The OCaml system release 5.0: Documentation and user's manual

This manual documents the release 5.0 of the OCaml system. It is organized as follows. Part I, "An introduction to OCaml", gives an overview of the language. Part II, "The OCaml language", is the reference description of the language. Part III, "The OCaml tools", documents the compilers, toplevel system, and programming utilities. Part IV, "The OCaml library", describes the modules provided in the standard library. Part V, “Indexes”, contains an index of all identifiers defined in the standard library, and an index of keywords

The early bee catches the flower - circadian rhythmicity influences learning performance in honey bees, Apis mellifera

Circadian rhythmicity plays an important role for many aspects of honey bees’ lives. However, the question whether it also affects learning and memory remained unanswered. To address this question, we studied the effect of circadian timing on olfactory learning and memory in honey bees Apis mellifera using the olfactory conditioning of the proboscis extension reflex paradigm. Bees were differentially conditioned to odours and tested for their odour learning at four different “Zeitgeber” time points. We show that learning behaviour is influenced by circadian timing. Honey bees perform best in the morning compared to the other times of day. Additionally, we found influences of the light condition bees were trained at on the olfactory learning. This circadian-mediated learning is independent from feeding times bees were entrained to, indicating an inherited and not acquired mechanism. We hypothesise that a co-evolutionary mechanism between the honey bee as a pollinator and plants might be the driving force for the evolution of the time-dependent learning abilities of bees

Conformational Determinants of Phosphotyrosine Peptides Complexed with the Src SH2 Domain

The inhibition of specific SH2 domain mediated protein-protein interactions as an effective chemotherapeutic approach in the treatment of diseases remains a challenge. That different conformations of peptide-ligands are preferred by different SH2 domains is an underappreciated observation from the structural analysis of phosphotyrosine peptide binding to SH2 domains that may aid in future drug design. To explore the nature of ligand binding, we use simulated annealing (SA) to sample the conformational space of phosphotyrosine-containing peptides complexed with the Src SH2 domain. While in good agreement with the crystallographic and NMR studies of high-affinity phosphopeptide-SH2 domain complexes, the results suggest that the structural basis for phopsphopeptide- Src SH2 interactions is more complex than the “two-pronged plug two-hole socket” model. A systematic study of peptides of type pYEEX, where pY is phosphotyrosine and X is a hydrophobic residue, indicates that these peptides can assume two conformations, one extended and one helical, representing the balance between the interaction of residue X with the hydrophobic hole on the surface of the Src SH2 domain, and its contribution to the inherent tendency of the two glutamic acids to form an α-helix. In contrast, a β-turn conformation, almost identical to that observed in the crystal structure of pYVNV bound to the Grb2 SH2 domain, predominates for pYXNX peptides, even in the presence of isoleucine at the third position. While peptide binding affinities, as measured by fluorescence polarization, correlate with the relative proportion of extended peptide conformation, these results suggest a model where all three residues C-terminal to the phosphotyrosine determine the conformation of the bound phosphopeptide. The information obtained in this work can be used in the design of specific SH2 domain inhibitors

How Thioredoxin Dissociates Its Mixed Disulfide

The dissociation mechanism of the thioredoxin (Trx) mixed disulfide complexes is unknown and has been debated for more than twenty years. Specifically, opposing arguments for the activation of the nucleophilic cysteine as a thiolate during the dissociation of the complex have been put forward. As a key model, the complex between Trx and its endogenous substrate, arsenate reductase (ArsC), was used. In this structure, a Cys29Trx-Cys89ArsC intermediate disulfide is formed by the nucleophilic attack of Cys29Trx on the exposed Cys82ArsC-Cys89ArsC in oxidized ArsC. With theoretical reactivity analysis, molecular dynamics simulations, and biochemical complex formation experiments with Cys-mutants, Trx mixed disulfide dissociation was studied. We observed that the conformational changes around the intermediate disulfide bring Cys32Trx in contact with Cys29Trx. Cys32Trx is activated for its nucleophilic attack by hydrogen bonds, and Cys32Trx is found to be more reactive than Cys82ArsC. Additionally, Cys32Trx directs its nucleophilic attack on the more susceptible Cys29Trx and not on Cys89ArsC. This multidisciplinary approach provides fresh insights into a universal thiol/disulfide exchange reaction mechanism that results in reduced substrate and oxidized Trx

Convergent functional genomics of anxiety disorders: translational identification of genes, biomarkers, pathways and mechanisms

Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug—yohimbine, and an anti-anxiety drug—diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippocampus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain–blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as cAMP signaling) and mechanisms for anxiety disorders—notably signal transduction and reactivity to environment, with a prominent role for the hippocampus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain

Processing of Body Odor Signals by the Human Brain

Brain development in mammals has been proposed to be promoted by successful adaptations to the social complexity as well as to the social and non-social chemical environment. Therefore, the communication via chemosensory signals might have been and might still be a phylogenetically ancient communication channel transmitting evolutionary significant information. In humans, the neuronal underpinnings of the processing of social chemosignals have been investigated in relation to kin recognition, mate choice, the reproductive state and emotional contagion. These studies reveal that human chemosignals are probably not processed within olfactory brain areas but through neuronal relays responsible for the processing of social information. It is concluded that the processing of human social chemosignals resembles the processing of social signals originating from other modalities, except that human social chemosignals are usually communicated without the allocation of attentional resources, that is below the threshold of consciousness. Deviances in the processing of human social chemosignals might be related to the development and maintenance of mental disorders