| 1. |
- Mullins, N., et al.
(författare)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 2. |
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| 3. |
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| 4. |
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| 5. |
- Domínguez-Gil, B., et al.
(författare)
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The Reality of Inadequate Patient Care and the Need for a Global Action Framework in Organ Donation and Transplantation
- 2022
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Ingår i: Transplantation. ; 106:11, s. 2111-2117
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Transplant therapy is considered the best and often the only available treatment for thousands of patients with organ failure that results from communicable and noncommunicable diseases. The number of annual organ transplants is insufficient for the worldwide need. METHODS: We elaborate the proceedings of the workshop entitled "The Role of Science in the Development of International Standards of Organ Donation and Transplantation," organized by the Pontifical Academy of Sciences and cosponsored by the World Health Organization in June 2021. RESULTS: We detail the urgency and importance of achieving national self-sufficiency in organ transplantation as a public health priority and an important contributor to reaching relevant targets of the United Nations Agenda for Sustainable Development. It details the elements of a global action framework intended for countries at every level of economic development to facilitate either the establishment or enhancement of transplant activity. It sets forth a proposed plan, by addressing the technical considerations for developing and optimizing organ transplantation from both deceased and living organ donors and the regulatory oversight of practices. CONCLUSIONS: This document can be used in governmental and policy circles as a call to action and as a checklist for actions needed to enable organ transplantation as treatment for organ failure. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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| 6. |
- Wang, J., et al.
(författare)
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Final report of the CCQM-K145 : Toxic and essential elements in bovine liver
- 2020
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Ingår i: Metrologia. - : IOP Publishing Ltd. - 0026-1394 .- 1681-7575. ; 57:1 A
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Tidskriftsartikel (refereegranskat)abstract
- Liver plays a major role in metabolism and acts as a source of energy for the body by storing glycogen. With the growing interest and investigation in the biological effects in recent years, it is important and necessary to develop accurate and comparable analytical methods for elements in bio-samples. It has, however, been 10 years since the tissue sample (bovine liver) of CCQM-K49 key comparison. The purpose of CCQM-K145 is to ensure the comparable and traceable measurement results for essential and toxic elements such as P, S, Zn, Mn, Ni, Mo, Sr, Cr, Co, Pb, As and Hg in bovine liver among NMIs and other designated measurement bodies worldwide. The comparison was agreed by IAWG as 6th IAWG Benchmarking Exercise with Zn and Ni as exemplary elements at the meeting in Korea in the early October 2016. The results of CCQM-K145 are expected to cover the measurement capability and support CMCs claiming for inorganic elements in the similar biological tissue materials and food samples. 30 NMIs and DIs registered in CCQM-K145. With respect to the methodology, a variety of techniques such as IDMS, ICP-OES, ICP-MS(non-ID), AAS and NAA were adopted by the participants. For Zn, Ni, Sr, Pb and Hg measurements, most participants chose ID-ICP-MS method, which showed the better performance in terms of consistency and reliability of the measurement results. In aspect of the traceability for the measurement results in CCQM-K145, most participants used their own (in house) CRMs or other NMI's CRMs to guarantee trace to SI unit. Most participants used similar matrix CRMs for quality control or method validation. Base on different statistic way to calculate the reference mass fraction values and associated uncertainties for each measurand, removal of the suspected extreme values, and discussion at the IAWG meetings, the median values are proposed as the KCRV for Zn, Ni, Mn, Mo, Cr, Pb and Hg; the arithmetic mean values are proposed as the KCRV for P, S, Sr, Co and As. In general, the performances of the majority of CCQM-K145 participants are very good, illustrating their measurement capabilities for Zn, Ni, P, S, Mn, Mo, Sr, Cr, As, Co, Pb and Hg in a complex biological tissue matrix. Bovine liver contains many kinds of nutrients and microelements, it can be regarded as a typical representative material of biological tissue and food. In CCQM-K145, the analytes involved alkali metals and transition elements, metalloids/semi-metals and non metals with a range of mass fraction from mg/g to μg/kg. CCQM-K145 also tested the ability of NMIs/DIs to determine elements that were easy to be lost and polluted, and interfered significantly. The chemical pretreatment methods of samples used in the comparison is suitable for general food and biological matrix samples. A variety of measurement methods used in the comparison represent the main instrumental technology for elemental analysis. Therefore, for supporting CMC claim, CCQM-K145 is readily applicable to measurement of more elements in a wide range of biological materials (including liquids and solids) and meat products. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
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| 7. |
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| 8. |
- Giovannucci, TA, et al.
(författare)
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Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound
- 2021
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 12:10, s. 914-
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Tidskriftsartikel (refereegranskat)abstract
- Malignant cells display an increased sensitivity towards drugs that reduce the function of the ubiquitin-proteasome system (UPS), which is the primary proteolytic system for destruction of aberrant proteins. Here, we report on the discovery of the bioactivatable compound CBK77, which causes an irreversible collapse of the UPS, accompanied by a general accumulation of ubiquitylated proteins and caspase-dependent cell death. CBK77 caused accumulation of ubiquitin-dependent, but not ubiquitin-independent, reporter substrates of the UPS, suggesting a selective effect on ubiquitin-dependent proteolysis. In a genome-wide CRISPR interference screen, we identified the redox enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) as a critical mediator of CBK77 activity, and further demonstrated its role as the compound bioactivator. Through affinity-based proteomics, we found that CBK77 covalently interacts with ubiquitin. In vitro experiments showed that CBK77-treated ubiquitin conjugates were less susceptible to disassembly by deubiquitylating enzymes. In vivo efficacy of CBK77 was validated by reduced growth of NQO1-proficient human adenocarcinoma cells in nude mice treated with CBK77. This first-in-class NQO1-activatable UPS inhibitor suggests that it may be possible to exploit the intracellular environment in malignant cells for leveraging the impact of compounds that impair the UPS.
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| 9. |
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| 10. |
- Busker, S., et al.
(författare)
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Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death
- 2020
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 6:12
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Tidskriftsartikel (refereegranskat)abstract
- Because of its key role in cancer development and progression, STAT3 has become an attractive target for developing new cancer therapeutics. While several STAT3 inhibitors have progressed to advanced stages of development, their underlying biology and mechanisms of action are often more complex than would be expected from specific binding to STAT3. Here, we have identified and optimized a series of compounds that block STAT3-dependent luciferase expression with nanomolar potency. Unexpectedly, our lead compounds did not bind to cellular STAT3 but to another prominent anticancer drug target, TrxR1. We further identified that TrxR1 inhibition induced Prx2 and STAT3 oxidation, which subsequently blocked STAT3-dependent transcription. Moreover, previously identified inhibitors of STAT3 were also found to inhibit TrxR1, and likewise, established TrxR1 inhibitors block STAT3-dependent transcriptional activity. These results provide new insights into the complexities of STAT3 redox regulation while highlighting a novel mechanism to block aberrant STAT3 signaling in cancer cells.
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| 11. |
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| 12. |
- Roziková, M., et al.
(författare)
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Electrolytic conductivity at pure water level final report
- 2020
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Ingår i: Metrologia. - : IOP Publishing Ltd. - 0026-1394 .- 1681-7575. ; 58:1 A
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Tidskriftsartikel (refereegranskat)abstract
- Electrolytic conductivity in aqueous solutions is one of the most common electrochemical measurement techniques in industry. Since it is sensitive to the amount content of dissolved ions in a solution, a limiting value for conductivity is a clear and simple quality criterium for the ionic purity of water. The relevant measuring range for pure water applications is roughly between 0.055 μS cm-1 (ultrapure water) and 150 μS cm-1 at 25 °C. For instance, the European, Japanese and United States (USP) Pharmacopoeia have specified the requirements for purified water, highly purified water and water for injection for pharmaceutical use based on conductiv-ity. Sectors that also use conductivity limits for water purity are electrical power production, food industry, electronic industry and analytical laboratories. At low conductivity levels it is not feasible to circulate water samples for comparison measure-ments, since the conductivity value is instable due to inevitable ionic contamination. The main contamination results from carbon dioxide in ambient air that dissolves in water and builds H3O+ and hydrogen carbonate ions. The contribution of these ions to conductivity is around 1 μS cm-1. Hence, it is impossible to provide stable samples having usable uncertainties in the conductivity range of interest. EURAMET 1271, performed in 2013, was the first successful comparison measurement of pure water conductivity. In the meanwhile, more NMIs, the majority of which is situated in Europe, have built measurement capabilities in the pure water range. EURAMRET 1271 covered a measurement range up to 50 μS cm-1, whereas more and more customers request conductivity cell calibration in the range up to 150 μS cm-1. Consequently, this comparison intends to extend the measurement range and to enable more NMIs to get support for potential CMCs. Therefore, this comparison is additionally intended being a supplementary CCQM comparison. A commercial conductivity measurement meter, including a conductivity measurement cell, was used for the comparison in a Round-Robin scheme. The devices were provided by PTB and were sent from one institute to another. Each institute had to measure the conductivity of a reference solution using the conductivity meter. The reference solution could either be pure water or a measurement standard solution that was reasonably stable in the range of interest. In the first scheme, the cell had to be integrated in a closed pure water flow though system to minimize impurification by CO2. An adequate fixture for this setup was provided by PTB. In the second scheme, the cell was immersed into the measurement standard solution under tem-perature-controlled conditions. Essentially, the institutes had to report the conductivity values indicated by the conductivity meter and the conductivity reference value assigned to the water in the flow though system or that of the measurement standard solution, respectively. The co-ordinating institute calculated adjusted cell constants for the cell from the reported values, which were used to calculate linking conductivities, the actual quantities to be finally compared. The results showed good equivalence in all conductivity ranges, with only a few inconsistent values. Adequate comparison reference values are suggested that can serve to calculate robust degrees of equivalences for the participants usable to support respective CMC claims.
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| 13. |
- van Der Heijden, L. H., et al.
(författare)
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Quantitative food web modeling unravels the importance of the microphytobenthos-meiofauna pathway for a high trophic transfer by meiofauna in soft-bottom intertidal food webs
- 2020
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Ingår i: Ecological Modelling. - : Elsevier BV. - 0304-3800. ; 430
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Tidskriftsartikel (refereegranskat)abstract
- Meiofauna are known to have an important role on many ecological processes, although, their role in food web dynamics is often poorly understood, partially as they have been an overlooked and under sampled organism group. Here, we used quantitative food web modeling to evaluate the trophic relationship between meiofauna and their food sources and how meiofauna can mediate the carbon flow to higher trophic levels in five contrasting soft-bottom intertidal habitats (including seagrass beds, mudflats and sandflats). Carbon flow networks were constructed using the linear inverse model-Markov chain Monte Carlo technique, with increased resolution of the meiofauna compartments (i.e. biomass and feeding ecology of the different trophic groups of meiofauna) compared to most previous modeling studies. These models highlighted that the flows between the highly productive microphytobenthos and the meiofauna compartments play an important role in transferring carbon to the higher trophic levels, typically more efficiently so than macrofauna. The pathway from microphytobenthos to meiofauna represented the largest flow in all habitats and resulted in high production of meiofauna independent of habitat. All trophic groups of meiofauna, except for selective deposit feeders, had a very high dependency on microphytobenthos. Selective deposit feeders relied instead on a wider range of food sources, with varying contributions of bacteria, microphytobenthos and sediment organic matter. Ecological network analyses (e.g. cycling, throughput and ascendency) of the modeled systems highlighted the close positive relationship between the food web efficiency and the assimilation of high-quality food sources by primary consumers, e.g. meiofauna and macrofauna. Large proportions of these flows can be attributed to trophic groups of meiofauna. The sensitivity of the network properties to the representation of meiofauna in the models leads to recommending a greater attention in ecological data monitoring and integrating meiofauna into food web models.
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| 14. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 15. |
- Haraldsson, Matilda, 1980, et al.
(författare)
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How to model social-ecological systems? – A case study on the effects of a future offshore wind farm on the local society and ecosystem, and whether social compensation matters
- 2020
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Ingår i: Marine Policy. - : Elsevier BV. - 0308-597X. ; 119
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Tidskriftsartikel (refereegranskat)abstract
- Models of social-ecological systems (SES) are acknowledged as an important tool to understand human-nature relations. However, many SES models fail to integrate adequate information from both the human and ecological subsystems. With an example model of a future Offshore Wind Farm development and its effects on both the ecosystem and local human population, we illustrate a method facilitating a “balanced” SES model, in terms of including information from both subsystems. We use qualitative mathematical modeling, which allows to quickly analyze the structure and dynamics of a system without including quantitative data, and therefore to compare alternative system structures based on different understandings of how the system works. By including similar number of system variables in the two subsystems, we balanced the complexity between them. Our analyses show that this complexity is important in order to predict indirect and sometimes counterintuitive effects. We also highlight some conceptually important questions concerning social compensations during developmental projects in general, and wind farms in particular. Our results suggest that the more project holders get involved in various manner in the local socio-ecological system, the more society will benefit as a whole. Increased involvement through e.g. new projects or job-opportunities around the windfarm has the capacity to offset the negative effects of the windfarm on the local community. These benefits are enhanced when there is an overall acceptance and appropriation of the project. We suggest this method as a tool to support the decision-making process and to facilitate discussions between stakeholders, especially among local communities.
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| 16. |
- Lindberg, K., et al.
(författare)
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The HILUS-Trial—a Prospective Nordic Multicenter Phase 2 Study of Ultracentral Lung Tumors Treated With Stereotactic Body Radiotherapy
- 2021
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Ingår i: Journal of Thoracic Oncology. - : Elsevier BV. - 1556-0864. ; 16:7, s. 1200-1210
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Stereotactic body radiation therapy of thoracic tumors close to the central airways implies risk of severe toxicity. We report a prospective multicenter phase 2 trial for tumors located less than or equal to 1 cm from the proximal bronchial tree with primary end point of local control and secondary end point of toxicity. Methods: Stereotactic body radiation therapy with 7 Gy × 8 was prescribed to the 67% isodose encompassing the planning target volume. The patients were stratified to group A (tumors ≤ 1 cm from the main bronchi and trachea) or group B (all other tumors). Risk factors for treatment-related death were tested in univariate analysis, and a logistic regression model was developed for fatal bronchopulmonary bleeding versus dose to the main bronchi and trachea. Results: A total of 65 patients (group A/group B, n = 39/26) were evaluated. The median distance between the tumor and the proximal bronchial tree was 0 mm (0–10 mm). The 2-year local control was 83%. Grade 3 to 5 toxicity was noted in 22 patients, including 10 cases of treatment-related death (bronchopulmonary hemorrhage, n = 8; pneumonitis, n = 1; fistula, n = 1). Dose to the combined structure main bronchi and trachea and tumor distance to the main bronchi were important risk factors. Dose modeling revealed minimum dose to the “hottest” 0.2 cc to the structure main bronchi and trachea as the strongest predictor for lethal bronchopulmonary hemorrhage. Conclusions: On the basis of the presented data, 7 Gy × 8, prescribed to the planning target volume-encompassing isodose, should not be used for tumors located within 1 cm from the main bronchi and trachea. Group B-type tumors may be considered for the treatment on the basis of an individual risk-benefit assessment and a maximum dose to the main bronchi and trachea in the order of 70 to 80 Gy (equivalent dose in 2 Gy fractions). © 2021 International Association for the Study of Lung Cancer
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| 17. |
- Nordgren, Kenneth, 1962-, et al.
(författare)
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Rektorers uppfattningar om undervisningens villkor och en skola på vetenskaplig grund : En uppföljande enkätstudie till undersökningen Lärares planering och efterarbete av lektioner: Infrastrukturer för kollegialt samarbete och forskningssamverkan
- 2022
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Rapport (refereegranskat)abstract
- Föreliggande rapport redovisar resultat från en enkätstudie som riktades till rektorer på grundskola och gymnasium. Undersökningen genomfördes under hösten 2019 inom ramen för ULF (Utbildning, Lärande, Forskning), som är en nationell försöksverksamhet. Målet med försöksverksamheten är att utveckla och pröva hållbara samverkansmodeller mellan akademi och skola vad gäller forskning, skolverksamhet och lärarutbildning.Enkätstudien syftar till att undersöka om kollegial samverkan runt planering och efterarbete kan utgöra en grund för skolutveckling och forskningssamverkan mellan skola och akademi. Enkäten efterfrågade även hur rektorer ser på forskningens roll i skolan. I rapporten sätts resultat från rektorsenkäten även i relation till en lärarenkät genomförd 2018 (Nordgren et al., 2019).Våra studier visar att kollegial samplanering runt undervisning skulle kunna vara central för en samverkan om forskning och utveckling. Resultaten påvisar emellertid stora skillnader mellan hur rektorer och lärare uppfattar villkoren för, och organisationen av utvecklingsarbetet runt undervisning. Ett annat centralt resultat är att rektorer och lärare visar sig intresserade av forskning och samverkan mellan skola och akademi, men båda grupperna ger uttryck för att deras villkor att systematiskt utveckla sin verksamhet är begränsade.Denna rapport ger ett omfattande och rikt underlag för lärare, rektorer, forskare och skolpolitiker att reflektera över vilka strategier som kan vara långsiktiga och hållbara för att understödja en skola på vetenskaplig grund.
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| 18. |
- Oddsson, Asmundur, et al.
(författare)
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Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.
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| 19. |
- Shafagh, Reza Zandi, et al.
(författare)
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Facile Nanoimprinting of Robust High-Aspect-Ratio Nanostructures for Human Cell Biomechanics
- 2020
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Ingår i: ACS Applied Bio Materials. - : American Chemical Society (ACS). - 2576-6422. ; 3:12, s. 8757-8767
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Tidskriftsartikel (refereegranskat)abstract
- High-aspect-ratio and hierarchically nanostructured surfaces are common in nature. Synthetic variants are of interest for their specific chemical, mechanic, electric, photonic, or biologic properties but are cumbersome in fabrication or suffer from structural collapse. Here, we replicated and directly biofunctionalized robust, large-area, and high-aspect-ratio nanostructures by nanoimprint lithography of an off-stoichiometric thiol–ene-epoxy polymer. We structured—in a single-step process—dense arrays of pillars with a diameter as low as 100 nm and an aspect ratio of 7.2; holes with a diameter of 70 nm and an aspect ratio of >20; and complex hierarchically layered structures, all with minimal collapse and defectivity. We show that the nanopillar arrays alter mechanosensing of human hepatic cells and provide precise spatial control of cell attachment. We speculate that our results can enable the widespread use of high-aspect-ratio nanotopograhy applications in mechanics, optics, and biomedicine.
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| 20. |
- Sticker, D., et al.
(författare)
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Using oxygen-consuming thermoset plastics to generate hypoxic conditions in microfluidic devices for potential cell culture applications
- 2020
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Ingår i: 21st International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2017. - : Chemical and Biological Microsystems Society. ; , s. 812-813
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Konferensbidrag (refereegranskat)abstract
- The precise control of the oxygen concentration in a cellular environment allows the study of cells under physiologically relevant conditions. This work reports on a novel method for the generation of reduced dissolved oxygen concentrations in microfluidic chambers for cell- and organ-on-chip applications. Using a thermoset polymeric material (OSTEMERTM), which effectively scavenges dissolved oxygen (DO), microfluidic devices have been fabricated where oxygen was rapidly depleted from the microfluidic chamber. It is shown that hypoxic and anaerobic conditions can be generated through the inherent scavenging property of the material itself, without any additional chemical additives.
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