| 1. |
- 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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| 2. |
- Beal, Jacob, et al.
(författare)
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Robust estimation of bacterial cell count from optical density
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 3. |
- 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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| 4. |
- Wierenga, Lara M., et al.
(författare)
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Greater male than female variability in regional brain structure across the lifespan
- 2022
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Ingår i: Human Brain Mapping. - : John Wiley & Sons. - 1065-9471 .- 1097-0193. ; 43:1, s. 470-499
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Tidskriftsartikel (refereegranskat)abstract
- For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.
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| 5. |
- Alvarez-Baron, Claudia P, et al.
(författare)
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The two-pore domain potassium channel KCNK5 : induction by estrogen receptor alpha and role in proliferation of breast cancer cells.
- 2011
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Ingår i: Molecular Endocrinology. - : The Endocrine Society. - 0888-8809 .- 1944-9917. ; 25:8, s. 1326-36
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Tidskriftsartikel (refereegranskat)abstract
- The growth of many human breast tumors requires the proliferative effect of estrogen acting via the estrogen receptor α (ERα). ERα signaling is therefore a clinically important target for breast cancer prevention and therapeutics. Although extensively studied, the mechanism by which ERα promotes proliferation remains to be fully established. We observed an up-regulation of transcript encoding the pH-sensitive two-pore domain potassium channel KCNK5 in a screen for genes stimulated by 17β-estradiol (E2) in the ERα(+) breast cancer cell lines MCF-7 and T47D. KCNK5 mRNA increased starting 1 h after the onset of E2 treatment, and protein levels followed after 12 h. Estrogen-responsive elements are found in the enhancer region of KCNK5, and chromatin immunoprecipitation assays revealed binding of ERα to the KCNK5 enhancer in E2-treated MCF-7 cells. Cells treated with E2 also showed increases in the amplitude of pH-sensitive potassium currents, as assessed by whole-cell recordings. These currents are blocked by clofilium. Although confocal microscopy suggested that most of the channels are located in intracellular compartments, the increase in macroscopic currents suggests that E2 treatment increases the number of active channels at the cell surface. Application of small interfering RNA specific for KCNK5 decreased pH-sensitive potassium currents and also reduced the estrogen-induced proliferation of T47D cells. We conclude that E2 induces the expression of KCNK5 via ERα(+) in breast cancer cells, and this channel plays a role in regulating proliferation in these cell lines. KCNK5 may therefore represent a useful target for treatment, for example, of tamoxifen-resistant breast cancer.
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| 6. |
- Andersson, Sandra, et al.
(författare)
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Insufficient antibody validation challenges oestrogen receptor beta research
- 2017
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of oestrogen receptor beta (ER beta/ESR2) was a landmark discovery. Its reported expression and homology with breast cancer pharmacological target ER alpha (ESR1) raised hopes for improved endocrine therapies. After 20 years of intense research, this has not materialized. We here perform a rigorous validation of 13 anti-ER beta antibodies, using well-characterized controls and a panel of validation methods. We conclude that only one antibody, the rarely used monoclonal PPZ0506, specifically targets ER beta in immunohistochemistry. Applying this antibody for protein expression profiling in 44 normal and 21 malignant human tissues, we detect ER beta protein in testis, ovary, lymphoid cells, granulosa cell tumours, and a subset of malignant melanoma and thyroid cancers. We do not find evidence of expression in normal or cancerous human breast. This expression pattern aligns well with RNA-seq data, but contradicts a multitude of studies. Our study highlights how inadequately validated antibodies can lead an exciting field astray.
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| 7. |
- Brose, Ulrich, et al.
(författare)
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Body sizes of consumers and their resources
- 2005
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Ingår i: Ecology. - : Ecological Society of America. - 0012-9658 .- 1939-9170. ; 86:9, s. 2545-2545
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Tidskriftsartikel (refereegranskat)abstract
- Trophic information—who eats whom—and species’ body sizes are two of the most basic descriptions necessary to understand community structure as well as ecological and evolutionary dynamics. Consumer–resource body size ratios between predators and their prey, and parasitoids and their hosts, have recently gained increasing attention due to their important implications for species’ interaction strengths and dynamical population stability. This data set documents body sizes of consumers and their resources. We gathered body size data for the food webs of Skipwith Pond, a parasitoid community of grass-feeding chalcid wasps in British grasslands; the pelagic community of the Benguela system, a source web based on broom in the United Kingdom; Broadstone Stream, UK; the Grand Caric¸aie marsh at Lake Neuchaˆtel, Switzerland; Tuesday Lake, USA; alpine lakes in the Sierra Nevada of California; Mill Stream, UK; and the eastern Weddell Sea Shelf, Antarctica. Further consumer–resource body size data are included for planktonic predators, predatory nematodes, parasitoids, marine fish predators, freshwater invertebrates, Australian terrestrial consumers, and aphid parasitoids. Containing 16 807 records, this is the largest data set ever compiled for body sizes of consumers and their resources. In addition to body sizes, the data set includes information on consumer and resource taxonomy, the geographic location of the study, the habitat studied, the type of the feeding interaction (e.g., predacious, parasitic) and the metabolic categories of the species (e.g., invertebrate, ectotherm vertebrate). The present data set was gathered with the intent to stimulate research on effects of consumer–resource body size patterns on food-web structure, interaction-strength distributions, population dynamics, and community stability. The use of a common data set may facilitate cross-study comparisons and understanding of the relationships between different scientific approaches and models.
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| 8. |
- Brose, Ulrich, et al.
(författare)
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Consumer-resource body-size relationships in natural food webs
- 2006
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Ingår i: Ecology. - : Ecological Society of America esa. - 0012-9658 .- 1939-9170. ; 87:10, s. 2411-2417
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Tidskriftsartikel (refereegranskat)abstract
- It has been suggested that differences in body size between consumer and resource species may have important implications for interaction strengths, population dynamics, and eventually food web structure, function, and evolution. Still, the general distribution of consumer-'resource body-size ratios in real ecosystems, and whether they vary systematically among habitats or broad taxonomic groups, is poorly understood. Using a unique global database on consumer and resource body sizes, we show that the mean body-size ratios of aquatic herbivorous and detritivorous consumers are several orders of magnitude larger than those of carnivorous predators. Carnivorous predator-prey body-size ratios vary across different habitats and predator and prey types (invertebrates, ectotherm, and endotherm vertebrates). Predator-prey body-size ratios are on average significantly higher (1) in freshwater habitats than in marine or terrestrial habitats, (2) for vertebrate than for invertebrate predators, and (3) for invertebrate than for ectotherm vertebrate prey. If recent studies that relate body-size ratios to interaction strengths are general, our results suggest that mean consumer-resource interaction strengths may vary systematically across different habitat categories and consumer types.
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| 9. |
- Budtz-Lilly, Jacob, et al.
(författare)
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European Multicentric Experience With Fenestrated-branched ENDOvascular Stent Grafting After Previous FAILed Infrarenal Aortic Repair The EU-FBENDO-FAIL Registry
- 2023
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Ingår i: Annals of Surgery. - : Ovid Technologies (Wolters Kluwer Health). - 0003-4932 .- 1528-1140. ; 278:2, s. E389-E395
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Tidskriftsartikel (refereegranskat)abstract
- Objective:To report the mid-term outcomes of fenestrated-branched endovascular aneurysm repair (F-BEVAR) following a failed previous endovascular aneurysm repair (pEVAR) or previous open aneurysm repair (pOAR).Methods:Data from consecutive patients who underwent F-BEVAR for pEVAR or pOAR from 2006 to 2021 from 17 European vascular centers were analyzed. Endpoints included technical success, major adverse events, 30-day mortality, and 5-year estimates of survival, target vessel primary patency, freedom from reinterventions, type I/III endoleaks, and sac growth >5 mm.Background:Treatment of a failed previous abdominal aortic aneurysm repair is a complex undertaking. F-BEVAR is becoming an increasingly attractive option, although comparative data are limited regarding associated risk factors, indications for treatment, and various outcomes.Results:There were 526 patients included, 268 pOAR and 258 pEVAR. The median time from previous repair to F-BEVAR was 7 (interquartile range, 4-12) years, 5 (3-8) for pEVAR, and 10 (6-14) for pOAR, P<0.001. Predominant indication for treatment was type Ia endoleak for pEVAR and progression of the disease for pOAR. Technical success was 92.8%, pOAR (92.2%), and pEVAR (93.4%), P=0.58. The 30-day mortality was 6.5% overall, 6.7% for pOAR, and 6.2% for pEVAR, P=0.81. There were 1853 treated target vessels with 5-year estimates of primary patency of 94.4%, pEVAR (95.2%), and pOAR (94.4%), P=0.03. Five-year estimates for freedom from type I/III endoleaks were similar between groups; freedom from reintervention was lower for pEVAR (38.3%) than for pOAR (56.0%), P=0.004. The most common indication for reinterventions was for type I/III endoleaks (37.5%).Conclusions:Repair of a failed pEVAR or pOARis safe and feasible with comparable technical success and survival rates. While successful treatment can be achieved, significant rates of reintervention should be anticipated, particularly for issues related to instability of target vessels/bridging stents.
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| 10. |
- Conley, Daniel, et al.
(författare)
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Hypoxia is increasing in the coastal zone of the Baltic Sea
- 2011
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 45:16, s. 6777-6783
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxia is a well-described phenomenon in the offshore waters of the Baltic Sea with both the spatial extent and intensity of hypoxia known to have increased due to anthropogenic eutrophication, however, an unknown amount of hypoxia is present in the coastal zone. Here we report on the widespread unprecedented occurrence of hypoxia across the coastal zone of the Baltic Sea. We have identified 115 sites that have experienced hypoxia during the period 1955-2009 increasing the global total to ca. 500 sites, with the Baltic Sea coastal zone containing over 20% of all known sites worldwide. Most sites experienced episodic hypoxia, which is a precursor to development of seasonal hypoxia. The Baltic Sea coastal zone displays an alarming trend with hypoxia steadily increasing with time since the 1950s effecting nutrient biogeochemical processes, ecosystem services, and coastal habitat.
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