic engineering systems, the ability to choose the most effective solutions, and the emergence of complex forms of consciousness at different levels confirm the importance of mind-action directed processes in biological evolution, as suggested by Alfred Russel Wallace. Although the main Darwinian principles will remain a crucial component of our understanding of evolution, a radical rethinking of the conceptual structure of the neo-Darwinian theory is needed.
Genetically modified or engineered organisms (GMOs, GEOs) are utilised in agriculture, expressing traits of interest, such as insect or herbicide resistance. Soybean, maize, cotton and oilseed rape are the GM crops with the largest acreage in the world. The distribution of GM acreage in the different countries is related with the different positions concerning labelling of GMO products: based on the principle of substantial equivalence, or rather based on the precautionary principle. The paper provides an overview on how the risks associated with release of GMO in the environments can be analysed and predicted, in view of a possible coexistence of GM and non-GM organisms in agriculture.Risk assessment procedures, both qualitative and quantitative, are compared in the context of application to GMOs considering also legislation requirements (Directive 2001/18/EC). Criteria and measurable properties to assess harm for human health and environmental safety are listed, and the possible consequences are evaluated in terms of significance.Finally, a mapping of the possible risks deriving from GMO release is reported, focusing on gene transfer to related species, horizontal gene transfer, direct and indirect effects on non target organisms, development of resistance in target organisms, and effects on biodiversity.
T lymphocytes play crucial role in immune responses. Effector T helper (Th) cells derive from progenitor naïve CD4+ T cells, after maturational process induced by antigenic stimulation. Their commitment depends on complex interactions with antigen-presenting cells in a permissive milieu, including antigenic type and load, costimulatory molecules and cytokine signaling. Committed CD4+ T cells may differentiate into Th1, Th2, TH17 phenotypes (the effector Th cell triade), with distinct cytokine products and biological functions, or evolve into the inducible regulatory T (Treg) lineage, with immunomodulatory functions. Th1 subset, primarily addressed to face intracellular pathogens, produces interleukin (IL)-2, IL-3, interferon-gamma and tumour necrosis factor-beta, peculiarly supporting cellular immunity. Th2 cells, essential in eliminating extracellular pathogens, including helminthes, express IL-4, IL-5, IL-6, IL-10, IL-13, and IL-25, supporting humoral immunity. Th17 subset, determinant in fighting Gram-negative bacteria, fungi, and some protozoa, secretes IL-17, IL-21, and IL-22, with strong proinflammatory effects. Th responses are tightly controlled to avoid self antigen reactivity or excessive reactions to non-self antigens. In fact, dysregulated Th1 response drives cell-mediated autoimmune disorders, and enhanced Th2 activity is involved in atopy, whereas Th17 cells are probably responsible for chronic tissue inflammation. Skewing of response away from Treg cells may lead to the onset and/or progression of autoimmune diseases or acute transplant rejection in humans. A better understanding of Th triade functions, and a clearer definition of Th response regulatory mechanisms may provide novel therapeutic opportunities in treating immunopathologies.
In eukaryotic cells, the protein degradation is a highly regulated and selective process. Membrane-associated or extracellular proteins are degraded in lysosomes, whereas intracellular protein dismantling is primarily non-lysosomal, being realized by complex, not-membrane enclosed and energy-dependent effectors, the proteasomes, localized in both cytoplasm and nucleus. In mammals, the proteasomes constitute a structurally and functionally heterogeneous system, with shared general architecture, different molecular compositions and functions, and tissue-specific distribution. The proteasomes regulate a wide range of cellular processes, including protein quality control, gene transcription, cell cycle and death, while a proteasomal subpopulation, the immunoproteasomes, is responsible for the generation of peptides acting as immunogenic epitopes in antigen presentation to the immune cells. Due to the multitude of the targeted substrates and the involved processes, it is not surprising that alterations in the proteasome functions may play a pivotal role in the pathogenesis of several human diseases, such as solid or hematologic malignancies, neurodegenerative, immune and inflammatory disorders. Enormous benefits are emerging from the identification and clinical use of proteasome inhibitors, exhibiting a broad array of biologic properties and providing new and even unpredictable therapeutic opportunities.
The Bov-A2 is one of the most common short interspersed nucleotide elements (SINEs) in ruminants. The genomic distribution and evolution of this retroelement were analysed in order to highlight its possible functional role. Several regions containing an entire Bov-A2 were amplified and polymorphisms were identified by direct sequencing of the amplification products. The obtained sequences were used together with entire Bov-A2 sequences of the public database to analyse their evolutionary pathway. A site-specific micro-recombination followed by gene conversion or unequal crossing-over might be responsible for the high amount of genetic variation of Bov-A2 sequences. Short cDNAs copied by the reverse transcriptase might be the donor sequences for the micro-recombination, according to the RT-mutatorsome mechanism of the somatic hyper-mutation (SHM) process in the hypervariable regions of immunoglobulin and major histocompatibility complex (MHC) genes. The Bov-A2 is generally present in the non-coding regions of several genes preferentially expressed during the cell response to environmental stresses or activation signals. In particular, the presence of Bov-A2 sequence in the 3' untranslated regions of mRNAs involved in cell growth and differentiation during the immune response might be related to an important functional role in the post-transcriptional regulation of gene expression. This hypothesis is supported by the similarity between the conserved "core" sequences motives CACTn (n = 3, 4, 3) of Bov-A2 and elements affecting the messengers stability as several microRNAs (miRNAs). Using primers based on the "core" sequence and bovine, ovine and human cDNAs in RT-PCR experiments, we demonstrate that the mRNAs containing the "core" sequence are present at high levels in lymphocytes only after their activation. Our results suggest the existence of a system based on environmental and epigenetic signals that is able to spread and mutate the Bov-A2 sequence in the genes expressed during the response to cellular activation signals. By means of this adaptive system a reverse flow of information from environment to genes might reinforce and diversify the stress response at cellular and individual levels.
Within the reductionist paradigm that has dominated the cancer research scene over the past 50 years, the definition of cancer and the explanation of its origin have always been given at the molecular genetic level. The neoplastic process is thus commonly explained as the accumulation of somatic mutations in certain genes that thus give rise to tumor cells, with consequent assignment of function to those genes involved. Nevertheless, the search for an essential definition of this disease has shifted attention from molecular components toward the functional properties of the tumor itself, which seems to present specific capabilities, emerging over the course of the disease, so that the functional test is always required to test the properties of certain genes to give tumors. The aim of this work will be to analyze how functions are attributed within the reductionist paradigm, and then proceed to the hypothesis of cancer as a phenomenon linked to loss of organic function and discuss how this notion is consistent with a number of theories already present in the literature and could provide a more unified interpretation of the neoplastic process itself. From this analysis, some elements emerge that highlight the inadequacy of the reductionist interpretation of cancer, with some reasons for the inherent contradiction deriving from the attribution of function to the parts of a biological system when one wants to explain the whole. We also suggest that the characteristics of cancer cells could be functions recovered coincident with the loss of certain functions of the organism as a whole. In this light, a different relation emerges between cancer and selective pressure.
Following any threat to tissutal integrity, innate immune system promptly recognizes foreign/damage-associated molecules and orchestrates the global immune response, inducing inflammation, chemotaxis, phagocytosis and production of antimicrobial effector molecules, as well as providing instruction to the adaptive immune system. Innate immune cells detect both exogenous and endogenous danger signals through invariant germline-encoded pattern recognition receptors, including Toll-like receptors, retinoic acid-inducible gene I-like receptors, and nucleotide binding domain and leucine reach repeat containing receptors (NLRs). The recruitment of NLRs, namely IPAF, NAIPs and NALPs, by various potentially harmful stimuli leads to the assembly of inflammasomes, multimeric caspase-activating complexes entailing the sensor NLR, intracellular adaptor proteins, and procaspase-1 and -5. The caspase activation is necessarily required for the processing and secretion of proinflammatory cytokines, such as interleukin (IL)-1b, IL-18, and IL-33. Therefore, the inflammasomes are critical regulators of the inflammatory response. Dysregulation of such a versatile sentry system is involved in the pathogenesis of human autoinflammatory diseases, autoimmune disorders, and microcrystalline arthritides. A better knowledge of the inflammasome crucial role in the immune response may provide possible future therapeutic improvements in protection against invading pathogens and in vaccine efficacy, as well as in the treatment of human inflammatory diseases.
The central theme of this work is self-organization "interpreted" both from the point of view of theoretical biology, and from a philosophical point of view. By analysing, on the one hand, those which are now considered--not only in the field of physics--some of the most important discoveries, that is complex systems and deterministic chaos and, on the other hand, the new frontiers of systemic biology, this work highlights how large thermodynamic systems which are open can spontaneously stay in an orderly regime. Such systems can represent the natural source of the order required for a stable self-organization, for homoeostasis and for hereditary variations. The order, emerging in enormous randomly interconnected nets of binary variables, is almost certainly only the precursor of similar orders emerging in all the varieties of complex systems. Hence, this work, by finding new foundations for the order pervading the living world, advances the daring hypothesis according to which Darwinian natural selection is not the only source of order in the biosphere. Thus, the article, by examining the passage from Prigogine's dissipative structures theory to the contemporary theory of biological complexity, highlights the development of a coherent and continuous line of research which is set to individuate the general principles marking the profound reality of that mysterious self-organization characterizing the complexity of life.
Excitability and response properties of a neuron may vary in different environmental conditions of temperature. Increase/decrease of membrane potential has been observed under increase/decrease of temperature in the external side of membrane compared with internal temperature, i.e. the internal cell environment becomes more electronegative/electropositive in relation to the external one. Changes in temperature affected the amplitude of action potentials, measured as the voltage difference between the threshold and the peak, and their duration, measured as the width of the action potential at the threshold. As the temperature is increased, the amplitude of action potential is decreased and its duration is reduced. This parameter may influence the functioning of a neuron through the temperature dependence of ion channel conductance and time constants of channel activation/inactivation factors. Alterations in temperature affect the rates of diffusion through ion channels, the rates of conformational changes that lead to their activation and inactivation, and the rates of the biochemical reactions with which ion channels are modulated and transported into and out of membranes. Measurements of the propagated action potentials at different temperatures show that temperature has a double effect on the action potential: an increase of the Nernst equilibrium potentials when the absolute temperature is decreased and a change of the rate constants by a temperature factor. Temperature induced changes in the equilibrium potentials alone have little effect on the duration and amplitude of any action potentials but, because the cell membranes are permeable to more than one ion, the relation between the membrane potential and the Nernst equilibrium potentials shows different importance of the different ionic species in determining both resting and action potentials. In contrast, the temperature induced scaling of the rate constants can have quite dramatic effects on the duration of the action potential. As well as affecting the rate of action potential propagation, temperature influences the rate of neuron firing: the changes of action potential frequencies with temperature are associated, although not in a simple manner, with changes in resting potentials. Cooling reduces the resting potential (depolarization) and this leads to a rise in action potential frequencies; but certain nerve cells show a frequency increase when temperature is raised.
Homeostasis is a function indispensable for Life that is accomplished through chemical and physical processes. The mechanisms of this function have been disclosed beginning from the 1920s, when Walther Cannon formulated clear rules that transformed an old concept into paradigm. The concept of harmonic equilibrium among bodily humors dates back to the pre-Hellenic thinkers and was converted into medical suggestions by the Hippocratic school. This concept was handed down to posterity by the several schools of Medicine before being resumed by the great naturalist Jean-Baptiste Lamarck in purely physical terms. The experimental Physiology of the second half of the nineteenth-century elaborated a new conception, the so-called milieu intérieur theorised by Claude Bernard. Toward the half of the 20th century, biochemists imposed the functional basis of the concept, whose mechanisms were definitely established as "feedback" and "allostery".
The Major Histocompatibility Complex (MHC) is considered a system completely defined and only connected with the immune response. However, in addition to the well-known correlation between MHC and the non-self recognition, the MHC region controls a lot of other functions: the recognition of genetic individuality in social relationships, the mate choice and the feto-maternal interplay. Starting from protocordates, the first MHC function was the individual self-identification inside a group, but then it turned into an inter-individual recognition system, which could transmit information about the MHC genotypes. In mammals, the MHC system is functionally and physically linked to the olfactory receptors: when smelling each other, we are able to make a direct genetic analysis through the nose. The MHC individual genetic recognition system plays a fundamental role, both in mate choice and in foeto-maternal selection, from the very start of implantation. All these data suggest that the MHC polymorphism is driven not only by pathogen selection, but also by sexual reproductive-mechanisms. Questions remain about the relative involvement of these two selective forces in MHC evolution.
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