Magnetic Resonance Materials in Physics, Biology and Medicine - Fluorine-19 (19F) MRI with intravenously applied perfluorocarbons allows the in vivo monitoring of infiltrating immune cells as... 相似文献
The surfaces of influenza A virus (IAV) particles are packed with hundreds of homo-trimeric hemagglutinins (HAs). Monovalent sugars have low affinity for HA, but distance-optimized bivalent sialyl-LacNAc (SLN) conjugates bind it with 103-fold enhanced potency. Herein, we describe the oligomerization of distance-optimized bivalent binders by branched and linear hybridization on long repetitive DNA templates. The most effective complexes fully inhibited IAVs at a DNA template concentration of 10−9 m . Although a 10−2 m concentration of free trisaccharide ligand is required for full inhibition of the virus, DNA templating enables a 104-fold reduction in the amount of sugar required. Notably, hybridization-induced rigidification of the DNA templates increased the serospecificity. Cryo-TEM analysis revealed that both spaghetti-type linear forms and cotton-ball-like clusters are able to bridge several adjacent HA molecules on the IAV surface. Programmed self-assembly of ligand–nucleic acid conjugates on long DNA templates might provide generic access to target-specific, high-affinity binders of proteins on globular objects such as cells and viruses. 相似文献
Life relies on a myriad of carefully orchestrated processes, in which proteins and their direct interplay ultimately determine cellular function and disease. Modulation of this complex crosstalk has recently attracted attention, even as a novel therapeutic strategy. Herein, we describe the synthesis and characterization of two visible-light-responsive peptide backbone photoswitches based on azobenzene derivatives, to exert optical control over protein–protein interactions (PPI). The novel peptidomimetics undergo fast and reversible isomerization with low photochemical fatigue under alternatively blue-/green-light irradiation cycles. Both bind in the nanomolar range to the protein of interest. Importantly, the best peptidomimetic displays a clear difference between isomers in its protein-binding capacity and, in turn, in its potential to inhibit enzymatic activity through PPI disruption. In addition, crystal structure determination, docking and molecular dynamics calculations allow a molecular interpretation and open up new avenues in the design and synthesis of future photoswitchable PPI modulators. 相似文献
Aerobic oxidative dehydrogenation reactions of benzylamines to imines were studied and the efficiencies of various ground‐ and excited state quinone organocatalysts were compared. Long wave‐absorbing anthraquinones readily catalyze the aerobic photodehydrogenation of primary and secondary benzylamines to benzylidenebenzylamines with high rate and selectivity, and the reaction mechanism was studied by laser flash photolysis. Further, branched α‐benzyl dibenzyl‐amines undergo a regioselective photocatalytic dehydrogenation to branched aldimines, which can efficiently be converted into cis‐1,3‐diaryl tetrahydro‐isoquinolines through diastereoselective super acid‐mediated Pictet‐Spengler cyclizations.
Symmetries and tunability are of fundamental importance in wave scattering control, but symmetries are often obvious upon visual inspection, which constitutes a significant vulnerability of metamaterial wave devices to reverse-engineering risks. Here, it is theoretically and experimentally shown that a symmetry in the reduced basis of the “primary meta-atoms” that are directly connected to the outside world is sufficient; meanwhile, a suitable topology of non-local interactions between them, mediated by the internal “secondary” meta-atoms, can hide the symmetry from sight in the canonical basis. Covert symmetry-based scattering control in a cable-network metamaterial featuring a hidden parity (P$mathcal {P}$) symmetry in combination with hidden-P$mathcal {P}$-symmetry-preserving and hidden-P$mathcal {P}$-symmetry-breaking tuning mechanisms is experimentally demonstrated. Physical-layer security in wired communications is achieved using the domain-wise hidden P$mathcal {P}$-symmetry as a shared secret between the sender and the legitimate receiver. Within the approximation of negligible absorption, the first tuning of a complex scattering metamaterial without mirror symmetry to feature exceptional points (EPs) of PT$mathcal {PT}$-symmetric reflectionless states, as well as quasi-bound states in the continuum, is reported. These results are reproduced in metamaterials involving non-reciprocal interactions between meta-atoms, including the first observation of reflectionless EPs in a non-reciprocal system. 相似文献
Male patients with Fabry disease (FD) are at high risk for the formation of antibodies to recombinant α-galactosidase A (AGAL), used for enzyme replacement therapy. Due to the rapid disease progression, the identification of patients at risk is highly warranted. However, currently suitable references and standardized protocols for anti-drug antibodies (ADA) determination do not exist. Here we generate a comprehensive patient-derived antibody mixture as a reference, allowing ELISA-based quantification of antibody titers from individual blood samples. Serum samples of 22 male patients with FD and ADAs against AGAL were pooled and purified by immune adsorption. ADA-affinities against agalsidase-α, agalsidase-β and Moss-AGAL were measured by quartz crystal microbalance with dissipation monitoring (QCM-D). AGAL-specific immune adsorption generated a polyclonal ADA mixture showing a concentration-dependent binding and inhibition of AGAL. Titers in raw sera and from purified total IgGs (r2 = 0.9063 and r2 = 0.8952, both p < 0.0001) correlated with the individual inhibitory capacities of ADAs. QCM-D measurements demonstrated comparable affinities of the reference antibody for agalsidase-α, agalsidase-β and Moss-AGAL (KD: 1.94 ± 0.11 µM, 2.46 ± 0.21 µM, and 1.33 ± 0.09 µM, respectively). The reference antibody allows the ELISA-based ADA titer determination and quantification of absolute concentrations. Furthermore, ADAs from patients with FD have comparable affinities to agalsidase-α, agalsidase-β and Moss-AGAL. 相似文献
Up to 40% of advance lung, melanoma and breast cancer patients suffer from brain metastases (BM) with increasing incidence. Here, we assessed whether circulating tumor cells (CTCs) in peripheral blood can serve as a disease surrogate, focusing on CD44 and CD74 expression as prognostic markers for BM. We show that a size-based microfluidic approach in combination with a semi-automated cell recognition system are well suited for CTC detection in BM patients and allow further characterization of tumor cells potentially derived from BM. CTCs were found in 50% (7/14) of breast cancer, 50% (9/18) of non-small cell lung cancer (NSCLC) and 36% (4/11) of melanoma patients. The next-generation sequencing (NGS) analysis of nine single CTCs from one breast cancer patient revealed three different CNV profile groups as well as a resistance causing ERS1 mutation. CD44 and CD74 were expressed on most CTCs and their expression was strongly correlated, whereas matched breast cancer BM tissues were much less frequently expressing CD44 and CD74 (negative in 46% and 54%, respectively). Thus, plasticity of CD44 and CD74 expression during trafficking of CTCs in the circulation might be the result of adaptation strategies. 相似文献
Amphiphilic diisobutylene/maleic acid (DIBMA) copolymers extract lipid-encased membrane proteins from lipid bilayers in a detergent-free manner, yielding nanosized, discoidal DIBMA lipid particles (DIBMALPs). Depending on the DIBMA/lipid ratio, the size of DIBMALPs can be broadly varied which makes them suitable for the incorporation of proteins of different sizes. Here, we examine the influence of the DIBMALP sizes and the presence of protein on the dynamics of encased lipids. As shown by a set of biophysical methods, the stability of DIBMALPs remains unaffected at different DIBMA/lipid ratios. Coarse-grained molecular dynamics simulations confirm the formation of viable DIBMALPs with an overall size of up to 35 nm. Electron paramagnetic resonance spectroscopy of nitroxides located at the 5th, 12th or 16th carbon atom positions in phosphatidylcholine-based spin labels reveals that the dynamics of enclosed lipids are not altered by the DIBMALP size. The presence of the membrane protein sensory rhodopsin II from Natronomonas pharaonis (NpSRII) results in a slight increase in the lipid dynamics compared to empty DIBMALPs. The light-induced photocycle shows full functionality of DIBMALPs-embedded NpSRII and a significant effect of the protein-to-lipid ratio during preparation on the NpSRII dynamics. This study indicates a possible expansion of the applicability of the DIBMALP technology on studies of membrane protein–protein interaction and oligomerization in a constraining environment. 相似文献
