University of Copenhagen
  • Copenhagen, Denmark
Recent publications
Didaktiske eksperimenter på natur- og sundhedsvidenskab har vist at læringsaktiviteter der giver universitetsstuderende relevante sansemotoriske erfaringer, styrker forståelse og hukommelse, men betydningen af sansning og bevægelse i humanioraundervisning er underbelyst. Gennem to pilotstudier med fokus på design, deltagelse og evaluering undersøger denne artikel kropsforankret læring på Humaniora i to læringskontekster: digital undervisning på Zoom og auditorieundervisning på campus. Undersøgelsen viser at det også i humanioraundervisning er muligt at udvikle kropsforankrede læringsaktiviteter med stærk konceptuel integration, at de studerende deltog aktivt, og at de evaluerede aktiviteterne meget positivt. Sammenligningen af det fysiske og digitale læringsrum viser at kropsforankrede læringsaktiviteter fungerede godt i begge, med tilpasning til læringskonteksternes forskellige praktiske begrænsninger og muligheder. Auditoriet er en potentielt mere sårbar kontekst fordi deltagelse er synlig for alle, men samtidig åbner samværet i et fælles fysisk og socialt rum mulighed for aktiviteter hvor samspillet mellem de studerendes kroppe er grundlaget for læringsaktiviteternes konceptuelle integration.
Amyloid‐ β inspired biocompatible short peptide amphiphile (sPA) molecule was used for controlled and targeted delivery of bioactive silver nanoparticles via transforming sPA nanostructures. Such sPA‐AgNPs hybrid structures can be further used to develop antibacterial materials to combat emerging bacterial resistance. It is due to the excellent antibacterial activity of silver, the growths of clinically relevant bacteria were inhibited in the presence of AgNPs‐sPA hybrids. The bacterial test demonstrated that owing to high biocompatibility and less cytotoxicity of the designed sPA worked as a model drug delivery agent and therefore can show great potential in locally addressing bacterial infections. Our study suggested that these nanodevices have the potential to trap, followed by facile delivery of chemical payload at the target site therefore can work as potential delivery material and may have potential therapeutic value for the treatment of microbiota triggered a progression of neurodegenerative diseases.
The transcriptional regulator CueR is activated by the binding of Cu I , Ag I , or Au I to two cysteinates in a near‐linear fashion. The C‐terminal CCHHRAG sequence in Escherichia coli CueR present potential additional metal binding ligands and here we explore the effect of deleting this fragment on the binding of Ag I to CueR. CD‐spectroscopic and ESI‐MS data indicate that the high Ag I ‐binding affinity of WT‐CueR is significantly reduced in Δ7C‐CueR. 111 Ag PAC spectroscopy demonstrates that the WT‐CueR metal site structure (AgS 2 ) is conserved, but less populated in the truncated variant. Thus, the function of the C‐terminal fragment may be to stabilize the two‐coordinate metal site for cognate monovalent metal ions. In a broader perspective this is an example of residues beyond the second coordination sphere affecting metal site physico‐chemical properties while leaving the structure unperturbed.
The complexation of MgII with adenosine 5’‐triphosphate (ATP) is omnipresent in biochemical energy conversion, but is difficult to interrogate directly. Here we used the spin‐½ β‐emitter 31Mg to study MgII‐ATP complexation in 1‐ethyl‐3‐methylimidazolium acetate (EMIM‐Ac) solutions using β‐radiation‐detected nuclear magnetic resonance (β‐NMR). We demonstrate that (nuclear) spin‐polarized 31Mg, following ion‐implantation from an accelerator beamline into EMIM‐Ac, binds to ATP within its radioactive lifetime before depolarizing. The evolution of the spectra with solute concentration indicates that the implanted 31Mg initially bind to the solvent acetate anions, whereafter they undergo dynamic exchange and form either a mono‐ (31Mg‐ATP) or di‐nuclear (31MgMg‐ATP) complex. The chemical shift of 31Mg‐ATP is observed up‐field of 31MgMg‐ATP, in accord with quantum chemical calculations. These observations constitute a crucial advance towards using β‐NMR to probe biologically relevant contexts.
The complexation of MgII with adenosine 5’‐triphosphate (ATP) is omnipresent in biochemical energy conversion, but is difficult to interrogate directly. Here we used the spin‐½ β‐emitter 31Mg to study MgII‐ATP complexation in 1‐ethyl‐3‐methylimidazolium acetate (EMIM‐Ac) solutions using β‐radiation‐detected nuclear magnetic resonance (β‐NMR). We demonstrate that (nuclear) spin‐polarized 31Mg, following ion‐implantation from an accelerator beamline into EMIM‐Ac, binds to ATP within its radioactive lifetime before depolarizing. The evolution of the spectra with solute concentration indicates that the implanted 31Mg initially bind to the solvent acetate anions, whereafter they undergo dynamic exchange and form either a mono‐ (31Mg‐ATP) or di‐nuclear (31MgMg‐ATP) complex. The chemical shift of 31Mg‐ATP is observed up‐field of 31MgMg‐ATP, in accord with quantum chemical calculations. These observations constitute a crucial advance towards using β‐NMR to probe biologically relevant contexts.
Biosensing approaches that combine small engineered antibodies (nanobodies) with nanoparticles are often complicated. Here, we show that nanobodies with different C‐terminal tags can be efficiently attached to a range of the most widely used biocompatible semiconductor quantum dots (QDs). Direct implementation into simplified assay formats was demonstrated by designing a rapid and wash‐free mix‐and‐measure immunoassay for the epidermal growth factor receptor (EGFR). Terbium complex (Tb)‐labeled hexahistidine‐tagged nanobodies were specifically displaced from QD surfaces via EGFR‐nanobody binding, leading to an EGFR concentration‐dependent decrease of the Tb‐to‐QD Förster resonance energy transfer (FRET) signal. The detection limit of 80±20 pM (16±4 ng/mL) was 3‐fold lower than the clinical cut‐off concentration for soluble EGFR and up to 10‐fold lower compared to conventional sandwich FRET assays that required a pair of different nanobodies.
Biosensing approaches that combine small engineered antibodies (nanobodies) with nanoparticles are often complicated. Here, we show that nanobodies with different C‐terminal tags can be efficiently attached to a range of the most widely used biocompatible semiconductor quantum dots (QDs). Direct implementation into simplified assay formats was demonstrated by designing a rapid and wash‐free mix‐and‐measure immunoassay for the epidermal growth factor receptor (EGFR). Terbium complex (Tb)‐labeled hexahistidine‐tagged nanobodies were specifically displaced from QD surfaces via EGFR‐nanobody binding, leading to an EGFR concentration‐dependent decrease of the Tb‐to‐QD Förster resonance energy transfer (FRET) signal. The detection limit of 80±20 pM (16±4 ng/mL) was 3‐fold lower than the clinical cut‐off concentration for soluble EGFR and up to 10‐fold lower compared to conventional sandwich FRET assays that required a pair of different nanobodies.
Intelligent forest management is the key to mitigating climate warming, fostering a green economy, and protecting valuable habitats. Detailed knowledge about forests is a prerequisite for such management but is conventionally based on costly plot-scale data, rarely available at resolution of relevance for management strategies. Here, we present a deep learning-based framework that provides location, crown area and height for each individual tree from aerial images at country scale. We quantify and characterize all individual trees in Denmark and show that 26% of the trees grow outside forests, which is typically unrecognized in national inventories. Furthermore, we demonstrate that only marginal effort is needed to transfer our framework to Finland, despite markedly dissimilar landscapes and data sources. Our work lays the foundation for a global database, where every tree has its digital twin and is spatially traceable and manageable.
Summary Catecholamine‐triggered β‐adrenoceptor (β‐AR) signaling is essential for the correct functioning of the heart. Although both β1‐ and β2‐AR subtypes are expressed in cardiomyocytes, drugs selectively targeting β1‐AR have proven this receptor as the main target for the therapeutic effects of beta blockers in the heart. Here, we report a new strategy for the light‐control of β1‐AR activation by means of photoswitchable drugs with a high level of β1‐/β2‐AR selectivity. All reported molecules allow for an efficient real‐time optical control of receptor function in vitro . Moreover, using confocal microscopy we demonstrate that the binding of our best hit, pAzo‐2, can be reversibly photocontrolled. Strikingly, pAzo‐2 also enables a dynamic cardiac rhythm management on living zebrafish larvae using light, thus highlighting the therapeutic and research potential of the developed photoswitches. Overall, this work provides the first proof of precise control of the therapeutic target β1‐AR in native environments using light.
Summary Catecholamine‐triggered β‐adrenoceptor (β‐AR) signaling is essential for the correct functioning of the heart. Although both β1‐ and β2‐AR subtypes are expressed in cardiomyocytes, drugs selectively targeting β1‐AR have proven this receptor as the main target for the therapeutic effects of beta blockers in the heart. Here, we report a new strategy for the light‐control of β1‐AR activation by means of photoswitchable drugs with a high level of β1‐/β2‐AR selectivity. All reported molecules allow for an efficient real‐time optical control of receptor function in vitro . Moreover, using confocal microscopy we demonstrate that the binding of our best hit, pAzo‐2, can be reversibly photocontrolled. Strikingly, pAzo‐2 also enables a dynamic cardiac rhythm management on living zebrafish larvae using light, thus highlighting the therapeutic and research potential of the developed photoswitches. Overall, this work provides the first proof of precise control of the therapeutic target β1‐AR in native environments using light.
Parkinson’s disease, Multiple System Atrophy, and Lewy Body Dementia are incurable diseases called α-synucleinopathies as they are mechanistically linked to the protein, α-synuclein (α-syn). α-syn exists in different structural forms which have been linked to clinical disease distinctions. However, sleeping disorders (SDs) are common in the prodromal phase of all three α-synucleinopathies, which suggests that sleep-controlling neurons are affected by multiple forms of α-syn. To determine whether a structure-independent neuronal impact of α-syn exists, we compared and contrasted the cellular effect of three different α-syn forms on neurotransmitter-defined cells of two sleep-controlling nuclei located in the brainstem: the Laterodorsal Tegmental nucleus and the Pedunculopontine Tegmental nucleus. We utilized size exclusion chromatography, fluorescence spectroscopy, circular dichroism spectroscopy and transmission electron microscopy to precisely characterize timepoints in the α-syn aggregation process with three different dominating forms of this protein (monomeric, oligomeric and fibril) and we conducted an in-depth investigation of the underlying neuronal mechanism behind cellular effects of the different forms of the protein using electrophysiology, multiple-cell calcium imaging, single-cell calcium imaging and live-location tracking with fluorescently-tagged α-syn. Interestingly, α-syn altered membrane currents, enhanced firing, increased intracellular calcium and facilitated cell death in a structure-independent manner in sleep-controlling nuclei, and postsynaptic actions involved a G-protein-mediated mechanism. These data are novel as the sleep-controlling nuclei are the first brain regions reported to be affected by α-syn in a structure-independent manner. These regions may represent highly important targets for future neuroprotective therapy to modify or delay disease progression in α-synucleinopathies.
Background: The efficacy of psychoeducation as an add-on treatment to pharmacotherapy is well documented in treating symptoms and in relapse prevention for persons with bipolar disorder in western countries. Yet, no studies on psychosocial interventions for persons with bipolar disorder have been conducted in a low-income country in Africa. Aim : To develop a bipolar group psychoeducation program contextualized to the Rwandese setting, and determine its effect on symptom severity, medical adherence, and internalized stigma. Methods: A culturally adapted guide manual will be developed by local mental health professionals, including nurses, psychologists, and medical doctors. In-depth interviews with participants will be held prior to and after the intervention to address the cultural aspect of living with bipolar disease and the impact of the program. A two-armed randomized controlled trial will be set up at the tertiary mental health hospitals in Rwanda, with an intervention- and a waiting-list-arm. A sample size of at least 50 in each arm will be required. The study’s primary outcome measure will be the difference in relapse rate measured on the Young Mania Rating Scale and Hamilton Depression Scale-17. Differences in mean change on scales for medical adherence and internalized-stigma will be secondary outcomes. Data will be analyzed according to the intention-to-treat principle. Participants will be assessed at baseline, then at the end of the intervention period, and three months and 12 months post-intervention. Discussion: This study will be one of the first intervention trials on bipolar disorder in a low-income country. If proven successful in reducing morbidity and increasing the quality of life in persons with bipolar disorder, it is anticipated that the psychoeducation program can be implemented at the district and community level and act as inspiration for other low-resource settings. Trial registration : ClinicalTrials.gov, Identifier: NCT04671225, Registered retrospectively in November 2020.
Trees sustain livelihoods and mitigate climate change, but a predominance of trees outside forests and limited resources make it difficult for many developing countries to conduct frequent nation-wide inventories. Here, we propose a rapid and accurate approach to map the carbon stock of each individual tree and shrub at the national scale of Rwanda using aerial imagery and deep learning. We show that 72% of the mapped trees are located in farmlands and savannas, and 15% in plantations. These non-forest trees account for 41% of the national carbon stocks. Natural forests cover 5% of the country and 11% of the total tree count, but comprise 59% of the national carbon stocks. The mapping of all trees facilitates any landscape stratification and is urgently needed for effective planning and monitoring of landscape restoration activities as well as for optimization of carbon sequestration, biodiversity and economic benefits of trees.
Based on H‐cell measurements, gold (Au) is one of the most selective catalysts for the CO 2 reduction reaction (CO 2 RR) to CO. To ensure a high dispersion, typically Au small nanoparticles (NPs) are used as catalyst. However, the preparation of small Au NPs based on conventional synthesis methods often requires the use of surfactants such as polyvinylpyrrolidone (PVP). Here, we present a systematic evaluation of the performance of laser‐generated, surfactant‐free Au NPs for the CO 2 RR in a gas diffusion electrode (GDE) setup and compare the results to investigations in an H‐cell configuration. The GDE setup supplies a continuous CO 2 stream at the electrode−electrolyte interface to circumvent CO 2 mass transport limitations encountered in conventional H‐cells. We investigate the influence of the catalyst loading and the effect of PVP. Comparing the two screening methods, i.e. GDE and H‐cell measurements, it is shown that the performance of the same catalyst can be substantially different in the two environments. In the GDE setup without liquid electrolyte‐catalyst interface a higher reaction rate, but lower faradaic efficiendy is determined. Independent of the setup, the presence of PVP favours the hydrogen evolution reaction (HER), however, in the GDE setup PVP is more detrimental for the performance than in the H‐cell.
Background : Atrial fibrillation (AF) is the most common cardiac arrhythmia following coronary artery bypass grafting (CABG). We hypothesized that measures of left atrial (LA) function would be useful in predicting AF in patients undergoing CABG. Methods and Results In the study, 611 patients were included after CABG. All patients had echocardiograms performed preoperatively and LA functional measurements were assessed. These measurements were LA maximum volume index (LAVmax), LA minimum volume index (LAVmin) and LA emptying fraction (LAEF). The endpoint was AF occurring >14 days after surgery. During the follow-up period of a median of 3.7 years, 52 (9%) developed AF. The mean age was 67 years, 84% were male and the average left ventricle ejection fraction was 50 %. No differences were observed between the patients developing AF and those who did not develop AF. No functional LA measurements were significant predictors of AF in the whole CABG population. However, in patients with normal-sized LA (n=532, events: 49), both LAEF and LAVmin were univariable predictors of AF. When the functional measurements were adjusted for the CHADS score, both LAVmin (HR=1.07 (1.01-1.13), p=0.014 ) and LAEF (HR: 1.02 (1.00-1.03, p= 0.023)), remained significant predictors. Conclusion No echocardiographic measurements were significant predictors of AF after CABG. In patients with a normal LA size, LAVmin as well as LAEF were significant predictors of AF. Keywords: atrial fibrillation; cardiac surgery; left atrium; echocardiography
Sirtuin 5 (SIRT5) is a protein lysine deacylase enzyme that regulates diverse biology by hydrolyzing -N-carboxyacyllysine posttranslational modifications in the cell. Inhibition of SIRT5 has been linked to potential treatment of several cancers but potent compounds with activity in cells have been lacking. Here we developed mechanism-based inhibitors that incorporate isosteres of a carboxylic acid residue that is important for high-affinity binding to the enzyme active site. By masking of the tetrazole moiety of the most potent candidate from our initial SAR study, we achieved potent and cytoselective growth inhibition for the treatment of SIRT5-dependent leukemic cancer cell lines in culture. Thus, we provide an efficient, cellularly active small molecule that targets SIRT5, which can help elucidate its function and potential as a future drug target. This work shows that masked biosisosteres of carboxylic acids are viable chemical motifs for the development of inhibitors that target mitochondrial enzymes, which may have applications beyond the sirtuin field. TOC graphic (11×2.5 cm) TOC text (450 Characters) SAR study of mechanism-based inhibitors of the sirtuin 5 (SIRT5) hydrolase, containing isosteres of an essential carboxylic acid moiety, furnished heterocycles with excellent potency and slow, tight-binding kinetics against the enzyme. Evaluation of selected compounds in cells, revealed that transient masking of the heterocycle provided improved inhibitors with high lvel of target engagement in cultured cells.
Background: The prognosis for kidney survival is poor in patients presenting with circulating anti-glomerular basement membrane (GBM) antibodies and severe kidney injury. It is unknown if treatment with an endopeptidase that cleaves circulating and kidney bound IgG can alter the prognosis. Methods: An investigator-driven phase 2a one-arm study (EudraCT 2016-004082-39) was performed in 17 hospitals in five European countries. A single dose of 0.25 mg/kg of imlifidase was given to 15 adults with circulating anti-GBM antibodies and an eGFR <15 ml/min per 1.73m2. All patients received standard treatment with cyclophosphamide and corticosteroids, but plasma exchange only if autoantibodies rebounded. The primary outcomes were safety and dialysis independency at 6 months. Results: At inclusion, ten patients were dialysis dependent and the other five had eGFR levels between 7 and 14 ml/min per 1.73m2. The median age was 61 years (range 19-77), six were women, and six were also positive for anti-neutrophil cytoplasmic antibodies. Then 6 hours after imlifidase infusion, all patients had anti-GBM antibodies levels below the reference range of a prespecified assay. At 6 months 67% (ten out of 15) were dialysis independent. This is significantly higher compared with 18% (nine out of 50) in a historical control cohort (P<0.001, Fisher's exact test). Eight serious adverse events (including one death) were reported, none assessed as probably or possibly related to the study drug. Conclusions: In this pilot study, the use of imlifidase was associated with a better outcome compared with earlier publications, without major safety issues, but the findings need to be confirmed in a randomized controlled trial.Clinical Trial registration number: EUDRACT 2016-004082-39 https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-001377-28/results.
Dyslipidaemia is a modifiable cause of increased mortality in patients with mental illness. We described prevalence, aetiology and treatment of dyslipidaemia in patients with mental illness. Patients with mental illness have a higher prevalence of dyslipidaemia than the general population due to genetic predisposition, unhealthy lifestyle and/or psychotropic medications. Attention towards early identification of dyslipidaemia, close monitoring, and a low threshold for initiating treatment with lifestyle interventions and lipid-lowering agents are warranted in patients with mental illness.
Membrane proteins are of biological and pharmaceutical significance. However, their structural study is extremely challenging mainly due to the fact that only a small number of chemical tools is suitable for stabilizing membrane proteins in solution. Detergents are widely used in membrane protein study, but conventional detergents are generally poor at stabilizing challenging membrane proteins such as G protein‐coupled receptors and protein complexes. In the current study, we prepared tandem triazine‐based maltosides (TZMs) with two amphiphilic triazine units connected by different diamine linkers, hydrazine (TZM‐Hs) and 1,2‐ethylenediamine (TZM‐Es). These TZMs were consistently superior to a gold standard detergent (DDM) in terms of stabilizing a few membrane proteins. In addition, the TZM‐Es containing a long linker showed more general protein stabilization efficacy with multiple membrane proteins than the TZM‐Hs containing a short linker. This result indicates that introduction of the flexible1,2‐ethylenediamine linker between two rigid triazine rings enables the TZM‐Es to fold into favourable conformations in order to promote membrane protein stability. The novel concept of detergent foldability introduced in the current study has potential use for rational detergent design and membrane protein applications.
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