| 1. |
- Almet, Axel A., et al.
(author)
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A Roadmap for a Consensus Human Skin Cell Atlas and Single-Cell Data Standardization
- 2023
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In: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 143:9, s. 1667-1677
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Research review (peer-reviewed)abstract
- Single-cell technologies have become essential to driving discovery in both basic and translational investigative dermatology. Despite the multitude of available datasets, a central reference atlas of normal human skin, which can serve as a reference resource for skin cell types, cell states, and their molecular signatures, is still lacking. For any such atlas to receive broad acceptance, participation by many investigators during atlas construction is an essential prerequisite. As part of the Human Cell Atlas project, we have assembled a Skin Biological Network to build a consensus Human Skin Cell Atlas and outline a roadmap toward that goal. We define the drivers of skin diversity to be considered when selecting sequencing datasets for the atlas and list practical hurdles during skin sampling that can result in data gaps and impede comprehensive representation and technical considerations for tissue processing and computational analysis, the accounting for which should minimize biases in cell type enrichments and exclusions and decrease batch effects. By outlining our goals for Atlas 1.0, we discuss how it will uncover new aspects of skin biology.
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| 4. |
- Dore, Riccardo, et al.
(author)
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Resistance to thyroid hormone induced tachycardia in RTHα syndrome
- 2023
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In: Nature Communications. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- Mutations in thyroid hormone receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart. Surprisingly, we report that treatment of RTHα patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TRα1 mutant, mice indicates that such persistent bradycardia is caused by an intrinsic cardiac defect and not due to altered autonomic control. Transcriptomic analyses show preserved, thyroid hormone (T3)-dependent upregulation of pacemaker channels (Hcn2, Hcn4), but irreversibly reduced expression of several ion channel genes controlling heart rate. Exposure of TRα1 mutant male mice to higher maternal T3 concentrations in utero, restores altered expression and DNA methylation of ion channels, including Ryr2. Our findings indicate that target genes other than Hcn2 and Hcn4 mediate T3-induced tachycardia and suggest that treatment of RTHα patients with thyroxine in high dosage without concomitant tachycardia, is possible.
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| 6. |
- Garcia-Closas, Montserrat, et al.
(author)
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Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics
- 2008
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In: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 4:4, s. e1000054-
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Journal article (peer-reviewed)abstract
- A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.
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| 7. |
- Jones, Geraint H., et al.
(author)
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The Comet Interceptor Mission
- 2024
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In: Space Science Reviews. - : Springer Nature. - 0038-6308 .- 1572-9672. ; 220:1
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Journal article (peer-reviewed)abstract
- Here we describe the novel, multi-point Comet Interceptor mission. It is dedicated to the exploration of a little-processed long-period comet, possibly entering the inner Solar System for the first time, or to encounter an interstellar object originating at another star. The objectives of the mission are to address the following questions: What are the surface composition, shape, morphology, and structure of the target object? What is the composition of the gas and dust in the coma, its connection to the nucleus, and the nature of its interaction with the solar wind? The mission was proposed to the European Space Agency in 2018, and formally adopted by the agency in June 2022, for launch in 2029 together with the Ariel mission. Comet Interceptor will take advantage of the opportunity presented by ESA’s F-Class call for fast, flexible, low-cost missions to which it was proposed. The call required a launch to a halo orbit around the Sun-Earth L2 point. The mission can take advantage of this placement to wait for the discovery of a suitable comet reachable with its minimum Δ V capability of 600 ms − 1 . Comet Interceptor will be unique in encountering and studying, at a nominal closest approach distance of 1000 km, a comet that represents a near-pristine sample of material from the formation of the Solar System. It will also add a capability that no previous cometary mission has had, which is to deploy two sub-probes – B1, provided by the Japanese space agency, JAXA, and B2 – that will follow different trajectories through the coma. While the main probe passes at a nominal 1000 km distance, probes B1 and B2 will follow different chords through the coma at distances of 850 km and 400 km, respectively. The result will be unique, simultaneous, spatially resolved information of the 3-dimensional properties of the target comet and its interaction with the space environment. We present the mission’s science background leading to these objectives, as well as an overview of the scientific instruments, mission design, and schedule.
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| 8. |
- Koller, Julian Phillip Johann, et al.
(author)
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Fuel-Efficient Control of Merging Maneuvers for Heavy-Duty Vehicle Platooning
- 2015
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In: IEEE Conference on Intelligent Transportation Systems, Proceedings, ITSC. - : IEEE conference proceedings. - 9781467365956 - 9781467365956 - 9781467365956 - 9781467365956 ; , s. 1702-1707
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Conference paper (peer-reviewed)abstract
- The formation of groups of closely-spaced heavy-duty vehicles, known as platoons, reduces the overall aerodynamic drag and therefore leads to reduced fuel consumption and reduced greenhouse gas emissions. This paper focuses on the optimal control of merging maneuvers for the formation of a growing platoon. Hereto, the merging problem is formulated as a hybrid optimal control problem and an algorithm for the computation of optimal merging times and corresponding optimal vehicle trajectories is developed by exploiting an extension of Pontryagin's maximum principle. Moreover, a model predictive control approach on the basis of this algorithm is presented that makes the merging maneuvers robust to modelling uncertainties and external disturbances. The results are illustrated by evaluating a scenario involving three vehicles, which indicates fuel savings of up to 13% with respect to the vehicles driving alone.
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| 10. |
- Mauritsen, Thorsten, et al.
(author)
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Developments in the MPI-M Earth System Model version 1.2 (MPI-ESM1.2) and Its Response to Increasing CO2
- 2019
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In: Journal of Advances in Modeling Earth Systems. - 1942-2466. ; 11:4, s. 998-1038
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Journal article (peer-reviewed)abstract
- A new release of the Max Planck Institute for Meteorology Earth System Model version 1.2 (MPI-ESM1.2) is presented. The development focused on correcting errors in and improving the physical processes representation, as well as improving the computational performance, versatility, and overall user friendliness. In addition to new radiation and aerosol parameterizations of the atmosphere, several relatively large, but partly compensating, coding errors in the model's cloud, convection, and turbulence parameterizations were corrected. The representation of land processes was refined by introducing a multilayer soil hydrology scheme, extending the land biogeochemistry to include the nitrogen cycle, replacing the soil and litter decomposition model and improving the representation of wildfires. The ocean biogeochemistry now represents cyanobacteria prognostically in order to capture the response of nitrogen fixation to changing climate conditions and further includes improved detritus settling and numerous other refinements. As something new, in addition to limiting drift and minimizing certain biases, the instrumental record warming was explicitly taken into account during the tuning process. To this end, a very high climate sensitivity of around 7 K caused by low-level clouds in the tropics as found in an intermediate model version was addressed, as it was not deemed possible to match observed warming otherwise. As a result, the model has a climate sensitivity to a doubling of CO2 over preindustrial conditions of 2.77 K, maintaining the previously identified highly nonlinear global mean response to increasing CO2 forcing, which nonetheless can be represented by a simple two-layer model.
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| 11. |
- Schnitzbauer, Andreas A, et al.
(author)
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A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma.
- 2010
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In: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 10
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Journal article (peer-reviewed)abstract
- The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.
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| 12. |
- Scutelnic, Adrian, et al.
(author)
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Management of Cerebral Venous Thrombosis Due to Adenoviral COVID-19 Vaccination.
- 2022
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In: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 92:4, s. 562-573
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Journal article (peer-reviewed)abstract
- Cerebral venous thrombosis (CVT) caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus-based severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality.We used data from an international prospective registry of patients with CVT after the adenovirus-based SARS-CoV-2 vaccination. We analyzed possible, probable, or definite VITT-CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis.Ninety-nine patients with VITT-CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in-line with VITT recommendations (p<0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR]=0.43, 95% confidence interval [CI]=0.16-1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR=0.19, 95% CI=0.06-0.58). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR=0.70, 95% CI=0.24-2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR=2.19, 95% CI=0.74-6.54).In patients with VITT-CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT-CVT. ANN NEUROL 2022;92:562-573.
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| 14. |
- Van De Munckhof, Anita, et al.
(author)
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Outcomes of cerebral venous thrombosis due to vaccine-induced immune thrombotic thrombocytopenia after the acute phase
- 2022
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In: Stroke. - : American Heart Association. - 0039-2499 .- 1524-4628. ; 53:10, s. 3206-3210
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Journal article (peer-reviewed)abstract
- Background: Cerebral venous thrombosis (CVT) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe condition, with high in-hospital mortality rates. Here, we report clinical outcomes of patients with CVT-VITT after SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) vaccination who survived initial hospitalization.Methods: We used data from an international registry of patients who developed CVT within 28 days of SARS-CoV-2 vaccination, collected until February 10, 2022. VITT diagnosis was classified based on the Pavord criteria. Outcomes were mortality, functional independence (modified Rankin Scale score 0-2), VITT relapse, new thrombosis, and bleeding events (all after discharge from initial hospitalization).Results: Of 107 CVT-VITT cases, 43 (40%) died during initial hospitalization. Of the remaining 64 patients, follow-up data were available for 60 (94%) patients (37 definite VITT, 9 probable VITT, and 14 possible VITT). Median age was 40 years and 45/60 (75%) patients were women. Median follow-up time was 150 days (interquartile range, 94-194). Two patients died during follow-up (3% [95% CI, 1%-11%). Functional independence was achieved by 53/60 (88% [95% CI, 78%-94%]) patients. No new venous or arterial thrombotic events were reported. One patient developed a major bleeding during follow-up (fatal intracerebral bleed).Conclusions: In contrast to the high mortality of CVT-VITT in the acute phase, mortality among patients who survived the initial hospitalization was low, new thrombotic events did not occur, and bleeding events were rare. Approximately 9 out of 10 CVT-VITT patients who survived the acute phase were functionally independent at follow-up.
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