'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'

Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model. By using live cell imaging and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the YG8R FRDA mouse model, causing a decrease in mitochondrial membrane potential (▵Ψm) due to an inhibition of Complex I, which is partially compensated by an overactivation of Complex II. This complex activity imbalance leads to ROS generation in both mitochondrial matrix and cytosol, which results in glutathione depletion and increased lipid peroxidation. Preventing this increase in lipid peroxidation, in neurons, protects against in cell death. This work describes the pathophysiological properties of the mitochondria in neurons from a FRDA mouse model and shows that lipid peroxidation could be an important target for novel therapeutic strategies in FRDA, which still lacks a cure

Alignment of the ALICE Inner Tracking System with cosmic-ray tracks

37 pages, 15 figures, revised version, accepted by JINSTALICE (A Large Ion Collider Experiment) is the LHC (Large Hadron Collider) experiment devoted to investigating the strongly interacting matter created in nucleus-nucleus collisions at the LHC energies. The ALICE ITS, Inner Tracking System, consists of six cylindrical layers of silicon detectors with three different technologies; in the outward direction: two layers of pixel detectors, two layers each of drift, and strip detectors. The number of parameters to be determined in the spatial alignment of the 2198 sensor modules of the ITS is about 13,000. The target alignment precision is well below 10 micron in some cases (pixels). The sources of alignment information include survey measurements, and the reconstructed tracks from cosmic rays and from proton-proton collisions. The main track-based alignment method uses the Millepede global approach. An iterative local method was developed and used as well. We present the results obtained for the ITS alignment using about 10^5 charged tracks from cosmic rays that have been collected during summer 2008, with the ALICE solenoidal magnet switched off.Peer reviewe

Final amalgamation of the Central Asian Orogenic Belt in NE China: Paleo-Asian Ocean closure versus Paleo-Pacific plate subduction - A review of the evidence

The Central Asian Orogenic Belt (CAOB) evolved through complex closure of the Paleo-Asian Ocean from the Neoproterozoic to the late Phanerozoic. This caused the Chinese cratons to collide with Eurasia and led to the formation of the world's largest Phanerozoic orogenic belt. Ocean closure commenced in the west and was completed in the east near Changchun. Closure of the Paleo-Asian Ocean in NE China was along the Solonker-Xar Moron-Changchun-Yanji suture and this was likely completed in the Late Permian, although associated activity continued into the Triassic. There was an overlap in the latest Permian-Early Triassic between terminal activity associated with Paleo-Asian Ocean closure and the onset of tectonism associated with subduction of the Paleo-Pacific plate. This switch in geodynamic setting occurred at ~. 260-250. Ma, and is reflected by a relaxing of north-south directed compression and the onset of east-west directed processes related to Paleo-Pacific subduction. By the Early Jurassic, events associated with the westward advance of the Paleo-Pacific plate dominated, leading to extensive development of I-type granites as far inland as the Great Xing'an Range. From ~. 140. Ma, the Paleo-Pacific plate retreated eastward, resulting in an extensional setting in the Early Cretaceous, the effects of which were enhanced by regional thinning of the lithosphere, commonly attributed to delamination. Throughout this period, the eastern Asian margin was tectonically complex. The north-south oriented Jiamusi-Khanka(-Bureya) block was rifted away from the eastern margin of the CAOB in the Late Triassic, but was then re-united in the Jurassic by westward-advancing subduction that affected both the western and eastern margins of the block. Accretionary complexes continued to evolve in the Cretaceous along the whole eastern margin of Asia, with final accretion of the Nadanhada Terrane (part of the Sikhote-Alin accretionary terrane) with the CAOB at ~. 130. Ma, followed by the emplacement of S-type granites