| 1. |
- Colyn Bwanika, Henri, et al.
(författare)
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Limiting the Effects of Radiation Damage in MicroED through Dose Selection during Data Processing
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Microcrystal electron diffraction (MicroED), also known as three-dimensional electron diffraction (3D ED), allows collection of diffraction data from submicron-sized crystals under low electron dose conditions, typically around 5-6 e-Å-2 in total. Despite having several advantages of MicroED over most conventional X-ray crystallographic techniques, susceptibility to radiation damage is a big problem that remains to be solved. Similar to X-ray crystallography, radiation damage to the macromolecular crystal structures in MicroED manifests in two forms, the global damage that affects the overall crystal lattice order and the site-specific damage that affects highly sensitive residues and moieties in macromolecules. In this study, we investigated data processing strategies that could be used to limit the effects of radiation damage to the crystal even when data collection is performed at high electron doses. During MicroED data collection, radiation damage increases with the number of acquired ED frames because the accumulated electron dose increases. To limit the damage, we propose to process only the first few frames of a dataset with a certain low dose cutoff. Data collected from several crystals and processed in this way can be merged to increase completeness and subsequently be used for structure refinement. According to our results, this approach improves the resolution of the data, the data statistics, the structure determination, and the quality of the final structure. The suggested approach could be especially useful in MicroED structure-based drug discovery where atomic resolution structures will provide detailed information about ligand-protein binding properties, which are essential during library screening and hit identification.
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| 2. |
- Klaric, Lucija, et al.
(författare)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Annan publikation (övrigt vetenskapligt/konstnärligt)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.
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| 3. |
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| 4. |
- Macdonald-Dunlop, Erin, et al.
(författare)
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Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases
- 2021
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.
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| 5. |
- Nicoll, Rachel, et al.
(författare)
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Diabetes and male gender are key risk factor predictors of CAC extent : a Euro-CCAD study
- 2016
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Although much has been written about the risk factor predictors of CAC extent, few studies have been carried out on symptomatic patients. Similarly, no study has directly compared predictors of CAC extent and zero CAC.Methods: From the European Calcific Coronary Artery Disease (Euro-CCAD) cohort, we retrospectively investigated 6309 symptomatic patients, 62% male, from Denmark, France, Germany, Italy, Spain and USA. All had risk factor assessment and CT scanning for CAC scoring. Results: Among all patients, male gender (β = 1.36, p<0.001) and diabetes (β = 0.47, p<0.001) were the most important risk factors of CAC extent, with age, diabetes (DM), obesity, family history of CAD and number of risk factors also being predictive. Among patients with CAC, DM, hypertension (HT) and dyslipidaemia (DL) were predictors of an increasing CAC score in males and females, with DM being the strongest (p<0.001 for both). These results were echoed in quantile regression, where DM was consistently the most important predictor of CAC extent in every quantile in both males and females. HT and DL were also predictive but to a lesser extent, with HT being predictive in the high CAC quantiles and DL in the low CAC quantiles. Conclusion: In addition to male gender, DM is the most important predictor of CAC extent in both genders.
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| 6. |
- Wang, Zhao, et al.
(författare)
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Strong secrecy for interference channels : Achievable rate region and degrees of freedom
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The achievable rate region and degrees of freedom are studied for interference channels with confidential messages under strong secrecy constraints. The problem is studied based on the framework of Han and Verd$\acute{\textrm{u}}$'s channel resolvability theory. It is shown that if the random binning rate for securing a confidential message is slightly above the resolution of its corresponding wiretapped channel, strong secrecy can be guaranteed. At first, the information-spectrum method introduced by Han and Verd$\acute{\textrm{u}}$ is generalized to an arbitrary interference channel to obtain a direct channel resolvability result. After specifying the channel transition probability, the derived resolvability results are shown to be the achievable strong secrecy rates for the stationary and memoryless interference channel. As an application, the secure degrees of freedom (SDOF) for the $K$-user Gaussian interference channel with confidential messages are investigated under strong secrecy constraints. It is shown that the optimal SDOF of the considered network is $\frac{K-1}{2K-1}$ for each user, which equals to its counterpart with weak secrecy constraints. The optimal SDOF scheme is achieved by combining the resolvability-based secrecy coding and artificial noise alignment on the real line. A suboptimal ergodic secure alignment is also proposed for the time-varying interference channels to achieve a sum SDOF of $\frac{K-3}{2K-2}$ for each user. Following the footsteps of Hayashi and of Bloch and Laneman, our results provide further evidence that channel resolvability can be a powerful and general framework for strong secrecy analysis in multiuser networks.
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| 7. |
- Yang, Li Li, 1980-, et al.
(författare)
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Mg diffusion in Zn0.94Mg0.06O/ZnO heterostructures grown by MOCVD
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Zn0.94Mg0.06O/ZnO heterostructures were grown on 2 inch sapphire wafer by MOCVD equipment. Photoluminescence mapping demonstrated that Mg uniformly distributed on the entire wafer with average concentration of ~6%. The annealing effects on the Mg diffusion behaviors were investigated by secondary ion mass spectrometry (SIMS). All Mg SIMS depth profiles were fitted by three Gaussian distribution functions. The Mg diffusion coefficient in the as-grown Zn0.94Mg0.06O layer deposited at 700 oC was two order of magnitude lower than that of annealed samples, which indicated that the deposition temperature of 700 oC is much more beneficial to grow ZnMgO/ZnO heterostructures or quantum wells.
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| 8. |
- Zhao, Wang, et al.
(författare)
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Secrecy degrees of freedom of wireless X networks using artificial noise alignment
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The problem of transmitting confidential messages in $M \times K$ wireless X networks is considered, in which each transmitter intends to send one confidential message to every receiver. In particular, the secrecy degrees of freedom (SDOF) of the considered network achieved by an artificial noise alignment (ANA) approach, which integrates interference alignment and artificial noise transmission, are studied. At first, an SDOF upper bound is derived for the $M \times K$ X network with confidential messages (XNCM) to be $\frac{K(M-1)}{K+M-2}$. By proposing an ANA approach, it is shown that the SDOF upper bound is tight when either $K=2$ or $M=2$ for the considered XNCM with time/frequency varying channels. For $K,M \geq 3$, it is shown that an SDOF $\frac{K(M-1)}{K+M-1}$ can be achieved, even when an external eavesdropper appears. The key idea of the proposed scheme is to inject artificial noise to the network, which can be aligned in the interference space at receivers for confidentiality. Moreover, for the network with no channel state information at transmitters, a blind ANA scheme is proposed to achieve the SDOF $\frac{K(M-1)}{K+M-1}$ for $K,M \geq 2$, with reconfigurable antennas at receivers. The proposed method provides a linear approach to handle secrecy coding and interference alignment.
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