Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype

The genome instability syndrome, ataxia-telangiectasia (A-T) is caused by null mutations in the ATM gene, that lead to complete loss or inactivation of the gene's product, the ATM protein kinase. ATM is the primary mobilizer of the cellular response to DNA double-strand breaks (DSBs) – a broad signaling network in which many components are ATM targets. The major clinical feature of A-T is cerebellar atrophy, characterized by relentless loss of Purkinje and granule cells. In Atm-knockout (Atm-KO) mice, complete loss of Atm leads to a very mild neurological phenotype, suggesting that Atm loss is not sufficient to markedly abrogate cerebellar structure and function in this organism. Expression of inactive (“kinase-dead”) Atm (AtmKD) in mice leads to embryonic lethality, raising the question of whether conditional expression of AtmKD in the murine nervous system would lead to a more pronounced neurological phenotype than Atm loss. We generated two mouse strains in which AtmKD was conditionally expressed as the sole Atm species: one in the CNS and one specifically in Purkinje cells. Focusing our analysis on Purkinje cells, the dynamics of DSB readouts indicated that DSB repair was delayed longer in the presence of AtmKD compared to Atm loss. However, both strains exhibited normal life span and displayed no gross cerebellar histological abnormalities or significant neurological phenotype. We conclude that the presence of AtmKD is indeed more harmful to DSB repair than Atm loss, but the murine central nervous system can reasonably tolerate the extent of this DSB repair impairment. Greater pressure needs to be exerted on genome stability to obtain a mouse model that recapitulates the severe A-T neurological phenotype

Differential survival throughout the full annual cycle of a migratory bird presents a life-history trade-off.

Long-distance migrations are among the most physically demanding feats animals perform. Understanding the potential costs and benefits of such behaviour is a fundamental question in ecology and evolution. A hypothetical cost of migration should be outweighed by higher productivity and/or higher annual survival, but few studies on migratory species have been able to directly quantify patterns of survival throughout the full annual cycle and across the majority of a species' range. Here, we use telemetry data from 220 migratory Egyptian vultures Neophron percnopterus, tracked for 3,186 bird months and across approximately 70% of the species' global distribution, to test for differences in survival throughout the annual cycle. We estimated monthly survival probability relative to migration and latitude using a multi-event capture-recapture model in a Bayesian framework that accounted for age, origin, subpopulation and the uncertainty of classifying fates from tracking data. We found lower survival during migration compared to stationary periods (β = −0.816; 95% credible interval: −1.290 to −0.318) and higher survival on non-breeding grounds at southern latitudes (<25°N; β = 0.664; 0.076-1.319) compared to on breeding grounds. Survival was also higher for individuals originating from Western Europe (β = 0.664; 0.110-1.330) as compared to further east in Europe and Asia, and improved with age (β = 0.030; 0.020-0.042). Anthropogenic mortalities accounted for half of the mortalities with a known cause and occurred mainly in northern latitudes. Many juveniles drowned in the Mediterranean Sea on their first autumn migration while there were few confirmed mortalities in the Sahara Desert, indicating that migration barriers are likely species-specific. Our study advances the understanding of important fitness trade-offs associated with long-distance migration. We conclude that there is lower survival associated with migration, but that this may be offset by higher non-breeding survival at lower latitudes. We found more human-caused mortality farther north, and suggest that increasing anthropogenic mortality could disrupt the delicate migration trade-off balance. Research to investigate further potential benefits of migration (e.g. differential productivity across latitudes) could clarify how migration evolved and how migrants may persist in a rapidly changing world

The Endosomal–Lysosomal Pathway Is Dysregulated by APOE4 Expression in Vivo

Possession of the ε4 allele of apolipoprotein E (APOE) is the major genetic risk factor for late-onset Alzheimer's disease (AD). Although numerous hypotheses have been proposed, the precise cause of this increased AD risk is not yet known. In order to gain a more comprehensive understanding of APOE4's role in AD, we performed RNA-sequencing on an AD-vulnerable vs. an AD-resistant brain region from aged APOE targeted replacement mice. This transcriptomics analysis revealed a significant enrichment of genes involved in endosomal–lysosomal processing, suggesting an APOE4-specific endosomal–lysosomal pathway dysregulation in the brains of APOE4 mice. Further analysis revealed clear differences in the morphology of endosomal–lysosomal compartments, including an age-dependent increase in the number and size of early endosomes in APOE4 mice. These findings directly link the APOE4 genotype to endosomal–lysosomal dysregulation in an in vivo, AD pathology-free setting, which may play a causative role in the increased incidence of AD among APOE4 carriers

Spatial and Temporal Variability in Migration of a Soaring Raptor Across Three Continents

© Copyright © 2019 Phipps, López-López, Buechley, Oppel, Álvarez, Arkumarev, Bekmansurov, Berger-Tal, Bermejo, Bounas, Alanís, de la Puente, Dobrev, Duriez, Efrat, Fréchet, García, Galán, García-Ripollés, Gil, Iglesias-Lebrija, Jambas, Karyakin, Kobierzycki, Kret, Loercher, Monteiro, Morant Etxebarria, Nikolov, Pereira, Peške, Ponchon, Realinho, Saravia, Sekercioğlu, Skartsi, Tavares, Teodósio, Urios and Vallverdú. Disentangling individual- and population-level variation in migratory movements is necessary for understanding migration at the species level. However, very few studies have analyzed these patterns across large portions of species' distributions. We compiled a large telemetry dataset on the globally endangered Egyptian Vulture Neophron percnopterus (94 individuals, 188 completed migratory journeys), tracked across ~70% of the species' global range, to analyze spatial and temporal variability of migratory movements within and among individuals and populations. We found high migratory connectivity at large spatial scales (i.e., different subpopulations showed little overlap in wintering areas), but very diffuse migratory connectivity within subpopulations, with wintering ranges up to 4,000 km apart for birds breeding in the same region and each subpopulation visiting up to 28 countries (44 in total). Additionally, Egyptian Vultures exhibited a high level of variability at the subpopulation level and flexibility at the individual level in basic migration parameters. Subpopulations differed significantly in travel distance and straightness of migratory movements, while differences in migration speed and duration differed as much between seasons and among individuals within subpopulations as between subpopulations. The total distances of the migrations completed by individuals from the Balkans and Caucasus were up to twice as long and less direct than those in Western Europe, and consequently were longer in duration, despite faster migration speeds. These differences appear to be largely attributable to more numerous and wider geographic barriers (water bodies) along the eastern flyway. We also found that adult spring migrations to Western Europe and the Balkans were longer and slower than fall migrations. We encourage further research to assess the underlying mechanisms for these differences and the extent to which environmental change could affect Egyptian Vulture movement ecology and population trends