| 1. |
- Beverborg, Niels Grote, et al.
(author)
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Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy
- 2021
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In: Nature Communications. - Stockholm : Karolinska Institutet, Dept of Cell and Molecular Biology. - 2041-1723.
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Journal article (peer-reviewed)abstract
- Heart failure (HF) is a major cause of morbidity and mortality worldwide, highlighting an urgent need for novel treatment options, despite recent improvements. Aberrant Ca2+ handling is a key feature of HF pathophysiology. Restoring the Ca2+ regulating machinery is an attractive therapeutic strategy supported by genetic and pharmacological proof of concept studies. Here, we study antisense oligonucleotides (ASOs) as a therapeutic modality, interfering with the PLN/SERCA2a interaction by targeting Pln mRNA for downregulation in the heart of murine HF models. Mice harboring the PLN R14del pathogenic variant recapitulate the human dilated cardiomyopathy (DCM) phenotype; subcutaneous administration of PLN-ASO prevents PLN protein aggregation, cardiac dysfunction, and leads to a 3-fold increase in survival rate. In another genetic DCM mouse model, unrelated to PLN (Cspr3/Mlp−/−), PLN-ASO also reverses the HF phenotype. Finally, in rats with myocardial infarction, PLN-ASO treatment prevents progression of left ventricular dilatation and improves left ventricular contractility. Thus, our data establish that antisense inhibition of PLN is an effective strategy in preclinical models of genetic cardiomyopathy as well as ischemia driven HF.
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| 2. |
- De Genst, Erwin, et al.
(author)
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Blocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure
- 2022
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In: Nature Communications. - Stockholm : Karolinska Institutet, Dept of Cell and Molecular Biology. - 2041-1723.
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Journal article (peer-reviewed)abstract
- The dysregulated physical interaction between two intracellular membrane proteins, the sarco/endoplasmic reticulum Ca2+ ATPase and its reversible inhibitor phospholamban, induces heart failure by inhibiting calcium cycling. While phospholamban is a bona-fide therapeutic target, approaches to selectively inhibit this protein remain elusive. Here, we report the in vivo application of intracellular acting antibodies (intrabodies), derived from the variable domain of camelid heavy-chain antibodies, to modulate the function of phospholamban. Using a synthetic VHH phage-display library, we identify intrabodies with high affinity and specificity for different conformational states of phospholamban. Rapid phenotypic screening, via modified mRNA transfection of primary cells and tissue, efficiently identifies the intrabody with most desirable features. Adeno-associated virus mediated delivery of this intrabody results in improvement of cardiac performance in a murine heart failure model. Our strategy for generating intrabodies to investigate cardiac disease combined with modified mRNA and adeno-associated virus screening could reveal unique future therapeutic opportunities.
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| 3. |
- Aaij, R., et al.
(author)
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Study of the doubly charmed tetraquark T-cc(+)
- 2022
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 13:1
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Journal article (peer-reviewed)abstract
- Quantum chromodynamics, the theory of the strong force, describes interactions of coloured quarks and gluons and the formation of hadronic matter. Conventional hadronic matter consists of baryons and mesons made of three quarks and quark-antiquark pairs, respectively. Particles with an alternative quark content are known as exotic states. Here a study is reported of an exotic narrow state in the (DD0)-D-0 pi(+) mass spectrum just below the D*+D-0 mass threshold produced in proton-proton collisions collected with the LHCb detector at the Large Hadron Collider. The state is consistent with the ground isoscalar T-cc(+), tetraquark with a quark content of cc (u) over bar(d) over bar and spin-parity quantum numbers J(P) =1(+). Study of the DD mass spectra disfavours interpretation of the resonance as the isovector state. The decay structure via intermediate off-shell D*(+) mesons is consistent with the observed D-0 pi(+) mass distribution. To analyse the mass of the resonance and its coupling to the DID system, a dedicated model is developed under the assumption of an isoscalar axial-vector T-cc(+), state decaying to the D*D channel. Using this model, resonance parameters including the pole position, scattering length, effective range and compositeness are determined to reveal important information about the nature of the T-cc(+), state. In addition, an unexpected dependence of the production rate on track multiplicity is observed.
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| 4. |
- Abdellah, Tebani, et al.
(author)
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Integration of molecular profiles in a longitudinal wellness profiling cohort.
- 2020
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies andimmune cell profiling, complementedwith gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
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| 5. |
- Adderley, Jack D., et al.
(author)
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Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention
- 2020
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- Intracellular pathogens mobilize host signaling pathways of their host cell to promote their own survival. Evidence is emerging that signal transduction elements are activated in a-nucleated erythrocytes in response to infection with malaria parasites, but the extent of this phenomenon remains unknown. Here, we fill this knowledge gap through a comprehensive and dynamic assessment of host erythrocyte signaling during infection with Plasmodium falciparum. We used arrays of 878 antibodies directed against human signaling proteins to interrogate the activation status of host erythrocyte phospho-signaling pathways at three blood stages of parasite asexual development. This analysis reveals a dynamic modulation of many host signalling proteins across parasite development. Here we focus on the hepatocyte growth factor receptor (c-MET) and the MAP kinase pathway component B-Raf, providing a proof of concept that human signaling kinases identified as activated by malaria infection represent attractive targets for antimalarial intervention.
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| 6. |
- Adhikari, Subash, et al.
(author)
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A high-stringency blueprint of the human proteome
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Research review (peer-reviewed)abstract
- The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP’s tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases.
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| 7. |
- Agirre, E, et al.
(author)
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Splicing-associated chromatin signatures: a combinatorial and position-dependent role for histone marks in splicing definition
- 2021
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 682-
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Journal article (peer-reviewed)abstract
- Alternative splicing relies on the combinatorial recruitment of splicing regulators to specific RNA binding sites. Chromatin has been shown to impact this recruitment. However, a limited number of histone marks have been studied at a global level. In this work, a machine learning approach, applied to extensive epigenomics datasets in human H1 embryonic stem cells and IMR90 foetal fibroblasts, has identified eleven chromatin modifications that differentially mark alternatively spliced exons depending on the level of exon inclusion. These marks act in a combinatorial and position-dependent way, creating characteristic splicing-associated chromatin signatures (SACS). In support of a functional role for SACS in coordinating splicing regulation, changes in the alternative splicing of SACS-marked exons between ten different cell lines correlate with changes in SACS enrichment levels and recruitment of the splicing regulators predicted by RNA motif search analysis. We propose the dynamic nature of chromatin modifications as a mechanism to rapidly fine-tune alternative splicing when necessary.
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| 8. |
- Aguirre-Gutierrez, Jesus, et al.
(author)
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Long-term droughts may drive drier tropical forests towards increased functional, taxonomic and phylogenetic homogeneity
- 2020
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- Tropical ecosystems adapted to high water availability may be highly impacted by climatic changes that increase soil and atmospheric moisture deficits. Many tropical regions are experiencing significant changes in climatic conditions, which may induce strong shifts in taxonomic, functional and phylogenetic diversity of forest communities. However, it remains unclear if and to what extent tropical forests are shifting in these facets of diversity along climatic gradients in response to climate change. Here, we show that changes in climate affected all three facets of diversity in West Africa in recent decades. Taxonomic and functional diversity increased in wetter forests but tended to decrease in forests with drier climate. Phylogenetic diversity showed a large decrease along a wet-dry climatic gradient. Notably, we find that all three facets of diversity tended to be higher in wetter forests. Drier forests showed functional, taxonomic and phylogenetic homogenization. Understanding how different facets of diversity respond to a changing environment across climatic gradients is essential for effective long-term conservation of tropical forest ecosystems. Different aspects of biodiversity may not necessarily converge in their response to climate change. Here, the authors investigate 25-year shifts in taxonomic, functional and phylogenetic diversity of tropical forests along a spatial climate gradient in West Africa, showing that drier forests are less stable than wetter forests.
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| 9. |
- Ah-King, Malin, 1973-
(author)
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The history of sexual selection research provides insights as to why females are still understudied
- 2022
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13
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Journal article (peer-reviewed)abstract
- While it is widely acknowledged that Darwin’s descriptions of females were gender-biased, gender bias in current sexual selection research is less recognized. An examination of the history of sexual selection research shows prevalent male precedence—that research starts with male-centered investigations or explanations and thereafter includes female-centered equivalents. In comparison, the incidence of female precedence is low. Furthermore, a comparison between the volume of publications focusing on sexual selection in males versus in females shows that the former far outnumber the latter. This bias is not only a historical pattern; sexual selection theory and research are still male-centered—due to conspicuous traits, practical obstacles, and continued gender bias. Even the way sexual selection is commonly defined contributes to this bias. This history provides an illustrative example by which we can learn to recognize biases and identify gaps in knowledge. I conclude with a call for the scientific community to interrogate its own biases and suggest strategies for alleviating biases in this field and beyond.
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| 10. |
- Ahlberg, Martina, et al.
(author)
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Freezing and thawing magnetic droplet solitons
- 2022
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Journal article (peer-reviewed)abstract
- Magnetic droplets are a type of non-topological magnetic soliton, which are stabilised and sustained by spin-transfer torques for instance. Without this, they would collapse. Here Ahlberg et al show that by decreasing the applied magnetic field, droplets can be frozen, forming a static nanobubble Magnetic droplets are non-topological magnetodynamical solitons displaying a wide range of complex dynamic phenomena with potential for microwave signal generation. Bubbles, on the other hand, are internally static cylindrical magnetic domains, stabilized by external fields and magnetostatic interactions. In its original theory, the droplet was described as an imminently collapsing bubble stabilized by spin transfer torque and, in its zero-frequency limit, as equivalent to a bubble. Without nanoscale lateral confinement, pinning, or an external applied field, such a nanobubble is unstable, and should collapse. Here, we show that we can freeze dynamic droplets into static nanobubbles by decreasing the magnetic field. While the bubble has virtually the same resistance as the droplet, all signs of low-frequency microwave noise disappear. The transition is fully reversible and the bubble can be thawed back into a droplet if the magnetic field is increased under current. Whereas the droplet collapses without a sustaining current, the bubble is highly stable and remains intact for days without external drive. Electrical measurements are complemented by direct observation using scanning transmission x-ray microscopy, which corroborates the analysis and confirms that the bubble is stabilized by pinning.
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