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- Morales, J. C., et al.
(författare)
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A giant exoplanet orbiting a very-low-mass star challenges planet formation models
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 365:6460, s. 1441-1445
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Tidskriftsartikel (refereegranskat)abstract
- Surveys have shown that super-Earth and Neptune-mass exoplanets are more frequent than gas giants around low-mass stars, as predicted by the core accretion theory of planet formation. We report the discovery of a giant planet around the very-low-mass star GJ 3512, as determined by optical and near-infrared radial-velocity observations. The planet has a minimum mass of 0.46 Jupiter masses, very high for such a small host star, and an eccentric 204-day orbit. Dynamical models show that the high eccentricity is most likely due to planet-planet interactions. We use simulations to demonstrate that the GJ 3512 planetary system challenges generally accepted formation theories, and that it puts constraints on the planet accretion and migration rates. Disk instabilities may be more efficient in forming planets than previously thought.
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- Butler-Laporte, G, et al.
(författare)
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Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
- 2022
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 18:11, s. e1010367-
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Tidskriftsartikel (refereegranskat)abstract
- Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
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- Shiri, I, et al.
(författare)
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High-dimensional multinomial multiclass severity scoring of COVID-19 pneumonia using CT radiomics features and machine learning algorithms
- 2022
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1, s. 14817-
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to construct a prediction model based on computed tomography (CT) radiomics features to classify COVID-19 patients into severe-, moderate-, mild-, and non-pneumonic. A total of 1110 patients were studied from a publicly available dataset with 4-class severity scoring performed by a radiologist (based on CT images and clinical features). The entire lungs were segmented and followed by resizing, bin discretization and radiomic features extraction. We utilized two feature selection algorithms, namely bagging random forest (BRF) and multivariate adaptive regression splines (MARS), each coupled to a classifier, namely multinomial logistic regression (MLR), to construct multiclass classification models. The dataset was divided into 50% (555 samples), 20% (223 samples), and 30% (332 samples) for training, validation, and untouched test datasets, respectively. Subsequently, nested cross-validation was performed on train/validation to select the features and tune the models. All predictive power indices were reported based on the testing set. The performance of multi-class models was assessed using precision, recall, F1-score, and accuracy based on the 4 × 4 confusion matrices. In addition, the areas under the receiver operating characteristic curves (AUCs) for multi-class classifications were calculated and compared for both models. Using BRF, 23 radiomic features were selected, 11 from first-order, 9 from GLCM, 1 GLRLM, 1 from GLDM, and 1 from shape. Ten features were selected using the MARS algorithm, namely 3 from first-order, 1 from GLDM, 1 from GLRLM, 1 from GLSZM, 1 from shape, and 3 from GLCM features. The mean absolute deviation, skewness, and variance from first-order and flatness from shape, and cluster prominence from GLCM features and Gray Level Non Uniformity Normalize from GLRLM were selected by both BRF and MARS algorithms. All selected features by BRF or MARS were significantly associated with four-class outcomes as assessed within MLR (All p values < 0.05). BRF + MLR and MARS + MLR resulted in pseudo-R2 prediction performances of 0.305 and 0.253, respectively. Meanwhile, there was a significant difference between the feature selection models when using a likelihood ratio test (p value = 0.046). Based on confusion matrices for BRF + MLR and MARS + MLR algorithms, the precision was 0.856 and 0.728, the recall was 0.852 and 0.722, whereas the accuracy was 0.921 and 0.861, respectively. AUCs (95% CI) for multi-class classification were 0.846 (0.805–0.887) and 0.807 (0.752–0.861) for BRF + MLR and MARS + MLR algorithms, respectively. Our models based on the utilization of radiomic features, coupled with machine learning were able to accurately classify patients according to the severity of pneumonia, thus highlighting the potential of this emerging paradigm in the prognostication and management of COVID-19 patients.
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- Arabi, Azadeh, et al.
(författare)
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Accumulation of c-Myc and proteasomes at the nucleoli of cells containing elevated c-Myc protein levels
- 2003
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Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 116:9, s. 1707-1717
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Tidskriftsartikel (refereegranskat)abstract
- c-Myc is a predominately nuclear transcription factor that is a substrate for rapid turnover by the proteasome system. Cancer-related mutations in c-Myc lead to defects in its degradation and thereby contribute to the increase in its cellular level that is associated with the disease. Little is known about the mechanisms that target c-Myc to the proteasomes. By using a GFP fusion protein and live analysis we show that c-Myc shuttles between the nucleus and cytoplasm and thus it could be degraded in either compartment. Strikingly, at elevated levels of expression c-Myc accumulates at nucleoli in some cells, consistent with saturation of a nucleolus-associated degradation system in these cells. This idea is further supported by the observation that proteasome inhibitor treatment causes accumulation of c-Myc at the nucleoli of essentially all cells. Under these conditions c-Myc is relatively stably associated with the nucleolus, as would be expected if the nucleolus functions as a sequestration/degradation site for excess c-Myc. Furthermore, during elevated c-Myc expression or proteasome inhibition, nucleoli that are associated with c-Myc also accumulate proteasomes. c-Myc and proteasomes co-localise in intranucleolar regions distinct from the dense fibrillar component of the nucleolus. Based on these results we propose a model for c-Myc downregulation where c-Myc is sequestered at the nucleoli. Sequestration of c-Myc is accompanied by recruitment of proteasomes and may lead to subsequent degradation.
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- Axfors, Cathrine, et al.
(författare)
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Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
- 2021
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I-2=0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I-2=0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities. Hydroxychloroquine and chloroquine have been investigated as a potential treatment for Covid-19 in several clinical trials. Here the authors report a meta-analysis of published and unpublished trials, and show that treatment with hydroxychloroquine for patients with Covid-19 was associated with increased mortality, and there was no benefit from chloroquine.
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- Shiue, Chiou-Nan, et al.
(författare)
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Nucleolar organization, growth control and cancer
- 2010
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Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 5:3, s. 200-205
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Tidskriftsartikel (refereegranskat)abstract
- The nucleolus is a dynamic region of the nucleus that is disassembled and reformed each cell cycle and whose size is correlated with cell growth rate. Nucleolar size is a prognostic measure of cancer disease severity and increasing evidence suggests a causative role of nucleolar lesions in many cancers. In recent work (Shiue et al. Oncogene 28, 1833-42, 2009) we showed that the c-Myc oncoprotein induces changes in the higher order structure of rDNA chromatin in the nucleolus of growth stimulated quiescent rat cells. Here we show that c-Myc induces similar changes in human cells, that c-Myc plays a role in the overall structural integrity of the nucleolus and that c-Myc and its antagonistic partner Mad1 interact to program the epigenetic status of rDNA chromatin. These changes are discussed in relation to current knowledge about nucleolar structure as well as the organization of chromosomes and transcription factories in nuclear regions outside the nucleolus.
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