Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses (Batten disease)

Sheep with naturally occurring CLN5 and CLN6 forms of neuronal ceroid lipofuscinoses (Batten disease) share the key clinical features of the human disease and represent an ideal model system in which the clinical efficacy of gene therapies is developed and test. However, it was first important to characterize the neuropathological changes that occur with disease progression in affected sheep. This study compared neurodegeneration, neuroinflammation, and lysosomal storage accumulation in CLN5 affected Borderdale, CLN6 affected South Hampshire, and Merino sheep brains from birth to end-stage disease at ≤24 months of age. Despite very different gene products, mutations, and subcellular localizations, the pathogenic cascade was remarkably similar for all three disease models. Glial activation was present at birth in affected sheep and preceded neuronal loss, with both spreading from the visual and parieto-occipital cortices most prominently associated with clinical symptoms to the entire cortical mantle by end-stage disease. In contrast, the subcortical regions were less involved, yet lysosomal storage followed a near-linear increase across the diseased sheep brain with age. Correlation of these neuropathological changes with published clinical data identified three potential therapeutic windows in affected sheep—presymptomatic (3 months), early symptomatic (6 months), and a later symptomatic disease stage (9 months of age)—beyond which the extensive depletion of neurons was likely to diminish any chance of therapeutic benefit. This comprehensive natural history of the neuropathological changes in ovine CLN5 and CLN6 disease will be integral in determining what impact treatment has at each of these disease stages

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

Effects of auditory stimuli on electrical activity in the brain during cycle ergometry

© 2017 The Authors. The present study sought to further understanding of the brain mechanisms that underlie the effects of music on perceptual, affective, and visceral responses during whole-body modes of exercise. Eighteen participants were administered light-to-moderate intensity bouts of cycle ergometer exercise. Each exercise bout was of 12-min duration (warm-up [3 min], exercise [6 min], and warm-down [3 min]). Portable techniques were used to monitor the electrical activity in the brain, heart, and muscle during the administration of three conditions: music, audiobook, and control. Conditions were randomized and counterbalanced to prevent any influence of systematic order on the dependent variables. Oscillatory potentials at the Cz electrode site were used to further understanding of time–frequency changes influenced by voluntary control of movements. Spectral coherence analysis between Cz and frontal, frontal-central, central, central-parietal, and parietal electrode sites was also calculated. Perceptual and affective measures were taken at five timepoints during the exercise bout. Results indicated that music reallocated participants' attentional focus toward auditory pathways and reduced perceived exertion. The music also inhibited alpha resynchronization at the Cz electrode site and reduced the spectral coherence values at Cz–C4 and Cz–Fz. The reduced focal awareness induced by music led to a more autonomous control of cycle movements performed at light-to-moderate-intensities. Processing of interoceptive sensory cues appears to upmodulate fatigue-related sensations, increase the connectivity in the frontal and central regions of the brain, and is associated with neural resynchronization to sustain the imposed exercise intensity.Coordination for the Improvement of Higher Education Personnel (CAPES)

See Hear: Psychological Effects of Music and Music-Video During Treadmill Running

© 2014, The Society of Behavioral Medicine.Background: There is a paucity of work addressing the distractive, affect-enhancing, and motivational influences of music and video in combination during exercise. Purpose: We examined the effects of music and music-and-video on a range of psychological and psychophysical variables during treadmill running at intensities above and below ventilatory threshold (VT). Methods: Participants (N = 24) exercised at 10 % of maximal capacity below VT and 10 % above under music-only, music-and-video, and control conditions. Results: There was a condition × intensity × time interaction for perceived activation and state motivation, and an intensity × time interaction for state attention, perceived exertion (RPE), and affective valence. The music-and-video condition elicited the highest levels of dissociation, lowest RPE, and most positive affective responses regardless of exercise intensity. Conclusions: Attentional manipulations influence psychological and psychophysical variables at exercise intensities above and below VT, and this effect is enhanced by the combined presentation of auditory and visual stimuli

Curation of pig traits in the Online Mendelian Inheritance in Animals (OMIA) database

Online Mendelian Inheritance in Animals (OMIA) is a freely available curated database that contains information on inherited traits and disorders (called phenes in OMIA) across more than 250 species. OMIA entries relating to pigs were reviewed, as a relatively low number of Mendelian phenes, as well as low number of phenes for which likely causal variants were listed, were noted when compared to other companion and livestock species. Of the 277 pig phenes recorded within the database at the beginning of this study in March 2020, 228 were classified as defects, 87 were Mendelian traits and for 37 of these, 45 likely causal variants were published. This study aimed to identify gaps in the information for pig phenes within OMIA. Changes to 30 pig phenes were made with a focus on updating information in OMIA's downloadable tables of known likely causal variants, One phene had previously been missed and was added, and 8 phenes were added as part of ongoing curation