| 1. |
- Muus, Christoph, et al.
(författare)
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Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:3, s. 546-559
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Tidskriftsartikel (refereegranskat)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.
(författare)
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An integrated cell atlas of the lung in health and disease
- 2023
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Ingår i: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 29:6, s. 1563-1577
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Tidskriftsartikel (refereegranskat)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. |
- Knuuttila, M., et al.
(författare)
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Intratumoral androgen levels are linked to TMPRSS2-ERG fusion in prostate cancer
- 2018
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Ingår i: Endocrine-Related Cancer. - : Bioscientifica. - 1351-0088 .- 1479-6821. ; 25:9, s. 807-819
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Tidskriftsartikel (refereegranskat)abstract
- Intratumoral androgen biosynthesis is one of the mechanisms involved in the progression of prostate cancer, and an important target for novel prostate cancer therapies. Using gas chromatography-tandem mass spectrometry and genome-wide RNA sequencing, we have analyzed androgen concentrations and androgen-regulated gene expression in cancerous and morphologically benign prostate tissue specimens and serum samples obtained from 48 primary prostate cancer patients. Intratumoral dihydrotestosterone (DHT) concentrations were significantly higher in the cancerous tissues compared to benign prostate (P < 0.001). The tissue/serum ratios of androgens were highly variable between the patients, indicating individual patterns of androgen metabolism and/or uptake of androgens within the prostate tissue. An unsupervised hierarchical clustering analysis of intratissue androgen concentrations indicated that transmembrane protease, serine 2/ETS-related gene (TMPRSS2-ERG)-positive patients have different androgen profiles compared to TMPRSS2-ERG- negative patients. TMPRSS2-ERG gene fusion status was also associated with an enhanced androgen-regulated gene expression, along with altered intratumoral androgen metabolism, demonstrated by reduced testosterone concentrations and increased DHT/testosterone ratios in TMPRSS2-ERG-positive tumors. TMPRSS2-ERG-positive and - negative prostate cancer specimens have distinct intratumoral androgen profiles, possibly due to activation of testosterone-independent DHT biosynthesis via the alternative pathway in TMPRSS2-ERG-positive tumors. Thus, patients with TMPRSS2-ERG-positive prostate cancer may benefit from novel inhibitors targeting the alternative DHT biosynthesis.
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| 4. |
- Adam, M., et al.
(författare)
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Hydroxysteroid (17 beta) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice
- 2018
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Ingår i: Faseb Journal. - 0892-6638. ; 32:6, s. 3434-3447
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Tidskriftsartikel (refereegranskat)abstract
- Hydroxysteroid (17(3) dehydrogenases (HSD17Bs) form an enzyme family characterized by their ability to catalyze reactions in steroid and lipid metabolism. In the present study, we characterized the phenotype of HSD17B13-knockout (HSD17B13KO) mice deficient in Hsd1 7b13. In these studies, hepatic steatosis was detected in HSD17B13KO male mice, indicated by histologic analysis and by the increased triglyceride concentration in the liver, whereas reproductive performance and serum steroid concentrations were normal in HSD17B13KO mice. In line with these changes, the expression of key proteins in fatty acid synthesis, such as FAS, acetyl-CoA carboxylase 1, and SCD1, was increased in the HSD17B13KO liver. Furthermore, the knockout liver showed an increase in 2 acylcamitines, suggesting impaired mitochondrial beta-oxidation in the presence of unaltered malonyl CoA and AMPK expression. The glucose tolerance did not differ between wild-type and HSD17B13KO mice in the presence of lower levels of glucose 6-phosphatase in HSD17B13KO liver compared with wild-type liver. Furthermore, microgranulomas and increased portal inflammation together with up-regulation of immune response genes were observed in HSD17B13KO mice. Our data indicate that disruption of Hsdl7b13 impairs hepatic-lipid metabolism in mice, resulting in liver steatosis and inflammation, but the enzyme does not play a major role in the regulation of reproductive functions.
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| 5. |
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| 6. |
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| 7. |
- Elo, S L, et al.
(författare)
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Validity and utilization of epidemiological data: a study of ischaemic heart disease and coronary risk factors in a local population.
- 2009
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Ingår i: Public health. - : Elsevier BV. - 1476-5616 .- 0033-3506. ; 123:1, s. 52-7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To calculate the burden of ischaemic heart disease (IHD) and coronary risk factors in a defined population using data from all public providers of health care, i.e. inpatient and outpatient care in all settings. STUDY DESIGN: Cross-sectional, 1-year retrospective study. METHODS: The main outcome measures were the number of individuals by diagnosis and by care setting, and gender- and age-specific event rates by diagnosis. RESULTS: Less than half of the individuals who visited any care provider for IHD or coronary risk factors were identified in the hospital discharge register. Calculation of the actual burden of disease in the population showed that when hospital discharge data were combined with outpatient data, there were no or slight differences in the age-specific rates of acute myocardial infarction (AMI), while the rates of angina were between two-fold and four-fold higher, and unspecified IHD was between three-fold and ten-fold higher in individuals aged > or =50 years compared with using hospital discharge data alone. The rates of hypertension, diabetes and lipid disorders increased in all age groups when outpatient data were added to hospital discharge data. The differences in the rates were more pronounced in women aged 50-79 years. However, the age-specific rates were higher in men except for hypertension which was higher in older women. CONCLUSION: Data for epidemiological analyses of diseases are often based on hospital discharge data. This study found that hospital discharge data provide limited information on patients treated for IHD and coronary risk factors, except for AMI. These findings suggest that hospital discharge data should be combined with outpatient care data to provide a more comprehensive estimate of the burden of IHD and its risk factors.
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| 8. |
- Elo, T., et al.
(författare)
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Ectodysplasin target gene Fgf20 regulates mammary bud growth and ductal invasion and branching during puberty
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Mammary gland development begins with the appearance of epithelial placodes that invaginate, sprout, and branch to form small arborized trees by birth. The second phase of ductal growth and branching is driven by the highly invasive structures called terminal end buds (TEBs) that form at ductal tips at the onset of puberty. Ectodysplasin (Eda), a tumor necrosis factor-like ligand, is essential for the development of skin appendages including the breast. In mice, Eda regulates mammary placode formation and branching morphogenesis, but the underlying molecular mechanisms are poorly understood. Fibroblast growth factor (Fgf) receptors have a recognized role in mammary ductal development and stem cell maintenance, but the ligands involved are ill-defined. Here we report that Fgf20 is expressed in embryonic mammary glands and is regulated by the Eda pathway. Fgf20 deficiency does not impede mammary gland induction, but compromises mammary bud growth, as well as TEB formation, ductal outgrowth and branching during puberty. We further show that loss of Fgf20 delays formation of Eda-induced supernumerary mammary buds and normalizes the embryonic and postnatal hyperbranching phenotype of Eda overexpressing mice. These findings identify a hitherto unknown function for Fgf20 in mammary budding and branching morphogenesis.
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| 9. |
- Hendi, Arun S., et al.
(författare)
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The implications of changing education distributions for life expectancy gradients
- 2021
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Ingår i: Social Science and Medicine. - : Elsevier BV. - 0277-9536 .- 1873-5347. ; 272
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Tidskriftsartikel (refereegranskat)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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| 10. |
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| 11. |
- Huhtaniemi, R., et al.
(författare)
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Adrenals Contribute to Growth of Castration-Resistant VCaP Prostate Cancer Xenografts
- 2018
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 0002-9440. ; 188:12, s. 2890-2901
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Tidskriftsartikel (refereegranskat)abstract
- The role of adrenal androgens as drivers for castration-resistant prostate cancer (CRPC) growth in humans is generally accepted; however, the value of preclinical mouse models of CRPC is debatable, because mouse adrenals do not produce steroids activating the androgen receptor. In this study, we confirmed the expression of enzymes essential for de novo synthesis of androgens in mouse adrenals, with high intratissue concentration of progesterone (P4) and moderate levels of androgens, such as androstenedione, testosterone, and dihydrotestosterone, in the adrenal glands of both intact and orchectomized (ORX) mice. ORX alone had no effect on serum P4 concentration, whereas orchectomized and adrenalectomized (ORX + ADX) resulted in a significant decrease in serum P4 and in a further reduction in the low levels of serum androgens (androstenedione, testosterone, and dihydrotestosterone), measured by mass spectrometry. In line with this, the serum prostate-specific antigen and growth of VCaP xenografts in mice after ORX + ADX were markedly reduced compared with ORX alone, and the growth difference was not abolished by a glucocorticoid treatment. Moreover, ORX + ADX altered the androgen-dependent gene expression in the tumors, similar to that recently shown for the enzalutamide treatment. These data indicate that in contrast to the current view, and similar to humans, mouse adrenals synthesize significant amounts of steroids that contribute to the androgen receptor–dependent growth of CRPC. © 2018 American Society for Investigative Pathology
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| 12. |
- Huhtaniemi, R., et al.
(författare)
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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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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:5
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Tidskriftsartikel (refereegranskat)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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| 13. |
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| 14. |
- Mehmood, Arfa, et al.
(författare)
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Systematic evaluation of differential splicing tools for RNA-seq studies
- 2020
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Ingår i: Briefings in Bioinformatics. - : Oxford University Press. - 1467-5463 .- 1477-4054. ; 21:6, s. 2052-2065
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Tidskriftsartikel (refereegranskat)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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| 15. |
- Randall, Ricardo S., et al.
(författare)
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AINTEGUMENTA and the D-type cyclin CYCD3;1 regulate root secondary growth and respond to cytokinins
- 2015
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Ingår i: Biology Open. - : The Company of Biologists. - 2046-6390. ; 4:10, s. 1229-1236
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Tidskriftsartikel (refereegranskat)abstract
- Higher plant vasculature is characterized by two distinct developmental phases. Initially, a well-defined radial primary pattern is established. In eudicots, this is followed by secondary growth, which involves development of the cambium and is required for efficient water and nutrient transport and wood formation. Regulation of secondary growth involves several phytohormones, and cytokinins have been implicated as key players, particularly in the activation of cell proliferation, but the molecular mechanisms mediating this hormonal control remain unknown. Here we show that the genes encoding the transcription factor AINTEGUMENTA (ANT) and the D-type cyclin CYCD3;1 are expressed in the vascular cambium of Arabidopsis roots, respond to cytokinins and are both required for proper root secondary thickening. Cytokinin regulation of ANT and CYCD3 also occurs during secondary thickening of poplar stems, suggesting this represents a conserved regulatory mechanism.
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| 16. |
- Ruohonen, S. T., et al.
(författare)
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Selective loss of kisspeptin signaling in oocytes causes progressive premature ovulatory failure
- 2022
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Ingår i: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 37:4, s. 806-821
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Tidskriftsartikel (refereegranskat)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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