Defending PhD student, looking over their thesis: “If I knew then what I know now, I could’ve done all of this in like 9 months.” A thread about my favorite pioneering cave explorers and why I don’t think AI will ever “solve” biology.

@science.org Deep contrastive learning enables genome-wide virtual screening | Science www.science.org/doi/10.1126/...

I guess I should re-post from the Bird Site "The Rules For Academic Success here": I always get asked for advice about starting/surviving the tenure track. Here are the rules I've found useful. Thought I'd put it out there for the masses... This list gets longer all the time

This is a great and welcome acknowledgment that we need more publishing venues explicitly dedicated to limiting publication bias journals.plos.org/plosbiology/...

It feels to me as if this is missing something about getting out of projects that are floundering with *something* to show for the effort and investment of funds.

Blog post: Just quit Quitting projects in science is hard, but we should be doing a lot more of it. open.substack.com/pub/arjunraj...

A new community-driven lab handbook for reducing conflict and creating more positive and equitable work environments gets strong support from a survey of 200 researchers. buff.ly/K7CGFLV

Our call for 27 PULSE #postdocs is OPEN! PhD within the last 3 years looking to grow your life science career? SciLifeLab PULSE (MSCA Cofund) offers 3-year postdoc fellowships at Swedish universities with academic & industry secondments 🧪 🖥️ 🧬 📅 Apply Dec 15, 2025-Mar 16, 2026 👉 bit.ly/3MD7Pwz

Increasing TET expression and 5-hydroxymethylcytosine formation by a carbocyclic 5-aza-2'-deoxy-cytidine antimetabolite https://www.biorxiv.org/content/10.1101/2025.11.26.690736v1

Treatment with ATC, an investigational azanucleoside, invariably leads to BCP-ALL in immunodeficient mice. Read the full article in Blood Neoplasia: buff.ly/wnGzwQt

NUDT5 regulates the global efficacy of nucleoside analog drugs by coordinating purine synthesis and PRPP allocation https://www.biorxiv.org/content/10.1101/2025.11.20.689348v1

Our data complements recent works from the Yang, Kubicek/Huber, DeBerardinis, and Jourdain labs to position NUDT5 as a core regulator of nucleotide metabolism and rheostat of NA drug efficacy. A huge thanks to the Altun lab, SciLifeLab DDDP, @seanrudd.bsky.social, and others. 3/n

We find that NUDT5-depleted cells are stuck in de novo purine biosynthesis (DNPB) with impaired nucleotide salvage. NUDT5 binds PPAT, the rate-limiting enzyme of DNPB, and appears to regulate its activity and PRPP availability to impair salvage-mediated NA drug activation. 2/n

Happy to share a new preprint on NUDT5's role in regulating nucleoside analog (NA) drug efficacy. 🔗 👇 🧵: We show that perturbing NUDT5 abundance by RNAi or a PROTAC (DDD2), but not inhibition with TH5427, desensitizes cells to thiopurines and most NA drugs in a titratable manner. 1/n

1/New paper from Zheng Wu, Phong Nguyen et al. @cri-utsw.bsky.social shows how cells balance the two pathways that produce purine nucleotides: de novo purine biosynthesis (DNPB) and purine salvage. The surprising mechanism involves NUDT5, a Nudix hydrolase www.science.org/doi/10.1126/...

New preprint from the lab for any DNA repair or replication stress geeks out there! www.biorxiv.org/content/10.1...

PREACH! www.nature.com/articles/s41...

From descriptive to quantitative biocatalysis “The 1913 study ‘Die Kinetik der Invertinwirkung’, by Michaelis and Menten, marked a pivotal advancement in enzymology by illustrating the application of mechanistic models and quantitative kinetics to biocatalysis.” doi.org/10.1038/s419...

Ribonucleotide incorporation into mitochondrial DNA drives inflammation www.nature.com/articles/s41... Congratulations to the Langer lab @mpiage.bsky.social, Amir, and the rest of the team!

Excited to share our lab’s latest preprint! We identify DDIAS as a novel single-stranded DNA-binding component of the TOPBP1–CIP2A complex, which acts in a mitotic DNA damage response pathway to protect chromosome integrity. Short summary below, and read it here: www.biorxiv.org/content/10.1...

Excited to share our discovery of potent TRIM21 molecular glues with anticancer activity, online today @CD_AACR: "Defining the antitumor mechanism of action of a clinical-stage compound as a selective degrader of the nuclear pore complex". 1/18

Glioblastoma, an aggressive brain cancer, depends on the amino acid serine as a fuel source go.nature.com/4mIcCtD

My first post on bsky to share our latest research in @nature.com: “DNA2 enables growth by restricting recombination-restarted replication” - defines DNA2’s essential function & elucidates links with primordial dwarfism and cancer. Thanks to the lab, collaborators & @ukri.org @acmedsci.bsky.social

Check our new website – night-science.org – and consider also helping us to launch the Night Science Institute!

It is not always safe to repair DNA Damage. Sometimes, cells "just bypass it". During DNA replication, repair of lesions on DNA can be dangerous. Cells instead "tolerate" DNA damage and focus on finishing replication. Read our review and find out why and how: doi.org/10.1016/j.ti...

Classical macrophage activation reprograms nucleotide metabolism by suppressing de novo synthesis and enhancing salvage pathways (through nitric oxide...) @natmetabolism.nature.com doi.org/10.1038/s422... 🧪 Great N&V's on metabolic immune control by @ryanlab.bsky.social www.nature.com/artic...

High tide or low tide: the transport and metabolism of mitochondrial nucleotides portlandpress.com/biochemj/art...

new out in Nature www.nature.com/articles/s41...

A missing enzyme-rescue metabolite as cause of a rare skeletal dysplasia share.google/dUNL7g7DkUle...

New review: Mellor, Larson, and @drmengwang.bsky.social discuss the molecular mechanisms of mammalian genomic instability arising from folate deficiency and how this impacts genome biology in health and disease. rupress.org/jcb/article/... #CellMetabolism

"if we do the work only for rewards and recognition, we have gone astray. It becomes hollow. Creative work of every sort (not just science) occurs in a niche where the inner drive to understand or express and the outer drive to be rewarded achieve some balance."

#ResearchHighlight 🚨 In a recent study, the Nussenzweig lab investigated the mechanisms underlying #cytarabine-induced neurotoxicity and provide a mechanistic explanation for the differing neurotoxicity profiles of #gemcitabine. 📖⬇️

A paper from the JUMP Cell Painting Consortium presents image-based phenotypic profiles for 75% of the protein coding genome of human U-2 OS cells, offering a valuable resource for exploring gene relationships. @shantanu-singh.cc @drannecarpenter.bsky.social www.nature.com/articles/s41...

Happy to share a paper from our lab out in @hemasphere-journal.bsky.social -Resistance to antimetabolites, glucocorticoids & doxorubicin = poorer relapse-free survival -Molecular profiling reveals pre-treatment resistance signatures Huge thanks to all the co-authors and funders for their support

Interesting paper and N&V from @ryanlab.bsky.social www.nature.com/articles/s42... www.nature.com/articles/s42...

On-target toxicity limits the efficacy of CDK11 inhibition against cancers with 1p36 deletions https://www.biorxiv.org/content/10.1101/2025.08.03.668359v1

We wrote a review on the free nucleotide pool as a central playground in human, bacterial, and plant immunity – now out in Nature Reviews in Immunology www.nature.com/articles/s41... Was fun to write this piece with Dina Hochhauser! Here is a thread to explain the premises 1/

Two is better than one: Pancreatic ductal adenocarcinoma cells can become resistant to treatment with autophagy inhibitors, but combination with pyrimidine analogues shows promise. New #preLight by Hannah Pletcher covers the #preprint of Suzanne Dufresne and colleagues. Have a look!

Better version of the meme.

New preprint! We solve a mystery you didn't know existed. Mitotic cells lack new transcription but require ongoing translation. Interphase mRNA half life is only 2-4 hrs. So how do cells arrest in mitosis for hours without depleting their transcriptomes? www.biorxiv.org/content/10.1...

A novel, high-density CRISPR activation platform for mapping cancer dependencies and resistance pathways ex vivo and in vivo https://www.biorxiv.org/content/10.1101/2025.07.22.666069v1

these two threads complement each other spectacularly 1) 👇🏽 use of AI as an attack on expertise and evidence based thinking in resistance to authoritarianism

Deficiency in POLE exonuclease causes synthetic lethality in highly aneuploid cancer cells https://www.biorxiv.org/content/10.1101/2025.07.16.665237v1

Fabulous post by @randomwalker.bsky.social & Sayash raising the same concern many of us have about whether we're on the right track with how we're using AI for science. Everyone should read it, take a deep breath & think through the implications. www.aisnakeoil.com/p/could-ai-s...

Designed protein pockets recognize intrinsically disordered protein regions @science.org www.science.org/doi/10.1126/... www.science.org/doi/10.1126/... www.statnews.com/2025/07/17/n...

Our new review on how the initiation of DNA replication is coordinated with transcription is now online! Congratulations to @syedshahidmusvi.bsky.social! www.sciencedirect.com/science/arti...

Peer review meltdown in one diagram. Greater emphasis on glamour journals leads people to try their luck with mediocre papers. This drains the review pool (they often have to be re-reviewed elsewhere). That drops the accuracy of peer review, creating more incentive to submit mediocre papers…

This paper is absolutely bananas and a tour de force of structural bioinformatics. Some random tidbits:

A few years back we discovered a dual hybrid protein modification composed of ADP-ribose dinucleotide and ubiquitin (ADPr-Ub). Now we reveal that ADPr-Ub can be further ubiquitinated by the E3 ubiquitin ligase RNF114! www.nature.com/articles/s41... www.science.org/doi/10.1126/...

It is finally out 👍😀. Great job of the team (mostly absent from Bsky) and @m-saponaro.bsky.social CDK-driven phosphorylation of TRAIP is essential for mitotic replisome disassembly and MiDAS url: academic.oup.com/nar/article/...