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PNAS Studies on Age-Related Macular Degeneration Target, Lion History, Arsenic Metabolism

Researchers at Genentech and elsewhere describe efforts to find markers of activity against the protein encoded by HTRA1 in the context of age-related macular degeneration (AMD). Following from past genome-wide association studies that linked HTRA1 gene polymorphisms to the progressive eye disease, the team used mouse models, deep sequencing, protein interaction assays, proteomics, and other approaches to assess the HtrA1 enzyme's role in AMD, along with substrates that might be used as markers of HtrA1-targeting compounds such as the so-called Fab fragment. "A set of proteomic and analytical tools was established to characterize HtrA1 activity and discover in vivo HtrA1 substrates," the authors report. "These efforts led to the identification of an eye-specific and clinically applicable pharmacodynamic biomarker of anti-HtrA1 Fab activity."

An international team led by investigators in Spain and Denmark takes a look back at the evolutionary history of lions, with whole-genome resequencing data for representatives from modern-day and ancient lion species stretching back 30,000 years. Based on sequences from half a dozen modern lions from Africa or India, 12 lion samples collected in the 15th and 20th century, and two cave lions from the Yukon and Siberia dated at 30,000 years old, the researchers estimated that the split between modern and cave lions occurred within the last 500,000 years, followed by a split into two lion lineages roughly 70,000 years ago. "Our analyses show the Pleistocene cave lion as maximally distinct with no evidence of hybridization with other lion groups based on the level of population structure and admixture," they report, arguing that the study "provides views on the complex nature of the global lion species-complex and its evolution, and provides conservation data for modern lion regional populations."

Investigators in China, Germany, and the US retrace the history of genetic pathways involved in arsenic metabolism, particularly since the Earth's atmosphere became oxygen-rich. Using a molecular clock analysis spanning more than a dozen known arsenic-resistance and arsenic cycling pathways in nearly 650 bacteria, along with dozens of archaea and eukaryotic representatives, they saw signs that some arsenic-related pathways have their roots in oxygen-poor environments that preceded atmospheric oxygenation. "The oxygenation of the atmosphere about 2.4 billion years ago remodeled global cycles of toxic, redox-sensitive metal(loids), including that of arsenic, which must have represented a cataclysm in the history of life," the researchers write. "By estimating the timing of genetic systems for arsenic detoxification, we reveal an expansion of enzymes and pathways that accompanied adaptations to the biotoxicity of oxidized arsenic species produced by [the] Great Oxidation Event."