HIV treatment models with time delay

The present paper shows possible effects of antiretroviral treatment on the dynamics of the spread of the disease of human immunodeficiency virus infection in a population of varying size. By introducing time delays, we model the latency period and the delayed onset of positive treatment effects in the patients. The Hopf bifurcation and stability behaviour of the delay differential-equation model are analysed and simulations for different scenarios depending on the size of the treatment-induced delay are presented, and the results are discussed in detail.     

Effects of mating stimuli and oxytocin on plasma cortisol concentration in gilts

The involvement of oxytocin (OT) in the regulation of glucocorticoid secretion during stress reaction, parturition, and suckling has been documented in various species. In this study four in vivo experiments were conducted on gilts (1) to demonstrate the influence of mating stimuli on plasma cortisol concentration, (2) to test the effect of OT alone and (3) OT combined with OT-antagonist on cortisol secretion and (4) to clarify the role of progesterone and estradiol in cortisol response to exogenous OT. In experiment 1, plasma cortisol concentration in gilts (n=4) increased (p<0.05) from 16.1 +/- 5.3 ng ml(-)1 (control period: 30 min before mating) to 42.8 +/- 11.6 ng ml(-1) and 46.6 +/- 9.6 ng ml(-1) at the time of leaving the pen and during the first visual and olfactory contact with the boar, respectively. During coitus the elevation was maintained (48.8 +/- 9.8 ng ml(-1); p<0.05 vs. control). The plasma cortisol concentration returned to pre-mating levels within 30 min after mating. In experiment 2, gilts (n=7) were treated, according to Latin square design, with saline (2 ml; i.v.) and OT (10, 20, and 30 IU; i.v.). The magnitude of cortisol response (area under cortisol curve) was higher (p<0.01) only after treatments with 20 and 30 IU OT vs. control period (30 min before OT). Gilts (n=3) of experiment 3 were infused with OT-antagonist (Atosiban; 25 mg per gilt per 2 hours; i.v.) and then were injected with OT (20 IU; i.v.) 60 min after the beginning of Atosiban administration. Blockage of OT receptors by Atosiban reversed the stimulatory effect of OT on cortisol secretion. In experiment 4, ovariectomized gilts (n=25) primed (i.m.) with corn oil (n=7), progesterone (P4; n=7), estradiol benzoate (EB; n=4) or EB+P4 (n=7) were treated with OT (20 IU; i.v.). Plasma cortisol concentrations were increased following OT administration in all gilts of experiment 4. The highest cortisol response to OT was noted in gilts primed with EB+P4 (p<0.01 vs. other groups). In conclusion: (1) leaving the pens, visual and olfactory contact with the boar as well as coitus, increased plasma cortisol concentrations in gilts to similar levels; (2) exogenous OT (20 and 30 IU per gilt) increased cortisol plasma concentration, (3) this effect was abolished by OT-antagonist and (4) E2+P4 elevated cortisol response to OT. Oxytocin may be included to secretagogues of the hypothalamus-pituitary-adrenocortical axis in pigs.     

Journeying Between Desire and Anthropology: A Story in Suspense

Anthropology is a discipline based on the motif of the journey and ‘the myth of the eternal return’. This is the journey out to the ‘other’in order to return to constitute ‘self, and this movement is a movement of desire. The desire is for wholeness, for self‐presence, for a unified self. It is a desire for origins. And this desire is evident in anthropological practices as it is in myths and fairytales—all tell stories that speak of the desire for a separate, an original, self. Yet ‘the myth of the eternal return’reveals that the enactment of the story is itself originating. The origin is not a thing to be hunted down and appropriated—it is no thing. Like the archetypes which flow through stories, it is alive in the telling. The story I tell in this paper is about my own desires. It speaks of the desire to undergo the rite of passage of anthropology, and of how this journey was interrupted by the anthropologist who always journeys before me. And yet. it is through the inextricable relations with the writings of the “other‘ anthropologist that alluring moments of different desiring are fleetingly revealed. In the end. my relations with anthropology tell of a paradox: of the desire for a transcendental journey in order to constitute self and the seductive desire for immersion—to lose self, the story remains in suspense.     

Species differences in localization of cardiac cAMP-phosphodiesterase activity: A cytochemical study

The localization of the membrane-bound cyclic 3,5-AMP phosphodiesterasein cardiac tissues of both, rat and dog was studied by cytochemical method.40 µm thick slices from glutaraldehyde fixed heart tissue wereincubated in the medium with cAMP as a substrate and Pb ions as a capturemetal of the reaction product. The cAMP-PDE activity in the rat ventriclewas only shown positive on the sarcolemma. Whereas, in canine ventriculartissue the cAMP-PDE activity in cardiomyocytes was shown on the sarcolemma,on the junctional sarcoplasmic reticulum and on subsarcolemmal cisternae.The results confirm differences in the localization of cAMP-PDE in dog andrat heart.     

Manganese metabolism is impaired in the Belgrade laboratory rat

Homozygous Belgrade rats have a hypochromic anaemia due to impaired iron transport across the cell membrane of immature erythroid cells. This study aimed at investigating whether there are also abnormalities of Mn metabolism in erythroid and other types of cells. The experiments were performed with homozygous (b/b) and heterozygous (+/b) Belgrade rats and Wistar rats and included measurements of Mn uptake by reticulocytes in vitro, Mn absorption from in situ closed loops of the duodenum, and plasma clearance and uptake by several organs after intravenous injection of radioactive Mn bound to transferrin (Tf ) or mixed with serum. Similar measurements were made with ⁵⁹Fe-labelled Fe in several of the experiments. Mn uptake by reticulocytes and absorption from the duodenum was impaired in b/b rats compared with +/b or Wistar rats. The plasma clearance of Mn-Tf was much slower than Mn-serum, but both were faster than the clearance of Fe-Tf. Uptake of ⁵⁴Mn by the kidneys, brain and femurs was less in b/b than Wistar or +/b rats, but uptake by the liver was greater in b/b rats. Similar differences were found for ⁵⁹Fe uptake by kidneys, brain and femurs but ⁵⁹Fe uptake by the liver was also impaired in the liver. It is concluded that the genetic abnormality present in b/b rats affects Mn metabolism as well as Fe metabolism and that Mn and Fe share similar transport mechanisms in the cells of erythroid tissue, duodenal mucosa, kidney and blood-brain barrier. Accepted: 20 February 1997     

RNA editing

The term RNA editing describes those molecular processes in which the information content is altered in an RNA molecule. To date such changes have been observed in tRNA. rRNA and mRNA molecules of eukaryotes, but not prokaryotes. The demonstration of RNA editing in prokaryotes may only be a matter of time, considering the range of species in which the various RNA editing processes have been found. RNA editing occurs in the nucleus, as well as in mitochondria and plastids, which are thought to have evolved from prokaryotic-like endosymbionts. Most of the RNA editing processes, however, appear to be evolutionarily recent acquisitions that arose independently. The diversity of RNA editing mechanisms includes nucleoside modifications such as C to U and A to I deaminations, as well as non-templated nucleotide additions and insertions. RNA editing in mRNAs effectively alters the amino acid sequence of the encoded protein so that it differs from that predicted by the genomic DNA sequence.     

CpG-methylation silences the activity of the RNA polymerase III transcribed EBER-1 promoter of Epstein-Barr virus

CpG-methylation blocks the activity of RNA polymerase II transcribed promoters in most cases. In contrast, the role of DNA methylation in the regulation of RNA polymerase III transcribed promoters is less clarified. There are two untranslated viral RNAs (EBER-1 and EBER-2) in most malignant cells carrying latent Epstein-Barr virus (EBV) genomes. We found that in vitro methylation blocked binding of the cellular proteins c-Myc and ATF to the 5'-region of the EBER-1 gene, and silenced the expression of the EBER-1 and EBER-2 genes, transcribed by RNA polymerase III, in transfected cells.     

Lipid-derived aldehydes accelerate light chain amyloid and amorphous aggregation

Antibody light chain (LC) aggregation in vivo leads to the systemic deposition of Ig light chain domains in the form of either amyloid fibrils (AL-amyloidosis) or amorphous deposits, light-chain deposition disease (LCDD), in mainly cardiac or renal tissue and is a pathological condition that is often fatal. Molecular factors that may contribute to the propensity of LCs to aggregate in vivo, such as the protein primary structure or local environment, are intensive areas of study. Herein, we show that the aggregation of a human antibody kappa-(kappa-MJM) and lambda-(lambda-L155) light chain (1 mg/mL) can be accelerated in vitro when they are incubated under physiologically relevant conditions, PBS, pH 7.4 and 37 degrees C, in the presence of a panel of biologically relevant lipid-derived aldehydes, 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), glyoxal (GLY), atheronal-A (KA), and atheronal-B (ALD). Thioflavin-T (ThT) and Congo Red (CR) binding assays coupled with turbidity studies reveal that this aldehyde-induced aggregation can be associated with alteration of protein secondary structure to an increased beta-sheet conformation. We observed that the nature of the conformational change is primarily dependent upon the lipidic aldehyde studied, not the protein sequence. Thus, the cholesterol 5,6-secosterols, KA and ALD, cause an amorphous-type aggregation which is ThT and CR negative for both the kappa-MJM and lambda-L155 light chains, whereas 4-HNE, MDA, and GLY induce aggregates that bind both ThT and CR. TEM analysis revealed that amyloid fibrils were formed during the 4-HNE-mediated aggregation of kappa-MJM and lambda-L155 light chains, whereas ALD-induced aggregates of these LCs where amorphous in nature. Kinetic profiles of LC aggregation reveal clear differences between the aldehydes, KA and ALD, causing a classic nucleated polymerization-type aggregation, with a lag phase (of approximately 150 h) followed by a growth phase that plateaus, whereas 4-HNE, MDA, and GLY trigger a seeded-type aggregation process that has no lag phase. In-depth studies of the 4-HNE-accelerated aggregation of kappa-MJM and lambda-L155 reveal a clear aldehyde concentration dependence and a process that can be inhibited by the naturally occurring osmolyte trimethylamine N-oxide (TMAO). Given these data, we feel our recently discovered paradigm of inflammatory aldehyde-induced protein misfolding may now extend to LC aggregation.     

The properties of phosphodiesterase 11A4 GAF domains are regulated by modifications in its N-terminal domain

The tandem GAF domain of human phosphodiesterase 11A4 (hPDE11A4) requires 72 microm cGMP for half-maximal effective concentration (EC(50)) of a cyanobacterial adenylyl cyclase used as a reporter enzyme. Here we examine whether modifications in the N-terminus of PDE11A4 affect cGMP signalling. The N-terminus has two phosphorylation sites for cyclic nucleotide monophosphate-dependent protein kinases (Ser117, Ser168). Phosphorylation of both by cAMP-dependent protein kinase decreased the EC(50) value for cGMP from 72 to 23 microm. Phosphomimetic point mutations (S117D/S167D), which project complete phosphorylation, lowered the EC(50) value to 16 microm. Structural and sequence data indicate that 196 amino acids precede the start of the GAF domain in hPDE11A4. Removal of 197 amino acids yielded unregulated cyclase activity, whereas truncation by 196 amino acids resulted in a cGMP-regulated protein with a cGMP EC(50) value of 7.6 microm. Truncation by 176 amino acids was required for cGMP EC(50) values to decrease to below 10 microm; a construct truncated by 168 amino acids had an EC(50) value of 224 microm. The decrease in EC(50) values was accompanied by a sixfold increase in basal activity; the extent of cGMP stimulation remained unaffected, however. We conclude that N-terminal modifications strongly affect cGMP regulation of hPDE11A4.