Interaction of the antioestrogen ICI 164,384 with the oestrogen receptor

The use of partially purified preparations of the human uterine oestrogen receptor has enabled, for the first time, a study of the binding of the steroidal, pure antioestrogen ICI 164,384 [N-n-butyl-11-(3,17 beta-dihydroxy-oestra-1,3,5(10)-trien-7 alpha-yl)N-methyl-undecamide] to the oestrogen receptor. Scatchard analyses of the binding of [3H]oestradiol and [3H]ICI 164,384 to the receptor show that the equilibrium dissociation constants for the interactions of these ligands with the receptor at 0 degrees C are 0.44 and 0.69 nM respectively. The concentration of receptor binding sites for the agonist was 1986 fmol/mg protein whilst that for the antagonist was 1400 fmol/mg protein. The affinity of the antioestrogen-receptor complex for DNA-cellulose does not increase following exposure to conditions that transform the oestrogen-receptor complex.     

Effect of dextran-charcoal treatment on the dissociation kinetics of glucocorticoid-receptor complexes: possible involvement of lipid

Dissociation kinetics were determined at 0 degrees C for molybdate-stabilized glucocorticoid-receptor complexes in rat thymus cytosol. Exposure of complexes to dextran-coated charcoal had no effect on their chromatographic properties or transformation status, but dissociation rates measured after charcoal treatment were significantly lower than those determined by displacement with excess competing steroid. The dissociation rate of the [2,4,6,7-3H]prednisolone-receptor complex was similarly modified by chromatography on Lipidex 1000, but not by chromatography on Sephadex G-25 or G-75. It is concluded that treatment of glucocorticoid-receptor complexes with dextran-charcoal or Lipidex 1000 brings about a change in dissociation rate as a consequence of the removal of a lipid component from the complex.     

Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1

Toll-like receptor 4 (TLR4) and TLR2 agonists from bacterial origin require acylated saturated fatty acids in their molecules. Previously, we reported that TLR4 activation is reciprocally modulated by saturated and polyunsaturated fatty acids in macrophages. However, it is not known whether fatty acids can modulate the activation of TLR2 or other TLRs for which respective ligands do not require acylated fatty acids. A saturated fatty acid, lauric acid, induced NFkappaB activation when TLR2 was co-transfected with TLR1 or TLR6 in 293T cells, but not when TLR1, 2, 3, 5, 6, or 9 was transfected individually. An n-3 polyunsaturated fatty acid (docosahexaenoic acid (DHA)) suppressed NFkappaB activation and cyclooxygenase-2 expression induced by the agonist for TLR2, 3, 4, 5, or 9 in a macrophage cell line (RAW264.7). Because dimerization is considered one of the potential mechanisms for the activation of TLR2 and TLR4, we determined whether the fatty acids modulate the dimerization. However, neither lauric acid nor DHA affected the heterodimerization of TLR2 with TLR6 as well as the homodimerization of TLR4 as determined by co-immunoprecipitation assays in 293T cells in which these TLRs were transiently overexpressed. Together, these results demonstrate that lauric acid activates TLR2 dimers as well as TLR4 for which respective bacterial agonists require acylated fatty acids, whereas DHA inhibits the activation of all TLRs tested. Thus, responsiveness of different cell types and tissues to saturated fatty acids would depend on the expression of TLR4 or TLR2 with either TLR1 or TLR6. These results also suggest that inflammatory responses induced by the activation of TLRs can be differentially modulated by types of dietary fatty acids.     

Evidence indicating that UDP-N-acetylglucosamine does not appear to stimulate hepatic microsomal UDP-glucuronosyltransferase by interaction with the catalytic unit of the enzyme

The binding studies in this paper indicate that the catalytic unit(s) of microsomal UDP glucuronosyltransferase(s) is not accessible to N-ethylmaleimide or UDP-N-acetylglucosamine, when the enzyme is in its membrane environment. Thus a separate regulatory factor may exist within the endoplasmic reticulum membrane that mediates the stimulation of UDPglucuronosyltransferase(s) by UDP-N-acetylglucosamine. The possible role and the mode of interaction of the putative regulatory factor with the multiple forms of UDPglucuronosyltransferase are discussed.     

Why the ovotestis of Helix aspersa is innervated

Although Schmalz described the innervation of the ovotestis in pulmonate snails as early as 1914, no functions have been attributed to it. In H. aspersa, the intestinal nerve branches profusely within the ovotestis and terminates in the walls of the acini and in the sheath surrounding the early portion of the hermaphroditic duct. We found both sensory and motor functions for this innervation. Significantly, there is a tonic sensory discharge generated by the mechanical pressure of growing oocytes, and the level of tonic afferent activity is strongly correlated with the number of ripe oocytes; this is probably a permissive signal that gates ovulation. Tactile stimulation of the ovotestis causes a phasic sensory discharge and a pronounced cardio activation. Also, an efferent discharge is elicited in the ovotestis branch of the intestinal nerve. To study the motor consequences of efferent activity, the ovotestis branch was electrically stimulated. We found that such stimulation evokes peristaltic contractions of the initial portion of the hermaphroditic duct and increases beat frequencies of the cilia that line the interior of the duct. These effects could facilitate the transport of oocytes down the duct. Still other functions of afferent activity are implied by changes in the spontaneous activity of mesocerebral cells following nerve stimulation. Putative sensory neurons and putative motoneurons have been identified in the visceral and right parietal ganglia.     

Performance of human groups in social foraging: the role of communication in consensus decision making

Early hominids searched for dispersed food sources in a patchy, uncertain environment, and modern humans encounter equivalent spatial-temporal coordination problems on a daily basis. A fundamental, but untested assumption is that our evolved capacity for communication is integral to our success in such tasks, allowing information exchange and consensus decisions based on mutual consideration of pooled information. Here we examine whether communication enhances group performance in humans, and test the prediction that consensus decision-making underlies group success. We used bespoke radio-tagging methodology to monitor the incremental performance of communicating and non-communicating human groups (small group sizes of two to seven individuals), during a social foraging experiment. We found that communicating groups (n = 22) foraged more effectively than non-communicating groups (n = 21) and were able to reach consensus decisions (an 'agreement' on the most profitable foraging resource) significantly more often than non-communicating groups. Our data additionally suggest that gesticulations among group members played a vital role in the achievement of consensus decisions, and therefore highlight the importance of non-verbal signalling of intentions and desires for successful human cooperative behaviour.     

Saturated and polyunsaturated fatty acids reciprocally modulate dendritic cell functions mediated through TLR4

TLRs provide critical signals to induce innate immune responses in APCs such as dendritic cells (DCs) that in turn link to adaptive immune responses. Results from our previous studies demonstrated that saturated fatty acids activate TLRs, whereas n-3 polyunsaturated fatty acids inhibit agonist-induced TLR activation. These results raise a significant question as to whether fatty acids differentially modulate immune responses mediated through TLR activation. The results presented in this study demonstrate that the saturated fatty acid, lauric acid, up-regulates the expression of costimulatory molecules (CD40, CD80, and CD86), MHC class II, and cytokines (IL-12p70 and IL-6) in bone marrow-derived DCs. The dominant negative mutant of TLR4 or its downstream signaling components inhibits lauric acid-induced expression of a CD86 promoter-reporter gene. In contrast, an n-3 polyunsaturated fatty acid, docosahexaenoic acid, inhibits TLR4 agonist (LPS)-induced up-regulation of the costimulatory molecules, MHC class II, and cytokine production. Similarly, DCs treated with lauric acid show increased T cell activation capacity, whereas docosahexaenoic acid inhibits T cell activation induced by LPS-treated DCs. Together, our results demonstrate that the reciprocal modulation of both innate and adaptive immune responses by saturated fatty acid and n-3 polyunsaturated fatty acid is mediated at least in part through TLRs. These results imply that TLRs are involved in sterile inflammation and immune responses induced by nonmicrobial endogenous molecules. These results shed new light in understanding how types of dietary fatty acids differentially modulate immune responses that could alter the risk of many chronic diseases.     

Modulation of heart activity during withdrawal reflexes in the snail <Emphasis Type="Italic">Helix aspersa</Emphasis>

The beating activity of the molluscan heart is myogenic, but it is influenced by nervous signals of central origin. Previous studies have demonstrated changes in cardiac output during feeding and other behaviors. Here, we describe a short latency, transient cardiac response that accompanies withdrawal reflexes. When evoked by electrical stimulation of peripheral nerves, the response was detected within one or two heartbeats. Beat amplitudes increased on average 11.6%, and inter-beat intervals decreased on average 2.1%. The mean duration of the response was 28.1 s. A transient inhibitory phase often preceded the excitatory response. Results from testing various nerves and tissues show that the cardiac responses invariably occur whenever contractions of the tentacle retractor muscle are elicited. Even stimulation of the ovotestis and the kidney elicit responses despite their protected locations within the mantle cavity. Three excitatory cardioactive neurons are identified in the central nervous system of Helix aspersa, and their involvement in the reflex response is documented. The results suggest that the heart output is initially inhibited to relax the hydroskeleton and thereby aid withdrawal movements. A delayed increase in cardiac output then facilitates the re-inflation, hence eversion, of the withdrawn body parts.     

A Numerical Simulation of the Diffusion of Near Infrared Light Through Brain Tissue

A numerical simulation of the transport of light energy in the near infrared region of the spectrum through human brain tissue is presented. This simulation models the use of near infrared spectroscopic techniques to quantify the levels of oxygen present in brain tissue. Successful application of the technique requires knowledge of the optical pathlength in the tissue, and it is the goal of this simulation to quantify the relationship of the optical pathlength and the oxygenation state of the tissue. Both implicit and explicit finite element schemes for unstructured grids are implemented and discussed. Several application simulations using three tissue grids of varying degrees of physiological accuracy are then conducted, and figures for the optical pathlength of light through the tissue at varying levels of oxygenation are computed. These results are then used to develop a quantitative relationship between the pathlength and the absorption parameter for the three tissue models which we explore.