| 1. |
|
|
| 2. |
- Klaric, Lucija, et al.
(author)
-
Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
-
In: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
-
Other publication (other academic/artistic)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
|
|
| 3. |
|
|
| 4. |
- Repetto, Linda, et al.
(author)
-
Unraveling Neuro-Proteogenomic Landscape and Therapeutic Implications for Human Behaviors and Psychiatric Disorders.
- 2023
-
Other publication (other academic/artistic)abstract
- Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioral traits and the disease etiology of neuropsychiatric disorders. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits such as sleeping, smoking, feelings, alcohol intake, mental health, and psychiatric disorders. Integrating with established drug information, we validated 13 out of 13 matched combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets. This consortium effort provides a large-scale proteogenomic resource for biomedical research on human behaviors and other neuro-related phenotypes.
|
|
| 5. |
|
|
| 6. |
- Engberg, David L. J., et al.
(author)
-
Solid Solution and Segregation Effects in Arc-Deposited Ti1-xSixN Thin Films Resolved on the nanometer scale by 15N Isotopic Substitution in AtomP robe Tomography
-
Other publication (other academic/artistic)abstract
- Nanostructured TiSiN is an important material in wear--‐resistant coatings for extending the lifetime of cutting tools. Yet, the understanding regarding the structure, phase composition, and bonding on the detailed nanometer scale, which determines the properties of TiSiN, is lacking. This limits our understanding of the growth phenomena and eventually a larger exploitation of the material. By substituting natN2 with 15N2 during reactive arc deposition of TiSiN thin films, atom probe tomography (APT) gives elemental sensitivity and sub-nanometer resolution, a finer scale than what can be obtained by commonly employed energy dispersive electron spectroscopy in scanning transmission electron microscopy. Using a combination of analytical transmission electron microscopy and APT we show that arc-deposited Ti0.92Si0.0815N and Ti0.81Si0.1915N exhibit Si segregation on the nanometer scale in the alloy films. APT composition maps and proximity histograms from domains with higher than average Ti content show that the TiN domains contain at least ~2 at. % Si for Ti0.92Si0.08N and ~5 at. % Si for Ti0.81Si0.19N, thus confirming the formation of solid solutions. The formation of relatively pure SiNy domains in the Ti0.81Si0.19N films is tied to pockets between microstructured, columnar features in the film. Finer SiNy enrichments seen in APT possibly correspond to tissue layers around TiN crystallites, thus effectively hindering growth of TiN crystallites, causing TiN renucleation and thus explaining the featherlike nanostructure within the columns of these films. For the stoichiometry of the TiN phase, we establish a global under stoichiometry, in accordance with the tendency for SiNy films to have tetrahedral bonding coordination towards a nominal Si3N4 composition.
|
|
| 7. |
- GEJJI, SP, et al.
(author)
-
CONFORMATIONAL-CHANGES INDUCED BY METAL-ION COORDINATION - LITHIUM (I)-DIGLYME
- 1995
-
In: COMPUTATIONAL POLYMER SCIENCE. - : PRA PRESS. ; 5:3
-
Other publication (other academic/artistic)abstract
- Conformational changes in diethylene glycol dimethyl ether (diglyme) induced by lithium ion coordination have been investigated by ab initio calculations at the HF/3-21G and HF/6-31G** levels. The calculations resulted in two stable lithium-diglyme 1:1 c
|
|
| 8. |
|
|
| 9. |
- Johansson, Camilla, et al.
(author)
-
Identification of Gene-Therapy Responsive Blood Biomarkers for Duchenne Muscular Dystrophy
-
Other publication (other academic/artistic)abstract
- IntroductionAssessing muscle dystrophin expression systemically is important for understanding the effect of dystrophin-restoring therapies in Duchenne muscular dystrophy (DMD). Many potential blood biomarkers have been identified in DMD patients which are either more or less abundant in blood samples compared to healthy individuals and that have been shown to change with disease progression or respond to pharmacological treatment. In this study, it was suggested that a panel of such blood biomarker candidates could be used to monitor dystrophin rescue in microdystrophin therapies. MethodsPlasma samples from mdx mice treated with the microdystrophin therapy SGT-001 were analysed with an antibody suspension bead array consisting of 87 antibodies targeting 83 proteins previously identified as biomarker candidates for DMD. Each sample was assayed at two different plasma dilutions to cover a broader concentration range. Median fluorescent intensities (MFI) for each antibody were correlated to dystrophin expression in muscle tissue, as measured by immunohistochemistry and Western blot. 13 targets were selected and validated in a DMD and Becker muscular dystrophy (BMD) longitudinal natural history cohort using a suspension bead array. Results10 proteins were found significantly elevated in untreated mdx mice compared to C57 wild-type mice and 10 were found to correlate with dystrophin expression (Spearman’s correlation, FDR < 0.05) upon gene transfer. Abundance of TTN, ADSSL1, LONP1, OTUD5, MYL3 as well as DMD protein were associated with dystrophin expression in BMD patients. Of these, MYL3 and ADSSL1 had different abundance in DMD compared to healthy individuals, and MYL3 also displayed different age trajectories between DMD and BMD patients. DiscussionThe ten proteins identified in mouse plasma are related to muscle contraction (ADSSL1, ASAH1, CA3, MYL3, TTN), microtubule formation (TPI1), and protein degradation (PSMA2, OTUD4, LONP1). Of these, MYL3 and ADSSL1 showed the most promise as a dystrophin monitoring biomarker in patient samples.
|
|
| 10. |
- Johansson, Daniel, 1975, et al.
(author)
-
Multi - model analyses of the economic and energy implications for China and India in a post-Kyoto climate regime
- 2012
-
Other publication (other academic/artistic)abstract
- This paper presents a modeling comparison project on how the2°C climate target could affect economic and energy systems development in China and India. The analysis uses a framework that harmonizes baseline developments and soft-links seven national and global models being either economy wide (CGE models) or energy system models. The analysis is based on a global greenhouse gas emission pathway that aims at a radiative forcing of 2.9 W/m2 in 2100 and with a policy regime based on convergence of per capita CO2 emissions with emissions trading. Economic and energy implications for China and India vary across models. Decreased energy intensity is the most important abatement approach in the CGE models, while decreased carbon intensity is most important in the energy system models. Reliance on Coal without Carbon Capture and Storage (CCS) is significantly reduced in most models, while CCS is a central abatement technology in energy system models, as is renewable and nuclear energy. Concerning economic impacts China bears in general a higher cost than India, as China benefits less from emissions trading. Costs are also affected by changes in fossil fuel prices, currency appreciation from capital inflow from carbon trading and timing of emission reductions.
|
|
