| 1. |
- Clothier, Richard, et al.
(författare)
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A database of IC50 values and principal component analysis of results from six basal cytotoxicity assays, for use in the modelling of the in vivo and in vitro data of the EU ACuteTox project.
- 2008
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Ingår i: Altern Lab Anim. - 0261-1929. ; 36:5, s. 503-19
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Tidskriftsartikel (refereegranskat)abstract
- The main aim of the ACuteTox project (part of the EU 6th Framework programme) is to demonstrate that animal tests for acute systemic toxicity can be replaced by alternative in vitro assays. In this project, data for 97 reference chemicals were collected in the AcuBase database, designed to handle deposited in vitro and in vivo (human and animal) data. To demonstrate the applicability of in vitro basal cytotoxicity tests and in vitro-in vivo modelling, it was deemed necessary to obtain data that were generated via defined standard operating procedures. The molar basal cytotoxicity IC50 values (the 50% inhibitory concentrations for the endpoint measured) for a mouse fibroblast cell line (3T3), a human hepatic cell line (HepG2), a rat hepatic cell line (Fa32), and a human neutrophil cell line (HL-60), were compared, and gave an R(2) correlation of 0.83. To identify chemicals that showed differential cytotoxicity to the various cell types involved, principal component analysis (PCA) was undertaken independently, once all the results had been returned. This showed that colchicine, cycloheximide, digoxin, 5-fluorouracil and hexachlorobenzene gave the lowest correlations with the first score vector of the PCA. The results presented are to be used to identify outliers that need to be further studied via the use of tissue-specific in vitro assays.
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| 2. |
- Docherty, Anna R, et al.
(författare)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Tidskriftsartikel (refereegranskat)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 3. |
- Kmiec-Wisniewska, Beata, et al.
(författare)
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Evolution of protein import pathways
- 2012
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Ingår i: Mitochondrial genome evolution. - London : Academic Press. - 9780123942791 ; , s. 315-346
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Bokkapitel (refereegranskat)abstract
- Although a single endosymbiotic event is accepted to have led to the evolution of mitochondria, the machinery that is necessary to import the hundreds of cytosol-synthesized precursor proteins has diverged between various lineages. Plants have the additional requirement to sort protein between mitochondria and plastids, and yet there are also many cases of dual-targeted proteins. The machinery that achieved this process, the mitochondrial protein import apparatus, is composed of a variety of multi-subunit protein complexes on the outer and inner mitochondrial membranes. In plant mitochondria, there are differences in protein composition and/or function in the translocase of the outer membrane and in the intermembrane space. Furthermore, whereas the inner membrane translocases appear more conserved, there is an expansion in the preprotein and amino acid transporter (PRAT) family of proteins that suggest that neofunctionalization has occurred within this family. Our understanding of the processing and degradation of mitochondrial targeting signals in all systems is based on the intensive studies in plants.
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| 4. |
- Labbé, Catherine, et al.
(författare)
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Role for the microtubule-associated protein tau variant p.A152T in risk of α-synucleinopathies.
- 2015
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Ingår i: Neurology. - 1526-632X. ; 85:19, s. 1680-1686
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Tidskriftsartikel (refereegranskat)abstract
- Objective:To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies. Methods:In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls. Results:The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63-2.98, p = 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62-20.51, p = 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04-12.17, p = 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85-25.72, p = 0.08) but this was not statistically significant and therefore should be interpreted with caution. Conclusions:Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies
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| 5. |
- Li, Lu, et al.
(författare)
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Characterization of a novel β-barrel protein (AtOM47) from the mitochondrial outer membrane of Arabidopsis thaliana
- 2016
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Ingår i: Journal of Experimental Botany. - : Oxford University Press. - 0022-0957 .- 1460-2431. ; 67:21, s. 6061-6075
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Tidskriftsartikel (refereegranskat)abstract
- In plant cells, mitochondria are major providers of energy and building blocks for growth and development as well as abiotic and biotic stress responses. They are encircled by two lipid membranes containing proteins that control mitochondrial function through the import of macromolecules and metabolites. Characterization of a novel β-barrel protein, OUTER MEMBRANE PROTEIN 47 (OM47), unique to the green lineage and related to the voltage-dependent anion channel (VDAC) protein family, showed that OM47 can complement a VDAC mutant in yeast. Mutation of OM47 in Arabidopsis thaliana by T-DNA insertion had no effect on the import of proteins, such as the β-barrel proteins translocase of the outer membrane 40 (TOM40) or sorting and assembly machinery 50 (SAM50), into mitochondria. Molecular and physiological analyses revealed a delay in chlorophyll breakdown, higher levels of starch, and a delay in the induction of senescence marker genes in the mutant lines. While there was a reduction of >90% in OM47 protein in mitochondria isolated from 3-week-old om47 mutants, in mitochondria isolated from 8-week-old plants OM47 levels were similar to that of the wild type. This recovery was achieved by an up-regulation of OM47 transcript abundance in the mutants. Combined, these results highlight a role in leaf senescence for this plant-specific β-barrel protein, probably mediating the recovery and recycling of chloroplast breakdown products by transporting metabolic intermediates into and out of mitochondria.
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| 6. |
- Mullins, Niamh, et al.
(författare)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 7. |
- Mullins, Niamh, et al.
(författare)
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GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores
- 2019
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Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 176:8, s. 651-660
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Tidskriftsartikel (refereegranskat)abstract
- Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.
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| 10. |
- Tobias, Deirdre K, et al.
(författare)
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Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine
- 2023
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Ingår i: Nature Medicine. - 1546-170X. ; 29:10, s. 2438-2457
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Forskningsöversikt (refereegranskat)abstract
- Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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