The amyloid state of proteins occurs in many different contexts in Nature and in modern society, ranging from the pathological kind (neurodegenerative diseases and amyloidosis) via man-made forms (food processing and - to a much smaller extent - protein biologics) to functional versions (bacterial biofilm, peptide hormones and signal transmission). These classes all come together in the human body which endogenously produces amyloidogenic protein able to form pathological human amyloid (PaHA), hosts a microbiome which continuously makes functional bacterial amyloid (FuBA) and ingests food which can contain amyloid. This can have grave consequences, given that PaHA can spread throughout the body in a "hand-me-down" fashion from cell to cell through small amyloid fragments, which can kick-start growth of new amyloid wherever they encounter monomeric amyloid precursors. Amyloid proteins can also self- and cross-seed across dissimilar peptide sequences. While it is very unlikely that ingested amyloid plays a role in this crosstalk, FuBA-PaHA interactions are increasingly implicated in vivo amyloid propagation. We are now in a position to understand the structural and bioinformatic basis for this cross-talk, thanks to the very recently obtained atomic-level structures of the two major FuBAs CsgA (E. coli) and FapC (Pseudomonas). While there are many reports of homology-driven heterotypic interactions between different PaHA, the human proteome does not harbor significant homology to CsgA and FapC. Yet we and others have uncovered significant cross-stimulation (and in some cases inhibition) of FuBA and PaHA both in vitro and in vivo, which we here rationalize based on structure and sequence. These interactions have important consequences for the transmission and development of neurodegenerative diseases, not least because FuBA and PaHA can come into contact via the gut-brain interface, recurrent infections with microbes and potentially even through invasive biofilm in the brain. Whether FuBA and PaHA first interact in the gut or the brain, they can both stimulate and block each other's aggregation as well as trigger inflammatory responses. The microbiome may also affect amyloidogenesis in other ways, e.g. through their own chaperones which recognize and block growth of both PaHA and FuBA as we show both experimentally and computationally. Heterotypic interactions between and within PaHA and FuBA both in vitro and in vivo are a vital part of the amyloid phenomenon and constitute a vibrant and exciting frontier for future research.

An essential structural component of bacterial biofilms is functional amyloid (FuA), which also has great potential as an engineerable nano‐biomaterial. However, experimentally based high resolution structures of FuA that resolve individual residues are lacking. A fully experimentally based 3.2 Å resolution cryo‐electron microscopy density map of the FuA protein FapC from Pseudomonas sp. UK4 is presented, which reveals a Greek key‐shaped protofilament. The structure supports bioinformatic identification of conserved motifs and is broadly consistent with the AlphaFold prediction but with important modifications. Each FapC monomer consists of three imperfect repeats (IRs), with each repeat forming one cross‐β layer. An array of highly conserved Asn and Gln residues with an extensive H‐bonding network underpins this conserved Greek key‐shape and reveals the role of heterogeneous cross‐β stacking in amyloid cross‐seeding. The covariation of residues in the hydrophobic core among different IRs suggests a cooperative monomer folding process during fibril elongation, while heterogeneous stacking of IRs reduces charge repulsion between layers to stabilize the monomer fold. The FapC fibrils show intrinsic catalytic activity and strain‐dependent nanomechanical properties. Combined with mutagenesis data, the structure provides mechanistic insights into formation of FapC FuA from disordered monomers and a structural foundation for the design of novel biomaterials.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world. Platelets play an important role in thrombosis, inflammation, and tumors. This study tries to gain a pathway-based view of platelets-related samples for understanding metabolic disorders and identifying novel biomarkers in HCC by combining proteomics and metabolomics. Forty-five HCC patients and thirty-four healthy controls were included in the study. We performed label-free proteomic analysis of platelets from 14 HCC patients and 14 healthy controls. Target metabolomics analysis was performed on platelet-rich plasma (PRP) from 31 HCC patients and 20 healthy controls. Western blotting was performed to validate the results of proteomics. Glutamine (Gln) deprivation assay was conducted to evaluate the effect of Gln metabolism on the platelet-induced proliferation, migration, and invasion of HCC cells. Proteomics analysis revealed dysregulation of platelets function and energy metabolism in HCC patients compared with healthy controls. Target metabolomics analysis showed widespread dysregulation of amino acids in HCC patients. Integrating analysis of differential proteins and metabolites revealed five significant dysregulated pathways in HCC patients. Western blotting validation results showed that the expression levels of SDHB, CISY, and FUMH were significantly up-regulated in HCC patients compared to healthy controls, which was consistent with the proteomics findings. Biological function revealed that Gln-free weakens the ability of platelet-induced proliferation, migration, and invasion of HCC cells. Diagnostic evaluation demonstrated superior discriminatory power for SDHB (AUC = 0.929) compared to alpha-fetoprotein (AFP) in platelet proteomics. Furthermore, a triad of tricarboxylic acid cycle intermediates (succinic acid, fumaric acid, and malic acid) significantly enhanced the AUC, specificity, and sensitivity of distinguishing HCC patients from healthy controls compared to AFP. Through multi-omics characterization of platelets-related samples, the network of altered proteins and metabolites provides a comprehensive view of altered metabolism in the peripheral circulation of HCC patients. Gln deprivation inhibited the ability of platelet-induced malignant biology function in HCC cells. Collectively, proteomics and metabolomics provide evidence for possible future non-invasive or minimally invasive biopsies for patients with HCC.

Amyloids, once viewed solely as pathological hallmarks, are now recognized as widespread and versatile functional protein assemblies. Bacterial functional amyloids (FuBAs), particularly curli (CsgA) from Escherichia coli and FapC from Pseudomonas , have emerged as paradigms for understanding amyloid structure, assembly, and function. The recent cryo‐EM‐based structure of FapC, together with others’ combined cryo‐EM and integrative computational studies on CsgA, reveal a β‐solenoid fold stabilized by imperfect repeats, producing fibrils of exceptional stability and low polymorphism, whose biogenesis is tightly controlled through dedicated accessory factors, ensuring precise secretion and nucleation. FuBAs not only scaffold biofilms but also display intrinsic catalytic activity, expanding the biochemical repertoire of extracellular matrices. They also exhibit hierarchical mechanical properties ranging from GPa stiffness at the fibril core to kPa elasticity in hydrated biofilms. FuBA operons are phylogenetically widespread, with repeat variation contributing to sequence diversity and functional adaptability. FuBAs might be seen as evolutionary intermediates between disordered peptides with significant self‐interaction tendencies and highly structured globular proteins. Their simple structures make them robust platforms for biomaterial engineering. Understanding the interplay between sequence repeats, fibril architecture, and emergent functions opens avenues for harnessing amyloids as programmable nanomaterials with applications in catalysis, synthetic biology, and biofilm control.