Emergence of hormonal and redox regulation of galectin-1 in placental mammals: implication in maternal-fetal immune tolerance

Galectin-1 is an anti-inflammatory lectin with pleiotropic regulatory functions at the crossroads of innate and adaptive immunity. It is expressed in immune privileged sites and is implicated in establishing maternal–fetal immune tolerance, which is essential for successful pregnancy in eutherian mammals. Here, we show conserved placental localization of galectin-1 in primates and its predominant expression in maternal decidua. Phylogenetic footprinting and shadowing unveil conserved cis motifs, including an estrogen responsive element in the 5′ promoter of LGALS1, that were gained during the emergence of placental mammals and could account for sex steroid regulation of LGALS1 expression, thus providing additional evidence for the role of galectin-1 in immune–endocrine cross-talk. Maximum parsimony and maximum likelihood analyses of 27 publicly available vertebrate and seven newly sequenced primate LGALS1 coding sequences reveal that intense purifying selection has been acting on residues in the carbohydrate recognition domain and dimerization interface that are involved in immune functions. Parsimony- and codon model-based phylogenetic analysis of coding sequences show that amino acid replacements occurred in early mammalian evolution on key residues, including gain of cysteines, which regulate immune functions by redox status-mediated conformational changes that disable sugar binding and dimerization, and that the acquired immunoregulatory functions of galectin-1 then became highly conserved in eutherian lineages, suggesting the emergence of hormonal and redox regulation of galectin-1 in placental mammals may be implicated in maternal–fetal immune tolerance.     

Effects of PACAP on the Circadian Changes of Signaling Pathways in Chicken Pinealocytes

Pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in the regulation of circadian rhythms. In mammals, the brain's biological clock is the suprachiasmatic nucleus, receiving photic information from the retina through the retinohypothalamic pathway, where PACAP is the main cotransmitter of glutamate. The primary conductor of circadian rhythms of birds is the pineal gland. The presence of PACAP has been demonstrated both in the rat and avian pineal gland, where PACAP stimulates melatonin synthesis. The signaling mechanism, by which PACAP modulates melatonin synthesis and circadian rhythmic functions of the pineal gland, is only partially known. The aim of the present study was to investigate the effects of PACAP on the changes of p38 mitogen-activated protein kinase (MAPK) and 14-3-3 protein in chick pineal cell culture both of which have been shown to participate in the regulation of rhythmic functions. Pineal cells were treated with 1, 10, or 100 nM PACAP38 every 4 h during a 24-h period. The phosphorylation of p38 MAPK showed obvious changes during the observed 24 h, while the level of 14-3-3 protein did not. We found that the lowest used dose of PACAP did not cause any phase alteration in p38 MAPK phosphorylation. Ten nM PACAP induced a 4-h-long delay and 100 nM abolished the circadian changes of p38 MAPK phosphorylation. PACAP was not effective on the level of 14-3-3 protein in the early morning hours, and only the highest tested dose (100 nM) could evoke a change in the appearance of 14-3-3 between midday and midnight hours. In summary, PACAP modulated the phosphorylation of p38 MAPK and the appearance of 14-3-3 protein in the chicken pineal cells, but these effects were dose dependent and also depended on the time of day.     

Incidence and progression of diabetic retinopathy in an Aboriginal Australian population: results from the Katherine Region Diabetic Retinopathy Study (KRDRS). Report no. 2

BACKGROUND: The Katherine Region Diabetic retinopathy Study (KRDRS) was carried out in the Lower Top End of the Northern Territory of Australia between 1993 and 1996 as part of the Northern Territory Eye Health Program. It investigated diabetic eye conditions and their determinants in the Australian Aboriginal population of the region. METHODS: The KRDRS was comprised of two cross-sectional surveys, in 1993 and in 1996, and involved a total of 477 subjects with diabetes. Ninety-six subjects were seen in both surveys and met the criteria for inclusion in the longitudinal study. Each subject underwent a general eye examination and retinal photography. RESULTS: The annual incidence rates of retinopathy were 5.6% (95% CI 3.0-10.0%) and 4.2% (95% CI 2.5-7.0%) in subjects and eyes, respectively. This compares with 8% (in subjects) of the overall Australian diabetic population found in the Newcastle Study of Diabetic Retinopathy. However, each year 1.2% of subjects (95% CI 0.2-3.8%) and 1.3% of eyes (95% CI 0.2-4.5%) with no pre-existing retinopathy developed vision-threatening retinopathy. The respective findings for maculopathy were 2.2% (95% CI 0.7-4.6%) and 1.7% (95% CI 0.7-3.2%), and for clinically significant macula oedema (CSME) 1.1% (95% CI 0.2-3.1%) and 0.9% (95% CI 0.3-2.2%). The annual incidence of CSME in those with no maculopathy when first seen was 1.1% (95% CI 0.2-3.3%) and 0.9% (95% CI 0.3-2.2%) in subjects and eyes, respectively. The annual progression to CSME in those with maculopathy was 4.8% (95% CI 0.1-26.5%) and 6.1% (0.7-21.9%) in subjects and eyes, respectively. CONCLUSION: Results of the KRDRS show that despite a lower overall incidence of diabetic retinopathy among Aboriginal diabetics compared to the general Australian diabetic population, there are important reasons to consider Aboriginal diabetics at special risk. These reasons include the highest reported incidence of vision-threatening retinopathy in Australia, one of the highest ever reported incidences of CSME in the world and the likelihood that the severity of the problem may be underestimated because of the relatively short observation time and the low average time since diagnosis. It is also acknowledged that the small numbers in the study limit our ability to reliably detect progression between subsets of the population and much larger studies are required to make statistically significant comparisons.     

Detecting location-specific neuronal firing rate increases in the hippocampus of freely-moving monkeys

The spatial properties of the firing of hippocampal neurons have mainly been studied in (a) freely moving rodents, (b) non-human primates seated in a moveable primate chair with head fixed, and (c) epileptic patients subjected to virtual navigation. Although these studies have all revealed the ability of hippocampal neurons to generate spatially selective discharges, the detected firing patterns have been found to be considerably different, even conflicting, in many respects. The present cellular electrophysiological study employed squirrel monkeys (Saimiri sciureus), which moved freely on the walls and floor of a large test chamber. This permitted the examination of the spatial firing of hippocampal neurons in nearly ideal conditions, similar to those used in rodents, yet in a species that belongs to the primate Suborder Anthropoidea. The major findings were that: (1) a group of slow-firing complex-spike cells increased their basal, awake firing rate more than 20-fold, often above 30 spikes/s, when the monkey was in a particular location in the chamber, (2) these location-specific discharges occurred consistently, forming 4-25 s action potential volleys, and (3) fast-firing cells displayed no such electrical activity. Thus, during free movement in three dimensions, primate hippocampal complex-spike cells do generate high-frequency, location-specific action potential volleys. Since these cells are components of the medial temporal lobe memory system, their uncovered firing pattern may well be involved in the formation of declarative memories on places.     

Spatial memory performance of freely-moving squirrel monkeys

Few experiments have addressed the problem of cognitive map formation in non-human primates. Therefore, a paradigm was developed to assess spatial memory formation in squirrel monkeys (Saimiri sciureus) moving freely in three dimensions. While moving on the walls and floor of a large test chamber, the animals learned to collect pieces of cereal from baited food-ports interspersed among non-baited ports. The cereal-pellets were not visible to the monkeys, so the animals needed to develop spatial memory to visit only the baited ports for food and avoid the non-baited ones. A session consisted of ten consecutive trials, and 3 successive sessions were conducted on each day for a 5-day period. For each trial, correct choices (CC; number of visited baited-ports) and incorrect choices (IC; number of visited non-baited ports) were registered, and spatial memory performance index (SMPI; ranging from 0.00 to 1.00) was calculated as follows: SMPI=(CC−IC)/CC. For each session, mean SMPI, session duration, total reaches into the non-baited ports, and total reaches into the baited ports were documented. In an 8-port task, where 4 food-ports were baited and 4 were non-baited, the mean SMPI was higher than 0 in the first session (day 1), indicating the development of short-term spatial memory. By the fifth session (day 2), this index was significantly higher than in the first session, indicating the build-up of long-term spatial memory. These changes were related to a significant decrease in the total reaches into the non-baited ports. At the same time, the duration of the sessions and the total reaches into the baited ports did not change significantly. This paradigm can be used for (1) studying cognitive map formation in primates, (2) examining the underlying cellular and molecular mechanisms in integrative neurobiological experiments, and (3) screening cognition-enhancer drugs in a monkey model.