Sono-responsive smart nanoliposomes for precise and rapid hemostasis application.

Massive hemorrhage caused by injuries and surgical procedures is a major challenge in emergency medical scenarios. Conventional means of hemostasis often fail to rapidly and efficiently control bleeding, especially in inaccessible locations. Herein, a type of smart nanoliposome with ultrasonic responsiveness, loaded with thrombin (thrombin@liposome, named TNL) was developed to serve as an efficient and rapid hemostatic agent. Firstly, the hydrophilic cavities of the liposomes were loaded onto the sono-sensitive agent protoporphyrin. Secondly, a singlet oxygen-sensitive chemical bond was connected with the hydrophobic and hydrophilic ends of liposomes in a chemical bond manner. Finally, based on the host guest effect between ultrasound and the sono-sensitizer, singlet oxygen is continuously generated, which breaks the hydrophobic and hydrophilic ends of liposome fragments, causing spatial collapse of the TNL structure, swiftly releases thrombin loaded in the hydrophilic capsule cavity, thereby achieving accurate and rapid local hemostasis (resulted in a reduction of approximately 67% in bleeding in the rat hemorrhage model). More importantly, after thorough assessments of biocompatibility and biodegradability, it has been confirmed that TNL possesses excellent biosafety, providing a new avenue for efficient and precise hemostasis.

Intra-membrane oligomerization and extra-membrane oligomerization of amyloid-ß peptide are competing processes as a result of distinct patterns of motif interplay.

Soluble oligomers of amyloid-ß peptide (Aß) are emerging as the primary neurotoxic species in Alzheimer disease, however, whether the membrane is among their direct targets that mediate the downstream adverse effects remains elusive. Herein, we show that multiple soluble oligomeric Aß preparations, including Aß-derived diffusible ligand, protofibril, and zinc-induced Aß oligomer, exhibit much weaker capability to insert into the membrane than Aß monomer. Aß monomers prefer incorporating into membrane rather than oligomerizing in solution, and such preference can be reversed by the aggregation-boosting factor, zinc ion. Further analyses indicate that the membrane-embedded oligomers of Aß are derived from rapid assembly of inserted monomers but not due to the insertion of soluble Aß oligomers. By comparing the behavior of a panel of Aß truncation variants, we demonstrate that the intra- and extra-membrane oligomerization are mutually exclusive processes that proceed through distinct motif interplay, both of which require the action of amino acids 37-40/42 to overcome the auto-inhibitory interaction between amino acids 29-36 and the N-terminal portion albeit via different mechanisms. These results indicate that intra- and extra-membrane oligomerization of Aß are competing processes and emphasize a critical regulation of membrane on the behavior of Aß monomer and soluble oligomers, which may determine distinct neurotoxic mechanisms.

Structural insights into the architecture and allostery of full-length AMP-activated protein kinase.

AMP-activated protein kinase (AMPK) is a heterotrimeric complex composed of α catalytic subunit, ß scaffolding subunit, and γ regulatory subunit with critical roles in maintaining cellular energy homeostasis. However, the molecular architecture of the intact complex and the allostery associated with the adenosine binding-induced regulation of kinase activity remain unclear. Here, we determine the three-dimensional reconstruction and subunit organization of the full-length rat AMPK (α1ß1γ1) through single-particle electron-microscopy. By comparing the structures of AMPK in ATP- and AMP-bound states, we are able to visualize the sequential conformational changes underlying kinase activation that transmits from the adenosine binding sites in the γ subunit to the kinase domain of the α subunit. These results not only make substantial revision to the current model of AMPK assembly, but also highlight a central role of the linker sequence of the α subunit in mediating the allostery of AMPK.