Transiently delocalized states enhance hole mobility in organic molecular semiconductors.

Evidence shows that charge carriers in organic semiconductors self-localize because of dynamic disorder. Nevertheless, some organic semiconductors feature reduced mobility at increasing temperature, a hallmark for delocalized band transport. Here we present the temperature-dependent mobility in two record-mobility organic semiconductors: dinaphtho[2,3-b:2',3'-f]thieno[3,2-b]-thiophene (DNTT) and its alkylated derivative, C8-DNTT-C8. By combining terahertz photoconductivity measurements with atomistic non-adiabatic molecular dynamics simulations, we show that while both crystals display a power-law decrease of the mobility (µ) with temperature (T) following µ ∝ T -n, the exponent n differs substantially. Modelling reveals that the differences between the two chemically similar semiconductors can be traced to the delocalization of the different states that are thermally accessible by charge carriers, which in turn depends on their specific electronic band structure. The emerging picture is that of holes surfing on a dynamic manifold of vibrationally dressed extended states with a temperature-dependent mobility that provides a sensitive fingerprint for the underlying density of states.

Understanding Stimulation of Conjugal Gene Transfer by Nonantibiotic Compounds: How Far Are We?

A myriad of nonantibiotic compounds is released into the environment, some of which may contribute to the dissemination of antimicrobial resistance by stimulating conjugation. Here, we analyzed a collection of studies to (i) identify patterns of transfer stimulation across groups and concentrations of chemicals, (ii) evaluate the strength of evidence for the proposed mechanisms behind conjugal stimulation, and (iii) examine the plausibility of alternative mechanisms. We show that stimulatory nonantibiotic compounds act at concentrations from 1/1000 to 1/10 of the minimal inhibitory concentration for the donor strain but that stimulation is always modest (less than 8-fold). The main proposed mechanisms for stimulation via the reactive oxygen species/SOS cascade and/or an increase in cell membrane permeability are not unequivocally supported by the literature. However, we identify the reactive oxygen species/SOS cascade as the most likely mechanism. This remains to be confirmed by firm molecular evidence. Such evidence and more standardized and high-throughput conjugation assays are needed to create technologies and solutions to limit the stimulation of conjugal gene transfer and contribute to mitigating global antibiotic resistance.

Optical Absorption Properties in Pentacene/Tetracene Solid Solutions.

Modifying the optical and electronic properties of crystalline organic thin films is of great interest for improving the performance of modern organic semiconductor devices. Therein, the statistical mixing of molecules to form a solid solution provides an opportunity to fine-tune optical and electronic properties. Unfortunately, the diversity of intermolecular interactions renders mixed organic crystals highly complex, and a holistic picture is still lacking. Here, we report a study of the optical absorption properties in solid solutions of pentacene and tetracene, two prototypical organic semiconductors. In the mixtures, the optical properties can be continuously modified by statistical mixing at the molecular level. Comparison with time-dependent density functional theory calculations on occupationally disordered clusters unravels the electronic origin of the low energy optical transitions. The disorder partially relaxes the selection rules, leading to additional optical transitions that manifest as optical broadening. Furthermore, the contribution of diabatic charge-transfer states is modified in the mixtures, reducing the observed splitting in the 0-0 vibronic transition. Additional comparisons with other blended systems generalize our results and indicate that changes in the polarizability of the molecular environment in organic thin-film blends induce shifts in the absorption spectrum.

Vessel distance mapping: A novel methodology for assessing vascular-induced cognitive resilience.

The association between cerebral blood supply and cognition has been widely discussed in the recent literature. One focus of this discussion has been the anatomical variability of the circle of Willis, with morphological differences being present in more than half of the general population. While previous studies have attempted to classify these differences and explore their contribution to hippocampal blood supply and cognition, results have been controversial. To disentangle these previously inconsistent findings, we introduce Vessel Distance Mapping (VDM) as a novel methodology for evaluating blood supply, which allows for obtaining vessel pattern metrics with respect to the surrounding structures, extending the previously established binary classification into a continuous spectrum. To accomplish this, we manually segmented hippocampal vessels obtained from high-resolution 7T time-of-flight MR angiographic imaging in older adults with and without cerebral small vessel disease, generating vessel distance maps by computing the distances of each voxel to its nearest vessel. Greater values of VDM-metrics, which reflected higher vessel distances, were associated with poorer cognitive outcomes in subjects affected by vascular pathology, while this relation was not observed in healthy controls. Therefore, a mixed contribution of vessel pattern and vessel density is proposed to confer cognitive resilience, consistent with previous research findings. In conclusion, VDM provides a novel platform, based on a statistically robust and quantitative method of vascular mapping, for addressing a variety of clinical research questions.

Closing the loop: autonomous experiments enabled by machine-learning-based online data analysis in synchrotron beamline environments.

Recently, there has been significant interest in applying machine-learning (ML) techniques to the automated analysis of X-ray scattering experiments, due to the increasing speed and size at which datasets are generated. ML-based analysis presents an important opportunity to establish a closed-loop feedback system, enabling monitoring and real-time decision-making based on online data analysis. In this study, the incorporation of a combined one-dimensional convolutional neural network (CNN) and multilayer perceptron that is trained to extract physical thin-film parameters (thickness, density, roughness) and capable of taking into account prior knowledge is described. ML-based online analysis results are processed in a closed-loop workflow for X-ray reflectometry (XRR), using the growth of organic thin films as an example. Our focus lies on the beamline integration of ML-based online data analysis and closed-loop feedback. Our data demonstrate the accuracy and robustness of ML methods for analyzing XRR curves and Bragg reflections and its autonomous control over a vacuum deposition setup.

Biophysical Determinants for the Viscosity of Concentrated Monoclonal Antibody Solutions.

Monoclonal antibodies (mAbs) are particularly relevant for therapeutics due to their high specificity and versatility, and mAb-based drugs are hence used to treat numerous diseases. The increased patient compliance of self-administration motivates the formulation of products for subcutaneous (SC) administration. The associated challenge is to formulate highly concentrated antibody solutions to achieve a significant therapeutic effect, while limiting their viscosity and preserving their physicochemical stability. Protein-protein interactions (PPIs) are in fact the root cause of several potential problems concerning the stability, manufacturability, and delivery of a drug product. The understanding of macroscopic viscosity requires an in-depth knowledge on protein diffusion, PPIs, and self-association/aggregation. Here, we study the self-diffusion of different mAbs of the IgG1 subtype in aqueous solution as a function of the concentration and temperature by quasi-elastic neutron scattering (QENS). QENS allows us to probe the short-time self-diffusion of the molecules and therefore to determine the hydrodynamic mAb cluster size and to gain information on the internal mAb dynamics. Small-angle neutron scattering (SANS) is jointly employed to probe structural details and to understand the nature and intensity of PPIs. Complementary information is provided by molecular dynamics (MD) simulations and viscometry, thus obtaining a comprehensive picture of mAb diffusion.

Structural Insights into Polymer-Bounded Lipid Nanodiscs.

Membrane proteins are an essential part of signaling and transport processes and are targeted by multiple drugs. To isolate and investigate them in their native state, polymer-bounded nanodiscs have become valuable tools. In this study, we investigate the lipid model system dimyristoyl-phosphocholine (DMPC) with the nanodisc-forming copolymers styrene maleic acid (SMA) and diisobutylene maleic acid (DIBMA). Using small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS), we studied the influence of polymer concentration and temperature on the nanodisc structure. In Tris buffer, the size of nanodiscs formed with SMA is smaller compared to DIBMA at the same polymer ratio. In both cases, the size decreases monotonically with increasing polymer concentration, and this effect is more pronounced when using SMA. Measurements at temperatures (T) between 5 and 30 °C in phosphate buffer showed an incomplete solubilization at high T even at polymer/lipid ratios above that required for complete lipid solubilization. For DIBMA, the nanodiscs developed at lower temperatures are stable and the net repulsion increases, while for SMA, the individual nanodiscs possess smaller sizes and are less affected by T. However, using DLS, one can observe SMA agglomerates at low T. Interestingly, for both polymers, no drastic changes of the observable parameters (radius and bilayer thickness) are seen upon cooling, which would indicate a sharp (first-order) phase transition from liquid-crystalline to gel, but only gradual changes. Hence, we conclude that the transition from a gel toward a liquid-crystalline lipid phase proceeds over a broad T-range compared to a continuous lipid bilayer. These results can pave the way toward the development of better protocols for studying membrane proteins stabilized in this type of membrane mimics.

Effective interactions and phase behavior of protein solutions in the presence of hexamine cobalt(III) chloride.

It is well established that deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) exhibit a reentrant condensation (RC) phase behavior in the presence of the trivalent hexamine cobalt(III) cations (Hac) which can be important for their packing and folding. A similar behavior can be observed for negatively charged globular proteins in the presence of trivalent metal cations, such as Y3+ or La3+. This phase behavior is mainly driven by charge inversion upon an increasing salt concentration for a fixed protein concentration (cp). However, as Hac exhibits structural differences compared to other multivalent metal cations, with six ammonia ligands (NH3) covalently bonded to the central cobalt atom, it is not clear that Hac can induce a similar phase behavior for proteins. In this work, we systematically investigate whether negatively charged globular proteins ß-lactoglobulin (BLG), bovine serum albumin (BSA), human serum albumin (HSA) and ovalbumin (OVA) feature Hac-induced RC. Effective protein-protein interactions were investigated by small-angle X-ray scattering. The reduced second virial coefficient (B2/B2HS) was obtained as a function of salt concentration. The virial coefficient analysis performed confirms the reentrant interaction (RI) behavior for BLG without actually inducing RC, given the insufficient strengths of the interactions for the latter to occur. In contrast, the strength of attraction for BSA, HSA and OVA are too weak to show RC. Model free analysis of the inverse intensity [Formula: see text] also supports this finding. Looking at different q-range by employing static (SLS) and dynamic light scattering experiments, the presence of RI behavior can be confirmed. The results are further discussed in view of metal cation binding sites in nucleic acids (DNA and RNA), where Hac induced RC phase behavior.

Effects of flexibility in coarse-grained models for bovine serum albumin and immunoglobulin G.

We construct a coarse-grained, structure-based, low-resolution, 6-bead flexible model of bovine serum albumin (BSA, PDB: 4F5S), which is a popular example of a globular protein in biophysical research. The model is obtained via direct Boltzmann inversion using all-atom simulations of a single molecule, and its particular form is selected from a large pool of 6-bead coarse-grained models using two suitable metrics that quantify the agreement in the distribution of collective coordinates between all-atom and coarse-grained Brownian dynamics simulations of solutions in the dilute limit. For immunoglobulin G (IgG), a similar structure-based 12-bead model has been introduced in the literature [Chaudhri et al., J. Phys. Chem. B 116, 8045 (2012)] and is employed here to compare findings for the compact BSA molecule and the more anisotropic IgG molecule. We define several modified coarse-grained models of BSA and IgG, which differ in their internal constraints and thus account for a variation of flexibility. We study denser solutions of the coarse-grained models with purely repulsive molecules (achievable by suitable salt conditions) and address the effect of packing and flexibility on dynamic and static behavior. Translational and rotational self-diffusivity is enhanced for more elastic models. Finally, we discuss a number of effective sphere sizes for the BSA molecule, which can be defined from its static and dynamic properties. Here, it is found that the effective sphere diameters lie between 4.9 and 6.1 nm, corresponding to a relative spread of about ±10% around a mean of 5.5 nm.

An alternative approach to the osmotic second virial coefficient of protein solutions and its application to liquid-liquid phase separation.

The osmotic second virial coefficient B2 is an important parameter to describe the interactions and phase behavior of protein solutions, including colloidal systems and macromolecular solutions. Another key parameter to describe the driving force of the nucleation of a new phase is the supersaturation, which is used in the classical nucleation theory framework and is connected with the favorable contribution in the Gibbs free energy in the bulk solution. In this article, we establish a connection between B2 calculated from small angle x-ray scattering (SAXS) data and the values of B2 obtained from supersaturation measurements using thermodynamics considerations. The values of the second virial coefficient calculated employing this method agree with those determined via SAXS in the region near the liquid-liquid phase separation border for human serum albumin and bovine serum albumin. The general relations adopted are shown to be useful for the estimation of the second virial coefficient B2 for globular proteins, in the proximity of the binodal biphasic coexistent region.

Effects of temperature and ionic strength on the microscopic structure and dynamics of egg white gels.

We investigate the thermal gelation of egg white proteins at different temperatures with varying salt concentrations using x-ray photon correlation spectroscopy in the geometry of ultra-small angle x-ray scattering. Temperature-dependent structural investigation suggests a faster network formation with increasing temperature, and the gel adopts a more compact network, which is inconsistent with the conventional understanding of thermal aggregation. The resulting gel network shows a fractal dimension δ, ranging from 1.5 to 2.2. The values of δ display a non-monotonic behavior with increasing amount of salt. The corresponding dynamics in the q range of 0.002-0.1 nm-1 is observable after major change of the gel structure. The extracted relaxation time exhibits a two-step power law growth in dynamics as a function of waiting time. In the first regime, the dynamics is associated with structural growth, whereas the second regime is associated with the aging of the gel, which is directly linked with its compactness, as quantified by the fractal dimension. The gel dynamics is characterized by a compressed exponential relaxation with a ballistic-type of motion. The addition of salt gradually makes the early stage dynamics faster. Both gelation kinetics and microscopic dynamics show that the activation energy barrier in the system systematically decreases with increasing salt concentration.

Peripheral Nerve Ultrasound for the Differentiation between ALS, Inflammatory, and Hereditary Polyneuropathies.

Background and Objectives: Ultrasound (US) is a non-invasive tool for the in vivo detection of peripheral nerve alterations. Materials and Methods: In this study, we applied nerve US to assist the discrimination between the spectrum of amyotrophic lateral sclerosis (ALS, n = 11), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 5), and genetically confirmed Charcot-Marie-Tooth disease (CMT, n = 5). All participants and n = 15 controls without neurological diseases underwent high-resolution US of the bilateral tibial nerve. The nerve cross-sectional area (CSA) and nerve microvascular blood flow were compared between the groups and related to cerebrospinal fluid (CSF) measures, clinical symptoms, and nerve conduction studies. The analyses are part of a larger multimodal study on the comparison between US and 7 Tesla (7T) magnetic resonance neurography (MRN). Results: The patients and controls were matched with respect to their demographical data. CMT had the longest disease duration, followed by CIDP and ALS. CSA was related to age, weight, and disease duration. CSA was larger in CMT and CIDP compared to ALS and controls. The blood flow was greatest in CIDP, and higher than in CMT, ALS, and controls. In ALS, greater CSA was correlated with greater CSF total protein and higher albumin quotient. The US measures did not correlate with clinical scores or nerve conduction studies in any of the subgroups. Conclusion: Our results point towards the feasibility of CSA and blood flow to discriminate between ALS, CIDP, and CMT, even in groups of small sample size. In ALS, larger CSA could indicate an inflammatory disease subtype characterized by reduced blood-nerve barrier integrity. Our upcoming analysis will focus on the additive value of 7T MRN in combination with US to disentangle the spectrum between more inflammatory or more degenerative disease variants among the disease groups.

Multilayer Langmuir Film of Monodisperse Au Nanoclusters: Unusual Growth via Bilayers.

The assembly of nanomaterials into thin films is an important area in the nanofabrication of novel devices. The monodispersity of nanoparticles plays an essential role in the resulting quality of the assembled mono- and multilayers. Larger polydispersity leads to smaller lateral correlation lengths and smaller domains of aligned nanoparticles, thus resulting in more point and line defects. Perfectly monodisperse nanoparticles should therefore minimize the number of defects in the assembled films. Despite tremendous progress in reducing the polydispersity of nanoparticles, there has been limited research on the assembly of thin films out of perfectly monodisperse nanoclusters. Here, we show a formation of Langmuir films using perfectly monodisperse gold nanoclusters with composition Au32(nBu3P)12Cl8 exhibiting a diameter of 1.8 nm. Using both in situ and ex situ small-angle X-ray scattering, we show that the monolayer formed on a Langmuir-Blodgett trough exhibits long-range order. Moreover, after compressing the monolayer, we found that the stress accumulated prior to the monolayer collapse triggers a transition to a short-range order not previously reported. If such monolayer is compressed further, the second layer is not formed as in the case of standard nanoparticles. Instead, a growth of islands by an odd number of layers is observed, leading to a thin film with a structure consisting of two different orientations of the hexagonal lattice. Such anomalous behavior may have implications for the possibilities of thin-film formation.

Role of entropy in determining the phase behavior of protein solutions induced by multivalent ions.

Recent experiments have reported lower critical solution temperature (LCST) phase behavior of aqueous solutions of proteins induced by multivalent ions, where the solution phase separates upon heating. This phenomenon is linked to complex hydration effects that result in a net entropy gain upon phase separation. To decipher the underlying molecular mechanism, we use all-atom molecular dynamics simulations along with the two-phase thermodynamic method for entropy calculation. Based on simulations of a single BSA protein in various salt solutions (NaCl, CaCl2, MgCl2, and YCl3) at temperatures (T) ranging 283-323 K, we find that the cation-protein binding affinity increases with T, reflecting its thermodynamic driving force to be entropic in origin. We show that in the cation binding process, many tightly bound water molecules from the solvation shells of a cation and the protein are released to the bulk, resulting in entropy gain. To rationalize the LCST behavior, we calculate the ζ-potential that shows charge inversion of the protein for solutions containing multivalent ions. The ζ-potential increases with T. Performing simulations of two BSA proteins, we demonstrate that the protein-protein binding is mediated by multiple cation bridges and involves similar dehydration effects that cause a large entropy gain which more than compensates for rotational and translational entropy losses of the proteins. Thus, the LCST behavior is entropy-driven, but the associated solvation effects are markedly different from hydrophobic hydration. Our findings have direct implications for tuning the phase behavior of biological and soft-matter systems, e.g., protein condensation and crystallization.

Short-range organization and photophysical properties of CdSe quantum dots coupled with aryleneethynylenes.

Hybrid organic-inorganic nanomaterials composed of organic semiconductors and inorganic quantum dots (QDs) are promising candidates for opto-electronic devices in a sustainable internet of things. Especially their ability to combine the advantages of both compounds in one material with new functionality, the energy-efficient production possibility and the applicability in thin films with little resource consumption are key benefits of these materials. However, a major challenge one is facing for these hybrid materials is the lack of a detailed understanding of the organic-inorganic interface which hampers the widespread application in devices. We advance the understanding of this interface by studying the short-range organization and binding motif of aryleneethynylenes coupled to CdSe QDs as an example system with various experimental methods. Clear evidence for an incorporation of the organic ligands in between the inorganic QDs is found, and polarization-modulation infrared reflection-absorption spectroscopy is shown to be a powerful technique to directly detect the binding in such hybrid thin-film systems. A monodentate binding and a connection of neighboring QDs by the aryleneethynylene molecules is identified. Using steady-state and time resolved spectroscopy, we further investigated the photophysics of these hybrid systems. Different passivation capabilities resulting in different decay dynamics of the QDs turned out to be the main influence of the ligands on the photophysics.

Cytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply.

Mitochondrial oxidative phosphorylation (OXPHOS) and cellular workload are tightly balanced by the key cellular regulator, calcium (Ca2+). Current models assume that cytosolic Ca2+ regulates workload and that mitochondrial Ca2+ uptake precedes activation of matrix dehydrogenases, thereby matching OXPHOS substrate supply to ATP demand. Surprisingly, knockout (KO) of the mitochondrial Ca2+ uniporter (MCU) in mice results in only minimal phenotypic changes and does not alter OXPHOS. This implies that adaptive activation of mitochondrial dehydrogenases by intramitochondrial Ca2+ cannot be the exclusive mechanism for OXPHOS control. We hypothesized that cytosolic Ca2+, but not mitochondrial matrix Ca2+, may adapt OXPHOS to workload by adjusting the rate of pyruvate supply from the cytosol to the mitochondria. Here, we studied the role of malate-aspartate shuttle (MAS)-dependent substrate supply in OXPHOS responses to changing Ca2+ concentrations in isolated brain and heart mitochondria, synaptosomes, fibroblasts, and thymocytes from WT and MCU KO mice and the isolated working rat heart. Our results indicate that extramitochondrial Ca2+ controls up to 85% of maximal pyruvate-driven OXPHOS rates, mediated by the activity of the complete MAS, and that intramitochondrial Ca2+ accounts for the remaining 15%. Of note, the complete MAS, as applied here, included besides its classical NADH oxidation reaction the generation of cytosolic pyruvate. Part of this largely neglected mechanism has previously been described as the "mitochondrial gas pedal." Its implementation into OXPHOS control models integrates seemingly contradictory results and warrants a critical reappraisal of metabolic control mechanisms in health and disease.

Nanoscale Phase Segregation in Supramolecular π-Templating for Hybrid Perovskite Photovoltaics from NMR Crystallography.

The use of layered perovskites is an important strategy to improve the stability of hybrid perovskite materials and their optoelectronic devices. However, tailoring their properties requires accurate structure determination at the atomic scale, which is a challenge for conventional diffraction-based techniques. We demonstrate the use of nuclear magnetic resonance (NMR) crystallography in determining the structure of layered hybrid perovskites for a mixed-spacer model composed of 2-phenylethylammonium (PEA+) and 2-(perfluorophenyl)ethylammonium (FEA+) moieties, revealing nanoscale phase segregation. Moreover, we illustrate the application of this structure in perovskite solar cells with power conversion efficiencies that exceed 21%, accompanied by enhanced operational stability.

Microscopic Dynamics of Liquid-Liquid Phase Separation and Domain Coarsening in a Protein Solution Revealed by X-Ray Photon Correlation Spectroscopy.

While the interplay between liquid-liquid phase separation (LLPS) and glass formation in biological systems is highly relevant for their structure formation and thus function, the exact underlying mechanisms are not well known. The kinetic arrest originates from the slowdown at the molecular level, but how this propagates to the dynamics of microscopic phase domains is not clear. Since with diffusion, viscoelasticity, and hydrodynamics, distinctly different mechanisms are at play, the dynamics needs to be monitored on the relevant time and length scales and compared to theories of phase separation. Using x-ray photon correlation spectroscopy, we determine the LLPS dynamics of a model protein solution upon low temperature quenches and find distinctly different dynamical regimes. We observe that the early stage LLPS is driven by the curvature of the free energy and speeds up upon increasing quench depth. In contrast, the late stage dynamics slows down with increasing quench depth, fingerprinting a nearby glass transition. The dynamics observed shows a ballistic type of motion, implying that viscoelasticity plays an important role during LLPS. We explore possible explanations based on the Cahn-Hilliard theory with nontrivial mobility parameters and find that these can only partially explain our findings.

Kinetics of Network Formation and Heterogeneous Dynamics of an Egg White Gel Revealed by Coherent X-Ray Scattering.

The kinetics of heat-induced gelation and the microscopic dynamics of a hen egg white gel are probed using x-ray photon correlation spectroscopy along with ultrasmall-angle x-ray scattering. The kinetics of structural growth reveals a reaction-limited aggregation process with a gel fractal dimension of ≈2 and an average network mesh size of ca. 400 nm. The dynamics probed at these length scales reveals an exponential growth of the characteristic relaxation times followed by an intriguing steady state in combination with a compressed exponential correlation function and a temporal heterogeneity. The degree of heterogeneity increases with decreasing length scale. We discuss our results in the broader context of experiments and models describing attractive colloidal gels.

Molecular Flexibility of Antibodies Preserved Even in the Dense Phase after Macroscopic Phase Separation.

Antibody therapies are typically based on high-concentration formulations that need to be administered subcutaneously. These conditions induce several challenges, inter alia a viscosity suitable for injection, sufficient solution stability, and preservation of molecular function. To obtain systematic insights into the molecular factors, we study the dynamics on the molecular level under strongly varying solution conditions. In particular, we use solutions of antibodies with poly(ethylene glycol), in which simple cooling from room temperature to freezing temperatures induces a transition from a well-dispersed solution into a phase-separated and macroscopically arrested system. Using quasi-elastic neutron scattering during in situ cooling ramps and in prethermalized measurements, we observe a strong decrease in antibody diffusion, while internal flexibility persists to a significant degree, thus ensuring the movement necessary for the preservation of molecular function. These results are relevant for a more dynamic understanding of antibodies in high-concentration formulations, which affects the formation of transient clusters governing the solution viscosity.