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The investigations carried out within the project in NE-Nigeria since 1989 have been focussing on the late Pleistocene and Holocene landscape development of the south eastern Chad basin. Areas of interest include palaeodune fields, clay plains and former beach ridge systems of Lake Chad. Transgressions and regressions of Lake Chad played an important role in the younger landscape history of NE-Nigeria and have also caused great environmental changes. The term „Megachad“ is well known and describes an enormous lake with an extension comparable with the Caspian Sea of today. The term „Microchad“ stands for the other recent extreme in terms of the lake dimensions varying during the times. Environmental changes in the surroundings of Lake Chad are closely connected with transgressions and regressions of the lake. These lake level changes can be climatically induced as well as non-climatically, due to human impact. Nearly all land units have more or less been influenced by the lake, spatially as well as temporally. It is important, though, to notice the scales of the changes. Some changes took place in a millennial scale, some in the scales of centuries or decades, and at least – as can be observed every year – in a seasonal scale.
Numerous ecologists postulate that West African savannas are mostly the result of degradation of formerly closed forests. This hypothesis can only be tested by palaeoecological investigations. The palynological results summarised in this paper document the history of the Sudanian and Sahelian savanna of NE-Nigeria during the last 11.500 years (uncal. BP). Both sites investigated provide evidence for the persistence of savanna throughout the entire Holocene. Patches of closed dry forest may have occurred, but never completely displaced the savanna vegetation. Humid conditions during the early and mid Holocene (from 10.000 BP onwards) caused a rapid spread of Guinean and Sudanian taxa into the northern vegetation zones. A slow return to drier climatic conditions between ca. 6800 BP and ca. 5500 BP can be recorded at both sites. Finally, between 3800 BP and 3300 BP a strong aridification resulted in the establishment of the modern vegetation zones. In both the Sahelian and Sudanian zone the vegetational changes appear to have been primarily controlled by climatic changes, whereas the effects of human activities remain palynologically silent even for the late Holocene.
Two sites situated in the Sahelian and Sudanian zones of NE-Nigeria were chosen for pollen analysis. A sediment core from an interdunal depression in the eastern Manga Grassland provides information on the Holocene vegetation history of the Sahel between c. 9600-3400 B.P. The 3 m pollen record indicates an open savanna during the mid-Holocene. The presence of Sudano-Guinean taxa, which were mainly restricted to the interdunal depressions, points to more humid conditions. Already before c. 4000 B.P., a slow change towards drier conditions and the establishment of the modern Sahelian vegetation is visible in the diagram. This development was accompanied by high fire frequencies. A 16 m core from a crater lake (Lake Tilla) in the Sudanian zone of NE-Nigeria provides a pollen record which can be dated back to approximately 11-12000 B.P. Preliminary pollen spectra show a relatively constant pattern with a dominance of grass pollen even during the middle Holocene.
Soluble guanylyl cyclase (sGC) is a cytosolic enzyme producing the intracellular messenger cyclic guanosine monophosphate (cGMP) on activation with nitric oxide (NO) which leads to the activation of GMP dependent protein kinases and to vasodilation. NO signaling may be affected by altered expression of sGC subunits, as has been shown in different pathological and physiological conditions and developmental stages. The molecular mechanisms underlying altered sGC expression in these and other conditions have not yet been revealed. Gene expression can also be regulated at the level of mRNA through alterations in translational efficiency and in mRNA stability. HuR (Human R) is a ubiquitously expressed member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins. Among other RNAs, there has been recent evidence that the expression of sGC is subject to post-transcriptional regulation by HuR. It has been shown that chronic hypertension induces changes in HuR expression and activity, which account for decreased sGC expression and activity in the aorta of hypertensive rats. This thesis should study was performed in an effort to provide some insight to the transcriptional and post-transcriptional regulation of sGC expression in a mammal, the rat. We investigated rat sGC alpha-1 transcriptional regulation in rat lung fibroblast (RLF-6) cells. The 3000bp 5' upstream region of the alpha-1 sGC gene was isolated and analyzed for promoter activity by using luciferase reporter constructs- Alpha3000 (with -2794 bp), Alpha1100 (-1092 bp), Alpha350 (-346 bp) and Alpha200 (-200 bp). The promoter activity was the highest in the 200bp construct (about 6-fold higher than Alpha3000) suggesting that this fragment contains all the crucial elements necessary to support basal transcription of the alpha-1 sGC gene. Analysis of the 200 bp of the 5’ UTR of the alpha-1 gene was performed using the MATINSPECTOR V2.2 software for putative transcription factors. The constructs containing the deleted sites for NFY and Sp1 showed a significant decrease in constitutive promoter activity by almost 80% and 60% respectively, implying that these transcription factors are crucial elements in the basal expression of the of sGC alpha-1 subunit. Treatment of RLF-6 cells with genistein 50 microM and mithramycinA 100 nM, known to inhibit the NFY and Sp1 binding to DNA respectively, reflected the same effects. Furthermore the cGMP content of the cells was significantly reduced by both inhibitors, almost completely by genistein, and by about 40 % by mithramycinA. Electrophoretic mobility-shift assay (EMSA) clearly showed the formation of multiple complexes with the biotinylated ODN (decoy oligodeoxynucleotide) probes for NFY and Sp1 when incubated with RLF-6 nuclear extract. A “supershift” observed in the presence of antibodies to the individual transcription factors confirmed that these factors were present in the shifted band, indeed. NFY and Sp1 are instrumental in several physiological and pathophysiological effects mediated by several growth factors in smooth muscle cells. Thus the regulation of the promoter, in response to serum, was also analysed. 10% foetal calf serum led to decreased alpha-1 sGC level as shown by western blots performed with rat aorta. Decreased sGC alpha-1 mRNA expression was observed in RLF-6 cells and cultured rat aortic smooth muscle cells incubated with FCS for 24 hours. This decrease was reflected in the promoter activity in RLF-6 cells using both Alpha3000 and Alpha200 constructs confirming that the regulation took place at promoter level. EMSA performed with nuclear extracts from FCS treated RLF-6 cells led to diminished binding to NFY, but to an enhanced binding to Sp1 site. We concluded that the factors Sp1 and NFY (the sites overlapping) compete for binding, and in the presence of FCS, it is Sp1 that binds stronger, and hence results in diminishing promoter activity. In order to delineate the post-transcriptional regulation of sGC alpha-1 subunit, studies were performed to demonstrate the regulation of expression of the mRNA stabilizing protein HuR. It has been observed that exposure of isolated rat aortic segments to the activator of adenylyl cyclase, forskolin, strongly reduced sGC alpha-1/beta-1 and HuR protein and mRNA expression in a time-dependent and actinomycin D-sensitive fashion. Transcription factor decoy approach proved that the cAMP-induced down-regulation of HuR is mediated by the activation of AP-1. It has been established that HuR stabilises the sGC alpha-1 and beta-1 mRNA. However the pathway underlying this regulation remains unknown. In order to identify the mechanism of this regulation, we looked for HuR interacting proteins employing the yeast two hybrid assay. The enzyme of the polyamine catabolic pathway spermidine/spermine N1-acetyltransferase (SSAT) was found to interact with the hinge region of HuR. This interaction was confirmed by performing immunoprecipitation and GST-pulldown experiments. A direct effect of these proteins on each other’s biological activity was not visible as tested through the SSAT activity assay and HuR gel shift. It might be possible that SSAT-mediated modulation of local polyamine concentrations enhances/reduces HuR activity and sGC expression to affect cell proliferation. In summary, this study represents an analysis of the rat sGC alpha-1 promoter regulation in rat fibroblast cells and identifies NFY and Sp1 as important factors in sGC alpha-1 expression. It also gives first evidence of sGC regulation at the transcriptional level in response to an external stimulus, and proposes the possible mechanism. It also identifies SSAT as a HuR interacting protein. These might have implications in the various pathophysiological conditions where sGC plays an important role.
Boswellia serrata gum resin extracts (frankincense) have been used for centuries in folk medicine in Asia and Africa. They have shown beneficial therapeutic effects, particularly in the treatment of chronic inflammatory diseases. Clinical studies on humans confirmed an anti-inflammatory and anti-cancer potential of Frankincense preparations. Boswellic acids (BAs) are the major ingredients, responsible for the pharmacological action of the extracts. Molecular and cellular studies with BAs revealed a number of targets including 5-lipoxygenase (LO), topoisomerases and the NF-κB pathway. Since there is little information on the modulation of cellular physiology by BAs, this work was designed to provide a detailed investigation of the cellular and molecular effects of BAs in several cell types related to inflammation. We report that 11-keto-BAs are potent activators of functional responses in human neutrophils, a type of leukocytes mediating acute inflammatory processes. Neutrophil activation by 11-keto-BAs is reflected by enhanced generation of oxygen radicals, release of arachidonic acid (AA) and the subsequent transformation of AA to pro-inflammatory eicosanoids. Investigation of the participating signalling pathways identified Ca2+, phosphoinositide-3 kinase, and members of the MAP kinase family (ERKs) as mediators. Second, we present a detailed study of the modulation of human platelet physiology and intracellular signalling events by BAs. Intriguingly, we discovered an inverse structure-activity relationship of BAs regarding platelet activation, with 11-methylene-BAs being superior over 11-keto-BAs. Thus, 11-methylene-BAs stimulated platelet Ca2+ mobilisation, MAP kinase and Akt activation, AA release, 12-LO and cyclooxygenase product formation, and thrombin generation. Novel Ca2+-independent activation pathways of platelet lipid metabolism were discovered. In contrast, 11-keto-BAs were inactive but found to inhibit platelet (p)12-LO directly. Interaction with p12-LO was confirmed in a pulldown assay using immobilised BAs as bait. Finally, BAs were shown to attenuate the activation of monocytes, a cell type responsible for the maintenance of chronic inflammatory states. Impairment of Ca2+ homeostasis is likely conferred by inhibition of Ca2+ influx channels. Taken together, our results shed light on the modulation of intracellular physiology of inflammatory cells by BAs, contributing to a better understanding of the anti-inflammatory effects exerted by frankincense preparations.
Background: Growth rate is central to the development of cells in all organisms. However, little is known about the impact of changing growth rates. We used continuous cultures to control growth rate and studied the transcriptional program of the model eukaryote Saccharomyces cerevisiae, with generation times varying between 2 and 35 hours.
Results: A total of 5930 transcripts were identified at the different growth rates studied. Consensus clustering of these revealed that half of all yeast genes are affected by the specific growth rate, and that the changes are similar to those found when cells are exposed to different types of stress (>80% overlap). Genes with decreased transcript levels in response to faster growth are largely of unknown function (>50%) whereas genes with increased transcript levels are involved in macromolecular biosynthesis such as those that encode ribosomal proteins. This group also covers most targets of the transcriptional activator RAP1, which is also known to be involved in replication. A positive correlation between the location of replication origins and the location of growth-regulated genes suggests a role for replication in growth rate regulation.
Conclusion: Our data show that the cellular growth rate has great influence on transcriptional regulation. This, in turn, implies that one should be cautious when comparing mutants with different growth rates. Our findings also indicate that much of the regulation is coordinated via the chromosomal location of the affected genes, which may be valuable information for the control of heterologous gene expression in metabolic engineering.
Alzheimer's disease-related mutations in the presenilin-1 gene (PS1) are leading to an elevated production of neurotoxic beta-amyloid 1-42 and may additionally enhance oxidative stress. Here, we provide in vivo evidence indicating that brains of transgenic mice expressing different human Alzheimer-linked PS1 mutations exhibit a reduced activity of two antioxidant enzymes. For this purpose, mice transgenic for human PS1 and for single and multiple PS1 mutations were generated. Mice with multiple PS1 mutations showed a significantly decreased activity of the antioxidant enzymes Cu/Zn superoxide dismutase and glutathione reductase already at an age of 3-4 months. As expected, this effect was less pronounced for the mice with a single PS1 mutation. By contrast, animals bearing normal human PS1 showed significantly elevated enzyme activities relative to non-transgenic littermate controls.
Background Reliable taxonomic identification at the species level is the basis for many biological disciplines. In order to distinguish species, it is necessary that taxonomic characters allow for the separation of individuals into recognisable, homogeneous groups that differ from other such groups in a consistent way. We compared here the suitability and efficacy of traditionally used shell morphology and DNA-based methods to distinguish among species of the freshwater snail genus Radix (Basommatophora, Pulmonata). Results Morphometric analysis showed that shell shape was unsuitable to define homogeneous, recognisable entities, because the variation was continuous. On the other hand, the Molecularly defined Operational Taxonomic Units (MOTU), inferred from mitochondrial COI sequence variation, proved to be congruent with biological species, inferred from geographic distribution patterns, congruence with nuclear markers and crossing experiments. Moreover, it could be shown that the phenotypically plastic shell variation is mostly determined by the environmental conditions experienced. Conclusion Contrary to DNA-taxonomy, shell morphology was not suitable for delimiting and recognising species in Radix. As the situation encountered here seems to be widespread in invertebrates, we propose DNA-taxonomy as a reliable, comparable, and objective means for species identification in biological research.
Enhanced apoptosis and elevated levels of reactive oxygen species (ROS) play a major role in aging. In addition, several neurodegenerative diseases are associated with increased oxidative stress and apoptosis in neuronal tissue. Antioxidative treatment has neuro-protective effects. The aim of the present study was to evaluate changes of susceptibility to apoptotic cell death by oxidative stress in aging and its inhibition by the antioxidant Ginkgo biloba extract EGb761. We investigated basal and ROS-induced levels of apoptotic lymphocytes derived from the spleen in young (3 months) and old (24 months) mice. ROS were induced by 2-deoxy-D-ribose (dRib) that depletes the intracellular pool of reduced glutathione. Lymphocytes from aged mice accumulate apoptotic cells to a significantly higher extent under basal conditions compared to cells from young mice. Treatment with dRib enhanced this difference, implicating a higher sensitivity to ROS in aging. Apoptosis can be reduced in vitro by treatment with EGb761. In addition, mice were treated daily with 100mg/kg EGb761 per os over a period of two weeks. ROS-induced apoptosis was significantly reduced in the EGb761 group. Interestingly, this effect seemed to be more pronounced in old mice.
Apoptosis seems to be involved in immunosenescence associated with aging. Moreover, in lymphocytes (PBL) of patients with Alzheimer's disease, an increased susceptibility to the apoptotic pathway has been described possibly due to impaired protection of oxidative stress. Accordingly, it seemed to be of particular interest to investigate the contribution of normal aging to the susceptibility from human lymphocytes to programmed cell death. We could show that PBL from elderly individuals (>60 years) accumulate apoptosing cells to a significant higher extent in spontaneous and activation-induced cell death compared to younger controls (<35 years). Treatment with the oxidative stressor 2-deoxy-D-ribose or with agonistic-CD95-antibody pronounced this effect even more implicating a higher sensitivity to reactive oxygen species and a higher functional CD95 expression, respectively. In addition, expression of the activation markers HLA-DR and CD95 was significantly increased in CD3+-cells of aged subjects, while expression of CD25 did not seem to be affected by age. Expression of Bcl-2 was increased in aging and correlated with the number of apoptotic cells.