| 1. |
- Steinacker, J. M., et al.
(författare)
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Global Alliance for the Promotion of Physical Activity: the Hamburg Declaration
- 2023
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Ingår i: Bmj Open Sport & Exercise Medicine. ; 9:3
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Tidskriftsartikel (refereegranskat)abstract
- Non-communicable diseases (NCDs), including coronary heart disease, stroke, hypertension, type 2 diabetes, dementia, depression and cancers, are on the rise worldwide and are often associated with a lack of physical activity (PA). Globally, the levels of PA among individuals are below WHO recommendations. A lack of PA can increase morbidity and mortality, worsen the quality of life and increase the economic burden on individuals and society. In response to this trend, numerous organisations came together under one umbrella in Hamburg, Germany, in April 2021 and signed the 'Hamburg Declaration'. This represented an international commitment to take all necessary actions to increase PA and improve the health of individuals to entire communities. Individuals and organisations are working together as the 'Global Alliance for the Promotion of Physical Activity' to drive long-term individual and population-wide behaviour change by collaborating with all stakeholders in the community: active hospitals, physical activity specialists, community services and healthcare providers, all achieving sustainable health goals for their patients/clients. The 'Hamburg Declaration' calls on national and international policymakers to take concrete action to promote daily PA and exercise at a population level and in healthcare settings.
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| 2. |
- Rauschmeier, R, et al.
(författare)
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Bhlhe40 function in activated B and TFH cells restrains the GC reaction and prevents lymphomagenesis
- 2021
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 219:2
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Tidskriftsartikel (refereegranskat)abstract
- The generation of high-affinity antibodies against pathogens and vaccines requires the germinal center (GC) reaction, which relies on a complex interplay between specialized effector B and CD4 T lymphocytes, the GC B cells and T follicular helper (TFH) cells. Intriguingly, several positive key regulators of the GC reaction are common for both cell types. Here, we report that the transcription factor Bhlhe40 is a crucial cell-intrinsic negative regulator affecting both the B and T cell sides of the GC reaction. In activated CD4 T cells, Bhlhe40 was required to restrain proliferation, thus limiting the number of TFH cells. In B cells, Bhlhe40 executed its function in the first days after immunization by selectively restricting the generation of the earliest GC B cells but not of early memory B cells or plasmablasts. Bhlhe40-deficient mice with progressing age succumbed to a B cell lymphoma characterized by the accumulation of monoclonal GC B-like cells and polyclonal TFH cells in various tissues.
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| 3. |
- Abid, Abdul Rahman, et al.
(författare)
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The effect of relative humidity on CaCl2 nanoparticles studied by soft X-ray absorption spectroscopy
- 2021
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Ingår i: RSC Advances. - : Royal Society of Chemistry. - 2046-2069. ; 11:4, s. 2103-2111
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Tidskriftsartikel (refereegranskat)abstract
- Ca- and Cl-containing nanoparticles are common in atmosphere, originating for example from desert dust and sea water. The properties and effects on atmospheric processes of these aerosol particles depend onthe relative humidity (RH) as they are often both hygroscopic and deliquescent. We present here a study of surface structure of free-flying CaCl2 nanoparticles (CaCl2-NPs) in the 100 nm size regime prepared at different humidity levels (RH: 11–85%). We also created mixed nanoparticles by aerosolizing a solution ofCaCl2 and phenylalanine (Phe), which is a hydrophobic amino acid present in atmosphere. Information of hydration state of CaCl2-NPs and production of mixed CaCl2 + Phe nanoparticles was obtained using soft X-ray absorption spectroscopy (XAS) at Ca 2p, Cl 2p, C 1s, and O 1s edges. We also report Ca 2p andCl 2p X-ray absorption spectra of an aqueous CaCl2 solution. The O 1s X-ray absorption spectra measured from hydrated CaCl2-NPs resemble liquid-like water spectrum, which is heavily influenced by the presence of ions. Core level spectra of Ca2+ and Cl- ions do not show a clear dependence of % RH, indicating that the first coordination shell remains similar in all measured hydrated CaCl2-NPs, but they differ from aqueous solution and solid CaCl2.
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| 4. |
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| 5. |
- Dehlin, Mats, 1968, et al.
(författare)
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Impact of psoriasis disease activity and other risk factors on serum urate levels in patients with psoriasis and psoriatic arthritis-a post-hoc analysis of pooled data from three phase 3 trials with secukinumab
- 2021
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Ingår i: Rheumatology Advances in Practice. - : Oxford University Press (OUP). - 2514-1775. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. Our aims were to determine if the Psoriasis Area Severity Index (PASI) score and serum urate (SU) levels were associated at baseline and whether the change in PASI score during 12 weeks of treatment resulted in a significant change in SU, adjusted for relevant confounders. Methods. Data from patients with psoriasis/PsA (n = 1042/204) in three phase 3 randomized control trials treated with secukinumab (dose 300 mg, n = 628) or placebo (n = 414) were pooled. At baseline, values for SU, PASI and the following covariates were assessed: age, sex, BMI, estimated glomerular filtration rate, and medication with diuretics. To assess the changes in PASI (DPASI) and SU (Durate), the differences (week 12 minus baseline) in patients receiving the active drug were used. Multivariable linear regression, adjusting for covariates, was used to assess the association between PASI and SU at baseline with all patients pooled and to assess the association between Durate and DPASI over 12 weeks of treatment with secukinumab. Results. The degree of skin involvement of psoriasis showed a statistically significant, albeit modest, association with SU (R-2 = 0.014, P < 0.0001 univariately), whereas known risk factors for hyperuricaemia had a much larger impact cross-sectionally at baseline (R-2 = 0.33, P < 0.0001). Furthermore, a substantial improvement in PASI score resulted in only a modest decrease of SU over 12 weeks of treatment with secukinumab (R-2 = 0.014, P < 0.0001 univariately). Conclusions. There is a statistically significant, albeit modest, association with both extent and change in PASI score and SU in patients with psoriasis, compatible with a potential pathophysiological relationship between urate and psoriasis.
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| 6. |
- Morcos, M. N. F., et al.
(författare)
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Continuous mitotic activity of primitive hematopoietic stem cells in adult mice
- 2020
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 217:6
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Tidskriftsartikel (refereegranskat)abstract
- The proliferative activity of aging hematopoietic stem cells (HSCs) is controversially discussed. Inducible fluorescent histone 2B fusion protein (H2B-FP) transgenic mice are important tools for tracking the mitotic history of murine HSCs in label dilution experiments. A recent study proposed that primitive HSCs symmetrically divide only four times to then enter permanent quiescence. We observed that background fluorescence due to leaky H2B-FP expression, occurring in all H2B-FP transgenes independent of label induction, accumulated with age in HSCs with high repopulation potential. We argue that this background had been misinterpreted as stable retention of induced label. We found cell division-independent half-lives of H2B-FPs to be short, which had led to overestimation of HSC divisional activity. Our data do not support abrupt entry of HSCs into permanent quiescence or sudden loss of regeneration potential after four divisions, but show that primitive HSCs of adult mice continue to cycle rarely.
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| 7. |
- Nilsen-Moe, Astrid, et al.
(författare)
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Proton-Coupled Electron Transfer from Tyrosine in the Interior of a de novo Protein : Mechanisms and Primary Proton Acceptor
- 2020
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 142:26, s. 11550-11559
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Tidskriftsartikel (refereegranskat)abstract
- Proton-coupled electron transfer (PCET) from tyrosine produces a neutral tyrosyl radical (Y-center dot) that is vital to many catalytic redox reactions. To better understand how the protein environment influences the PCET properties of tyrosine, we have studied the radical formation behavior of Y-32 in the alpha Y-3 model protein. The previously solved alpha Y-3 solution NMR structure shows that Y-32 is sequestered similar to 7.7 +/- 0.3 angstrom below the protein surface without any primary proton acceptors nearby. Here we present transient absorption kinetic data and molecular dynamics (MD) simulations to resolve the PCET mechanism associated with Y-32 oxidation. Y-32(center dot). was generated in a bimolecular reaction with [Ru(bpy)(3)](3+) formed by flash photolysis. At pH > 8, the rate constant of Y-32(center dot). formation (k(P)(CET)) increases by one order of magnitude per pH unit, corresponding to a proton-first mechanism via tyrosinate (PTET). At lower pH < 7.5, the pH dependence is weak and shows a previously measured KIE approximate to 2.5, which best fits a concerted mechanism. k(PC)(ET) is independent of phosphate buffer concentration at pH 6.5. This provides clear evidence that phosphate buffer is not the primary proton acceptor. MD simulations show that one to two water molecules can enter the hydrophobic cavity of alpha Y-3 and hydrogen bond to Y-32, as well as the possibility of hydrogen-bonding interactions between Y-32 and E-13, through structural fluctuations that reorient surrounding side chains. Our results illustrate how protein conformational motions can influence the redox reactivity of a tyrosine residue and how PCET mechanisms can be tuned by changing the pH even when the PCET occurs within the interior of a protein.
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| 8. |
- Noort, S., et al.
(författare)
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Analysis of rare driving events in pediatric acute myeloid leukemia
- 2023
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 108:1, s. 48-60
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Tidskriftsartikel (refereegranskat)abstract
- Elucidating genetic aberrations in pediatric acute myeloid leukemia (AML) provides insight in biology and may impact on risk-group stratification and clinical outcome. This study aimed to detect such aberrations in a selected series of samples without known (cyto)genetic aberration using molecular profiling. A cohort of 161 patients was selected from various study groups: DCOG, BFM, SJCRH, NOPHO and AEIOP. Samples were analyzed using RNA sequencing (n=152), whole exome (n=135) and/or whole genome sequencing (n=100). In 70 of 156 patients (45%), of whom RNA sequencing or whole genome sequencing was available, rearrangements were detected, 22 of which were novel; five involving ERG rearrangements and four NPM1 rearrangements. ERG rearrangements showed self-renewal capacity in vitro, and a distinct gene expression pattern. Gene set enrichment analysis of this cluster showed upregulation of gene sets derived from Ewing sarcoma, which was confirmed comparing gene expression profiles of AML and Ewing sarcoma. Furthermore, NPM1-rearranged cases showed cytoplasmic NPM1 localization and revealed HOXA/B gene overexpression, as described for NPM1 mutated cases. Single-gene mutations as identified in adult AML were rare. Patients had a median of 24 coding mutations (range, 7-159). Novel recurrent mutations were detected in UBTF (n=10), a regulator of RNA transcription. In 75% of patients an aberration with a prognostic impact could be detected. Therefore, we suggest these techniques need to become standard of care in diagnostics.
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| 9. |
- Pearson, A. D. J., et al.
(författare)
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Paediatric Strategy Forum for medicinal product development for acute myeloid leukaemia in children and adolescents ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration
- 2020
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049. ; 136, s. 116-129
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives. Methods: The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents. Results: CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field. Conclusion: These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes. (C) 2020 Elsevier Ltd. All rights reserved.
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| 10. |
- Schiffer, Christian, et al.
(författare)
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Vp/Vs ratios in the Parnaíba Basin from joint active-passive seismic analysis : Implications for continental amalgamation and basin formation
- 2021
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Ingår i: Tectonophysics. - : Elsevier. - 0040-1951 .- 1879-3266. ; 801
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Tidskriftsartikel (refereegranskat)abstract
- The Phanerozoic intracontinental Parnaíba Basin in northeast Brazil lies atop crust composed of Archaean to Mesoproterozoic cratonic blocks and Neoproterozoic mobile belts. Recently, active and passive source geophysical surveys characterised the crustal structure beneath the basin. We use information from published active-source seismic and new, coincident receiver function (RF) data to obtain Vp/Vs ratios for sedimentary and crustal structure and make inferences about crustal compositions and tectonic evolution. In our approach, sedimentary and crustal Vp/Vs ratios are adjusted to match common conversion point (CCP) images of RFs and known Moho and basement geometry. We use a P-wave model from published wide-angle reflection/refraction (WARR) seismics, and structural features from a deep seismic reflection (DSR) profile. CCP images of the primary RF conversions were used to model the crust, whilst conversions of multiples were used for the sediment-basement interface. The maximum uncertainties in Vp/Vs are estimated to be 0.15 for the basin and 0.03 for the crust. Vp/Vs ratios in the basin were estimated between 1.7 and 2.2. Lower values correlate with the exposure of older units primarily in the east of the basin, whilst higher values coincide with exposed younger units of the Parnaíba Basin. The obtained crustal Vp/Vs ratios between 1.73 and 1.81 support the previously published segmentation of the crust. In particular, we identified three regions of elevated Vp/Vs ratios, which can be related to proposed Neoproterozoic suture zones underlying the Parnaíba Basin, as well as high velocity lower crust beneath. The high Vp/Vs ratios can be explained by mafic compositions, for example metamorphosed or intruded crust, or fluids and sedimentary rocks entrained into highly deformed crust, typical for modifications related to suture zones. These new deep geophysical models provide important and complementary evidence for crustal amalgamation and the formation of the Parnaíba Basin.
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