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- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 2. |
- Wiessner, M., et al.
(författare)
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Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia
- 2021
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:5, s. 1422-1434
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Tidskriftsartikel (refereegranskat)abstract
- Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays. © 2021 The Author(s).
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| 3. |
- Pinese, Mark, et al.
(författare)
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The Medical Genome Reference Bank contains whole genome and phenotype data of 2570 healthy elderly
- 2020
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB individuals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing. Healthspan and healthy aging are areas of research with potential socioeconomic impact. Here, the authors present the Medical Genome Reference Bank (MGRB) which consist of over 4,000 individuals aged 70 years and older without a history of the major age-related diseases and report on results from whole-genome sequencing and association analyses.
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| 7. |
- Boudet, S., et al.
(författare)
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Growth mode and self-organization of LuPc2 on Si(001)-2 x 1 vicinal surfaces : An optical investigation
- 2012
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 86:11, s. 115413-
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Tidskriftsartikel (refereegranskat)abstract
- We report an investigation of the initial growth and of the self-organization of lutetium biphthalocyanine LuPc2 on Si(001)-2 x 1 vicinal surfaces. Using surface-sensitive optical spectroscopies, namely, surface-difference-reflectance spectroscopy (SDRS) and reflectance-anisotropy spectroscopy (RAS), together with local-probe microscopies, we are able to propose a scenario for the growth mode up to about 20 nm. We demonstrate that the growth mode initially proceeds through the formation of a wetting layer, followed by the formation of clusters whose sizes increase while keeping a constant shape in which the molecules are inclined. Moreover, the LuPc2 molecules are self-organized along the step edges, and we are able to estimate that about 30% to 100% of the molecules are aligned when considering that the molecules are tilted by 45 degrees to 63 degrees with respect to the surface normal.
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| 8. |
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| 9. |
- Lacaze, J., et al.
(författare)
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Numerical Simulation of Brazing Aluminium Alloys with Al-Si Alloys
- 2018
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Ingår i: Transactions of the Indian Institute of Metals. - : SPRINGER INDIA. - 0972-2815 .- 0975-1645. ; 71:11, s. 2623-2629
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Tidskriftsartikel (refereegranskat)abstract
- Joining parts using low-melting temperature alloys has long been used for manufacturing complex components such as heat exchangers made of aluminium alloys. Investigations of the process have shown that core/clad interaction during heating and brazing can lead to a significant decrease in the amount of liquid available for joint formation. This study presents a transient one-dimensional model for the process that takes into account the diffusion of silicon and the movement of the core/clad interface, with the model equations being implemented in the finite element software COMSOL Multiphysics;the results are compared to literature experimental data. Silicon profiles in the core are well described, while there appears a significant difference between predicted and experimental values of remaining clads which suggest a strong effect of silicon diffusion and liquid penetration at core grain boundaries.
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| 10. |
- Normann, Erik, et al.
(författare)
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Isolation of Non-Activated Monocytes from Human Umbilical Cord Blood
- 2010
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Ingår i: American Journal of Reproductive Immunology and Microbiology. - : Wiley. - 8755-8920 .- 1046-7408. ; 63:1, s. 66-72
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Tidskriftsartikel (refereegranskat)abstract
- Problem Methods for monocyte purification are common but few work with umbilical cord monocytes that do not activate the cell for subsequent culture analysis. Methods of study The collection procedure avoids use of needles and procedures that variably activate blood clotting and uses a purification procedure that involves diluted Ficoll, autologous serum to remove platelets and 42% and 51% Percoll step gradients for the final purification. The resulting monocytes were stimulated with bacterial lipopolysaccharide and formalin-treated bacteria Escherichia coli and group B streptococci (GBS) to secrete TNF-alpha and IL-1 beta, measured by ELISA. Results The purification procedure results in non-active but stimulation-competent monocytes with high yields (2.3-9 x 107 cells) and purity (from 70% to 98%). Conclusion We describe a procedure that is easy, uses common reagents and provides a uniformly high yield and purity of non-activated fetal monocytes for studies of innate defense responses.
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| 11. |
- Vynnycky, Michael, et al.
(författare)
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On the modelling of joint formation in dissolutive brazing processes
- 2019
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Ingår i: Journal of Engineering Mathematics. - : SPRINGER. - 0022-0833 .- 1573-2703. ; 116:1, s. 73-99
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, earlier dissolutive wetting models describing the dynamics of an axisymmetric alloy drop spreading on pure metal substrate are extended to describe reactive wetting and subsequent joint formation in brazing processes. A two-dimensional time-dependent problem is formulated, and the model equations are nondimensionalized, revealing the possibilities for asymptotic model reduction. Whilst the numerical solution of the time-dependent problem, which contains two moving contact lines and would not in general be amenable to lubrication theory, is relegated to future work, the steady-state problem is analyzed in detail. The analysis offers an arguably more transparent alternative to an earlier energy minimization approach for finding the location of the meniscus, which ultimately constitutes the joint. The results of the present model are found to compare favourably to those of earlier experimental and theoretical work.
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