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| 2. |
- Coenen-Stass, Anna M. L., et al.
(author)
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Comprehensive RNA-Sequencing Analysis in Serum and Muscle Reveals Novel Small RNA Signatures with Biomarker Potential for DMD
- 2018
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In: Molecular Therapy Nucleic Acids. - : Elsevier BV. - 2162-2531. ; 13, s. 1-15
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Journal article (peer-reviewed)abstract
- Extracellular small RNAs (sRNAs), including microRNAs (miRNAs), are promising biomarkers for diseases such as Duchenne muscular dystrophy (DMD), although their biological relevance is largely unknown. To investigate the relationship between intracellular and extracellular sRNA levels on a global scale, we performed sRNA sequencing in four muscle types and serum from wild-type, dystrophic mdx, and mdx mice in which dystrophin protein expression was restored by exon skipping. Differentially abundant sRNAs were identified in serum (mapping to miRNA, small nuclear RNA [snRNA], and PIWI-interacting RNA [piRNA] loci). One novel candidate biomarker, miR-483, was increased in both mdx serum and muscle, and also elevated in DMD patient sera. Dystrophin restoration induced global shifts in miRNA (including miR-483) and snRNA-fragment abundance toward wild-type levels. Specific serum piRNA-like sRNAs also responded to exon skipping therapy. Absolute miRNA expression in muscle was positively correlated with abundance in the circulation, although multiple highly expressed miRNAs in muscle were not elevated in mdx serum, suggesting that both passive and selective release mechanisms contribute to serum miRNA levels. In conclusion, this study has revealed new insights into the sRNA biology of dystrophin deficiency and identified novel DMD biomarkers.
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| 3. |
- Cowan, E., et al.
(author)
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MicroRNA 29 modulates β-cell mitochondrial metabolism and insulin secretion via underlying miR-29-OXPHOS complex pathways
- 2024
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In: Acta Physiologica. - 1748-1708. ; 240:8
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Journal article (peer-reviewed)abstract
- Aim: MicroRNAs (miRNAs) regulate β-cell function, and β-cell mitochondria and insulin secretion are perturbed in diabetes. We aimed to identify key miRNAs regulating β-cell mitochondrial metabolism and novel β-cell miRNA-mitochondrial pathways. Methods: TargetScan (http://www.targetscan.org/) was used to predict if 16 miRNAs implicated in β-cell function target 27 cis-eGenes implicated in mitochondrial activity. The expression of candidate miRNAs and insulin secretion after 24 and 1 h pre-incubation in 2.8, 11.1- and 16.7-mM glucose was measured in clonal INS-1 832/13 β-cells. MiR-29 silenced INS-1 832/13 cells were assessed for insulin secretion (glucose, pyruvate, and K+), target cis-eGene expression (Ndufv3 and Ndufa10 components of mitochondrial complex I (CI)), OXPHOS (CI-V) protein expression, and mitochondrial OXPHOS respiration/activity. The expression of differentially expressed miR-29 miRNAs was evaluated in Goto-Kakizaki (GK) rat, db/db mouse and type 2 diabetic (T2D) human islets, as well as NMRI mouse islets cultured under glucolipotoxic conditions. Results: MiR-29, miR-15 and miR-124 were predicted to regulate ~20 cis-eGenes, while miR-29 alone was predicted to regulate ≥12 of these in rat and human species. MiR-29 expression and insulin secretion were reduced in INS-1 832/13 cells after 24 h in elevated glucose. MiR-29 knockdown increased all tested insulin secretory responses, Nudfv3, Ndufa10, complex I and II expression, and cellular mitochondrial OXPHOS. MiR-29 expression was reduced in db/db islets but increased in GK rat and T2D human islets. Conclusion: We conclude miR-29 is a key miRNA in regulating β-cell mitochondrial metabolism and insulin secretion via underlying miR-29-OXPHOS complex pathways. Furthermore, we infer reduced miR-29 expression compensatorily enhances insulin secretion under glucotoxicity.
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| 6. |
- Masarapu, Yuvarani, et al.
(author)
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Spatially resolved multiomics on the neuronal effects induced by spaceflight in mice
- 2024
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- Impairment of the central nervous system (CNS) poses a significant health risk for astronauts during long-duration space missions. In this study, we employed an innovative approach by integrating single-cell multiomics (transcriptomics and chromatin accessibility) with spatial transcriptomics to elucidate the impact of spaceflight on the mouse brain in female mice. Our comparative analysis between ground control and spaceflight-exposed animals revealed significant alterations in essential brain processes including neurogenesis, synaptogenesis and synaptic transmission, particularly affecting the cortex, hippocampus, striatum and neuroendocrine structures. Additionally, we observed astrocyte activation and signs of immune dysfunction. At the pathway level, some spaceflight-induced changes in the brain exhibit similarities with neurodegenerative disorders, marked by oxidative stress and protein misfolding. Our integrated spatial multiomics approach serves as a stepping stone towards understanding spaceflight-induced CNS impairments at the level of individual brain regions and cell types, and provides a basis for comparison in future spaceflight studies. For broader scientific impact, all datasets from this study are available through an interactive data portal, as well as the National Aeronautics and Space Administration (NASA) Open Science Data Repository (OSDR).
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| 8. |
- Tropé, C, et al.
(author)
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Doxorubicin-melphalan with and without cisplatin in advanced ovarian cancer--ten-year survival results from a prospective randomized study by the Swedish Cooperative Ovarian Cancer Study Group
- 1996
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In: Acta oncologica (Stockholm, Sweden). - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 35 Suppl 8, s. 18-109
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Journal article (peer-reviewed)abstract
- In a controlled prospective randomized study the regimen doxorubicin (A) 40 mg/m2 + melphalan (M) 0.4 mg/kg was compared with A + M + cisplatin (C) 50 mg/m2 given every four weeks in advanced ovarian cancer, FIGO stage III or IV and with serous or anaplastic histology. From 1981 to 1983, 300 patients entered the study and 295 patients were evaluable for response, toxicity and long-term survival. All patients were followed for at least 10 years. The majority of patients had large residual tumours >2 cm. Patients treated with MAC had a higher response rate compared with patients treated with MA (76% vs. 50%, p < 0.01) and treatment with MAC resulted in significantly more pathological complete responders than MA. There was a significant difference in median duration of response (19 months vs. 13 months, p < 0.006) and in median survival time (26 months vs. 19 months, p = 0.05). After 5- and 10 years a significant difference in progression-free and overall survival was found. The independent prognostic factors in this study were residual tumour after primary surgery, treatment with MAC, tumour grade, ascites, and stage. Objective and subjective side effects were significantly worse with MAC, although tolerable. In conclusion, this study shows that incorporating C into MA improves the duration of progression-free survival and overall survival in women with incompletely resected Stage III or Stage IV ovarian epithelial cancer. A 5- and 10-year survival of 25% and 18%, respectively, is impressive.
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| 9. |
- Vromman, Marieke, et al.
(author)
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Large-scale benchmarking of circRNA detection tools reveals large differences in sensitivity but not in precision
- 2023
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In: Nature Methods. - 1548-7091 .- 1548-7105. ; 20:8, s. 1159-1169
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Journal article (peer-reviewed)abstract
- The detection of circular RNA molecules (circRNAs) is typically based on short-read RNA sequencing data processed using computational tools. Numerous such tools have been developed, but a systematic comparison with orthogonal validation is missing. Here, we set up a circRNA detection tool benchmarking study, in which 16 tools detected more than 315,000 unique circRNAs in three deeply sequenced human cell types. Next, 1,516 predicted circRNAs were validated using three orthogonal methods. Generally, tool-specific precision is high and similar (median of 98.8%, 96.3% and 95.5% for qPCR, RNase R and amplicon sequencing, respectively) whereas the sensitivity and number of predicted circRNAs (ranging from 1,372 to 58,032) are the most significant differentiators. Of note, precision values are lower when evaluating low-abundance circRNAs. We also show that the tools can be used complementarily to increase detection sensitivity. Finally, we offer recommendations for future circRNA detection and validation. This study describes benchmarking and validation of computational tools for detecting circRNAs, finding most to be highly precise with variations in sensitivity and total detection. The study also finds over 315,000 putative human circRNAs.
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| 10. |
- Waldenström, C, et al.
(author)
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The Natural Resource Turn : Challenges for Rural Areas
- 2009
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In: International Journal of Rural Management. - Canada. - 0973-0052 .- 0973-0680. ; 4:1, s. 102-117
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Journal article (peer-reviewed)abstract
- Forecasts for demographic change and long-term economic growth in the world indicate a probable critical growth in demand for biological resources such as food, bioenergy, and forest products over the next few decades. In Sweden, as in other western economies where the rural economy and the rural population have been declining since the Second World War, such an expected natural resource turn may have major implications for social and economic change in rural areas. In this paper we explore the research needs that follow from the perspective of a natural resource turn, which we define as a long-term economic upgrading of natural resources following on critical growth in demand. Based on the situation in Sweden, we elaborate on four themes, considered as central to understanding natural resource turn–related rural change from a future perspective: (a) the production and management of biological resources and landscapes; (b) demographic change; (c) the location of economic activity to rural areas; and (d) social transformations in rural communities. Finally, some policy implications of these changes are outlined.
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