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| 2. |
- 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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| 3. |
- Spierings, Julia, et al.
(author)
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A randomised, open-label trial to assess the optimal treatment strategy in early diffuse cutaneous systemic sclerosis : The UPSIDE study protocol
- 2021
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In: BMJ Open. - : BMJ. - 2044-6055. ; 11:3
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Journal article (peer-reviewed)abstract
- Introduction Systemic sclerosis (SSc) is a chronic, autoimmune connective tissue disease associated with high morbidity and mortality, especially in diffuse cutaneous SSc (dcSSc). Currently, there are several treatments available in early dcSSc that aim to change the disease course, including immunosuppressive agents and autologous haematopoietic stem cell transplantation (HSCT). HSCT has been adopted in international guidelines and is offered in current clinical care. However, optimal timing and patient selection for HSCT are still unclear. In particular, it is unclear whether HSCT should be positioned as upfront therapy or rescue treatment for patients refractory to immunosuppressive therapy. We hypothesise that upfront HSCT is superior and results in lower toxicity and lower long-term medical costs. Therefore, we propose this randomised trial aiming to determine the optimal treatment strategy for early dcSSc by comparing two strategies used in standard care: (1) upfront autologous HSCT versus (2) immunosuppressive therapy (intravenous cyclophosphamide pulse therapy followed by mycophenolate mofetil) with rescue HSCT in case of treatment failure. Methods and analysis The UPSIDE (UPfront autologous hematopoietic Stem cell transplantation vs Immunosuppressive medication in early DiffusE cutaneous systemic sclerosis) study is a multicentre, randomised, open-label, controlled trial. In total, 120 patients with early dcSSc will be randomised. The primary outcome is event-free survival at 2 years after randomisation. Secondary outcomes include serious adverse events, functional status and health-related quality of life. We will also evaluate changes in nailfold capillaroscopy pattern, pulmonary function, cardiac MR and high-resolution CT of the chest. Follow-up visits will be scheduled 3-monthly for 2 years and annually in the following 3 years. Ethics and dissemination The study was approved by the Dutch Central Committee on Research Concerning Human Subjects (NL72607.041.20). The results will be disseminated through patient associations and conventional scientific channels. Trial registration numbers NCT04464434; NL 8720.
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| 5. |
- Scheers, Ellen M, et al.
(author)
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Cytotoxicity of amino alcohols to rat hepatoma-derived Fa32 cells.
- 2002
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In: ATLA (Alternatives to Laboratory Animals). - 0261-1929. ; 30:3, s. 309-12
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Journal article (peer-reviewed)abstract
- Amino alcohols are used as emulsifying agents in dry-cleaning soaps, wax removers, cosmetics, paints and insecticides. The cytotoxicities of 12 amino alcohols, which differed in chain length, position of the amino and alcohol groups, and the presence of an additional phenyl group, were determined by the neutral red uptake inhibition assay with normally cultured, glutathione-depleted or antioxidant-enriched Fa32 rat hepatoma-derived cells. Glutathione depletion and antioxidant enrichment were achieved by including 50(M L-buthionine-S,R-sulphoximine (BSO) or 100(M (-tocopherol acetate (vitamin E) in the culture medium for 24 hours before and during the assay. The cytotoxicity of the amino alcohols observed after treatment for 24 hours was expressed as the concentration of compound needed to induce a 50% reduction in neutral red uptake (NI50). The observed NI50 values ranged from 3mM to 30mM. The individual stereoisomers and a racemic mixture of 1-amino-2-propanol exhibited similar cytotoxicities (with normally cultured Fa32 cells, and vitamin E- and BSO-treated cultures). Similar NI50 values for D-(+)-2-amino-1-propanol, 3-amino-1-propanol and the L-, D- or DL- forms of 1-amino-2-propanol, indicated that the position of the amino group had little influence on the cytotoxicities of the amino alcohols. In contrast, the position of the hydroxyl group appeared to play an important role for the toxicity of the compound, as indicated by the significantly different NI50 values for 4-amino-1-butanol and 4-amino-2-butanol. An additional phenyl group greatly increased the cytotoxicity of 2-amino-1,3-propanediol. For most of the compounds, cytotoxicity increased when GSH was depleted, and decreased when the cells were enriched with vitamin E. This indicated that most of the tested chemicals interact with GSH, either directly or indirectly, by processes which generate oxygen free-radicals. Decreased toxicity was found for most of the chemicals administered to vitamin E-enriched cells, indicating that reactive oxygen species could be involved in the toxicity of the amino alcohols.
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| 6. |
- Sigeman, Hanna, et al.
(author)
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Repeated sex chromosome evolution in vertebrates supported by expanded avian sex chromosomes
- 2019
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In: Royal Society of London. Proceedings B. Biological Sciences. - : The Royal Society. - 1471-2954. ; 286:1916
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Journal article (peer-reviewed)abstract
- Sex chromosomes have evolved from the same autosomes multiple times across vertebrates, suggesting that selection for recombination suppression has acted repeatedly and independently on certain genetic backgrounds. Here, we perform comparative genomics of a bird clade (larks and their sister lineage; Alaudidae and Panuridae) where multiple autosome-sex chromosome fusions appear to have formed expanded sex chromosomes. We detected the largest known avian sex chromosome (195.3 Mbp) and show that it originates from fusions between parts of four avian chromosomes: Z, 3, 4A and 5. Within these four chromosomes, we found evidence of five evolutionary strata where recombination had been suppressed at different time points, and show that stratum age explained the divergence rate of Z-W gametologs. Next, we analysed chromosome content and found that chromosome 3 was significantly enriched for genes with predicted sex-related functions. Finally, we demonstrate extensive homology to sex chromosomes in other vertebrate lineages: chromosomes Z, 3, 4A and 5 have independently evolved into sex chromosomes in fish (Z), turtles (Z, 5), lizards (Z, 4A), mammals (Z, 4A) and frogs (Z, 3, 4A, 5). Our results provide insights into and support for repeated evolution of sex chromosomes in vertebrates.
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| 7. |
- Stervander, Martin, et al.
(author)
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High MHC gene copy number maintains diversity despite homozygosity in a Critically Endangered single-island endemic bird, but no evidence of MHC-based mate choice
- 2020
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In: Molecular Ecology. - : John Wiley & Sons. - 0962-1083 .- 1365-294X. ; 29:19, s. 3578-3592
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Journal article (peer-reviewed)abstract
- Small population sizes can, over time, put species at risk due to the loss of genetic variation and the deleterious effects of inbreeding. Losing diversity in the major histocompatibility complex (MHC) could be particularly harmful, given its key role in the immune system. Here, we assess MHC class I (MHC-I) diversity and its effects on mate choice and survival in the Critically Endangered Raso larkAlauda razae, a species restricted to the 7 km(2)islet of Raso, Cape Verde, since similar to 1460, whose population size has dropped as low as 20 pairs. Exhaustively genotyping 122 individuals, we find no effect of MHC-I genotype/diversity on mate choice or survival. However, we demonstrate that MHC-I diversity has been maintained through extreme bottlenecks by retention of a high number of gene copies (at least 14), aided by cosegregation of multiple haplotypes comprising 2-8 linked MHC-I loci. Within-locus homozygosity is high, contributing to low population-wide diversity. Conversely, each individual had comparably many alleles, 6-16 (average 11), and the large and divergent haplotypes occur at high frequency in the population, resulting in high within-individual MHC-I diversity. This functional immune gene diversity will be of critical importance for this highly threatened species' adaptive potential.
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