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The reconstruction and control of supramolecular ropes using minimalist building units remains a fundamental challenge. Here the authors demonstrate self-assembly of cyclo-tryptophan-proline dipeptide stereoisomers into crystalline supramolecular triple-helical structures with tunable S- or Z- twists governed by the configuration of tryptophan residues.

Authors study links between amyloid secondary nucleation and growth defects, demonstrating these sites on Aβ40/Aβ42 fibrils are rare compared to the number of protein molecules. Re-analysis of published data suggests that defects may also drive secondary nucleation generally.

Neurodegenerative disorders remain poorly treated despite their growing disease burden. Here, authors developed a multiplexed screening platform that identified DNAJB6 as a modulator of condensate maturation and suppressor ALS/FTD-linked toxicity.

pH is a critical regulator of (bio)chemical processes and therefore tightly regulated in nature. Now, proteins have been shown to possess the functionality to drive pH gradients without requiring energy input or membrane enclosure but through condensation. Protein condensates can drive unique pH gradients that modulate biochemical activity in both living and artificial systems.

Nixon-Abell et al. show that ANXA11 condensation on lysosomal membranes causes a coupled phase transition of the underlying lipids and mechanical stiffening of the overall ensemble involved in RNP granule-lysosome tethering and co-trafficking.

The organization of supramolecular peptide polymers determines their properties; however, controlling their dimensions still remains a problem. Here, Gazitet al. show the spontaneous elongation and shortening of these polymers at an individual nano-assembly level by using a microfluidic platform.

Biomolecular phase separation arises from collective molecular interactions and is emerging as a key theme for biological function. Here the authors propose a broadly applicable method to quantify these interactions based on compositional and energetic parameters.

The cytoskeleton, a network of fibrils, controls how cells divide. Here, the authors show that synthetic protein fibrils added to an emulsion can control the division of droplets and that this method can be used to control the morphology of microparticles during biomaterial preparation.

The formation of protein aggregates is a hallmark of Parkinson’s disease, with small oligomeric species implicated as a major source of toxicity. In this work, Xu et al. determine their mechanism of formation and role in aggregation.

Using RFdiffusion, a general method for targeting intrinsically disordered proteins and regions for protein design has been developed.

Molecular chaperones from the Hsp70 family can break up protein aggregates, including amyloids. Here, the authors utilize microfluidic diffusional sizing to assess the mechanism of α-synuclein (αS) disaggregation by the Hsc70–DnaJB1–Apg2 system, and show that single αS molecules are removed directly from the fibril ends.

Experiments and computations show that the organization and dynamics of molecules within and at interfaces of biomolecular condensates are governed by differential interaction strengths leading to the classification of adsorbents versus scaffolds.

Biological photovoltaic devices (BPVs) use photosynthetic microorganisms to generate electricity, but their efficiency is low. Here the authors report power densities of over 0.5 W per m² for a flow-based BPV system, by decoupling the charging and the power delivery units.

Ruth Loos and colleagues report results of a large genome-wide association study for body mass index. They identify 18 new loci associated with this trait, some of which map near key hypothalamic regulators of energy balance.

Protein aggregation and amyloid deposition are associated with a wide range of medical disorders, including Alzheimer's disease and type II diabetes. Studies into the amyloid state are revealing fundamental principles that underlie the maintenance of protein homeostasis, and the origins of aberrant protein behaviour and disease.

Small unilamellar vesicles composed of the negatively charged lipid DMPS enhance the aggregation of the Lewy Body disease protein α-synuclein by increasing the rate of primary nucleation by a thousandfold.

Cecilia Lindgren and colleagues report results of a large-scale genome-wide association study for waist-to-hip ratio, a measure of body fat distribution. They identify 13 new loci associated with this trait, several of which show stronger effects in women than in men.

Physical characterisation of proteins is challenging. Here the authors report single-molecule microfluidic diffusional sizing (smMDS) to enable calibration-free single-molecule diffusional-sizing based monitoring of protein hydrodynamic radii even within heterogenous multicomponent mixtures.

Biomolecular condensates help cells organise their content in space and time. Here the authors report a machine learning driven methodology to predict the composition of biomolecular condensates and they then validate their predictions against the composition of known biomolecular condensates.

There are limitations with current protein sensing methods. Here the authors report DigitISA, a digital immunosensor assay based on microchip electrophoretic separation and single-molecule detection that enables quantitation of protein biomarkers in a single, solution-phase step.

The elastic energy built up during peptide self-assembly is exploited in the realization of a microactuator. The energy stored is released on millisecond timescales via a buckling instability controlled with droplet microfluidics.

A dissipative self-assembly system was developed by re-engineering a naturally hexameric adenosine 5′-triphosphatase (ATPase) enzyme (filamentous temperature-sensitive protease H) to form transient one-dimensional tubular structures in an ATP-dependent fashion. These tubular structures in turn exert negative feedback on the ATP-dependent activation of the protein building blocks.

Biomolecular condensates can contain multiple phases. The number of droplets of each phase and their location give the condensate a certain architecture. Here the authors present a method to create a range of transient architectures in biomolecular condensates, making the architecture or interfacial area controllable design variables in experiments.

Short peptides derived from the HIV-1 glycoprotein form nanofibrils that can be used to improve viral gene delivery and concentrate viruses without the need for ultracentrifugation.

The effects of four antibodies on the aggregation pathway of Aβ are examined via an in-depth kinetics approach, revealing the specific molecular steps affected by each antibody.

The H-latch is a well-defined structural change occurring in PrP^C bound to the neurotoxic antibody POM1, and its presence shows a positive correlation with neurotoxicity. Inhibition of the H-latch prolongs the lifespan of prion-diseased mice.

Suparmolecular polymers are built by monomers via non-covalent bonds, whilst the pathway of their nucleation processes is not yet clear. Here, Levin et al.show that the self-assembly of monomers proceeds through a series of metastable states, which are energetically governed by Ostwald’s rule of stages.

Aggregated forms of α-synuclein are characteristic of Parkinson’s disease. Here the authors show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules: the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein primary nucleation in the aggregation process.

The kinetics of prion aggregation are now dissected in mice, revealing slower PrP^Sc replication in vivo than in vitro and the contribution of aggregate fragmentation.

A central concept for characterising phase-separating systems is the phase diagram but generation of such diagrams for biomolecular systems is typically slow and low-throughput. Here the authors describe PhaseScan, a combinatorial droplet microfluidic platform for high-resolution acquisition of multidimensional biomolecular phase diagrams.

Biomolecular condensates with internal structure allow cells to further organise their processes. In this work the authors investigate how condensates can obtain an internal structure with droplets of dilute phase inside via kinetic, rather than purely thermodynamic driving forces.

Biomolecular condensates form via phase separation of multivalent macromolecules. Phase separation is governed by solubility whereas multivalence drives percolation, also known as gelation. The authors in this work identify the distinct energy and length scales that influence phase separation versus percolation.

Extrusion bioprinting can be used to produce living materials but controlling cell microenvironments is challenging. Here, the authors use a type of core-shell microgel ink that decouples cell culture from material processing to produce functional materials with a range of potential applications.

Well-ordered and highly rigid macroscopic films can be self-assembled from amyloid protein fibrils.

In this work the authors describe antimicrobial peptides (AMPs)-driven phase transitions of intracellular nucleic acids, whereby AMPs induce compaction and phase separation of nucleic acids, resulting in their sequestration and eventual cell death.

Developing disease-modifying drugs for neurodegenerative diseases has been very challenging. Now a machine learning approach has been used to identify small molecule inhibitors of α-synuclein aggregation, a process implicated in Parkinson’s disease and other synucleinopathies. Compounds that bind to the catalytic sites on the surface of the aggregates were identified and then progressively optimized into secondary nucleation inhibitors.

Cholesterol embedded in lipid membranes strongly promotes the aggregation of Aβ42 that is associated with Alzheimer's disease. Now, a kinetic analysis has shown that the mechanism of action responsible for this effect involves the introduction of a heterogeneous nucleation pathway that enhances the primary nucleation rate of Aβ42 aggregation by up to 20-fold.

Molecular chaperones are recognized to interfere with protein aggregation, yet the underlying mechanisms are largely unknown. Here, the authors develop a kinetic model that reveals the variety of distinct microscopic mechanisms through which molecular chaperones act to suppress amyloid formation.

All-aqueous emulsions are useful for delivering and processing biomolecules, but their stability is constrained by low interfacial adsorption energy. Song et al. solve this problem using protein nanofibrils that form a crosslinked network, whose stability is superior to conventional colloidal capsules.

α-synuclein aggregates cause neuronal damage, but their heterogeneity complicates studying their toxic properties. Here, the authors analyze α-synuclein aggregates in vitro and study post-mortem brain samples, providing evidence that small aggregates are the main culprit for neuronal death in Parkinson’s disease.

Fluorescence microscopy and kinetics analyses reveal that Aβ42 oligomers generated through secondary nucleation are responsible for membrane disruption.

Amyloid fibril formation from amyloid-beta peptides is a key feature of Alzheimer’s disease, yet the mechanisms of its spatial and temporal spread remain unclear. Here, the authors reveal that amyloid-beta 42 aggregation propagates via diffusion of oligomers in solution, highlighting these species as key drivers of the spatial spreading of aggregation.

Droplet microfluidics enables the precise fabrication of microgels, which are microscale hydrogel particles that serve as modular building blocks for biomaterials. This Review outlines principles of microfluidic microgel production, strategies for tailoring structure and functionality, and applications spanning drug delivery, cell culture and tissue engineering, while highlighting current challenges and future directions.

Labelling biomolecules to improve the sensitivity of analysis can perturb their interactions. Now, microfluidic and chemical tools have been used to allow simple, sensitive detection of a labelled system to reveal the behaviour of the native and physiologically relevant unlabelled system. The system was used to characterize the solution-phase behaviour of a clinically relevant protein–protein interaction.

An approach to design proteins that can capture amyloidogenic protein regions present in, for example, tau and Aβ42 has now been developed. These designer proteins can inhibit the formation of pathogenic amyloid fibrils and protect cells from toxic species.