Thank you for another brilliant thread! Extraordinary that you were able to perform this massive service while directing a dept, writing a textbook, and (BTW) running & supporting a world-class research program. Could all be full-time jobs... pls consider future Bluetorial on time management!

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And thank you for posting this very thread today! Had no idea the multi-unit history was so complex and dramatic. Makes it all the more impressive that the JHU biophysics ecosystem has been so effective.

Experimental studies were led by Erika Ding, with Takashi Yokokura conducting hugely insightful SCFT modeling under Prof. Rui Wang's guidance. Erika and Takashi are incredibly talented and motivated ChemE PhD students ... if you see one or both in a future faculty search, give them a close look!

This may explain why M makes such important functional contributions in mouse genetic models, and why H is so thoroughly phosphorylated (another longstanding mystery) ... though additional experiments with M and H mutants reveal a much more complex picture - see paper for details.

Conversely, H's charges are much more mixed, yielding a more condensed structure. However, H does swell and approach the brush periphery when H is charged via multi-site phosphorylation at its KSP repeats – just as it is typically found in the axon.

Very briefly, we show that despite M's smaller size, it populates the outer reaches of the brush at physiol ionic strength bc a key portion of the protein has a relatively segregated charge distribution. As a result M behaves like a polyelectrolyte, with charge repulsion driving chain expansion.

Since AFM can only measure an aggregate brush height, the expts were also closely coupled to (and guided by) SCFT-based modeling led by Rui Wang's lab to gain insight into internal brush structure.

We sought to gain insight into this longstanding paradox by preparing recombinant L, M, and H, assembling them as oriented, mixed-subunit "brushes" on surfaces, and characterizing these brushes w AFM and related surface techniques.

As the name implies, H is larger than M and should protrude further from the NF core and drive network assembly. However, mouse genetics studies from the 90s/00s implicates M much more strongly in governing axonal caliber and radial growth. H is practically dispensable. How can this be?

NFs are IFs composed of 3 subunits (light, medium, heavy a.k.a. L, M & H) that co-assemble into bottlebrush-like structures. The C terminal IDRs of M and H (and to a lesser extent L) form the "bristles" of the brush and have been long presumed to mediate interactions between adjacent NFs.

As a JHU trainee of that era, these backstories are riveting. Pls keep them coming! Would love a thread on JHU biophysics... Impressively tight culture given the 2 campus/dept/PhD program setup. And so much informal dialogue, e.g. fac chalk talk dinners. How did it start and what made it work?

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Paper also includes AFM measurements of both normal and tumor-laden brain to help guide material design. Congrats to Emily and other authors!

We show that VE matrices support a special leader follower mode of invasion in which leader cells use hyaluronidases to pave paths, with followers then exploit. Invasive morphologies closely resemble those previousy seen by intravital imaging