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Author

Oliver Müller

Other affiliations: University of Basel
Bio: Oliver Müller is an academic researcher from University of Strasbourg. The author has contributed to research in topics: Galaxy & Dwarf galaxy. The author has an hindex of 27, co-authored 91 publications receiving 2563 citations. Previous affiliations of Oliver Müller include University of Basel.


Papers
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Journal ArticleDOI
07 Mar 2013-Nature
TL;DR: Age-induced expression of miR-34a and inhibition of its target PNUTS is identified as a key mechanism that regulates cardiac contractile function during ageing and after acute myocardial infarction, by inducing DNA damage responses and telomere attrition.
Abstract: Ageing is the predominant risk factor for cardiovascular diseases and contributes to a significantly worse outcome in patients with acute myocardial infarction. MicroRNAs (miRNAs) have emerged as crucial regulators of cardiovascular function and some miRNAs have key roles in ageing. We propose that altered expression of miRNAs in the heart during ageing contributes to the age-dependent decline in cardiac function. Here we show that miR-34a is induced in the ageing heart and that in vivo silencing or genetic deletion of miR-34a reduces age-associated cardiomyocyte cell death. Moreover, miR-34a inhibition reduces cell death and fibrosis following acute myocardial infarction and improves recovery of myocardial function. Mechanistically, we identified PNUTS (also known as PPP1R10) as a novel direct miR-34a target, which reduces telomere shortening, DNA damage responses and cardiomyocyte apoptosis, and improves functional recovery after acute myocardial infarction. Together, these results identify age-induced expression of miR-34a and inhibition of its target PNUTS as a key mechanism that regulates cardiac contractile function during ageing and after acute myocardial infarction, by inducing DNA damage responses and telomere attrition.

708 citations

Journal ArticleDOI
TL;DR: Clinical and genetic risk stratification may lead to prospective trials of primary implantation of cardioverter defibrillators in people with hereditary cardiomyopathy.

182 citations

Journal ArticleDOI
02 Feb 2018-Science
TL;DR: In this paper, the kinematics of satellite galaxies around the Centaurus A galaxy around the Milky Way and Andromeda galaxies are used to test the assumption that most satellite galaxy systems are close to isotropic with random motions, so those two wellstudied systems are often interpreted as rare statistical outliers.
Abstract: The Milky Way and Andromeda galaxies are each surrounded by a thin plane of satellite dwarf galaxies that may be corotating. Cosmological simulations predict that most satellite galaxy systems are close to isotropic with random motions, so those two well-studied systems are often interpreted as rare statistical outliers. We test this assumption using the kinematics of satellite galaxies around the Centaurus A galaxy. Our statistical analysis reveals evidence for corotation in a narrow plane: Of the 16 Centaurus A satellites with kinematic data, 14 follow a coherent velocity pattern aligned with the long axis of their spatial distribution. In standard cosmological simulations,

121 citations

Journal ArticleDOI
13 Sep 2018-Nature
TL;DR: In this paper, the radial velocities of ten luminous globular-cluster-like objects in the ultra-diffuse galaxy NGC1052-DF2 have been analyzed.
Abstract: Galaxies normally have far more dark matter than normal matter, but the dynamics of objects within the ultra-diffuse galaxy NGC1052–DF2 suggest that it has a very little dark matter component. Most galaxies studied need a component of dark matter associated with them in order to explain their observed properties. Normally there is far more dark matter than normal matter, with an average of 30 times more for galaxies about the mass of the Milky Way. Dwarf galaxies are thought to have even higher ratios of dark to normal matter (more than 400 times as much). Pieter van Dokkum and colleagues report that the ultra-diffuse galaxy NGC1052–DF2 has a dynamical mass, determined by the motions of globular-cluster-like objects, that is essentially the same as the mass in stars, meaning that it does not have a dark matter component. Studies of galaxy surveys in the context of the cold dark matter paradigm have shown that the mass of the dark matter halo and the total stellar mass are coupled through a function that varies smoothly with mass. Their average ratio Mhalo/Mstars has a minimum of about 30 for galaxies with stellar masses near that of the Milky Way (approximately 5 × 1010 solar masses) and increases both towards lower masses and towards higher masses1,2. The scatter in this relation is not well known; it is generally thought to be less than a factor of two for massive galaxies but much larger for dwarf galaxies3,4. Here we report the radial velocities of ten luminous globular-cluster-like objects in the ultra-diffuse galaxy5 NGC1052–DF2, which has a stellar mass of approximately 2 × 108 solar masses. We infer that its velocity dispersion is less than 10.5 kilometres per second with 90 per cent confidence, and we determine from this that its total mass within a radius of 7.6 kiloparsecs is less than 3.4 × 108 solar masses. This implies that the ratio Mhalo/Mstars is of order unity (and consistent with zero), a factor of at least 400 lower than expected2. NGC1052–DF2 demonstrates that dark matter is not always coupled with baryonic matter on galactic scales.

105 citations

Journal ArticleDOI
TL;DR: In this article, the authors conducted an extensive CCD imaging survey for faint, unresolved dwarf galaxies of very low surface brightness in the whole Centaurus group region, encompassing the Cen A and M 83 subgroups lying at a distance of roughly 4 and 5 Mpc, respectively.
Abstract: Context. The distribution of satellite galaxies around the Milky Way and Andromeda and their correlation in phase space pose a major challenge to the standard ΛCDM model of structure formation. Other nearby groups of galaxies are now being scrutinized to test for the ubiquity of the phenomenon. Aims. We conducted an extensive CCD imaging survey for faint, unresolved dwarf galaxies of very low surface brightness in the whole Centaurus group region, encompassing the Cen A and M 83 subgroups lying at a distance of roughly 4 and 5 Mpc, respectively. The aim is to significantly increase the sample of known Centaurus group members down to a fainter level of completeness, serving as a basis for future studies of the 3D structure of the group.Methods. Following our previous survey of 60 square degrees covering the M 83 subgroup, we extended and completed our survey of the Centaurus group region by imaging another 500 square degrees area in the g and r bands with the wide-field Dark Energy Survey camera at the 4 m Blanco telescope at CTIO. The surface brightness limit reached for unresolved dwarf galaxies is μ r ≈ 29 mag arcsec-2 . The faintest suspected Centaurus members found have m r ≈ 19.5 mag or M r ≈ −8.8 mag at the mean distance of the group. The images were enhanced using different filtering techniques.Results. We found 41 new dwarf galaxy candidates, which together with the previously discovered 16 dwarf candidates in the M 83 subgroup amounts to almost a doubling of the number of known galaxies in the Centaurus complex, if the candidates are confirmed. We carried out surface photometry in g and r , and report the photometric parameters derived therefrom, for all new candidates as well as previously known members in the surveyed area. The photometric properties of the candidates, when compared to those of Local Group dwarfs and previously known Centaurus dwarfs, suggest membership in the Centaurus group. The sky distribution of the new objects is generally following a common envelope around the Cen A and M 83 subgroups. How the new dwarfs are connected to the intriguing double-planar feature recently reported must await distance information for the candidates.

89 citations


Cited by
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Journal ArticleDOI
05 Dec 2012-Nature
TL;DR: It is shown that the exogenous administration of selected microRNAs (miRNAs) markedly stimulates cardiomyocyte proliferation and promotes cardiac repair and the miRNAs identified hold great promise for the treatment of cardiac pathologies consequent to cardiomeocyte loss.
Abstract: In mammals, enlargement of the heart during embryonic development is primarily dependent on the increase in cardiomyocyte numbers. Shortly after birth, however, cardiomyocytes stop proliferating and further growth of the myocardium occurs through hypertrophic enlargement of the existing myocytes. As a consequence of the minimal renewal of cardiomyocytes during adult life, repair of cardiac damage through myocardial regeneration is very limited. Here we show that the exogenous administration of selected microRNAs (miRNAs) markedly stimulates cardiomyocyte proliferation and promotes cardiac repair. We performed a high-content microscopy, high-throughput functional screening for human miRNAs that promoted neonatal cardiomyocyte proliferation using a whole-genome miRNA library. Forty miRNAs strongly increased both DNA synthesis and cytokinesis in neonatal mouse and rat cardiomyocytes. Two of these miRNAs (hsa-miR-590 and hsa-miR-199a) were further selected for testing and were shown to promote cell cycle re-entry of adult cardiomyocytes ex vivo and to promote cardiomyocyte proliferation in both neonatal and adult animals. After myocardial infarction in mice, these miRNAs stimulated marked cardiac regeneration and almost complete recovery of cardiac functional parameters. The miRNAs identified hold great promise for the treatment of cardiac pathologies consequent to cardiomyocyte loss.

908 citations

Journal ArticleDOI
TL;DR: New approaches to engineer and improve AAV vectors and their genetic cargo are increasingly helping to overcome barriers to extension of clinical gene therapy successes to many other human diseases.
Abstract: Clinical gene therapy has been increasingly successful owing both to an enhanced molecular understanding of human disease and to progressively improving gene delivery technologies. Among these technologies, delivery vectors based on adeno-associated viruses (AAVs) have emerged as safe and effective and, in one recent case, have led to regulatory approval. Although shortcomings in viral vector properties will render extension of such successes to many other human diseases challenging, new approaches to engineer and improve AAV vectors and their genetic cargo are increasingly helping to overcome these barriers.

647 citations

Journal ArticleDOI
TL;DR: The molecular understanding of the function of the pumps has received great impetus from the solution of the three-dimensional structure of one of them, the SERCA pump, which has paralleled the rapid expansion of knowledge in the topic of Ca2+-signaling dysfunction.
Abstract: Ca2+-ATPases (pumps) are key actors in the regulation of Ca2+ in eukaryotic cells and are thus essential to the correct functioning of the cell machinery They have high affinity for Ca2+ and can efficiently regulate it down to very low concentration levels Two of the pumps have been known for decades (the SERCA and PMCA pumps); one (the SPCA pump) has only become known recently Each pump is the product of a multigene family, the number of isoforms being further increased by alternative splicing of the primary transcripts The three pumps share the basic features of the catalytic mechanism but differ in a number of properties related to tissue distribution, regulation, and role in the cellular homeostasis of Ca2+ The molecular understanding of the function of the pumps has received great impetus from the solution of the three-dimensional structure of one of them, the SERCA pump These spectacular advances in the structure and molecular mechanism of the pumps have been accompanied by the emergence and rapid expansion of the topic of pump malfunction, which has paralleled the rapid expansion of knowledge in the topic of Ca2+-signaling dysfunction Most of the pump defects described so far are genetic: when they are very severe, they produce gross and global disturbances of Ca2+ homeostasis that are incompatible with cell life However, pump defects may also be of a type that produce subtler, often tissue-specific disturbances that affect individual components of the Ca2+-controlling and/or processing machinery They do not bring cells to immediate death but seriously compromise their normal functioning

593 citations

Journal ArticleDOI
TL;DR: This study validates DNA family shuffling and viral peptide display as two powerful and compatible approaches to the molecular evolution of novel AAV vectors for human gene therapy applications.
Abstract: Adeno-associated virus (AAV) serotypes differ broadly in transduction efficacies and tissue tropisms and thus hold enormous potential as vectors for human gene therapy. In reality, however, their use in patients is restricted by prevalent anti-AAV immunity or by their inadequate performance in specific targets, exemplified by the AAV type 2 (AAV-2) prototype in the liver. Here, we attempted to merge desirable qualities of multiple natural AAV isolates by an adapted DNA family shuffling technology to create a complex library of hybrid capsids from eight different wild-type viruses. Selection on primary or transformed human hepatocytes yielded pools of hybrids from five of the starting serotypes: 2, 4, 5, 8, and 9. More stringent selection with pooled human antisera (intravenous immunoglobulin [IVIG]) then led to the selection of a single type 2/type 8/type 9 chimera, AAV-DJ, distinguished from its closest natural relative (AAV-2) by 60 capsid amino acids. Recombinant AAV-DJ vectors outperformed eight standard AAV serotypes in culture and greatly surpassed AAV-2 in livers of naive and IVIG-immunized mice. A heparin binding domain in AAV-DJ was found to limit biodistribution to the liver (and a few other tissues) and to affect vector dose response and antibody neutralization. Moreover, we report the first successful in vivo biopanning of AAV capsids by using a new AAV-DJ-derived viral peptide display library. Two peptides enriched after serial passaging in mouse lungs mediated the retargeting of AAV-DJ vectors to distinct alveolar cells. Our study validates DNA family shuffling and viral peptide display as two powerful and compatible approaches to the molecular evolution of novel AAV vectors for human gene therapy applications.

576 citations