I sometimes make fun of microglia, because they were (unfairly) given a name that means “tiny glue.” They deserve better: these are immune cells that live in the brain and attend to numerous important matters (none of which involve glue). A new paper in Cell Reports shows that microglia in mice are strikingly different between males and females, and for me this adds to their mystique as quiet heroes of the brain and to the pathos of their silly name.

So, what is strikingly different? PLX3397 is an inhibitor of the CSF1 receptor, but what matters to us mere mortals is that its action causes loss of microglia from a treated brain. The drug is used widely to erase microglia, facilitating subsequent experimental manipulations. The authors show that its effects differ based on sex and that the difference is likely connected to very different actions of the surviving microglia: in males, the survivors make more mitochondria; in females, the survivors invest in protein retention and recycling (proteostasis and autophagy). As the authors conclude in their abstract: “These findings suggest sex-dependent microglial survival mechanisms, which might contribute to the well-documented sex differences in various neurological disorders.” That is an interesting and important result. But one more thing. The title was, I think, written for specialists who know a lot about CSF1 and who know what PLX3397 does. Those excluded from this company discover the key difference at the end of the title, which (please humor me) could have been “Sex differences in microglia are revealed by differential response to inhibition of Colony-stimulating factor.” Just a thought.

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The microglial response to inhibition of Colony-stimulating-factor-1 receptor by PLX3397 differs by sex in adult mice
In Cell Reports, 25 January 2025
From the lab of Ania K. Majewska.

Snippet by Stephen Matheson

Image credit: graphical abstract from Le et al. linked above.

Polar bears are classic examples of “charismatic megafauna,” finishing a solid 8th in a 2018 survey of the most charismatic species on earth. (The Top 20 ranking includes zero birds, and 4 of the top 7 are murderous cats, which reveals more about humans than it does about other animals.) I certainly agree that they are charismatic, having watched them perform at a zoo many years ago, though I admit my fanhood was diminished by watching them hunt baby belugas in the not-very-deep blue sea.*

One thing that stands out is that fur. It’s not actually white—it’s hollow and thereby provides insulation. Maybe you knew that, but did you know that polar bear fur doesn’t accumulate ice? It should (water and cold and all) but it doesn’t, and a recent paper in Science Advances explains why: the fur contains a lot of greasy secretions. NPR already did a great job on the story, in which the lead author connects her team’s findings to people and the past: “We didn’t discover it,” she says. “It’s been known to Arctic people for centuries.” Their abstract notes that the work “builds on Inuit knowledge of natural anti-icing materials.”

In that vein, here is some nice writing in the Introduction, that caught my eye for its opening of a window to the past:

…polar bears are known to slide on snow and ice (Fig. 1A). An early account of this behavior is given by the Inuk hunter and artist Jakob Danielsen (1888 to 1938). He writes: The (polar bear) mother plays a lot with her young. We see in the mountains that they have made slides on the snow slopes down which they go on their tail all in the same track (25) (p. 317).

See bottom for a picture of a bear doing that! It’s Figure 1 of the paper.

*Listen to “Baby Beluga” by Raffi if my phrasing seems weird to you.

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Anti-icing properties of polar bear fur
in Science Advances, 29 January 2025
From the lab/group of Bodil Holst.

Snippet by Stephen Matheson.

Is age really just a number? Hundreds of “aging clocks” developed over the last 10–15 years suggest that it is. These clocks aim to measure biological age rather than chronological age—initially using DNA methylation, more recent examples use, e.g., blood proteins. A recent preprint goes a step further by developing “tissue clocks” that predict the biological age of different human tissues from images or even blood samples. The authors reason that tissue structure, with its direct links to physiological fitness, is a better indicator of aging than molecular and cellular changes. For example, dwindling blood vessel numbers and accumulating fibrosis (scarring) are tell-tale signs of tissue aging—wrinkles are not just skin-deep… Perhaps we will soon be able to test which of our organs are aging faster than others, taking personalized medicine to a new level.

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Tissue clocks derived from histological signatures of biological aging enable tissue-specific aging predictions from blood
bioRxiv, November 2024
From the lab of André F. Rendeiro.

Snippet by Katrina Woolcock.

Consider whether you would read an article that reached a conclusion like this: “Our results thus reveal a range of strategies for investing resources in the most expensive machines at the heart of this process.” I probably wouldn’t, since words like “invest” and “expensive” are—shall we say—unattractive to me. But what if the sentence is actually this: “Our results thus reveal a range of strategies for investing resources in the molecular machines at the heart of cellular self-replication.” That’s a sentence from the abstract of this interesting paper in Nature Communications, “Single-cell data reveal heterogeneity of investment in ribosomes across a bacterial population.” The authors looked at ribosome numbers and synthesis in individual bacterial cells and found surprising diversity in ribosomal mass and in the timing of responses of individual cells to challenges. Populations are known to respond to metabolic challenges with corresponding shifts in allocation of resources to ribosomal synthesis, but the new paper shows that individual cells vary dramatically in how they do this.

The authors end their paper with this clear and compelling overview, brimming with great metaphors:

…we thus quantified, using a combination of reporter genes and statistical inference algorithms, dynamic investment in ribosomes on the single-cell level. The results reveal a surprising variability in the allocation of resources to ribosomes, the most costly molecular machine in bacterial cells, during both balanced and unbalanced growth. This raises fundamental questions on the role of the variability of ribosome concentrations in shaping the growth of a bacterial population and its adaptation to changing environments. Given the importance of growth and adaptation in biomedical and biotechnological applications, we expect our findings to have practical implications as well.

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Single-cell data reveal heterogeneity of investment in ribosomes across a bacterial population
Nature Communications 2 Jan 2025
From the labs of Johannes Geiselmann and Hidde de Jong.

Snippet by Stephen Matheson

Bats are wonders. These are mammals with powered flight, a group of species with a diverse array of senses (sonar!) and lifestyles, that dart around the Sonoran desert where I live, eating flying insects and pollinating native plants. Okay, so they’re also vast reservoirs of coronaviruses, but even that is wildly interesting. Consider a new paper in Nature that just added ten new bat genomes to the genomeosphere (it’s part of an effort called Bat1K; what a time to be alive). They describe scores of immune-related adaptations in bats, many of them clearly positively selected during bat evolution. That alone is interesting, but the work adds to our answers to some big questions: why are bats so tolerant of coronaviruses (they harbor zillions of them but don’t get sick), and how did that come to be in bat lineages? The possible answers are related: bats don’t respond to viral infections (of all kinds) with inflammatory outbursts, and one postulated reason for that is the need for flying mammals, with huge metabolic rates, to avoid triggering inflammation just by being intense. The new paper strengthens this hypothesis by describing significant evolution of immune-related genes in bat lineages, beginning in the ancestral lineage.

Here is some nice science writing from the Results section (lightly edited to remove figure references):

…the ancestral chiropteran branch has almost twice as many immune genes under selection than expected […], thus exhibiting a higher excess of immune gene selection than ancestral branches of all other orders (for example, 42 versus 25 for Afrotheria and 20 versus 21 for Rodentia). A similar pattern is observed for GO ‘immune response’ and SARS-CoV-2 relevant immune pathways. By contrast, genes that are potentially relevant for other bat adaptations (such as longevity and echolocation) show no excess of selection. Together, these data indicate that chiropteran immune system changes are distinctive adaptations that originated early in the chiropteran lineage at the branch in which powered flight also evolved.

 

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Bat genomes illuminate adaptations to viral tolerance and disease resistance
Nature 29 Jan 2025
From the labs of Michael Hiller and Aaron Irving

Snippet by Stephen Matheson