Neural correlates of context-dependent memory : the role of the insula in episodic encoding and recognition memory ; an fMRI experiment

Magdeburg, Univ., Med. Fak., Diss., 2014

The importance of dietary calcium consumption in two species of semi-terrestrial grapsoid crabs

Calcium (Ca) is essential for crustaceans, due to calcium carbonate (CaCO3) deposition in the new exoskeleton to harden it. The purpose of this work was to study short term Ca balance in terms of dietary Ca ingestion in two phylogenetically related crabs (Superfamily Grapsoidea) showing different degrees of terrestrial adaptations: Sesarma rectum Randall, 1840 and Neohelice granulata (Dana, 1851). Dietary Ca ingestion was studied using purified diets with different Ca concentrations (0, 2.2 and 6.66 % Ca), together with measurements of Ca excretion and Ca hemolymph levels. The results showed that both crabs had the same response to foods containing different levels of Ca, with both species eating more of the high Ca diet. However, S. rectum consumed more per mg body mass at all Ca concentrations (6 mg.g-1 for S. rectum against 3 mg.g-1 for N. granulata). Both species excreted/egested Ca differently: S. rectum excreted Ca proportionally to ingestion, whereas N. granulata maintained constant faecal Ca output at all dietary Ca levels. Moreover, Ca hemolymph levels for crabs fed the different diets were independent of dietary Ca. In conclusion, both S. rectum and N. granulata seem to regulate the consumption of diets containing more Ca, which suggests a fine balance for Ca intake.

Imunidade e permeabilidade celular

After going through the more important theories on cellular permeability, researches were undertaken with the purpose of proving the actual influence of the various degrees of cellular permeability on the phenomena of organic resistance against infections, and on the production of antibodies. Three groups of substances known to have action on cellular permeability were used; the first consisting of the following permeable substances: testos-terona, acetylcholine, and the spreading-factor of the staphyloccocus. The second group included substances which help in developing low cellular permeability: atropin, adrenalin and calcium. Finally, the third group consisted of a substance which helps to maintain normal permeability: cortin (an extract of the suprarenal cortex). In order to study the process developed by these elements with regard to organic resistance against infections, adult mice were inoculated with the following germs: K. pneumoniae, P. aeruginosa, S. enteriditis and D. pneumoniae, in the smallest possible amount capable of starting a mortal sep infection in approximately 24 hours, exception made of D. pneumonias which causes death in 48 hours. The animals were divided into groups of 10, a before taking the injections containing the germs, they were given the sub lances under observation, through their peritoneum of intramuscularly. T. animals that died were autopsied and blood was taken from their hearts an aseptic process so as not to introduce extraneous organisms. For the purpose of determining the development of antibodies (hem lysins, precipitins and aglutinins), rabbits were used, which had been prep ously immunized by a treatment consisting of 6 intravenous injections of polyvolent antigen made of sheep blood cells, fresh human serum, and of suspension of S. enteriditis. It was concluded that: Cellular permeability plays a very important part in the development infections. Permeable substances help the development of germ infections. Substances helping to develop low permeability proved not to have any influence worth mentioning. Substances helping to maintain normal permeability, such as coffin, it crease resistance against infections. The different substances used which have action on cellular permeability had no influence worth mentioning on the development of certain ant bodies (hemolysins, precipitins and aglutinins). It was admitted that the phenomena under study relative to resistance against infections are closely connected to the dynamics of the cellular elements, which circumstance is basically dependent on the permeability of Citations of cells.

Payoff-dependent balancedness and cores (revised version)

We prove the non-emptiness of the core of an NTU game satisfying a condition of payoff-dependent balancedness, based on transfer rate mappings. We also define a new equilibrium condition on transfer rates and we prove the existence of core payoff vectors satisfying this condition. The additional requirement of transfer rate equilibrium refines the core concept and allows the selection of specific core payoff vectors. Lastly, the class of parametrized cooperative games is introduced. This new setting and its associated equilibrium-core solution extend the usual cooperative game framework and core solution to situations depending on an exogenous environment. A non-emptiness result for the equilibrium-core is also provided in the context of a parametrized cooperative game. Our proofs borrow mathematical tools and geometric constructions from general equilibrium theory with non convexities. Applications to extant results taken from game theory and economic theory are given.

Loss of Cutaneous TSLP-Dependent Immune Responses Skews the Balance of Inflammation from Tumor Protective to Tumor Promoting.

Inflammation can promote or inhibit cancer progression. In this study we have addressed the role of the proinflammatory cytokine thymic stromal lymphopoietin (TSLP) during skin carcinogenesis. Using conditional loss- and gain-of-function mouse models for Notch and Wnt signaling, respectively, we demonstrate that TSLP-mediated inflammation protects against cutaneous carcinogenesis by acting directly on CD4 and CD8 T cells. Genetic ablation of TSLP receptor (TSLPR) perturbs T-cell-mediated protection and results in the accumulation of CD11b(+)Gr1(+) myeloid cells. These promote tumor growth by secreting Wnt ligands and augmenting β-catenin signaling in the neighboring epithelium. Epithelial specific ablation of β-catenin prevents both carcinogenesis and the accumulation of CD11b(+)Gr1(+) myeloid cells, suggesting tumor cells initiate a feed-forward loop that induces protumorigenic inflammation.

Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice.

A role for the gastro-intestinal tract in controlling bone remodeling is suspected since serum levels of bone remodeling markers are affected rapidly after a meal. Glucose-dependent insulinotropic polypeptide (GIP) represents a suitable candidate in mediating this effect. The aim of the present study was to investigate the effect of total inhibition of GIP signaling on trabecular bone volume, microarchitecture and quality. We used GIP receptor (GIPR) knockout mice and investigated trabecular bone volume and microarchitecture by microCT and histomorphometry. GIPR-deficient animals at 16 weeks of age presented with a significant (20%) increase in trabecular bone mass accompanied by an increase (17%) in trabecular number. In addition, the number of osteoclasts and bone formation rate was significantly reduced and augmented, respectively in these animals when compared with wild-type littermates. These modifications of trabecular bone microarchitecture are linked to a remodeling in the expression pattern of adipokines in the GIPR-deficient mice. On the other hand, despite significant enhancement in bone volume, intrinsic mechanical properties of the bone matrix was reduced as well as the distribution of bone mineral density and the ratio of mature/immature collagen cross-links. Taken together, these results indicate an increase in trabecular bone volume in GIPR KO animals associated with a reduction in bone quality.

Insulin secretion is regulated by the glucose-dependent production of islet beta cell macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF), originally identified as a cytokine secreted by T lymphocytes, was found recently to be both a pituitary hormone and a mediator released by immune cells in response to glucocorticoid stimulation. We report here that the insulin-secreting beta cell of the islets of Langerhans expresses MIF and that its production is regulated by glucose in a time- and concentration-dependent manner. MIF and insulin colocalize by immunocytochemistry within the secretory granules of the pancreatic islet beta cells, and once released, MIF appears to regulate insulin release in an autocrine fashion. In perifusion studies performed with isolated rat islets, immunoneutralization of MIF reduced the first and second phase of the glucose-induced insulin secretion response by 39% and 31%, respectively. Conversely, exogenously added recombinant MIF was found to potentiate insulin release. Constitutive expression of MIF antisense RNA in the insulin-secreting INS-1 cell line inhibited MIF protein synthesis and decreased significantly glucose-induced insulin release. MIF is therefore a glucose-dependent, islet cell product that regulates insulin secretion in a positive manner and may play an important role in carbohydrate metabolism.

Glutathione deficit during development induces anomalies in the rat anterior cingulate GABAergic neurons: Relevance to schizophrenia.

A series of studies in schizophrenic patients report a decrease of glutathione (GSH) in prefrontal cortex (PFC) and cerebrospinal fluid, a decrease in mRNA levels for two GSH synthesizing enzymes and a deficit in parvalbumin (PV) expression in a subclass of GABA neurons in PFC. GSH is an important redox regulator, and its deficit could be responsible for cortical anomalies, particularly in regions rich in dopamine innervation. We tested in an animal model if redox imbalance (GSH deficit and excess extracellular dopamine) during postnatal development would affect PV-expressing neurons. Three populations of interneurons immunolabeled for calcium-binding proteins were analyzed quantitatively in 16-day-old rat brain sections. Treated rats showed specific reduction in parvalbumin immunoreactivity in the anterior cingulate cortex, but not for calbindin and calretinin. These results provide experimental evidence for the critical role of redox regulation in cortical development and validate this animal model used in schizophrenia research.

Nedd4-2-dependent ubiquitylation and regulation of the cardiac potassium channel hERG1.

The voltage-gated cardiac potassium channel hERG1 (human ether-à-gogo-related gene 1) plays a key role in the repolarization phase of the cardiac action potential (AP). Mutations in its gene, KCNH2, can lead to defects in the biosynthesis and maturation of the channel, resulting in congenital long QT syndrome (LQTS). To identify the molecular mechanisms regulating the density of hERG1 channels at the plasma membrane, we investigated channel ubiquitylation by ubiquitin ligase Nedd4-2, a post-translational regulatory mechanism previously linked to other ion channels. We found that whole-cell hERG1 currents recorded in HEK293 cells were decreased upon neural precursor cell expressed developmentally down-regulated 4-2 (Nedd4-2) co-expression. The amount of hERG1 channels in total HEK293 lysates and at the cell surface, as assessed by Western blot and biotinylation assays, respectively, were concomitantly decreased. Nedd4-2 and hERG1 interact via a PY motif located in the C-terminus of hERG1. Finally, we determined that Nedd4-2 mediates ubiquitylation of hERG1 and that deletion of this motif affects Nedd4-2-dependent regulation. These results suggest that ubiquitylation of the hERG1 protein by Nedd4-2, and its subsequent down-regulation, could represent an important mechanism for modulation of the duration of the human cardiac action potential.

Proximity-dependent pollen performance in Silene vulgaris.

BACKGROUND AND AIMS: Pollen and seed dispersal in herbaceous insect-pollinated plants are often restricted, inducing strong population structure. To what extent this influences mating within and among patches is poorly understood. This study investigates the influence of population structure on pollen performance using controlled pollinations and genetic markers. METHODS: Population structure was investigated in a patchily distributed population of gynodioecious Silene vulgaris in Switzerland using polymorphic microsatellite markers. Experimental pollinations were performed on 21 hermaphrodite recipients using pollen donors at three spatial scales: (a) self-pollination; (b) within-patch cross-pollinations; and (c) between-patch cross-pollinations. Pollen performance was then compared with respect to crossing distance. KEY RESULTS: The population of S. vulgaris was characterized by a high degree of genetic sub-structure, with neighbouring plants more related to one another than to distant individuals. Inbreeding probably results from both selfing and biparental inbreeding. Pollen performance increased with distance between mates. Between-patch pollen performed significantly better than both self- and within-patch pollen donors. However, no significant difference was detected between self- and within-patch pollen donors. CONCLUSIONS: The results suggest that population structure in animal-pollinated plants is likely to influence mating patterns by favouring cross-pollinations between unrelated plants. However, the extent to which this mechanism could be effective as a pre-zygotic barrier preventing inbred mating depends on the patterns of pollinator foraging and their influence on pollen dispersal.

Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells.

NKG2D is an activation receptor that allows natural killer (NK) cells to detect diseased host cells. The engagement of NKG2D with corresponding ligand results in surface modulation of the receptor and reduced function upon subsequent receptor engagement. However, it is not clear whether in addition to modulation the NKG2D receptor complex and/or its signaling capacity is preserved. We show here that the prolonged encounter with tumor cell-bound, but not soluble, ligand can completely uncouple the NKG2D receptor from the intracellular mobilization of calcium and the exertion of cell-mediated cytolysis. However, cytolytic effector function is intact since NKG2D ligand-exposed NK cells can be activated via the Ly49D receptor. While NKG2D-dependent cytotoxicity is impaired, prolonged ligand exposure results in constitutive interferon gamma (IFNgamma) production, suggesting sustained signaling. The functional changes are associated with a reduced presence of the relevant signal transducing adaptors DNAX-activating protein of 10 kDa (DAP-10) and killer cell activating receptor-associated protein/DNAX-activating protein of 12 kDa (KARAP/DAP-12). That is likely the consequence of constitutive NKG2D engagement and signaling, since NKG2D function and adaptor expression is restored to normal when the stimulating tumor cells are removed. Thus, the chronic exposure to tumor cells expressing NKG2D ligand alters NKG2D signaling and may facilitate the evasion of tumor cells from NK cell reactions.

Pathfinding of corticothalamic axons relies on a rendezvous with thalamic projections.

Major outputs of the neocortex are conveyed by corticothalamic axons (CTAs), which form reciprocal connections with thalamocortical axons, and corticosubcerebral axons (CSAs) headed to more caudal parts of the nervous system. Previous findings establish that transcriptional programs define cortical neuron identity and suggest that CTAs and thalamic axons may guide each other, but the mechanisms governing CTA versus CSA pathfinding remain elusive. Here, we show that thalamocortical axons are required to guide pioneer CTAs away from a default CSA-like trajectory. This process relies on a hold in the progression of cortical axons, or waiting period, during which thalamic projections navigate toward cortical axons. At the molecular level, Sema3E/PlexinD1 signaling in pioneer cortical neurons mediates a "waiting signal" required to orchestrate the mandatory meeting with reciprocal thalamic axons. Our study reveals that temporal control of axonal progression contributes to spatial pathfinding of cortical projections and opens perspectives on brain wiring.

β-Arrestin2 influences the response to methadone in opioid-dependent patients.

β-Arrestin2 (ARRB2) is a component of the G-protein-coupled receptor complex and is involved in μ-opioid and dopamine D(2) receptor signaling, two central processes in methadone signal transduction. We analyzed 238 patients in methadone maintenance treatment (MMT) and identified a haplotype block (rs34230287, rs3786047, rs1045280 and rs2036657) spanning almost the entire ARRB2 locus. Although none of these single nucleotide polymorphisms (SNPs) leads to a change in amino-acid sequence, we found that for all the SNPs analyzed, with exception of rs34230287, homozygosity for the variant allele confers a nonresponding phenotype (n=73; rs1045280C and rs2036657G: OR=3.1, 95% CI=1.5-6.3, P=0.004; rs3786047A: OR=2.5, 95% CI=1.2-5.1, P=0.02) also illustrated by a 12-fold shorter period of negative urine screening (P=0.01). The ARRB2 genotype may thus contribute to the interindividual variability in the response to MMT and help to predict response to treatment.