The majority of isoform pairs (of alternatively spliced transcripts) share less than 50% of their interactions. In the context of interactome networks, alternative isoforms tend to behave like distinct proteins rather than minor variants of each other.

Proteoforms encoded by the same gene have different interactomes. This challenges: 1⃣ The interpretation of data from affinity reagents directed towards shared epitopes. 2⃣ The assignment of functions to genes. When will biological research focus on such functional differences?

People are talking about the “language of cells” and the “language of biology”, merging science and poetry. I continue to prefer rigorously defined terminology. Metaphors can be beautiful, appropriate, and useful, but rigorous science is better served by nonfiction prose.

My commute to PTI.

As an undergrad at MIT, I attended many VC presentations. They hammered home the same point: ✅ The most important success factor is the team. In the ensuing decades, I've seen evidence for it over and over. I much prefer a great team over a pile of cash.

Discuss. What are the implications for student learning and evaluation.

George Boole was born exactly 210 years ago today. He was largely self‑taught, the son of a shoemaker, yet founded what we now call Boolean algebra.

𝐶𝑜𝑚𝑏𝑖𝑛𝑎𝑡𝑜𝑟𝑖𝑎𝑙 scaling may unlock a new level of throughput. This is enabling a long-awaited experiment ! Our team, led by Jason Derks, enabled combinatorial-scaling of mass spec proteomics throughput by developing multiplexing in the time domain, timePlex. 1/n

One gene can code for proteoforms with: ◼️ different functions ◼️ different sequences ◼️ different regulation ◼️ different cell type expression Such examples should inform the interpretation of gene deletion experiments seeking to infer "gene functions".

What are effective ways to increase the rigor of scientific research and results reporting ?

Nascent proteins may be phosphorylated during translation & the phosphosite buried in the protein’s inner core Such buried phosphosite are found in ~ 1/3 of the phosphorylated human proteins. They can influence protein abundance (👇), providing another example for proteoform specific regulation.

Protein degradation plays major roles in aging physiology & pathology. We can start analyzing it quantitatively at higher resolution & scale. A promising new direction for aging research 🚀

@slavov-n.bsky.social and @anshulkundaje.bsky.social on current trends of escalating hype in #AntiScience

Aging is associated with changes in protein abundance in many organs and tissues. We find that the protein changes are cell-type specific, and thus muted in previous bulk analysis. Protein clearance rates change with age and drive the ... www.biorxiv.org/content/10.1...

I reread an old blog post that seems current. Let's have courage to defend what is right even against overwhelming might. blog.slavovlab.net/2015/06/15/v...

The ‘‘inactive’’ X chromosome (Xi) is active. Xi regulates gene expression from the active X. 1/n

Mechanotransduction in the nucleus Multiple TFs transmit mechanical forces into transcriptional regulation. Nuclear shape, size, and chromatin abnormalities are common features of many diseases.

High-protein diets are in vogue, often based on dubious quality supplements. Yet, low-protein diets appear to have aging benefits. Those are the subject of this new article in Cell: Protein restriction reprograms the multi-organ proteomic landscape of mouse aging

Many articles reported using an antibody ... that didn’t even bind the key protein in Laflamme’s testing. Those articles had been cited over 3,000 times. A key question is: ◼️ 𝐂𝐚𝐧 𝐩𝐫𝐨𝐭𝐞𝐢𝐧 𝐛𝐢𝐧𝐝𝐞𝐫𝐬 𝐚𝐜𝐡𝐢𝐞𝐯𝐞 𝐡𝐢𝐠𝐡 𝐬𝐩𝐞𝐜𝐢𝐟𝐢𝐜𝐢𝐭𝐲 𝐟𝐨𝐫 𝐞𝐯𝐞𝐫𝐲 𝐞𝐩𝐢𝐭𝐨𝐩𝐞 & 𝐩𝐫𝐨𝐭𝐞𝐨𝐟𝐨𝐫𝐦? Some investors assume an answer.

Very concerning. New research coordinated by the European Broadcasting Union (EBU) and led by the BBC has found that AI assistants – already a daily information gateway for millions of people – routinely misrepresent news content no matter which language, territory, or AI platform is tested.

How quantitative are protein abundance estimates based on affinity reagents ? These distributions of T cell lineage markers (CD3, CD4) were estimated by CITE-seq. They benefit from using some of the best antibodies available. Yet, they are highly variable across batches.

My recent meetings with pharma leadership were united by a resonant theme: - "𝑀𝑦 𝑡𝑎𝑟𝑔𝑒𝑡𝑠 𝑎𝑟𝑒 𝑝𝑟𝑜𝑡𝑒𝑖𝑛𝑠, 𝑎𝑛𝑑 𝐼 𝑛𝑒𝑒𝑑 𝑡𝑜 𝑚𝑒𝑎𝑠𝑢𝑟𝑒 𝑡ℎ𝑒𝑚 𝑑𝑖𝑟𝑒𝑐𝑡𝑙𝑦" Remarkably, very smart colleagues were unaware of the tools that can support their objectives. This is due to ...

The Science Sanz Hub did a podcast highlighting our recent preprint. www.youtube.com/watch?v=LZTX...

When the weirdo variant protein versions outnumber the “real” ones:

The big picture: Tracing the arc of conceptual milestones in life sciences over the past century, centered around major discoveries driven by evolving technologies. We are excited about the progress & the research enabled by tech from @ParallelSqTech. youtu.be/SrzoLGBVTsY?...

Deep-learning integrates heterogeneous perturbation experiments, models the context, and achieves good predictions. I like the name: - large perturbation model (LPM) It describes the model without unrealistic overstatements.

A thoughtful highlight of our results on alternate RNA decoding: Highlight: www.science.org/content/blog... Preprint: www.biorxiv.org/content/10.1...

Mechanical confinement can trigger cancer invasion. Mechanical forces regulate the switching of melanoma cell behavior between proliferation and invasion.

This community is building foundational capabilities for technological progress. Its nonprofit initiatives allow broadly sharing these capabilities. I am happy to support this mission 🚀

This article is a homecoming for me. As a PhD student, I focused on the growth-rate transcriptional regulation in yeast. Now, ~ 20 years later, we report protein regulation scaling with the growth rates of single cells in mammalian tissues. www.biorxiv.org/content/10.1...

Is your research important ? If important, make it count. Make it easy to reproduce. Share the data. Share the code. Share the metadata. Use community guidelines to facilitate reanalysis & reuse of your results. nature.com/articles/s41...

Dimensionality reduction usually loses information. - PCA loses the non-linear cycling. - t-SNE distorts the distances between the three populations -- Diffusion maps compress the early state cells and lose the cycling. Fig. 2e from nature.com/articles/s41...

Scientists often generate novel hypotheses about cancer cellular behavior, which are experimentally validated in living cells.

What is the relationship between the transcriptional induction of a gene and the fitness effect of its deletion ? This study reported remarkably low correlations in the context of heat shock response and survival.

Putting in context the gargantuan task of sequencing a human genome. blog.slavovlab.net/2023/09/23/t...

Changing 4 amino acid residues confers longevity benefits across different species. The changes maintain cGAS at a low level of ubiquitination, which facilitates DNA repair.

Overloaded slides don’t inform - they overwhelm. Deliver 1–2 takeaways, well.

A new article in nature shows linear increase accumulation in sperms cells with aging. On average, 1.67 mutations are added per year per haploid genome.

Academia is not about publishing papers. It’s about creating knowledge and teaching it to the world. It’s about asking big bold questions and mentioning the next generation of intellectual leaders. The difference makes a huge difference.

Perturb-seq datasets show a clear difference in emphasis: 1️⃣ Tahoe aimed to maximize cell numbers 2️⃣ X-Atlas/Orion aimed to maximize coverage depth What are the tradeoffs of these strategies ? What inferences benefit from 1️⃣ vs. 2️⃣ ❓

What was once a projection is now reality. Exciting times for quantitative single-cell analysis !

It's good to look back and see how far we have come since Research Fest took place almost six months ago. Over the next few weeks, we will post some throwback videos from the presentations. Let's start with opening remarks by PTI's Director, @slavov-n.bsky.social: youtu.be/Sc2QLXb84XI

Earlier this year, @parallelsq.bsky.social hosted a research fest. We began with a broad perspective: ◾️ A century of remarkable progress! Proteomics drove conceptual discoveries and medical treatments. Listen to what's next! Proteomics: The arc of progress youtu.be/Sc2QLXb84XI?...

In this article, I shared my perspective on AI. AI excels at supervised learning, and well annotated datasets can help unlock new AI capabilities. 🔗 www.nature.com/articles/s42... OA 🔗 rdcu.be/eI4JW

𝐏𝐫𝐨𝐭𝐞𝐚𝐬𝐨𝐦𝐞𝐬 𝐩𝐥𝐚𝐲 𝐤𝐞𝐲 𝐫𝐨𝐥𝐞𝐬 𝐢𝐧 𝐧𝐞𝐮𝐫𝐨𝐝𝐞𝐠𝐞𝐧𝐞𝐫𝐚𝐭𝐢𝐨𝐧 Neuronal inflammation induces PSMB8 Integrating PSMB8 into neuronal proteasomes reduces their activity This causes PFKFB3 accumulation, a metabolic switch, and ferroptosis 🧵

Recently, Sam Altman stated that limited compute may force OpenAI to choose between curing cancer and educating the world. Now, they are prioritizing their limited compute towards another TikTok-like app. Tough choices.

I am looking forward to ICSB next week. I will present: 1⃣ New technology from @parallelsq.bsky.social: parallelsq.org/blog/proteom... 2⃣ New biology from @slavovlab.bsky.social biorxiv.org/content/10.1...

mRNA-mRNA correlations across the single cells from a tissue are rarely interpreted. They differ from the corresponding protein-protein correlations? 𝐖𝐡𝐲 ❓ www.biorxiv.org/content/10.1... 🧵

Interesting questions: Why long-lived proteins exist in metabolically active cellular environments ? How are these proteins maintained over time ?

These 3-L bottles contain one million tiny colored spheres each. One sphere is black (1 ppm). Finding the black sphere is comparable to detecting a protein present at ~ 6,000 copies in the proteome of a human cell. Quantifying the protein requires analyzing multiple jars.