Chronic Treatment with the IDO1 Inhibitor 1-Methyl-D-Tryptophan Minimizes the Behavioural and Biochemical Abnormalities Induced by Unpredictable Chronic Mild Stress in Mice - Comparison with Fluoxetine

We demonstrated that confronting mice to the Unpredictable Chronic Mild Stress (UCMS) procedure—a validated model of stress-induced depression—results in behavioural alterations and biochemical changes in the kynurenine pathway (KP), suspected to modify the glutamatergic neurotransmission through the imbalance between downstream metabolites such as 3-hydroxykynurenine, quinolinic and kynurenic acids. We showed that daily treatment with the IDO1 inhibitor 1-methyl-D-tryptophan partially rescues UCMS-induced KP alterations as does the antidepressant fluoxetine. More importantly we demonstrated that 1-methyl-D-tryptophan was able to alleviate most of the behavioural changes resulting from UCMS exposure. We also showed that both fluoxetine and 1-methyl-D-tryptophan robustly reduced peripheral levels of proinflammatory cytokines in UCMS mice suggesting that their therapeutic effects might occur through anti-inflammatory processes. KP inhibition might be involved in the positive effects of fluoxetine on mice behaviour and could be a relevant strategy to counteract depressive-like symptoms.     

A Clinical,Neuropathological and Genetic Study of Homozygous A467T POLG-Related Mitochondrial Disease

Mutations in the nuclear gene POLG (encoding the catalytic subunit of DNA polymerase gamma) are an important cause of mitochondrial disease. The most common POLG mutation, A467T, appears to exhibit considerable phenotypic heterogeneity. The mechanism by which this single genetic defect results in such clinical diversity remains unclear. In this study we evaluate the clinical, neuropathological and mitochondrial genetic features of four unrelated patients with homozygous A467T mutations. One patient presented with the severe and lethal Alpers-Huttenlocher syndrome, which was confirmed on neuropathology, and was found to have a depletion of mitochondrial DNA (mtDNA). Of the remaining three patients, one presented with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), one with a phenotype in the Myoclonic Epilepsy, Myopathy and Sensory Ataxia (MEMSA) spectrum and one with Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO). All three had secondary accumulation of multiple mtDNA deletions. Complete sequence analysis of muscle mtDNA using the MitoChip resequencing chip in all four cases demonstrated significant variation in mtDNA, including a pathogenic MT-ND5 mutation in one patient. These data highlight the variable and overlapping clinical and neuropathological phenotypes and downstream molecular defects caused by the A467T mutation, which may result from factors such as the mtDNA genetic background, nuclear genetic modifiers and environmental stressors.     

Network Analysis of Metabolite GWAS Hits: Implication of CPS1 and the Urea Cycle in Weight Maintenance

Background and Scope

Weight loss success is dependent on the ability to refrain from regaining the lost weight in time. This feature was shown to be largely variable among individuals, and these differences, with their underlying molecular processes, are diverse and not completely elucidated. Altered plasma metabolites concentration could partly explain weight loss maintenance mechanisms. In the present work, a systems biology approach has been applied to investigate the potential mechanisms involved in weight loss maintenance within the Diogenes weight-loss intervention study.

Methods and Results

A genome wide association study identified SNPs associated with plasma glycine levels within the CPS1 (Carbamoyl-Phosphate Synthase 1) gene (rs10206976, p-value = 4.709e-11 and rs12613336, p-value = 1.368e-08). Furthermore, gene expression in the adipose tissue showed that CPS1 expression levels were associated with successful weight maintenance and with several SNPs within CPS1 (cis-eQTL). In order to contextualize these results, a gene-metabolite interaction network of CPS1 and glycine has been built and analyzed, showing functional enrichment in genes involved in lipid metabolism and one carbon pool by folate pathways.

Conclusions

CPS1 is the rate-limiting enzyme for the urea cycle, catalyzing carbamoyl phosphate from ammonia and bicarbonate in the mitochondria. Glycine and CPS1 are connected through the one-carbon pool by the folate pathway and the urea cycle. Furthermore, glycine could be linked to metabolic health and insulin sensitivity through the betaine osmolyte. These considerations, and the results from the present study, highlight a possible role of CPS1 and related pathways in weight loss maintenance, suggesting that it might be partly genetically determined in humans.     

The convergent trajectories of bird communities along ecological successions in european forests

Summary There is much more variation in the composition of bird communities in the earlier open and semi-open seral stages of ecological successions in forested landscapes of Europe than later on in preforested and forested climactic stages. The demonstration of this trend is achieved from the study of four habitat gradients, two in the mediterranean region (Provence and Corsica) and two in central Europe (Burgundy, France and Poland). A multivariate analysis has been used to illustrate the dynamics of communities along these succession. Displays of the results in bivariate space as well as an illustration of the distributional profiles of some of the most characteristic species show that: i) there is a discrimination between the two mediterranean gradients and the two medioeuropean ones and ii) each succession starts with a very distinct set of species and then the four gradients regularly converge in the last climactic stage where there is almost no discrimination between communities. These results are discussed in the light of the history of European biotas during the Pleistocene. The reason why there is more variation in species composition in the earlier seral stages than in the later forested stages are discussed according to current theories on the role of habitat selection on speciation processes.     

Assignment of the gene encoding the catalytic subunit Cβ of CAMP-dependent protein kinase to the p36 band on chromosome

Summary A cDNA for the human catalytic subunit (C) of cAMP-dependent protein kinase (PKA) has been cloned from a testis cDNA library. In the present study, we have determined the chromosomal localization of this gene using a cDNA for C as a probe. Southern blot analysis of genomic DNA from human/mouse cell hybrids revealed that the presence or absence of a 20-kbXbaI fragment, which hybridized with the C probe, was concordant with the presence of human chromosome 1.In situ hybridization to metaphase chromosome confirmed the somatic cell hybrid data and regionally mapped the C gene of PKA to the p36 band on chromosome 1.     

Ultrastructural modifications of the glandular epithelium of the receptaculum seminis in Thermobia domestica (Insecta: Thysanura) during the moulting period

Summary The wall of the receptaculum seminis of Thermobia domestica is composed of numerous glandular units, each with four enveloping cells (denoted 1 to 4) separated by ordinary epithelial cells and associated with a cuticular apparatus. During the moulting periods, which continue to occur in the adult stage, these cells undergo a series of transformations. Just before apolysis there is a dedifferentiation of numerous cytoplasmic organelles, but no mitosis has been observed. When the intima lifts off, the apical system of each glandular unit, i.e. the distal parts of the C2 and C3 cells surrounding the end apparatus, is also eliminated. Then at the apex of each glandular unit, a new ductule is formed in the cavity of which a long ciliary process grows up from cell C1. Finally comes the phase of cuticle formation, i.e., epicuticle for the ductules, epi-and endocuticle for the intima lining the central cavity of the receptaculum. Various cell types participate in secretion of cuticle, the ciliary cells (C1) being responsible for the formation of the porous end apparatus. At ecdysis almost all of the new intima has been secreted and the apical systems are once more differentiated. These transformations are compared with those recently described in other exocrine glands of arthropods, e.g., tegumentary glands and accessory glands of the genital ducts.     

Some prerequisites for a study of the evolution of cognition in the animal kingdom

A distinction is made between two definitions of animal cognition: the one most frequently employed in cognitive sciences considers cognition as extracting and processing information; a more phenomenologically inspired model considers it as attributing to a form of the outside world a significance, linked to the state of the animal. The respective fields of validity of these two models are discussed along with the limitations they entail, and the questions they pose to evolutionary biologists are emphasized. This is followed by a presentation of a general overview of what might be the study of the evolution of knowledge in animals.     

AGAP1, an endosome-associated,phosphoinositide-dependent ADP-ribosylation factor GTPase-activating protein that affects actin cytoskeleton

We have identified three members of the AGAP subfamily of ASAP family ADP-ribosylation factor GTPase-activating proteins (Arf GAPs). In addition to the Arf GAP domain, these proteins contain GTP-binding protein-like, ankyrin repeat and pleckstrin homology domains. Here, we have characterized the ubiquitously expressed AGAP1/KIAA1099. AGAP1 had Arf GAP activity toward Arf1>Arf5>Arf6. Phosphatidylinositol 4,5-bisphosphate and phosphatidic acid synergistically stimulated GAP activity. As found for other ASAP family Arf GAPs, the pleckstrin homology domain was necessary for activity. Deletion of the GTP-binding protein-like domain affected lipid dependence of Arf GAP activity. In vivo effects of AGAP1 were distinct from other ASAP family Arf GAPs. Overexpressed AGAP1 induced the formation of and was associated with punctate structures containing the endocytic markers transferrin and Rab4. AP1 was redistributed from the trans-Golgi to the punctate structures. Like other ASAP family members, AGAP1 overexpression inhibited the formation of PDGF-induced ruffles. However, distinct from other ASAP family members, AGAP1 also induced the loss of actin stress fibers. Thus, AGAP1 is a phosphoinositide-dependent Arf GAP that impacts both the endocytic compartment and actin.     

Cloning and characterization of the durable tomato mosaic virus resistance gene Tm-22 from Lycopersicon esculentum

In tomato, infections by tomato mosaic virus are controlled by durable Tm-2² resistance. In order to gain insight into the processes underlying disease resistance and its durability, we cloned and analysed the Tm-2² resistance gene and the susceptible allele, tm-2. The Tm-2² gene was isolated by transposon tagging using a screen in which plants with a destroyed Tm-2² gene survive. The Tm-2² locus consists of a single gene that encodes an 861 amino acid polypeptide, which belongs to the CC-NBS-LRR class of resistance proteins. The putative tm-2 allele was cloned from susceptible tomato lines via PCR with primers based on the Tm-2² sequence. Interestingly, the tm-2 gene has an open reading frame that is comparable to the Tm-2² allele. Between the tm-2 and the Tm-2² polypeptide 38 amino acid differences are present of which 26 are located in the second half of the LRR-domain. Susceptible tomato plants, which were transformed with the Tm-2² gene, displayed resistance against ToMV infection. In addition, virus specificity, displayed by the Tm-2² resistance was conserved in these transgenic lines. To explain the durability of this resistance, it is proposed that the Tm-2²-encoded resistance is aimed at the Achilles' heel of the virus.     

QTLs for enzyme activities and soluble carbohydrates involved in starch accumulation during grain filling in maize

ADPglucose, the essential substrate for starch synthesis, is synthesized in maize by a pathway involving at least invertases, sucrose synthase, and ADPglucose pyrophosphorylase, as shown by the starch-deficient mutants, mn1, sh1, and bt2 or sh2, respectively. To improve understanding of the relationship between early grain-filling traits and carbohydrate composition in mature grain, QTLs linked to soluble invertase, sucrose synthase, and ADPglucose pyrophosphorylase activities and to starch, sucrose, fructose, and glucose concentrations were investigated. In order to take into account the specific time-course of each enzyme activity during grain filling, sampling was carried out at three periods (15, 25, and 35 d after pollination) on 100 lines from a recombinant inbred family, grown in the field. The MQTL method associated with QTL interaction analysis revealed numerous QTLs for all traits, but only one QTL was consistently observed at the three sampling periods. Some chromosome zones were heavily labelled, forming clusters of QTLs. Numerous possible candidate genes of the starch synthetic pathway co-located with QTLs. Four QTLs were found close to the locus Sh1 (bin 9.01) coding for the sucrose synthase. In order to confirm the importance of this locus, the CAPS polymorphism of the Sh1 gene was analysed in 45 genetically unrelated maize lines from various geographical origins. The DNA polymorphism was significantly associated with phenotypic traits related to grain filling (starch and amylose content, grain matter, and ADPglucose pyrophosphorylase activity at 35 DAP). Thus, the Sh1 locus could provide a physiologically pertinent marker for maize selection.