Elisabeth Knust leads a team of researchers from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, Germany, who describe an essential role for one such metabolic pathway in maintaining retinal health under conditions of stress. They studied the classic Drosophila genes cinnabar, cardinal, white, and scarlet, originally characterized decades ago and named due to their role in eye color pigmentation, in particular the formation of the brown pigment of the fly eye. These genes encode components of the kynurenine pathway, whose activity converts the amino acid tryptophan by various steps into other products. In this study, the authors have highlighted the function of this metabolic pathway in retinal health, independent of its role in pigment formation.

The Kynurenine pathway is an evolutionary conserved metabolic pathway that regulates a variety of biological processes. Its disruption can result in the buildup of either toxic or protective biomolecules or metabolites, which can worsen or improve, respectively, the health of the brain, including the retina. Knowledge on this important metabolic pathway was recently extended by the research team, led by Elisabeth Knust, Director Emerita at the MPI-CBG, in their publication in the journal Plos Genetics. Being aware of the remarkable conservation of this metabolic pathway and the genes that regulate it, they used flies as a model system to unravel the role of individual metabolites in retinal health. The researchers looked at four genes — cinnabar, cardinal, white, and scarlet – named after abnormal eye colors following their loss in flies. “Since the Kynurenine pathway is conserved from flies to humans, we asked whether these genes regulate retinal health independent of their role in pigment formation,” says Sarita Hebbar, one of the lead authors of the study.

To find this out, the scientists used a combination of genetics, dietary changes, and biochemical analysis of metabolites to study different mutations of the fruit fly, Drosophila melanogaster. Sofia Traikov, a co-author, developed a method for the biochemical analysis of the metabolites of the Kynurenine pathway. This allowed the researchers to link different metabolite levels to the health state of the retina. They found that one metabolite, 3-hydroxykynurenine (3OH-K), is damaging to the retina. More importantly, they could show that the degree of degeneration is influenced by the balance between toxic 3OH-K and protective metabolites, such as Kynurenic Acid (KYNA), and not just by their absolute amounts. Sarita continues: “We also fed two of these metabolites to normal (non-mutant) flies and found that 3OH-K enhanced stress-induced retinal damage, whereas KYNA protected the retina from stress-related damage.” This means that retinal health in certain conditions can be improved by altering the ratio of metabolites of the Kynurenine pathway.

Furthermore, by targeting these four genes and therefore four distinct steps within the pathway, the researchers were able to demonstrate that not only the accumulation of 3OH-K as such, but also its location in the cell and hence its availability in further reactions, is important for retinal health.

“This work shows that the Kynurenine pathway is important not only in pigment formation but that the level of individual metabolites fulfills important roles in maintaining retinal health,” says Elisabeth Knust, who supervised the study. She concludes, “In the future, the ratio of the various metabolites and the specific sites of their accumulation and activity should be taken into account in therapeutic strategies for diseases with impaired Kynurenine pathway function, observed in various neurodegenerative conditions.”

Researchers at the Ancient Genomics Laboratory at the Crick studied available genome-wide DNA from 677 individuals dating to Stone Age Europe, spanning the movement of Neolithic farmers from the Near East into Europe about 8000 years ago, where they mixed with Mesolithic hunter-gatherers already in Europe.

They were interested in whether any particular genes might have coded for adaptations important to early farming groups, and looked for evidence of rapid evolution in these populations.

Since about 20% of the ancestry of descendant late Stone Age people could be traced to the local European hunter-gatherers, the researchers also asked whether any particular genes showed evidence of more hunter-gatherer ancestry.

They found that a large genetic region responsible for immune responses to diseases — the major histocompatibility complex (MHC) — showed both the strongest evidence of rapid evolution, and more Mesolithic hunter-gatherer ancestry than expected, suggesting that genetic variants in the MHC region already present in Europe were passed down preferentially.

It has previously been thought that the transition to farming was associated with increased natural selection on immunity variants, as people started living closer to animals and eating more animal products. This research supports this view, but also shows that diversity in immune genes may be just as important as adaptation to lifestyle.

The research team speculates that either the hunter-gatherers already had genetic adaptations against bacteria, viruses or other microorganisms in Europe, or that having many different forms of the genes was advantageous.

Tom Davy, PhD student at the Francis Crick Institute and lead author, said: “It was really exciting to see for the first time that immunity is important for the transition to farming in a prehistoric population. The later Neolithic people had far more farmer ancestry in general, so we expected to see the same at the MHC region, especially as many diseases have been linked to Neolithic periods. But we saw about 50:50 ancestry from Neolithic farmers and Mesolithic hunter-gatherers here, showing that natural selection favoured genes from the hunter-gatherers already in Europe.

“At the moment we’re not quite sure whythis happened, but a proposal is that the European hunter-gatherers had genetic variations which allowed them to fight Europe-specific diseases. Or picking up a variety of genes from both hunter-gatherers and farmers was beneficial because it resulted in lots of diversity at this major group of genes, allowing people to better fight off disease.”

The team also confirmed results from previous studies, showing that genes coding for skin pigmentation showed the greatest representation for Neolithic farmer ancestry, with these variations coming into Europe from the Near East. This may be to maintain vitamin D levels when sources, such as diet and exposure to sunlight, change.

Pontus Skoglund, Group Leader of the Ancient Genomics Laboratory at the Crick, said: “The shift to farming was an important transition all over the world, resulting in changing diets and exposure to infectious disease.

“Previous research has suggested that adaptation in genetic regions relating to immunity, such as the MHC, has been important in recent time periods, and this research now provides similar evidence for adaptation in prehistory. By growing the ancient genomic record, we will be able to better understand the role of immunity in other periods of the human past.”

“Six different models have been published in an attempt to explain the radar signatures of the icy moons that orbit Jupiter and Saturn,” said Hofgartner, first author of the study, which was published this month in Nature Astronomy. “The way these objects scatter radar is drastically different than that of the rocky worlds, such as Mars and Earth, as well as smaller bodies such as asteroids and comets.”

The objects are also extremely bright, even in areas where they should be darker.

“When we look up at Earth’s moon it looks like a circular disk, even though we know it’s a sphere. Planets and other moons similarly look like disks through telescopes,” Hofgartner said. “While making radar observations, the center of the disk is very bright and the edges much darker. The change from center to edge is very different for these icy satellites than for rocky worlds.”

In collaboration with Dr. Kevin Hand of NASA’s Jet Propulsion Laboratory, Hofgartner argues that the extraordinary radar properties of these satellites, such as their reflectiveness and polarization (the orientation of light waves as they propagate through space) is very likely to be explained by the coherent backscatter opposition effect (CBOE).

“When you’re at opposition, the Sun is positioned directly behind you on the line between you and an object, the surface appears much brighter than it would otherwise,” Hofgartner said. “This is known as the opposition effect. In the case of radar, a transmitter stands in for the Sun and a receiver for your eyes.”

An icy surface, Hofgartner explained, has an even stronger opposition effect than normal. For every scattering path of light bouncing through the ice, at opposition there is a path in the exact opposite direction. Because the two paths have precisely the same length, they combine coherently, resulting in further brightening.

In the 1990s, studies were published stating that the CBOE was one explanation for the anomalous radar signatures of icy satellites, but other explanations could explain the data equally well. Hofgartner and Hand improved the polarization description of the CBOE model and also showed that their modified CBOE model is the only published model that can explain all of the icy satellite radar properties.

“I think that tells us that the surfaces of these objects and their subsurfaces down to many meters are very tortured,” Hofgartner said. “They’re not very uniform. Icy rocks dominate the landscape, perhaps looking somewhat like the chaotic mess after a landslide. That would explain why the light is bouncing in so many different directions, giving us these unusual polarization signatures.”

The radar observations Hofgartner and Hand used were from the Arecibo Observatory, which was one of only two telescopes making radar observations of icy satellites until it was severely damaged by the collapse of its support structure, antenna and dome assembly and subsequently decommissioned. The researchers hope to make follow-up observations when possible and plan to study additional archival data that may shed even more light on icy satellites and the CBOE, as well as radar studies of ice at the poles of Mercury, the Moon, and Mars.