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Since the previous publication of Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines in 1997, there has been a substantial increase in evidence-based treatment options for bipolar disorder. The present guidelines review the new evidence and use criteria to rate strength of evidence and incorporate effectiveness, safety, and tolerability data to determine global clinical recommendations for treatment of various phases of bipolar disorder. The guidelines suggest that although pharmacotherapy forms the cornerstone of management, utilization of adjunctive psychosocial treatments and incorporation of chronic disease management model involving a healthcare team are required in providing optimal management for patients with bipolar disorder. Lithium, valproate and several atypical antipsychotics are first-line treatments for acute mania. Bipolar depression and mixed states are frequently associated with suicidal acts; therefore assessment for suicide should always be an integral part of managing any bipolar patient. Lithium, lamotrigine or various combinations of antidepressant and mood-stabilizing agents are first-line treatments for bipolar depression. First-line options in the maintenance treatment of bipolar disorder are lithium, lamotrigine, valproate and olanzapine. Historical and symptom profiles help with treatment selection. With the growing recognition of bipolar II disorders, it is anticipated that a larger body of evidence will become available to guide treatment of this common and disabling condition. These guidelines also discuss issues related to bipolar disorder in women and those with comorbidity and include a section on safety and monitoring.

The Universal Protein Resource (UniProt) provides the scientific community with a single, centralized, authoritative resource for protein sequences and functional information. Formed by uniting the Swiss-Prot, TrEMBL and PIR protein database activities, the UniProt consortium produces three layers of protein sequence databases: the UniProt Archive (UniParc), the UniProt Knowledgebase (UniProt) and the UniProt Reference (UniRef) databases. The UniProt Knowledgebase is a comprehensive, fully classified, richly and accurately annotated protein sequence knowledgebase with extensive cross-references. This centrepiece consists of two sections: UniProt/Swiss-Prot, with fully, manually curated entries; and UniProt/TrEMBL, enriched with automated classification and annotation. During 2004, tens of thousands of Knowledgebase records got manually annotated or updated; we introduced a new comment line topic: TOXIC DOSE to store information on the acute toxicity of a toxin; the UniProt keyword list got augmented by additional keywords; we improved the documentation of the keywords and are continuously overhauling and standardizing the annotation of post-translational modifications. Furthermore, we introduced a new documentation file of the strains and their synonyms. Many new database cross-references were introduced and we started to make use of Digital Object Identifiers. We also achieved in collaboration with the Macromolecular Structure Database group at EBI an improved integration with structural databases by residue level mapping of sequences from the Protein Data Bank entries onto corresponding UniProt entries. For convenient sequence searches we provide the UniRef non-redundant sequence databases. The comprehensive UniParc database stores the complete body of publicly available protein sequence data. The UniProt databases can be accessed online (http://www.uniprot.org) or downloaded in several formats (ftp://ftp.uniprot.org/pub). New releases are published every two weeks.

To provide the scientific community with a single, centralized, authoritative resource for protein sequences and functional information, the Swiss-Prot, TrEMBL and PIR protein database activities have united to form the Universal Protein Knowledgebase (UniProt) consortium. Our mission is to provide a comprehensive, fully classified, richly and accurately annotated protein sequence knowledgebase, with extensive cross-references and query interfaces. The central database will have two sections, corresponding to the familiar Swiss-Prot (fully manually curated entries) and TrEMBL (enriched with automated classification, annotation and extensive cross-references). For convenient sequence searches, UniProt also provides several non-redundant sequence databases. The UniProt NREF (UniRef) databases provide representative subsets of the knowledgebase suitable for efficient searching. The comprehensive UniProt Archive (UniParc) is updated daily from many public source databases. The UniProt databases can be accessed online (http://www.uniprot.org) or downloaded in several formats (ftp://ftp.uniprot.org/pub). The scientific community is encouraged to submit data for inclusion in UniProt.

The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms, non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for non-protein-coding RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources needed for the exploration of human biology and pathology., An international team has systematically validated and annotated just over 21,000 human genes using full-length cDNA, thereby providing a valuable new resource for the human genetics community

The SWISS-PROT protein knowledgebase (http://www.expasy.org/sprot/ and http://www.ebi.ac.uk/swissprot/) connects amino acid sequences with the current knowledge in the Life Sciences. Each protein entry provides an interdisciplinary overview of relevant information by bringing together experimental results, computed features and sometimes even contradictory conclusions. Detailed expertise that goes beyond the scope of SWISS-PROT is made available via direct links to specialised databases. SWISS-PROT provides annotated entries for all species, but concentrates on the annotation of entries from human (the HPI project) and other model organisms to ensure the presence of high quality annotation for representative members of all protein families. Part of the annotation can be transferred to other family members, as is already done for microbes by the High-quality Automated and Manual Annotation of microbial Proteomes (HAMAP) project. Protein families and groups of proteins are regularly reviewed to keep up with current scientific findings. Complementarily, TrEMBL strives to comprise all protein sequences that are not yet represented in SWISS-PROT, by incorporating a perpetually increasing level of mostly automated annotation. Researchers are welcome to contribute their knowledge to the scientific community by submitting relevant findings to SWISS-PROT at swiss-prot@expasy.org.

Background Selecting a drug according to the treatment response in a relative has been widely accepted advice in the management of mood disorders. However, this recommendation has not been adequately substantiated in the literature. We tested the hypothesis that response to long-term lithium treatment is a familial trait. Method We compared response to long-term lithium treatment in bipolar relatives of bipolar lithium responders and bipolar controls. Twenty-four relatives with bipolar disorder (as determined using the Schedule for Affective Disorders and Schizophrenia-Lifetime version [SADS-L] and Research Diagnostic Criteria [RDC]) were identified in families of 106 patients with lithium-responsive bipolar disorder. A consecutive series of 40 lithium-treated patients in a bipolar clinic (meeting RDC and DSM-IV criteria for bipolar disorder) served as a comparison group. Lithium response was evaluated on a rating scale reflecting the quality and quantity of available data. Results The prevalence of unequivocal response among the relatives was 67%, as compared with the response rate of 35% in the comparison group (chi2 = 6.04, df = 1, p = .014). Conclusion This highly significant difference in response between relatives and the control group supports the view that the response to lithium prophylaxis clusters in families.

1. Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, WC1E 6JF. 2. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD. 3. Computational Medicine, School of Social and Community Medicine, University of Bristol, Bristol, BS8 2BN. 4. Institute of Cardiovascular Science, University College London, London, WC1E 6JF. 5. Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands. 6. King's College London, King's BHF Centre, London SE5 9NU

The availability of the human genome sequence has enabled the exploration and exploitation of the human genome and proteome to begin. Research has now focussed on the annotation of the genome and in particular of the proteome. With expert annotation extracted from the literature by biologists as the foundation, it has been possible to expand into the areas of data mining and automatic annotation. With further development and integration of pattern recognition methods and the application of alignments clustering, proteome analysis can now be provided in a meaningful way. These various approaches have been integrated to attach, extract and combine as much relevant information as possible to the proteome. This resource should be valuable to users from both research and industry.

Summary: QuickGO is a web-based tool that allows easy browsing of the Gene Ontology (GO) and all associated electronic and manual GO annotations provided by the GO Consortium annotation groups QuickGO has been a popular GO browser for many years, but after a recent redevelopment it is now able to offer a greater range of facilities including bulk downloads of GO annotation data which can be extensively filtered by a range of different parameters and GO slim set generation. Availability and Implementation: QuickGO has implemented in JavaScript, Ajax and HTML, with all major browsers supported. It can be queried online at http://www.ebi.ac.uk/QuickGO. The software for QuickGO is freely available under the Apache 2 licence and can be downloaded from http://www.ebi.ac.uk/QuickGO/installation.html Contact: goa@ebi.ac.uk; dbinns@ebi.ac.uk

SUMMARY: One of the distinguishing criteria of the SWISS-PROT protein sequence data bank is minimal redundancy. The introduction of TrEMBL as a supplementary database ensured the comprehensiveness of SWISS-PROT and TrEMBL but introduced some degree of redundancy. We developed a strategy to identify the redundancy present within and between SWISS-PROT and TrEMBL and its subsequent removal. AVAILABILITY: The tools mentioned in this paper are available on request.

Introduction Neuroprotective effects of lithium have been well documented in tissue cultures and animal models. The evidence for lithium related neuroprotection in human subjects is limited and inconsistent, likely due to methodological heterogeneity. Aims To investigate the effects of lithium on brain chemistry and structure, we recruited bipolar patients selected for substantial illness burden and varied the exposure to lithium by using strict inclusion criteria. Methods We obtained 1.5T magnetic resonance imaging data from 27 bipolar patients with at least 2 years of ongoing lithium treatment (Li group), 16 subjects with 2 years ago (non-Li group) and 21 healthy controls. Patient groups had to have at least 10 years of illness and 5 episodes. Results The non-Li group had significantly lower hippocampal volumes (t = 4.68,corrected p Conclusions Among patients selected for substantial illness burden, only those with no or minimal lifetime Li exposure had significantly lower prefrontal NAA levels and hippocampal volumes than controls. Patients with at least 2 years of ongoing Li treatment showed no such changes, despite substantial burden of illness. These findings provide indirect support for neuroprotective effects of lithium and negative effects of illness burden on brain chemistry and structure in patients with bipolar disorders.

The UniProt Knowledgebase (UniProtKB) acts as a central hub of protein knowledge by providing a unified view of protein sequence and functional information. Manual and automatic annotation procedures are used to add data directly to the database while extensive cross-referencing to more than 120 external databases provides access to additional relevant information in more specialized data collections. UniProtKB also integrates a range of data from other resources. All information is attributed to its original source, allowing users to trace the provenance of all data. The UniProt Consortium is committed to using and promoting common data exchange formats and technologies, and UniProtKB data is made freely available in a range of formats to facilitate integration with other databases. Database URL: http://www.uniprot.org/

The promise of genome sequencing was that the vast undiscovered country would be mapped out by comparison of the multitude of sequences available and would aid researchers in deciphering the role of each gene in every organism. Researchers recognize that there is a need for high quality data. However, different annotation procedures, numerous databases, and a diminishing percentage of experimentally determined gene functions have resulted in a spectrum of annotation quality. NCBI in collaboration with sequencing centers, archival databases, and researchers, has developed the first international annotation standards, a fundamental step in ensuring that high quality complete prokaryotic genomes are available as gold standard references. Highlights include the development of annotation assessment tools, community acceptance of protein naming standards, comparison of annotation resources to provide consistent annotation, and improved tracking of the evidence used to generate a particular annotation. The development of a set of minimal standards, including the requirement for annotated complete prokaryotic genomes to contain a full set of ribosomal RNAs, transfer RNAs, and proteins encoding core conserved functions, is an historic milestone. The use of these standards in existing genomes and future submissions will increase the quality of databases, enabling researchers to make accurate biological discoveries.

SWISS-PROT is a curated protein sequence database which strives to provide a high level of annotation, a minimal level of redundancy and high level of integration with other databases. Ongoing genome sequencing projects have dramatically increased the number of protein sequences to be incorporated into SWISS-PROT. Since we do not want to dilute the quality standards of SWISS-PROT by incorporating sequences without proper sequence analysis and annotation, we cannot speed up the incorporation of new incoming data indefinitely. However, as we also want to make the sequences available as fast as possible, we introduced TREMBL (TRanslation of EMBL nucleotide sequence database), a supplement to SWISS-PROT. TREMBL consists of computer-annotated entries in SWISS-PROT format derived from the translation of all coding sequences (CDS) in the EMBL nucleotide sequence database, except for CDS already included in SWISS-PROT. While TREMBL is already of immense value, its computer-generated annotation does not match the quality of SWISS-PROTs. The main difference is in the protein functional information attached to sequences. With this in mind, we are dedicating substantial effort to develop and apply computer methods to enhance the functional information attached to TREMBL entries.

The Gene Ontology Consortium (GOC) is a major bioinformatics project that provides structured controlled vocabularies to classify gene product function and location. GOC members create annotations to gene products using the Gene Ontology (GO) vocabularies, thus providing an extensive, publicly available resource. The GO and its annotations to gene products are now an integral part of functional analysis, and statistical tests using GO data are becoming routine for researchers to include when publishing functional information. While many helpful articles about the GOC are available, there are certain updates to the ontology and annotation sets that sometimes go unobserved. Here we describe some of the ways in which GO can change that should be carefully considered by all users of GO as they may have a significant impact on the resulting gene product annotations, and therefore the functional description of the gene product, or the interpretation of analyses performed on GO datasets. GO annotations for gene products change for many reasons, and while these changes generally improve the accuracy of the representation of the underlying biology, they do not necessarily imply that previous annotations were incorrect. We additionally describe the quality assurance mechanisms we employ to improve the accuracy of annotations, which necessarily changes the composition of the annotation sets we provide. We use the Universal Protein Resource (UniProt) for illustrative purposes of how the GO Consortium, as a whole, manages these changes.

Cognitive impairment in patients with bipolar disorder (BD) is not restricted to symptomatic phases. It is also present in euthymia. There is evidence of differences in the brain’s structure between bipolar patients and healthy individuals, as well as changes over time in patients. Lithium constitutes the gold standard in long-term prophylactic treatment. Appropriate therapy that prevents new episodes improves the disease’s course and reduces the frequency of harmful outcomes. Interestingly, preclinical data suggest that lithium has a (additional) neuroprotective effect. There is limited data on its related effects in humans and even less on its long-term application. In this multi-center cross-sectional study from the International Group for the Study of Lithium-treated Patients (IGSLi), we compared three groups: bipolar patients without long-term lithium treatment (non-Li group

This presentation, made during the ELIXIR Implementation Study on Standardizing fluxomics workflows kick-off meeting provides an overview of the standardisation efforts in the field of Fluxomics and Stable Isotope Resolved Metabolomics (SIRM). The presentation covers syntax and controlled terminologies for structuring experimental metadata of such studies to prepare for deposition to the European public repository Metabolights at EMBL-EBI. It introduces semantic resources such as MSIO, the Metabolomics Standards Initiative Ontology, the ISA format using by Metabolights, but also a proposal for extending UIPAC InChi specifications to enable unambiguous description of chemical entities (isotopologues and isotopomers). This extension is central to the regularised reporting of SIRM studies and the creation of FAIR data matrices., {"references":["https://www.nature.com/articles/sdata201618","https://doi.org/10.6084/m9.figshare.7150964.v1"]}