Science Advances最新文献

Recent studies show that systemic administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist is sufficient to attenuate cocaine seeking. However, the neural mechanisms mediating these effects and the role of endogenous central GLP-1 signaling in cocaine seeking remain unknown. Here, we show that voluntary cocaine taking decreased plasma GLP-1 levels in rats and that chemogenetic activation of GLP-1-producing neurons in the nucleus tractus solitarius that project to the ventral tegmental area (VTA) decreased cocaine seeking. Single-nuclei transcriptomics and FISH studies revealed that GLP-1Rs are expressed primarily on GABA neurons in the VTA. Using in vivo fiber photometry, we found that the efficacy of a systemic GLP-1R agonist to attenuate cocaine seeking was associated with increased activity of VTA GABA neurons and decreased activity of VTA dopamine neurons. Together, these findings suggest that targeting central GLP-1 circuits may be an effective strategy toward reducing cocaine relapse and highlight a functional role of GABAergic GLP-1R-expressing midbrain neurons in drug seeking.

Rotary ATPases, including F₁F_O-, V₁V_O-, and A₁A_O-ATPases, are molecular motors that exhibit rotational movements for energy conversion. In the gliding bacterium, Mycoplasma mobile, a dimeric F₁-like ATPase forms a chain structure within the cell, which is proposed to drive the gliding motility. However, the mechanisms of force generation and transmission remain unclear. We determined the electron cryomicroscopy (cryo-EM) structure of the dimeric F₁-like ATPase complex. The structure revealed an assembly distinct from those of dimeric F₁F_O-ATPases. The F₁-like ATPase unit associated by two subunits GliD and GliE was named G₁-ATPase as an R₁ domain of rotary ATPases. G₁-β subunit, a homolog of the F₁-ATPase catalytic subunit, exhibited a specific N-terminal region that incorporates the glycolytic enzyme, phosphoglycerate kinase into the complex. Structural features of the ATPase displayed strong similarities to F₁-ATPase, suggesting a rotation based on the rotary catalytic mechanism. Overall, the cryo-EM structure provides insights into the mechanism through which G₁-ATPase drives the Mycoplasma gliding motility.

Vesicle fusion is a key process in cellular communication and membrane trafficking. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins drive vesicle fusion, and SNARE proteins seem to be partially assembled before fusion occurs. However, the molecular mechanisms of the vesicle fusion arrest and how vesicle fusion is rescued from the arrest remain not fully understood. We have previously shown that as a lipid catalyst, phosphatidylinositol 4,5-bisphosphate (PIP2) electrostatically triggers vesicle fusion by lowering the hydration energy, and masking PIP2 arrests vesicle fusion in a state of the partial SNARE assembly. In this study, we show that calmodulin and protein kinase C-epsilon unmask PIP2 through the dissociation of myristoylated alanine-rich C-kinase substrate from membranes and, thus, rescue basal fusion and potentiate synaptotagmin-1-mediated Ca²⁺-dependent vesicle fusion. We provide the model in which the arrest of vesicle fusion can be rescued by the unmasking of PIP2, a lipid catalyst for fusion.

Naturally occurring extracellular vesicles (EVs) and synthetic nanoparticles like liposomes have revolutionized precision diagnostics and medicine. EVs excel in biocompatibility and cell targeting, while liposomes offer enhanced drug loading capacity and scalability. The clinical translation of EVs is hindered by challenges including low yield and heterogeneity, whereas liposomes face rapid immune clearance and limited targeting efficiency. To bridge these gaps, biomimetic synthetic vesicles (SVs) have emerged as innovative platforms, combining the advantageous properties of EVs and liposomes. This review emphasizes critical aspects of EV biology, such as mechanisms of EV-cell interaction and source-dependent functionalities in targeting, immune modulation, and tissue regeneration, informing biomimetic SV engineering. We reviewed a broad array of biomimetic SVs, with a focus on lipid bilayered vesicles functionalized with proteins. These include cell-derived nanovesicles, protein-functionalized liposomes, and hybrid vesicles. By addressing current challenges and highlighting opportunities, this review aims to advance biomimetic SVs for transformative biomedical applications.

Nitrogen-coordinated metal sites (MN_x) in metal- and nitrogen-codoped carbon (M-N-C) catalysts offer promising electrocatalytic activity, but selective synthetic design of MN_x sites with specific coordination environments remains challenging. Here, we manipulate the formation statistics of MN_x sites by using sacrifice alkali metals (AM = Li, Na, and K) to form metal vacancy-N_x carbon (AM-MVN_x-C) templates, which are used to direct the solution-phase formation of CoN₄ sites in Co-N-C catalysts. We build a probability weight function based on the embedding energy of M in MN_x sites as the descriptor for MN_x formation statistics, and we predict that the alkali metals are prone to induce the formation of MVN₄ sites. By coordinating Co²⁺ ions with AM-MVN_x-C templates, we synthesize Co-N-C with CoN₄ sites, demonstrating remarkable oxygen reduction activity in anion exchange membrane fuel cells. These results highlight the statistical thermodynamics of MN_x formation and open up the possibility for the rational design of complex M-N-C electrocatalysts with well-defined MN_x sites.