Pb2+ tolerance by Frankia sp. strain EAN1pec involves surface-binding

Several Frankia strains have been shown to be lead-resistant. The mechanism of lead resistance was investigated for Frankia sp. strain EAN1pec. Analysis of the cultures by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDAX) and Fourier transforming infrared spectroscopy (FTIR) demonstrated that Frankia sp. strain EAN1pec undergoes surface modifications and binds high quantities of Pb +2 . Both labelled and unlabelled shotgun proteomics approaches were used to determine changes in Frankia sp. strain EAN1pec protein expression in response to lead and zinc. Pb 2+ specifically induced changes in exopolysaccharides, the stringent response, and the phosphate (pho) regulon. Two metal transporters (a Cu2+-ATPase and cation diffusion facilitator), as well as several hypothetical transporters, were also upregulated and may be involved in metal export. The exported Pb2+ may be precipitated at the cell surface by an upregulated polyphosphate kinase, undecaprenyl diphosphate synthase and inorganic diphosphatase. A variety of metal chaperones for ensuring correct cofactor placement were also upregulated with both Pb+2 and Zn+2 stress. Thus, this Pb+2 resistance mechanism is similar to other characterized systems. The cumulative interplay of these many mechanisms may explain the extraordinary resilience of Frankia sp. strain EAN1pec to Pb+2. A potential transcription factor (DUF156) binding site was identified in association with several proteins identified as upregulated with heavy metals. This site was also discovered, for the first time, in thousands of other organisms across two kingdoms

CancerResource: a comprehensive database of cancer-relevant proteins and compound interactions supported by experimental knowledge

During the development of methods for cancer diagnosis and treatment, a vast amount of information is generated. Novel cancer target proteins have been identified and many compounds that activate or inhibit cancer-relevant target genes have been developed. This knowledge is based on an immense number of experimentally validated compound–target interactions in the literature, and excerpts from literature text mining are spread over numerous data sources. Our own analysis shows that the overlap between important existing repositories such as Comparative Toxicogenomics Database (CTD), Therapeutic Target Database (TTD), Pharmacogenomics Knowledge Base (PharmGKB) and DrugBank as well as between our own literature mining for cancer-annotated entries is surprisingly small. In order to provide an easy overview of interaction data, it is essential to integrate this information into a single, comprehensive data repository. Here, we present CancerResource, a database that integrates cancer-relevant relationships of compounds and targets from (i) our own literature mining and (ii) external resources complemented with (iii) essential experimental and supporting information on genes and cellular effects. In order to facilitate an overview of existing and supporting information, a series of novel information connections have been established. CancerResource addresses the spectrum of research on compound–target interactions in natural sciences as well as in individualized medicine; CancerResource is available at: http://bioinformatics.charite.de/cancerresource/

The Human Urine Metabolome

Urine has long been a “favored” biofluid among metabolomics researchers. It is sterile, easy-to-obtain in large volumes, largely free from interfering proteins or lipids and chemically complex. However, this chemical complexity has also made urine a particularly difficult substrate to fully understand. As a biological waste material, urine typically contains metabolic breakdown products from a wide range of foods, drinks, drugs, environmental contaminants, endogenous waste metabolites and bacterial by-products. Many of these compounds are poorly characterized and poorly understood. In an effort to improve our understanding of this biofluid we have undertaken a comprehensive, quantitative, metabolome-wide characterization of human urine. This involved both computer-aided literature mining and comprehensive, quantitative experimental assessment/validation. The experimental portion employed NMR spectroscopy, gas chromatography mass spectrometry (GC-MS), direct flow injection mass spectrometry (DFI/LC-MS/MS), inductively coupled plasma mass spectrometry (ICP-MS) and high performance liquid chromatography (HPLC) experiments performed on multiple human urine samples. This multi-platform metabolomic analysis allowed us to identify 445 and quantify 378 unique urine metabolites or metabolite species. The different analytical platforms were able to identify (quantify) a total of: 209 (209) by NMR, 179 (85) by GC-MS, 127 (127) by DFI/LC-MS/MS, 40 (40) by ICP-MS and 10 (10) by HPLC. Our use of multiple metabolomics platforms and technologies allowed us to identify several previously unknown urine metabolites and to substantially enhance the level of metabolome coverage. It also allowed us to critically assess the relative strengths and weaknesses of different platforms or technologies. The literature review led to the identification and annotation of another 2206 urinary compounds and was used to help guide the subsequent experimental studies. An online database containing the complete set of 2651 confirmed human urine metabolite species, their structures (3079 in total), concentrations, related literature references and links to their known disease associations are freely available at http://www.urinemetabolome.ca

HMDB: the Human Metabolome Database

The Human Metabolome Database (HMDB) is currently the most complete and comprehensive curated collection of human metabolite and human metabolism data in the world. It contains records for more than 2180 endogenous metabolites with information gathered from thousands of books, journal articles and electronic databases. In addition to its comprehensive literature-derived data, the HMDB also contains an extensive collection of experimental metabolite concentration data compiled from hundreds of mass spectra (MS) and Nuclear Magnetic resonance (NMR) metabolomic analyses performed on urine, blood and cerebrospinal fluid samples. This is further supplemented with thousands of NMR and MS spectra collected on purified, reference metabolites. Each metabolite entry in the HMDB contains an average of 90 separate data fields including a comprehensive compound description, names and synonyms, structural information, physico-chemical data, reference NMR and MS spectra, biofluid concentrations, disease associations, pathway information, enzyme data, gene sequence data, SNP and mutation data as well as extensive links to images, references and other public databases. Extensive searching, relational querying and data browsing tools are also provided. The HMDB is designed to address the broad needs of biochemists, clinical chemists, physicians, medical geneticists, nutritionists and members of the metabolomics community. The HMDB is available at

Exome Sequencing and the Management of Neurometabolic Disorders

BACKGROUND: Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. METHODS: To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient's clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. RESULTS: We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%). CONCLUSIONS: Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children's Hospital Foundation and others.)

Barriers and facilitators to primary care for people with mental health and/or substance use issues: a qualitative study

Abstract Background Mental health and/or substance use issues are associated with significant disparities in morbidity and mortality. The aim of this study was to identify the mechanisms underlying poor primary care access for this population. Method This was a community-based participatory action qualitative study, in which 85 adults who self-identified as having a serious mental health and/or substance use issue and 17 service providers from various disciplines who worked with this population participated in a semi-structured interview. Results Client, service provider and health system barriers to access were identified. Client factors, including socioeconomic and psychological barriers, make it difficult for clients to access primary care, keep appointments, and/or prioritize their own health care. Provider factors, including knowledge and personal values related to mental health and substance use, determine the extent to which clients report their specific needs are met in the primary care setting. Health system factors, such as models of primary care delivery, determine the context within which both client and service provider factors operate. Conclusions This study helps elucidate the mechanisms behind poor primary health care access among people with substance use and/or mental health issues. The results suggest that interdisciplinary, collaborative models of primary healthcare may improve accessibility and quality of care for this population, and that more education about mental health and substance use issues may be needed to support service providers in providing adequate care for their clients

Is There an Association Between Untreated Hearing Loss and Psychosocial Outcomes?

Objective: Age-related hearing loss is one of the leading causes of disability in older adults. This cross-sectional study investigated the association between untreated hearing loss, social (perception of quality and quantity of social network) and emotional loneliness (perception of limited emotional support), social isolation (size of the social network), social support (actual or perceived availability of resources from the social network) and psychological discomfort (depression, anxiety, and stress) in older adults. Study Design: Cross-sectional study design. Methods: A total of 202 community derived sample of volunteers, age range 40–89 years, mean age (M) = 65.3 ± 11.0 years were recruited. Of these 115 were females (M = 63.2 ± 12.0 years) and 87 were males (M = 68.2 ± 8.9 years). All participants completed a hearing assessment, social interaction and support questionnaire and a social and emotional loneliness questionnaire. Results: Hearing loss significantly contributed to both moderate [P < 0.001, B (95% CI): 0.01 (0.99–1.02)] and intense levels [P < 0.001, 0.02 (1.00–1.04)] of emotional loneliness. Depression was significantly associated with satisfaction with social support [P < 0.001; −0.17 (−0.23 to −0.11), social interaction [P = 0.01; −0.07 (−0.12 to −0.01)], and moderate [P < 0.001; 0.31 (1.22–1.53)] and intense [P < 0.001; 0.29 (1.20–1.50)] levels of emotional loneliness and intense levels of social loneliness [P = 0.01; 0.12 (1.05–1.21)]. Conclusion: Untreated hearing loss significantly increases the odds of being emotionally lonely. Depression significantly contributes to social and emotional loneliness, satisfaction with social support and social loneliness. Given the higher prevalence of loneliness and psychological discomfort and their associations with untreated hearing loss, hearing-impaired older adults are at significant risk of developing loneliness and psychological discomfort. Therefore, hearing health professionals should be aware of the psychosocial burden that may accompany hearing loss, in order to provide appropriate advice and support

Is there an association between untreated hearing loss and psychosocial outcomes?

OBJECTIVE : Age-related hearing loss is one of the leading causes of disability in older adults. This cross-sectional study investigated the association between untreated hearing loss, social (perception of quality and quantity of social network) and emotional loneliness (perception of limited emotional support), social isolation (size of the social network), social support (actual or perceived availability of resources from the social network) and psychological discomfort (depression, anxiety, and stress) in older adults. STUDY DESIGN : Cross-sectional study design. METHODS : A total of 202 community derived sample of volunteers, age range 40–89 years, mean age (M) = 65.3 ± 11.0 years were recruited. Of these 115 were females (M = 63.2 ± 12.0 years) and 87 were males (M = 68.2 ± 8.9 years). All participants completed a hearing assessment, social interaction and support questionnaire and a social and emotional loneliness questionnaire. RESULTS : Hearing loss significantly contributed to both moderate [P < 0.001, B (95% CI): 0.01 (0.99–1.02)] and intense levels [P < 0.001, 0.02 (1.00–1.04)] of emotional loneliness. Depression was significantly associated with satisfaction with social support [P < 0.001; −0.17 (−0.23 to −0.11), social interaction [P = 0.01; −0.07 (−0.12 to −0.01)], and moderate [P < 0.001; 0.31 (1.22–1.53)] and intense [P < 0.001; 0.29 (1.20–1.50)] levels of emotional loneliness and intense levels of social loneliness [P = 0.01; 0.12 (1.05–1.21)]. CONCLUSION : Untreated hearing loss significantly increases the odds of being emotionally lonely. Depression significantly contributes to social and emotional loneliness, satisfaction with social support and social loneliness. Given the higher prevalence of loneliness and psychological discomfort and their associations with untreated hearing loss, hearing-impaired older adults are at significant risk of developing loneliness and psychological discomfort. Therefore, hearing health professionals should be aware of the psychosocial burden that may accompany hearing loss, in order to provide appropriate advice and support.https://www.frontiersin.org/journals/aging-neurosciencedm2022Speech-Language Pathology and Audiolog

SMPDB 2.0: big improvements to the small molecule pathway database

The Small Molecule Pathway Database (SMPDB, http://www.smpdb.ca) is a comprehensive, colorful, fully searchable and highly interactive database for visualizing human metabolic, drug action, drug metabolism, physiological activity and metabolic disease pathways. SMPDB contains >600 pathways with nearly 75% of its pathways not found in any other database. All SMPDB pathway diagrams are extensively hyperlinked and include detailed information on the relevant tissues, organs, organelles, subcellular compartments, protein cofactors, protein locations, metabolite locations, chemical structures and protein quaternary structures. Since its last release in 2010, SMPDB has undergone substantial upgrades and significant expansion. In particular, the total number of pathways in SMPDB has grown by >70%. Additionally, every previously entered pathway has been completely redrawn, standardized, corrected, updated and enhanced with additional molecular or cellular information. Many SMPDB pathways now include transporter proteins as well as much more physiological, tissue, target organ and reaction compartment data. Thanks to the development of a standardized pathway drawing tool (called PathWhiz) all SMPDB pathways are now much more easily drawn and far more rapidly updated. PathWhiz has also allowed all SMPDB pathways to be saved in a BioPAX format. Significant improvements to SMPDB's visualization interface now make the browsing, selection, recoloring and zooming of pathways far easier and far more intuitive. Because of its utility and breadth of coverage, SMPDB is now integrated into several other databases including HMDB and DrugBank. \ua9 2013 The Author(s). Published by Oxford University Press.Peer reviewed: YesNRC publication: Ye