| 1. |
- Allentoft, Morten E., et al.
(author)
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100 ancient genomes show repeated population turnovers in Neolithic Denmark
- 2024
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In: Nature. - 0028-0836 .- 1476-4687. ; 625, s. 329-337
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Journal article (peer-reviewed)abstract
- Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1–4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5–7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.
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| 2. |
- Allentoft, Morten E., et al.
(author)
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Population genomics of post-glacial western Eurasia
- 2024
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In: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 301-311
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Journal article (peer-reviewed)abstract
- Western Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
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| 3. |
- Kjær, Kurt H., et al.
(author)
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A 2-million-year-old ecosystem in Greenland uncovered by environmental DNA
- 2022
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In: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 612:7939, s. 283-291
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Journal article (peer-reviewed)abstract
- Late Pliocene and Early Pleistocene epochs 3.6 to 0.8 million years ago1 had climates resembling those forecasted under future warming2. Palaeoclimatic records show strong polar amplification with mean annual temperatures of 11–19 °C above contemporary values3,4. The biological communities inhabiting the Arctic during this time remain poorly known because fossils are rare5. Here we report an ancient environmental DNA6 (eDNA) record describing the rich plant and animal assemblages of the Kap København Formation in North Greenland, dated to around two million years ago. The record shows an open boreal forest ecosystem with mixed vegetation of poplar, birch and thuja trees, as well as a variety of Arctic and boreal shrubs and herbs, many of which had not previously been detected at the site from macrofossil and pollen records. The DNA record confirms the presence of hare and mitochondrial DNA from animals including mastodons, reindeer, rodents and geese, all ancestral to their present-day and late Pleistocene relatives. The presence of marine species including horseshoe crab and green algae support a warmer climate than today. The reconstructed ecosystem has no modern analogue. The survival of such ancient eDNA probably relates to its binding to mineral surfaces. Our findings open new areas of genetic research, demonstrating that it is possible to track the ecology and evolution of biological communities from two million years ago using ancient eDNA.
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| 4. |
- Toussaint, Laura, et al.
(author)
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Inter-observer variation in target delineation and dose trade-off for radiotherapy of paediatric ependymoma
- 2022
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In: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 61:2, s. 235-238
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Journal article (peer-reviewed)abstract
- Postoperative radiotherapy for intracranial paediatric ependymoma is challenging both for target definition and treatment planning [1]. Delineation of the tumour bed is difficult, as structures in prior contact with the tumour will shift back into their original positions after surgery. In infratentorial cases, the target is adjacent to the brainstem and upper spinal cord, therefore the relatively high prescription dose and sparing of surrounding organs at risk (OARs) need to be balanced. Through the radiotherapy working-group of the Nordic Organization of Pediatric Hematology and Oncology (NOPHO) and in collaboration with the Westdeutsches Protonentherapizentrum Essen (WPE), a study was performed to quantify inter-centre variations in target delineation and treatment plans for these tumours.
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| 5. |
- Ahlgren, Hans, 1984-, et al.
(author)
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The Baltic grey seal : A 9000-year history of presence and absence
- 2022
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In: The Holocene. - : SAGE Publications. - 0959-6836 .- 1477-0911. ; 32:6, s. 569-577
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Journal article (peer-reviewed)abstract
- The grey seal (Halichoerus grypus) has been part of the Baltic Sea fauna for more than 9000 years and has ever since been subjected to extensive human hunting, particularly during the early phases of its presence in the Baltic Sea, but also in the early 20th century. In order to study their temporal genetic structure and to investigate whether there has been a genetically continuous grey seal population in the Baltic, we generated mitochondrial control region data from skeletal remains from ancient grey seals from the archaeological sites Stora Förvar (Sweden) and Neustadt (Germany) and compared these with modern grey seal data. We found that the majority of the Mesolithic grey seals represent haplotypes that is not found in contemporary grey seals, indicating that the Baltic Sea population went extinct, likely due to human overexploitation and environmental change. We hypothesize that grey seals recolonised the Baltic Sea from the North Sea. during the Bronze Age or Iron Age, and that the contemporary Baltic grey seal population is direct descendants of this recolonisation. Our study highlights the power of biomolecular archaeology to understand the factors that shape contemporary marine diversity.
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| 6. |
- Andreasson, Louise Munkholm, et al.
(author)
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Airway hyperresponsiveness correlates with airway TSLP in asthma independent of eosinophilic inflammation
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In: Journal of Allergy and Clinical Immunology. - 0091-6749.
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Journal article (peer-reviewed)abstract
- Background: Thymic stromal lymphopoietin (TSLP) is released from the airway epithelium in response to various environmental triggers, inducing a type-2 inflammatory response, and is associated with airway inflammation, airway hyperresponsiveness (AHR), and exacerbations. TSLP may also induce AHR via a direct effect on airway smooth muscle and mast cells, independently of type-2 inflammation, although association between airway TSLP and AHR across asthma phenotypes has been described sparsely. Objectives: This study sought to investigate the association between AHR and levels of TSLP in serum, sputum, and bronchoalveolar lavage in patients with asthma with and without type-2 inflammation. Methods: A novel ultrasensitive assay was used to measure levels of TSLP in patients with asthma (serum, n = 182; sputum, n = 81; bronchoalveolar lavage, n = 85) and healthy controls (serum, n = 47). The distribution and association among airway and systemic TSLP, measures of AHR, type-2 inflammation, and severity of disease were assessed. Results: TSLP in sputum was associated with AHR independently of levels of eosinophils and fractional exhaled nitric oxide (ρ = 0.49, P = .005). Serum TSLP was higher in both eosinophil-high and eosinophil-low asthma compared to healthy controls: geometric mean: 1600 fg/mL (95% CI: 1468-1744 fg/mL) and 1294 fg/mL (95% CI: 1167-1435 fg/mL) versus 846 fg/mL (95% CI: 661-1082 fg/mL), but did not correlate with the level of AHR. Increasing age, male sex, and eosinophils in blood were associated with higher levels of TSLP in serum, whereas lung function, inhaled corticosteroid dose, and symptom score were not. Conclusions: The association between TSLP in sputum and AHR to mannitol irrespective of markers of type-2 inflammation further supports a role of TSLP in AHR that is partially independent of eosinophilic inflammation.
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| 7. |
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| 8. |
- Birk Jørgensen, Morten, et al.
(author)
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Les villes nordiques, une ingéniosité territoriale par nécessité
- 2019
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In: Perspective: actualité en histoire de l'art. - Paris : L'Institut national d'histoire de l'art. - 1777-7852 .- 2269-7721. ; :1, s. 69-96
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Journal article (peer-reviewed)abstract
- Un débat entre Bilo Høegh Stigsen, Anja Kervanto Nevanlinna, Morten Birk Jørgensen, Tor Lindstrand et Håkan Nilsson, mené par Nicolas Escach
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| 9. |
- Bomholt, Tobias, et al.
(author)
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The Accuracy of Hemoglobin A1c and Fructosamine Evaluated by Long-Term Continuous Glucose Monitoring in Patients with Type 2 Diabetes Undergoing Hemodialysis
- 2022
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In: Blood Purification. - : S. Karger. - 0253-5068 .- 1421-9735. ; 51:7, s. 608-616
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Journal article (peer-reviewed)abstract
- INTRODUCTION: The accuracy of hemoglobin A1c (HbA1c) as a glycemic marker in patients with type 2 diabetes (T2D) receiving hemodialysis (HD) remains unknown. To assess accuracy, we compared HbA1c and fructosamine levels with interstitial glucose measured by continuous glucose monitoring (CGM) in patients with T2D receiving HD.METHODS: Thirty patients in the HD group and 36 patients in the control group (T2D and an estimated glomerular filtration rate >60 mL/min/1.73 m2) completed the study period of 17 weeks. CGM (Ipro2®, Medtronic) was performed 5 times for periods of up to 7 days (with 4-week intervals) during a 16-week period. HbA1c (mmol/mol), the estimated mean plasma glucose from HbA1c (eMPGA1c [mmol/L]) and fructosamine (μmol/L) was measured at week 17 and compared with mean sensor glucose levels from CGM.FINDINGS: In the HD group, mean sensor glucose was 1.4 mmol/L (95% confidence interval [CI]: 1.0-1.8) higher than the eMPGA1c, whereas the difference for controls was 0.1 mmol/L (95% CI: -0.1-[0.4]; p < 0.001). Adjusted for mean sensor glucose, HbA1c was lower in the HD group (-7.3 mmol/mol, 95% CI: -10.0-[-4.7]) than in the control group (p < 0.001), with no difference detected for fructosamine (p = 0.64).DISCUSSION: HbA1c evaluated by CGM underestimates plasma glucose levels in patients receiving HD. The underestimation represents a clinical challenge in optimizing glycemic control in the HD population. Fructosamine is unaffected by the factors affecting HbA1c and appears to be more accurate for glycemic monitoring. CGM or fructosamine could thus complement HbA1c in obtaining more accurate glycemic control in this patient group.
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| 10. |
- Bro-Jørgensen, Maiken Hemme, 1990-
(author)
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Ancient genomics of Baltic seals : Insights on the past Baltic grey seal and harp seal populations
- 2021
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Doctoral thesis (other academic/artistic)abstract
- This thesis aims to study and describe the ancient populations of grey and harp seals in the Baltic Sea, and to present new methodological approaches for general use in ancient DNA studies.The dissertation is comprised of five studies: a review of the use of paleogenetics in studying ancient human-marine mammal interactions; a method paper investigating patterns of DNA preservation in ancient pinniped samples; a method paper presenting a genetic sex identification method for ancient pinnipeds; a population genomic study of the Baltic grey seal; and a population genomic study of the now extinct Baltic harp seal.Guidelines for ancient DNA sample selections were deduced from broad-scale statistical modelling of factors influencing DNA preservation in pinniped bones, the most significant of which included type of bone element, collagen content, and whether the bone derive from a cave context. Modern ringed seal samples with known sex were used to test an alternative pinniped sex identification method using the annotated dog genome as a reference for quantification of the relative representation of X chromosome reads. Reliable sex identification was shown to require a minimum of 5,000 total reads mapped to the reference genome. A total of 69 mitochondrial control regions were generated for Baltic grey seals, which revealed that the Mesolithic data largely represent extinct haplotypes, the main of which continued until the Early Neolithic. A population replacement prior to the early Bronze Age introduced mitochondrial variation resembling that of modern Baltic greys seals. The level of genetic differentiation between the Baltic harp seal population and the three contemporary breeding populations, suggests that the White Sea population is the most likely ancestor of the Baltic harp seal breeding population. An increase in genetic diversity, following a hiatus with no Baltic harp seals, combined with the measures of genetic differentiation from this period, further suggests that a second colonization likely occurred from the White Sea during the early Bronze Age.
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| 11. |
- Bro-Jørgensen, Maiken Hemme, et al.
(author)
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Genomic insights on the extinct Baltic harp seal population
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Other publication (other academic/artistic)abstract
- The harp seal is a cold adapted seal species, which requires a suitable formation of pack ice during winter and spring to secure successfully breeding. Today harp seals live in sub-Arctic regions and the North Atlantic, but during the middle Holocene Period, a breeding population existed in the Baltic Sea. In order to investigate the genetic affinity and faith of the now extinct Baltic harp seal population we analysed contemporary and ancient mitogenomes from across the species contemporary and ancient range. Ancient mitochondrial genomes were generated for a total of 49 Baltic harp seals ranging from Late Mesolithic to the Iron Age, together with five Neolithic samples from the White Sea and two Neolithic samples from the Northwest Atlantic Ocean. The ancient data was compared to published modern harp seal data assigned to the present breeding populations around Newfoundland, the Greenland Sea and the White Sea. Surprisingly only limited phylogenetic resolution was found among the ancient and modern localities. The statistical measures for genetic differentiation, however, identified significant levels of population genetic differentiation between the Baltic harp seal population and all modern populations, which suggest an independent breeding population in the Baltic Sea. The low level of genetic differentiation to the White Sea population indicate a shared ancestry between the Baltic and White Sea. The generated Skyline plot suggest second wave of colonization after a hiatus in the Baltic Sea. Interestingly, the genetic diversity in the Baltic harp seal population was significantly higher than in any of the modern populations. However, a drastic decrease in genetic diversity is observed from the Bronze Age to the Iron Age, which might be linked to effects of high hunting pressure and climatic changes towards the final extirpation of harp seals in the Baltic.
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| 12. |
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| 13. |
- Christensen, Christian Kolle, et al.
(author)
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Beam damage in operando X-ray diffraction studies of Li-ion batteries
- 2023
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In: Journal of Synchrotron Radiation. - 0909-0495. ; 30:Pt 3, s. 561-570
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Journal article (peer-reviewed)abstract
- Operando powder X-ray diffraction (PXRD) is a widely employed method for the investigation of structural evolution and phase transitions in electrodes for rechargeable batteries. Due to the advantages of high brilliance and high X-ray energies, the experiments are often carried out at synchrotron facilities. It is known that the X-ray exposure can cause beam damage in the battery cell, resulting in hindrance of the electrochemical reaction. This study investigates the extent of X-ray beam damage during operando PXRD synchrotron experiments on battery materials with varying X-ray energies, amount of X-ray exposure and battery cell chemistries. Battery cells were exposed to 15, 25 or 35 keV X-rays (with varying dose) during charge or discharge in a battery test cell specially designed for operando experiments. The observed beam damage was probed by μPXRD mapping of the electrodes recovered from the operando battery cell after charge/discharge. The investigation reveals that the beam damage depends strongly on both the X-ray energy and the amount of exposure, and that it also depends strongly on the cell chemistry, i.e. the chemical composition of the electrode.
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| 14. |
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| 15. |
- Eriksson, Daniel, et al.
(author)
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GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility
- 2021
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10-8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10-25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h2).
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| 16. |
- Gonzalez-Franquesa, Alba, et al.
(author)
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Discovery of thymosin β4 as a human exerkine and growth factor
- 2021
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In: American Journal of Physiology - Cell Physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 321:5, s. 770-778
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Journal article (peer-reviewed)abstract
- Skeletal muscle is an endocrine organ secreting exercise-induced factors (exerkines), which play a pivotal role in interorgan cross talk. Using mass spectrometry (MS)-based proteomics, we characterized the secretome and identified thymosin b4 (TMSB4X) as the most upregulated secreted protein in the media of contracting C2C12 myotubes. TMSB4X was also acutely increased in the plasma of exercising humans irrespective of the insulin resistance condition or exercise mode. Treatment of mice with TMSB4X did not ameliorate the metabolic disruptions associated with diet induced-obesity, nor did it enhance muscle regeneration in vivo. However, TMSB4X increased osteoblast proliferation and neurite outgrowth, consistent with its WADA classification as a prohibited growth factor. Therefore, we report TMSB4X as a human exerkine with a potential role in cellular cross talk.
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| 17. |
- Gunst, Jesper D., et al.
(author)
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Efficacy of the TMPRSS2 inhibitor camostat mesilate in patients hospitalized with Covid-19-a double-blind randomized controlled trial
- 2021
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In: eClinicalMedicine. - : Elsevier. - 2589-5370. ; 35
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Journal article (peer-reviewed)abstract
- Background: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials.Methods: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as ≥2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load. ClinicalTrials.gov Identifier: NCT04321096. EudraCT Number: 2020-001,200-42.Findings: 137 patients were assigned to receive camostat mesilate and 68 to placebo. Median time to clinical improvement was 5 days (interquartile range [IQR], 3 to 7) in the camostat group and 5 days (IQR, 2 to 10) in the placebo group (P = 0·31). The hazard ratio for 30-day mortality in the camostat compared with the placebo group was 0·82 (95% confidence interval [CI], 0·24 to 2·79; P = 0·75). The frequency of adverse events was similar in the two groups. Median change in viral load from baseline to day 5 in the camostat group was -0·22 log10 copies/mL (p <0·05) and -0·82 log10 in the placebo group (P <0·05).Interpretation: Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for Covid-19 and did not affect time to clinical improvement, progression to ICU admission or mortality.
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| 18. |
- Hagdrup, Morten, et al.
(author)
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A Riccati-Based Interior Point Method for Efficient Model Predictive Control of SISO Systems
- 2017
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In: IFAC-PapersOnLine. - : Elsevier BV. - 2405-8963. ; 50:1, s. 10672-10678
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Journal article (peer-reviewed)abstract
- This paper presents an algorithm for Model Predictive Control of SISO systems. Based on a quadratic objective in addition to (hard) input constraints it features soft upper as well as lower constraints on the output and an input rate-of-change penalty term. It keeps the deterministic and stochastic model parts separate. The controller is designed based on the deterministic model, while the Kalman filter results from the stochastic part. The controller is implemented as a primal-dual interior point (IP) method using Riccati recursion and the computational savings possible for SISO systems. In particular the computational complexity scales linearly with the control horizon. No warm-start strategies are considered. Numerical examples are included illustrating applications to Artificial Pancreas technology. We provide typical execution times for a single iteration of the IP algorithm and the number of iterations required for convergence in different situations.
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| 19. |
- Hauge, Camilla, et al.
(author)
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Mechanism for activation of the growth factor-activated AGC kinases by turn motif phosphorylation.
- 2007
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In: EMBO Journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 26:9
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Journal article (peer-reviewed)abstract
- The growth factor/insulin-stimulated AGC kinases share an activation mechanism based on three phosphorylation sites. Of these, only the role of the activation loop phosphate in the kinase domain and the hydrophobic motif (HM) phosphate in a C-terminal tail region are well characterized. We investigated the role of the third, so-called turn motif phosphate, also located in the tail, in the AGC kinases PKB, S6K, RSK, MSK, PRK and PKC. We report cooperative action of the HM phosphate and the turn motif phosphate, because it binds a phosphoSer/Thr-binding site above the glycine-rich loop within the kinase domain, promoting zipper-like association of the tail with the kinase domain, serving to stabilize the HM in its kinase-activating binding site. We present a molecular model for allosteric activation of AGC kinases by the turn motif phosphate via HM-mediated stabilization of the alphaC helix. In S6K and MSK, the turn motif phosphate thereby also protects the HM from dephosphorylation. Our results suggest that the mechanism described is a key feature in activation of upto 26 human AGC kinases.
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| 20. |
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| 21. |
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| 22. |
- Keighley, Xénia, et al.
(author)
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Predicting sample success for large-scale ancient DNA studies on marine mammals
- 2021
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In: Molecular Ecology Resources. - : Wiley. - 1755-098X .- 1755-0998. ; 21:4, s. 1149-1166
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Journal article (peer-reviewed)abstract
- In recent years, non-human ancient DNA studies have begun to focus on larger sample sizes and whole genomes, offering the potential to reveal exciting and hitherto unknown answers to ongoing biological and archaeological questions. However, one major limitation to the feasibility of such studies is the substantial financial and time investments still required during sample screening, due to uncertainty regarding successful sample selection. This study investigates the effect of a wide range of sample properties including latitude, sample age, skeletal element, collagen preservation, and context on endogenous content and DNA damage profiles for 317 ancient and historic pinnipedsamples collected from across the North Atlantic. Using generalised linear and mixed-effectmodels, we found that a range of factors affected DNA preservation within each of the species under consideration. The most important findings were that endogenous content varied significantly according to context, the type of skeletal element, the collagen content and collection year. There also appears to be an effect of the sample’s geographic origin, with samples from the Arcticgenerally showing higher endogenous content and lower damage rates. Both latitude and sample age were found to have significant relationships with damage levels, but only for walrus samples. Sex, ontogenetic age and extraction material preparation were not found to have any significantrelationship with DNA preservation. Overall, the skeletal element and sample context were found to be the most influential factors and should therefore be considered when selecting samples for large-scale ancient genome studies.
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| 23. |
- Kjaerum, Morten, et al.
(author)
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The Multiplicity of the Human Being
- 2004
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In: Danmark på afveje : Kritik af den herskende orden - Kritik af den herskende orden.
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Book chapter (peer-reviewed)
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| 24. |
- Sachs, Mikkel Lindskov, et al.
(author)
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Danish Physicians' Views on the Appropriateness of the Involvement of Patients with Type 2 Diabetes in Regulatory Decision Making : A Qualitative Study.
- 2019
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In: Pharmaceutical Medicine. - : Springer Science and Business Media LLC. - 1178-2595 .- 1179-1993. ; 33:2, s. 99-107
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Journal article (peer-reviewed)abstract
- BACKGROUND: Regulators, the pharmaceutical industry, and patient organizations expect an increased inclusion of patients' risk preferences in medical regulatory decisions, for example, with regard to market approval. Merging of input from patients with, for example, multiple sclerosis, with expertise from health professionals in regulatory decisions has already occurred. The complex task of involving larger and more heterogeneous patient populations (e.g. with diabetes mellitus, asthma), however, remains.OBJECTIVE: This study aimed to understand physicians' experiences with factors influencing patients with diabetes mellitus perceived risks of their medicines and to explore how physicians, based on these experiences, perceive patients with diabetes to be suited for involvement in regulatory decisions. This study will provide knowledge that can improve the inclusion of heterogeneous patient groups in regulatory decisions.METHODS: We conducted five semi-structured interviews with physicians with different types of experiences with patients' risk perceptions (for example, being in contact with individual patients vs. being involved in developing guidelines at the population level) and one focus group interview with eight general practitioners in Sjælland, Denmark. We applied a thematic analysis to explore physicians' experiences of the risk perceptions of patients with type 2 diabetes and their perceptions of patients' fitness for involvement in regulatory decisions.RESULTS: The risk perceptions and preferences of patients with diabetes were perceived to be rather diverse. Four drivers behind this diversity were described: past experiences, personality, prognosis ability, and knowledge. The legitimacy of patient preferences was not questioned, but the diversity of risk perceptions made the respondents question the existence of a uniform 'patient voice' useful for regulatory decision making.CONCLUSION: The respondents acknowledged the relevance and legitimacy of the patient perspective, but it was a concern that patient risk perceptions, at present, are too diverse to be included in regulatory decisions. Whether patients make regulatory decisions as perceived by physicians needs to be confirmed by future studies.
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| 25. |
- Sachs, Mikkel Lindskov, et al.
(author)
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Risk Perceptions in Diabetic Patients Who Have Experienced Adverse Events : Implications for Patient Involvement in Regulatory Decisions.
- 2017
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In: Pharmaceutical Medicine. - : Springer Science and Business Media LLC. - 1178-2595 .- 1179-1993. ; 31:4, s. 245-255
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Journal article (peer-reviewed)abstract
- BACKGROUND: Increasingly, patients are expected to influence decisions previously reserved for regulatory agencies, pharmaceutical companies, and healthcare professionals. Individual patients have previously represented their patient population when rare, serious adverse events (AEs) were weighed as part of a benefit-risk assessment. However, the degree of heterogeneity of the patient population is critical for how accurately they can be represented by individuals.OBJECTIVES: This study aims to explore patients' risk perception of rare, serious adverse effects of medicines with regard to blood glucose-lowering antidiabetics used by the individual patient.METHODS: Semi-structured interviews were conducted with 18 patients with diabetes with self-perceived serious, but not necessarily rare, AEs (e.g. stroke or valve or bypass surgery). The interviews explored the patients' history of disease, perceptions of the terms rare and serious, and overall levels of risk aversion. A thematic analysis of the interviews, including a consensus discussion, was carried out.RESULTS: Interestingly, respondents rarely made a clear distinction between medicines-induced AEs and complications related to disease progression. Concerns regarding AEs were apparently diverse but were systematically related to the personal experiences of the respondents. Respondents routinely ignored information about possible rare, serious AEs, unless it could be related to personal experience. In the absence of experience, concerns were focused on common and less serious AEs, thus disregarding rare and more serious events.CONCLUSION: The study suggests that experience of AEs, related to either medicines or disease, constitutes an important factor of patient risk perception. We therefore propose that serious adverse experiences should be added to the traditional panel of socioeconomic factors that are accounted for when patients are invited to give input on regulatory decisions.
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| 26. |
- Sahin, Cagla, et al.
(author)
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Structural basis for dityrosine-mediated inhibition of alpha-synuclein fibrillation
-
Other publication (other academic/artistic)abstract
- α-synuclein (aSyn) is a small intrinsically disordered protein which can self-assemble into highly organized β-sheet structures that are found to accumulate in plaques in the brain of Parkinson’s Disease patients. Oxidative stress has been shown to be important for aSyn and its self-assembly. Here we characterize the molecular and structural effects that mild oxidation has on aSyn monomer and its aggregation. Using a combination of biophysical methods, SAXS and native ion mobility mass spectrometry, we find that oxidation leads to formation of intramolecular dityrosine cross-linkages that reduce aSyn’s size by a factor of √2. MD simulations support our experimental results showing a stable and compact aSyn conformation that prevents self-assembly and amyloid formation by steric hindrance, suggesting an important role of mild oxidation in preventing amyloid formation.
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| 27. |
- Sahin, Cagla, et al.
(author)
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Structural Basis for Dityrosine-Mediated Inhibition of α-Synuclein Fibrillization
- 2022
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 144:27, s. 11949-11954
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Journal article (peer-reviewed)abstract
- α-Synuclein (α-Syn) is an intrinsically disordered protein which self-assembles into highly organized β-sheet structures that accumulate in plaques in brains of Parkinson’s disease patients. Oxidative stress influences α-Syn structure and self-assembly; however, the basis for this remains unclear. Here we characterize the chemical and physical effects of mild oxidation on monomeric α-Syn and its aggregation. Using a combination of biophysical methods, small-angle X-ray scattering, and native ion mobility mass spectrometry, we find that oxidation leads to formation of intramolecular dityrosine cross-linkages and a compaction of the α-Syn monomer by a factor of √2. Oxidation-induced compaction is shown to inhibit ordered self-assembly and amyloid formation by steric hindrance, suggesting an important role of mild oxidation in preventing amyloid formation.
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| 28. |
- Trelle, Morten Beck, et al.
(author)
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Hydrogen/deuterium exchange mass spectrometry reveals specific changes in the local flexibility of plasminogen activator inhibitor 1 upon binding to the somatomedin B domain of vitronectin.
- 2012
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In: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 51:41
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Journal article (peer-reviewed)abstract
- The native fold of plasminogen activator inhibitor 1 (PAI-1) represents an active metastable conformation that spontaneously converts to an inactive latent form. Binding of the somatomedin B domain (SMB) of the endogenous cofactor vitronectin to PAI-1 delays the transition to the latent state and increases the thermal stability of the protein dramatically. We have used hydrogen/deuterium exchange mass spectrometry to assess the inherent structural flexibility of PAI-1 and to monitor the changes induced by SMB binding. Our data show that the PAI-1 core consisting of β-sheet B is rather protected against exchange with the solvent, while the remainder of the molecule is more dynamic. SMB binding causes a pronounced and widespread stabilization of PAI-1 that is not confined to the binding interface with SMB. We further explored the local structural flexibility in a mutationally stabilized PAI-1 variant (14-1B) as well as the effect of stabilizing antibody Mab-1 on wild-type PAI-1. The three modes of stabilizing PAI-1 (SMB, Mab-1, and the mutations in 14-1B) all cause a delayed latency transition, and this effect was accompanied by unique signatures on the flexibility of PAI-1. Reduced flexibility in the region around helices B, C, and I was seen in all three cases, which suggests an involvement of this region in mediating structural flexibility necessary for the latency transition. These data therefore add considerable depth to our current understanding of the local structural flexibility in PAI-1 and provide novel indications of regions that may affect the functional stability of PAI-1.
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| 29. |
- Zakhrabekova, Shakhira, et al.
(author)
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Identification of a candidate dwarfing gene in Pallas, the first commercial barley cultivar generated through mutational breeding
- 2023
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In: Frontiers in Genetics. - 1664-8021. ; 14
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Journal article (peer-reviewed)abstract
- Many induced mutants are available in barley (Hordeum vulgare L.). One of the largest groups of induced mutants is the Erectoides (ert) mutants, which is characterized by a compact and upright spike and a shortened culm. One isolated mutant, ert-k.32, generated by X-ray treatment and registered in 1958 under the named “Pallas”, was the first ever induced barley mutant to be released on the market. Its value was improved culm strength and enhanced lodging resistance. In this study, we aimed to identify the casual gene of the ert-k.32 mutant by whole genome sequencing of allelic ert-k mutants. The suggested Ert-k candidate gene, HORVU.MOREX.r3.6HG0574880, is located in the centromeric region of chromosome 6H. The gene product is an alpha/beta hydrolase with a catalytic triad in the active site composed of Ser-167, His-261 and Asp-232. In comparison to proteins derived from the Arabidopsis genome, ErtK is most similar to a thioesterase with de-S-acylation activity. This suggests that ErtK catalyzes post-translational modifications by removing fatty acids that are covalently attached to cysteine residues of target proteins involved in regulation of plant architecture and important commercial traits such as culm stability and lodging resistance.
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