| 1. |
- Abazajian, Kevork, et al.
(author)
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CMB-S4 : Forecasting Constraints on Primordial Gravitational Waves
- 2022
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
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Journal article (peer-reviewed)abstract
- CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL.
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| 2. |
- Benson, Erik
(author)
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Design and analysis of wireframe DNA nanostructures
- 2018
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Doctoral thesis (other academic/artistic)abstract
- In the last decades, the powerful self-assembly properties of DNA have been harnessed to produce complex structures at the nanoscale with high precision and yield. DNA origami is one of the most robust examples of this, where a 7000-nucleotide strand of biological origin is folded by hybridizing with hundreds of synthetic oligonucleotides, the programmed sequence of these “staple strands” determines the shape of the assembled object. The long “scaffold strand” permeates every helix of the assembled object acting as a backbone, finding the path for the scaffold strand is trivial in designs where the helices are packed on a parallel lattice but becomes challenging in other designs. In this thesis we expand the design space of DNA origami to wireframe structures based on polyhedral meshes by the introduction of a software package consisting of: a routing algorithm for finding A-trail Eulerian circuits, a rapid physical simulation for converting the mesh to a DNA design with low strain, and vHelix, a graphical user interface for manual modification of the structure and processing of DNA sequences (Paper I). We find that this method can produce wireframe DNA origami structures with refined shapes and features, and we investigate these structures with negative stainedand cryo electron microscopy. The helices in these structures are not packed on a tight lattice and we find that they can assemble and remain stable at physiological salt concentrations unlike previously demonstrated 3D DNA origami. We then expand this method to two-dimensional sheets (Paper II), first by generating three rectangular sheets with different vertex geometries and investigating them with atomic force microscopy to find that six-armed vertices are needed for non-distorted structures. The geometry with six-arm vertices is then used to generate four flat sheets with complex internal and external features, these structures fold with high yield to their programmed shape. It is apparent from electron microscopy that these structures are not as rigid as structures based on the parallel packing of helices. In Paper III we study the effect of design choices on the rigidity of wireframe structures, specifically on rods where the flexibility can be estimated by measuring the persistence length. In addition to experiments we use coarse-grained molecular dynamics simulations to evaluate the rigidity in silico. We find that the rigidity of rods increases with increasing number of facets in the cross-section, and that the breakpoints between staples negatively affects rigidity and that his effect can be reduced by enzymatic ligation. The simulations reveal that the rigidity of the structures is greatly reduced by increasing the salt concentration. In Paper IV we further explore the power of coarse-grained molecular dynamics simulation to predict the dynamics of DNA nanostructures. First, we track the end to end distance of the helices of a structure throughout a simulation and find that the behavior varies greatly between helices where some are practically rigid and others show large deformations. We then implement this concept in an iterative fashion where a structures rigidity is estimated by simulation and from this first generation a number of mutant structures are created by modifying one or more edges. These mutant structures are then simulated and the effect of the modifications are measured on their adjacent helices or on the entire structure, and modifications that are beneficial are inherited in the next generation of the structure. Using these methods, we are able to create a moderate evolution towards a lower flexibility in wireframe DNA origami structures.
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| 3. |
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| 4. |
- Benson, Erik, et al.
(author)
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Reconfigurable self-assembled DNA devices
- 2023
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In: SCIENCE ROBOTICS. - : American Association for the Advancement of Science (AAAS). - 2470-9476. ; 8:77
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Journal article (other academic/artistic)
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| 5. |
- de Zwarte, Sonja M. C., et al.
(author)
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Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder
- 2022
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In: Human Brain Mapping. - : John Wiley & Sons. - 1065-9471 .- 1097-0193. ; 43:1, s. 414-430
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Journal article (peer-reviewed)abstract
- First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
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| 6. |
- de Zwarte, Sonja M. C., et al.
(author)
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The association between familial risk and brain abnormalities is disease specific : an ENIGMA-relatives study of schizophrenia and bipolar disorder
- 2019
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In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 86:7, s. 545-556
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Journal article (peer-reviewed)abstract
- BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.RESULTS: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.
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| 7. |
- Gawel, Danuta, et al.
(author)
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A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases
- 2019
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In: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 11
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Journal article (peer-reviewed)abstract
- Background: Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs. Methods: The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs. Results: We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model. Conclusions: Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.
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| 8. |
- Gawel, Danuta, et al.
(author)
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Clinical translation of genomic medicine : Stor potential när genomikdata kan implementeras i klinisk rutin.
- 2021
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In: Läkartidningen. - 1652-7518. ; 118
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Journal article (peer-reviewed)abstract
- Recent technical developments and early clinical examples support that precision medicine has potential to provide novel diagnostic and therapeutic solutions for patients with complex diseases, who are not responding to existing therapies. Those solutions will require integration of genomic data with routine clinical, imaging, sensor, biobank and registry data. Moreover, user-friendly tools for informed decision support for both patients and clinicians will be needed. While this will entail huge technical, ethical, societal and regulatory challenges, it may contribute to transforming and improving health care towards becoming predictive, preventive, personalised and participatory (4P-medicine).
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| 9. |
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| 10. |
- Gawel, Danuta R., 1988-
(author)
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Identification of genes and regulators that are shared across T cell associated diseases
- 2018
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Doctoral thesis (other academic/artistic)abstract
- Genome-wide association studies (GWASs) of hundreds of diseases and millions of patients have led to the identification of genes that are associated with more than one disease. The aims of this PhD thesis were to a) identify a group of genes important in multiple diseases (shared disease genes), b) identify shared up-stream disease regulators, and c) determine how the same genes can be involved in the pathogenesis of different diseases. These aims have been tested on CD4+ T cells because they express the T helper cell differentiation pathway, which was the most enriched pathway in analyses of all disease associated genes identified with GWASs.Combining information about known gene-gene interactions from the protein-protein interaction (PPI) network with gene expression changes in multiple T cell associated diseases led to the identification of a group of highly interconnected genes that were miss-expressed in many of those diseases – hereafter called ‘shared disease genes’. Those genes were further enriched for inflammatory, metabolic and proliferative pathways, genetic variants identified by all GWASs, as well as mutations in cancer studies and known diagnostic and therapeutic targets. Taken together, these findings supported the relevance of the shared disease genes.Identification of the shared upstream disease regulators was addressed in the second project of this PhD thesis. The underlying hypothesis assumed that the determination of the shared upstream disease regulators is possible through a network model showing in which order genes activate each other. For that reason a transcription factor–gene regulatory network (TF-GRN) was created. The TF-GRN was based on the time-series gene expression profiling of the T helper cell type 1 (Th1), and T helper cell type 2 (Th2) differentiation from Native T-cells. Transcription factors (TFs) whose expression changed early during polarization and had many downstream predicted targets (hubs) that were enriched for disease associated single nucleotide polymorphisms (SNPs) were prioritised as the putative early disease regulators. These analyses identified three transcription factors: GATA3, MAF and MYB. Their predicted targets were validated by ChIP-Seq and siRNA mediated knockdown in primary human T-cells. CD4+ T cells isolated from seasonal allergic rhinitis (SAR) and multiple sclerosis (MS) patients in their non-symptomatic stages were analysed in order to demonstrate predictive potential of those three TFs. We found that those three TFs were differentially expressed in symptom-free stages of the two diseases, while their TF-GRN{predicted targets were differentially expressed during symptomatic disease stages. Moreover, using RNA-Seq data we identified a disease associated SNP that correlated with differential splicing of GATA3.A limitation of the above study is that it concentrated on TFs as main regulators in cells, excluding other potential regulators such as microRNAs. To this end, a microRNA{gene regulatory network (mGRN) of human CD4+ T cell differentiation was constructed. Within this network, we defined regulatory clusters (groups of microRNAs that are regulating groups of mRNAs). One regulatory cluster was differentially expressed in all of the tested diseases, and was highly enriched for GWAS SNPs. Although the microRNA processing machinery was dynamically upregulated during early T-cell activation, the majority of microRNA modules showed specialisation in later time-points.In summary this PhD thesis shows the relevance of shared genes and up-stream disease regulators. Putative mechanisms of why shared genes can be involved in pathogenesis of different diseases have also been demonstrated: a) differential gene expression in different diseases; b) alternative transcription factor splicing variants may affect different downstream gene target group; and c) SNPs might cause alternative splicing.
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