| 1. |
- Armengaud, E., et al.
(författare)
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Physics potential of the International Axion Observatory (IAXO)
- 2019
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Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :6
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Tidskriftsartikel (refereegranskat)abstract
- We review the physics potential of a next generation search for solar axions: the International Axion Observatory (IAXO). Endowed with a sensitivity to discover axion-like particles (ALPs) with a coupling to photons as small as g(a gamma) similar to 10(-12) GeV-1, or to electrons g(ae) similar to 10(-13), IAXO has the potential to find the QCD axion in the 1 meV similar to 1 eV mass range where it solves the strong CP problem, can account for the cold dark matter of the Universe and be responsible for the anomalous cooling observed in a number of stellar systems. At the same time, IAXO will have enough sensitivity to detect lower mass axions invoked to explain: 1) the origin of the anomalous transparency of the Universe to gamma-rays, 2) the observed soft X-ray excess from galaxy clusters or 3) some inflationary models. In addition, we review string theory axions with parameters accessible by IAXO and discuss their potential role in cosmology as Dark Matter and Dark Radiation as well as their connections to the above mentioned conundrums.
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| 4. |
- Muller-Deile, J., et al.
(författare)
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Identification of cell and disease specific microRNAs in glomerular pathologies
- 2019
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Ingår i: Journal of Cellular and Molecular Medicine. - : Wiley. - 1582-1838 .- 1582-4934. ; 23:6, s. 3927-3939
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression in physiological processes as well as in diseases. Currently miRs are already used to find novel mechanisms involved in diseases and in the future, they might serve as diagnostic markers. To identify miRs that play a role in glomerular diseases urinary miR-screenings are a frequently used tool. However, miRs that are detected in the urine might simply be filtered from the blood stream and could have been produced anywhere in the body, so they might be completely unrelated to the diseases. We performed a combined miR-screening in pooled urine samples from patients with different glomerular diseases as well as in cultured human podocytes, human mesangial cells, human glomerular endothelial cells and human tubular cells. The miR-screening in renal cells was done in untreated conditions and after stimulation with TGF-beta. A merge of the detected regulated miRs led us to identify disease-specific, cell type-specific and cell stress-induced miRs. Most miRs were down-regulated following the stimulation with TGF-beta in all cell types. Up-regulation of miRs after TGF-beta was cell type-specific for most miRs. Furthermore, urinary miRs from patients with different glomerular diseases could be assigned to the different renal cell types. Most miRs were specifically regulated in one disease. Only miR-155 was up-regulated in all disease urines compared to control and therefore seems to be rather unspecific. In conclusion, a combined urinary and cell miR-screening can improve the interpretation of screening results. These data are useful to identify novel miRs potentially involved in glomerular diseases.
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| 5. |
- Muller-Deile, J., et al.
(författare)
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Overexpression of preeclampsia induced microRNA-26a-5p leads to proteinuria in zebrafish
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- So far the pathomechanism of preeclampsia in pregnancy is focussed on increased circulating levels of soluble fms-like tyrosin kinase-1 (sFLT-1) that neutralizes glomerular VEGF-A expression and prevents its signaling at the glomerular endothelium. As a result of changed glomerular VEGF-A levels endotheliosis and podocyte foot process effacement are typical morphological features of preeclampsia. Recently, microRNA-26a-5p (miR-26a-5p) was described to be also upregulated in the preeclamptic placenta. We found that miR-26a-5p targets VEGF-A expression by means of PIK3C2a in cultured human podocytes and that miR-26a-5p overexpression in zebrafish causes proteinuria, edema, glomerular endotheliosis and podocyte foot process effacement. Interestingly, recombinant zebrafish Vegf-Aa protein could rescue glomerular changes induced by miR-26a-5p. In a small pilot study, preeclamptic patients with podocyte damage identified by podocyturia, expressed significantly more urinary miR-26a-5p compared to healthy controls. Thus, functional and ultrastructural glomerular changes after miR-26a-5p overexpression can resemble the findings seen in preeclampsia and indicate a potential pathophysiological role of miR-26a-5p in addition to sFLT-1 in this disease.
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| 6. |
- Muller-Deile, J., et al.
(författare)
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Podocytes regulate the glomerular basement membrane protein nephronectin by means of miR-378a-3p in glomerular diseases
- 2017
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538. ; 92:4, s. 836-849
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Tidskriftsartikel (refereegranskat)abstract
- The pathophysiology of many proteinuric kidney diseases is poorly understood, and microRNAs (miRs) regulation of these diseases has been largely unexplored. Here, we tested whether miR-378a-3p is a novel regulator of glomerular diseases. MiR-378a-3p has two predicted targets relevant to glomerular function, the glomerular basement membrane matrix component, nephronectin (NPNT), and vascular endothelial growth factor VEGF-A. In zebrafish (Danio rerio), miR-378a-3p mimic injection or npnt knockdown by a morpholino oligomer caused an identical phenotype consisting of edema, proteinuria, podocyte effacement, and widening of the glomerular basement membrane in the lamina rara interna. Zebrafish vegf-A protein could not rescue this phenotype. However, mouse Npnt constructs containing a mutated 3'UTR region prevented the phenotype caused by miR-378a-3p mimic injection. Overexpression of miR-378a-3p in mice confirmed glomerular dysfunction in a mammalian model. Biopsies from patients with focal segmental glomerulosclerosis and membranous nephropathy had increased miR-378a-3p expression and reduced glomerular levels of NPNT. Thus, miR-378a-3p-mediated suppression of the glomerular matrix protein NPNT is a novel mechanism for proteinuria development in active glomerular diseases.
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| 7. |
- Padula, William V., et al.
(författare)
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Cost-effectiveness of Tyrosine Kinase Inhibitor Treatment Strategies for Chronic Myeloid Leukemia in Chronic Phase After Generic Entry of Imatinib in the United States
- 2016
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 108:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: We analyzed the cost-effectiveness of treating incident chronic myeloid leukemia in chronic phase (CML-CP) with generic imatinib when it becomes available in United States in 2016. In the year following generic entry, imatinib's price is expected to drop 70% to 90%. We hypothesized that initiating treatment with generic imatinib in these patients and then switching to the other tyrosine-kinase inhibitors (TKIs), dasatinib or nilotinib, because of intolerance or lack of effectiveness ("imatinib-first") would be cost-effective compared with the current standard of care: "physicians' choice" of initiating treatment with any one of the three TKIs. Methods: We constructed Markov models to compare the five-year cost-effectiveness of imatinib-first vs physician's choice from a US commercial payer perspective, assuming 3% annual discounting ($US 2013). The models' clinical endpoint was five-year overall survival taken from a systematic review of clinical trial results. Per-person spending on incident CML-CP treatment overall care components was estimated using Truven's MarketScan claims data. The main outcome of the models was cost per quality-adjusted life-year (QALY). We interpreted outcomes based on a willingness-to-pay threshold of $100 000/QALY. A panel of European LeukemiaNet experts oversaw the study's conduct. Results: Both strategies met the threshold. Imatinib-first ($277 401, 3.87 QALYs) offered patients a 0.10 decrement in QALYs at a savings of $88 343 over five years to payers compared with physician's choice ($365 744, 3.97 QALYs). The imatinibfirst incremental cost-effectiveness ratio was approximately $883 730/QALY. The results were robust to multiple sensitivity analyses. Conclusion: When imatinib loses patent protection and its price declines, its use will be the cost-effective initial treatment strategy for CML-CP.
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| 10. |
- Zinner, Christoph, et al.
(författare)
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Sprint interval training or arms and legs elevates peak VO2 and improves arm exercise economy
- 2015
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Konferensbidrag (refereegranskat)abstract
- IntroductionInterval cycle sprint training (SIT) has been shown to improve anaerobic capacity, VO2max and biomarkers of muscle oxidative capacity in as little as 2 weeks in previously untrained adults. The present study was designed to characterize and compare systemic VO2 and exercise performance after SIT engaging the arms and legs. MethodsSixteen healthy, untrained men (23.9 ± 3.7 yrs; 183.8 ± 6.8 cm; 80.3 ± 14.1 kg) performed six sessions of 4-6x30 sec all-out sprints with the legs then arms (or vice versa) separated by a 1-h recovery over an 11-day period. Limb-specific VO2peak, anaerobic capacity (2x30-sec Wingate tests with 4 min of recovery), a 4-min submaximal work economy test, and a 5-min all-out time trial (TT) were conducted before and after the training program. Muscle biopsies (from the m. vastus lateralis and m. triceps brachii) were taken before and after the training period. ResultsVO2peak increased by 10.6% and 5.9% with arm and leg training, respectively (p<0.05), with the increase in the arms significantly greater than in the legs (p=0.02). Work economy was improved for the arms (-9.8%, p<0.05), but not for the legs (-0.9%). Mean power during the TT rose by 13.5% for the arms and 11.8% for the legs (p<0.05). Peak power output and mean power during the two Wingate tests were elevated in both the arms (PPO: 6.7% (p<0.01) and 13.3% (p<0.01); MPO: 6.1% (p<0.01) and 8.4% (p<0.01)) and legs (PPO: 3.1% (p=0.07) and 7.1% (p=0.02); MPO: 3.3% (p<0.01) and 5.6% (p<0.01)). The activity of 3-hydroxyacyl-CoA dehydrogenase (HAD) and levels of muscle glycogen were unchanged in both limbs. DiscussionSprint interval training with arm or leg cycling exercise increased peak pulmonary VO2 during their respective modes over an 11-day training period with a greater increase in the arms. Sprint performance rose to a similar extent in both extremities, yet work economy was improved only in the arms. These findings suggest some limb-specific responsiveness to SIT training.
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