Electronic doping in organic materials has remained an elusive concept for several decades. It drew considerable attention in the early days in the quest for organic materials with high electrical ...conductivity, paving the way for the pioneering work on pristine organic semiconductors (OSCs) and their eventual use in a plethora of applications. Despite this early trend, however, recent strides in the field of organic electronics have been made hand in hand with the development and use of dopants to the point that are now ubiquitous. Here, we give an overview of all important advances in the area of doping of organic semiconductors and their applications. We first review the relevant literature with particular focus on the physical processes involved, discussing established mechanisms but also newly proposed theories. We then continue with a comprehensive summary of the most widely studied dopants to date, placing particular emphasis on the chemical strategies toward the synthesis of molecules with improved functionality. The processing routes toward doped organic films and the important doping–processing–nanostructure relationships, are also discussed. We conclude the review by highlighting how doping can enhance the operating characteristics of various organic devices.
Evaluating protein structures in living cells remains a challenge. Here, we investigate Interleukin-4 receptor alpha (IL-4Rα) into which the non-canonical amino acid bicyclo6.1.0nonyne-lysine (BCNK) ...is incorporated by genetic code expansion. Bioorthogonal click labeling is performed with tetrazine-conjugated dyes. To quantify the reaction yield in situ, we develop brightness-calibrated ratiometric imaging, a protocol where fluorescent signals in confocal multi-color images are ascribed to local concentrations. Screening receptor mutants bearing BCNK in the extracellular domain uncovered site-specific variations of both click efficiency and Interleukin-4 binding affinity, indicating subtle well-defined structural perturbations. Molecular dynamics and continuum electrostatics calculations suggest solvent polarization to determine site-specific variations of BCNK reactivity. Strikingly, signatures of differential click efficiency, measured for IL-4Rα in ligand-bound and free form, mirror sub-angstrom deformations of the protein backbone at corresponding locations. Thus, click efficiency by itself represents a remarkably informative readout linked to protein structure and dynamics in the native plasma membrane.
Understanding the core content of quantum mechanics requires us to disentangle the hidden logical relationships between the postulates of this theory. Here we show that the mathematical structure of ...quantum measurements, the formula for assigning outcome probabilities (Born's rule) and the post-measurement state-update rule, can be deduced from the other quantum postulates, often referred to as "unitary quantum mechanics", and the assumption that ensembles on finite-dimensional Hilbert spaces are characterized by finitely many parameters. This is achieved by taking an operational approach to physical theories, and using the fact that the manner in which a physical system is partitioned into subsystems is a subjective choice of the observer, and hence should not affect the predictions of the theory. In contrast to other approaches, our result does not assume that measurements are related to operators or bases, it does not rely on the universality of quantum mechanics, and it is independent of the interpretation of probability.
The spatiotemporal organization of cytokine receptors in the plasma membrane is still debated with models ranging from ligand-independent receptor pre-dimerization to ligand-induced receptor ...dimerization occurring only after receptor uptake into endosomes. Here, we explore the molecular and cellular determinants governing the assembly of the type II interleukin-4 receptor, taking advantage of various agonists binding the receptor subunits with different affinities and rate constants. Quantitative kinetic studies using artificial membranes confirm that receptor dimerization is governed by the two-dimensional ligand-receptor interactions and identify a critical role of the transmembrane domain in receptor dimerization. Single molecule localization microscopy at physiological cell surface expression levels, however, reveals efficient ligand-induced receptor dimerization by all ligands, largely independent of receptor binding affinities, in line with the similar STAT6 activation potencies observed for all IL-4 variants. Detailed spatiotemporal analyses suggest that kinetic trapping of receptor dimers in actin-dependent microcompartments sustains robust receptor dimerization and signalling.
Donor CD4(+)Foxp3(+) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT allo-HCT). Current clinical study ...protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2- and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo.
The ability to adapt to changing internal and external conditions is a key feature of biological systems. Homeostasis refers to a regulatory process that stabilizes dynamic systems to counteract ...perturbations. In the nervous system, homeostatic mechanisms control neuronal excitability, neurotransmitter release, neurotransmitter receptors, and neural circuit function. The neuromuscular junction (NMJ) of Drosophila melanogaster has provided a wealth of molecular information about how synapses implement homeostatic forms of synaptic plasticity, with a focus on the transsynaptic, homeostatic modulation of neurotransmitter release. This review examines some of the recent findings from the Drosophila NMJ and highlights questions the field will ponder in coming years.
At the larval Drosophila neuromuscular junction (NMJ), neurotransmitter receptor (blue) perturbation in the muscle cell (gray cylinder) enhances neurotransmitter release (green, “Presynaptic homeostatic potentiation”, PHP) from the motor neuron. This review summarizes recent updates on this evolutionarily conserved form of transsynaptic plasticity.
Voltage- and Ca2+-dependent, slow-activating vacuolar (SV) channels represent the major cation conductance of the plant vacuole membrane and have been implicated in calcium-induced calcium release ...(CICR) from intracellular stores.Encoded by the TWO PORE CHANNEL 1 gene, the Arabidopsis thaliana SV channel AtTPC1 has become a paradigm in understanding the synergistic action of membrane potential and cytosolic Ca2+ transients for channel gating.Novel AtTPC1 structural data give rise to emerging models describing the intermediate conformational transitions during channel opening and the resulting functional consequences.
Across phyla, voltage-gated ion channels (VGICs) allow excitability. The vacuolar two-pore channel AtTPC1 from the tiny mustard plant Arabidopsis thaliana has emerged as a paradigm for deciphering the role of voltage and calcium signals in membrane excitation. Among the numerous experimentally determined structures of VGICs, AtTPC1 was the first to be revealed in a closed and resting state, fueling speculation about structural rearrangements during channel activation. Two independent reports on the structure of a partially opened AtTPC1 channel protein have led to working models that offer promising insights into the molecular switches associated with the gating process. We review new structure–function models and also discuss the evolutionary impact of two-pore channels (TPCs) on K+ homeostasis and vacuolar excitability.
Cytosolic calcium homeostasis is pivotal for intracellular signaling and requires sensing of calcium concentrations in the cytosol and accessible stores. Numerous Ca²⁺ binding sites have been ...characterized in cytosolic proteins. However, little is known about Ca²⁺ binding inside organelles, like the vacuole. The slow vacuolar (SV) channel, encoded by Arabidopsis thaliana TPC1, is regulated by luminal Ca²⁺. However, the D454/fou2 mutation in TPC1 eliminates vacuolar calcium sensitivity and increases store calcium content. In a search for the luminal calcium binding site, structure modeling indicated a possible coordination site formed by residues Glu-450, Asp-454, Glu-456, and Glu-457 on the luminal side of TPC1. Each Glu residue was replaced by Gin, the modified genes were transiently expressed in loss-of-TPC1-function protoplasts, and SV channel responses to luminal calcium were recorded by patch clamp. SV channels lacking any of the four negatively charged residues appeared altered in calcium sensitivity of channel gating. Our results indicate that Glu-450 and Asp-454 are directly involved in Ca²⁺ binding, whereas Glu-456 and Glu-457 are probably involved in connecting the luminal Ca²⁺ binding site to the channel gate. This novel vacuolar calcium binding site represents a potential tool to address calcium storage in plants.
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