Early-Onset Progressive Degeneration of the Area Centralis in RPE65-Deficient Dogs.

PURPOSE: Retinal epithelium-specific protein 65 kDa (RPE65)-deficient dogs are a valuable large animal model species that have been used to refine gene augmentation therapy for Leber congenital amaurosis type-2 (LCA2). Previous studies have suggested that retinal degeneration in the dog model is slower than that observed in humans. However, the area centralis of the dog retina is a cone and rod photoreceptor rich region comparable to the human macula, and the effect of RPE65 deficiency specifically on this retinal region, important for high acuity vision, has not previously been reported. METHODS: Spectral-domain optical coherence tomography, fundus photography, and immunohistochemistry of retinal wholemounts and sagittal frozen sections were used to define the time-course and cell-types affected in degeneration of the area centralis in affected dogs. RESULTS: Area centralis photoreceptor degeneration was evident from 6 weeks of age, and progressed to involve the inner retina. Immunohistochemistry showed that RPE65-deficient dogs developed early loss of S-cone outer segments, with slower loss of L/M-cone outer segments and rods. CONCLUSIONS: Early-onset severe photoreceptor degeneration in the area centralis of dogs with RPE65-deficiency offers a model of the early foveal/perifoveal degeneration in some patients with LCA2. This model could be used to refine interventions aiming to improve function and halt the progression of foveal/perifoveal photoreceptor degeneration

A large animal model of RDH5-associated retinopathy recapitulates important features of the human phenotype

Pathogenic variants in retinol dehydrogenase 5 (RDH5) attenuate supply of 11-cis-retinal to photoreceptors leading to a range of clinical phenotypes including night blindness due to markedly slowed rod dark adaptation and in some patients, macular atrophy. Current animal models (such as Rdh5-/- mice) fail to recapitulate the functional or degenerative phenotype. Addressing this need for a relevant animal model we present a new domestic cat model with a loss-of-function missense mutation in RDH5 (c.542G > T; p.Gly181Val). As with patients, affected cats have a marked delay in recovery of dark adaptation. Additionally, the cats develop a degeneration of the area centralis (equivalent to the human macula). This recapitulates the development of macular atrophy that is reported in a subset of patients with RDH5 mutations and is shown in this paper in 7 patients with biallelic RDH5 mutations. There is notable variability in the age at onset of the area centralis changes in the cat, with most developing changes as juveniles but some not showing changes over the first few years of age. There is similar variability in development of macular atrophy in patients and while age is a risk factor, it is hypothesized that genetic modifying loci influence disease severity, and we suspect the same is true in the cat model. This novel cat model provides opportunities to improve molecular understanding of macular atrophy and test therapeutic interventions for RDH5-associated retinopathies

Social network structures and the politics of public goods provision: evidence from the Philippines

We study the relationship between social structure and political incentives for public goods provision. We argue that when politicians—rather than communities—are responsible for the provision of public goods, social fractionalization may decrease the risk of elite capture and lead to increased public goods provision and electoral competition. We test this using large-scale data on family networks from over 20 million individuals in 15,000 villages of the Philippines. We take advantage of naming conventions to assess intermarriage links between families and use community detection algorithms to identify the relevant clans in those villages. We show that there is more public goods provision and political competition in villages with more fragmented social networks, a result that is robust to controlling for a large number of village characteristics and to alternative estimation techniques

Politician family networks and electoral outcomes: evidence from the Philippines

We demonstrate the importance of politician social networks for electoral outcomes. Using largescale data on family networks from over 20 million individuals in 15,000 villages in the Philippines, we show that candidates for public office are disproportionately drawn from more central families and family network centrality contributes to higher vote shares during the elections. Consistent with our theory of political intermediation, we present evidence that family network centrality facilitates relationships of political exchange. Moreover, we show that family networks exercise an effect independent of wealth, historical elite status, or previous electoral success

Politician family networks and electoral outcomes: evidence from the Philippines

We demonstrate the importance of politician social networks for electoral outcomes. Using largescale data on family networks from over 20 million individuals in 15,000 villages in the Philippines, we show that candidates for public office are disproportionately drawn from more central families and family network centrality contributes to higher vote shares during the elections. Consistent with our theory of political intermediation, we present evidence that family network centrality facilitates relationships of political exchange. Moreover, we show that family networks exercise an effect independent of wealth, historical elite status, or previous electoral success

The real winner's curse

Traditional theories of democracy suggest that political representation of excluded groups can reduce their incentives to engage in conflict and lead to lower violence. However, this argument ignores the response of established elites when (1) their interests are threatened by the policy stance of new political actors and (2) elites have a comparative advantage in the exercise of violence. Using a regression discontinuity approach, we show that the narrow election of previously excluded left‐wing parties to local executive office in Colombia results in a one standard deviation increase in violent events by right‐wing paramilitaries. We interpret this surge in violence as a reaction of traditional elites to offset the increase in outsiders' access to formal political power. Consistent with this interpretation, we find that violence by left‐wing guerrillas and other actors is unaffected and that violence is not influenced by the victory of right‐wing or other new parties in close elections

Changes in mental disorder prevalence among conflict-affected populations: a prospective study in Sri Lanka (COMRAID-R).

BACKGROUND: Longitudinal data are lacking on mental health trajectories following conflict resolution and return migration. COMRAID-R is a follow-up study of Muslims displaced by conflict from Northern Sri Lanka 20 years ago who are now beginning to return. METHODS: Of 450 participants in displacement interviewed in 2011, 338 (75.1%) were re-interviewed a year later, and a supplementary random sample (n = 228) was drawn from return migrants with a comparable displacement history. Common mental disorder (CMD; Patient Health Questionnaire) and post-traumatic stress disorder (CIDI-subscale) were measured. RESULTS: A CMD prevalence of 18.8% (95%CI 15.2-22.5) at baseline had reduced to 8.6% (5.6-11.7) at follow-up in those remaining in displacement, and was 10.3% (6.5-14.1) in return migrants. PTSD prevalences were 2.4%, 0.3% and 1.6% respectively. CONCLUSIONS: We observed a substantial decrease in CMD prevalence in this population over a short period, which may reflect the prospect of return migration and associated optimism following conflict resolution

Behavior of Major and Trace Elements during Ore Deposition: Example from the Low-Sulfidation Pantingan Gold System, Mount Mariveles, Bataan, Philippines

The evaluation of the relatively fresh host rock and altered rock samples associated with the Pantingan Gold System exposed in Mount Mariveles, Bataan yield several notable observations that are useful in pinpointing potential gold pathfinder elements. Geochemical and petrologic analysis showed that the altered rocks can be subdivided into rocks that underwent propylitic alteration (group 1), argillized rocks with silica contents similar to those of the fresh host rocks (group 2), argillized but not strongly silicified rocks (group 3) and argillized and strongly silicified rocks (group 4). Selected element ratio patterns in the altered rocks and gold concentrations in gold-bearing quartz veins vary between the rock groups. Moreover, mass balance calculation also reflected the geochemical observations pertaining to the gains and losses of SiO2, Fe2O3 + MgO, CaO + Na2O and K2O, which are believed to be chemical reactions (i.e. breakdown of plagioclase, silica inundation or leaching, sulfide and calcite formation) caused by the influx of hydrothermal fluids. © 2007 The Authors Journal compilation © 2007 The Society of Resource Geology.link_to_subscribed_fulltex