| 21. |
- Lorenzini, Luigi, et al.
(författare)
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Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals
- 2024
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Ingår i: ALZHEIMERS & DEMENTIA. - 1552-5260 .- 1552-5279.
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. METHODS: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. RESULTS: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. DISCUSSION: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. Highlights Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.
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| 22. |
- Lorenzini, Luigi, et al.
(författare)
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The Open-Access European Prevention of Alzheimer?s Dementia (EPAD) MRI dataset and processing workflow
- 2022
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Ingår i: NeuroImage. - : Elsevier. - 2213-1582. ; 35
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Tidskriftsartikel (refereegranskat)abstract
- The European Prevention of Alzheimer Dementia (EPAD) is a multi-center study that aims to characterize the preclinical and prodromal stages of Alzheimer's Disease. The EPAD imaging dataset includes core (3D T1w, 3D FLAIR) and advanced (ASL, diffusion MRI, and resting-state fMRI) MRI sequences. Here, we give an overview of the semi-automatic multimodal and multisite pipeline that we developed to curate, preprocess, quality control (QC), and compute image-derived phenotypes (IDPs) from the EPAD MRI dataset. This pipeline harmonizes DICOM data structure across sites and performs standardized MRI pre-processing steps. A semi-automated MRI QC procedure was implemented to visualize and flag MRI images next to site-specific distributions of QC features - i.e. metrics that represent image quality. The value of each of these QC features was evaluated through comparison with visual assessment and step-wise parameter selection based on logistic regression. IDPs were computed from 5 different MRI modalities and their sanity and potential clinical relevance were ascertained by assessing their relationship with biological markers of aging and dementia. The EPAD v1500.0 data release encompassed core structural scans from 1356 participants 842 fMRI, 831 dMRI, and 858 ASL scans. From 1356 3D T1w images, we identified 17 images with poor quality and 61 with moderate quality. Five QC features - Signal to Noise Ratio (SNR), Contrast to Noise Ratio (CNR), Coefficient of Joint Variation (CJV), Foreground-Background energy Ratio (FBER), and Image Quality Rate (IQR) - were selected as the most informative on image quality by comparison with visual assessment. The multimodal IDPs showed greater impairment in associations with age and dementia biomarkers, demonstrating the potential of the dataset for future clinical analyses
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| 23. |
- MacKinnon, Ralph, et al.
(författare)
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Defining and measuring quality in acute paediatric trauma stabilisation : a phenomenographic study
- 2019
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Ingår i: Advances in Simulation. - : Springer Science and Business Media LLC. - 2059-0628. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesTrauma is the leading cause of death in children. The lack of an accepted definition of what constitutes a high-quality stabilisation of a traumatically injured child has limited the evaluation of direct interventions in simulation-based education and service-delivery models to improve trauma care. The aim of this study was to create a framework that delineates quality by exploring the perceptions of the multi-disciplinary team providing and improving this initial care.MethodsInterviews were conducted with 36 experienced UK trauma team members and governance administrators (clinical directors to executive board level), from three standard UK trauma units. This study used a phenomenographic approach to explore the relationships and hierarchy between the contrasting perceptions of quality and evaluation of quality in this acute context.ResultsThe findings show that defining quality is a more complex concept than simple proxy measurements, such as time to CT scanning. They also show that the concept of quality requires the consideration of a spectrum of perspectives that range from the simple to the more sophisticated.This study highlights the importance of teamwork, individualised perspectives and the culture of care provision, when describing quality. A novel framework to delineate quality is presented, comprising System, Team, Process, Individual, Data and Culture.ConclusionsThis study has created a framework of understanding of acute paediatric trauma care quality and its measurement from the perspectives of team members and administrators. A framework and future tools to capture and disseminate the System, Team, Process, Individual, Data and Culture perspectives of the quality of trauma stabilisations could be a key advance in the care of severely injured children.
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| 24. |
- Peona, Valentina, et al.
(författare)
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Teaching transposon classification as a means to crowd source the curation of repeat annotation : a tardigrade perspective
- 2024
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Ingår i: Mobile DNA. - : BioMed Central (BMC). - 1759-8753. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe advancement of sequencing technologies results in the rapid release of hundreds of new genome assemblies a year providing unprecedented resources for the study of genome evolution. Within this context, the significance of in-depth analyses of repetitive elements, transposable elements (TEs) in particular, is increasingly recognized in understanding genome evolution. Despite the plethora of available bioinformatic tools for identifying and annotating TEs, the phylogenetic distance of the target species from a curated and classified database of repetitive element sequences constrains any automated annotation effort. Moreover, manual curation of raw repeat libraries is deemed essential due to the frequent incompleteness of automatically generated consensus sequences.ResultsHere, we present an example of a crowd-sourcing effort aimed at curating and annotating TE libraries of two non-model species built around a collaborative, peer-reviewed teaching process. Manual curation and classification are time-consuming processes that offer limited short-term academic rewards and are typically confined to a few research groups where methods are taught through hands-on experience. Crowd-sourcing efforts could therefore offer a significant opportunity to bridge the gap between learning the methods of curation effectively and empowering the scientific community with high-quality, reusable repeat libraries.ConclusionsThe collaborative manual curation of TEs from two tardigrade species, for which there were no TE libraries available, resulted in the successful characterization of hundreds of new and diverse TEs in a reasonable time frame. Our crowd-sourcing setting can be used as a teaching reference guide for similar projects: A hidden treasure awaits discovery within non-model organisms.
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| 25. |
- Perry, John R. B., et al.
(författare)
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Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:3, s. 535-544
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 x 10(-5)], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.
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| 26. |
- Schuschke, Christian, et al.
(författare)
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Solar energy storage at an atomically defined organic-oxide hybrid interface
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Molecular photoswitches provide an extremely simple solution for solar energy conversion and storage. To convert stored energy to electricity, however, the photoswitch has to be coupled to a semiconducting electrode. In this work, we report on the assembly of an operational solar-energy-storing organic-oxide hybrid interface, which consists of a tailor-made molecular photoswitch and an atomically-defined semiconducting oxide film. The synthesized norbornadiene derivative 2-cyano-3-(4-carboxyphenyl)norbornadiene (CNBD) was anchored to a well-ordered Co3O4(111) surface by physical vapor deposition in ultrahigh vacuum. Using a photochemical infrared reflection absorption spectroscopy experiment, we demonstrate that the anchored CNBD monolayer remains operational, i.e., can be photo-converted to its energy-rich counterpart 2-cyano-3-(4-carboxyphenyl)quadricyclane (CQC). We show that the activation barrier for energy release remains unaffected by the anchoring reaction and the anchored photoswitch can be charged and discharged with high reversibility. Our atomically-defined solar-energy-storing model interface enables detailed studies of energy conversion processes at organic/oxide hybrid interfaces.
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| 27. |
- Schwarz, Hubert, et al.
(författare)
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Small-scale bioreactor supports high density HEK293 cell perfusion culture for the production of recombinant Erythropoietin
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Process intensification in mammalian cell culture-based recombinant protein production has been achieved by high cell density perfusion exceeding 108 cells/mL in the recent years. As the majority of therapeutic proteins are produced in Chinese Hamster Ovary (CHO) cells, intensified perfusion processes have been mainly developed for this type of host cell line. However, the use of CHO cells can result in non-human posttranslational modifications of the protein of interest, which may be disadvantageous compared with human cell lines.In this study, we developed a high cell density perfusion process of Human Embryonic Kidney (HEK293) cells producing recombinant human Erythropoietin (rhEPO). Firstly, a small-scale perfusion system from commercial bench-top screening bioreactors was developed for <250 mL working volume. Then, after the first trial runs with CHO cells, the system was modified for HEK293 cells (more sensitive than CHO cells) to achieve a higher oxygen transfer under mild aeration and agitation conditions. Steady states for medium (20 x 106 cells/mL) and high cell densities (80 x 106 cells/mL), normal process temperature (37 °C) and mild hypothermia (33 °C) as well as different cell specific perfusion rates (CSPR) from 10 to 60 pL/cell/day were applied to study the performance of the culture. The volumetric productivity was maximized for the high cell density steady state but decreased when an extremely low CSPR of 10 pL/cell/day was applied. The shift from high to low CSPR strongly reduced the nutrient uptake rates. The results from our study show that human cell lines, such as HEK293 can be used for intensified perfusion processes.
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| 28. |
- Schwarz, Hubert, et al.
(författare)
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Small-scale bioreactor supports high density HEK293 cell perfusion culture for the production of recombinant Erythropoietin
- 2020
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Ingår i: Journal of Biotechnology. - : Elsevier. - 0168-1656 .- 1873-4863. ; 309, s. 44-52
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Tidskriftsartikel (refereegranskat)abstract
- Process intensification in mammalian cell culture-based recombinant protein production has been achieved by high cell density perfusion exceeding 10(8) cells/mL in the recent years. As the majority of therapeutic proteins are produced in Chinese Hamster Ovary (CHO) cells, intensified perfusion processes have been mainly developed for this type of host cell line. However, the use of CHO cells can result in non-human posttranslational modifications of the protein of interest, which may be disadvantageous compared with human cell lines. In this study, we developed a high cell density perfusion process of Human Embryonic Kidney (HEK293) cells producing recombinant human Erythropoietin (rhEPO). Firstly, a small-scale perfusion system from commercial bench-top screening bioreactors was developed for < 250 mL working volume. Then, after the first trial runs with CHO cells, the system was modified for HEK293 cells (more sensitive than CHO cells) to achieve a higher oxygen transfer under mild aeration and agitation conditions. Steady states for medium (20 x 10(6) cells/mL) and high cell densities (80 x 10(6) cells/mL), normal process temperature (37 degrees C) and mild hypothermia (33 degrees C) as well as different cell specific perfusion rates (CSPR) from 10 to 60 pL/cell/day were applied to study the performance of the culture. The volumetric productivity was maximized for the high cell density steady state but decreased when an extremely low CSPR of 10 pL/cell/day was applied. The shift from high to low CSPR strongly reduced the nutrient uptake rates. The results from our study show that human cell lines, such as HEK293 can be used for intensified perfusion processes.
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| 29. |
- Vizheh, Mehdi Mohammadi, et al.
(författare)
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Constrained 2D inversion of radio-magnetotelluric and controlled-source audio-magnetotelluric data using high-resolution reflection seismic data : An example in groundwater surveying from Heby, Sweden
- 2023
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Ingår i: Geophysics. - : Society of Exploration Geophysicists. - 0016-8033 .- 1942-2156. ; 88:2, s. B79-B90
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Tidskriftsartikel (refereegranskat)abstract
- We advance a previously established method for 2D inversion of electromagnetic data, in which the smoothness constraints are locally reweighted according to the seismic envelope fractional gradients (SEFGs). As the first step of our modifications, seis-mic envelope values are edited and normalized. This results in the rejection of noise-contaminated parts, clipping the envelope outliers and increasing the reflectivity power of weak seismic signals. Second, we introduce a weighting matrix in the normali-zation process to incorporate prior information in the con-strained inversion regarding the relative contrasts of electrical resistivity in the given parts of the model. Third, due to normal-izing the SEFG, there is no need to search for an optimum sta-bilization factor to modify local smoothing weights, and hence, we set it to a constant value. Finally, an Occam inversion with additional Levenberg-Marquardt damping is used to mitigate possible artifacts in the resistivity model generated by reflection seismic constraints. In applying the proposed scheme to a syn-thetic example, interfaces of various geologic units are restored as sharp boundaries. In addition, artifacts generated in the origi-nal approach are effectively mitigated thanks to the applied nor-malization process. For the first time, we apply the method to radio-magnetotelluric (RMT) and controlled-source audio-mag-netotelluric (CSAMT) field data acquired along a profile across a known aquifer in Heby, Sweden. Our inversion models com-pare favorably to previously presented results from seismic and geoelectric data. By modifying the smoothness weights based on SEFG, the depth to the bedrock is recovered well, being con-strained by the corresponding interfaces in the seismic image. The resistivity models from seismically constrained inversions of RMT and CSAMT data reveal steeply dipping and possibly fractured bedrock underneath the valley-shaped aquifer in the area. This interpretation is verified by borehole logs.
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| 30. |
- Walker, Christopher K., et al.
(författare)
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Orbiting Astronomical Satellite for Investigating Stellar Systems (OASIS): “Following water from galaxies, through protostellar systems, to oceans”
- 2021
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Ingår i: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE. - 0277-786X .- 1996-756X. ; 11820
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Konferensbidrag (refereegranskat)abstract
- Orbiting Astronomical Satellite for Investigating Stellar Systems (OASIS) is a space-based, MIDEX-class mission concept that employs a 17-meter diameter inflatable aperture with cryogenic heterodyne receivers, enabling high sensitivity and high spectral resolution (resolving power >106) observations at terahertz frequencies. OASIS science is targeting submillimeter and far-infrared transitions of H2O and its isotopologues, as well as deuterated molecular hydrogen (HD) and other molecular species from 660 to 80 µm, which are inaccessible to ground-based telescopes due to the opacity of Earth’s atmosphere. OASIS will have >20x the collecting area and ~5x the angular resolution of Herschel, and it complements the shorter wavelength capabilities of the James Webb Space Telescope. With its large collecting area and suite of terahertz heterodyne receivers, OASIS will have the sensitivity to follow the water trail from galaxies to oceans, as well as directly measure gas mass in a wide variety of astrophysical objects from observations of the ground-state HD line. OASIS will operate in a Sun-Earth L1 halo orbit that enables observations of large numbers of galaxies, protoplanetary systems, and solar system objects during the course of its 1-year baseline mission. OASIS embraces an overarching science theme of “following water from galaxies, through protostellar systems, to oceans.” This theme resonates with the NASA Astrophysics Roadmap and the 2010 Astrophysics Decadal Survey, and it is also highly complementary to the proposed Origins Space Telescope’s objectives.
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