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The axon-initial-segment (AIS) of mature neurons contains microtubule (MT) fascicles (linear bundles) implicated as retrograde diffusion barriers in the retention of MT-associated protein (MAP) tau inside axons. Tau dysfunction and leakage outside of the axon is associated with neurodegeneration. We report on the structure of steady-state MT bundles in varying concentrations of Mg²⁺or Ca²⁺divalent cations in mixtures containing αβ-tubulin, full-length tau, and GTP at 37 °C in a physiological buffer. A concentration-time kinetic phase diagram generated by synchrotron SAXS reveals a wide-spacing MT bundle phase (B_ws), a transient intermediate MT bundle phase (B_int), and a tubulin ring phase. SAXS with TEM of plastic-embedded samples provides evidence of a viscoelastic intervening network (IN) of complexes of tubulin oligomers and tau stabilizing MT bundles. In this model, αβ-tubulin oligomers in the IN are crosslinked by tau’s MT binding repeats, which also link αβ-tubulin oligomers to αβ-tubulin within the MT lattice. The model challenges whether the cross-bridging of MTs is attributed entirely to MAPs. Tubulin-tau complexes in the IN or bound to isolated MTs are potential sites for enzymatic modification of tau, promoting nucleation and growth of tau fibrils in tauopathies.

Understanding the propagation of shortening, especially the interaction of shallow and deep structural levels in space and time is important to understand the accretion process of a compressional orogen as well as to fully understand earthquake hazards to populated foreland basins. Here we combine evidence from geologic maps and stream‐terrace surveys to construct a set of retrodeformable cross‐sections of the western North Qilian Shan foreland. The uplifted, severely tilted Mesozoic and older rock units suggest the presence of both deep and shallow décollements in western and central part of our research area, and that these structures alternated activity since commencement of the latest phase of the North Qilian Shan uplift. Conversely, in the east, the absence of foreland fold‐and‐thrust belt and the moderately tilted Mesozoic rocks indicate the deformation is dominated by thick‐skinned uplift. Based on our cross‐sections, we estimate the long‐term shortening rate of the Jiuxi foreland basin of 1.2–1.8 m/Kyr. Deformed foreland terraces show that, from west to east in our research area, active deformation switches between different structural levels. This trade‐off between deformation styles in time and space shows that two décollement levels bound a crustal‐scale duplex as the foreland is incorporated into the orogen. We suggest the complex and out‐of‐sequence deformation pattern may relate to pre‐existing weakness within the basement rocks and is likely a common characteristic of the North Qilian foreland. This may impose an additional challenge for seismic hazard estimation of the region.

Lipid carriers of hydrophobic paclitaxel (PTX) are used in clinical trials for cancer chemotherapy. Improving their loading capacity requires enhanced PTX solubilization. We compared the time-dependence of PTX membrane solubility as a function of PTX content in cationic liposomes (CLs) with lipid tails containing one (oleoyl; DOPC/DOTAP) or two (linoleoyl; DLinPC/newly synthesized DLinTAP)cisdouble bonds by using microscopy to generate kinetic phase diagrams. The DLin lipids displayed significantly increased PTX membrane solubility over DO lipids. Remarkably, 8 mol% PTX in DLinTAP/DLinPC CLs remained soluble for approximately as long as 3 mol% PTX (the solubility limit, which has been the focus of most previous studies and clinical trials) in DOTAP/DOPC CLs. The increase in solubility is likely caused by enhanced molecular affinity between lipid tails and PTX, rather than by the transition in membrane structure from bilayers to inverse cylindrical micelles observed with small-angle X-ray scattering. Importantly, the efficacy of PTX-loaded CLs against prostate cancer cells (their IC50 of PTX cytotoxicity) was unaffected by changing the lipid tails, and toxicity of the CL carrier was negligible. Moreover, efficacy was approximately doubled against melanoma cells for PTX-loaded DLinTAP/DLinPC over DOTAP/DOPC CLs. Our findings demonstrate the potential of chemical modifications of the lipid tails to increase the PTX membrane loading while maintaining (and in some cases even increasing) the efficacy of CLs. The increased PTX solubility will aid the development of liposomal PTX carriers that require significantly less lipid to deliver a given amount of PTX, reducing side effects and costs.

Peptides naturally have stimuli‐adaptive structural conformations that are advantageous for endowing synthetic materials with dynamic functionalities. Here, we report a carbodiimide‐based approach, combined with electrostatic modulation, to instruct π‐conjugated peptides to self‐assemble and be responsive to thermal disassembly cues upon consumption of the assembly trigger. Quaterthiophene‐functionalized peptides are utilized as a model system herein to study the formation of nanostructures at non‐equilibrium states. Peptides were designed to have aspartic acid at the termini to allow intramolecular anhydride formation upon adding carbodiimide, which consequentially reduces the electrostatic repulsion and facilitates assembly. We show that the carbodiimide‐fueled assembly and subsequent thermally assisted disassembly can be modulated by the net charge of the peptidic monomers, suggesting an assembly mechanism that can be encoded by sequence design. This carbodiimide‐based approach for the assembly of designer π‐conjugated systems offers a unique opportunity to develop bioelectronic supramolecular materials with controllable formation of dynamic and stimuli‐responsive structures.