The 13th J. A. F. Stevenson memorial lecture. Sexual differentiation of the brain: possible mechanisms and implications

The mammalian brain appears to be inherently feminine and the action of testicular hormones during development is necessary for the differentiation of the masculine brain both in terms of functional potential and actual structure. Experimental evidence for this statement is reviewed in this discussion. Recent discoveries of marked structural sex differences in the central nervous system, such as the sexually dimorphic nucleus of the preoptic area in the rat, offer model systems to investigate potential mechanisms by which gonadal hormones permanently modify neuronal differentiation. Although effects of these steroids on neurogenesis and neuronal migration and specification have not been conclusively eliminated, it is currently believed, but not proven, that the principle mechanism of steroid action is to maintain neuronal survival during a period of neuronal death. The structural models of the sexual differentiation of the central nervous system also provide the opportunity to identify sex differences in neurochemical distribution. Two examples in the rat brain are presented: the distribution of serotonin-immunoreactive fibers in the medial preoptic nucleus and of tyrosine hydroxylase-immunoreactive fibers and cells in the anteroventral periventricular nucleus. It is likely that sexual dimorphisms will be found to be characteristic of many neural and neurochemical systems. The final section of this review raises the possibility that the brain of the adult may, in response to steroid action, be morphologically plastic, and considers briefly the likelihood that the brain of the human species is also influenced during development by the hormonal environment.     

The 1987 James A. F. Stevenson memorial lecture. The development of fetal behavioural patterns

The development of fetal behaviour is reviewed. Fetal cutaneous and muscle sensory receptors are developed by the time movements are first seen. Human infants certainly respond to painful stimuli at 28 weeks. There is no clear evidence that prenatal "stress," e.g., maternal exposure to random noise and bright lights, impairs fetal development in the rat, on the contrary. Fetal diurnal rhythms appear in man and sheep before the development of sleep states; they are dependent on maternal corticosteroids, but the fetal mechanism is uncertain. With the development of sleep states (in late gestation in man and sheep, postnatally in the rat), the complex central control of behaviour is gradually established, but wakefulness is still of low incidence. The location of the sleep cycle generator is uncertain; the results of experimental lesions of the brainstem in fetal lambs appear incompatible with studies in adult rats and cats.     

Chemistry,clones, and circadian control of the dinoflagellate bioluminescent system. The Marlene DeLuca memorial lecture

Bioluminescence in the dinoflagellate Gonyaulax polyedra occurs as brief bright flashes, originating from many (～400) small (～0.5 μm) cytoplasmic organelles which protrude into the acidic vacuole, and are thus surrounded by the tonoplast. Biochemically, the substrate is unusual; it is an open chain tetrapyrrole, highly unstable to air but protected in the cell at pH? 8 by virtue of a luciferin binding protein (LBP). This molecule is a dimer of 72 kDa subunits which, upon a decrease in pH, releases luciferin to react with oxygen in the luciferase (～140 kDa) catalysed luminescent reaction. cDNAs for both luciferase and LBP have been isolated and cloned, and the identity of LBP was confirmed by hybrid selection and in vitro translation of the message. The tenfold circadian (day to night) change in the amount of LBP, which parallels the in vivo rhythm of luminescence, is due to de novo synthesis and subsequent degradation of the protein each day. The LBP mRNA levels, as determined by in vitro translations and by Northern hybridizations, do not vary over the daily cycle, indicating that circadian control of bioluminescence in this species is mediated at the level of translation.     

Failla memorial lecture. Risk, research, and radiation protection

Radiation protection concerns the risk of stochastic late effects, especially cancer, and limits on radiation exposure both occupationally and for the public tend to be based on these risks. The risks are determined, mainly by expert committees, from the steadily growing information on exposed human populations, especially the survivors of the atomic bombs dropped in Japan in 1945. Risks of cancer estimated up to the early 1980s were in the range 1 to 5 X 10(-2)/Sv, but recent revisions in the dosimetry of the Japanese survivors and additional cycles of epidemiological information suggest values now probably at the high end of this range. These are likely to require an increase in the values used for radiation protection. A major problem with risk estimation is that data are available only for substantial doses and must be extrapolated down to the low-dose region of interest in radiation protection. Thus the shape of the dose-response curve is important, and here we must turn to laboratory research. Of importance are studies involving (1) dose rate, which affects the response to low-LET radiation and often to high-LET radiation as well; (2) radiation quality, since the shapes of the dose-response curves for high- and low-LET radiation differ and thus the RBE, the ratio between them, varies, reaching a maximum value RBEM at low doses; and (3) modifiers of the carcinogenic response, which either enhance or reduce the effect of a given dose. Radiation protection depends both on risk information, and especially also on comparisons with other occupational and public risks, and on research, not only for extrapolations of risk to low doses but also in areas where human information is lacking such as in the effects of radiation quality and in modifications of response.     

The 1990 James A. F. Stevenson Memorial Lecture. Gonadotropin-releasing hormone and its actions

Gonadotropin-releasing hormone (GnRH) stimulates the release and biosynthesis of gonadotropins, luteinizing hormone, and follicle-stimulating hormone from the pituitary gland. Additionally, GnRH regulates the number of its own receptors on pituitary gonadotropes causing both up- and down-regulation of receptors as well as biosynthesis of GnRH receptors. After exposure to GnRH, gonadotropes become desensitized to further stimulation by GnRH. The mechanisms through which these actions of GnRH are mediated appear to differ. Effects dependent upon extracellular calcium include gonadotropin biosynthesis and release as well as up-regulation of GnRH receptors. Additional actions of GnRH, such as down-regulation of receptors, biosynthesis of receptors, and desensitization, appear to be independent of extracellular calcium. Subsequent studies have ascribed roles for calmodulin and protein kinase C in mediating specific effects of GnRH.     

Interactions between the amyloid and cholinergic mechanisms in Alzheimer's disease

Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by memory and cognitive loss, the formation of senile plaques containing amyloid-beta (Abeta) peptide, degeneration of the cholinergic neurons and the development of neurofibrillary tangles. The build-up of Abeta is considered to be a central feature in the pathogenesis of AD. However, other critical molecular and neurochemical alterations too occur, such as a cholinergic dysfunction. As concerns the pathomechanism of the disease, both the amyloid cascade hypothesis and the cholinergic hypothesis of AD are widely accepted. This review surveys recent in vitro and in vivo experimental evidence relating to these two hypotheses. Bidirectional pathways linking them as regards the cholinergic neurotoxicity of Abeta and the regulatory mechanisms of cholinergic receptor activation or enzyme inhibition in the processing of the amyloid precursor protein are also discussed. Further work is warranted to elucidate the exact effects in the interactions between the cholinergic and amyloid hypotheses of the candidate drugs used in AD therapy.     

Alzheimer's disease through the eye of a mouse. Acceptance lecture for the 2001 Gayle A. Olson and Richard D. Olson prize

There is now ample evidence that beta-amyloid proteins decrease memory. The SAMP8 mouse (P8) develops an early decline in the ability to learn and to retain new information. The studies reviewed here suggest that this is due to overproduction of beta-amyloid. Both antibodies to beta-amyloid and specific antisense to the amyloid precursor protein reverse these deficits in the P8 mouse. This antisense can cross the blood brain barrier. It is hypothesized that the overproduction of beta-amyloid leads to a decline in Delta(9) desaturase activity with an alteration in membrane fatty acids. This results in altered membrane mobility leading to a decline in neurotransmitter activity and a decreased release of acetylcholine. This decreased cholinergic activity results in a decreased ability of the P8 mouse to learn and retain new information.     

Flexibility and rigidity, requirements for the function of proteins and protein pigment complexes. Eleventh Keilin memorial lecture

Proteins may be rigid or flexible to various degrees as required for optimum function. Flexibility at the level of amino acid side-chains occurs universally and is important for binding and catalysis. Flexibility of large parts of a protein which rearrange or move are particularly interesting and will be discussed here. We differentiate between certain categories of large-scale flexibility although the boundaries between them are diffuse: flexibility of peptide segments, domain motions and order-disorder transitions of spatially contigous regions. The domains may be flexibly linked to allow rather unrestricted motion or the motion may be constrained to certain modes. The polypeptide segments linking the domains show characteristic structural features. The various categories of flexibility will be illustrated with the following examples. (a) Small protein proteinase inhibitors which are rather rigid molecules which provide binding surfaces complementary to their cognate proteases, but also show limited segmental flexibility and adaptation. (b) Large plasma inhibitors which exhibit large conformational changes upon interaction with proteases probably for regulatory purposes. (c) Pancreatic serine proteases which employ a disorder-order transition of their activation domain as a means to regulate enzymic activity. (d) Immunoglobulins in which rather unrestricted and also hinged domain motions occur in different parts of the molecule probably to allow binding to antigens in different arrangements. (e) Citrate synthase which adopts open and closed forms by a hinged domain motion to bind substrates and release products and to perform the catalytic condensation reaction, respectively. (f) The bifunctional multienzyme complex riboflavin synthase in which two enzymes (alpha and beta) catalyse two consecutive enzymic reactions. The beta-subunits form a shell, in which the alpha-subunits are enclosed. Diffusional motion of the catalytic intermediates is therefore restricted. In addition, segmental rearrangement occurs in the assembly of the beta-subunit. In contrast, rigidity is the dominant impression provided by the structures of the light harvesting complexes and the reaction centres involved the photosynthetic light reactions. These are large protein complexes in which the proteins serve as matrices to hold the pigments in the appropriate conformation and relative arrangement. Since motion would contribute to deactivation of the photo-excited states of the pigments and diminish the efficiency of light energy and electron transfer, a functional role for rigidity is easy to rationalize for these proteins.