| 1. |
- Andréasson, Måns, 1994-, et al.
(författare)
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Exploring the dispersion and electrostatic components in arene-arene interactions between ligands and G4 DNA to develop G4-ligands
- 2024
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 67:3, s. 2202-2219
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Tidskriftsartikel (refereegranskat)abstract
- G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene-arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets.
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| 2. |
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| 3. |
- Berner, Andreas, et al.
(författare)
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G4-ligand-conjugated oligonucleotides mediate selective binding and stabilization of individual G4 DNA structures
- 2023
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 146:10, s. 6926-6935
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Tidskriftsartikel (refereegranskat)abstract
- G-quadruplex (G4) DNA structures are prevalent secondary DNA structures implicated in fundamental cellular functions, such as replication and transcription. Furthermore, G4 structures are directly correlated to human diseases such as cancer and have been highlighted as promising therapeutic targets for their ability to regulate disease-causing genes, e.g., oncogenes. Small molecules that bind and stabilize these structures are thus valuable from a therapeutic perspective and helpful in studying the biological functions of the G4 structures. However, there are hundreds of thousands of G4 DNA motifs in the human genome, and a long-standing problem in the field is how to achieve specificity among these different G4 structures. Here, we developed a strategy to selectively target an individual G4 DNA structure. The strategy is based on a ligand that binds and stabilizes G4s without selectivity, conjugated to a guide oligonucleotide, that specifically directs the G4-Ligand-conjugated oligo (GL-O) to the single target G4 structure. By employing various biophysical and biochemical techniques, we show that the developed method enables the targeting of a unique, specific G4 structure without impacting other off-target G4 formations. Considering the vast amount of G4s in the human genome, this represents a promising strategy to study the presence and functions of individual G4s but may also hold potential as a future therapeutic modality.
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| 4. |
- Berner, Andreas, et al.
(författare)
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STREET: Swedish Tool for Risk/Resource Estimation at EvenTs. Part one, risk assessment – face validity and inter–rater reliability
- 2015
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Ingår i: Journal of Acute Disease. - 2221-6189. ; 4:1, s. 37-43
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Tidskriftsartikel (refereegranskat)abstract
- Objective To develop a validated and generalized high reliability organizations collaborative tool in order to conduct common assessments and information sharing of potential risks during mass-gatherings. Methods The Swedish resource and risk estimation guide was used as foundation for the development of the generalized collaborative tool, by three different expert groups, and then analyzed. Analysis of inter-rater reliability was conducted through simulated cases that showed weighted and unweight κ-statistics. Results The results revealed a mean of unweight κ-value from the three cases of 0.37 and a mean accuracy of 62% of the tool. Conclusions The collaboration tool, “STREET”, showed acceptable reliability and validity to be used as a foundation for high reliability organization collaboration in a simulated environment. However, the lack of reliability in one of the cases highlights the challenges of creating measurable values from simulated cases. A study on real events can provide higher reliability but need, on the other hand, an already developed tool.
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| 5. |
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| 6. |
- Carlström, Eric, 1957, et al.
(författare)
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Medical Emergencies During a Half Marathon Race - The Influence of Weather
- 2019
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Ingår i: International Journal of Sports Medicine. - Stuttgart : Georg Thieme Verlag KG. - 0172-4622 .- 1439-3964. ; 40:5, s. 312-316
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to analyze the influence of weather conditions on medical emergencies in a half-marathon, specifically by evaluating its relation to the number of non-finishers, ambulance-required assistances, and collapses in need of ambulance as well as looking at the location of such emergencies on the race course. Seven years of data from the world's largest half marathon were used. Meteorological data were obtained from a nearby weather station, and the Physiological Equivalent Temperature (PET) index was used as a measure of general weather conditions. Of the 315,919 race starters, 104 runners out of the 140 ambulance-required assistances needed ambulance services due to collapses. Maximum air temperature and PET significantly co-variated with ambulance-required assistances, collapses, and non-finishers (R (2) =0.65-0.92; p=0.001-0.03). When air temperatures vary between 15-29 degrees C, an increase of 1 degrees C results in an increase of 2.5 (0.008/1000) ambulance-required assistances, 2.5 (0.008/1000) collapses (needing ambulance services), and 107 (0.34/1000) non-finishers. The results also indicate that when the daily maximum PET varies between 18-35 degrees C, an increase of 1 degrees C PET results in an increase of 1.8 collapses (0.006/1000) needing ambulance services and 66 non-finishers (0.21/1000).
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| 7. |
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| 8. |
- Doimo, Mara, et al.
(författare)
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Enhanced mitochondrial G-quadruplex formation impedes replication fork progression leading to mtDNA loss in human cells.
- 2023
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Ingår i: Nucleic acids research. - : Oxford University Press. - 1362-4962 .- 0305-1048. ; 51:14, s. 7392-7408
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial DNA (mtDNA) replication stalling is considered an initial step in the formation of mtDNA deletions that associate with genetic inherited disorders and aging. However, the molecular details of how stalled replication forks lead to mtDNA deletions accumulation are still unclear. Mitochondrial DNA deletion breakpoints preferentially occur at sequence motifs predicted to form G-quadruplexes (G4s), four-stranded nucleic acid structures that can fold in guanine-rich regions. Whether mtDNA G4s form in vivo and their potential implication for mtDNA instability is still under debate. In here, we developed new tools to map G4s in the mtDNA of living cells. We engineered a G4-binding protein targeted to the mitochondrial matrix of a human cell line and established the mtG4-ChIP method, enabling the determination of mtDNA G4s under different cellular conditions. Our results are indicative of transient mtDNA G4 formation in human cells. We demonstrate that mtDNA-specific replication stalling increases formation of G4s, particularly in the major arc. Moreover, elevated levels of G4 block the progression of the mtDNA replication fork and cause mtDNA loss. We conclude that stalling of the mtDNA replisome enhances mtDNA G4 occurrence, and that G4s not resolved in a timely manner can have a negative impact on mtDNA integrity.
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| 9. |
- Kasho, Kazutoshi, et al.
(författare)
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A unique arginine cluster in PolDIP2 enhances nucleotide binding and DNA synthesis by PrimPol
- 2021
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Ingår i: Nucleic acids research. - : Oxford University Press (OUP). - 1362-4962 .- 0305-1048. ; 49:4, s. 2179-2191
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Tidskriftsartikel (refereegranskat)abstract
- Replication forks often stall at damaged DNA. To overcome these obstructions and complete the DNA duplication in a timely fashion, replication can be restarted downstream of the DNA lesion. In mammalian cells, this repriming of replication can be achieved through the activities of primase and polymerase PrimPol. PrimPol is stimulated in DNA synthesis through interaction with PolDIP2, however the exact mechanism of this PolDIP2-dependent stimulation is still unclear. Here, we show that PrimPol uses a flexible loop to interact with the C-terminal ApaG-like domain of PolDIP2, and that this contact is essential for PrimPol's enhanced processivity. PolDIP2 increases primer-template and dNTP binding affinities of PrimPol, which concomitantly enhances its nucleotide incorporation efficiency. This stimulation is dependent on a unique arginine cluster in PolDIP2. Since the polymerase activity of PrimPol alone is very limited, this mechanism, where the affinity for dNTPs gets increased by PolDIP2 binding, might be critical for the in vivo function of PrimPol in tolerating DNA lesions at physiological nucleotide concentrations. © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
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| 10. |
- Kattge, Jens, et al.
(författare)
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TRY plant trait database - enhanced coverage and open access
- 2020
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Ingår i: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Tidskriftsartikel (refereegranskat)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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| 11. |
- Khorram-Manesh, Amir, 1958, et al.
(författare)
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Facilitating Multiagency Collaboration Before Mass Gatherings - The Development of MAGRAT (Mass Gathering Risk Assessment Tool
- 2020
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Ingår i: Biomedical Journal of Scientific and Technical Research. - 2574-1241. ; 24:5, s. 18607-18616
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Tidskriftsartikel (refereegranskat)abstract
- the community hosting the event and create security and public health challenges. We aimed to explore whether a mutual planning and risk assessment tool used by emergency public agencies (EPA=emergency medical services, police officers, and firefighters), and organizers may improve planning and resource utilization before any mass gathering. Study Design and Methods: Action research based on interdisciplinary group exercises using a validated method “Three Level Collaboration” and real scenarios. Results: The use of the assessment tool increased the grade of collaboration between public agencies, and organizers and improved the preplanning phase of a mass gathering, particularly for healthcare providers. It was easy to use, feasible for different scenarios and highlighted the significant role and responsibility of organizers in pre-event risk assessment. Conclusion: The new assessment tool (MAGRAT= Mass Gathering Risk Assessment Tool) is an innovative tool for pre-event
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| 12. |
- Lerouge, Frederic, et al.
(författare)
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In vivo targeting and multimodal imaging of cerebral amyloid-beta aggregates using hybrid GdF3 nanoparticles
- 2022
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Ingår i: Nanomedicine. - : FUTURE MEDICINE LTD. - 1743-5889 .- 1748-6963. ; 17:29, s. 2173-2187
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To propose a new multimodal imaging agent targeting amyloid-beta (A beta) plaques in Alzheimers disease. Materials & methods: A new generation of hybrid contrast agents, based on gadolinium fluoride nanoparticles grafted with a pentameric luminescent-conjugated polythiophene, was designed, extensively characterized and evaluated in animal models of Alzheimers disease through MRI, two-photon microscopy and synchrotron x-ray phase-contrast imaging. Results & conclusion: Two different grafting densities of luminescent-conjugated polythiophene were achieved while preserving colloidal stability and fluorescent properties, and without affecting biodistribution. In vivo brain uptake was dependent on the blood-brain barrier status. Nevertheless, multimodal imaging showed successful A beta targeting in both transgenic mice and A beta fibril-injected rats.
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| 13. |
- Walton, Esther, et al.
(författare)
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Brain Structure in Acutely Underweight and Partially Weight-Restored Individuals With Anorexia Nervosa : A Coordinated Analysis by the ENIGMA Eating Disorders Working Group
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 92:9, s. 730-738
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in gray matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy control subjects. Recent weight regain before scanning may explain some of this heterogeneity. To clarify the extent, magnitude, and de-pendencies of gray matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data.METHODS: We analyzed T1-weighted structural magnetic resonance imaging scans assessed with standardized methods from 685 female patients with AN and 963 female healthy control subjects across 22 sites worldwide. In addition to a case-control comparison, we conducted a 3-group analysis comparing healthy control subjects with acutely underweight AN patients (n = 466) and partially weight-restored patients in treatment (n = 251).RESULTS: In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area were sizable (Cohen's d up to 0.95), widespread, and colocalized with hub regions. Highlighting the effects of un-dernutrition, these deficits were associated with lower body mass index in the AN sample and were less pronounced in partially weight-restored patients.CONCLUSIONS: The effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population.
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| 14. |
- Warncke, Katharina, et al.
(författare)
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Elevations in blood glucose before and after the appearance of islet autoantibodies in children
- 2022
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 132:20
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Tidskriftsartikel (refereegranskat)abstract
- The etiology of type 1 diabetes has polygenic and environmental determinants that lead to autoimmune responses against pancreatic β cells and promote β cell death. The autoimmunity is considered silent without metabolic consequences until late preclinical stages,and it remains unknown how early in the disease process the pancreatic β cell is compromised. To address this, we investigated preprandial nonfasting and postprandial blood glucose concentrations and islet autoantibody development in 1,050 children with high genetic risk of type 1 diabetes. Pre-And postprandial blood glucose decreased between 4 and 18 months of age and gradually increased until the final measurements at 3.6 years of age. Determinants of blood glucose trajectories in the first year of life included sex, body mass index, glucose-related genetic risk scores, and the type 1 diabetes-susceptible INS gene. Children who developed islet autoantibodies had early elevations in blood glucose concentrations. A sharp and sustained rise in postprandial blood glucose was observed at around 2 months prior to autoantibody seroconversion, with further increases in postprandial and, subsequently, preprandial values after seroconversion. These findings show heterogeneity in blood glucose control in infancy and early childhood and suggest that islet autoimmunity is concurrent or subsequent to insults on the pancreatic islets.
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