Interleukin-6 and alpha-2-macroglobulin indicate an acute-phase state in Alzheimer's disease cortices.

Recent studies indicated that the formation of a major constituent of Alzheimer's disease (AD) senile plaques, called beta A4-peptide, does not result from normal processing of its precursor, amyloid precursor protein (APP). Since proteolytic cleavage of APP inside its beta A4 sequence was found to be part of APP processing the formation of the beta A4-peptide seems to be prevented under normal conditions. We considered whether in AD one of the endogenous proteinase inhibitors might interfere with APP processing. After we had recently found that cultured human neuronal cells synthesize the most potent of the known human proteinase inhibitors, alpha-2-macroglobulin (alpha 2M), upon stimulation with the inflammatory mediator interleukin-6 (IL-6) we now investigated whether alpha 2M and IL-6 could be detected in AD brains. Here we report that AD cortical senile plaques display strong alpha 2M and IL-6 immunoreactivity while no such immunoreactivity was found in age-matched control brains. Strong perinuclear alpha 2M immunoreactivity in hippocampal CA1 neurons of Alzheimer's disease brains indicates that neuronal cells are the site of alpha 2M synthesis in AD brains. We did not detect elevated IL-6 or alpha 2M levels in the cerebrospinal fluid of AD patients. Our data indicate that a sequence of immunological events which seem to be restricted to the local cortical environment is part of AD pathology.     

Modelling of concentration profiles in tower fermenter. The influence of the axial dispersion coefficient

The production of CO₂ in tower fermenters which can cause back mixing, and thereby reducing the efficiency of such fermenters has been modelled with respect to fermentation. It is confirmed that the effect is significant. The effect of variations in the kinetic parameters, the maximum specific growth rate and the biomass yield coefficient was found to be insignificant. A good correlation between experimental and calculated data was obtained.     

Analysis of the pivotal residues of the immunodominant and highly uveitogenic determinant of interphotoreceptor retinoid-binding protein.

Interphotoreceptor retinoid-binding protein (IRBP), a retinal-specific Ag, induces experimental autoimmune uveitis in a variety of animals. We have previously shown that sequence 1169-1191 of bovine IRBP is the immunodominant epitope of this protein in Lewis rats and is highly immunogenic and uveitogenic in these rats. The active site of peptide 1169-1191 was determined by testing its truncated forms. The shortest peptide to be immunologically active was found to be 1182-1190 (WEGVGVVPD). To determine the role of individual residues of this sequence, we have tested the immunologic activities of nine analogs of peptide 1181-1191, in which each of residues 1182-1190 was substituted with alanine (A). The tested activities included the capacity to induce experimental autoimmune uveitis and cellular responses in immunized rats, as well as the capability to stimulate lymphocytes sensitized against IRBP or the parent peptide 1181-1191. Analogs that did not stimulate these lymphocytes were also tested for their capacity to competitively inhibit the proliferative response to 1181-1191. Analogs A(1184), A(1186), and A(1187) resembled 1181-1191 in their activities, whereas the other analogs exhibited remarkably reduced activities, with several patterns being noticed. Analog A(1182) was inactive in all tests. Analog A(1190) was very weakly uveitogenic and non-immunogenic, but it stimulated lymphocytes sensitized against IRBP or 1181-1191 when added at exceedingly high concentrations. Analogs A(1183) and A(1185) resembled A(1190) in being weakly uveitogenic and A(1185) was also found to be poorly immunogenic. In addition, relatively high concentrations of A(1183) and A(1185) were needed to stimulate lymphocytes sensitized against IRBP or 1181-1191. However, a different pattern of activities was exhibited by analogs A(1188) and A(1189). These peptides were uveitogenic and immunogenic, but failed to stimulate lymphocytes sensitized to IRBP or 1181-1191. Furthermore, A(1188) and A(1189), but not A(1182), also inhibited the response to 1181-1191 of a cell line specific toward this parent peptide. The data are interpreted to show that residues 1188 and 1189 are involved in the interaction of the peptide with the TCR, whereas residues 1182 and 1190 and, perhaps, 1183 and 1185, are pivotal for the binding of peptide 1181-1190 to the MHC molecules on APC.     

MECHANISMS OF AVIAN IMPRINTING: A REVIEW

Filial imprinting is the process through which early social preferences become restricted to a particular object or class of objects. Evidence is presented showing that filial preferences are formed not only as a result of learning through exposure to an object, but also under the influence of visual and auditory predispositions. The development of these predispositions is dependent upon certain non-specific experience. There is little evidence for an endogenously affected sensitive period for imprinting. It is more likely that the end of sensitivity is a result of the imprinting process itself. Similarly, it is now firmly established that filial and sexual preferences are reversible. Evidence suggests, however, that the first stimulus to which the young animal is exposed may exert a greater influence on filial preferences than subsequent stimuli. The learning process of imprinting is often regarded as being different from conventional associative learning. However, the imprinting object itself can function as a reinforcer. Recent studies have attempted to test predictions from an interpretation of filial imprinting as a form of associative learning. The first results suggest that ‘blocking’ may occur in imprinting, whilst there is no evidence for ‘overshadowing’. Social interactions with siblings and parent(-surrogates) have been shown to affect the formation of filial and sexual preferences. The influence of these interactions is particularly prominent in sexual imprinting, making earlier claims about naive species-specific biases unlikely. Although auditory stimuli play an important role in the formation of social attachments, there is little evidence for auditory imprinting per se. Auditory preferences formed as a result of mere (pre- or postnatal) exposure are relatively weak and short-lasting. Exposure to visual stimuli during auditory training significantly improves auditory learning, possibly through a process of reinforcement. It is becoming increasingly clear that filial and sexual imprinting are two different (although perhaps analogous) processes. Different mechanisms are likely to underlie the two processes, although there is evidence to suggest that the same brain region is involved in recognition of familiar stimuli in both filial and sexual imprinting. There is little evidence for a direct role of hormones in the learning process of imprinting. Androgen metabolism may be a factor constraining the development of a predisposition in the chick. Research into the neural mechanism of filial imprinting in the chick has revealed that a restricted part of the forebrain (IMHV) is likely to be a site of memory storage. Changes in synapse morphology and in the number of NMDA receptors have been found, limited to this region, and correlated with the strength of preference.     

The cytoplasmic tail of CD4 targets chimeric molecules to a degradative pathway.

Many different cell surface receptors undergo endocytosis via coated pits. Once having entered the cell, the receptors are sorted into diverse pathways. Which path a given receptor will follow is determined by signals inherent in the receptor's structure. The nature of these structural features is not yet known. In this study, we have taken the approach of constructing chimeric molecules to localize the domain of the T-cell surface molecule CD4 which is responsible for targeting it for degradation. Chimeric molecules bearing the cytoplasmic domain of CD4 and the extracellular domain of either the low-density lipoprotein receptor or a major histocompatibility complex (MHC) class I molecule were both internalized in response to phorbol 12-myristate 13-acetate and were subsequently degraded, indicating that the cytoplasmic tail of CD4 contains all the information required for both processes. The ability to modulate the level of MHC class I molecules on the cell surface offers an approach to investigating quantitative aspects of antigen presentation, the initial possibilities of which are explored herein.