TRAM promotes Toll-like-receptor-free myddosome signal transduction.

September 23, 2026| Source: Nature

In the Toll-like receptor (TLR) signal transduction pathways, activated receptors are present for mere minutes within the initial, membrane-proximal signalling complexes called proto-myddosomes 1 . Proto-myddosomes are rapidly released from TLRs to self-assemble (that is, mature) into enzyme-rich, cytosolic supramolecular organizing centres called myddosomes 2-4 . Myddosomes induce hours-long inflammatory gene expression 5-10 . The mechanism controlling proto-myddosome release and its effect on signal transduction are undefined. Here we identify factors that regulate the maturation process of proto-myddosomes into receptor-free cytosolic myddosomes 11 . Through a genetic screen in macrophages, we identify TRAM, which was previously described to control MyD88-independent TLR signalling, as a regulator of myddosome assembly. Using biochemistry, live-cell imaging and activity reconstitution with recombinant proteins, we show that the plasma-membrane-associated adapter TIRAP seeds proto-myddosomes 12,13 , after which TRAM dissociates MyD88 from the TLR-TIRAP complex to enable myddosome maturation and downstream signal transduction 14-19 . In the absence of TRAM, MyD88 cannot dissociate from the TLR-TIRAP complex, resulting in abnormal and unstable MyD88 interactions with downstream signalling enzymes. These findings enabled us to identify TRAM-dependent long-lasting myddosome activities as the determinant of two TLR pathway hallmarks: hours-long NF-κB activation 20-24 and secondary response gene expression 25-27 . Chemical dissociation of cytosolic myddosomes disrupted existing inflammatory activities of TLR-stimulated cells in vitro and in vivo. Collectively, this work establishes TRAM as a regulator of myddosome maturation and signalling, providing the molecular basis for receptor-free signal transduction.

Read the original source →

Plant fiber exploitation contributed to the emergence of ground-edged cutting tools in North China.

Ground-edged cutting tools are widely regarded as technological hallmarks of early agriculture in North China, commonly hypothesized to have been developed primarily for cereal harvesting. Yet the functional foundations of this innovation remain insufficiently tested. This study integrates use-wear and microfossil analyses of 140 stone tools from the Peiligang site, with experimental data, to reassess their roles within long-term trajectories of technological change from the Late Paleolithic to

Artificial IntelligenceSeptember 28, 2026

Neural network-augmented Pfaffian wave-functions for scalable simulations of interacting fermions.

Developing accurate numerical methods for strongly interacting fermions is crucial for improving our understanding of various quantum many-body phenomena, especially unconventional superconductivity. Recently, neural quantum states have emerged as a promising approach for studying correlated fermions, highlighted by the hidden fermion and backflow methods, which use neural networks to model corrections to fermionic quasiparticle orbitals. In this work, we expand these ideas to the space of Pfaff

Artificial IntelligenceSeptember 26, 2026

Why friends in common reveal network stars.

The Friendship Paradox states that, on average, your friends have more friends than you do. We extend this to common friends-those who appear in multiple people's friend lists. We show that the more people who share a common friend, the more connected that person tends to be, and we derive an expression quantifying this progression. In a regional Facebook network, a common friend to three randomly sampled individuals has on average more friends than 99.9% of the network. In a citation network, a

Artificial IntelligenceSeptember 26, 2026

Sensory context improves language prediction in humans and LLMs.

Language is a fundamental human capacity. Large language models (LLMs) have presented the first viable model of language outside of humans, yet how these models learn and use language differs significantly from humans. Here, we compare LLMs and humans predicting language with varying levels of sensory information-from disembodied written text to audiovisual videos of speakers-to demonstrate that, in both humans and LLMs, sensory context is critical for optimal performance. We asked human partici

Artificial IntelligenceSeptember 22, 2026

Multimodal integration supports neural processing of grammatical negation.

Negation is a fundamental aspect of human cognition and grammar, expressed across different modalities. Yet, little is known about multimodal processing of negation, especially grammatical negation (e.g., "I did not sleep"), and the contribution of gestures and prosodic markers to its neural processing remains unexplored. This study investigates the neurocognition of multimodal negation in Turkish, a verb-final language where standard verbal negation is expressed morphologically with a postverba