Exascale integrated modeling of low-order wavefront sensing and control for the Roman Coronagraph instrument.

Astronomical instruments to detect exoplanets require extreme wavefront stability. For these missions to succeed, comprehensive and precise modeling is required to design and analyze suitable coronagraphs and their wavefront control systems. In this paper, we describe techniques for integrated modeling at scale that is, to the best of our knowledge, 1000 times faster than previously published works. We show how this capability has been used to validate performance and perform uncertainty quantification for the Roman Coronagraph instrument. Finally, we show how this modeling capacity may be necessary to design and build the next generation of space-based coronagraph instruments.

HMDB 5.0: the Human Metabolome Database for 2022.

The Human Metabolome Database or HMDB (https://hmdb.ca) has been providing comprehensive reference information about human metabolites and their associated biological, physiological and chemical properties since 2007. Over the past 15 years, the HMDB has grown and evolved significantly to meet the needs of the metabolomics community and respond to continuing changes in internet and computing technology. This year's update, HMDB 5.0, brings a number of important improvements and upgrades to the database. These should make the HMDB more useful and more appealing to a larger cross-section of users. In particular, these improvements include: (i) a significant increase in the number of metabolite entries (from 114 100 to 217 920 compounds); (ii) enhancements to the quality and depth of metabolite descriptions; (iii) the addition of new structure, spectral and pathway visualization tools; (iv) the inclusion of many new and much more accurately predicted spectral data sets, including predicted NMR spectra, more accurately predicted MS spectra, predicted retention indices and predicted collision cross section data and (v) enhancements to the HMDB's search functions to facilitate better compound identification. Many other minor improvements and updates to the content, the interface, and general performance of the HMDB website have also been made. Overall, we believe these upgrades and updates should greatly enhance the HMDB's ease of use and its potential applications not only in human metabolomics but also in exposomics, lipidomics, nutritional science, biochemistry and clinical chemistry.

CFM-ID 4.0: More Accurate ESI-MS/MS Spectral Prediction and Compound Identification.

In the field of metabolomics, mass spectrometry (MS) is the method most commonly used for identifying and annotating metabolites. As this typically involves matching a given MS spectrum against an experimentally acquired reference spectral library, this approach is limited by the coverage and size of such libraries (which typically number in the thousands). These experimental libraries can be greatly extended by predicting the MS spectra of known chemical structures (which number in the millions) to create computational reference spectral libraries. To facilitate the generation of predicted spectral reference libraries, we developed CFM-ID, a computer program that can accurately predict ESI-MS/MS spectrum for a given compound structure. CFM-ID is one of the best-performing methods for compound-to-mass-spectrum prediction and also one of the top tools for in silico mass-spectrum-to-compound identification. This work improves CFM-ID's ability to predict ESI-MS/MS spectra from compounds by (1) learning parameters from features based on the molecular topology, (2) adding a new approach to ring cleavage that models such cleavage as a sequence of simple chemical bond dissociations, and (3) expanding its hand-written rule-based predictor to cover more chemical classes, including acylcarnitines, acylcholines, flavonols, flavones, flavanones, and flavonoid glycosides. We demonstrate that this new version of CFM-ID (version 4.0) is significantly more accurate than previous CFM-ID versions in terms of both EI-MS/MS spectral prediction and compound identification. CFM-ID 4.0 is available at http://cfmid4.wishartlab.com/ as a web server and docker images can be downloaded at https://hub.docker.com/r/wishartlab/cfmid.

Histone deacetylase inhibition differentially attenuates cue-induced reinstatement: An interaction of environment and acH3K9 expression in the dorsal striatum.

Substance use disorder is driven by complex gene-environment interactions. Epigenetic histone regulation is a significant contributor to several behavioral phenotypes of drug abuse. The primary epigenetic mechanisms that drive drug taking and drug seeking are still being investigated, and it is unclear how environmental conditions alter epigenetic histone acetylation to change behaviors geared toward drug reward. This study examined the effects of environmental condition on amphetamine self-administration, and whether drug-taking and drug-seeking behaviors could be influenced through inhibition of an epigenetic regulator, histone deacetylase (HDAC). Male rats reared for 30 days in enriched (EC), isolated (IC), or standard conditions (SC) prior to amphetamine (0.03, 0.05, 0.1 mg/kg/infusion, IV) self-administration, extinction, and reinstatement sessions. The HDAC inhibitor, Trichostatin A (TsA; 0.3 mg/kg, IV), was injected 30 min prior to operant sessions. After amphetamine-induced reinstatement (0.25 mg/kg, subcutaneous [s.c.]), tissue was extracted for Western blot analyses of acetylated histone H3 lysine 9 (acH3K9) in the nucleus accumbens (NAc) and dorsal striatum (DSt). While TsA did not significantly affect amphetamine self-administration or extinction, TsA decreased cue-, but not drug-induced reinstatement in IC rats only. In the DSt, but not in the NAc, IC rats exhibited significantly less acH3K9 expression than EC and SC rats, irrespective of TsA treatment. HDAC inhibition decreases cue-induced reinstatement of amphetamine seeking in IC rats. While IC rats exhibit less acH3K9 expression in the DSt, future studies are needed to elucidate the critical epigenetic factors that drive substance abuse, particularly in vulnerable populations. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Subjective responses to amphetamine in young adults with previous mood elevation experiences.

RATIONALE: One risk factor for alcohol and substance misuse is hypomanic experiences, or periods of mood elevation. Young people who report hypomanic states are more likely to develop bipolar disorder (BP), and BP and other mood disorders increase the risk of addiction. We recently reported that young adults with a history of mood elevation experience less subjective effects from a low dose of alcohol, which may be predictive of future alcohol use. The finding with alcohol raised the question of whether this dampened response to a drug also applies to other drugs, such as amphetamine. OBJECTIVE: This study assessed responses of d-amphetamine in healthy young adults with varying experiences of mood elevation, as measured by the Mood Disorders Questionnaire (MDQ). METHODS: Healthy 18-19-year-olds (N = 30) with a range of MDQ scores participated in three 4-h laboratory sessions in which they received placebo, 10 mg, or 20 mg d-amphetamine. They completed mood questionnaires and cardiovascular measures. RESULTS: Individuals with higher MDQ scores reported less stimulation and euphoria after 10 mg, but not 20 mg, d-amphetamine, than individuals with lower scores. MDQ scores were not related to cardiovascular responses to the drug. CONCLUSIONS: A history of mood elevation experiences or hypomania states is related to dampened response to a low dose of a psychostimulant drug, extending previous findings with dampened response to alcohol. This phenotype for mood disorders of dampened responses to drugs may contribute to risk for subsequent drug use or misuse.

CFM-ID 3.0: Significantly Improved ESI-MS/MS Prediction and Compound Identification.

Metabolite identification for untargeted metabolomics is often hampered by the lack of experimentally collected reference spectra from tandem mass spectrometry (MS/MS). To circumvent this problem, Competitive Fragmentation Modeling-ID (CFM-ID) was developed to accurately predict electrospray ionization-MS/MS (ESI-MS/MS) spectra from chemical structures and to aid in compound identification via MS/MS spectral matching. While earlier versions of CFM-ID performed very well, CFM-ID's performance for predicting the MS/MS spectra of certain classes of compounds, including many lipids, was quite poor. Furthermore, CFM-ID's compound identification capabilities were limited because it did not use experimentally available MS/MS spectra nor did it exploit metadata in its spectral matching algorithm. Here, we describe significant improvements to CFM-ID's performance and speed. These include (1) the implementation of a rule-based fragmentation approach for lipid MS/MS spectral prediction, which greatly improves the speed and accuracy of CFM-ID; (2) the inclusion of experimental MS/MS spectra and other metadata to enhance CFM-ID's compound identification abilities; (3) the development of new scoring functions that improves CFM-ID's accuracy by 21.1%; and (4) the implementation of a chemical classification algorithm that correctly classifies unknown chemicals (based on their MS/MS spectra) in >80% of the cases. This improved version called CFM-ID 3.0 is freely available as a web server. Its source code is also accessible online.

Dynamic interactions of ceftriaxone and environmental variables suppress amphetamine seeking.

Extrasynaptic glutamate within the nucleus accumbens (NAc) is a driver of relapse. Cocaine, ethanol, and methamphetamine reduce the expression of cystine-glutamate antiporter (xCT) and primary glial glutamate transporter 1 (GLT1) leading to increased extrasynaptic glutamate. Ceftriaxone (CTX) restores xCT and GLT1 expression and effectively suppresses cocaine and ethanol reinstatement, however, the effects of CTX on amphetamine (AMP) reinstatement are not determined. Rodents were reared in an enriched condition (EC), isolated (IC), or standard condition (SC) and trained in AMP self-administration (0.1 mg/kg/infusion). EC, IC, and SC rats received injections of SAL or CTX (200 mg/kg) after daily extinction sessions. Then rats were tested in cue- and AMP-induced reinstatement tests. We hypothesized that EC rearing would reduce reinstatement by altering GLT1 or xCT expression in the NAc and medial prefrontal cortex (mPFC). In Experiment 2, pair-housed rats received once-daily AMP (1.0 mg/kg i.p.) or SAL for eight days followed by once-daily CTX (200 mg/kg i.p.) or SAL injections for 10 days. CTX treatment reduced cue-induced drug seeking in EC rats but not IC or SC rats. In an AMP-induced reinstatement test, CTX reduced AMP-induced drug seeking in EC and SC rats, but not IC rats. Western blot analyses revealed that AMP self-administration and non-contingent repeated AMP exposure did not downregulate GLT1 or xCT in the NAc or mPFC. Therefore, the ability for EC housing to reduce amphetamine seeking may work through other mechanisms.

PHAST, PHASTER and PHASTEST: Tools for finding prophage in bacterial genomes.

PHAST (PHAge Search Tool) and its successor PHASTER (PHAge Search Tool - Enhanced Release) have become two of the most widely used web servers for identifying putative prophages in bacterial genomes. Here we review the main capabilities of these web resources, provide some practical guidance regarding their use and discuss possible future improvements. PHAST, which was first described in 2011, made its debut just as whole bacterial genome sequencing and was becoming inexpensive and relatively routine. PHAST quickly gained popularity among bacterial genome researchers because of its web accessibility, its ease of use along with its enhanced accuracy and rapid processing times. PHASTER, which appeared in 2016, provided a number of much-needed enhancements to the PHAST server, including greater processing speed (to cope with very large submission volumes), increased database sizes, a more modern user interface, improved graphical displays and support for metagenomic submissions. Continuing developments in the field, along with increased interest in automated phage and prophage finding, have already led to several improvements to the PHASTER server and will soon lead to the development of a successor to PHASTER (to be called PHASTEST).

Rapid and reliable protein structure determination via chemical shift threading.

Protein structure determination using nuclear magnetic resonance (NMR) spectroscopy can be both time-consuming and labor intensive. Here we demonstrate how chemical shift threading can permit rapid, robust, and accurate protein structure determination using only chemical shift data. Threading is a relatively old bioinformatics technique that uses a combination of sequence information and predicted (or experimentally acquired) low-resolution structural data to generate high-resolution 3D protein structures. The key motivations behind using NMR chemical shifts for protein threading lie in the fact that they are easy to measure, they are available prior to 3D structure determination, and they contain vital structural information. The method we have developed uses not only sequence and chemical shift similarity but also chemical shift-derived secondary structure, shift-derived super-secondary structure, and shift-derived accessible surface area to generate a high quality protein structure regardless of the sequence similarity (or lack thereof) to a known structure already in the PDB. The method (called E-Thrifty) was found to be very fast (often < 10 min/structure) and to significantly outperform other shift-based or threading-based structure determination methods (in terms of top template model accuracy)-with an average TM-score performance of 0.68 (vs. 0.50-0.62 for other methods). Coupled with recent developments in chemical shift refinement, these results suggest that protein structure determination, using only NMR chemical shifts, is becoming increasingly practical and reliable. E-Thrifty is available as a web server at http://ethrifty.ca .

HMDB 4.0: the human metabolome database for 2018.

The Human Metabolome Database or HMDB (www.hmdb.ca) is a web-enabled metabolomic database containing comprehensive information about human metabolites along with their biological roles, physiological concentrations, disease associations, chemical reactions, metabolic pathways, and reference spectra. First described in 2007, the HMDB is now considered the standard metabolomic resource for human metabolic studies. Over the past decade the HMDB has continued to grow and evolve in response to emerging needs for metabolomics researchers and continuing changes in web standards. This year's update, HMDB 4.0, represents the most significant upgrade to the database in its history. For instance, the number of fully annotated metabolites has increased by nearly threefold, the number of experimental spectra has grown by almost fourfold and the number of illustrated metabolic pathways has grown by a factor of almost 60. Significant improvements have also been made to the HMDB's chemical taxonomy, chemical ontology, spectral viewing, and spectral/text searching tools. A great deal of brand new data has also been added to HMDB 4.0. This includes large quantities of predicted MS/MS and GC-MS reference spectral data as well as predicted (physiologically feasible) metabolite structures to facilitate novel metabolite identification. Additional information on metabolite-SNP interactions and the influence of drugs on metabolite levels (pharmacometabolomics) has also been added. Many other important improvements in the content, the interface, and the performance of the HMDB website have been made and these should greatly enhance its ease of use and its potential applications in nutrition, biochemistry, clinical chemistry, clinical genetics, medicine, and metabolomics science.

Cannabidiol Does Not Dampen Responses to Emotional Stimuli in Healthy Adults.

Introduction: Cannabidiol (CBD) is a nonpsychoactive constituent of whole plant cannabis that has been reported to reduce anxiety-like behaviors in both pre-clinical and human laboratory studies. Yet, no controlled clinical studies have demonstrated its ability to reduce negative mood or dampen responses to negative emotional stimuli in humans. The objective of this study was to investigate the effects of CBD on responses to negative emotional stimuli, as a model for its potential anxiety-reducing effects. Materials and Methods: The study used a double-blind, placebo (PLB)-controlled, within-subjects design in which 38 healthy, drug-free participants consumed oral CBD (300, 600, and 900 mg) or PLB before completing several behavioral tasks selected to assess reactivity to negative stimuli. Dependent measures included emotional arousal to negative and positive visual stimuli, perceptual sensitivity to emotional facial expressions, attentional bias toward emotional facial expressions, and feelings of social rejection. In addition, subjective drug effects and physiological data were also gathered during each experimental session to assess drug effects. Discussion: CBD did not dampen responses to negative emotional stimuli and did not affect feelings of social rejection. The high dose of CBD (900 mg) marginally reduced attentional bias toward happy and sad facial expressions, and produced a slight increase in late-session heart rate. CBD did not produce detectable subjective effects or alterations in mood or anxiety. Conclusion: These findings indicate that CBD has minimal behavioral and subjective effects in healthy volunteers, even when they are presented with emotional stimuli. Further research into the behavioral and neural mechanisms of CBD and other phytocannabinoids is needed to ascertain the clinical function of this drug.

YMDB 2.0: a significantly expanded version of the yeast metabolome database.

YMDB or the Yeast Metabolome Database (http://www.ymdb.ca/) is a comprehensive database containing extensive information on the genome and metabolome of Saccharomyces cerevisiae Initially released in 2012, the YMDB has gone through a significant expansion and a number of improvements over the past 4 years. This manuscript describes the most recent version of YMDB (YMDB 2.0). More specifically, it provides an updated description of the database that was previously described in the 2012 NAR Database Issue and it details many of the additions and improvements made to the YMDB over that time. Some of the most important changes include a 7-fold increase in the number of compounds in the database (from 2007 to 16 042), a 430-fold increase in the number of metabolic and signaling pathway diagrams (from 66 to 28 734), a 16-fold increase in the number of compounds linked to pathways (from 742 to 12 733), a 17-fold increase in the numbers of compounds with nuclear magnetic resonance or MS spectra (from 783 to 13 173) and an increase in both the number of data fields and the number of links to external databases. In addition to these database expansions, a number of improvements to YMDB's web interface and its data visualization tools have been made. These additions and improvements should greatly improve the ease, the speed and the quantity of data that can be extracted, searched or viewed within YMDB. Overall, we believe these improvements should not only improve the understanding of the metabolism of S. cerevisiae, but also allow more in-depth exploration of its extensive metabolic networks, signaling pathways and biochemistry.

PHASTER: a better, faster version of the PHAST phage search tool.

PHASTER (PHAge Search Tool - Enhanced Release) is a significant upgrade to the popular PHAST web server for the rapid identification and annotation of prophage sequences within bacterial genomes and plasmids. Although the steps in the phage identification pipeline in PHASTER remain largely the same as in the original PHAST, numerous software improvements and significant hardware enhancements have now made PHASTER faster, more efficient, more visually appealing and much more user friendly. In particular, PHASTER is now 4.3× faster than PHAST when analyzing a typical bacterial genome. More specifically, software optimizations have made the backend of PHASTER 2.7X faster than PHAST, while the addition of 80 CPUs to the PHASTER compute cluster are responsible for the remaining speed-up. PHASTER can now process a typical bacterial genome in 3 min from the raw sequence alone, or in 1.5 min when given a pre-annotated GenBank file. A number of other optimizations have also been implemented, including automated algorithms to reduce the size and redundancy of PHASTER's databases, improvements in handling multiple (metagenomic) queries and higher user traffic, along with the ability to perform automated look-ups against 14 000 previously PHAST/PHASTER annotated bacterial genomes (which can lead to complete phage annotations in seconds as opposed to minutes). PHASTER's web interface has also been entirely rewritten. A new graphical genome browser has been added, gene/genome visualization tools have been improved, and the graphical interface is now more modern, robust and user-friendly. PHASTER is available online at www.phaster.ca.

Heatmapper: web-enabled heat mapping for all.

Heatmapper is a freely available web server that allows users to interactively visualize their data in the form of heat maps through an easy-to-use graphical interface. Unlike existing non-commercial heat map packages, which either lack graphical interfaces or are specialized for only one or two kinds of heat maps, Heatmapper is a versatile tool that allows users to easily create a wide variety of heat maps for many different data types and applications. More specifically, Heatmapper allows users to generate, cluster and visualize: (i) expression-based heat maps from transcriptomic, proteomic and metabolomic experiments; (ii) pairwise distance maps; (iii) correlation maps; (iv) image overlay heat maps; (v) latitude and longitude heat maps and (vi) geopolitical (choropleth) heat maps. Heatmapper offers a number of simple and intuitive customization options for facile adjustments to each heat map's appearance and plotting parameters. Heatmapper also allows users to interactively explore their numeric data values by hovering their cursor over each heat map cell, or by using a searchable/sortable data table view. Heat map data can be easily uploaded to Heatmapper in text, Excel or tab delimited formatted tables and the resulting heat map images can be easily downloaded in common formats including PNG, JPG and PDF. Heatmapper is designed to appeal to a wide range of users, including molecular biologists, structural biologists, microbiologists, epidemiologists, environmental scientists, agriculture/forestry scientists, fish and wildlife biologists, climatologists, geologists, educators and students. Heatmapper is available at http://www.heatmapper.ca.

A robust algorithm for optimizing protein structures with NMR chemical shifts.

Over the past decade, a number of methods have been developed to determine the approximate structure of proteins using minimal NMR experimental information such as chemical shifts alone, sparse NOEs alone or a combination of comparative modeling data and chemical shifts. However, there have been relatively few methods that allow these approximate models to be substantively refined or improved using the available NMR chemical shift data. Here, we present a novel method, called Chemical Shift driven Genetic Algorithm for biased Molecular Dynamics (CS-GAMDy), for the robust optimization of protein structures using experimental NMR chemical shifts. The method incorporates knowledge-based scoring functions and structural information derived from NMR chemical shifts via a unique combination of multi-objective MD biasing, a genetic algorithm, and the widely used XPLOR molecular modelling language. Using this approach, we demonstrate that CS-GAMDy is able to refine and/or fold models that are as much as 10 Å (RMSD) away from the correct structure using only NMR chemical shift data. CS-GAMDy is also able to refine of a wide range of approximate or mildly erroneous protein structures to more closely match the known/correct structure and the known/correct chemical shifts. We believe CS-GAMDy will allow protein models generated by sparse restraint or chemical-shift-only methods to achieve sufficiently high quality to be considered fully refined and "PDB worthy". The CS-GAMDy algorithm is explained in detail and its performance is compared over a range of refinement scenarios with several commonly used protein structure refinement protocols. The program has been designed to be easily installed and easily used and is available at http://www.gamdy.ca.

Differential Rearing Alters Forced Swim Test Behavior, Fluoxetine Efficacy, and Post-Test Weight Gain in Male Rats.

Environmental factors play a key role in the etiology of depression. The rodent forced swim test (FST) is commonly used as a preclinical model of depression, with increases in escape-directed behavior reflecting antidepressant effects, and increases in immobility reflecting behavioral despair. Environmental enrichment leads to serotonergic alterations in rats, but it is unknown whether these alterations may influence the efficacy of common antidepressants. Male Sprague-Dawley rats were reared in enriched (EC), standard (SC), or isolated (IC) conditions. Following the rearing period, fluoxetine (10 or 20 mg/kg, i.p.) was administered 23.5 hrs, 5 hrs, and 1 hr before locomotor and FST measures. Following locomotor testing and FST exposure, rats were weighed to assess fluoxetine-, FST-, and environmental condition-induced moderations in weight gain. Results revealed an antidepressant effect of environmental enrichment and a depressant effect of isolation. Regardless of significant fluoxetine effects on locomotor activity, fluoxetine generally decreased swimming and increased immobility in all three environmental conditions, with IC-fluoxetine (10 mg/kg) rats and EC-fluoxetine (20 mg/kg) rats swimming less than vehicle counterparts. Subchronic 20 mg/kg fluoxetine also induced significant weight loss, and differential rearing appeared to moderate weight gain following FST stress. These results suggest that differential rearing has the ability to alter FST behaviors, fluoxetine efficacy, and post-stressor well-being. Moreover, 20 mg/kg fluoxetine, administered subchronically, may lead to atypical effects of those commonly observed in the FST, highlighting the importance and impact of both environmental condition and dosing regimen in common animal models of depression.

Accessible surface area from NMR chemical shifts.

Accessible surface area (ASA) is the surface area of an atom, amino acid or biomolecule that is exposed to solvent. The calculation of a molecule's ASA requires three-dimensional coordinate data and the use of a "rolling ball" algorithm to both define and calculate the ASA. For polymers such as proteins, the ASA for individual amino acids is closely related to the hydrophobicity of the amino acid as well as its local secondary and tertiary structure. For proteins, ASA is a structural descriptor that can often be as informative as secondary structure. Consequently there has been considerable effort over the past two decades to try to predict ASA from protein sequence data and to use ASA information (derived from chemical modification studies) as a structure constraint. Recently it has become evident that protein chemical shifts are also sensitive to ASA. Given the potential utility of ASA estimates as structural constraints for NMR we decided to explore this relationship further. Using machine learning techniques (specifically a boosted tree regression model) we developed an algorithm called "ShiftASA" that combines chemical-shift and sequence derived features to accurately estimate per-residue fractional ASA values of water-soluble proteins. This method showed a correlation coefficient between predicted and experimental values of 0.79 when evaluated on a set of 65 independent test proteins, which was an 8.2 % improvement over the next best performing (sequence-only) method. On a separate test set of 92 proteins, ShiftASA reported a mean correlation coefficient of 0.82, which was 12.3 % better than the next best performing method. ShiftASA is available as a web server ( http://shiftasa.wishartlab.com ) for submitting input queries for fractional ASA calculation.

CSI 3.0: a web server for identifying secondary and super-secondary structure in proteins using NMR chemical shifts.

The Chemical Shift Index or CSI 3.0 (http://csi3.wishartlab.com) is a web server designed to accurately identify the location of secondary and super-secondary structures in protein chains using only nuclear magnetic resonance (NMR) backbone chemical shifts and their corresponding protein sequence data. Unlike earlier versions of CSI, which only identified three types of secondary structure (helix, ß-strand and coil), CSI 3.0 now identifies total of 11 types of secondary and super-secondary structures, including helices, ß-strands, coil regions, five common ß-turns (type I, II, I', II' and VIII), ß hairpins as well as interior and edge ß-strands. CSI 3.0 accepts experimental NMR chemical shift data in multiple formats (NMR Star 2.1, NMR Star 3.1 and SHIFTY) and generates colorful CSI plots (bar graphs) and secondary/super-secondary structure assignments. The output can be readily used as constraints for structure determination and refinement or the images may be used for presentations and publications. CSI 3.0 uses a pipeline of several well-tested, previously published programs to identify the secondary and super-secondary structures in protein chains. Comparisons with secondary and super-secondary structure assignments made via standard coordinate analysis programs such as DSSP, STRIDE and VADAR on high-resolution protein structures solved by X-ray and NMR show >90% agreement between those made with CSI 3.0.

T3DB: the toxic exposome database.

The exposome is defined as the totality of all human environmental exposures from conception to death. It is often regarded as the complement to the genome, with the interaction between the exposome and the genome ultimately determining one's phenotype. The 'toxic exposome' is the complete collection of chronically or acutely toxic compounds to which humans can be exposed. Considerable interest in defining the toxic exposome has been spurred on by the realization that most human injuries, deaths and diseases are directly or indirectly caused by toxic substances found in the air, water, food, home or workplace. The Toxin-Toxin-Target Database (T3DB--www.t3db.ca) is a resource that was specifically designed to capture information about the toxic exposome. Originally released in 2010, the first version of T3DB contained data on nearly 2900 common toxic substances along with detailed information on their chemical properties, descriptions, targets, toxic effects, toxicity thresholds, sequences (for both targets and toxins), mechanisms and references. To more closely align itself with the needs of epidemiologists, toxicologists and exposome scientists, the latest release of T3DB has been substantially upgraded to include many more compounds (>3600), targets (>2000) and gene expression datasets (>15,000 genes). It now includes extensive data on 'normal' toxic compound concentrations in human biofluids as well as detailed chemical taxonomies, informative chemical ontologies and a large number of referential NMR, MS/MS and GC-MS spectra. This manuscript describes the most recent update to the T3DB, which was previously featured in the 2010 NAR Database Issue.

The effects of mGluR2/3 activation on acute and repeated amphetamine-induced locomotor activity in differentially reared male rats.

Environmental stimuli play a key role in affecting the likelihood to abuse drugs. Environmental enrichment can reduce that likelihood. The neurotransmitter glutamate contributes to both drug reward and rearing-induced changes in the brain. The current study investigated the effects of the Group-2 metabotropic glutamate receptor (mGluR2/3) agonist, LY-379268 (0.5, 1.0 mg/kg), on acute and repeated amphetamine-induced locomotor activity in differentially reared male rats. Male Sprague-Dawley rats were randomly assigned to one of 3 environmental conditions postweaning: enriched (EC), isolated (IC), or standard (SC), where they reared for 30 days. The effect of LY-379268 on acute amphetamine-induced locomotor activity was assessed. Rats were injected with either LY-379268 (0.5, 1.0 mg/kg) or saline prior to an amphetamine (0.5 mg/kg) or saline challenge injection. Rats were also administered amphetamine (0.5 mg/kg) or saline injections prior to 5 locomotor sessions. Following a rest period of 14-15 days, the effects of repeated amphetamine exposure were evaluated using LY-379268 (0.5, 1.0 mg/kg) or saline injections 30 min prior to receiving amphetamine (0.5 mg/kg). Results showed that LY-379268 administration dose-dependently attenuated acute amphetamine-induced locomotor activity, with EC rats generally displaying less attenuation than IC or SC rats. After repeated amphetamine administrations, the ability of LY-379268 to attenuate the final expression of amphetamine-induced locomotor activity in differentially reared rats was dose-dependent. The differing effect of LY-379268 observed in EC rats suggests enrichment-induced glutamatergic alterations that may protect against sensitivity to psychostimulants.