Michael Lin, MD PhD

"Your idea might not work, unlike these other proposals using existing technology. So, lower score for approach."

(Gets it to work, submits proposal to use it...)

"You need to add Dr. X as co-PI. He's good at using existing tech on this question. He just got lots of $$$ for it actually"

The quote is from the founding documents of the BRAIN Initiative. Its support has allowed voltage imaging to attain performance levels predicted to be impossible not so long ago.

So thx to NINDS, NIMH, and NIH for investing in technology development!

obamawhitehouse.archives.gov/node/300741

The Lin Lab is excited to bring voltage imaging to #SfN2025!

On Tuesday we'll present new ASAP sensors for spikes and subthreshold potentials, showing how even simple equipment can record multi-unit electrical activity "at the speed of thought"

See you in San Diego @sfn.org!

That, and voltage indicators residing in a thin layer of membrane, is what makes voltage imaging inherently more challenging than calcium imaging, even when the voltage indicators provide more signal per event per molecule than calcium indicators (and they do)

The traces also illustrate well why you *must* image at 400 Hz or faster. The AP-induced ASAP4e transient only lasts for one frame (≤2.5 ms). If you image at 30 Hz (33 ms integration) then you'll average down the response to noise.

So calcium transients mask real spike patterns, and may give a misleading, or at least over-persistent, impression of how sub-second sensations or motions are encoded.

They also performed calcium imaging with GCaMP6f. This gives a nice comparison of how calcium and voltage differ in kinetics.

Essentially the entire voltage trace above (4 sec) would fit into one medium-sized calcium transient below.

The FOV is 0.38mm x 0.15mm, containing 19 labelled neurons. ASAP4e spikes had dF/F of 40% and SNR of 5.5 – 7.4.

The results show nicely that voltage recordings with ASAP4e aren't difficult. You just have to image at ≥400 frames per second.

High-speed neural imaging with multiplexed miniaturized two-photon microscopy Zhang et al. develop two types of multiplexed miniaturized two-photon microscopes (M-MINI2Ps) that increase imaging speed via beam multiplexing while preserving spatial resolution and demonstrate thei...

Head-mounted 2-photon miniscope voltage imaging!

Weijian Yang's group at UC Davis sped up 2p scanning by multiplexing to achieve 400-Hz voltage imaging of ~20 neurons, using ASAP4e

These are the first freely moving single-cell voltage recordings as far as I know.

URL: www.cell.com/cell-reports...

A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers www.cell.com/cancer-cell...

Actually they don't want to pay very much for them afterwards either

Somewhere in there: thinking, reading, analyzing, advising, listening, presenting, writing papers.

Might be easier for others. Choosing to specialize in technology development is selecting difficulty mode for grant-writing... people want the tools but they don't want to pay for them in advance.

Was up until 5:30 am writing a grant, then up again at 730 for another full day to finish it today. Now done! 🎉

As academics know, it's not one job. It might be 4. With funding rates at 5%, grant-writing is 1 full-time job. Then there's letters, reviews, committee work, teaching — endless deadlines

Excited to share our latest @nature.com: How does naloxone (Narcan) stop an opioid overdose? We determined the first GDP-bound μ-opioid receptor–G protein structures and found naloxone traps a novel "latent” state, preventing GDP release and G protein activation.💊🧪 🧵👇 www.nature.com/articles/s41...

No problem!

My daughter made a series of Halloween cats using air clay. Can you recognize them all?

Would you mind posting a link to the article; I couldn't find it. Thanks!

Had the pleasure of visiting Prague as part of an advisory commission for the Czech Academy of Sciences Institute of Biotechnology. Got to check out exciting science and the impressive ultra-high resolution MS machine.

Great to see people working hard to expand knowledge, with public support too!

Kennedy’s Vaccine Panel Votes to Limit Access to Covid Shots

I cannot overstate how remarkable it is that under GOP rule, US federal health regulations have been captured by fringe crackpots who espouse views that the vast majority of the US public—and nearly 100% of health professionals—reject.

Gift link:

First clouds over Stanford since spring

I addressed this as well in the original thread. Thanks Christophe for linking to it

Thus the arbitrary 95% standard and how it is applied leads to contradictory conclusions, making scientists seem to hapless and clueless. So it harms public understanding and scientific support to insist on painting results in black or white rather than how they actually are: shades of gray.

And this is not just an academic exercise. How many times do you read in the news there is no association between risk factor X and outcome Y, only to read the opposite a few months later? These inconsistencies are often due to these Type 2 errors of declaring no difference when there was one.

It's more informative, accurate, and comprehensive than our current rules of saying yes or no when the answer is almost always different degrees of maybe. It would do justice to the concept of statistics, which is the supposed to be the science of quantifying degrees of certainty.

Then one can calmly and rationally consider whether that result provides some support for a hypothesis, together with what is mechanistically likely.

Again this would be for the 95% of non-clinical experiments that aren't addressing a hypothesis with treatment-chaning or financial implications.

This would be much more factual than "There was no significant difference between Groups A and B" or, even worse but too common, "There was no difference between Groups A and B".

Allow papers and proposals to show the graph of outcome distributions by condition and to state any possible or likely differences by the actual confidence level. For example, "Group B had 50% higher levels than Group A on average; the distributions were 90% likely non-random".

The defense of these arbitrary requirements is that they are necessary to prevent a high false-positive rate. But we don't have to generate a bunch of false negatives and throw out all discussion of actual likely differences to counteract that. There is a simple, easy, clear, and logical solution.

Thus the arbitrary 95% threshold and its enforcement by data non-discussion leads to a lot of false negative conclusions. Essentially real differences are being suppressed and thrown aside if they don't get to 95% confidence. It's wasteful and leads to actual wrong conclusions.

What makes the situation harmful is that we have imposed this arbitrary threshold of 95% confidence onto all experimental results, and reviewers for grants and papers are being instructed to not allow any discussion of differences if that threshold is not met.