Biochemical and molecular mechanisms regulating apoptosis

In eukaryotes, the regulation of tissue cell numbers is a critical homeostatic objective that is achieved through tight control of apoptosis, mitosis and differentiation. While much is known about the genetic regulation of cell growth and differentiation, the molecular basis of apoptosis is less well understood. Genes involved in both cell proliferation and apoptosis reflect the role of some stimuli in both of these processes, the cell response depending on the overall cellular milieu. Recent research has given fascinating insights into the complex genetic and molecular mechanisms regulating apoptosis. A picture is emerging of the initiation in certain cells, after an apoptotic trigger, of sequential gene expression and specific signal transduction cascades that guide cells along the cell death pathway. Changes in gene expression precede the better known biochemical and morphological changes of apoptosis. It seems possible that, as a result of increased understanding of the cellular events preceding cell death, apoptosis may become more amenable to manipulation by appropriate drug- and gene-based therapies.     

Epigenetic mechanisms regulating seed germination rate

Changes in epigenetic polymorphism degree within wheat seedlings’ population under radiation stimulating exposure of germination were investigated. Variations in seeds sample allocations by germination rate in both control and chronically exposed variants were estimated. Changes in DNA methylation patterns of seedlings from seeds with different germination rate were studied. Variations in epigenetic polymorphism–“distance” between DNA methylation patterns of “fast” and “slow” seedlings of different wheat varieties under radiation exposure were assessed. Indicated, that increased germination rate of seeds sample was associated with decreasing degree of epigenetic polymorphism. Issue concerning both role of epigenetic polymorphism in plant population stability and its decreasing degree that could initiate less effectiveness of production process was discussed.     

Cellular mechanisms regulating non-haemostatic plasmin generation

A variety of proteases have the potential to degrade the extracellular matrix (ECM), thereby influencing the behaviour of cells by removing physical barriers to cell migration, altering cell-ECM interactions or releasing ECM-associated growth factors. The plasminogen activation system of serine proteases is particularly implicated in this pericellular proteolysis and is involved in pathologies ranging from cancer invasion and metastasis to fibroproliferative vascular disorders and neurodegeneration. A central mechanism for regulating plasmin generation is through the binding of the two plasminogen activators to specific cellular receptors: urokinase-type plasminogen activator to the glycolipid-anchored membrane protein uPAR, and tissue plasminogen activator to a type-II transmembrane protein recently identified on vascular smooth muscle cells. These binary complexes interact with membrane-associated plasminogen to form higher order activation complexes that greatly reduce the K(m) for plasminogen activation and, in some cases, protect the proteases from their cognate serpin inhibitors. Various other proteins that are involved in cell adhesion and migration also interact with these complexes, modulating the activity of this efficient and spatially restricted proteolytic system. Recent observations demonstrate that certain forms of the prion protein can stimulate tissue plasminogen activator-catalysed plasminogen activation, which raises the possibility that these proteases may also have a role in the pathogenesis of the transmissible spongiform encephalopathies.     

Humoral mechanisms of regulating reparative osteogenesis

The effect of the blood serum of animals with active osteogenesis on the biosynthesis of nucleic acids, protein, and on the mineralization of the regenerating bone tissue was studied in experiments in vivo and in vitro. Incorporation of DNA and protein labeled precursors (3H-thymidine and 14 C-proline, respectively) was increased and the mineralization of the bone callus (85Sr incorporation) was accelerated in the recipients. Comparison of nucleic acids and protein biosynthesis stimulation sequency allows to suppose that the active serum principle promotes the increased cell proliferation in the fracture area.     

Effects of expiratory loading on respiration in humans

We examined the effects of expiratory resistive loads of 10 and 18 cmH2O.l-1.s in healthy subjects on ventilation and occlusion pressure responses to CO2, respiratory muscle electromyogram, pattern of breathing, and thoracoabdominal movements. In addition, we compared ventilation and occlusion pressure responses to CO2 breathing elicited by breathing through an inspiratory resistive load of 10 cmH2O.l-1.s to those produced by an expiratory load of similar magnitude. Both inspiratory and expiratory loads decreased ventilatory responses to CO2 and increased the tidal volume achieved at any given level of ventilation. Depression of ventilatory responses to Co2 was greater with the larger than with the smaller expiratory load, but the decrease was in proportion to the difference in the severity of the loads. Occlusion pressure responses were increased significantly by the inspiratory resistive load but not by the smaller expiratory load. However, occlusion pressure responses to CO2 were significantly larger with the greater expiratory load than control. Increase in occlusion pressure observed could not be explained by changes in functional residual capacity or chemical drive. The larger expiratory load also produced significant increases in electrical activity measured during both inspiration and expiration. These results suggest that sufficiently severe impediments to breathing, even when they are exclusively expiratory, can enhance inspiratory muscle activity in conscious humans.     

Molecular mechanisms regulating motor neuron development and degeneration

Motor neurons are a well-defined, although heterogeneous group of cells responsible for transmitting information from the central nervous system to the locomotor system. Spinal motor neurons are specified by soluble factors produced by structures adjacent to the primordial spinal cord, signaling through homeodomain proteins. Axonal pathfinding is regulated by cell-surface receptors that interact with extracellular lignads and once synaptic connections have formed, the survival of the somatic motor neuron is dependent on the provision of target-derived growth factors, although nontarget-derived factors, produced by either astrocytes or Schwann cells, are also potentially implicated. Somatic motor neuron degeneration leads to profound disability, and multiple pathogenetic mechanisms including aberrant growth factor signaling, abnormal neurofilament accumulation, excitotoxicity, and autoimmunity have been postulated to be responsible. Even when specific deficits have been identified, for example, mutations of the superoxide dismutase-1 gene in familial amyotrophic sclerosis and polyglutamine expansion of the androgen receptor in spinal and bulbar muscular atrophy, the mechanisms by which somatic motor neuronal degeneration occurs remain unclear. In order to treat motor system degeneration effectively, we will need to understand these mechanisms more thoroughly.     

Molecular mechanisms regulating persistent Mycobacterium tuberculosis infection

Establishing persistent infection and resisting elimination by the host's immune system are key factors contributing to latent infection by Mycobacterium tuberculosis. Recently, bacterial determinants regulating these processes have been identified. Here, we review molecular mechanisms regulating persistent infection and discuss the highly dynamic interaction of M. tuberculosis with the host.     

Molecular mechanisms regulating the activity of macrophages

This article reviews modern concepts of the most common types of macrophage activation: classical, alternative, and type II. Molecular mechanisms of induction and regulation of these three types of activation are discussed. Any population of macrophages was shown to change its properties depending on its microenvironment and concrete biological situation (the "functional plasticity of macrophages"). Many intermediate states of macrophages were described along with the most pronounced and well-known activation types (classical activation, alternative activation, and type II activation). These intermediate states are characterized by a variety of combinations of their biological properties, including elements of the three afore mentioned types of activation. Macrophage activity is regulated by a complex network of interrelated cascade mechanisms.     

Autocrine and paracrine mechanisms regulating primordial germ cell proliferation

Although several mitogens and survival factors have been previously shown to act on primordial germ cells (PGCs) in culture, it is not clear whether they are responsible for controlling proliferation of PGCs in the embryo. We show here that during their migratory phase, PGCs do not express FGF-4, FGF-8, or FGF-17, but these FGFs are expressed by neighboring cells. Thus, any FGF action on migrating PGCs would appear to be through a paracrine mechanism. We found that after entering into the gonads, PGCs start to express FGF-4 and FGF-8. On this basis, we hypothesize that FGF signaling is involved in both a paracrine manner in initiating PGC proliferation during their migration and an autocrine manner in sustaining PGC proliferation after their arrival in the gonads. We then studied the role of soluble stem cell factor (SCF), which acts as a survival factor or a mitogen in culture, to determine whether it interacts with FGFs. We found that SCF has a complex effect on PGC proliferation. On one hand, soluble SCF promoted PGC proliferation synergistically with FGF in the absence of membrane-bound SCF. Conversely, soluble SCF inhibited FGF-stimulated proliferation of PGCs in the presence of membrane-bound SCF. We account for these findings in a model involving regulation of PGC proliferation, in which SCF modulates the response to FGFs.