| 1. |
- Zamora, Juan Carlos, et al.
(author)
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Considerations and consequences of allowing DNA sequence data as types of fungal taxa
- 2018
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In: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
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Journal article (peer-reviewed)abstract
- Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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| 2. |
- Ladds, Marcus J. G. W., et al.
(author)
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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- 2018
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
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| 4. |
- Cagigi, Alberto, et al.
(author)
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Airway antibodies emerge according to COVID-19 severity and wane rapidly but reappear after SARS-CoV-2 vaccination
- 2021
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In: JCI Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 6:22
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Journal article (peer-reviewed)abstract
- Understanding the presence and durability of antibodies against SARS-CoV-2 in the airways is required to provide insights into the ability of individuals to neutralize the virus locally and prevent viral spread. Here, we longitudinally assessed both systemic and airway immune responses upon SARS-CoV-2 infection in a clinically well-characterized cohort of 147 infected individuals representing the full spectrum of COVID-19 severity, from asymptomatic infection to fatal disease. In addition, we evaluated how SARS-CoV-2 vaccination influenced the antibody responses in a subset of these individuals during convalescence as compared with naive individuals. Not only systemic but also airway antibody responses correlated with the degree of COVID-19 disease severity. However, although systemic IgG levels were durable for up to 8 months, airway IgG and IgA declined significantly within 3 months. After vaccination, there was an increase in both systemic and airway antibodies, in particular IgG, often exceeding the levels found during acute disease. In contrast, naive individuals showed low airway antibodies after vaccination. In the former COVID-19 patients, airway antibody levels were significantly elevated after the boost vaccination, highlighting the importance of prime and boost vaccinations for previously infected individuals to obtain optimal mucosal protection.
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| 5. |
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| 6. |
- Wuttke, Matthias, et al.
(author)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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In: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Journal article (peer-reviewed)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 7. |
- Gafar, Fajri, et al.
(author)
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Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents : a systematic review and individual patient data meta-analysis
- 2023
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In: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 61:3
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Research review (peer-reviewed)abstract
- Background Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.Methods We systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24 and Cmax were assessed with linear mixed-effects models.Results Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24 were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L−1), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L−1), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L−1) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L−1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0–24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24 and slow acetylators had higher isoniazid AUC0–24 than intermediate acetylators. Determinants of Cmax were generally similar to those for AUC0–24.Conclusions This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.
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| 8. |
- Hober, Sophia, Professor, 1965-, et al.
(author)
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Systematic evaluation of SARS-CoV-2 antigens enables a highly specific and sensitive multiplex serological COVID-19 assay
- 2021
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In: Clinical & Translational Immunology. - : Wiley. - 2050-0068. ; 10:7
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Journal article (peer-reviewed)abstract
- Objective. The COVID-19 pandemic poses an immense need for accurate, sensitive and high-throughput clinical tests, and serological assays are needed for both overarching epidemiological studies and evaluating vaccines. Here, we present the development and validation of a high-throughput multiplex bead-based serological assay. Methods. More than 100 representations of SARS-CoV-2 proteins were included for initial evaluation, including antigens produced in bacterial and mammalian hosts as well as synthetic peptides. The five best-performing antigens, three representing the spike glycoprotein and two representing the nucleocapsid protein, were further evaluated for detection of IgG antibodies in samples from 331 COVID-19 patients and convalescents, and in 2090 negative controls sampled before 2020. Results. Three antigens were finally selected, represented by a soluble trimeric form and the S1-domain of the spike glycoprotein as well as by the C-terminal domain of the nucleocapsid. The sensitivity for these three antigens individually was found to be 99.7%, 99.1% and 99.7%, and the specificity was found to be 98.1%, 98.7% and 95.7%. The best assay performance was although achieved when utilising two antigens in combination, enabling a sensitivity of up to 99.7% combined with a specificity of 100%. Requiring any two of the three antigens resulted in a sensitivity of 99.7% and a specificity of 99.4%. Conclusion. These observations demonstrate that a serological test based on a combination of several SARS-CoV-2 antigens enables a highly specific and sensitive multiplex serological COVID-19 assay.
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| 9. |
- Laszlo, K. D., et al.
(author)
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Loss of a close family member the year before or during pregnancy and the risk of placental abruption : a cohort study from Denmark and Sweden
- 2014
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In: Psychological Medicine. - 0033-2917 .- 1469-8978. ; 44:9, s. 1855-1866
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Journal article (peer-reviewed)abstract
- Background Maternal stress during pregnancy is associated with a modestly increased risk of fetal growth restriction and pre-eclampsia. Since placental abruption shares similar pathophysiological mechanisms and risk factors with fetal growth restriction and pre-eclampsia, we hypothesized that maternal stress may be implicated in abruption risk. We investigated the association between maternal bereavement during pregnancy and placental abruption. Method We studied singleton births in Denmark (1978-2008) and Sweden (1973-2006) (n=5103272). In nationwide registries, we obtained data on death of women's close family members (older children, siblings, parents, and partners), abruption and potential confounders. Results A total of 30312 (6/1000) pregnancies in the cohort were diagnosed with placental abruption. Among normotensive women, death of a child the year before or during pregnancy was associated with a 54% increased odds of abruption [95% confidence interval (CI) 1.30-1.82]; the increased odds were restricted to women who lost a child the year before or during the first trimester in pregnancy. In the group with chronic hypertension, death of a child the year before or in the first trimester of pregnancy was associated with eight-fold increased odds of abruption (odds ratio 8.17, 95% CI 3.17-21.10). Death of other relatives was not associated with abruption risk. Conclusions Loss of a child the year before or in the first trimester of pregnancy was associated with an increased risk of abruption, especially among women with chronic hypertension. Studies are needed to investigate the effect of less severe, but more frequent, sources of stress on placental abruption risk.
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| 10. |
- Linton, Steven J., 1952-, et al.
(author)
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The effect of the work environment on future sleep disturbances : a systematic review
- 2015
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In: Sleep Medicine Reviews. - : W. B. Saunders. - 1087-0792 .- 1532-2955. ; 23:Oktober, s. 10-19
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Research review (peer-reviewed)abstract
- Workers often attribute poor sleep to factors at work. Despite the large number of workers with sleep disturbances, there is a lack of consensus on the relationship between the work environment and sleep. The purpose of this systematic review therefore was to conduct a comprehensive evaluation. To this end, we employed standardized methods to systematically locate, review, and tabulate the results of prospective or randomized studies of the impact of work factors on sleep disturbances. From the 7981 articles located in five databases, 24 fulfilled our inclusion criteria and formed the base of the review including meta-analyses of the effect sizes. Results showed that the psychosocial work variables of social support at work, control, and organizational justice were related to fewer sleep disturbances, while high work demands, job strain, bullying, and effort-reward imbalance were related to more future sleep disturbances. Moreover, working a steady shift was associated with disturbances while exiting shift work was associated with less disturbed sleep. We conclude that psychosocial work factors and the scheduling of work have an impact on sleep disturbances and this might be utilized in the clinic as well as for planning work environments. Future research needs to employ better methodology and focus on underlying mechanisms.
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