| 1. |
- Beverborg, Niels Grote, et al.
(författare)
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Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy
- 2021
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Ingår i: Nature Communications. - Stockholm : Karolinska Institutet, Dept of Cell and Molecular Biology. - 2041-1723.
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Blocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure
- 2022
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Ingår i: Nature Communications. - Stockholm : Karolinska Institutet, Dept of Cell and Molecular Biology. - 2041-1723.
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Tidskriftsartikel (refereegranskat)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. |
- Lundqvist, Mikael, et al.
(författare)
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Working memory control dynamics follow principles of spatial computing
- 2023
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Ingår i: Nature communications. - Stockholm : Karolinska Institutet, Dept of Clinical Neuroscience. - 2041-1723.
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Tidskriftsartikel (refereegranskat)abstract
- Working memory (WM) allows us to remember and selectively control a limited set of items. Neural evidence suggests it is achieved by interactions between bursts of beta and gamma oscillations. However, it is not clear how oscillations, reflecting coherent activity of millions of neurons, can selectively control individual WM items. Here we propose the novel concept of spatial computing where beta and gamma interactions cause item-specific activity to flow spatially across the network during a task. This way, control-related information such as item order is stored in the spatial activity independent of the detailed recurrent connectivity supporting the item-specific activity itself. The spatial flow is in turn reflected in low-dimensional activity shared by many neurons. We verify these predictions by analyzing local field potentials and neuronal spiking. We hypothesize that spatial computing can facilitate generalization and zero-shot learning by utilizing spatial component as an additional information encoding dimension.
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| 4. |
- Aaij, R., et al.
(författare)
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Study of the doubly charmed tetraquark T-cc(+)
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)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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| 5. |
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| 6. |
- Abbey-Lee, Robin, et al.
(författare)
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Adaptive individual variation in phenological responses to perceived predation levels
- 2019
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The adaptive evolution of timing of breeding (a component of phenology) in response to environmental change requires individual variation in phenotypic plasticity for selection to act upon. A major question is what processes generate this variation. Here we apply multi-year manipulations of perceived predation levels (PPL) in an avian predator-prey system, identifying phenotypic plasticity in phenology as a key component of alternative behavioral strategies with equal fitness payoffs. We show that under low-PPL, faster (versus slower) exploring birds breed late (versus early); the pattern is reversed under high-PPL, with breeding synchrony decreasing in conjunction. Timing of breeding affects reproductive success, yet behavioral types have equal fitness. The existence of alternative behavioral strategies thus explains variation in phenology and plasticity in reproductive behavior, which has implications for evolution in response to anthropogenic change.
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| 7. |
- Abdellah, Tebani, et al.
(författare)
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Integration of molecular profiles in a longitudinal wellness profiling cohort.
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)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 and immune cell profiling, complemented with 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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| 8. |
- Aben, Ralf C. H., et al.
(författare)
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Cross continental increase in methane ebullition under climate change
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Methane (CH4) strongly contributes to observed global warming. As natural CH4 emissions mainly originate from wet ecosystems, it is important to unravel how climate change may affect these emissions. This is especially true for ebullition (bubble flux from sediments), a pathway that has long been underestimated but generally dominates emissions. Here we show a remarkably strong relationship between CH4 ebullition and temperature across a wide range of freshwater ecosystems on different continents using multi-seasonal CH4 ebullition data from the literature. As these temperature-ebullition relationships may have been affected by seasonal variation in organic matter availability, we also conducted a controlled year-round mesocosm experiment. Here 4 degrees C warming led to 51% higher total annual CH4 ebullition, while diffusion was not affected. Our combined findings suggest that global warming will strongly enhance freshwater CH4 emissions through a disproportional increase in ebullition (6-20% per 1 degrees C increase), contributing to global warming.
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| 9. |
- Abrahamsson, Katarina, 1957, et al.
(författare)
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Organic bromine compounds produced in sea ice in Antarctic winter
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- During polar springtime, active bromine drives ozone, a greenhouse gas, to near-zero levels. Bromine production and emission in the polar regions have so far been assumed to require sunlight. Here, we report measurements of bromocarbons in sea ice, snow, and air during the Antarctic winter that reveal an unexpected new source of organic bromine to the atmosphere during periods of no sunlight. The results show that Antarctic winter sea ice provides 10 times more bromocarbons to the atmosphere than Southern Ocean waters, and substantially more than summer sea ice. The inclusion of these measurements in a global climate model indicates that the emitted bromocarbons will disperse throughout the troposphere in the southern hemisphere and through photochemical degradation to bromine atoms, contribute similar to 10% to the tropospheric reactive bromine budget. Combined together, our results suggest that winter sea ice could potentially be an important source of atmospheric bromine with implications for atmospheric chemistry and climate at a hemispheric scale.
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| 10. |
- Abreu-Vieira, Gustavo, et al.
(författare)
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Cidea improves the metabolic profile through expansion of adipose tissue
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- In humans, Cidea (cell death-inducing DNA fragmentation factor alpha-like effector A) is highly but variably expressed in white fat, and expression correlates with metabolic health. Here we generate transgenic mice expressing human Cidea in adipose tissues (aP2-hCidea mice) and show that Cidea is mechanistically associated with a robust increase in adipose tissue expandability. Under humanized conditions (thermoneutrality, mature age and prolonged exposure to high-fat diet), aP2-hCidea mice develop a much more pronounced obesity than their wild-type littermates. Remarkably, the malfunctioning of visceral fat normally caused by massive obesity is fully overcome-perilipin 1 and Akt expression are preserved, tissue degradation is prevented, macrophage accumulation is decreased and adiponectin expression remains high. Importantly, the aP2-hCidea mice display enhanced insulin sensitivity. Our data establish a functional role for Cidea and suggest that, in humans, the association between Cidea levels in white fat and metabolic health is not only correlative but also causative.
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