The molecular pathology of pathogenic mitochondrial tRNA variants

Mitochondrial diseases are clinically and genetically heterogeneous disorders, caused by pathogenic variants in either the nuclear or mitochondrial genome. This heterogeneity is particularly striking for disease caused by variants in mitochondrial DNA-encoded tRNA (mt-tRNA) genes, posing challenges for both the treatment of patients and understanding the molecular pathology. In this review, we consider disease caused by the two most common pathogenic mt-tRNA variants: m.3243A>G (within MT-TL1, encoding mt-tRNA(Leu(UUR))) and m.8344A>G (within MT-TK, encoding mt-tRNA(Lys)), which together account for the vast majority of all mt-tRNA-related disease. We compare and contrast the clinical disease they are associated with, as well as their molecular pathologies, and consider what is known about the likely molecular mechanisms of disease. Finally, we discuss the role of mitochondrial-nuclear crosstalk in the manifestation of mt-tRNA-associated disease and how research in this area not only has the potential to uncover molecular mechanisms responsible for the vast clinical heterogeneity associated with these variants but also pave the way to develop treatment options for these devastating diseases.Peer reviewe

First test of Verlinde's theory of Emergent Gravity using weak gravitational lensing measurements

Verlinde (2016) proposed that the observed excess gravity in galaxies and clusters is the consequence of Emergent Gravity (EG). In this theory the standard gravitational laws are modified on galactic and larger scales due to the displacement of dark energy by baryonic matter. EG gives an estimate of the excess gravity (described as an apparent dark matter density) in terms of the baryonic mass distribution and the Hubble parameter. In this work we present the first test of EG using weak gravitational lensing, within the regime of validity of the current model. Although there is no direct description of lensing and cosmology in EG yet, we can make a reasonable estimate of the expected lensing signal of low redshift galaxies by assuming a background LambdaCDM cosmology. We measure the (apparent) average surface mass density profiles of 33,613 isolated central galaxies, and compare them to those predicted by EG based on the galaxies' baryonic masses. To this end we employ the ~180 square degrees overlap of the Kilo-Degree Survey (KiDS) with the spectroscopic Galaxy And Mass Assembly (GAMA) survey. We find that the prediction from EG, despite requiring no free parameters, is in good agreement with the observed galaxy-galaxy lensing profiles in four different stellar mass bins. Although this performance is remarkable, this study is only a first step. Further advancements on both the theoretical framework and observational tests of EG are needed before it can be considered a fully developed and solidly tested theory

The stellar-to-halo mass relation of GAMA galaxies from 100 deg2of KiDS weak lensing data

We study the stellar-to-halo mass relation of central galaxies in the range 9.7 5 × 1010h-2M&sun;, the stellar mass increases with halo mass as ˜ {}M_h^{0.25}. The ratio of dark matter to stellar mass has a minimum at a halo mass of 8 × 1011h-1M&sun; with a value of M_h/M_*=56_{-10}^{+16} [h]. We also use the GAMA group catalogue to select centrals and satellites in groups with five or more members, which trace regions in space where the local matter density is higher than average, and determine for the first time the stellar-to-halo mass relation in these denser environments. We find no significant differences compared to the relation from the full sample, which suggests that the stellar-to-halo mass relation does not vary strongly with local density. Furthermore, we find that the stellar-to-halo mass relation of central galaxies can also be obtained by modelling the lensing signal and stellar mass function of satellite galaxies only, which shows that the assumptions to model the satellite contribution in the halo model do not significantly bias the stellar-to-halo mass relation. Finally, we show that the combination of weak lensing with the stellar mass function can be used to test the purity of group catalogues

Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability

Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Integrating data types to estimate spatial patterns of avian migration across the Western Hemisphere

For many avian species, spatial migration patterns remain largely undescribed, especially across hemispheric extents. Recent advancements in tracking technologies and high-resolution species distribution models (i.e., eBird Status and Trends products) provide new insights into migratory bird movements and offer a promising opportunity for integrating independent data sources to describe avian migration. Here, we present a three-stage modeling framework for estimating spatial patterns of avian migration. First, we integrate tracking and band re-encounter data to quantify migratory connectivity, defined as the relative proportions of individuals migrating between breeding and nonbreeding regions. Next, we use estimated connectivity proportions along with eBird occurrence probabilities to produce probabilistic least-cost path (LCP) indices. In a final step, we use generalized additive mixed models (GAMMs) both to evaluate the ability of LCP indices to accurately predict (i.e., as a covariate) observed locations derived from tracking and band re-encounter data sets versus pseudo-absence locations during migratory periods and to create a fully integrated (i.e., eBird occurrence, LCP, and tracking/band re-encounter data) spatial prediction index for mapping species-specific seasonal migrations. To illustrate this approach, we apply this framework to describe seasonal migrations of 12 bird species across the Western Hemisphere during pre- and postbreeding migratory periods (i.e., spring and fall, respectively). We found that including LCP indices with eBird occurrence in GAMMs generally improved the ability to accurately predict observed migratory locations compared to models with eBird occurrence alone. Using three performance metrics, the eBird + LCP model demonstrated equivalent or superior fit relative to the eBird-only model for 22 of 24 species–season GAMMs. In particular, the integrated index filled in spatial gaps for species with over-water movements and those that migrated over land where there were few eBird sightings and, thus, low predictive ability of eBird occurrence probabilities (e.g., Amazonian rainforest in South America). This methodology of combining individual-based seasonal movement data with temporally dynamic species distribution models provides a comprehensive approach to integrating multiple data types to describe broad-scale spatial patterns of animal movement. Further development and customization of this approach will continue to advance knowledge about the full annual cycle and conservation of migratory birds

Cell-autonomous and non-cell autonomous effects of neuronal BIN1 loss in vivo.

BIN1 is the most important risk locus for Late Onset Alzheimer's Disease (LOAD), after ApoE. BIN1 AD-associated SNPs correlate with Tau deposition as well as with brain atrophy. Furthermore, the level of neuronal-specific BIN1 isoform 1 protein is decreased in sporadic AD cases in parallel with neuronal loss, despite an overall increase in BIN1 total mRNA. To address the relationship between reduction of BIN1 and neuronal cell loss in the context of Tau pathology, we knocked-down endogenous murine Bin1 via stereotaxic injection of AAV-Bin1 shRNA in the hippocampus of mice expressing Tau P301S (PS19). We observed a statistically significant reduction in the number of neurons in the hippocampus of mice injected with AAV-Bin1 shRNA in comparison with mice injected with AAV control. To investigate whether neuronal loss is due to deletion of Bin1 selectively in neurons in presence Tau P301S, we bred Bin1flox/flox with Thy1-Cre and subsequently with PS19 mice. Mice lacking neuronal Bin1 and expressing Tau P301S showed increased mortality, without increased neuropathology, when compared to neuronal Bin1 and Tau P301S-expressing mice. The loss of Bin1 isoform 1 resulted in reduced excitability in primary neurons in vitro, reduced neuronal c-fos expression as well as in altered microglia transcriptome in vivo. Taken together, our data suggest that the contribution of genetic variation in BIN1 locus to AD risk could result from a cell-autonomous reduction of neuronal excitability due to Bin1 decrease, exacerbated by the presence of aggregated Tau, coupled with a non-cell autonomous microglia activation

Claudien et la parole politique : de la délégation de parole dans l'invective à la parrhêsia

International audienceDans ses poèmes politiques, et particulièrement dans le Contre Rufin, Claudien entend imposer l’action de Stilicon à un public qui ne lui est pas forcément acquis, et attaquer en Rufin une figure légitime du gouvernement de l’Empire : comment imposer sa voix dans un contexte historique et politique qui limite la liberté de parole ? La uox poetae n’est pas la seule à retentir dans ce poème : l’objectif de cet article est de déterminer comment les passages de discours direct des personnages permettent au poète de dire ce qu’il ne peut pas dire en son nom. Notre démonstration s'appuie sur les similitudes thématiques, stylistiques et linguistiques qui rapprochent les propos du poète et les propos rapportés des personnages. En brouillant les frontières entre récit et discours des personnages, Claudien fait de ces derniers des doubles d’un narrateur d’épopée, et donne à son propos encomiastique ou polémique le souffle de la voix épique. Et, par des effets d’échos et de structure, des figures d’autorité viennent confirmer la vision politique de Claudien, tandis que le discours de ses cibles, en s’annulant lui-même, vient décrédibiliser celles-ci. Entre modèles et contre-modèles, les personnages servent de relais et confirment ou complètent ce que dit le poète lui-même, selon le degré d’irrévérence du contenu. Chez Claudien, la délégation de parole ouvre sur la parrhêsia, parce qu’elle masque la parole du poète : grâce à elle, il parvient à dépasser la poésie de circonstance et à tenir un discours qui ne soit pas seulement le reflet du discours officiel, mais bien un discours qui porte sa vision personnelle du pouvoir impérial et de Rome

mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease

Abstract Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and linear mixed modelling, we evaluated which commonly assayed tissue (blood N = 231, urine N = 235, skeletal muscle N = 77) represents the m.3243A>G mutation load and mitochondrial DNA (mtDNA) copy number most strongly associated with disease burden and progression. m.3243A>G levels are correlated in blood, muscle and urine (R2 = 0.61–0.73). Blood heteroplasmy declines by ~2.3%/year; we have extended previously published methodology to adjust for age. In urine, males have higher mtDNA copy number and ~20% higher m.3243A>G mutation load; we present formulas to adjust for this. Blood is the most highly correlated mutation measure for disease burden and progression in m.3243A>G‐harbouring individuals; increasing age and heteroplasmy contribute (R2 = 0.27, P G heteroplasmy is the most convenient and reliable measure for routine clinical assessment, additional factors such as mtDNA copy number may also influence disease severity