| 1. |
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| 2. |
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| 3. |
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| 4. |
- Lissek, T, et al.
(författare)
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Building Bridges through Science
- 2017
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Ingår i: Neuron. - : Elsevier BV. - 1097-4199 .- 0896-6273. ; 96:4, s. 730-735
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Bar, N., et al.
(författare)
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A reference map of potential determinants for the human serum metabolome
- 2020
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Ingår i: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 588:7836, s. 135-140
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Tidskriftsartikel (refereegranskat)abstract
- The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
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| 6. |
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| 7. |
- Helbig, K. L., et al.
(författare)
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De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias
- 2018
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 103:5, s. 666-678
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Tidskriftsartikel (refereegranskat)abstract
- Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha(1)-subunit of the voltage-gated Ca(V)2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca(V)2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
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| 8. |
- Abdo, A. A., et al.
(författare)
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FERMI LARGE AREA TELESCOPE OBSERVATIONS OF THE VELA PULSAR
- 2009
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 696:2, s. 1084-1093
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Tidskriftsartikel (refereegranskat)abstract
- The Vela pulsar is the brightest persistent source in the GeV sky and thus is the traditional first target for new gamma-ray observatories. We report here on initial Fermi Large Area Telescope observations during verification phase pointed exposure and early sky survey scanning. We have used the Vela signal to verify Fermi timing and angular resolution. The high-quality pulse profile, with some 32,400 pulsed photons at E >= 0.03 GeV, shows new features, including pulse structure as fine as 0.3 ms and a distinct third peak, which shifts in phase with energy. We examine the high-energy behavior of the pulsed emission; initial spectra suggest a phase-averaged power-law index of Gamma = 1.51(-0.04)(+0.05) with an exponential cutoff at E-c = 2.9 +/- 0.1 GeV. Spectral fits with generalized cutoffs of the form e(-(E/Ec)b) require b <= 1, which is inconsistent with magnetic pair attenuation, and thus favor outer-magnetosphere emission models. Finally, we report on upper limits to any unpulsed component, as might be associated with a surrounding pulsar wind nebula.
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| 9. |
- Abdo, A. A., et al.
(författare)
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Fermi Observations of High-Energy Gamma-Ray Emission from GRB 080916C
- 2009
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 323:5922, s. 1688-1693
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Tidskriftsartikel (refereegranskat)abstract
- Gamma-ray bursts (GRBs) are highly energetic explosions signaling the death of massive stars in distant galaxies. The Gamma-ray Burst Monitor and Large Area Telescope onboard the Fermi Observatory together record GRBs over a broad energy range spanning about 7 decades of gamma-ray energy. In September 2008, Fermi observed the exceptionally luminous GRB 080916C, with the largest apparent energy release yet measured. The high-energy gamma rays are observed to start later and persist longer than the lower energy photons. A simple spectral form fits the entire GRB spectrum, providing strong constraints on emission models. The known distance of the burst enables placing lower limits on the bulk Lorentz factor of the outflow and on the quantum gravity mass.
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| 10. |
- Auffray, C., et al.
(författare)
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COVID-19 and beyond : a call for action and audacious solidarity to all the citizens and nations, it is humanity’s fight
- 2020
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Ingår i: F1000 Research. - : F1000 Research Ltd. - 2046-1402. ; 9, s. 1130-18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) belongs to a subgroup of coronaviruses rampant in bats for centuries. It caused the coronavirus disease 2019 (COVID-19) pandemic. Most patients recover, but a minority of severe cases experience acute respiratory distress or an inflammatory storm devastating many organs that can lead to patient death. The spread of SARS-CoV-2 was facilitated by the increasing intensity of air travel, urban congestion and human contact during the past decades. Until therapies and vaccines are available, tests for virus exposure, confinement and distancing measures have helped curb the pandemic. Vision: The COVID-19 pandemic calls for safeguards and remediation measures through a systemic response. Self-organizing initiatives by scientists and citizens are developing an advanced collective intelligence response to the coronavirus crisis. Their integration forms Olympiads of Solidarity and Health. Their ability to optimize our response to COVID-19 could serve as a model to trigger a global metamorphosis of our societies with far-reaching consequences for attacking fundamental challenges facing humanity in the 21st century. Mission: For COVID-19 and these other challenges, there is no alternative but action. Meeting in Paris in 2003, we set out to "rethink research to understand life and improve health." We have formed an international coalition of academia and industry ecosystems taking a systems medicine approach to understanding COVID-19 by thoroughly characterizing viruses, patients and populations during the pandemic, using openly shared tools. All results will be publicly available with no initial claims for intellectual property rights. This World Alliance for Health and Wellbeing will catalyze the creation of medical and health products such as diagnostic tests, drugs and vaccines that become common goods accessible to all, while seeking further alliances with civil society to bridge with socio-ecological and technological approaches that characterise urban systems, for a collective response to future health emergencies.
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| 11. |
- Blacher, E., et al.
(författare)
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Potential roles of gut microbiome and metabolites in modulating ALS in mice
- 2019
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 572:7770
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.
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| 12. |
- Brownstein, Catherine A., et al.
(författare)
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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| 13. |
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| 14. |
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| 15. |
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| 16. |
- Kurilshikov, Alexander, et al.
(författare)
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Large-scale association analyses identify host factors influencing human gut microbiome composition
- 2021
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 53:2, s. 156-165
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Tidskriftsartikel (refereegranskat)abstract
- To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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| 17. |
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| 18. |
- Pulit, SL, et al.
(författare)
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Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.
- 2016
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Ingår i: The Lancet. Neurology. - 1474-4465. ; 15:2, s. 174-84
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16851 cases with state-of-the-art phenotyping data and 32473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20941 cases and 364736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50×10(-8); joint OR 1·19, 1·12-1·26, p=1·30×10(-9)). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26×10(-19); joint OR 1·37, 1·30-1·45, p=2·79×10(-32)) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93×10(-7); joint OR 1·17, 1·11-1·23, p=2·29×10(-10)) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50×10(-8); joint OR 1·24, 1·15-1·33, p=4·52×10(-9)) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82×10(-8); joint OR 1·17, 1·11-1·23, p=2·92×10(-9)). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.US National Institute of Neurological Disorders and Stroke, National Institutes of Health.
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| 19. |
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| 20. |
- Alcorn, J, et al.
(författare)
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Basic instrumentation for Hall A at Jefferson Lab
- 2004
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Ingår i: Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. - : Elsevier BV. - 0167-5087 .- 0168-9002. ; 522:3, s. 294-346
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Tidskriftsartikel (refereegranskat)abstract
- The instrumentation in Hall A at the Thomas Jefferson National Accelerator Facility was designed to study electro-and photo-induced reactions at very high luminosity and good momentum and angular resolution for at least one of the reaction products. The central components of Hall A are two identical high resolution spectrometers, which allow the vertical drift chambers in the focal plane to provide a momentum resolution of better than 2 x 10(-4). A variety of Cherenkov counters, scintillators and lead-glass calorimeters provide excellent particle identification. The facility has been operated successfully at a luminosity well in excess of 10(38) CM-2 s(-1). The research program is aimed at a variety of subjects, including nucleon structure functions, nucleon form factors and properties of the nuclear medium. (C) 2003 Elsevier B.V. All rights reserved.
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| 21. |
- Barzilay, R., et al.
(författare)
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CD44 Deficiency Is Associated with Increased Susceptibility to Stress-Induced Anxiety-like Behavior in Mice
- 2016
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Ingår i: Journal of Molecular Neuroscience : MN. - : Springer Science and Business Media LLC. - 0895-8696 .- 1559-1166. ; 60:4, s. 548-558
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Tidskriftsartikel (refereegranskat)abstract
- CD44 is a cell surface adhesion molecule and its principal ligand is hyaluronic acid (HA), a key component of the brain’s extracellular matrix. CD44 levels are decreased in the cerebrospinal fluid (CSF) of depressed individuals, and the CD44 gene has been identified in genome wide association study as a possible risk gene in suicidal behavior. In order to define the pathobiological mechanisms by which CD44 may affect behavior, we investigated the role of CD44 using male CD44 knockout (CD44KO) and wild-type mice that underwent chronic mild stress (CMS). Behavior was characterized using the sucrose preference and forced swim tests, open field, novel object recognition, social preference, and the elevated plus maze tests. Gene expression in hippocampus was evaluated using quantitative real-time PCR. Brain monoamines and their metabolites were assessed by high-performance liquid chromatography and serum HA and IL-1β levels were measured using ELISA and electrochemiluminescence assays. CD44KO mice were more susceptible to stress-induced anxiety-like behavior and displayed increased anhedonia and despair than the wild-type controls. The behavioral phenotype of stressed CD44KO mice was associated with reduced cortical serotonergic and striatal dopaminergic turnover. The hippocampal expression of the receptor for HA-mediated motility (RHAMM) was reduced in the non- stressed CD44KO mice compared with WT mice, in a value similar to that observed in WT mice following exposure to stress. Taken together, our experiments suggest that CD44 plays a key role in stress response in mice.
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| 22. |
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| 23. |
- Bellenguez, Celine, et al.
(författare)
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Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:3, s. 141-328
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 x 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
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| 24. |
- Cameron, D., et al.
(författare)
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Replica Management in the European Data Grid Project
- 2004
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Ingår i: Journal of Grid Computing. - 1570-7873 .- 1572-9184. ; 2:4, s. 341-351
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Tidskriftsartikel (refereegranskat)abstract
- Within the European DataGrid project, Work Package 2 has designed and implemented a set of integrated replica management services for use by data intensive scientific applications. These services, based on the web services model, enable movement and replication of data at high speed from one geographical site to another, management of distributed replicated data, optimization of access to data, and the provision of a metadata management tool. In this paper we describe the architecture and implementation of these services and evaluate their performance under demanding Grid conditions.
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| 25. |
- Ebrahimi-Fakhari, Darius, et al.
(författare)
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Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia
- 2020
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Ingår i: Brain. - OXFORD ENGLAND : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:10, s. 2929-2944
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Tidskriftsartikel (refereegranskat)abstract
- Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 +/- 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 +/- 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 +/- 5.1 years, SD) and later tetraplegia (mean age: 16.1 +/- 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 +/- 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 +/- 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
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| 26. |
- Fromentin, S., et al.
(författare)
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Microbiome and metabolome features of the cardiometabolic disease spectrum
- 2022
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:2, s. 303-314
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Tidskriftsartikel (refereegranskat)abstract
- By studying individuals along a spectrum of cardiometabolic disease and adjusting for effects of lifestyle and medication, this investigation identifies alterations of the metabolome and microbiome from dysmetabolic conditions, such as obesity and type 2 diabetes, to ischemic heart disease. Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages-acute coronary syndrome, chronic IHD and IHD with heart failure-and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features.
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| 27. |
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| 28. |
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| 29. |
- Kottyan, Leah C., et al.
(författare)
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The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.
- 2015
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:2, s. 582-596
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Tidskriftsartikel (refereegranskat)abstract
- Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögrens syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.
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| 30. |
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| 31. |
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| 33. |
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| 34. |
- Liu, Ke, et al.
(författare)
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X Chromosome Dose and Sex Bias in Autoimmune Diseases : Increased 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome
- 2016
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 68:5, s. 1290-1300
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX, 1 in ∼1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls.METHODS:We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR).RESULTS:We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ∼404 SLE women and ∼344 SS women. 47,XXX was present in excess among SLE and SS subjects.CONCLUSION:The estimated prevalence of SLE and SS in women with 47,XXX was respectively ∼2.5 and ∼2.9 times higher than in 46,XX women and ∼25 and ∼41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity. This article is protected by copyright. All rights reserved.
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| 35. |
- Marinov, Amnon, et al.
(författare)
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Existence of long-lived isomeric states in naturally-occuring neutron-deficient Th isotopes
- 2007
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 76:2
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Tidskriftsartikel (refereegranskat)abstract
- Four long-lived neutron-deficient Th isotopes with atomic mass numbers 211 to 218 and abundances of (1-10)x10(-11) relative to Th-232 have been found in a study of naturally-occurring Th using inductively coupled plasma-sector field mass spectrometry. It is deduced that long-lived isomeric states exist in these isotopes. The hypothesis that they might belong to a new class of long-lived high spin super- and hyperdeformed isomeric states is discussed.
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| 36. |
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| 37. |
- Podsiadlo, P., et al.
(författare)
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Baseline trabecular bone and its relation to incident radiographic knee osteoarthritis and increase in joint space narrowing score : directional fractal signature analysis in the MOST study
- 2016
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Ingår i: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 24:10, s. 1736-1744
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To explore the association of baseline trabecular bone structure with incident tibiofemoral (TF) osteoarthritis (OA) and with increase in joint space narrowing (JSN) score. Methods The Multicenter Osteoarthritis Study (MOST) includes subjects with or at risk for knee OA. Knee radiographs were scored for Kellgren–Lawrence (KL) grade and JSN at baseline, 30, 60 and 84 months. Knees (KL ≤ 1) at baseline were assessed for incident OA (KL ≥ 2) and increases in JSN score. For each knee image at baseline, a variance orientation transform method (VOT) was applied to subchondral tibial bone regions of medial and lateral compartments. Seventeen fractal parameters were calculated per region. Associations of each parameter with OA incidence and with medial and lateral JSN increases were explored using logistic regression. Analyses were stratified by digitized film (DF) vs computer radiography (CR) and adjusted for confounders. Results Of 894 knees with CR and 1158 knees with DF, 195 (22%) and 303 (26%) developed incident OA. Higher medial bone roughness was associated with increased odds of OA incidence at 60 and 84 months and also, medial and lateral JSN increases (primarily vertical). Lower medial and lateral anisotropy was associated with increased odds of medial and lateral JSN increase. Compared to DF, CR had more associations and also, similar results at overlapping scales. Conclusion Baseline trabecular bone texture was associated with incident radiographic OA and increase of JSN scores independently of risk factors for knee OA. Higher roughness and lower anisotropy were associated with increased odds for radiographic OA change.
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| 38. |
- Santa-Maria, Miriam G., et al.
(författare)
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HCN emission from translucent gas and UV-illuminated cloud edges revealed by wide-field IRAM 30 m maps of the Orion B GMC: Revisiting its role as a tracer of the dense gas reservoir for star formation
- 2023
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Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 679
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Tidskriftsartikel (refereegranskat)abstract
- Context. Massive stars form within dense clumps inside giant molecular clouds (GMCs). Finding appropriate chemical tracers of the dense gas (n(H2) > several 104 cm-3 or AV > 8 mag) and linking their line luminosity with the star formation rate is of critical importance. Aims. Our aim is to determine the origin and physical conditions of the HCN-emitting gas and study their relation to those of other molecules. Methods. In the context of the IRAM 30m ORION-B large program, we present 5 deg2 (~250 pc2) HCN, HNC, HCO+, and CO J =1-0 maps of the Orion B GMC, complemented with existing wide-field [CI] 492 GHz maps, as well as new pointed observations of rotationally excited HCN, HNC, H13CN, and HN13C lines. We compare the observed HCN line intensities with radiative transfer models including line overlap effects and electron excitation. Furthermore, we study the HCN/HNC isomeric abundance ratio with updated photochemical models. Results. We spectroscopically resolve the HCN J = 1-0 hyperfine structure (HFS) components (and partially resolved J = 2-1 and 3-2 components). We detect anomalous HFS line intensity (and line width) ratios almost everywhere in the cloud. About 70% of the total HCN J = 1-0 luminosity, L′(HCN J = 1-0) = 110 K km s-1 pc-2, arises from AV < 8 mag. The HCN/CO J = 1-0 line intensity ratio, widely used as a tracer of the dense gas fraction, shows a bimodal behavior with an inflection point at AV < 3 mag typical of translucent gas and illuminated cloud edges. We find that most of the HCN J = 1-0 emission arises from extended gas with n(H2) < 104 cm-3, and even lower density gas if the ionization fraction is χe ≥10-5 and electron excitation dominates. This result contrasts with the prevailing view of HCN J = 1-0 emission as a tracer of dense gas and explains the low-AV branch of the HCN/CO J = 1-0 intensity ratio distribution. Indeed, the highest HCN/CO ratios (~ 0.1) at AV < 3 mag correspond to regions of high [CI] 492 GHz/CO J = 1-0 intensity ratios (>1) characteristic of low-density photodissociation regions. The low surface brightness (≲ 1 K km s-1) and extended HCN and HCO+ J = 1-0 emission scale with IFIR -a proxy of the stellar far-ultraviolet (FUV) radiation field -in a similar way. Together with CO J = 1-0, these lines respond to increasing IFIR up to G0 ≅ 20. On the other hand, the bright HCN J = 1-0 emission (> 6 K km s-1) from dense gas in star-forming clumps weakly responds to IFIR once the FUV field becomes too intense (G0 > 1500). In contrast, HNC J = 1-0 and [CI] 492 GHz lines weakly respond to IFIR for all G0. The different power law scalings (produced by different chemistries, densities, and line excitation regimes) in a single but spatially resolved GMC resemble the variety of Kennicutt-Schmidt law indexes found in galaxy averages. Conclusions. Given the widespread and extended nature of the [CI] 492 GHz emission, as well as its spatial correlation with that of HCO+, HCN, and 13CO J = 1-0 lines (in this order), we argue that the edges of GMCs are porous to FUV radiation from nearby massive stars. Enhanced FUV radiation favors the formation and excitation of HCN on large scales, not only in dense star-forming clumps, and it leads to a relatively low value of the dense gas mass to total luminosity ratio, α (HCN) = 29 M⊙ /(K km s-1pc2) in Orion B. As a corollary for extragalactic studies, we conclude that high HCN/CO J = 1-0 line intensity ratios do not always imply the presence of dense gas, which may be better traced by HNC than by HCN.
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| 39. |
- Segal, I, et al.
(författare)
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Acute pancreatitis in Soweto, South Africa: Relationship between trypsinogen load, trypsinogen activation, and fibrinolysis
- 2002
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Ingår i: American Journal of Gastroenterology. - 1572-0241. ; 97:4, s. 883-892
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Tidskriftsartikel (refereegranskat)abstract
- Objective: It is not known why acute pancreatitis in Soweto, South Africa, pursues an aggressive course. We sought clues from circulating trypsinogen load at admission as marker of initial acinar injury, trypsinogen activation using the carboxypeptidase B activation peptide as surrogate, proteinase inhibitors, the coagulation-fibrinolysis axis, indicators of inflammation, oxidative stress markers, and antioxidant status. This article reports on the first four aspects. Methods: The study involved 24 consecutive patients with a first attack. All of them were admitted within 24 h, and 22 were alcoholic. Urine was analyzed for anionic trypsinogen and the carboxypeptidase B activation peptide. Serum was tested for anionic and cationic trypsinogen, alpha(1) proteinase inhibitor and alpha(2) macroglobulin. Plasma from a subset was assayed for soluble fibrin, cross-linked fibrin degradation products (surrogates for thrombin and plasmin activity, respectively), and tissue-type plasminogen activator and inhibitor. Results: Soweto controls had higher serum anionic trypsinogen (p=0.004) and plasminogen activator:inhibitor ratio (p=0.047) than U.K. controls. The outcome of acute pancreatitis was mild in 17 but severe in seven with three deaths, two on day 2. In mild pancreatitis, intense plasmin activity (p<0.001) accompanied the surge in trypsinogen, especially anionic (p<0.001), but without increased thrombin activity and in five patients without trypsinogen activation. In severe pancreatitis, further significant increments in plasmin activity and trypsinogens were accompanied by increased thrombin activity (p=0.013) and trypsinogen activation (p=0.046). There was no correlation between surrogates of plasmin and thrombin activity, or between either and the carboxypeptidase B activation peptide. which showed a curvilinear relationship to total serum trypsinogen. Conclusions: The aggressive nature of alcoholic acute pancreatitis in Soweto seems to reflect early profound fibrinolysis, which precedes coagulation and is initially independent of trypsin. Subclinical acinar-cell injury and a profibrinolytic diathesis in outwardly healthy Sowetans may predispose to this problem.
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| 40. |
- Singel, Kelly L., et al.
(författare)
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Mature neutrophils suppress T cell immunity in ovarian cancer microenvironment
- 2019
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Ingår i: JCI Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 4:5
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Tidskriftsartikel (refereegranskat)abstract
- Epithelial ovarian cancer (EOC) often presents with metastases and ascites. Granulocytic myeloid-derived suppressor cells are an immature population that impairs antitumor immunity. Since suppressive granulocytes in the ascites of patients with newly diagnosed EOC were morphologically mature, we hypothesized that PMN were rendered suppressive in the tumor microenvironment (TME). Circulating PMN from patients were not suppressive but acquired a suppressor phenotype (defined as ≥1 log10 reduction of anti-CD3/CD28-stimulated T cell proliferation) after ascites supernatant exposure. Ascites supernatants (20 of 31 supernatants) recapitulated the suppressor phenotype in PMN from healthy donors. T cell proliferation was restored with ascites removal and restimulation. PMN suppressors also inhibited T cell activation and cytokine production. PMN suppressors completely suppressed proliferation in naive, central memory, and effector memory T cells and in engineered tumor antigen-specific cytotoxic T lymphocytes, while antigen-specific cell lysis was unaffected. Inhibition of complement C3 activation and PMN effector functions, including CR3 signaling, protein synthesis, and vesicular trafficking, abrogated the PMN suppressor phenotype. Moreover, malignant effusions from patients with various metastatic cancers also induced the C3-dependent PMN suppressor phenotype. These results point to PMN impairing T cell expansion and activation in the TME and the potential for complement inhibition to abrogate this barrier to antitumor immunity.
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