A One Base Pair Deletion in the Canine ATP13A2 Gene Causes Exon Skipping and Late-Onset Neuronal Ceroid Lipofuscinosis in the Tibetan Terrier

Neuronal ceroid lipofuscinosis (NCL) is a progressive neurodegenerative disease characterized by brain and retinal atrophy and the intracellular accumulation of autofluorescent lysosomal storage bodies resembling lipofuscin in neurons and other cells. Tibetan terriers show a late-onset lethal form of NCL manifesting first visible signs at 5–7 years of age. Genome-wide association analyses for 12 Tibetan-terrier-NCL-cases and 7 Tibetan-terrier controls using the 127K canine Affymetrix SNP chip and mixed model analysis mapped NCL to dog chromosome (CFA) 2 at 83.71–84.72 Mb. Multipoint linkage and association analyses in 376 Tibetan terriers confirmed this genomic region on CFA2. A mutation analysis for 14 positional candidate genes in two NCL-cases and one control revealed a strongly associated single nucleotide polymorphism (SNP) in the MAPK PM20/PM21 gene and a perfectly with NCL associated single base pair deletion (c.1620delG) within exon 16 of the ATP13A2 gene. The c.1620delG mutation in ATP13A2 causes skipping of exon 16 presumably due to a broken exonic splicing enhancer motif. As a result of this mutation, ATP13A2 lacks 69 amino acids. All known 24 NCL cases were homozygous for this deletion and all obligate 35 NCL-carriers were heterozygous. In a sample of 144 dogs from eleven other breeds, the c.1620delG mutation could not be found. Knowledge of the causative mutation for late-onset NCL in Tibetan terrier allows genetic testing of these dogs to avoid matings of carrier animals. ATP13A2 mutations have been described in familial Parkinson syndrome (PARK9). Tibetan terriers with these mutations provide a valuable model for a PARK9-linked disease and possibly for manganese toxicity in synucleinopathies

The Persistency of the India-Pakistan Conflict: Chances and Obstacles of the Bilateral Composite Dialogue

This article investigates the underlying causes for the persistency of the India–Pakistan conflict and, on this basis, the chances and obstacles of the bilateral composite dialogue initiated in 2004. In particular, it wants to provide a theoretically grounded account of the factors that facilitated and constrained the bilateral composite dialogue process. Drawing on the regional security complex theory, this article examines the rivalry between the two South Asian nuclear powers on four levels of analysis: the domestic, the regional, the interregional and the global level. The analysis shows that there have been some substantial changes on all four levels in the recent decade or so and that these changes have provided more beneficial conditions for a peace process. These changes include, inter alia, India’s new regional policy, the consequences of the 9/11 terrorist attacks for the region and India’s growing power capacities. However, major obstacles to the India–Pakistan dialogue and a permanent conflict resolution continue to persist: the dominant role of the military in Pakistan, conflicting national identities and the still partially contested nature of statehood in India and Pakistan, which is in the case of Pakistan linked to the growing power of Islamic fundamentalists

Increased zinc and manganese in parallel with neurodegeneration, synaptic protein changes and activation of Akt/GSK3 signaling in ovine CLN6 neuronal ceroid lipofuscinosis

Mutations in the CLN6 gene cause a variant late infantile form of neuronal ceroid lipofuscinosis (NCL; Batten disease). CLN6 loss leads to disease clinically characterized by vision impairment, motor and cognitive dysfunction, and seizures. Accumulating evidence suggests that alterations in metal homeostasis and cellular signaling pathways are implicated in several neurodegenerative and developmental disorders, yet little is known about their role in the NCLs. To explore the disease mechanisms of CLN6 NCL, metal concentrations and expression of proteins implicated in cellular signaling pathways were assessed in brain tissue from South Hampshire and Merino CLN6 sheep. Analyses revealed increased zinc and manganese concentrations in affected sheep brain in those regions where neuroinflammation and neurodegeneration first occur. Synaptic proteins, the metal-binding protein metallothionein, and the Akt/GSK3 and ERK/MAPK cellular signaling pathways were also altered. These results demonstrate that altered metal concentrations, synaptic protein changes, and aberrant modulation of cellular signaling pathways are characteristic features in the CLN6 ovine form of NCL

Resonant Coupling of Ion-Cyclotron Waves to Energetic Helium-Ions

First measurements were performed to test a model prediction which states that the off-axis coupling of ion-cyclotron waves to energetic helium ions can generate either an inward or an outward drift of these particles. Ion-cyclotron waves with a power or up to 1 MW are coupled to energetic particles at the high field side, the low field side, or in the center by varying the toroidal magnetic field. When changing the heating power or the resonance location, the variation of the concentration of the energetic helium in the plasma agrees qualitatively with the model predictions

Review of Recent Advances in Heating and Current Drive on Textor

Co-injection (DO --> D+) applied to TEXTOR leads to a hot ion node regime with enhanced confinement. A synergistic increase of the beam effects is observed with the addition of ICRH at omega = 2omega(cD) = omega(cH) (H minority heating scenario) resulting, beside other reviewed effects, in a significant increase of the ion temperature and of the beam driven current (respectively larger than 30 % and 50 % for the addition of an RF power comparable to the NBI one). The large ion heating efficiency of ICRH also remains when ICRH is added to balanced injection and the hot ion mode regime remains up to the maximum achieved beta (=2/3 of the Troyan limit with more than 6MW of auxiliary heating). ICRH also leads to the formation of a more \u27isotropic\u27 tail. These results are interpreted with the help of a Fokker-Planck code which computes the beam distribution function in presence of RF and of TRANSP simulations. The amount of RF absorption by the H minority by the ion beam and die bulk plasma is theoretically evaluated. It is shown that a large part of the synergistic effects can be explained by the rise of the electron temperature due to the minority heating which increases the beam slowing down time and its critical energy. A smaller contribution to the effects is due to direct coupling of the RF power to the beam (less than 10 % of the total RF absorbed power) and to the decrease of the plasma toroidal rotation induced by the RF. ICRH has also been added to co-injection at omega = 3omega(CD). In this case no minority heating is present and the RF energy coupling to the beam is one of the dominant effects. It leads to the formation of a very energetic tail of the ion beam with a strong increase of the beam-target neutron reactivity