Scientific publications

Dynamically adjustable gene- and cell-based therapies are recognized as next-generation medicine. However, the translation of precision therapies into clinics is limited by lack of specific switches controlled by inducers that are safe and ready for clinical use. Ferulic acid (FA) is a phytochemical with a wide range of therapeutic effects, and its salt sodium ferulate (SF) is used as an antithrombotic drug in clinics. Here, we describe an FA/SF-adjustable transcriptional switch controlled by the clinically licensed drug SF. We demonstrated that SF-responsive switches can be engineered to control CRISPR-Cas9 systems for on-command genome/epigenome engineering. In addition, we integrated FA-controlled switches into programmable biocomputers to process logic operations. We further demonstrated the dose-dependent SF-inducible transgene expression in mice by oral administration of SF tablets. Engineered switches responsive to small-molecule clinically licensed drugs to achieve adjustable transgene expression profiles provide new opportunities for dynamic interventions in gene- and cell-based precision medicine. Copyright © 2020 The Authors

Shape, dynamics, and viscoelastic properties of eukaryotic cells are primarily governed by a thin, reversibly cross-linked actomyosin cortex located directly beneath the plasma membrane. We obtain time-dependent rheological responses of fibroblasts and MDCK II cells from deformation-relaxation curves using an atomic force microscope to access the dependence of cortex fluidity on prestress. We introduce a viscoelastic model that treats the cell as a composite shell and assumes that relaxation of the cortex follows a power law giving access to cortical prestress, area-compressibility modulus, and the power law exponent (fluidity). Cortex fluidity is modulated by interfering with myosin activity. We find that the power law exponent of the cell cortex decreases with increasing intrinsic prestress and area-compressibility modulus, in accordance with previous finding for isolated actin networks subject to external stress. Extrapolation to zero tension returns the theoretically predicted power law exponent for transiently cross-linked polymer networks. In contrast to the widely used Hertzian mechanics, our model provides viscoelastic parameters independent of indenter geometry and compression velocity.

Migration of immune cells within the human body allows them to fulfill their main function of detecting pathogens. We present experimental evidence showing the optimality of the search strategy of these cells, which is of crucial importance to achieve an efficient immune response. We find that the speed and directional persistence of migrating dendritic cells in our in vitro experiments are highly correlated, which enables them to reduce their search time. We introduce theoretically a new class of random search optimization problems by minimizing the mean first-passage time (MFPT) with respect to the strength of the coupling between influential parameters. We derive an analytical expression for the MFPT in a confined geometry and verify that the correlated motion enhances the search efficiency if the mean persistence length is sufficiently shorter than the confinement size. Our correlated search optimization approach provides an efficient searching recipe and predictive power in a broad range of correlated stochastic processes.

Smart biocatalysts, in which enzymes are conjugated to stimuli-responsive polymers, have gained considerable attention because of their catalytic switchability and recyclability. Although many systems have been developed, they require separate laboratory techniques for their recovery, making them unsuitable for many practical applications. To address these issues, we designed a thermomagneto-responsive biocatalyst by immobilizing an enzyme on the terminal of thermo-responsive polymer brushes tethered on magnetic nanoparticle (NP) clusters. The concept is demonstrated by a system consisting of iron oxide NPs, poly(N-isopropyl-acrylamide), and a malonyl-Coenzyme A synthetase (MatB). By using free malonate and coenzyme A (CoA), the designed catalyst exhibits adequate activity for the production of malonyl-CoA. Thanks to the use of a magnetic NP cluster, whose magnetic moment is high, this system is fully recoverable under the magnetic field at above 32 °C because of the collapse of the thermo-responsive polymer shell in the clusters. In addition, the recycled catalyst maintains moderate activity even after three cycles, and it also shows excellent catalytic switchability, that is, negligible catalytic activity at 25 °C because of the blockage of the active sites of the enzyme by the extended hydrophilic polymer chains but great catalytic activity at a temperatures above the lower critical solution temperature at which the enzymes are exposed to the reaction medium because of the thermo-responsive contraction of polymer chains. Because the azide functionality in our system can be easily functionalized depending upon our need, such catalytically switchable, fully recoverable, and recyclable multiresponsive catalytic systems can be of high relevance for other cell-free biosynthetic approaches.

The manufacturing of conventional enzymatic biosensors produced via a layer-by-layer (LbL) approach requires expensive instrumentation, and in most cases involves a complex, resource and time-consuming fabrication process. Moreover, LbL assemblies are prone to mechanical instability that leads to irreversible changes in sensor architecture and morphology resulting in degradation of enzymatic activities and insufficient signal reproducibility. Hence, novel fabrication techniques for the production of enzymatic biosensors that are instrumentally controlled and allow reproducible, simultaneous multi-analyte detection with high specificity, temporal and spatial resolution are greatly required. Herein, we report on the development of a novel, fully instrumentally controlled, one-step synthesis approach for the production of nanoparticle-based enzymatic biosensors. The approach relies on a simultaneous encapsulation of the enzyme (glucose and alcohol oxidases), a fluoropolymer (Nafion) and noble metal nanoparticles via co-deposition from a phosphate multiple electrolyte on top of the sensor surface. Remarkably, electrochemical studies revealed that nanoparticle-based biosensors produced by this novel fabrication approach display a significantly enhanced mechanical stability (more than several orders of magnitude higher) without loss of biological activity or leakage of the enzyme or Nafion, and advanced synthesis reproducibility (40 times higher) in comparison to LbL analogues.

Two-dimensional (2D) materials based on molybdenum sulfide (MoS2) have shown promising applications in semiconductors, optoelectronics, and catalysis. The variety of applications implies a controlled manipulation of purity, shape, and phase of such materials. This work elaborates on the structural characterization of MoS2 micro-assemblies produced in a chemical vapor deposition (CVD) system with emphasis on the pyramidal structures formed at high temperature and low gas rate, on a silicon dioxide (SiO2) substrate. A precise control of temperature and gas rate in the CVD process prompts the growth of pyramidal and other micron-size arrangements of MoS2 layers. An integrative set of high-resolution and analytical electron microscopy techniques, in conjunction with Raman and X-ray photoelectron spectroscopy (XPS), revealed the structural features of the MoS2 microstructures. Raman and XPS confirmed the presence of MoS2 and some residual oxide phases. Ultra-high-resolution scanning electron microscopy provided direct observation of the distinctive stacking of layers forming the pyramidal microstructures. Cross section samples from selected structures were done using focused ion beam. An extent of transmission electron microscopy and Cs-corrected scanning transmission electron microscopy (Cs-corrected STEM) results is discussed. This approach allowed to understand the growth mechanism of the triangular MoS2 microstructures through spiral grow around a screw dislocation, initiated at the center of the assembly.

How friction affects adhesion is addressed. The problem is considered in the context of a very stiff sphere adhering to a compliant, isotropic, linear elastic substrate and experiencing adhesion and frictional slip relative to each other. The adhesion is considered to be driven by very large attractive tractions between the sphere and the substrate that can act only at very small distances between them. As a consequence, the adhesion behavior can be represented by the Johnson–Kendall–Roberts model, and this is assumed to prevail also when frictional slip is occurring. Frictional slip is considered to be resisted by a uniform, constant shear traction at the slipping interface, a model that is considered to be valid for small asperities and for compliant elastomers in contact with stiff material. A simple model for the interaction of friction and adhesion is utilized, in which some of the work done against frictional resistance is assumed to be stored reversibly. This behavior is considered to arise from surface microstructures associated with frictional slip such as interface dislocations, where these microstructures store some elastic strain energy in a reversible manner. When it is assumed that a fixed fraction of the work done against friction is stored reversibly, we obtain good agreement with data.

A platform material composed of 2D gold (Au) nanodot plasmonic single-lattices (Au-nD-PSLs) featuring tailor-engineered geometric features for visible-NIR light-driven enhanced photocatalysis is presented. Au-nD-PSLs efficiently harness incident visible-NIR electromagnetic waves to accelerate photo-chemical reactions by localized surface plasmon resonance (LSPR) effects. Au-nD-PSLs are fabricated by a straightforward, industrially scalable template-assisted approach, using nanopatterned aluminum substrates as templates. The method overcomes the constraints of direct writing lithography and allows Au-nD-PSLs to be transferred to arbitrary functional flexible substrates. Triangular lattice Au-nD-PSLs feature tunable and controllable characteristic LSPR bands across the visible spectrum. Strongly localized electromagnetic fields around Au-nD-PSLs are responsible for the outstanding photocatalytic performance of these plasmonic nanostructures, as demonstrated by finite-difference time-domain simulations and experimental observations. Our approach of rational engineering of LSPR effects in Au-nD-PSLs provides exciting opportunities to develop high-performing and reusable photocatalysts that harvest the visible-NIR spectrum for a broad range of optoelectronic and plasmonic applications.

Use of lithium metal electrodes in solid state batteries requires well-balanced electrochemical and mechanical properties for high performance yet safe application. We present a new methodology to account for coupling mechanisms between electrochemistry and mechanics, understand morphological stability and deduce stability maps for solid polymer electrolytes adjacent to metal electrodes. We use a rigorous electro-chemo-mechanical description of the polymer electrolyte and its reaction kinetics to predict the interface current density along a deformed electrolyte interface as a function of e.g. mechanical stiffness, transport and interface properties. With these results, we explore the stability of the electrolyte-electrode interface in regard to the tendency for protrusions to grow on the metal electrode. We find that there is a critical Young’s modulus of the electrolyte above which protrusion growth is suppressed. However, the critical Young’s modulus depends on the charging rate, and on the electrochemical transport properties of the electrolyte and the interface. We develop a morphological stability map in which the critical Young’s modulus separating stable and unstable behavior is identified. The results agree well with experimental findings and might help in predicting new classes of polymer electrolytes which are more likely to perform well in the effort to suppress dendrite growth.