Our world is beset by deep crises.
What are well-reasoned, constructive visions for overcoming them ?
Please share comments or references to forward-looking perspectives focused on overcoming our political and societal problems.
Next week, @andrewleduc.bsky.social will present at the CSHL Systems Biology: Global Regulation of Gene Expression meeting.
His talk will focus on in vivo protein regulation in single cells, including results from this preprint:
www.biorxiv.org/content/10.1...
Americans are losing jobs, and the unemployment rate is rising.
... adversely affects the proteostasis and meiosis networks in human oocytes.
Single-cell proteomics reveals decreased abundance of proteostasis and meiosis proteins in advanced maternal age oocytes
academic.oup.com/molehr/artic...
Many human proteins are long-lived.
This includes proteins in oocytes, whose maintenance is essential for reproductive success.
Our results reveal lower levels of proteasomes & proteostasis regulators in advanced maternal age oocytes.
This suggests that advanced age ...
We have known that proteins are made of amino-acids for ~ 120 years.
In 1902, Fischer and Hofmeister proposed that the -NH2 of one amino acid binds the -C00H of another, resulting in a linear structure that Fischer termed "peptide".
...his strong and unapologetic opinions, and his deep, unwavering commitment to his students and to the broader scientific community.
Beyond his scientific contributions, Davidโs most enduring legacy may be the generations of scientists he trained and inspired.
www.online-tribute.com/DavidBotstein
David Botstein was a towering figure in genetics, genomics and biology. He was a mentor of extraordinary impact, which I experienced personally as a PhD student in his group at Princeton University.
He will be remembered for his incisive and formidable intellect, ...
Links to the article:
Journal: www.annualreviews.org/content/jour...
OA: slavovlab.net/Slavov-Lab-P...
When I think on the timescale of days and weeks, progress can be frustratingly slow.
Shifting to the timescale of years, the progress is spectacular: Often faster than expected.
Living through the arc of technology development has been awesome.
The best is yet to come ๐
The human brain consumes ~20โ25 W.
A substantial fraction of this energy is used for protein maintenance, synthesis and degradation.
Thus, the energy used directly for information processing 'compute' is less than ~20โ25 W
This turned out just as expected:
"Over the next few years, improvements in sample preparation, peptide separation and ionization, and instrumentation are likely to afford quantification of more than 5000 proteins across thousands of single cells, while targeted approaches are poised to ..."
Six years on from this perspective: science.org/doi/10.1126/...
The technology has rapidly advanced and spread beyond a few pioneering labs.
I am excited for the next phase, when the technology will increasingly enable mechanistic investigations & discoveries.
๐
This Quanta Magazine articles dives into the history and new evidence for the roles of astrocytes and their control over neurons:
"The results suggest that neuron-only brain models, such as connectomes, leave out a crucial layer of regulation."
www.quantamagazine.org/once-thought...
Understanding the brain requites more than neuron connectivity:
> These waves of calcium, rippling across astrocytes, reflect signaling dynamics that modulate neurons.
Neuromodulation is necessary for keeping the brainโs activity level in a functional range.
Real productivity means:
โข Asking meaningful questions
โข Testing them rigorously
โข Building knowledge stands the test of time
Letโs optimize for truth, not voluminous output.
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What do we call โproductiveโ research?
More papers?
More citations?
More references no one has actually read?
Publishing articles padded with unread or even nonexistent references isnโt productivity. Itโs a wasteful activity.
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This suggests a shift in how aging cells source amino acids: Relying more on internal recycling and less on extracellular supply.
We still donโt fully understand the mechanism and its contributions to aging.
3/
These distributions are over single cells from mice eating food labeled with heavily lysine for 5 days.
Data from: www.biorxiv.org/content/10.1...
They show a robust trend: When pulsed with heavy amino acids, old cells often incorporate less of the new (heavy) amino acids into proteins.
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Here is a robust biochemical & functional difference between young and old mammalian cells:
- The fraction of new amino acids incorporated into proteins.
The difference is consistent, quantitative, cell-type specific, and deeply intriguing.
What aging mechanisms cause it ?
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At the same time, some proteins are very long-lived. Some persist as long as the organism itself.
Protein lifetimes range from minutes to decades:
that's a dynamic range of ~6,000,000-fold.
Lifetimes vary across cell types & states, and these dynamics are essential to life!
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Most proteins in mammalian tissues are cleared in just a few days.
That's a remarkable rate of degradation & rebuilding !
Interestingly, degradation rates vary significantly across the cell types within a tissue.
www.biorxiv.org/content/10.1...
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Recently, the FDA granted Premarket Approval to IsoPSA for prostate cancer diagnosis.
This approval reflects a promising direction:
โผ๏ธ Improved diagnostic specificity based on protein modifications (proteoforms).
==> ๐๐๐ญ'๐ฌ ๐๐ฅ๐๐ฏ๐๐ญ๐ ๐จ๐ฎ๐ซ ๐๐ฌ๐ฌ๐๐ฒ๐ฌ -- ๐๐ง๐ ๐ญ๐ก๐ข๐ง๐ค๐ข๐ง๐ -- ๐ญ๐จ ๐ญ๐ก๐ ๐ฉ๐ซ๐จ๐ญ๐๐จ๐๐จ๐ซ๐ฆ ๐ฅ๐๐ฏ๐๐ฅ.
Many things are beyond our control, but we control how we treat other people.
We can choose to act with integrity.
We can choose to be authentic & empathetic.
We can choose to pay attention, help, support and encourage our colleagues.
๐๐ก๐จ๐จ๐ฌ๐ ๐ญ๐จ ๐๐๐ก๐๐ฏ๐ ๐๐ฌ ๐ญ๐ก๐ ๐ฉ๐๐ซ๐ฌ๐จ๐ง ๐ฒ๐จ๐ฎ ๐ฐ๐๐ง๐ญ ๐ญ๐จ ๐๐.
The "publish or perish" mentality is said to lead to low-quality publications.
There is truth to that.
But I never felt this pressure.
For me, publishing for the sake of publishing is a form of perishing โ much worse than leaving academia.
You can help enable the quantification of thousands of samples/day without sacrificing depth or accuracy.
What makes this position special is that these technologies are directly and tightly integrated with biological discovery.
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jobs.lever.co/convergentre...
A special opportunity for lovers of mass spectrometry proteomics to join a like-minded team at PTI.
Join a collaborative initiative to enable direct protein analysis at unprecedented scale, in partnership with leading instrument developers, academics, and industry leaders.
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A recurrent theme in ML:
โผ๏ธ Poorly trained models appear to excel at predictions.
"Because the sequence and its function are inexorably linked, even a maximally overfit model with no understanding of gene regulation can predict the expression of sequences that are similar to its training data."
Weโre testing conceptual hypotheses, dissecting disease progression, proteostasis, protein degradation, PTMs, and aggregation, all with focus on creative, rigorous data interpretation.
If you want to do science that changes how we think, this is it. ๐
jobs.lever.co/convergentre...
๐ฅ Weโre hiring! A rare opportunity to rethink neurodegeneration:
๐ฆ Develop creative, rigorous approaches to data interpretation toward mechanistic insights.
Join our team at PTI to study neurodegenerative disease using direct protein analysis at single-cell resolution.
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