Bridging past with progress: My mission in the world of polymers.

Akorfa Dagadu is a winner of the fourth annual Rising Black Scientists Awards for a scholar in the physical, data, earth, and environmental sciences. We asked emerging Black scientists to tell us about their scientific vision and goals, experiences that sparked their interest in science, how they want to contribute to a more inclusive scientific community, and how these all fit together on their journey. This is her story.

Signalling mechanisms and cellular functions of SUMO.

Sumoylation is an essential post-translational modification that is catalysed by a small number of modifying enzymes but regulates thousands of target proteins in a dynamic manner. Small ubiquitin-like modifiers (SUMOs) can be attached to target proteins as one or more monomers or in the form of polymers of different types. Non-covalent readers recognize SUMO-modified proteins via SUMO interaction motifs. SUMO simultaneously modifies groups of functionally related proteins to regulate predominantly nuclear processes, including gene expression, the DNA damage response, RNA processing, cell cycle progression and proteostasis. Recent progress has increased our understanding of the cellular and pathophysiological roles of SUMO modifications, extending their functions to the regulation of immunity, pluripotency and nuclear body assembly in response to oxidative stress, which partly occurs through the recently characterized mechanism of liquid-liquid phase separation. Such progress in understanding the roles and regulation of sumoylation opens new avenues for the targeting of SUMO to treat disease, and indeed the first drug blocking sumoylation is currently under investigation in clinical trials as a possible anticancer agent.

Mitotic chromosomes are self-entangled and disentangle through a topoisomerase-II-dependent two-stage exit from mitosis.

The topological state of chromosomes determines their mechanical properties, dynamics, and function. Recent work indicated that interphase chromosomes are largely free of entanglements. Here, we use Hi-C, polymer simulations, and multi-contact 3C and find that, by contrast, mitotic chromosomes are self-entangled. We explore how a mitotic self-entangled state is converted into an unentangled interphase state during mitotic exit. Most mitotic entanglements are removed during anaphase/telophase, with remaining ones removed during early G1, in a topoisomerase-II-dependent process. Polymer models suggest a two-stage disentanglement pathway: first, decondensation of mitotic chromosomes with remaining condensin loops produces entropic forces that bias topoisomerase II activity toward decatenation. At the second stage, the loops are released, and the formation of new entanglements is prevented by lower topoisomerase II activity, allowing the establishment of unentangled and territorial G1 chromosomes. When mitotic entanglements are not removed in experiments and models, a normal interphase state cannot be acquired.

Self-oscillating polymeric refrigerator with high energy efficiency.

Electrocaloric1,2 and electrostrictive3,4 effects concurrently exist in dielectric materials. Combining these two effects could achieve the lightweight, compact localized thermal management that is promised by electrocaloric refrigeration5. Despite a handful of numerical models and schematic presentations6,7, current electrocaloric refrigerators still rely on external accessories to drive the working bodies8-10 and hence result in a low device-level cooling power density and coefficient of performance (COP). Here we report an electrocaloric thin-film device that uses the electro-thermomechanical synergy provided by polymeric ferroelectrics. Under one-time a.c. electric stimulation, the device is thermally and mechanically cycled by the working body itself, resulting in an external-driver-free, self-cycling, soft refrigerator. The prototype offers a directly measured cooling power density of 6.5 W g-1 and a peak COP exceeding 58 under a zero temperature span. Being merely a 30-µm-thick polymer film, the device achieved a COP close to 24 under a 4 K temperature span in an open ambient environment (32% thermodynamic efficiency). Compared with passive cooling, the thin-film refrigerator could immediately induce an additional 17.5 K temperature drop against an electronic chip. The soft, polymeric refrigerator can sense, actuate and pump heat to provide automatic localized thermal management.

Force-controlled release of small molecules with a rotaxane actuator.

Force-controlled release of small molecules offers great promise for the delivery of drugs and the release of healing or reporting agents in a medical or materials context1-3. In polymer mechanochemistry, polymers are used as actuators to stretch mechanosensitive molecules (mechanophores)4. This technique has enabled the release of molecular cargo by rearrangement, as a direct5,6 or indirect7-10 consequence of bond scission in a mechanophore, or by dissociation of cage11, supramolecular12 or metal complexes13,14, and even by 'flex activation'15,16. However, the systems described so far are limited in the diversity and/or quantity of the molecules released per stretching event1,2. This is due to the difficulty in iteratively activating scissile mechanophores, as the actuating polymers will dissociate after the first activation. Physical encapsulation strategies can be used to deliver a larger cargo load, but these are often subject to non-specific (that is, non-mechanical) release3. Here we show that a rotaxane (an interlocked molecule in which a macrocycle is trapped on a stoppered axle) acts as an efficient actuator to trigger the release of cargo molecules appended to its axle. The release of up to five cargo molecules per rotaxane actuator was demonstrated in solution, by ultrasonication, and in bulk, by compression, achieving a release efficiency of up to 71% and 30%, respectively, which places this rotaxane device among the most efficient release systems achieved so far1. We also demonstrate the release of three representative functional molecules (a drug, a fluorescent tag and an organocatalyst), and we anticipate that a large variety of cargo molecules could be released with this device. This rotaxane actuator provides a versatile platform for various force-controlled release applications.

Chromatin jets define the properties of cohesin-driven in vivo loop extrusion.

Complex genomes show intricate organization in three-dimensional (3D) nuclear space. Current models posit that cohesin extrudes loops to form self-interacting domains delimited by the DNA binding protein CTCF. Here, we describe and quantitatively characterize cohesin-propelled, jet-like chromatin contacts as landmarks of loop extrusion in quiescent mammalian lymphocytes. Experimental observations and polymer simulations indicate that narrow origins of loop extrusion favor jet formation. Unless constrained by CTCF, jets propagate symmetrically for 1-2 Mb, providing an estimate for the range of in vivo loop extrusion. Asymmetric CTCF binding deflects the angle of jet propagation as experimental evidence that cohesin-mediated loop extrusion can switch from bi- to unidirectional and is controlled independently in both directions. These data offer new insights into the physiological behavior of in vivo cohesin-mediated loop extrusion and further our understanding of the principles that underlie genome organization.

Population-based heteropolymer design to mimic protein mixtures.

Biological fluids, the most complex blends, have compositions that constantly vary and cannot be molecularly defined1. Despite these uncertainties, proteins fluctuate, fold, function and evolve as programmed2-4. We propose that in addition to the known monomeric sequence requirements, protein sequences encode multi-pair interactions at the segmental level to navigate random encounters5,6; synthetic heteropolymers capable of emulating such interactions can replicate how proteins behave in biological fluids individually and collectively. Here, we extracted the chemical characteristics and sequential arrangement along a protein chain at the segmental level from natural protein libraries and used the information to design heteropolymer ensembles as mixtures of disordered, partially folded and folded proteins. For each heteropolymer ensemble, the level of segmental similarity to that of natural proteins determines its ability to replicate many functions of biological fluids including assisting protein folding during translation, preserving the viability of fetal bovine serum without refrigeration, enhancing the thermal stability of proteins and behaving like synthetic cytosol under biologically relevant conditions. Molecular studies further translated protein sequence information at the segmental level into intermolecular interactions with a defined range, degree of diversity and temporal and spatial availability. This framework provides valuable guiding principles to synthetically realize protein properties, engineer bio/abiotic hybrid materials and, ultimately, realize matter-to-life transformations.

A universal interface for plug-and-play assembly of stretchable devices.

Stretchable hybrid devices have enabled high-fidelity implantable1-3 and on-skin4-6 monitoring of physiological signals. These devices typically contain soft modules that match the mechanical requirements in humans7,8 and soft robots9,10, rigid modules containing Si-based microelectronics11,12 and protective encapsulation modules13,14. To make such a system mechanically compliant, the interconnects between the modules need to tolerate stress concentration that may limit their stretching and ultimately cause debonding failure15-17. Here, we report a universal interface that can reliably connect soft, rigid and encapsulation modules together to form robust and highly stretchable devices in a plug-and-play manner. The interface, consisting of interpenetrating polymer and metal nanostructures, connects modules by simply pressing without using pastes. Its formation is depicted by a biphasic network growth model. Soft-soft modules joined by this interface achieved 600% and 180% mechanical and electrical stretchability, respectively. Soft and rigid modules can also be electrically connected using the above interface. Encapsulation on soft modules with this interface is strongly adhesive with an interfacial toughness of 0.24 N mm-1. As a proof of concept, we use this interface to assemble stretchable devices for in vivo neuromodulation and on-skin electromyography, with high signal quality and mechanical resistance. We expect such a plug-and-play interface to simplify and accelerate the development of on-skin and implantable stretchable devices.

Water-responsive supercontractile polymer films for bioelectronic interfaces.

Connecting different electronic devices is usually straightforward because they have paired, standardized interfaces, in which the shapes and sizes match each other perfectly. Tissue-electronics interfaces, however, cannot be standardized, because tissues are soft1-3 and have arbitrary shapes and sizes4-6. Shape-adaptive wrapping and covering around irregularly sized and shaped objects have been achieved using heat-shrink films because they can contract largely and rapidly when heated7. However, these materials are unsuitable for biological applications because they are usually much harder than tissues and contract at temperatures higher than 90 °C (refs. 8,9). Therefore, it is challenging to prepare stimuli-responsive films with large and rapid contractions for which the stimuli and mechanical properties are compatible with vulnerable tissues and electronic integration processes. Here, inspired by spider silk10-12, we designed water-responsive supercontractile polymer films composed of poly(ethylene oxide) and poly(ethylene glycol)-α-cyclodextrin inclusion complex, which are initially dry, flexible and stable under ambient conditions, contract by more than 50% of their original length within seconds (about 30% per second) after wetting and become soft (about 100 kPa) and stretchable (around 600%) hydrogel thin films thereafter. This supercontraction is attributed to the aligned microporous hierarchical structures of the films, which also facilitate electronic integration. We used this film to fabricate shape-adaptive electrode arrays that simplify the implantation procedure through supercontraction and conformally wrap around nerves, muscles and hearts of different sizes when wetted for in vivo nerve stimulation and electrophysiological signal recording. This study demonstrates that this water-responsive material can play an important part in shaping the next-generation tissue-electronics interfaces as well as broadening the biomedical application of shape-adaptive materials.

Chemically defined cytokine-free expansion of human haematopoietic stem cells.

Haematopoietic stem cells (HSCs) are a rare cell type that reconstitute the entire blood and immune systems after transplantation and can be used as a curative cell therapy for a variety of haematological diseases1,2. However, the low number of HSCs in the body makes both biological analyses and clinical application difficult, and the limited extent to which human HSCs can be expanded ex vivo remains a substantial barrier to the wider and safer therapeutic use of HSC transplantation3. Although various reagents have been tested in attempts to stimulate the expansion of human HSCs, cytokines have long been thought to be essential for supporting HSCs ex vivo4. Here we report the establishment of a culture system that allows the long-term ex vivo expansion of human HSCs, achieved through the complete replacement of exogenous cytokines and albumin with chemical agonists and a caprolactam-based polymer. A phosphoinositide 3-kinase activator, in combination with a thrombopoietin-receptor agonist and the pyrimidoindole derivative UM171, were sufficient to stimulate the expansion of umbilical cord blood HSCs that are capable of serial engraftment in xenotransplantation assays. Ex vivo HSC expansion was further supported by split-clone transplantation assays and single-cell RNA-sequencing analysis. Our chemically defined expansion culture system will help to advance clinical HSC therapies.

Structure and desensitization of AMPA receptor complexes with type II TARP γ5 and GSG1L.

AMPA receptors (AMPARs) mediate the majority of excitatory neurotransmission. Their surface expression, trafficking, gating, and pharmacology are regulated by auxiliary subunits. Of the two types of TARP auxiliary subunits, type I TARPs assume activating roles, while type II TARPs serve suppressive functions. We present cryo-EM structures of GluA2 AMPAR in complex with type II TARP γ5, which reduces steady-state currents, increases single-channel conductance, and slows recovery from desensitization. Regulation of AMPAR function depends on its ligand-binding domain (LBD) interaction with the γ5 head domain. GluA2-γ5 complex shows maximum stoichiometry of two TARPs per AMPAR tetramer, being different from type I TARPs but reminiscent of the auxiliary subunit GSG1L. Desensitization of both GluA2-GSG1L and GluA2-γ5 complexes is accompanied by rupture of LBD dimer interface, while GluA2-γ5 but not GluA2-GSG1L LBD dimers remain two-fold symmetric. Different structural architectures and desensitization mechanisms of complexes with auxiliary subunits endow AMPARs with broad functional capabilities.

Self-assembly of emulsion droplets through programmable folding.

In the realm of particle self-assembly, it is possible to reliably construct nearly arbitrary structures if all the pieces are distinct1-3, but systems with fewer flavours of building blocks have so far been limited to the assembly of exotic crystals4-6. Here we introduce a minimal model system of colloidal droplet chains7, with programmable DNA interactions that guide their downhill folding into specific geometries. Droplets are observed in real space and time, unravelling the rules of folding. Combining experiments, simulations and theory, we show that controlling the order in which interactions are switched on directs folding into unique structures, which we call colloidal foldamers8. The simplest alternating sequences (ABAB...) of up to 13 droplets yield 11 foldamers in two dimensions and one in three dimensions. Optimizing the droplet sequence and adding an extra flavour uniquely encodes more than half of the 619 possible two-dimensional geometries. Foldamers consisting of at least 13 droplets exhibit open structures with holes, offering porous design. Numerical simulations show that foldamers can further interact to make complex supracolloidal architectures, such as dimers, ribbons and mosaics. Our results are independent of the dynamics and therefore apply to polymeric materials with hierarchical interactions on all length scales, from organic molecules all the way to Rubik's Snakes. This toolbox enables the encoding of large-scale design into sequences of short polymers, placing folding at the forefront of materials self-assembly.

The colloidal nature of complex fluids enhances bacterial motility.

The natural habitats of microorganisms in the human microbiome, ocean and soil ecosystems are full of colloids and macromolecules. Such environments exhibit non-Newtonian flow properties, drastically affecting the locomotion of microorganisms1-5. Although the low-Reynolds-number hydrodynamics of swimming flagellated bacteria in simple Newtonian fluids has been well developed6-9, our understanding of bacterial motility in complex non-Newtonian fluids is less mature10,11. Even after six decades of research, fundamental questions about the nature and origin of bacterial motility enhancement in polymer solutions are still under debate12-23. Here we show that flagellated bacteria in dilute colloidal suspensions display quantitatively similar motile behaviours to those in dilute polymer solutions, in particular a universal particle-size-dependent motility enhancement up to 80% accompanied by a strong suppression of bacterial wobbling18,24. By virtue of the hard-sphere nature of colloids, whose size and volume fraction we vary across experiments, our results shed light on the long-standing controversy over bacterial motility enhancement in complex fluids and suggest that polymer dynamics may not be essential for capturing the phenomenon12-23. A physical model that incorporates the colloidal nature of complex fluids quantitatively explains bacterial wobbling dynamics and mobility enhancement in both colloidal and polymeric fluids. Our findings contribute to the understanding of motile behaviours of bacteria in complex fluids, which are relevant for a wide range of microbiological processes25 and for engineering bacterial swimming in complex environments26,27.

Structure, substrate recognition and initiation of hyaluronan synthase.

Hyaluronan is an acidic heteropolysaccharide comprising alternating N-acetylglucosamine and glucuronic acid sugars that is ubiquitously expressed in the vertebrate extracellular matrix1. The high-molecular-mass polymer modulates essential physiological processes in health and disease, including cell differentiation, tissue homeostasis and angiogenesis2. Hyaluronan is synthesized by a membrane-embedded processive glycosyltransferase, hyaluronan synthase (HAS), which catalyses the synthesis and membrane translocation of hyaluronan from uridine diphosphate-activated precursors3,4. Here we describe five cryo-electron microscopy structures of a viral HAS homologue at different states during substrate binding and initiation of polymer synthesis. Combined with biochemical analyses and molecular dynamics simulations, our data reveal how HAS selects its substrates, hydrolyses the first substrate to prime the synthesis reaction, opens a hyaluronan-conducting transmembrane channel, ensures alternating substrate polymerization and coordinates hyaluronan inside its transmembrane pore. Our research suggests a detailed model for the formation of an acidic extracellular heteropolysaccharide and provides insights into the biosynthesis of one of the most abundant and essential glycosaminoglycans in the human body.

Continuous air purification by aqueous interface filtration and absorption.

The adverse impact of particulate air pollution on human health1,2 has prompted the development of purification systems that filter particulates out of air3-5. To maintain performance, the filter units must inevitably be replaced at some point, which requires maintenance, involves costs and generates solid waste6,7. Here we show that an ion-doped conjugated polymer-coated matrix infiltrated with a selected functional liquid enables efficient, continuous and maintenance-free air purification. As the air to be purified moves through the system in the form of bubbles, the functional fluid provides interfaces for filtration and for removal of particulate matter and pollutant molecules from air. Theoretical modelling and experimental results demonstrate that the system exhibits high efficiency and robustness: its one-time air purification efficiency can reach 99.6%, and its dust-holding capacity can reach 950 g m-2. The system is durable and resistant to fouling and corrosion, and the liquid acting as filter can be reused and adjusted to also enable removal of bacteria or odours. We anticipate that our purification approach will be useful for the development of specialist air purifiers that might prove useful in a settings such as hospitals, factories and mines.

Ensembles of synthetic polymers mimic biological fluids.

Recently a report by Ruan et al. in Nature described how relatively simple random heteropolymers can replicate the properties of biological fluids. These polymers capture the segmental-level interactions between proteins and could enhance folding of membrane proteins, improve stability, and enable DNA sequestration in a chemistry specific manner.

Direct prediction of intrinsically disordered protein conformational properties from sequence.

Intrinsically disordered regions (IDRs) are ubiquitous across all domains of life and play a range of functional roles. While folded domains are generally well described by a stable three-dimensional structure, IDRs exist in a collection of interconverting states known as an ensemble. This structural heterogeneity means that IDRs are largely absent from the Protein Data Bank, contributing to a lack of computational approaches to predict ensemble conformational properties from sequence. Here we combine rational sequence design, large-scale molecular simulations and deep learning to develop ALBATROSS, a deep-learning model for predicting ensemble dimensions of IDRs, including the radius of gyration, end-to-end distance, polymer-scaling exponent and ensemble asphericity, directly from sequences at a proteome-wide scale. ALBATROSS is lightweight, easy to use and accessible as both a locally installable software package and a point-and-click-style interface via Google Colab notebooks. We first demonstrate the applicability of our predictors by examining the generalizability of sequence-ensemble relationships in IDRs. Then, we leverage the high-throughput nature of ALBATROSS to characterize the sequence-specific biophysical behavior of IDRs within and between proteomes.

Engineering of a chitin deacetylase to generate tailor-made chitosan polymers.

Chitin deacetylases (CDAs) emerge as a valuable tool to produce chitosans with a nonrandom distribution of N-acetylglucosamine (GlcNAc) and glucosamine (GlcN) units. We hypothesized before that CDAs tend to bind certain sequences within the substrate matching their subsite preferences for either GlcNAc or GlcN units. Thus, they deacetylate or N-acetylate their substrates at nonrandom positions. To understand the molecular basis of these preferences, we analyzed the binding site of a CDA from Pestalotiopsis sp. (PesCDA) using a detailed activity screening of a site-saturation mutagenesis library. In addition, molecular dynamics simulations were conducted to get an in-depth view of crucial interactions along the binding site. Besides elucidating the function of several amino acids, we were able to show that only 3 residues are responsible for the highly specific binding of PesCDA to oligomeric substrates. The preference to bind a GlcNAc unit at subsite -2 and -1 can mainly be attributed to N75 and H199, respectively. Whereas an exchange of N75 at subsite -2 eliminates enzyme activity, H199 can be substituted with tyrosine to increase the GlcN acceptance at subsite -1. This change in substrate preference not only increases enzyme activity on certain substrates and changes composition of oligomeric products but also significantly changes the pattern of acetylation (PA) when N-acetylating polyglucosamine. Consequently, we could clearly show how subsite preferences influence the PA of chitosans produced with CDAs.

High-frequency and intrinsically stretchable polymer diodes.

Skin-like intrinsically stretchable soft electronic devices are essential to realize next-generation remote and preventative medicine for advanced personal healthcare1-4. The recent development of intrinsically stretchable conductors and semiconductors has enabled highly mechanically robust and skin-conformable electronic circuits or optoelectronic devices2,5-10. However, their operating frequencies have been limited to less than 100 hertz, which is much lower than that required for many applications. Here we report intrinsically stretchable diodes-based on stretchable organic and nanomaterials-capable of operating at a frequency as high as 13.56 megahertz. This operating frequency is high enough for the wireless operation of soft sensors and electrochromic display pixels using radiofrequency identification in which the base-carrier frequency is 6.78 megahertz or 13.56 megahertz. This was achieved through a combination of rational material design and device engineering. Specifically, we developed a stretchable anode, cathode, semiconductor and current collector that can satisfy the strict requirements for high-frequency operation. Finally, we show the operational feasibility of our diode by integrating it with a stretchable sensor, electrochromic display pixel and antenna to realize a stretchable wireless tag. This work is an important step towards enabling enhanced functionalities and capabilities for skin-like wearable electronics.

The Cell-Death-Associated Polymer PAR Feeds Forward α-Synuclein Toxicity in Parkinson's Disease.

Parkinson's disease (PD) is characterized by protein aggregates of α-synuclein in neurons. In a recent issue of Science, Kam et al. (2018) revealed a feedforward loop in which α-synuclein increases the levels of poly(adenosine 5'-diphosphate-ribose) (PAR) that in turn causes α-synuclein aggregates to be more toxic. This study advances our understanding of PD pathology.