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| 4. |
- Olijnik, Aude-Anais, et al.
(författare)
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Genetic and functional insights into CDA-I prevalence and pathogenesis
- 2021
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Ingår i: Journal of Medical Genetics. - : BMJ Publishing Group Ltd. - 0022-2593 .- 1468-6244. ; 58:3, s. 185-195
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Tidskriftsartikel (refereegranskat)abstract
- Background Congenital dyserythropoietic anaemia type I (CDA-I) is a hereditary anaemia caused by biallelic mutations in the widely expressed genes CDAN1 and C15orf41. Little is understood about either protein and it is unclear in which cellular pathways they participate. Methods Genetic analysis of a cohort of patients with CDA-I identifies novel pathogenic variants in both known causative genes. We analyse the mutation distribution and the predicted structural positioning of amino acids affected in Codanin-1, the protein encoded by CDAN1. Using western blotting, immunoprecipitation and immunofluorescence, we determine the effect of particular mutations on both proteins and interrogate protein interaction, stability and subcellular localisation. Results We identify six novel CDAN1 mutations and one novel mutation in C15orf41 and uncover evidence of further genetic heterogeneity in CDA-I. Additionally, population genetics suggests that CDA-I is more common than currently predicted. Mutations are enriched in six clusters in Codanin-1 and tend to affect buried residues. Many missense and in-frame mutations do not destabilise the entire protein. Rather C15orf41 relies on Codanin-1 for stability and both proteins, which are enriched in the nucleolus, interact to form an obligate complex in cells. Conclusion Stability and interaction data suggest that C15orf41 may be the key determinant of CDA-I and offer insight into the mechanism underlying this disease. Both proteins share a common pathway likely to be present in a wide variety of cell types; however, nucleolar enrichment may provide a clue as to the erythroid specific nature of CDA-I. The surprisingly high predicted incidence of CDA-I suggests that better ascertainment would lead to improved patient care.
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| 6. |
- Jiang, S., et al.
(författare)
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Magnetic droplet soliton pairs
- 2024
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Ingår i: Nature Communications. - : Nature Research. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- We demonstrate magnetic droplet soliton pairs in all-perpendicular spin-torque nano-oscillators (STNOs), where one droplet resides in the STNO free layer (FL) and the other in the reference layer (RL). Typically, theoretical, numerical, and experimental droplet studies have focused on the FL, with any additional dynamics in the RL entirely ignored. Here we show that there is not only significant magnetodynamics in the RL, but the RL itself can host a droplet driven by, and coexisting with, the FL droplet. Both single droplets and pairs are observed experimentally as stepwise changes and sharp peaks in the dc and differential resistance, respectively. While the single FL droplet is highly stable, the coexistence state exhibits high-power broadband microwave noise. Furthermore, micromagnetic simulations reveal that the pair dynamics display periodic, quasi-periodic, and chaotic signatures controlled by applied field and current. The strongly interacting and closely spaced droplet pair offers a unique platform for fundamental studies of highly non-linear soliton pair dynamics.
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| 8. |
- Benmahi, B., et al.
(författare)
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Monitoring of the evolution of H2O vapor in the stratosphere of Jupiter over an 18-yr period with the Odin space telescope
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 641
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Tidskriftsartikel (refereegranskat)abstract
- Context. The comet Shoemaker-Levy 9 impacted Jupiter in July 1994, leaving its stratosphere with several new species, with water vapor (H2O) among them. Aims. With the aid of a photochemical model, H2O can be used as a dynamical tracer in the Jovian stratosphere. In this paper, we aim to constrain the vertical eddy diffusion (Kzz) at levels where H2O is present. Methods. We monitored the H2O disk-averaged emission at 556.936 GHz with the space telescope between 2002 and 2019, covering nearly two decades. We analyzed the data with a combination of 1D photochemical and radiative transfer models to constrain the vertical eddy diffusion in the stratosphere of Jupiter. Results. Odin observations show us that the emission of H2O has an almost linear decrease of about 40% between 2002 and 2019. We can only reproduce our time series if we increase the magnitude of Kzz in the pressure range where H2O diffuses downward from 2002 to 2019, that is, from ~0.2 mbar to ~5 mbar. However, this modified Kzz is incompatible with hydrocarbon observations. We find that even if an allowance is made for the initially large abundances of H2O and CO at the impact latitudes, the photochemical conversion of H2O to CO2 is not sufficient to explain the progressive decline of the H2O line emission, which is suggestive of additional loss mechanisms. Conclusions. The Kzz we derived from the Odin observations of H2O can only be viewed as an upper limit in the ~0.2 mbar to ~5 mbar pressure range. The incompatibility between the interpretations made from H2O and hydrocarbon observations probably results from 1D modeling limitations. Meridional variability of H2O, most probably at auroral latitudes, would need to be assessed and compared with that of hydrocarbons to quantify the role of auroral chemistry in the temporal evolution of the H2O abundance since the SL9 impacts. Modeling the temporal evolution of SL9 species with a 2D model would naturally be the next step in this area of study.
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| 9. |
- 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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| 13. |
- Frisk, G, et al.
(författare)
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Evaluation of Whole Brain Radiotherapy among Lung Cancer Patients with Brain Metastases in Relation to Health Care Level and Survival
- 2022
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Ingår i: Life (Basel, Switzerland). - : MDPI AG. - 2075-1729. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Whole-brain radiotherapy (WBRT) as a treatment for brain metastases has been questioned over the last years. This study aimed to evaluate health care levels and survival after WBRT in a cohort of lung cancer patients with brain metastases receiving WBRT in Stockholm, Sweden, from 2008 to 2019 (n = 384). If the patients were able to come home again was estimated using logistic regression and odds ratios (OR) and survival by using Cox regression. The median age in the cohort was 65.6 years, the median survival following WBRT was 2.4 months (interquartile range (IQR) 1.2–6.2 months), and 84 (22%) patients were not able to come home after treatment. Significantly more males could come home again after WBRT compared to women (OR = 0.37, 95%CI 0.20–0.68). Patients with performance status scores WHO 3–4 had a median survival of 1.0 months, hazard ratio (HR) = 4.69 (95%CI 3.31–6.64) versus WHO score 0–1. Patients admitted to a palliative ward before WBRT had a median survival of 0.85 months, HR = 2.26 (95%CI 1.53–3.34) versus being at home. In conclusion, patients treated with WBRT had a short median survival and 20% could not be discharged from the hospital following treatment. Significantly more women did not come home again.
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| 14. |
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| 15. |
- Frisk, H, et al.
(författare)
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Feasibility and Accuracy of Thoracolumbar Pedicle Screw Placement Using an Augmented Reality Head Mounted Device
- 2022
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Ingår i: Sensors (Basel, Switzerland). - : MDPI AG. - 1424-8220. ; 22:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: To investigate the accuracy of augmented reality (AR) navigation using the Magic Leap head mounted device (HMD), pedicle screws were minimally invasively placed in four spine phantoms. Methods: AR navigation provided by a combination of a conventional navigation system integrated with the Magic Leap head mounted device (AR-HMD) was used. Forty-eight screws were planned and inserted into Th11-L4 of the phantoms using the AR-HMD and navigated instruments. Postprocedural CT scans were used to grade the technical (deviation from the plan) and clinical (Gertzbein grade) accuracy of the screws. The time for each screw placement was recorded. Results: The mean deviation between navigation plan and screw position was 1.9 ± 0.7 mm (1.9 [0.3–4.1] mm) at the entry point and 1.4 ± 0.8 mm (1.2 [0.1–3.9] mm) at the screw tip. The angular deviation was 3.0 ± 1.4° (2.7 [0.4–6.2]°) and the mean time for screw placement was 130 ± 55 s (108 [58–437] s). The clinical accuracy was 94% according to the Gertzbein grading scale. Conclusion: The combination of an AR-HMD with a conventional navigation system for accurate minimally invasive screw placement is feasible and can exploit the benefits of AR in the perspective of the surgeon with the reliability of a conventional navigation system.
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| 18. |
- Kobayashi Frisk, Mio, et al.
(författare)
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Eveningness is associated with sedentary behavior and increased 10-year risk of cardiovascular disease: the SCAPIS pilot cohort
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Chronotype reflects individual preferences for timing activities throughout the day, determined by the circadian system, environment and behavior. The relationship between chronotype, physical activity, and cardiovascular health has not been established. We studied the association between chronotype, physical activity patterns, and an estimated 10-year risk of first-onset cardiovascular disease (CVD) in the Swedish CArdioPulmonary bioImage Study (SCAPIS) pilot cohort. A cross-sectional analysis was performed in a middle-aged population (n = 812, 48% male). Self-assessed chronotype was classified as extreme morning, moderate morning, intermediate, moderate evening, or extreme evening. Time spent sedentary (SED) and in moderate to vigorous physical activity (MVPA) were derived from hip accelerometer. The newly introduced Systematic COronary Risk Evaluation 2 (SCORE2) model was used to estimate CVD risk based on gender, age, smoking status, systolic blood pressure, and non-HDL cholesterol. Extreme evening chronotypes exhibited the most sedentary lifestyle and least MVPA (55.3 +/- 10.2 and 5.3 +/- 2.9% of wear-time, respectively), with a dose-dependent relationship between chronotype and SED/MVPA (p < 0.001 and p = 0.001, respectively). In a multivariate generalized linear regression model, extreme evening chronotype was associated with increased SCORE2 risk compared to extreme morning type independent of confounders (beta = 0.45, SE = 0.21, p = 0.031). Mediation analysis indicated SED was a significant mediator of the relationship between chronotype and SCORE2. Evening chronotype is associated with unhealthier physical activity patterns and poorer cardiovascular health compared to morning chronotype. Chronotype should be considered in lifestyle counseling and primary prevention programs as a potential modifiable risk factor.
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| 21. |
- Måseide, Ragnhild J., et al.
(författare)
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Health-related quality of life and physical activity in Nordic patients with moderate haemophilia A and B (the MoHem study)
- 2024
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Ingår i: Haemophilia. - 1351-8216. ; 30:1, s. 98-105
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The impact of moderate haemophilia on health-related quality of life (HRQoL) and physical activity (PA) is not well known. In previous studies, persons with factor VIII/factor IX activity (FVIII/FIX:C) below 3 IU/dL were associated with a more severe bleeding phenotype than predicted. Aim: To explore HRQoL and PA in patients with moderate haemophilia A (MHA) and B (MHB). Methods: A cross-sectional, multicentre study covering patients with MHA and MHB in Sweden, Finland, and Norway. HRQoL was assessed with the EuroQoL 5-Dimensions (EQ-5D) form and PA with the International Physical Activity Questionnaire among participants aged ≥15 years. Results: We report on 104 patients aged 15–84 years from the MoHem study. Overall, EQ-5D utility was.85 (median) (Q1–Q3 0.73–1.0) with corresponding visual analogue scale (VAS) 80 (70–90), which were similar regardless of treatment modality, FVIII/FIX:C, and MHA or MHB. Pain and mobility were most frequently affected dimensions. Utility (r = -.54), VAS (r = -.42), and PA (r = -.32) correlated negatively with arthropathy (HJHS). Only patients aged 41–50 years displayed lower utility (p =.02) and VAS (p <.01) than the Norwegian population norm. Patients on prophylaxis aged 35–54 years reported higher PA than those treated on-demand (p =.01). Conclusion: Haemophilic arthropathy had negative impact on HRQoL and PA in Nordic patients with moderate haemophilia. Middle-aged patients captured lower utility and VAS than observed in the general population. Tailored prophylaxis and improved joint health may influence positively on HRQoL and PA also in moderate haemophilia.
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| 22. |
- Måseide, Ragnhild J., et al.
(författare)
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Joint health and treatment modalities in Nordic patients with moderate haemophilia A and B – The MoHem study
- 2020
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 26:5, s. 891-897
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The prevalence of arthropathy in moderate haemophilia A (MHA) and B (MHB) is not well known. Aim: We evaluated joint health in Nordic patients in relation to their treatment modality. Methods: A cross-sectional, multicentre study covering MHA and MHB in Sweden, Finland and Norway. Arthropathy was evaluated by ultrasound (HEAD-US) and Haemophilia Joint Health Score (HJHS). Results: We report on 145 patients: median age 28 years (IQR 13-52) and 61% MHA. Baseline factor VIII/factor IX activity (FVIII/FIX:C) was 2 IU/dL (median) (IQR 2-4): lower for MHB (2 IU/dL, IQR 1-2) than MHA (3 IU/dL, IQR 2-4) (P <.01). Eighty-five per cent of MHA and 73% MHB had a history of haemarthrosis (P =.07). Age at first joint bleed was lower for MHA (5 years [median], IQR 3-7) than MHB (7 years, IQR 5-12) (P =.01). Thirty-eight per cent received prophylaxis, started at median 10 years of age (IQR 4-24). Median joint bleeds and serious other bleeds during the last 12 months were both zero (IQR 0-1). Total HEAD-US captured 0/48 points (median) (IQR 0-2) and HJHS 4/120 points (IQR 1-10) with strong correlation between them (r =.72). FVIII/FIX:C ≤ 3 IU/dL was associated with higher HJHS (P =.04). Fifteen per cent had undergone orthopaedic surgery. Conclusion: The current joint health in Nordic moderate haemophilia patients was rather good, but a subgroup had severe arthropathy. FVIII/FIX:C ≤ 3 IU/dL and MHA were associated with a more severe bleeding phenotype. We suggest primary prophylaxis to all patients with FVIII/FIX:C ≤ 3 IU/dL.
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| 23. |
- Olofsson, Karl, et al.
(författare)
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Single cell resolution analysis of ultrasound-produced multi-cellular tumor spheroids
- 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. 955-956
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Konferensbidrag (refereegranskat)abstract
- We have previously presented an ultrasonic standing wave (USW) 3D culture platform enabling parallel production, staining and processing of 100 uniformly sized multi-cellular tumor spheroids (MCTS) [1]. Here, we use the system for single cell resolution analysis of A498 renal carcinoma MCTS by off-chip fluorescence-activated cell sorting (FACS) and on-chip automatic image analysis methods based on 3D confocal microscopy images.
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| 24. |
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| 25. |
- Ponten, E, et al.
(författare)
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A complex DICER1 syndrome phenotype associated with a germline pathogenic variant affecting the RNase IIIa domain of DICER1
- 2022
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Ingår i: Journal of medical genetics. - : BMJ. - 1468-6244 .- 0022-2593. ; 59:2, s. 141-146
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Tidskriftsartikel (refereegranskat)abstract
- Germline pathogenic variants in DICER1 cause DICER1 syndrome, an autosomal dominant, pleiotropic tumour predisposition syndrome with variable expressivity and reduced penetrance for specific dysplastic and neoplastic lesions. Recently, a syndrome with the acronym GLOW (Global developmental delay, Lung cysts, Overgrowth, Wilms tumour) was described in two children with mosaic missense mutations in hotspot residues of the DICER1 RNase IIIb domain.MethodsWhole genome sequencing, exome sequencing, Sanger sequencing, digital PCR and a review of Wilms tumours with DICER1 RNase III domain mutations were performed.ResultsA de novo heterozygous c.4031C>T (p.S1344L) variant in the sequence encoding the RNase IIIa domain of DICER1 was detected. Clinical investigations revealed a phenotype that resembles the GLOW subphenotype of DICER1 syndrome.ConclusionThe phenotypic overlap between patients with p.S1344L mutation and GLOW syndrome provide clinical support for recent discoveries that RNase IIIa-Ser1344 site mutations impede miRNA-5p biogenesis analogous to DICER1 hotspot mutations in the RNase IIIb domain. We show that an individual with a heterozygous germline p.S1344L mutation has a severe form of DICER1 syndrome (‘DICER1 syndrome plus’), with notable features of intellectual disability, macrocephaly, physical abnormalities, Wilms tumour and a well-differentiated fetal adenocarcinoma of the lung.
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| 26. |
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| 27. |
- Rodriguez-Wallberg, Kenny A., et al.
(författare)
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ProFertil study protocol for the investigation of gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy aiming at fertility protection of young women and teenagers with cancer in Sweden : a phase III randomised double-blinded placebo-controlled study
- 2023
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 13:12
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Tidskriftsartikel (refereegranskat)abstract
- Background Gonadotropin-releasing hormone agonists (GnRHa) cotreatment used to transiently suppress ovarian function during chemotherapy to prevent ovarian damage and preserve female fertility is used globally but efficacy is debated. Most clinical studies investigating a beneficial effect of GnRHa cotreatment on ovarian function have been small, retrospective and uncontrolled. Unblinded randomised studies on women with breast cancer have suggested a beneficial effect, but results are mixed with lack of evidence of improvement in markers of ovarian reserve. Unblinded randomised studies of women with lymphoma have not shown any benefit regarding fertility markers after long-term follow-up and no placebo-controlled study has been conducted so far. The aim of this study is to investigate if administration of GnRHa during cancer treatment can preserve fertility in young female cancer patients in a double-blind, placebo-controlled clinical trial.Methods and analysis A prospective, randomised, double-blinded, placebo-controlled, phase III study including 300 subjects with breast cancer. In addition, 200 subjects with lymphoma, acute leukemias and sarcomas will be recruited. Women aged 14–42 will be randomised 1:1 to treatment with GnRHa (triptorelin) or placebo for the duration of their gonadotoxic chemotherapy. Follow-up until 5 years from end of treatment (EoT). The primary endpoint will be change in anti-Müllerian hormone (AMH) recovery at follow-up 12 months after EoT, relative to AMH levels at EoT, comparing the GnRHa group and the placebo group in women with breast cancer.Ethics and dissemination This study is designed in accordance with the principles of Good Clinical Practice (ICH-GCP E6 (R2)), local regulations (ie, European Directive 2001/20/EC) and the ethical principles of the Declaration of Helsinki. Within 6 months of study completion, the results will be analysed and the study results shall be reported in the EudraCT database.Study registration The National Institutional review board in Sweden dnr:2021–03379, approval date 12 October 2021 (approved amendments 12 June 2022, dnr:2022-02924-02 and 13 December 2022, dnr:2022-05565-02). The Swedish Medical Product Agency 19 January 2022, Dnr:5.1-2021-98927 (approved amendment 4 February 2022). Manufacturing authorisation for authorised medicinal products approved 6 December 2021, Dnr:6.2.1-2020-079580. Stockholm Medical Biobank approved 22 June 2022, RBC dnr:202 253.Trial registration number NCT05328258; EudraCT number:2020-004780-71.
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| 28. |
- Vadiraj, A. M., et al.
(författare)
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Engineering the level structure of a giant artificial atom in waveguide quantum electrodynamics
- 2021
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Ingår i: Physical Review A. - 2469-9934 .- 2469-9926. ; 103:2
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Tidskriftsartikel (refereegranskat)abstract
- Engineering light-matter interactions at the quantum level has been central to the pursuit of quantum optics for decades. Traditionally, this has been done by coupling emitters, typically natural atoms and ions, to quantized electromagnetic fields in optical and microwave cavities. In these systems, the emitter is approximated as an idealized dipole, as its physical size is orders of magnitude smaller than the wavelength of light. Recently, artificial atoms made from superconducting circuits have enabled new frontiers in light-matter coupling, including the study of "giant" atoms which cannot be approximated as simple dipoles. Here, we explore an implementation of a giant artificial atom, formed from a transmon qubit coupled to propagating microwaves at multiple points along an open transmission line. The nature of this coupling allows the qubit radiation field to interfere with itself, leading to some striking giant-atom effects. For instance, we observe strong frequency-dependent couplings of the qubit energy levels to the electromagnetic modes of the transmission line. Combined with the ability to in situ tune the qubit energy levels, we show that we can modify the relative coupling rates of multiple qubit transitions by more than an order of magnitude. By doing so, we engineer a metastable excited state, allowing us to operate the giant transmon as an effective lambda system where we clearly demonstrate electromagnetically induced transparency.
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| 31. |
- Zheng, Yu, 1992, et al.
(författare)
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Gaussian conversion protocol for heralded generation of generalized Gottesman-Kitaev-Preskill states
- 2023
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Ingår i: Physical Review A. - 2469-9934 .- 2469-9926. ; 108:1
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Tidskriftsartikel (refereegranskat)abstract
- In the field of fault-tolerant quantum computing, continuous-variable systems can be utilized to protect quantum information from noise through the use of bosonic codes. These codes map qubit-type quantum information onto the larger bosonic Hilbert space, and can be divided into two main categories: translational-symmetric codes, such as Gottesman-Kitaev-Preskill (GKP) codes, and rotational-symmetric codes, including cat and binomial codes. The relationship between these families of codes has not yet been fully understood. We present an iterative protocol for converting between two instances of these codes - generalized GKP (so-called qunaught) states and fourfold-symmetric binomial states corresponding to a zero-logical encoded qubit - using only Gaussian operations. This conversion demonstrates the potential for universality of binomial states for all-Gaussian quantum computation and provides a method for the heralded preparation of GKP states. Through numerical simulation, we obtain GKP qunaught states with a fidelity of over 98% and a probability of approximately 3.14%, after only two steps of our iterative protocol, though higher fidelities can be achieved with additional iterations at the cost of lower success probabilities.
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