| 1. |
- Dolinska, Monika, et al.
(author)
-
Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies CXCL14 as a new therapeutic option
- 2023
-
In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
-
Journal article (peer-reviewed)abstract
- Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long -term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.
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| 2. |
- Abildgaard, Amanda B., et al.
(author)
-
HSP70-binding motifs function as protein quality control degrons
- 2023
-
In: Cellular and Molecular Life Sciences (CMLS). - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 80:1
-
Journal article (peer-reviewed)abstract
- Protein quality control (PQC) degrons are short protein segments that target misfolded proteins for proteasomal degradation, and thus protect cells against the accumulation of potentially toxic non-native proteins. Studies have shown that PQC degrons are hydrophobic and rarely contain negatively charged residues, features which are shared with chaperone-binding regions. Here we explore the notion that chaperone-binding regions may function as PQC degrons. When directly tested, we found that a canonical Hsp70-binding motif (the APPY peptide) functioned as a dose-dependent PQC degron both in yeast and in human cells. In yeast, Hsp70, Hsp110, Fes1, and the E3 Ubr1 target the APPY degron. Screening revealed that the sequence space within the chaperone-binding region of APPY that is compatible with degron function is vast. We find that the number of exposed Hsp70-binding sites in the yeast proteome correlates with a reduced protein abundance and half-life. Our results suggest that when protein folding fails, chaperone-binding sites may operate as PQC degrons, and that the sequence properties leading to PQC-linked degradation therefore overlap with those of chaperone binding.
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| 3. |
- Andersen, Paul Krüger, et al.
(author)
-
Response to the Proposal for a Directive on Corporate Sustainability Due Diligence by Nordic and Baltic Company Law Scholars
- 2022
-
Other publication (other academic/artistic)abstract
- On February 23, 2022, The EU Commission published its Proposal for a Directive of the European Parliament and of the Council on Corporate Sustainability Due Diligence and amending Directive (EU) 2019/1937 (“CSDDD” or “the Proposal”). The purpose of the Proposal, to further the “Union’s transition to a climate-neutral and green economy in line with the European Green Deal and in delivering on the UN Sustainable Development Goals”, is of great importance, and the Commission’s initiative is therefore commendable. However, it is our firm opinion that the Proposal should not be enacted in its present form, and that if it were to be, it would not only damage European businesses but also run the risk of having an adverse effect on both the transition to a climate-neutral economy as well as the goal of delivering on the UN Sustainable Development Goals. This is to a large extent because many of the Proposal’s provisions are excessive, unfounded and disproportionate and as such in violation of the fundamental principles of subsidiarity and proportionality safeguarded by Art. 5 TEU as well as having a questionable basis in Art. 50 TFEU. Furthermore and in regard of procedure, we find that the presentation of the Proposal by the Commission represents a disregard for the principles of better regulation that should not pass unnoticed and must be observed in the future to maintain trust in the legislative process of the Union.In this response to the consultation, we have presented an analysis of the key issues of the Proposal from a corporate governance perspective. We have divided the response into two parts: one on the pure corporate governance parts of the Proposal (article 15, 25 and 26) and one of the due diligence parts of the Proposal. With regards to the corporate governance parts of the Proposal, our conclusion is that they, by and large, should not be included in the proposed directive at all. Including them would in several ways be in breach of the EU principles on subsidiarity and proportionality, but perhaps more importantly, they are not only unsubstantiated by available empirical evidence on corporate behaviour, but also refuted by what we know. There is also good reason to believe that the proposed rules on director’s duties and environmental remuneration would risk decreasing the effectiveness of the stock markets within the EU contrary to the goal of a Capital Market Union, which also risk slowing down the necessary transition to a green economy and the goals of the EU Green Deal. The regulation necessary for the Capital Market Union and the EU Green Deal should complement each other, not collide as would be the outcome if the Proposal is adopted in its present form.With regards to the due diligence parts of the Proposal, our criticism is limited to corporate governance aspects and far less fundamental. We primarily believe that grounds for harmonisation needs further consideration in the present very challenging times, that Article 22 on Civil Liability might in several ways be counter-productive to the goals of the Proposal, that the effects on SMEs as well as for the financial companies included covered by the Proposal warrants further analysis, that the choice to focus the Proposal on individual companies instead of company groups needs to be reviewed, and that a risk based approach should be taken rather than an approach were companies are unable to focus their efforts to where they can be most effective. Overall, these issues can be worked out, but if they are not, then the proposed directive would not only have a severe adverse impact on EU companies and possibly capital markets, but might actually hinder EU companies from acting in the way that the Proposal aims for them to do.This joint response to the public consultation is made by a group of Nordic and Baltic company law scholars who, although we may not agree on every detail, do share the main arguments and grave concerns expressed here.
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| 4. |
- Asghar, Naveed, 1983-, et al.
(author)
-
Transient Expression of Flavivirus Structural Proteins in Nicotiana benthamiana
- 2022
-
In: Vaccines. - : MDPI. - 2076-393X. ; 10:10
-
Journal article (peer-reviewed)abstract
- Flaviviruses are a threat to public health and can cause major disease outbreaks. Tick-borne encephalitis (TBE) is caused by a flavivirus, and it is one of the most important causes of viral encephalitis in Europe and is on the rise in Sweden. As there is no antiviral treatment availa-ble, vaccination remains the best protective measure against TBE. Currently available TBE vaccines are based on formalin-inactivated virus produced in cell culture. These vaccines must be delivered by intramuscular injection, have a burdensome immunization schedule, and may exhibit vaccine failure in certain populations. This project aimed to develop an edible TBE vaccine to trigger a stronger immune response through oral delivery of viral antigens to mucosal surfaces. We demonstrated successful expression and post-translational processing of flavivirus structural pro-teins which then self-assembled to form virus-like particles in Nicotiana benthamiana. We performed oral toxicity tests in mice using various plant species as potential bioreactors and evaluated the immunogenicity of the resulting edible vaccine candidate. Mice immunized with the edible vaccine candidate did not survive challenge with TBE virus. Interestingly, immunization of female mice with a commercial TBE vaccine can protect their offspring against TBE virus infection.
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| 5. |
- Beaumont, Robin N, et al.
(author)
-
Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.
- 2023
-
In: Nature genetics. - 1546-1718 .- 1061-4036. ; 55:11, s. 1807-19
-
Journal article (peer-reviewed)abstract
- A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n=65,405), maternal (n=61,228) and paternal (n=52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.
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| 6. |
- Bergström, Petra, et al.
(author)
-
Herpes Simplex Virus 1 and 2 Infections during Differentiation of Human Cortical Neurons
- 2021
-
In: Viruses-Basel. - : MDPI AG. - 1999-4915. ; 13:10
-
Journal article (peer-reviewed)abstract
- Herpes simplex virus 1 (HSV-1) and 2 (HSV-2) can infect the central nervous system (CNS) with dire consequences; in children and adults, HSV-1 may cause focal encephalitis, while HSV-2 causes meningitis. In neonates, both viruses can cause severe, disseminated CNS infections with high mortality rates. Here, we differentiated human induced pluripotent stem cells (iPSCs) towards cortical neurons for infection with clinical CNS strains of HSV-1 or HSV-2. Progenies from both viruses were produced at equal quantities in iPSCs, neuroprogenitors and cortical neurons. HSV-1 and HSV-2 decreased viability of neuroprogenitors by 36.0% and 57.6% (p < 0.0001), respectively, 48 h post-infection, while cortical neurons were resilient to infection by both viruses. However, in these functional neurons, both HSV-1 and HSV-2 decreased gene expression of two markers of synaptic activity, CAMK2B and ARC, and affected synaptic activity negatively in multielectrode array experiments. However, unaltered secretion levels of the neurodegeneration markers tau and NfL suggested intact axonal integrity. Viral replication of both viruses was found after six days, coinciding with 6-fold and 22-fold increase in gene expression of cellular RNA polymerase II by HSV-1 and HSV-2, respectively. Our results suggest a resilience of human cortical neurons relative to the replication of HSV-1 and HSV-2.
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| 7. |
- Dahlgren, Madelene W., et al.
(author)
-
Type I Interferons Promote Germinal Centers Through B Cell Intrinsic Signaling and Dendritic Cell Dependent Th1 and Tfh Cell Lineages
- 2022
-
In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
-
Journal article (peer-reviewed)abstract
- Type I interferons (IFNs) are essential for antiviral immunity, appear to represent a key component of mRNA vaccine-adjuvanticity, and correlate with severity of systemic autoimmune disease. Relevant to all, type I IFNs can enhance germinal center (GC) B cell responses but underlying signaling pathways are incompletely understood. Here, we demonstrate that a succinct type I IFN response promotes GC formation and associated IgG subclass distribution primarily through signaling in cDCs and B cells. Type I IFN signaling in cDCs, distinct from cDC1, stimulates development of separable Tfh and Th1 cell subsets. However, Th cell-derived IFN-γ induces T-bet expression and IgG2c isotype switching in B cells prior to this bifurcation and has no evident effects once GCs and bona fide Tfh cells developed. This pathway acts in synergy with early B cell-intrinsic type I IFN signaling, which reinforces T-bet expression in B cells and leads to a selective amplification of the IgG2c+ GC B cell response. Despite the strong Th1 polarizing effect of type I IFNs, the Tfh cell subset develops into IL-4 producing cells that control the overall magnitude of the GCs and promote generation of IgG1+ GC B cells. Thus, type I IFNs act on B cells and cDCs to drive GC formation and to coordinate IgG subclass distribution through divergent Th1 and Tfh cell-dependent pathways.
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| 8. |
- Dolinska, Monika, et al.
(author)
-
Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients Identifies CXCL14 as a New Therapeutic Option
- 2023
-
In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
-
Journal article (peer-reviewed)abstract
- Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long-term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.
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| 9. |
- Feiz Aghaei, Roozbeh, et al.
(author)
-
Key performance indicators for biogas production : methodological insights on the life-cycle analysis of biogas production from source-separated food waste
- 2020
-
In: Energy. - : Elsevier. - 0360-5442 .- 1873-6785. ; 200
-
Journal article (peer-reviewed)abstract
- The anaerobic digestion of food waste can not only enhance the treatment of organic wastes, but also contributes to renewable energy production and the recirculation of nutrients. These multiple benefits are among the main reasons for the expansion of biogas production from food waste in many countries. We present methodological insights and recommendations on assessing the environmental and economic performance of these systems from a life-cycle perspective. We provide a taxonomy of the value chain of biogas from food waste which describes major activities, flows, and parameters across the value chain with a relatively high detail. By considering the multiple functions of biogas production from food waste, we propose a few key performance indicators (KPI) to allow comparison of different biogas production systems from the perspectives of climate impact, primary energy use, nutrients recycling, and cost. We demonstrate the operational use of our method through an example, where alternatives regarding the heat supply of the biogas plant are investigated. We demonstrate how global and local sensitivity analyses can be combined with the suggested taxonomy and KPIs for uncertainty management and additional analyses. The KPIs provide useful input into decision-making processes regarding the future development of biogas solutions from food waste. (C) 2020 Elsevier Ltd. All rights reserved.
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| 10. |
- Feizaghaii, Roozbeh, 1975-, et al.
(author)
-
The biogas yield, climate impact, energy balance, nutrient recovery, and resource cost of biogas production from household food waste — A comparison of multiple cases from Sweden
- 2022
-
In: Journal of Cleaner Production. - : Elsevier Science Ltd. - 0959-6526 .- 1879-1786. ; 378
-
Journal article (peer-reviewed)abstract
- The depletion of natural resources, climate change and energy security are some of today's societal challenges. One way to address these is through anaerobic digestion of food waste, which provides multiple benefits such as waste treatment, nutrient recycling and renewable energy, such as biogas. Biogas solutions tend to vary, so to gain a holistic understanding of their pros and cons there is a need to use a common analytical approach and simultaneously consider several issues. This study has analysed the climate impact, primary energy use, nutrient recycling potential, and resource cost of producing biogas from food waste in three Swedish biogas plants with different setups. In addition, several scenarios representing changes in the existing systems were analysed. The study aims to provide insights into factors that affect the performance of biogas production from food waste. The method applied is based on life cycle analysis and key performance indicators (KPIs), which were used to compare and analyse the performance of the biogas systems. The analysis synthesises a large amount of information about the performance of these systems and their sub-systems. Despite significant differences between the studied cases, all led to the production of biomethane with a low climate impact (62–80% less climate impact in grCO2eq/MJ compared with the fossil reference), low non-renewable primary energy use (16–31% MJ per MJ delivered biomethane), and significant nutrient recovery (e.g., 52–86% of phosphorus content of food waste was delivered as biofertilizer). In addition to the collection system, the efficiency of pretreatment, the choice of energy system (e.g., for heating the biogas plant), and a suitable digestate treatment were found to be among the main factors that influence the overall performance of these systems.
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