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Purushottam Dixit @pdixit.bsky.social · Jul 30

We look forward to submitting our revision. As always, our experience with the new reviewing model of @elife.bsky.social has been wonderful! 6/n n =6

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Purushottam Dixit @pdixit.bsky.social · Jul 30

The implications?
It’s not just who binds tighter, but who survives the network's non-equilibrium processing.

Ligand-specificity is an emergent property of the entire network architecture not just binding thermodynamics 5/n

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Purushottam Dixit @pdixit.bsky.social · Jul 30

This behavior emerges only when the system is driven out of equilibrium. Energy dissipation (via dissociation and degradation) enables sharp ligand discrimination—not possible in equilibrium systems. 4/n

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Purushottam Dixit @pdixit.bsky.social · Jul 30

This means:
➡️Increasing ligand affinity can decrease signaling.
➡️The system has an optimal “sweet spot” for specificity and kinase activity
➡️Ligands with similar affinities can produce very different outputs depending on cellular parameters 3/n

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Purushottam Dixit @pdixit.bsky.social · Jul 30

We built a minimal model of receptor signaling that includes common signaling receptor features: Multi-site phosphorylation, rapid dissociation, and Ligand-dependent receptor degradation. Together, they create non-monotonic responses to ligand affinity and kinase activity. 2/n

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Purushottam Dixit @pdixit.bsky.social · Jul 30

It’s often assumed that stronger ligand binding = stronger signaling with non-equilibrium effects further enhancing this preference (a.k.a. kinetic proofreading). But often, thermodynamics preference is reversed! We asked: could non-equilibrium mechanisms help explain why? 1/n

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Purushottam Dixit @pdixit.bsky.social · Jul 30

Just out: new preprint (with @ralitsamadsen.bsky.social) is now #Reviewed at @eLife! "Non-equilibrium strategies for ligand specificity in signaling networks". We show how cells use non-equilibrium strategies to discriminate between ligands in surprising ways 🔗 elifesciences.org/reviewed-pre...

Non-equilibrium strategies for ligand specificity in signaling networks

elifesciences.org

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Purushottam Dixit @pdixit.bsky.social · Jul 23

We have a funding for postdoctoral fellowship that needs to be filled very soon. We are exploring new directions (1) at the interface of non-equilibrium computations and physical learning and (2) in building ecologically motivated machine learning models for microbiomes. Please spread the word!

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Purushottam Dixit @pdixit.bsky.social · May 29

What about accessible surface area? You get to choose the size of the "probe" which may be useful: en.wikipedia.org/wiki/Accessi...

Accessible surface area - Wikipedia

en.wikipedia.org

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Purushottam Dixit @pdixit.bsky.social · Feb 26

Just learnt that our collaborative grant proposal on identifying master regulators of T cell metabolism in Lupus will not be reviewed as the study section was indefinitely postponed, along with many other grants that are vital to biomedical research.

Purushottam Dixit @pdixit.bsky.social · Feb 11

Ugh that sucks! Let's hope for the best..

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Purushottam Dixit @pdixit.bsky.social · Feb 11

Thank you! We submitted one last December, so it technically is before the expiration date in Jan 2025.

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Purushottam Dixit @pdixit.bsky.social · Feb 6

Has anybody looked at approximate Bayesian computation (ABC) using stat mech? The formulation used in rejection ABC: rho(S(D),S(D')) < eps (rho is discrepancy function, S is a summary stat, D is data, D' is simulated data) looks an awful lot like the microcanonical ensemble with an energy = S(D).

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Purushottam Dixit @pdixit.bsky.social · Dec 10

Our work on computational design of microbiomes with desired host properties using mechanistic models is now out in mSystems: journals.asm.org/doi/10.1128/...

Designing host-associated microbiomes using the consumer/resource model | mSystems

Generative models are extremely popular in modern biology. They have been used to model the variation of protein sequences, entire genomes, and RNA sequencing profiles. Importantly, generative models ...

journals.asm.org

Purushottam Dixit @pdixit.bsky.social · Nov 25

Analysis of available signaling network parameters suggests that LAGS is widely applicable. Moreover, preferential degradation is just one mechanism for integral feedback control. Therefore, other habituation mechanisms e.g. activity induced inactivation, should also work the same way!

Purushottam Dixit @pdixit.bsky.social · Nov 25

Additionally, when combined with receptor oligomerization, an increase in preferential degradation allows cells to sense relative ligand gradients over a larger range of background ligand concentrations. This is sometimes known as the Weber-Fechner law.

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Purushottam Dixit @pdixit.bsky.social · Nov 25

In LAGS, receptor activity is localized through receptor degradation or ligand unbinding. In contrast, uniform ligand sensitivity is maintained through receptor diffusion. Thus, increasing active receptor degradation and increasing diffusion of all receptors both sharpen receptor polarization.

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Purushottam Dixit @pdixit.bsky.social · Nov 25

This phenomenon can be summarized as a general principle: Localized Activity Global Sensitization (LAGS).

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Purushottam Dixit @pdixit.bsky.social · Nov 25

Many receptor families undergo activity-induced degradation. Additionally, receptors undergo lateral diffusion. Both these processes will blunt receptor polarization. Using a simple model, we show that two wrongs can make a right! The two processes in fact collaborate to enhance polarization.

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Purushottam Dixit @pdixit.bsky.social · Nov 25

Unlike small prokaryotes, large eukaryotic cells can sense chemical gradients on their cell surface via receptor polarization; asymmetric partitioning of ligand-bound activated receptors in alignment with extracellular gradients.

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Purushottam Dixit @pdixit.bsky.social · Nov 25

Happy to present our second paper on understanding ligand sensing using non-equilibrium reaction networks. Here, we look at some counterintuitive results on how eukaryotic cells sense extracellular spatial gradients in ligands (e.g. growth factors): www.biorxiv.org/content/10.1...

Receptor polarization through localized activity and global sensitization

Eukaryotic cells chemosense concentration gradients of extracellular ligands using membrane-bound receptors that polarize their activity. Receptors from several chemosensing families are preferentiall...

www.biorxiv.org

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Purushottam Dixit @pdixit.bsky.social · Nov 21

Could you please add me?

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Purushottam Dixit @pdixit.bsky.social · Nov 18

Given the ubiquity of receptor degradation and desensitization in signaling networks, we think that this mechanism is likely to be quite universal, e.g. in GPCRs and ligand gated ion channels.

Purushottam Dixit @pdixit.bsky.social · Nov 18

We stumbled on a mechanism, kinetic sorting, that is likely to be generally applicable. The signaling network sorts the flux of receptors towards degradation/desensitization depending on the bound ligand. This allows it to change its discrimination in favor of the weaker ligand.

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Purushottam Dixit @pdixit.bsky.social · Nov 18

We set out to explain this observation which goes against traditional proofreading, a non-equilibrium mechanism that typically enhances discrimination in favor of the high-affinity ligand beyond thermodynamic preference.

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