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Phase-separated biomolecular condensates that contain multiple coexisting phases are widespread in vitro and in cells. Multiphase condensates emerge readily within multi-component mixtures of biomolecules (e.g., proteins and nucleic acids) when the different components present sufficient physicochemical diversity (e.g., in intermolecular forces, structure, and chemical composition) to sustain separate coexisting phases. Because such diversity is highly coupled to the solution conditions (e.g., temperature, pH, salt, composition), it can manifest itself immediately from the nucleation and growth stages of condensate formation, develop spontaneously due to external stimuli or emerge progressively as the condensates age. Here, we investigate thermodynamic factors that can explain the progressive intrinsic transformation of single-component condensates into multiphase architectures during the nonequilibrium process of aging. We develop a multiscale model that integrates atomistic simulations of proteins, sequence-dependent coarse-grained simulations of condensates, and a minimal model of dynamically aging condensates with nonconservative intermolecular forces. Our nonequilibrium simulations of condensate aging predict that single-component condensates that are initially homogeneous and liquid like can transform into gel-core/liquid-shell or liquid-core/gelshell multiphase condensates as they age due to gradual and irreversible enhancement of interprotein interactions. The type of multiphase architecture is determined by the aging mechanism, the molecular organization of the gel and liquid phases, and the chemical makeup of the protein. Notably, we predict that interprotein disorder to order transitions within the prion-like domains of intracellular proteins can lead to the required nonconservative enhancement of intermolecular interactions. Our study, therefore, predicts a potential mechanism by which the nonequilibrium process of aging results in single-component multiphase condensates.

Understanding the characteristics of cancer cells is essential for the development of improved diagnosis and therapeutics. From a gene regulation perspective, the super‐enhancer concept has been introduced to systematically understand the molecular mechanisms underlying the identities of various cell types and has been extended to the analysis of cancer cells and cancer genome alterations. In addition, several characteristic features of super‐enhancers have led to the recognition of the link between gene regulation and biomolecular condensates, which is often mediated by liquid‐liquid phase separation. Several lines of evidence have suggested molecular and biophysical principles and their alterations in cancer cells, which are particularly associated with gene regulation and cell signaling (“ transcriptional” and “signaling” condensates). These findings collectively suggest that the modification of biomolecular condensates represents an important mechanism by which cancer cells acquire various cancer hallmark traits and establish functional innovation for cancer initiation and progression. The condensate model also provides the molecular basis of the vulnerability of cancer cells to transcriptional perturbation and further suggests the possibility of therapeutic targeting of condensates. This review summarizes recent findings regarding the relationships between super‐enhancers and biomolecular condensate models, multiple scenarios of condensate alterations in cancers, and the potential of the condensate model for therapeutic development. In this review, we summarize recent findings regarding the relationships between super‐enhancers and the biomolecular condensates, multiple scenarios of condensate alterations in cancer, and the potentials of the condensate model for therapeutic development. Modification of biomolecular condensates may be important mechanisms by which cancer cells acquire various cancer hallmark traits and establish functional innovation for cancer initiation and progression.

Many intrinsically disordered proteins (IDPs) may undergo liquid–liquid phase separation (LLPS) and participate in the formation of membraneless organelles in the cell, thereby contributing to the regulation and compartmentalization of intracellular biochemical reactions. The phase behavior of IDPs is sequence dependent, and its investigation through molecular simulations requires protein models that combine computational efficiency with an accurate description of intramolecular and intermolecular interactions. We developed a general coarse-grained model of IDPs, with residue-level detail, based on an extensive set of experimental data on single-chain properties. Ensemble-averaged experimental observables are predicted from molecular simulations, and a data-driven parameter-learning procedure is used to identify the residue-specific model parameters that minimize the discrepancy between predictions and experiments. The model accurately reproduces the experimentally observed conformational propensities of a set of IDPs. Through two-body as well as large-scale molecular simulations, we show that the optimization of the intramolecular interactions results in improved predictions of protein self-association and LLPS.

Biomolecular condensates formed via liquid–liquid phase separation of intrinsically disordered proteins (IDPs) enhance biosynthesis by concentrating clients while enabling free material exchange.A phase regulator was constructed to control the phase transition of condensates.The phase regulator includes the light-induced expression of Tobacco Etch Virus (TEV) protease and its recognition sequence within IDPs.The phase regulator realizes the programmable fluidity of condensates.The phase regulator serves as a universal tool for improving biosynthesis. Keeping condensates in liquid-like states throughout the biosynthesis process in microbial cell factories remains an ongoing challenge. Here, we present a light-controlled phase regulator, which maintains the liquid-like features of synthetic condensates on demand throughout the biosynthesis process upon light induction, as demonstrated by various live cell-imaging techniques. Specifically, the tobacco etch virus (TEV) protease controlled by light cleaves intrinsically disordered proteins (IDPs) to alter their valency and concentration for controlled phase transition and programmable fluidity of cellular condensates. As a proof of concept, we harness this capability to significantly improve the production of squalene and ursolic acid (UA) in engineered Saccharomyces cerevisiae. Our work provides a powerful approach to program the solid–liquid phase transition of biomolecular condensates for improved biosynthesis. [Display omitted] A phase regulator, comprising the light-induced expression of a protease and its recognition sequence within intrinsically disordered proteins, was constructed to control the phase transition of biomolecular condensates. This regulator can maintain the fluidity of condensates throughout the biosynthesis process and program the solid–liquid phase transition. To maintain liquid-like features of synthetic condensates on demand throughout the biosynthesis process, we developed a light-based phase regulator and realized the solid–liquid phase transition and programmable fluidity of condensates on demand during the biosynthesis process in Saccharomyces cerevisiae. This approach proved effective in improving the biosynthesis of various natural products in microbial cell factories, reaching a Technology Readiness Level (TRL) of 4. Challenges concerning the phase regulator include limited expression elements for the tobacco etch virus (TEV) protease expression system tailored for different microorganisms with distinct metabolic microenvironments. To enhance readiness, one must consider improved genetic tools to enhance the compatibility with their host microorganisms. Nevertheless, given the ongoing interest on the liquid–solid phase transition process of condensates, we anticipate that this approach will have a promising future.

Background Biomolecular condensates have been implicated in multiple cellular processes. However, the global role played by condensates in 3D chromatin organization remains unclear. At present, 1,6-hexanediol (1,6-HD) is the only available tool to globally disrupt condensates, yet the conditions of 1,6-HD vary considerably between studies and may even trigger apoptosis. Results In this study, we first analyzed the effects of different concentrations and treatment durations of 1,6-HD and found that short-term exposure to 1.5% 1,6-HD dissolved biomolecular condensates whereas long-term exposure caused aberrant aggregation without affecting cell viability. Based on this condition, we drew a time-resolved map of 3D chromatin organization and found that short-term treatment with 1.5% 1,6-HD resulted in reduced long-range interactions, strengthened compartmentalization, homogenized A-A interactions, B-to-A compartment switch and TAD reorganization, whereas longer exposure had the opposite effects. Furthermore, the long-range interactions between condensate-component-enriched regions were markedly weakened following 1,6-HD treatment. Conclusions In conclusion, our study finds a proper 1,6-HD condition and provides a resource for exploring the role of biomolecular condensates in 3D chromatin organization.

We investigate and model a method for producing entanglement between two spatially separated Bose-Einstein condensates (BECs). In our approach, a spin-polarized BEC is squeezed using a (Sz)2 interaction, then are split into two separate clouds. After the split, we consider that the particle number in each cloud collapses to a fixed number. We show that this procedure is equivalent to applying an interaction corresponding to squeezing each cloud individually plus an entangling operation. We analyze the system's inter-well entanglement properties and show that it can be detected using correlation-based entanglement criteria. The nature of the states is illustrated by Wigner functions and have the form of a correlated squeezed state. The conditional Wigner function shows high degrees of non-classicality for dimensionless squeezing times beyond 1 N , where N is the number of particles per BEC.

Biomolecular condensates regulate transcription by dynamically compartmentalizing the transcription machinery. Classic models of transcription regulation focus on the recruitment and regulation of RNA polymerase II by the formation of complexes at the 1–10 nm length scale, which are driven by structured and stoichiometric interactions. These complexes are further organized into condensates at the 100–1,000 nm length scale, which are driven by dynamic multivalent interactions often involving domain–ligand pairs or intrinsically disordered regions. Regulation through condensate-mediated organization does not supersede the processes occurring at the 1–10 nm scale, but it provides regulatory mechanisms for promoting or preventing these processes in the crowded nuclear environment. Regulation of transcription by transcriptional condensates is involved in cell state transitions during animal and plant development, cell signalling and cellular responses to the environment. These condensate-mediated processes are dysregulated in developmental disorders, cancer and neurodegeneration. In this Review, we discuss the principles underlying the regulation of transcriptional condensates, their roles in physiology and their dysregulation in human diseases. Transcriptional condensates, which are formed through dynamic multivalent interactions between proteins, RNA and chromatin, regulate transcription by compartmentalizing its machinery in the crowded nuclear environment. These condensates regulate animal and plant development, cell signalling and responses to the environment, and they are dysregulated in developmental disorders, cancer and neurodegeneration.

A hallmark of biomolecular condensates formed via liquid-liquid phase separation is that they dynamically exchange material with their surroundings, and this process can be crucial to condensate function. Intuitively, the rate of exchange can be limited by the flux from the dilute phase or by the mixing speed in the dense phase. Surprisingly, a recent experiment suggests that exchange can also be limited by the dynamics at the droplet interface, implying the existence of an ‘interface resistance’. Here, we first derive an analytical expression for the timescale of condensate material exchange, which clearly conveys the physical factors controlling exchange dynamics. We then utilize sticker-spacer polymer models to show that interface resistance can arise when incident molecules transiently touch the interface without entering the dense phase, i.e., the molecules ‘bounce’ from the interface. Our work provides insight into condensate exchange dynamics, with implications for both natural and synthetic systems.

In recent years, quantum fluids have been studied largely in gaseous form, such as the Bose-Einstein condensates (BECs) of alkali atoms and related species. Quantum liquids, other than liquid helium, have been comparatively more difficult to come by. Cabrera et al. combined two BECs and manipulated the atomic interactions to create droplets of a quantum liquid (see the Perspective by Ferrier-Barbut and Pfau). Because the interactions were not directional, the droplets had a roughly round shape. The simplicity of this dilute system makes it amenable to theoretical modeling, enabling a better understanding of quantum fluids. Science , this issue p. 301 ; see also p. 274 Tuning interatomic interactions in two ultracold gases of potassium atoms creates quantum liquid droplets. Quantum droplets are small clusters of atoms self-bound by the balance of attractive and repulsive forces. Here, we report on the observation of droplets solely stabilized by contact interactions in a mixture of two Bose-Einstein condensates. We demonstrate that they are several orders of magnitude more dilute than liquid helium by directly measuring their size and density via in situ imaging. We show that the droplets are stablized against collapse by quantum fluctuations and that they require a minimum atom number to be stable. Below that number, quantum pressure drives a liquid-to-gas transition that we map out as a function of interaction strength. These ultradilute isotropic liquids remain weakly interacting and constitute an ideal platform to benchmark quantum many-body theories.

Creation of stable intrinsically anisotropic self-bound states with embedded vorticity is a challenging issue. Previously, no such states in Bose−Einstein condensates (BECs) or other physical settings were known. Dipolar BEC suggests a unique possibility to predict stable two dimensional anisotropic vortex quantum droplets (2D-AVQDs). We demonstrate that they can be created with the vortex axis oriented perpendicular to the polarization of dipoles. The stability area and characteristics of the 2D-AVQDs in the parameter space are revealed by means of analytical and numerical methods. Further, the rotation of the polarizing magnetic field is considered, and the largest angular velocities, up to which spinning 2D-AVQDs can follow the rotation in clockwise and anti-clockwise directions, are found. Collisions between moving 2D-AVQDs are studied too, demonstrating formation of bound states with a vortex−antivortex−vortex structure. A stability domain for such stationary bound states is identified. Unstable dipolar states, that can be readily implemented by means of phase imprinting, quickly transform into robust 2D-AVQDs, which suggests a straightforward possibility for the creation of these states in the experiment.