| 1. |
- Muus, Christoph, et al.
(author)
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Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics
- 2021
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:3, s. 546-559
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Journal article (peer-reviewed)abstract
- Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2(+)TMPRSS2(+) cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention. An integrated analysis of over 100 single-cell and single-nucleus transcriptomics studies illustrates severe acute respiratory syndrome coronavirus 2 viral entry gene coexpression patterns across different human tissues, and shows association of age, smoking status and sex with viral entry gene expression in respiratory cell populations.
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| 2. |
- Sikkema, Lisa, et al.
(author)
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An integrated cell atlas of the lung in health and disease
- 2023
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In: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 29:6, s. 1563-1577
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Journal article (peer-reviewed)abstract
- Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1 + profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.
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| 3. |
- Hendi, Arun S., et al.
(author)
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The implications of changing education distributions for life expectancy gradients
- 2021
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In: Social Science and Medicine. - : Elsevier BV. - 0277-9536 .- 1873-5347. ; 272
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Journal article (peer-reviewed)abstract
- Recent research has proposed that shifting education distributions across cohorts are influencing estimates of educational gradients in mortality. We use data from the United States and Finland covering four decades to explore this assertion. We base our analysis around our new finding: a negative logarithmic relationship between relative education and relative mortality. This relationship holds across multiple age groups, both sexes, two very different countries, and time periods spanning four decades. The inequality parameters from this model indicate increasing relative mortality differentials over time. We use these findings to develop a method that allows us to compute life expectancy for any given segment of the education distribution (e.g., education quintiles). We apply this method to Finnish and American data to compute life expectancy gradients that are adjusted for changes in the education distribution. In Finland, these distribution-adjusted education differentials in life expectancy between the top and bottom education quintiles have increased by two years for men, and remained stable for women between 1971 and 2010. Similar distribution-adjusted estimates for the U.S. suggest that educational disparities in life expectancy increased by 3.3 years for non-Hispanic white men and 3.0 years for non-Hispanic white women between the 1980s and 2000s. For men and women, respectively, these differentials between the top and bottom education quintiles are smaller than the differentials between the top and bottom education categories by 18% and 39% in the U.S. and by 39% and 100% in Finland. Had the relative inequality parameters of mortality governing the Finnish and U.S. populations remained constant at their earliest period values, the difference in life expectancy between the top and bottom education quintiles would – because of overall mortality reductions – have declined moderately. The findings suggest that educational expansion may bias estimates of trends in educational differences in life expectancy upwards.
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| 4. |
- Huhtaniemi, R., et al.
(author)
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High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice
- 2022
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In: iScience. - : Elsevier BV. - 2589-0042. ; 25:5
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Journal article (peer-reviewed)abstract
- Antiandrogen treatment resistance is a major clinical concern in castration-resistant prostate cancer (CRPC) treatment. Using xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors. Furthermore, the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration. Reactivation of androgen signaling in enzalutamide-resistant tumors was further shown by the expression of several androgen-dependent genes. The data indicate that intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance and an indication of the need for further androgen blockade. The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone.
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| 5. |
- Mehmood, Arfa, et al.
(author)
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Systematic evaluation of differential splicing tools for RNA-seq studies
- 2020
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In: Briefings in Bioinformatics. - : Oxford University Press. - 1467-5463 .- 1477-4054. ; 21:6, s. 2052-2065
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Journal article (peer-reviewed)abstract
- Differential splicing (DS) is a post-transcriptional biological process with critical, wide-ranging effects on a plethora of cellular activities and disease processes. To date, a number of computational approaches have been developed to identify and quantify differentially spliced genes from RNA-seq data, but a comprehensive intercomparison and appraisal of these approaches is currently lacking. In this study, we systematically evaluated 10 DS analysis tools for consistency and reproducibility, precision, recall and false discovery rate, agreement upon reported differentially spliced genes and functional enrichment. The tools were selected to represent the three different methodological categories: exon-based (DEXSeq, edgeR, JunctionSeq, limma), isoform-based (cuffdiff2, DiffSplice) and event-based methods (dSpliceType, MAJIQ, rMATS, SUPPA). Overall, all the exon-based methods and two event-based methods (MAJIQ and rMATS) scored well on the selected measures. Of the 10 tools tested, the exon-based methods performed generally better than the isoform-based and event-based methods. However, overall, the different data analysis tools performed strikingly differently across different data sets or numbers of samples.
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| 6. |
- Ruohonen, S. T., et al.
(author)
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Selective loss of kisspeptin signaling in oocytes causes progressive premature ovulatory failure
- 2022
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In: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 37:4, s. 806-821
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Journal article (peer-reviewed)abstract
- STUDY QUESTION Does direct kisspeptin signaling in the oocyte have a role in the control of follicular dynamics and ovulation? SUMMARY ANSWER Kisspeptin signaling in the oocyte plays a relevant physiological role in the direct control of ovulation; oocyte-specific ablation of kisspeptin receptor, Gpr54, induces a state of premature ovulatory failure in mice that recapitulates some features of premature ovarian insufficiency (POI). WHAT IS KNOWN ALREADY Kisspeptins, encoded by the Kiss1 gene, are essential for the control of ovulation and fertility, acting primarily on hypothalamic GnRH neurons to stimulate gonadotropin secretion. However, kisspeptins and their receptor, Gpr54, are also expressed in the ovary of different mammalian species, including humans, where their physiological roles remain contentious and poorly characterized. STUDY DESIGN, SIZE, DURATION A novel mouse line with conditional ablation of Gpr54 in oocytes, named OoGpr54(-/-), was generated and studied in terms of follicular and ovulatory dynamics at different age-points of postnatal maturation. A total of 59 OoGpr54(-/-) mice and 47 corresponding controls were analyzed. In addition, direct RNA sequencing was applied to ovarian samples from 8 OoGpr54(-/-) and 7 control mice at 6 months of age, and gonadotropin priming for ovulatory induction was conducted in mice (N = 7) from both genotypes. PARTICIPANTS/MATERIALS, SETTING, METHODS Oocyte-selective ablation of Gpr54 in the oocyte was achieved in vivo by crossing a Gdf9-driven Cre-expressing transgenic mouse line with a Gpr54 LoxP mouse line. The resulting OoGpr54(-/-) mouse line was subjected to phenotypic, histological, hormonal and molecular analyses at different age-points of postnatal maturation (Day 45, and 2, 4, 6 and 10-11 months of age), in order to characterize the timing of puberty, ovarian follicular dynamics and ovulation, with particular attention to identification of features reminiscent of POI. The molecular signature of ovaries from OoGpr54(-/-) mice was defined by direct RNA sequencing. Ovulatory responses to gonadotropin priming were also assessed in OoGpr54(-/-) mice. MAIN RESULTS AND THE ROLE OF CHANCE Oocyte-specific ablation of Gpr54 caused premature ovulatory failure, with some POI-like features. OoGpr54(-/-) mice had preserved puberty onset, without signs of hypogonadism. However, already at 2 months of age, 40% of OoGpr54(-/-) females showed histological features reminiscent of ovarian failure and anovulation. Penetrance of the phenotype progressed with age, with >80% and 100% of OoGpr54(-/-) females displaying complete ovulatory failure by 6- and 10 months, respectively. This occurred despite unaltered hypothalamic Gpr54 expression and gonadotropin levels. Yet, OoGpr54(-/-) mice had decreased sex steroid levels. While the RNA signature of OoGpr54(-/-) ovaries was dominated by the anovulatory state, oocyte-specific ablation of Gpr54 significantly up- or downregulated of a set of 21 genes, including those encoding pituitary adenylate cyclase-activating polypeptide, Wnt-10B, matrix-metalloprotease-12, vitamin A-related factors and calcium-activated chloride channel-2, which might contribute to the POI-like state. Notably, the anovulatory state of young OoGpr54(-/-) mice could be rescued by gonadotropin priming. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Conditional ablation of Gpr54 in oocytes unambiguously caused premature ovulatory failure in mice; yet, the ultimate molecular mechanisms for such state of POI can be only inferred on the basis of RNAseq data and need further elucidation, since some of the molecular changes observed in OoGpr54(-/-) ovaries were secondary to the anovulatory state. Direct translation of mouse findings to human disease should be made with caution since, despite the conserved expression of Kiss1/kisspeptin and Gpr54 in rodents and humans, our mouse model does not recapitulate all features of common forms of POI. WIDER IMPLICATIONS OF THE FINDINGS Deregulation of kisspeptin signaling in the oocyte might be an underlying, and previously unnoticed, cause for some forms of POI in women. STUDY FUNDING/COMPETING INTEREST(S) This work was primarily supported by a grant to M.P. and M.T.-S. from the FiDiPro (Finnish Distinguished Professor) Program of the Academy of Finland. Additional financial support came from grant BFU2017-83934-P (M.T.-S.; Ministerio de Economia y Competitividad, Spain; co-funded with EU funds/FEDER Program), research funds from the IVIRMA International Award in Reproductive Medicine (M.T.-S.), and EFSD Albert Renold Fellowship Programme (S.T.R.). The authors have no conflicts of interest to declare in relation to the contents of this work.
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