| 1. |
- Bryois, J., et al.
(author)
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Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
- 2020
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:5, s. 482-493
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Journal article (peer-reviewed)abstract
- Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 2. |
- O'Connor, C. M., et al.
(author)
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Effect of nesiritide in patients with acute decompensated heart failure
- 2011
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In: The New England journal of medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 365:1, s. 32-43
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Journal article (peer-reviewed)abstract
- BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P
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| 3. |
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| 4. |
- Connor, T. M., et al.
(author)
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Mutations in mitochondrial DNA causing tubulointerstitial kidney disease
- 2017
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In: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 13:3
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Journal article (peer-reviewed)abstract
- Tubulointerstitial kidney disease is an important cause of progressive renal failure whose aetiology is incompletely understood. We analysed a large pedigree with maternally inherited tubulointerstitial kidney disease and identified a homoplasmic substitution in the control region of the mitochondrial genome (m.547A> T). While mutations in mtDNA coding sequence are a well recognised cause of disease affecting multiple organs, mutations in the control region have never been shown to cause disease. Strikingly, our patients did not have classical features of mitochondrial disease. Patient fibroblasts showed reduced levels of mitochondrial tRNA(Phe), tRNA(Leu1) and reduced mitochondrial protein translation and respiration. Mitochondrial transfer demonstrated mitochondrial transmission of the defect and in vitro assays showed reduced activity of the heavy strand promoter. We also identified further kindreds with the same phenotype carrying a homoplasmic mutation in mitochondrial tRNA Phe (m.616T> C). Thus mutations in mitochondrial DNA can cause maternally inherited renal disease, likely mediated through reduced function of mitochondrial tRNA(Phe)
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| 5. |
- Hudson, J. A., et al.
(author)
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Coupled T-H-M issues relating to radioactive waste repository design and performance
- 2001
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In: International Journal of Rock Mechanics And Mining Sciences. - 1365-1609 .- 1873-4545. ; 38:1, s. 143-161
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Journal article (peer-reviewed)abstract
- In this paper. coupled thermo-hydro-mechanical (THM) issues relating to nuclear waste repository design and performance are reviewed. Concise statements. that were developed from DECOVALEX discussions, on the current state-of-knowledge are presented. Section 1 describes the THM background and the interface with performance assessment (PA). The role of THM issues in the overall repository design context is amplified in Section 2, which includes a review of the processes in terms of repository excavation. operation and post-closure stages. It is important to understand the overall context, the detailed THM issues, the associated modelling and how these issues will be resolved in the wider framework. Also, because uncoupled and coupled numerical codes have been used fur this subject, there is discussion in Section 3 on the nature of the codes and how the content of the codes can be audited. To what extent does a particular code capture the essence of the problem in hand? Consideration is also given to the associated question of code selection and the future of numerical codes. The state-of-knowledge statements are presented in Section 4 under 11 headings which follow the repository design sequence. The overview conclusion is that A predictive THM capability is required to support repository design because precedent practice information is insufficient. Many aspects of THM processes and modelling are now well understood and there is a variety of numerical codes available to provide solutions for different host rock and repository conditions. However, modelling all the THM mechanisms in space and time is extremely complex and simplifications will have to be made - if only because it is not possible to obtain all the necessary detailed supporting information. Therefor, an important step is to clarify the THM modelling requirement within the PA context. This will help to indicate the complexity of THM modelling required and hence the models. mechanisms, type of computing, supporting data, laboratory and in situ testing, etc, required. An associated transparent and open audit trail should be developed. We also include comments from reviewers and highlight four outstanding issues which are currently being studied in the DECOVALEX III programme.
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| 6. |
- Hudson, J. A., et al.
(author)
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Coupled THMC modeling for safety assessment of geological disposal of radioactive wastes : The DECOVALEX project (1992-2015)
- 2017
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In: Rock Mechanics and Engineering Volume 3: Analysis, Modeling and Design. - : CRC Press. - 9781317481942 - 9781138027619 ; , s. 3-44
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Book chapter (other academic/artistic)abstract
- This Chapter describes a long-term research effort (1992 to the present) on coupled THMC processes in geological systems in the context of the safe geological disposal of radioactive wastes: the DECOVALEX project (DEvelopment of COupled models and their VAlidation through EXperiments). This project is a unique international co-operative research project which was initiated in 1991, officially started in 1992, has continued through a number of phases without interruption since then and is still continuing in the time of preparing this chapter by the authors. The overall objective of this research has been the development, validation and application of numerical modeling methods and techniques for the performance and safety assessments of geological disposal of radioactive waste (GDRW) in underground repositories. The cooperation has been financed by national waste management organizations, regulatory bodies and national research institutes and individual universities in Canada, China, Czech Republic, European Commission, Finland, France, Germany, Republic of Korea, Spain, Japan, Sweden, UK and USA.Over the period of 23 years, the project has made impressive advanced researches in the field of coupled THMC (Thermo- Hydro-Mechanical-Chemical) processes in geological systems, especially in fractured crystalline and sedimentary rocks and buffer/backfill materials, through integrated numerical modeling and laboratory and field experiments. The experiments cover scales ranging from laboratory-sized samples to in situ experiments in underground research laboratories (URLs) in different host rocks in different countries. The work has resulted in an impressive number ofmajor developments, as reported in scientific publications and helped to educate and train younger generations of researchers in this field. This Chapter presents the goals, structure, contents and approaches of the project, as well as achievements and lessons learned during this long-term project, at both the fundamental and application levels.
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| 7. |
- Hudson, J. A., et al.
(author)
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Demonstration of coupled models and their validation against experiment : The current phase DECOVALEX 2015
- 2013
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In: Rock Characterisation, Modelling and Engineering Design Methods - Proceedings of the 3rd ISRM SINOROCK 2013 Symposium. - : Taylor & Francis Group. ; , s. 391-396
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Conference paper (peer-reviewed)abstract
- The DECOVALEX Project (DEmonstration of COupled models and their VALidation against EXperiment) has been operating since 1992 with the objective of developing thermo-hydro-mechanical coupled computer modelling in order to provide the necessary support for the design of underground radioactive waste repositories. The Project consists of Benchmark Tests which are synthetic models for comparison of different research teams' computer modelling results (verification), and Test Cases which are simulations of actual physical cases to establish whether the modelling does in fact represent the rock reality (validation). An international consortium of Funding Organisations supports the DECOVALEX work, currently the following ten Funding Organisations: BGR/UFZ (Germany), CAS (China), DOE (USA), ENSI (Switzerland), IRSN (France), JAEA (Japan), KAERI (Korea), NDA (UK), NRC (USA) and RAWRA (Czech Republic). In this paper, we explain the 2011-2015 DECOVALEX modelling tasks which cover the range of argillaceous, sedimentary and crystalline rocks.
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| 8. |
- Jing, Lanru, et al.
(author)
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Fundamentals of the hydro-mechanical behaviour of rock fractures : roughness characterization and experimental aspects
- 2004
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In: International Journal of Rock Mechanics And Mining Sciences. - : Elsevier BV. - 1365-1609 .- 1873-4545. ; 41:3, s. 383-383
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Journal article (peer-reviewed)abstract
- The coupled hydro-mechanical behaviour of rock fractures plays an important role in design, performance and safety assessments of rock engineering projects. However, due to the complexity in the mathematical representation of the fracture surface geometry and its effects on the stress-flow behaviour of the fractures, and the limitations in the test conditions in laboratories, significant lack of knowledge still exists in testing and modelling approaches regarding rock fractures. Based on a general review of the roughness characterization and shear-flow testing of rock fractures, this paper presents the definition of the stationarity threshold of roughness, and a combined experimental-numerical approach for simulating rock fracture testing conditions for more general fluid flow behaviour of the rock fractures. The conclusions are that fracture roughness characterization must be conducted and represented in three-dimensions and the more general fluid flow behaviour cannot be observed with conventional parallel shear-flow tests or compressionradial flow tests. Numerical simulations are needed to reveal more general behaviour of stress-flow processes of rock fractures with boundary and loading conditions that are difficult or impractical in laboratory tests.
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| 9. |
- Jing, Lanru, et al.
(author)
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Numerical methods in rock mechanics
- 2002
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In: International Journal of Rock Mechanics And Mining Sciences. - 1365-1609 .- 1873-4545. ; 39:4, s. 409-427
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Research review (peer-reviewed)abstract
- The purpose of this CivilZone review paper is to present the techniques, advances, problems and likely future development directions in numerical modelling for rock mechanics and rock engineering. Such modelling is essential for Studying the fundamental processes occurring in rock,, for assessing the anticipated and actual performance of structures built on and in rock masses, and C hence for Supporting rock engineering design. We begin by providing the rock engineering design backdrop to the review in Section 1. The states-of-the-art of different types of numerical methods are outlined in Section 2, with focus on representations of fractures in the rock mass. In Section 3, the numerical methods for incorporating couplings between the thermal, hydraulic and mechanical processes are described. In Section 4, inverse solution techniques are summarized. Finally, in Section 5, we list the issues of special difficulty and importance in the subject. In the reference Est, 'significant' references are asterisked and 'very significant' references are doubly asterisked.
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| 10. |
- Koivula, Robert W., et al.
(author)
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Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes : descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium
- 2019
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In: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 62:9, s. 1601-1615
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Journal article (peer-reviewed)abstract
- Aims/hypothesis: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up).Methods: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at similar to 18 months (both cohorts) and at similar to 48 months (cohort 1) or similar to 36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe.Results: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean +/- SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m(2); fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m(2); fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l.Conclusions/interpretation: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.
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| 11. |
- Ljungqvist, Emil E., et al.
(author)
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A chemostat- and enzyme-constrained model-based analysis of the exceptionally high substrate consumption rate and respiratory capacity of Geobacillus sp. LC300
-
Other publication (other academic/artistic)abstract
- Geobacillus LC300 is a thermophilic bacterium displaying exceptionally fast growth and substrate utilization rates. Despite its potential, fundamental understanding of its metabolism and fast growth is lacking. Here, the metabolism of G. sp. LC300 was studied through a combination of chemostat cultivations, proteomics, and enzyme-constrained modeling. Glucose-limited chemostat cultivations revealed an unprecedented respiratory capacity of 48 mmolO2 gDW-1 h-1 and concomitant complete respiratory metabolism until very high growth rates. Respiro-fermentative metabolism, i.e. formation of acetate in addition to respiration, only occurred at growth rates above 1.7 h-1 and above glucose uptake rates of 23 mmolglc gDW-1 h-. Proteome analysis of batch cultures showed an optimization of central carbon metabolism, with high apparent catalytic rates allowing a redistribution of protein resources to respiration and biosynthetic pathways. An enzyme-constrained genome-scale model was constructed, able to accurately simulate chemostat and batch growth. Proteome allocation analysis at varying growth rates was studied in the model, and the overflow metabolism observed at growth rates above 1.7 h-1 was explained by a limited protein supply causing a downregulation of large respiratory enzymes in favor of ATP generation through acetate formation. These insights into G. sp. LC300’s metabolic capabilities enhance our understanding of fast-growing thermophilic microorganisms, which also paves the way for more efficient biomanufacturing applications.
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