Mechanobiology by the numbers: a close relationship between biology and physics.

Studies of mechanobiology lie at the interface of various scientific disciplines from biology to physics. Accordingly, quantification and mathematical modelling have been instrumental in fuelling the progress in this rapidly developing research field, assisting experimental work on many levels.

Near-frictionless ion transport within triazine framework membranes.

The enhancement of separation processes and electrochemical technologies such as water electrolysers1,2, fuel cells3,4, redox flow batteries5,6 and ion-capture electrodialysis7 depends on the development of low-resistance and high-selectivity ion-transport membranes. The transport of ions through these membranes depends on the overall energy barriers imposed by the collective interplay of pore architecture and pore-analyte interaction8,9. However, it remains challenging to design efficient, scaleable and low-cost selective ion-transport membranes that provide ion channels for low-energy-barrier transport. Here we pursue a strategy that allows the diffusion limit of ions in water to be approached for large-area, free-standing, synthetic membranes using covalently bonded polymer frameworks with rigidity-confined ion channels. The near-frictionless ion flow is synergistically fulfilled by robust micropore confinement and multi-interaction between ion and membrane, which afford, for instance, a Na+ diffusion coefficient of 1.18 × 10-9 m2 s-1, close to the value in pure water at infinite dilution, and an area-specific membrane resistance as low as 0.17 Ω cm2. We demonstrate highly efficient membranes in rapidly charging aqueous organic redox flow batteries that deliver both high energy efficiency and high-capacity utilization at extremely high current densities (up to 500 mA cm-2), and also that avoid crossover-induced capacity decay. This membrane design concept may be broadly applicable to membranes for a wide range of electrochemical devices and for precise molecular separation.

The Ebola virus VP40 matrix layer undergoes endosomal disassembly essential for membrane fusion.

Ebola viruses (EBOVs) assemble into filamentous virions, whose shape and stability are determined by the matrix viral protein 40 (VP40). Virus entry into host cells occurs via membrane fusion in late endosomes; however, the mechanism of how the remarkably long virions undergo uncoating, including virion disassembly and nucleocapsid release into the cytosol, remains unknown. Here, we investigate the structural architecture of EBOVs entering host cells and discover that the VP40 matrix disassembles prior to membrane fusion. We reveal that VP40 disassembly is caused by the weakening of VP40-lipid interactions driven by low endosomal pH that equilibrates passively across the viral envelope without a dedicated ion channel. We further show that viral membrane fusion depends on VP40 matrix integrity, and its disassembly reduces the energy barrier for fusion stalk formation. Thus, pH-driven structural remodeling of the VP40 matrix acts as a molecular switch coupling viral matrix uncoating to membrane fusion during EBOV entry.

Modelling cell shape in 3D structured environments: A quantitative comparison with experiments.

Cell shape plays a fundamental role in many biological processes, including adhesion, migration, division and development, but it is not clear which shape model best predicts three-dimensional cell shape in structured environments. Here, we compare different modelling approaches with experimental data. The shapes of single mesenchymal cells cultured in custom-made 3D scaffolds were compared by a Fourier method with surfaces that minimize area under the given adhesion and volume constraints. For the minimized surface model, we found marked differences to the experimentally observed cell shapes, which necessitated the use of more advanced shape models. We used different variants of the cellular Potts model, which effectively includes both surface and bulk contributions. The simulations revealed that the Hamiltonian with linear area energy outperformed the elastic area constraint in accurately modelling the 3D shapes of cells in structured environments. Explicit modelling the nucleus did not improve the accuracy of the simulated cell shapes. Overall, our work identifies effective methods for accurately modelling cellular shapes in complex environments.

Development of a multi-step screening procedure for redox active molecules in organic radical polymer anodes and as redox flow anolytes.

Benzo[d]-X-zolyl-pyridinyl (XO, S, NH) radicals represent a promising class of redox-active molecules for organic batteries. We present a multistep screening procedure to identify the most promising radical candidates. Experimental investigations and highly correlated wave function-based calculations are performed to determine benchmark redox potentials. Based on these, the accuracies of different methods (semi-empirical, density functional theory, wave function-based), solvent models, dispersion corrections, and basis sets are evaluated. The developed screening procedure consists of three steps: First, a conformer search is performed with CREST. The molecules are selected based on the redox potentials calculated using GFN2-xTB. Second, HOMO energies calculated with reparametrized B3LYP-D3(BJ) and the def2-SVP basis set are used as selection criteria. The final molecules are selected based on the redox potentials calculated from Gibbs energies using BP86-D3(BJ)/def2-TZVP. With this multistep screening approach, promising molecules can be suggested for synthesis, and structure-property relationships can be derived.

Optimization of Mixed Micelles Based on Oppositely Charged Block Copolymers by Machine Learning for Application in Gene Delivery.

The COVID-19 mRNA vaccines represent a milestone in developing non-viral gene carriers, and their success highlights the crucial need for continued research in this field to address further challenges. Polymer-based delivery systems are particularly promising due to their versatile chemical structure and convenient adaptability, but struggle with the toxicity-efficiency dilemma. Introducing anionic, hydrophilic, or "stealth" functionalities represents a promising approach to overcome this dilemma in gene delivery. Here, two sets of diblock terpolymers are created comprising hydrophobic poly(n-butyl acrylate) (PnBA), a copolymer segment made of hydrophilic 4-acryloylmorpholine (NAM), and either the cationic 3-guanidinopropyl acrylamide (GPAm) or the 2-carboxyethyl acrylamide (CEAm), which is negatively charged at neutral conditions. These oppositely charged sets of diblocks are co-assembled in different ratios to form mixed micelles. Since this experimental design enables countless mixing possibilities, a machine learning approach is applied to identify an optimal GPAm/CEAm ratio for achieving high transfection efficiency and cell viability with little resource expenses. After two runs, an optimal ratio to overcome the toxicity-efficiency dilemma is identified. The results highlight the remarkable potential of integrating machine learning into polymer chemistry to effectively tackle the enormous number of conceivable combinations for identifying novel and powerful gene transporters.

Advancements and Challenges in the Synthesis of Oxymethylene Ethers (OMEs) as Sustainable Transportation Fuels.

The urgent need for sustainable alternatives to fossil fuels in the transportation sector is driving research into novel energy carriers that can meet the high energy density requirements of heavy-duty vehicles without exacerbating the climate change. This concept article examines the synthesis, mechanisms, and challenges associated with oxymethylene ethers (OMEs), a promising class of synthetic fuels potentially derived from carbon dioxide and hydrogen. We highlight the importance of OMEs in the transition towards non-fossil energy sources due to their compatibility with the existing Diesel infrastructure and their cleaner combustion profile. The synthesis mechanisms, including the Schulz-Flory distribution and its implications for OME chain length specificity, and the role of various catalysts and starting materials are discussed in depth. Despite advancements in the field, significant challenges remain, such as overcoming the Schulz-Flory distribution, efficiently managing water byproducts, and improving the overall energy efficiency of the OME synthesis. Addressing these challenges is crucial for OMEs to become a viable alternative fuel, contributing to the reduction of greenhouse gas emissions and the transition to a sustainable energy future in the transportation sector.

Development of Novel Redox-Active Organic Materials Based on Benzimidazole, Benzoxazole, and Benzothiazole: A Combined Theoretical and Experimental Screening Approach.

Sustainability is one of the hot topics of today's research, in particular when it comes to energy-storage systems such as batteries. Redox-active molecules implemented in organic batteries represent a promising alternative to lithium-ion batteries, which partially rely on non-sustainable heavy metal salts. As an alternative, we propose benzothiazole, -oxazole and -imidazole derivatives as redox-active moieties for polymers in organic (radical) batteries. The target molecules were identified by a combination of theoretical and experimental approaches for the investigation of new organic active materials. Herein, we present the synthesis, electrochemical characterization and theoretical investigation of the proposed molecules, which can later be introduced into a polymer backbone and used in organic polymer batteries.

The role of the nucleus for cell mechanics: an elastic phase field approach.

The nucleus of eukaryotic cells typically makes up around 30% of the cell volume and has significantly different mechanics, which can make it effectively up to ten times stiffer than the surrounding cytoplasm. Therefore it is an important element for cell mechanics, but a quantitative understanding of its mechanical role during whole cell dynamics is largely missing. Here we demonstrate that elastic phase fields can be used to describe dynamical cell processes in adhesive or confining environments in which the nucleus acts as a stiff inclusion in an elastic cytoplasm. We first introduce and verify our computational method and then study several prevalent cell-mechanical measurement methods. For cells on adhesive patterns, we find that nuclear stress is shielded by the adhesive pattern. For cell compression between two parallel plates, we obtain force-compression curves that allow us to extract an effective modulus for the cell-nucleus composite. For micropipette aspiration, the effect of the nucleus on the effective modulus is found to be much weaker, highlighting the complicated interplay between extracellular geometry and cell mechanics that is captured by our approach. We also show that our phase field approach can be used to investigate the effects of Kelvin-Voigt-type viscoelasticity and cortical tension.

Exploiting Orthogonal C-C Cross-Coupling Reactions for Chemistry-on-the-Complex: Modular Assembly of 2,6-Di(quinolin-8-yl)pyridine Ruthenium(II) Photosensitizer Triads.

In this work, we present a concise modular assembly strategy using one universal heteroleptic 2,6-di(quinolin-8-yl)pyridine-based ruthenium(II) complex as a starting building block. Extending the concept from established ligand modifications and subsequent complexation (classical route), the later appearing chemistry-on-the-complex methodology was used for late-stage syntheses, i.e., assembling discrete building blocks to molecular architectures (here: dyad and triads). We focused on Suzuki-Miyaura and Sonogashira cross-couplings as two of the best-known C-C bond forming reactions. Both were performed on one building block complex bearing a bromine and TIPS-protected alkyne for functional group interconversion (bromine to TMS-protected alkyne, a benzyl azide, or a boronic acid pinacol ester moiety with ≥95% isolated yield and simple purification) as well as building block assemblies using both a triarylamine-based donor and a naphthalene diimide-based acceptor in up to 86% isolated yield. Additionally, the developed purification via automated flash chromatography is simple compared to tedious manual chromatography for ruthenium(II)-based substrates in the classical route. Based on the preliminary characterization by steady-state spectroscopy, the observed emission quenching in the triad (55%) serves as an entry to rationally optimize the modular units via chemistry-on-the-complex to elucidate energy and electron transfer.

Knowledge-Based Design of Multifunctional Polymeric Nanoparticles.

Conventional drug delivery systems (DDS) today still face several drawbacks and obstacles. High total doses of active pharmaceutical ingredients (API) are often difficult or impossible to deliver due to poor solubility of the API or undesired clearance from the body caused by strong interactions with plasma proteins. In addition, high doses lead to a high overall body burden, in particular if they cannot be delivered specifically to the target site. Therefore, modern DDS must not only be able to deliver a dose into the body, but should also overcome the hurdles mentioned above as examples. One of these promising devices are polymeric nanoparticles, which can encapsulate a wide range of APIs despite having different physicochemical properties. Most importantly, polymeric nanoparticles are tunable to obtain tailored systems for each application. This can already be achieved via the starting material, the polymer, by incorporating, e.g., functional groups. This enables the particle properties to be influenced not only specifically in terms of their interactions with APIs, but also in terms of their general properties such as size, degradability, and surface properties. In particular, the combination of size, shape, and surface modification allows polymeric nanoparticles to be used not only as a simple drug delivery device, but also to achieve targeting. This chapter discusses to what extent polymers can be designed to form defined nanoparticles and how their properties affect their performance.

Optimal ligand discrimination by asymmetric dimerization and turnover of interferon receptors.

In multicellular organisms, antiviral defense mechanisms evoke a reliable collective immune response despite the noisy nature of biochemical communication between tissue cells. A molecular hub of this response, the interferon I receptor (IFNAR), discriminates between ligand types by their affinity regardless of concentration. To understand how ligand type can be decoded robustly by a single receptor, we frame ligand discrimination as an information-theoretic problem and systematically compare the major classes of receptor architectures: allosteric, homodimerizing, and heterodimerizing. We demonstrate that asymmetric heterodimers achieve the best discrimination power over the entire physiological range of local ligand concentrations. This design enables sensing of ligand presence and type, and it buffers against moderate concentration fluctuations. In addition, receptor turnover, which drives the receptor system out of thermodynamic equilibrium, allows alignment of activation points for ligands of different affinities and thereby makes ligand discrimination practically independent of concentration. IFNAR exhibits this optimal architecture, and our findings thus suggest that this specialized receptor can robustly decode digital messages carried by its different ligands.

[Family-focused treatment approaches for drug-addicted parents]. / Familienzentrierte Behandlungsansätze für drogenabhängige Eltern.

BACKGROUND: In Germany 1.5-2.75 million children live in families affected by substance use disorders. Substance abuse can impact on family interactions in many ways. If a dependent parental drug use continues over a longer period of time, this can have pronounced psychological and social consequences for the (co)affected children. Nevertheless, family-focused treatment approaches are not yet widely used in the context of addiction treatment. AIM: This review article aims to provide an overview of the prevalence of parenthood among dependent drug users in Germany, the impact of dependent drug use on families and family-focused treatment approaches. METHODS AND RESULTS: Recording parenthood is particularly difficult in the case of dependent drug users as they often do not openly discuss it with their therapists because of the fear of consequences from youth welfare services. In order to change this, a structured recording of parenthood by the treatment providers is required. This is the prerequisite for being able to offer family-focused treatment to those affected. In Germany, three evidence-based therapy programs are available for this purpose: SHIFT, SHIFT Plus and MAMADAM. Additionally, a number of programs developed in the Anglo-American region can also be used. In contrast, the evidence for web-based programs is much weaker. DISCUSSION: In order to establish family-focused treatment approaches for drug-using parents across the board, long-term, secure funding is required. The necessary framework conditions must be created at a political level.

High curvature promotes fusion of lipid membranes: Predictions from continuum elastic theory.

The fusion of lipid membranes progresses through a series of hemifusion intermediates with two significant energy barriers related to the formation of stalk and fusion pore, respectively. These energy barriers determine the speed and success rate of many critical biological processes, including the fusion of highly curved membranes, for example synaptic vesicles and enveloped viruses. Here we use continuum elastic theory of lipid monolayers to determine the relationship between membrane shape and energy barriers to fusion. We find that the stalk formation energy decreases with curvature by up to 31 kBT in a 20-nm-radius vesicle compared with planar membranes and by up to 8 kBT in the fusion of highly curved, long, tubular membranes. In contrast, the fusion pore formation energy barrier shows a more complicated behavior. Immediately after stalk expansion to the hemifusion diaphragm, the fusion pore formation energy barrier is low (15-25 kBT) due to lipid stretching in the distal monolayers and increased tension in highly curved vesicles. Therefore, the opening of the fusion pore is faster. However, these stresses relax over time due to lipid flip-flop from the proximal monolayer, resulting in a larger hemifusion diaphragm and a higher fusion pore formation energy barrier, up to 35 kBT. Therefore, if the fusion pore fails to open before significant lipid flip-flop takes place, the reaction proceeds to an extended hemifusion diaphragm state, which is a dead-end configuration in the fusion process and can be used to prevent viral infections. In contrast, in the fusion of long tubular compartments, the surface tension does not accumulate due to the formation of the diaphragm, and the energy barrier for pore expansion increases with curvature by up to 11 kBT. This suggests that inhibition of polymorphic virus infection could particularly target this feature of the second barrier.

Force generation in human blood platelets by filamentous actomyosin structures.

Blood platelets are central elements of the blood clotting response after wounding. Upon vessel damage, they bind to the surrounding matrix and contract the forming thrombus, thus helping to restore normal blood circulation. The hemostatic function of platelets is directly connected to their mechanics and cytoskeletal organization. The reorganization of the platelet cytoskeleton during spreading occurs within minutes and leads to the formation of contractile actomyosin bundles, but it is not known if there is a direct correlation between the emerging actin structures and the force field that is exerted to the environment. In this study, we combine fluorescence imaging of the actin structures with simultaneous traction force measurements in a time-resolved manner. In addition, we image the final states with superresolution microscopy. We find that both the force fields and the cell shapes have clear geometrical patterns defined by stress fibers. Force generation is localized in a few hotspots, which appear early during spreading, and, in the mature state, anchor stress fibers in focal adhesions. Moreover, we show that, for a gel stiffness in the physiological range, force generation is a very robust mechanism and we observe no systematic dependence on the amount of added thrombin in solution or fibrinogen coverage on the substrate, suggesting that force generation after platelet activation is a threshold phenomenon that ensures reliable thrombus contraction in diverse environments.

The role of flow in the self-assembly of dragline spider silk proteins.

Hydrodynamic flow in the spider duct induces conformational changes in dragline spider silk proteins (spidroins) and drives their assembly, but the underlying physical mechanisms are still elusive. Here we address this challenging multiscale problem with a complementary strategy of atomistic and coarse-grained molecular dynamics simulations with uniform flow. The conformational changes at the molecular level were analyzed for single-tethered spider silk peptides. Uniform flow leads to coiled-to-stretch transitions and pushes alanine residues into ß sheet and poly-proline II conformations. Coarse-grained simulations of the assembly process of multiple semi-flexible block copolymers using multi-particle collision dynamics reveal that the spidroins aggregate faster but into low-order assemblies when they are less extended. At medium-to-large peptide extensions (50%-80%), assembly slows down and becomes reversible with frequent association and dissociation events, whereas spidroin alignment increases and alanine repeats form ordered regions. Our work highlights the role of flow in guiding silk self-assembly into tough fibers by enhancing alignment and kinetic reversibility, a mechanism likely relevant also for other proteins whose function depends on hydrodynamic flow.

KAHRP dynamically relocalizes to remodeled actin junctions and associates with knob spirals in Plasmodium falciparum-infected erythrocytes.

The knob-associated histidine-rich protein (KAHRP) plays a pivotal role in the pathophysiology of Plasmodium falciparum malaria by forming membrane protrusions in infected erythrocytes, which anchor parasite-encoded adhesins to the membrane skeleton. The resulting sequestration of parasitized erythrocytes in the microvasculature leads to severe disease. Despite KAHRP being an important virulence factor, its physical location within the membrane skeleton is still debated, as is its function in knob formation. Here, we show by super-resolution microscopy that KAHRP initially associates with various skeletal components, including ankyrin bridges, but eventually colocalizes with remnant actin junctions. We further present a 35 Å map of the spiral scaffold underlying knobs and show that a KAHRP-targeting nanoprobe binds close to the spiral scaffold. Single-molecule localization microscopy detected ~60 KAHRP molecules/knob. We propose a dynamic model of KAHRP organization and a function of KAHRP in attaching other factors to the spiral scaffold.

Microtubule number and length determine cellular shape and function in Plasmodium.

Microtubules are cytoskeletal filaments essential for many cellular processes, including establishment and maintenance of polarity, intracellular transport, division and migration. In most metazoan cells, the number and length of microtubules are highly variable, while they can be precisely defined in some protozoan organisms. However, in either case the significance of these two key parameters for cells is not known. Here, we quantitatively studied the impact of modulating microtubule number and length in Plasmodium, the protozoan parasite causing malaria. Using a gene deletion and replacement strategy targeting one out of two α-tubulin genes, we show that chromosome segregation proceeds in the oocysts even in the absence of microtubules. However, fewer and shorter microtubules severely impaired the formation, motility and infectivity of Plasmodium sporozoites, the forms transmitted by the mosquito, which usually contain 16 microtubules. We found that α-tubulin expression levels directly determined the number of microtubules, suggesting a high nucleation barrier as supported by a mathematical model. Infectious sporozoites were only formed in parasite lines featuring at least 10 microtubules, while parasites with 9 or fewer microtubules failed to transmit.

Nanoparticle Formulation Composition Analysis by Liquid Chromatography on Reversed-Phase Monolithic Silica.

Multifunctional nanoparticle (NP) formulations for medical purposes have already found their way toward envisaged translation. A persistent challenge of those systems is, next to NP size analysis, the compositional analysis of the NPs with the polymer as the matrix component and the encapsulated drug, particularly in a quantitative manner. Herein, we report the formulation of poly(lactic-co-glycolic acid) (PLGA) NPs by nanoprecipitation and the analysis of their integrity and size by dynamic light scattering (DLS) and scanning electron microscopy (SEM). Those NPs feature a variety of encapsulated drugs including the well-known ibuprofen (Ibu) as well as dexamethasone (Dex) and dexamethasone acetate (DexAce), with the latter being of potential interest for clinical treatment of SARS-CoV-2 patients. All those dissolved formulation compositions have been subjected to liquid chromatography on reversed-phase silica monolithic columns, allowing to quantitatively assess amounts of small molecule drug and NP constituting PLGA polymer in a single run. The chromatographically resolved hydrophobicity differences of the drugs correlated with their formulation loading and were clearly separated from the PLGA matrix polymer with high resolution. Our study identifies the viability of reversed-phase monolithic silica in the chromatography of both small drug molecules and particularly pharmapolymers in a repeatable and simultaneous fashion, and can provide a valuable strategy for analysis of diverse precursor polymer systems and drug components in multifunctional drug formulations.

Oxymethylene Ether (OME) Fuel Catalyst Screening Using In Situ NMR Spectroscopy.

Online NMR measurements are introduced in the current study as a new analytical setup for investigation of the oxymethylene dimethyl ether (OME) synthesis. For the validation of the setup, the newly established method is compared with state-of-the-art gas chromatographic analysis. Afterwards, the influence of different parameters, such as temperature, catalyst concentration and catalyst type on the OME fuel formation based on trioxane and dimethoxymethane is investigated. As catalysts, AmberlystTM 15 (A15) and trifluoromethanesulfonic acid (TfOH) are utilized. A kinetic model is applied to describe the reaction in more detail. Based on these results, the activation energy (A15: 48.0 kJ mol-1 and TfOH: 72.3 kJ mol-1 ) and the order in catalyst (A15: 1.1 and TfOH: 1.3) are calculated and discussed.