| 1. |
- Li, S. Y., et al.
(författare)
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Universal toxin-based selection for precise genome engineering in human cells
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Prokaryotic restriction enzymes, recombinases and Cas proteins are powerful DNA engineering and genome editing tools. However, in many primary cell types, the efficiency of genome editing remains low, impeding the development of gene- and cell-based therapeutic applications. A safe strategy for robust and efficient enrichment of precisely genetically engineered cells is urgently required. Here, we screen for mutations in the receptor for Diphtheria Toxin (DT) which protect human cells from DT. Selection for cells with an edited DT receptor variant enriches for simultaneously introduced, precisely targeted gene modifications at a second independent locus, such as nucleotide substitutions and DNA insertions. Our method enables the rapid generation of a homogenous cell population with bi-allelic integration of a DNA cassette at the selection locus, without clonal isolation. Toxin-based selection works in both cancer-transformed and non-transformed cells, including human induced pluripotent stem cells and human primary T-lymphocytes, as well as it is applicable also in vivo, in mice with humanized liver. This work represents a flexible, precise, and efficient selection strategy to engineer cells using CRISPR-Cas and base editing systems. Genome engineering in cell lines or human stem cells often has poor efficiency, limiting the development of research and therapeutic applications. Here, the authors use a toxin-based selection system for precise bi-allelic engineering in cells and in vivo.
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| 2. |
- Cotlarciuc, Ioana, et al.
(författare)
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Towards the genetic basis of cerebral venous thrombosis-the BEAST Consortium: a study protocol.
- 2016
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 6:11
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral venous thrombosis (CVT) is a rare cerebrovascular condition accounting for <1% of all stroke cases and mainly affects young adults. Its genetic aetiology is not clearly elucidated.To better understand the genetic basis of CVT, we have established an international biobank of CVT cases, Biorepository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) which aims to recruit highly phenotyped cases initially of European descent and later from other populations. To date we have recruited 745 CVT cases from 12 research centres. As an initial step, the consortium plans to undertake a genome-wide association analysis of CVT using the Illumina Infinium HumanCoreExome BeadChip to assess the association and impact of common and low-frequency genetic variants on CVT risk by using a case-control study design. Replication will be performed to confirm putative findings. Furthermore, we aim to identify interactions of genetic variants with several environmental and comorbidity factors which will likely contribute to improve the understanding of the biological mechanisms underlying this complex disease.BEAST meets all ethical standards set by local institutional review boards for each of the participating sites. The research outcomes will be published in international peer-reviewed open-access journals with high impact and visibility. The results will be presented at national and international meetings to highlight the contributions into improving the understanding of the mechanisms underlying this uncommon but important disease. This international DNA repository will become an important resource for investigators in the field of haematological and vascular disorders.
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| 3. |
- Pinese, Mark, et al.
(författare)
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The Medical Genome Reference Bank contains whole genome and phenotype data of 2570 healthy elderly
- 2020
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB individuals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing. Healthspan and healthy aging are areas of research with potential socioeconomic impact. Here, the authors present the Medical Genome Reference Bank (MGRB) which consist of over 4,000 individuals aged 70 years and older without a history of the major age-related diseases and report on results from whole-genome sequencing and association analyses.
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| 4. |
- Ranjan, Redoy, et al.
(författare)
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Coma in adult cerebral venous thrombosis: The BEAST study
- 2024
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Ingår i: EUROPEAN JOURNAL OF NEUROLOGY. - 1351-5101 .- 1468-1331. ; 31:8
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Coma is an independent predictor of poor clinical outcomes in cerebral venous thrombosis (CVT). We aimed to describe the association of age, sex, and radiological characteristics of adult coma patients with CVT. Methods: We used data from the international, multicentre prospective observational BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis) study. Only positively associated variables with coma with <10% missing data in univariate analysis were considered for the multivariate logistic regression model. Results: Of the 596 adult patients with CVT (75.7% women), 53 (8.9%) patients suffered coma. Despite being a female-predominant disease, the prevalence of coma was higher among men than women (13.1% vs. 7.5%, p = 0.04). Transverse sinus thrombosis was least likely to be associated with coma (23.9% vs. 73.3%, p < 0.001). The prevalence of superior sagittal sinus thrombosis was higher among men than women in the coma sample (73.6% vs. 37.5%, p = 0.01). Men were significantly older than women, with a median (interquartile range) age of 51 (38.5-60) versus 40 (33-47) years in the coma (p = 0.04) and 44.5 (34-58) versus 37 (29-48) years in the non-coma sample (p < 0.001), respectively. Furthermore, an age- and superior sagittal sinus-adjusted multivariate logistic regression model found male sex (odds ratio = 1.8, 95% confidence interval [CI] = 1.0-3.4, p = 0.04) to be an independent predictor of coma in CVT, with an area under the receiver operating characteristic curve of 0.61 (95% CI = 0.52-0.68, p = 0.01). Conclusions: Although CVT is a female-predominant disease, men were older and nearly twice as likely to suffer from coma than women.
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| 5. |
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| 6. |
- Silvis, Suzanne M, et al.
(författare)
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Postpartum Period Is a Risk Factor for Cerebral Venous Thrombosis.
- 2019
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Ingår i: Stroke. - 1524-4628. ; 50:2, s. 501-503
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose- Pregnancy and the postpartum period are generally considered to be risk factors for cerebral venous thrombosis (CVT), but no controlled studies have quantified the risk. Methods- Case-control study using data of consecutive adult patients with CVT from 5 academic hospitals and controls from the Dutch MEGA study (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis). Men, women over the age of 50, women using oral contraceptives or with a recent abortion or miscarriage were excluded. We adjusted for age and history of cancer, and stratified for pregnancy versus postpartum, and 0 to 6 versus 7 to 12 weeks postpartum. Results- In total 163/813 cases and 1230/6296 controls were included. Cases were younger (median 38 versus 41 years) and more often had a history of cancer (14% versus 4%) than controls. In total 41/163 (25%) cases and 82/1230 (7%) controls were pregnant or postpartum (adjusted odds ratio, 3.8; 95% CI, 2.4-6.0). The association was fully attributable to an increased risk of CVT during the postpartum period (adjusted odds ratio, 10.6; 95% CI, 5.6-20.0). We found no association between pregnancy and CVT (adjusted odds ratio, 1.2; 95% CI, 0.6-2.3). The risk was highest during the first 6 weeks postpartum (adjusted odds ratio, 18.7; 95% CI, 8.3-41.9). Conclusions- Women who have recently delivered are at increased risk of developing CVT, while there does not seem to be an increased risk of CVT during pregnancy.
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| 7. |
- Zuurbier, Susanna M, et al.
(författare)
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Cerebral Venous Thrombosis in Older Patients.
- 2018
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Ingår i: Stroke. - 1524-4628. ; 49:1, s. 197-200
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral venous thrombosis (CVT) is rare in older patients. We investigated whether clinical features and outcomes differ in older and younger patients.We used data from a multicenter observational registry of consecutive adult patients with CVT admitted between 1987 and 2016. We compared demographics, clinical manifestations, and outcomes between older (upper quartile of the age distribution) and younger (lower 3 quartiles of the age distribution) patients.Data for 843 patients with CVT were available. The median age was 43 years (interquartile range, 30-55 years). Older patients (≥55 years; n=222) were less often women than younger patients (48% versus 71%; P<0.001) and less often reported headache (63% versus 87%; P<0.001). Cancer was more common in older patients (24% versus 9%; P<0.001), especially solid malignancies (19% versus 5%; P<0.001). Outcome at follow-up was worse in older patients (modified Rankin Scale, 3-6; adjusted odds ratio, 2.68; 95% confidence interval, 1.78-4.03; mortality, adjusted odds ratio, 2.13; 95% confidence interval, 1.09-4.19).The sex ratio of CVT is evenly distributed in older patients, probably because of the dissipation of hormonal influences. Malignancy should be considered as a potential precipitant in older patients with CVT.
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| 8. |
- Downey, Harriet, et al.
(författare)
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Training future generations to deliver evidence-based conservation and ecosystem management
- 2021
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Ingår i: Ecological Solutions and Evidence. - : Wiley. - 2688-8319. ; 2:1
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Forskningsöversikt (refereegranskat)abstract
- 1. To be effective, the next generation of conservation practitioners and managers need to be critical thinkers with a deep understanding of how to make evidence-based decisions and of the value of evidence synthesis.2. If, as educators, we do not make these priorities a core part of what we teach, we are failing to prepare our students to make an effective contribution to conservation practice.3. To help overcome this problem we have created open access online teaching materials in multiple languages that are stored in Applied Ecology Resources. So far, 117 educators from 23 countries have acknowledged the importance of this and are already teaching or about to teach skills in appraising or using evidence in conservation decision-making. This includes 145 undergraduate, postgraduate or professional development courses.4. We call for wider teaching of the tools and skills that facilitate evidence-based conservation and also suggest that providing online teaching materials in multiple languages could be beneficial for improving global understanding of other subject areas.
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| 9. |
- Ibrahim, A. I. M., et al.
(författare)
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Design and Synthesis of Thionated Levofloxacin: Insights into a New Generation of Quinolones with Potential Therapeutic and Analytical Applications
- 2022
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Ingår i: Current Issues in Molecular Biology. - : MDPI AG. - 1467-3037 .- 1467-3045. ; 44:10, s. 4626-4638
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Tidskriftsartikel (refereegranskat)abstract
- Levofloxacin is a widely used fluoroquinolone in several infectious diseases. The structure-activity relationship of levofloxacin has been studied. However, the effect of changing the carbonyl into thiocarbonyl of levofloxacin has not been investigated up to the date of this report. In this work, levofloxacin structure was slightly modified by making a thionated form (compound 3), which was investigated for its antibacterial activity, biocompatibility, and cytotoxicity, as well as spectroscopic properties. The antibacterial susceptibility testing against five different bacteria showed promising minimum inhibitory concentrations (MICs), particularly against B. spizizenii and E. coli, with an MIC value of 1.9 mu M against both bacteria, and 7.8 mu M against P. mirabilis. The molecular docking experiment showed similar binding interactions of both levofloxacin and compound 3 with the active site residues of topoisomerase IV. The biocompatibility and cytotoxicity results revealed that compound 3 was more biocompatible with normal cells and more cytotoxic against cancer cells, compared to levofloxacin. Interestingly, compound 3 also showed an excitation profile with a distinctive absorption peak at lambda(max) 404 nm. Overall, our results suggest that the thionation of quinolones may provide a successful approach toward a new generation with enhanced pharmacokinetic and safety profiles and overall activity as potential antibacterial agents.
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| 10. |
- Sánchez Van Kammen, Mayte, et al.
(författare)
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Characteristics and Outcomes of Patients with Cerebral Venous Sinus Thrombosis in SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia
- 2021
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Ingår i: JAMA Neurology. - : American Medical Association. - 2168-6149 .- 2168-6157. ; 78:11, s. 1314-1323
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson).Objective: To describe the clinical characteristics and outcome of patients with cerebral venous sinus thrombosis (CVST) after SARS-CoV-2 vaccination with and without TTS.Design, Setting, and Participants: This cohort study used data from an international registry of consecutive patients with CVST within 28 days of SARS-CoV-2 vaccination included between March 29 and June 18, 2021, from 81 hospitals in 19 countries. For reference, data from patients with CVST between 2015 and 2018 were derived from an existing international registry. Clinical characteristics and mortality rate were described for adults with (1) CVST in the setting of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after SARS-CoV-2 vaccination not fulling criteria for TTS, and (3) CVST unrelated to SARS-CoV-2 vaccination.Exposures: Patients were classified as having TTS if they had new-onset thrombocytopenia without recent exposure to heparin, in accordance with the Brighton Collaboration interim criteria.Main Outcomes and Measures: Clinical characteristics and mortality rate.Results: Of 116 patients with postvaccination CVST, 78 (67.2%) had TTS, of whom 76 had been vaccinated with ChAdOx1 nCov-19; 38 (32.8%) had no indication of TTS. The control group included 207 patients with CVST before the COVID-19 pandemic. A total of 63 of 78 (81%), 30 of 38 (79%), and 145 of 207 (70.0%) patients, respectively, were female, and the mean (SD) age was 45 (14), 55 (20), and 42 (16) years, respectively. Concomitant thromboembolism occurred in 25 of 70 patients (36%) in the TTS group, 2 of 35 (6%) in the no TTS group, and 10 of 206 (4.9%) in the control group, and in-hospital mortality rates were 47% (36 of 76; 95% CI, 37-58), 5% (2 of 37; 95% CI, 1-18), and 3.9% (8 of 207; 95% CI, 2.0-7.4), respectively. The mortality rate was 61% (14 of 23) among patients in the TTS group diagnosed before the condition garnered attention in the scientific community and 42% (22 of 53) among patients diagnosed later.Conclusions and Relevance: In this cohort study of patients with CVST, a distinct clinical profile and high mortality rate was observed in patients meeting criteria for TTS after SARS-CoV-2 vaccination..
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