Human individual radiosensitivity: cytogenetical aspects

In accordance with the fundamental principles of the radiation cytogenetics the scheme of cytogenetical examinations of individual radiosensitivity of relatively healthy donors on the basis of chromosomal test (G2-assay) has been developed and tested.     

Molecular genetic aspects of individual differences in pain sensitivity and thermoregulation

The molecular genetic aspects of individual differences in thermoregulation and pain sensitivity that may be used to evaluate and predict the physical state of humans under contrast climate conditions, as well as during high physical and psychic loads, are reviewed. In response to abrupt changes in both external and internal temperature, the body activates internal resources that support homeostasis and adapts to the environment. Active movements are often associated with traumas accompanied by a sense of pain whose intensity and suppression depend on individual body characteristics. Understanding the functioning of the systems of thermoregulation and pain sensitivity at the molecular level and study of the polymorphism of genes involved in these processes is important for creation of optimal conditions for both rapid adaptation to the loads of everyday life and high physical activity and for success in sports.     

Individual human radiosensitivity: Cytogenetic aspects

A plan of cytogenetic investigations of individual radiosensitivity of relatively healthy individuals is developed and evaluated in accordance with the basic assumptions of radiation cytogenetics through the use of a chromosomal test (G₂ assay).     

Molecular aspects of allergy

Atopic diseases such as asthma, rhinitis, eczema and food allergies have increased in most industrialised countries of the world during the last 20 years. The reasons for this increase are not known and different hypotheses have been assessed including increased exposure to sensitising allergens or decreased stimulation of the immune system during critical periods of development.

In allergic diseases there is a polarisation of the Th2 response and an increase in the production of type 2 cytokines which are involved in the production of immunoglobulin E and the development of mast cells, basophils and eosinophils leading to inflammation and disease. The effector phase of atopy is initiated by interaction with FcRI expressed on effector cells such as mast cells and basophils but also found on an ever increasing list of cells. Binding of a polyvalent allergen to the variable part of IgE leads to a cross-link of the receptor that triggers the cell to release histamine and pharmacological mediators of the symptomatic allergic response. Cross-linking of FcRI by autoantibodies against the -chain of the FcRI, causing subsequent histamine release is thought to be involved in the pathogenesis of other diseases such as chronic idiopathic urticaria (CIU).

To date, most therapeutic strategies are aimed at inhibiting and controlling components of the inflammatory response. Recently, new treatment strategies have emerged that focus on the development of preventive and even curative treatments. The most promising therapeutic approaches are aimed at inhibiting the IgE–FcRI interaction with the use of non-anaphylactogenic anti-IgE or anti-FcRI autoantibodies. Clinical trials in humans using an humanised anti-IgE antibody showed that this antibody was well tolerated and reduced both symptoms and use of medication in asthma and allergic rhinitis. Thus interruption of the atopic cascade at the level of the IgE–FcRI interaction with the use of non-anaphylactogenic antibodies is effective and represents an attractive therapy for the treatment of atopic disease.     

Molecular aspects of bioelectrogenesis

The action potential is a dissipative process producing entropy and using free energy. This is well demonstrated by: 1) the evolution of the Na conductance under voltage clamping conditions, 2) the microcalorimetric measurements, 3) the analysis of heat evolution during the conductance changes. The most appropriate explanation must involve an exogenous energy source since the energy dissipated by the ionic flows or even the applied stimulus depolarization are far too small to account for the overall energy balance. Thiamine triphosphate is a likely candidate as specific operating substance. The more so, since it is specifically hydrolyzed by a triphosphatase the activity of which is modulated by various anions. It is therefore suggested that the control of the Cl-permeability, a process requiring the hydrolysis of thiamine triphosphate, is the key to our understanding of the energetics of the action potential.     

Molecular aspects of preeclampsia

Various hypotheses as to the origin of preeclampsia have been explored over time. Diseases of pregnancy are difficult to study for several reasons. One limitation is due to the fact that preeclampsia and associated diseases clinically present in the second and third trimenon, but seem to originate early in pregnancy. Comparisons with animal models are difficult due to the unique human nature of the disease. The creation of new methods including proteomics, genomics, lipidomics, metabolomics or mRNA microarray techniques supplement the traditional type of research access to approach mother and fetus. The clinical course will be discussed and pregnancy-related processes, which are thought to contribute to the disease. This includes implantation of the placenta/fetus, the adaptation of the endothelial activity to the pregnancy with respect to relaxin, matrix metalloproteinases and endothelin, nitric oxide, angiogenetic factors and TGF-b in normal and preeclamptic pregnancies. Furthermore, oxidative stress, genetics and hypothesis-generating molecular approaches are considered.     

A new biological index of radiosensitivity of individual mice in a closed colony

The new modified Mean Square Successive Difference (MSSD) is presented as an index to show the radiosensitivity of individual mice in a closed colony. The value of the new MSSD was calculated from daily body weight changes. The radiosensitivities of testes and hemopoiesis were less in mice with the intermediate value of the new MSSD than in mice with lower or higher values in a closed colony. The new MSSD is a useful index of individual differences.

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Zusammenfassung Ein neuer modifizierter Mean Square Successive Difference (MSSD) Index wird beschrieben und vorgeführt an der Strahlungsempfindlichkeit von einzeln gehaltenen Mäusen aus einer geschlossenen Zucht. Die Werte des neuen MSSD wurden aus den täglichen Veränderungen des Körpergewichts berechnet. Die Strahlungsempfindlichkeit der Hoden und der Hämatopoese war geringer bei Mäusen mit mittleren Werten nach dem neuen MSSD als bei Mäusen mit niedrigeren oder höheren Werten. Der neue MSSD Index ist brauchbar zur Erfassung von individuellen Unterschieden.

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Resume Une nouvelle "Mean Square Successive Difference" (MSSD) modifiée par l'auteur sert ici d'indice pour exprimer la sensibilité au rayonnement de souris provenant d'un même élevage, mais placées en cages individuelles. On a calculé les valeurs de la nouvelle MSSD en partant de la variation journalière du poids du corps. La sensibilité au rayonnement des testicules et de la hématopoièse était moins marquée chez les souris ayant une MSSD moyenne selon le nouveau mode de calcul que chez les animaux en présentant des valeurs élevées ou faibles. La nouvelle MSSD est donc utilisable pour déterminer des différences individuelles.

     

Molecular aspects of sex differentiation

Mammalian sex differentiation involves the action of a cascade of genes. Discovery of the sex-determining region of the Y chromosome (SRY) marked the beginning of the delineation of the genes in the cascade. Studies of the genetics of mammalian sex reversal and the embryogenesis of the mice are essential in this endeavor. A number of genes involved in the pathway have been identified and all except one of these genes have a putative role in male sex differentiation. Besides SRY being the master switch in male sex differentiation the hierarchical relationship of the genes identified are far from being understood. Similarly, our knowledge of the genetic regulation of female sex differentiation is minimal. Differential screening and gene expression profiling bring a new dimension to the pursuit with the identification of a number of genes previously unknown to be involved in sex differentiation. Wider application of functional genomic techniques and introduction of proteomic analyses are expected to shed light to our understanding of this complicated developmental process.     

Molecular aspects of implantation failure

Despite expanding global experience with advanced reproductive technologies, the majority of IVF attempts do not result in a successful pregnancy, foremost as a result of implantation failure. The process of embryo implantation, a remarkably dynamic and precisely controlled molecular and cellular event, appears inefficient in humans and is poorly understood. However, insights gained from clinical implantation failure, early pregnancy loss, and emerging techologies that enable molecular interrogation of endometrial–embryo interactions are unravelling this major limiting step in human reproduction. We review current molecular concepts thought to underlie implantation failure, consider the contribution of embryonic and endometrial factors, and discuss the clinical value of putative markers of impaired endometrial receptivity. Finally we highlight the nature of the dialogue between the maternal endometrium and the implanting embryo and discuss the concept of natural embryo selection. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.     

Molecular aspects of methionine biosynthesis

Methionine, lysine and threonine are essential amino acids required in the diets of non-ruminant animals. Major crops, such as corn, soybean and rice, are low in one or more of these amino acids. Currently, these amino acids are supplemented to animal feed to allow optimal growth--a costly process for farmers and consumer, therefore there is a great deal of interest in increasing essential amino acids in crops. The metabolism of methionine in plants is linked to the regulation of the aspartate pathway and is important for plant growth. In recent years, several key steps of this pathway have been identified at the molecular level, enabling us to initiate transgenic approaches to engineer the methionine content of plants.     

Molecular aspects of extracorporeal photochemotherapy

8-methoxypsoralen (8-MOP), activated upon exposure to long-wavelength ultraviolet radiation, is used therapeutically to treat the diseased blood cells of cutaneous T-cell lymphoma patients. The factors responsible for the efficacy of this therapy are reviewed. Primary among these are the plasma level of 8-MOP at the time of irradiation and the effective dose of UVA. 8-MOP plasma levels determined in a series of six patients demonstrated that the drug is absorbed at a highly variable rate (122 ng/ml +/- 67). A new liquid form of 8-MOP is absorbed with a modest increase in plasma levels (170 ng/ml) but with no improvement in the variability (+/- 163). An examination of the dose-response relationship between 8-MOP concentration and UVA dose indicated that properties such as 8-MOP photoadduct formation and PHA response are proportional to the combined doses of these two factors. A new molecular target for 8-MOP photomodification, cell membrane DNA, is described.     

Molecular aspects of photosystem I

Photosystem I (PSI) in higher plants consists of 17 polypeptide subunits. Cofactors are chlorophyll a and b , β-carotene, phylloquinone and iron-sulfur clusters. Eight subunits are specific for higher plants while the remaining ones are also present in cyanobacteria. Two 80-kDa subunits (PSI-A and -B) constitute the major part of PSI and bind most of the pigments and electron donors and acceptors. The 9-kDa PSI-C carries the remaining electron acceptors which are [4Fe-4S] iron sulfur clusters. PSI-D, -E and -H have importance for integrity and function at the stromal face of PSI while PSI-F has importance for function at the lumenal face. PSI-N is localized at the lumenal side, but its function is unknown. Four subunits are light-harvesting chlorophyll a/b -binding proteins. The remaining subunits are integral membrane proteins with poorly understood function. Subunit interactions have been studied in reconstitution experiments and by cross-linking studies. Based on these data, it is concluded that iron-sulfur cluster F_B is proximal to F_X and that F_A is the terminal acceptor in PSI. Similarities between PSI and the reaction center from green sulfur bacteria are discussed.