35 research outputs found
Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy
Leber's hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber's hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber's hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies.TelethonAssociazione Serena Talarico per i giovani nel mondo and Fondazione Giuseppe Tomasello O.N.L.U.S.Mitocon OnlusResearch to Prevent BlindnessInternational Foundation for Optic Nerve Diseases (IFOND)Struggling Within Leber'sPoincenot FamilyEierman FoundationNational Eye InstituteUniv Rome, Dept Radiol Oncol & Pathol, Rome, ItalyUniv Bologna, Dept Biomed & NeuroMotor Sci DIBINEM, Bologna, ItalyUniv Bari, Dept Biosci Biotechnol & Biopharmaceut, Bari, ItalyBellaria Hosp, IRCCS Ist Sci Neurol Bologna, I-40139 Bologna, ItalyUSC, Keck Sch Med, Dept Ophthalmol, Los Angeles, CA USAUSC, Keck Sch Med, Dept Neurosurg, Los Angeles, CA USAUniv Trieste, Dept Reprod Sci Dev & Publ Hlth, Trieste, ItalyUniv Trieste, IRCCS Burlo Garofolo Children Hosp, Trieste, ItalyNewcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, EnglandFdn Ist Neurol Carlo Besta IRCCS, Unit Mol Neurogenet, Milan, ItalyMRC Mitochondrial Biol Unit, Cambridge, EnglandFed Univ São Paulo UNIFESP, Dept Ophthalmol, São Paulo, BrazilUniv São Paulo, Inst Psychol, Dept Expt Psychol, São Paulo, BrazilStudio Oculist dAzeglio, Bologna, ItalyOsped San Giovanni Evangelista, Tivoli, ItalyAzienda Osped San Camillo Forlanini, Rome, ItalyUniv Rome, Dipartimento Metodi & Modelli Econ Finanza & Terr, Rome, ItalyUniv Rome, Dept Mol Med, Rome, ItalyFed Univ São Paulo UNIFESP, Dept Ophthalmol, São Paulo, BrazilTelethon: GGP06233Telethon: GGP11182Telethon: GPP10005National Eye Institute: EY03040Web of Scienc
Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy
Comparison of disease clusters in two elderly populations hospitalized in 2008 and 2010.
BACKGROUND: As chronicity represents one of the major challenges in the healthcare of aging populations, the understanding of how chronic diseases distribute and co-occur in this part of the population is needed.
OBJECTIVES: The aims of this study were to evaluate and compare patterns of diseases identified with cluster analysis in two samples of hospitalized elderly.
METHODS: Data were obtained from the multicenter 'Registry Politerapie SIMI (REPOSI)' that included people aged 65 or older hospitalized in internal medicine and geriatric wards in Italy during 2008 and 2010. The study sample from the first wave included 1,411 subjects enrolled in 38 hospitals wards, whereas the second wave included 1,380 subjects in 66 wards located in different regions of Italy. To analyze patterns of multimorbidity, a cluster analysis was performed including the same diseases (19 chronic conditions with a prevalence >5%) collected at hospital discharge during the two waves of the registry.
RESULTS: Eight clusters of diseases were identified in the first wave of the REPOSI registry and six in the second wave. Several diseases were included in similar clusters in the two waves, such as malignancy and liver cirrhosis; anemia, gastric and intestinal diseases; diabetes and coronary heart disease; chronic obstructive pulmonary disease and prostate hypertrophy.
CONCLUSION: These findings strengthened the idea of an association other than by chance of diseases in the elderly population
Science with the Cherenkov Telescope Array
The Cherenkov Telescope Array, CTA, will be the major global observatory forvery high energy gamma-ray astronomy over the next decade and beyond. Thescientific potential of CTA is extremely broad: from understanding the role ofrelativistic cosmic particles to the search for dark matter. CTA is an explorerof the extreme universe, probing environments from the immediate neighbourhoodof black holes to cosmic voids on the largest scales. Covering a huge range inphoton energy from 20 GeV to 300 TeV, CTA will improve on all aspects ofperformance with respect to current instruments. The observatory will operate arrays on sites in both hemispheres to providefull sky coverage and will hence maximize the potential for the rarestphenomena such as very nearby supernovae, gamma-ray bursts or gravitationalwave transients. With 99 telescopes on the southern site and 19 telescopes onthe northern site, flexible operation will be possible, with sub-arraysavailable for specific tasks. CTA will have important synergies with many ofthe new generation of major astronomical and astroparticle observatories.Multi-wavelength and multi-messenger approaches combining CTA data with thosefrom other instruments will lead to a deeper understanding of the broad-bandnon-thermal properties of target sources. The CTA Observatory will be operated as an open, proposal-driven observatory,with all data available on a public archive after a pre-defined proprietaryperiod. Scientists from institutions worldwide have combined together to formthe CTA Consortium. This Consortium has prepared a proposal for a CoreProgramme of highly motivated observations. The programme, encompassingapproximately 40% of the available observing time over the first ten years ofCTA operation, is made up of individual Key Science Projects (KSPs), which arepresented in this document
Science with the Cherenkov Telescope Array
213 pages, including references and glossary. Version 2: credits and references updated, some figures updated, and author list updatedInternational audienceThe Cherenkov Telescope Array, CTA, will be the major global observatory for very high energy gamma-ray astronomy over the next decade and beyond. The scientific potential of CTA is extremely broad: from understanding the role of relativistic cosmic particles to the search for dark matter. CTA is an explorer of the extreme universe, probing environments from the immediate neighbourhood of black holes to cosmic voids on the largest scales. Covering a huge range in photon energy from 20 GeV to 300 TeV, CTA will improve on all aspects of performance with respect to current instruments. The observatory will operate arrays on sites in both hemispheres to provide full sky coverage and will hence maximize the potential for the rarest phenomena such as very nearby supernovae, gamma-ray bursts or gravitational wave transients. With 99 telescopes on the southern site and 19 telescopes on the northern site, flexible operation will be possible, with sub-arrays available for specific tasks. CTA will have important synergies with many of the new generation of major astronomical and astroparticle observatories. Multi-wavelength and multi-messenger approaches combining CTA data with those from other instruments will lead to a deeper understanding of the broad-band non-thermal properties of target sources. The CTA Observatory will be operated as an open, proposal-driven observatory, with all data available on a public archive after a pre-defined proprietary period. Scientists from institutions worldwide have combined together to form the CTA Consortium. This Consortium has prepared a proposal for a Core Programme of highly motivated observations. The programme, encompassing approximately 40% of the available observing time over the first ten years of CTA operation, is made up of individual Key Science Projects (KSPs), which are presented in this document
Searching for very-high-energy electromagnetic counterparts to gravitational-wave events with the Cherenkov Telescope Array
The detection of electromagnetic (EM) emission following the gravitational wave (GW) event GW170817 opened the era of multi-messenger astronomy with GWs and provided the first direct evidence that at least a fraction of binary neutron star (BNS) mergers are progenitors of short Gamma-Ray Bursts (GRBs). GRBs are also expected to emit very-high energy (VHE, > 100 GeV) photons, as proven by the recent MAGIC and H.E.S.S. observations. One of the challenges for future multi-messenger observations will be the detection of such VHE emission from GRBs in association with GWs. In the next years, the Cherenkov Telescope Array (CTA) will be a key instrument for the EM follow-up of GW events in the VHE range, owing to its unprecedented sensitivity, rapid response, and capability to monitor a large sky area via scan-mode operation. We present the CTA GW follow-up program, with a focus on the searches for short GRBs possibly associated with BNS mergers. We investigate the possible observational strategies and we outline the prospects for the detection of VHE EM counterparts to transient GW events