Search

Amyloid precursor protein (APP) produces aggregable β‐amyloid peptides and its mutations are associated with familial Alzheimer's disease (AD), which makes it one of the most studied proteins. However, APP's role in the human brain remains unclear despite years of investigation. One problem is that most studies on APP have been carried out in cell lines or model organisms, which are physiologically different from human neurons in the brain. Recently, human‐induced neurons (hiNs) derived from induced pluripotent stem cells (iPSCs) provide a practical platform for studying the human brain in vitro. Here, we generated APP‐null iPSCs using CRISPR/Cas9 genome editing technology and differentiate them into matured human neurons with functional synapses using a two‐step procedure. During hiN differentiation and maturation, APP‐null cells exhibited less neurite growth and reduced synaptogenesis in serum‐free but not serum‐containing media. We have found that cholesterol (Chol) remedies those developmental defects in APP‐null cells, consistent with Chol's role in neurodevelopment and synaptogenesis. The phenotypic rescue was also achieved by coculturing those cells with wild‐type mouse astrocytes, suggesting that APP's developmental role is likely astrocytic. Next, we examined matured hiNs using patch‐clamp recording and detected reduced synaptic transmission in APP‐null cells. This change was largely due to decreased synaptic vesicle (SV) release and retrieval, which was confirmed by live‐cell imaging using two SV‐specific fluorescent reporters. Adding Chol shortly before stimulation mitigated the SV deficits in APP‐null iNs, indicating that APP facilitates presynaptic membrane Chol turnover during the SV exo‐/endocytosis cycle. Taken together, our study in hiNs supports the notion that APP contributes to neurodevelopment, synaptogenesis, and neurotransmission via maintaining brain Chol homeostasis. Given the vital role of Chol in the central nervous system, the functional connection between APP and Chol bears important implications in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

To improve the separation capacity of uranium in aqueous solutions, 3R-MoS2 nanosheets were prepared with molten salt electrolysis and further modified with polypyrrole (PPy) to synthesize a hybrid nanoadsorbent (PPy/3R-MoS2). The preparation conditions of PPy/3R-MoS2 were investigated and the obtained nanosheets were characterized with scanning electron microscope (SEM), high resolution transmission electron microscope (HRTEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS). The results showed that PPy/3R-MoS2 exhibited enhanced adsorption capacity toward U(VI) compared to pure 3R-MoS2 and PPy; the maximum adsorption was 200.4 mg/g. The adsorption mechanism was elucidated with XPS and FTIR: (1) negatively charged PPy/3R-MoS2 nanosheets attracted UO22+ by an electrostatic interaction; (2) exposed C, N, Mo, and S atoms complexed with U(VI) through coordination; (3) Mo in the complex partly reduced the adsorbed U(VI) to U(IV), which further regenerated the adsorption point and continuously adsorbed U(VI). The design of the PPy/3R-MoS2 composite with a high adsorption capacity and chemical stability provides a new direction for the removal of radionuclide. [ABSTRACT FROM AUTHOR]

The removal of uranyl ions (UO 2 2+ ) from water is challenging due to their chemical stability, low concentrations, complex water matrix, and technical limitations in extraction and separation. Herein, a novel molybdenum disulfide/graphene oxide heterojunction (MoS 2 /GO-H) is developed, serving as an effective electrode for capacitive deionization (CDI). By combining the inherent advantages of electroadsorption and electrocatalysis, an innovative electroadsorption-electrocatalysis system (EES) strategy is introduced. This system utilizes interface polarization at the MoS 2 and GO interface, creating an additional electric field that significantly influences carrier behavior. The MoS 2 /GO-H electrode, with its extraordinary adsorption capacity of 805.57 mg g -1 under optimal conditions, effectively treated uranium-laden wastewater from a mine, achieving over 90% removal efficiency despite the presence of numerous competing ions at concentrations significantly higher than UO 2 2+ . Employing density functional theory (DFT) and ab initio molecular dynamics (AIMD) simulations, it is found that the MoS 2 /GO-H total charge density at the Fermi level, enhanced by interfacial polarization, surpasses that of separate MoS 2 and GO, markedly boosting conductivity and electrocatalytic effectiveness., (© 2024 Wiley‐VCH GmbH.)

GPR37L1 is an orphan receptor that couples through heterotrimeric G-proteins to regulate physiological functions. Since its role in humans is not fully defined, we used an unbiased computational approach to assess the clinical significance of rare G-protein-coupled receptor 37-like 1 ( GPR37L1 ) genetic variants found among 51,289 whole-exome sequences from the DiscovEHR cohort. Rare GPR37L1 coding variants were binned according to predicted pathogenicity and analyzed by sequence kernel association testing to reveal significant associations with disease diagnostic codes for epilepsy and migraine, among others. Since associations do not prove causality, rare GPR37L1 variants were functionally analyzed in SK-N-MC cells to evaluate potential signaling differences and pathogenicity. Notably, receptor variants exhibited varying abilities to reduce cAMP levels, activate mitogen-activated protein kinase (MAPK) signaling, and/or upregulate receptor expression in response to the agonist prosaptide (TX14(A)), as compared with the wild-type receptor. In addition to signaling changes, knock-out (KO) of GPR37L1 or expression of certain rare variants altered cellular cholesterol levels, which were also acutely regulated by administration of the agonist TX14(A) via activation of the MAPK pathway. Finally, to simulate the impact of rare nonsense variants found in the large patient cohort, a KO mouse line lacking Gpr37l1 was generated. Although KO animals did not recapitulate an acute migraine phenotype, the loss of this receptor produced sex-specific changes in anxiety-related disorders often seen in chronic migraineurs. Collectively, these observations define the existence of rare GPR37L1 variants associated with neuropsychiatric conditions in the human population and identify the signaling changes contributing to pathological processes., (Copyright © 2024 the authors.)