GDI2 deletion alleviates neurodegeneration and memory loss in the 5xFAD mice model of Alzheimer's disease.

Accumulation of insoluble deposits of amyloid ß-peptide (Aß), derived from amyloid precursor protein (APP) processing, represents one of the major pathological hallmarks of Alzheimer's disease (AD). Perturbations in APP transport and hydrolysis could lead to increased Aß production. However, the precise mechanisms underlying APP transport remain elusive. The GDP dissociation inhibitor2 (GDI2), a crucial regulator of Rab GTPase activity and intracellular vesicle and membrane trafficking, was investigated for its impact on AD pathogenesis through neuron-specific knockout of GDI2 in 5xFAD mice. Notably, deficiency of GDI2 significantly ameliorated cognitive impairment, prevented neuronal loss in the subiculum and cortical layer V, reduced senile plaques as well as astrocyte activation in 5xFAD mice. Conversely, increased activated microglia and phagocytosis were observed in GDI2 ko mice. Further investigation revealed that GDI2 knockout led to more APP co-localized with the ER rather than the Golgi apparatus and endosomes in SH-SY5Y cells, resulting in decreased Aß production. Collectively, these findings suggest that GDI2 may regulate Aß production by modulating APP intracellular transport and localization dynamics. In summary, our study identifies GDI2 as a pivotal regulator governing APP transport and process implicated in AD pathology; thus highlighting its potential as an attractive pharmacological target for future drug development against AD.

[Research advances in the role of Rab GTPases in Alzheimer's disease].

Extracellular deposition of ß-amyloid (Aß) and intracellular hyperphosphorylated tau are the predominant pathological changes in Alzheimer's disease (AD). Increasing evidence demonstrates a critical role of a variety of small GTPases, namely Ras-related proteins (Rabs), in the pathogenesis of AD. As crucial regulators of intracellular membrane trafficking, alteration in Rab protein expression and function represents one of the primary factors contributing to the abnormal membrane trafficking in AD. Additionally, the Rab GTPases are also involved in the development of Aß, tau and other pathological changes associated with AD. In this article, we conduct a comprehensive review on the primary functions of multiple Rab proteins and their involvement in the pathogenesis of AD.

An ER-Horse Detonating Stress Cascade for Hepatocellular Carcinoma Nanotherapy.

Persisting and excessive endoplasmic reticulum stress (ERS) can evoke rapid cell apoptosis. Therapeutic interference of ERS signaling holds enormous potential for cancer nanotherapy. Herein, a hepatocellular carcinoma (HCC) cell-derived ER vesicle (ERV) encapsulating siGRP94, denoted as ER-horse, has been developed for precise HCC nanotherapy. Briefly, ER-horse, like the Trojan horse, was recognized via homotypic camouflage, imitated the physiological function of ER, and exogenously opened the Ca2+ channel. Consequently, the mandatory pouring-in of extracellular Ca2+ triggered the aggravated stress cascade (ERS and oxidative stress) and apoptosis pathway with the inhibition of unfolded protein response by siGRP94. Collectively, our findings provide a paradigm for potent HCC nanotherapy via ERS signaling interference and exploring therapeutic interference of physiological signal transduction pathways for precision cancer therapy.

Mice with the Rab10 T73V mutation exhibit anxiety-like behavior and alteration of neuronal functions in the striatum.

Hyperphosphorylated Rab10 has been implicated in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. However, the neurophysiological function of the evolutionarily conserved Thr73 phosphorylation of Rab10 remains poorly understood. Here, we generated a novel mouse model expressing the non-phosphorylatable T73V mutation of Rab10 and performed a comprehensive series of neurological analyses, including behavioral tests, synaptic evaluations, neuronal and glial staining, assessments of neurite arborization and spine morphogenesis. The Rab10 T73V mutantmice exhibited a characteristic anxiety-like phenotype with other behavioral modules relatively unaffected. Moreover, Rab10 T73V mutant mice displayed striatum-specific synaptic dysfunction, as indicated by aberrantly increased expression levels of synaptic proteins and impaired frequencies of miniature inhibitory postsynaptic currents. The genetic deletion of Rab10 phosphorylation enhanced neurite arborization and accelerated spine maturation in striatal medium spiny neurons. Our findings emphasize the specific role of intrinsic phospho-Rab10 in the regulation of the striatal circuitry and its related behaviors.

An "on-off" electrochemiluminescence immunosensor for PIVKA-II detection based on the dual quenching of CeO2-Au-g-C3N4 hybrids by Ag nanocubes-VB2.

Herein, we report a novel dual-quenching electrochemiluminescence (ECL) immunosensor for detecting protein induced by vitamin K absence or antagonist-II (PIVKA-II) based on ECL resonance energy transfer (ECL-RET). In this protocol, self-accelerated ECL hybrids of CeO2 and Au nanoparticles functionalized g-C3N4 nanosheets (CeO2-Au-g-C3N4) were prepared, which exhibited high ECL emission in the presence of S2O82- as a coreactant for "signal on" state. Concretely, CeO2 with a reproducible redox couple of Ce3+ and Ce4+ could act as an efficient co-reaction accelerator to generate more oxidizing intermediate (SO4•-) to significantly self-promote the ECL emission of g-C3N4 NSs/S2O82- ECL system. Besides, Au nanoparticles not only accelerated electron transfer in the ECL process, but also provided massive active sites for biomolecules immobilization. The dual quenching labels of Ag nanocubes modified with vitamin B2 (AgNCs-VB2) were firstly proposed towards g-C3N4 NSs/S2O82- ECL system by ECL-RET, resulting in the remarkable ECL decrease for "signal off" state. Based on the sandwich immunoreaction, the "on-off" PIVKA-II ECL immunosensor gratifyingly possessed excellent detection sensitivity with the linear range of 0.4 pg mL-1-10 ng mL-1 and the low detection limit of 28.46 fg mL-1 (S/N = 3). This presented strategy might provide a potential alternative tool for PIVKA-II detection in medical research and early clinical diagnostics of hepatocellular carcinoma.

Eco-Friendly Preparation of Epoxy-Rich Graphene Oxide for Wound Healing.

Despite the ever-growing endangerment caused by the multidrug resistance (MDR) of bacteria, the development of effective antibacterial materials still remains a global challenge. Current antibiotic therapies cannot simultaneously inactivate bacteria and accelerate wound healing. This study aimed to originally separate the intercalation of MnO3+ and the oxidation processes to synthesize epoxy-rich graphene oxide (erGO) nanofilms via an eco-friendly synthetic route, which possessed low density and large lamellar distribution and was rich in epoxide. Importantly, the MnO3+ could be separated from the product and recycled for preparing the next generation of erGO nanofilms, which was quite economical and eco-friendly. The erGO nanofilm was capable of successfully inhibiting Gram-negative bacteria and even had excellent growth-inhibitory effects on Gram-positive bacteria including multidrug resistance (MDR) bacteria, as evidenced by antibacterial phenomena. Additionally, the erGO nanofilm with high •C density formed from epoxide exerted excellent antibacterial effects through tight membrane wrapping and induction of lipid peroxidation. The wound-healing property of the erGO nanofilm was evaluated via treatments of wounds infected by Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), which not only killed bacteria but also accelerated wound healing in mice with a skin infection. The novel erGO nanofilm with dual antimicrobial mechanisms might serve as a promising multifunctional antimicrobial agent for medical wound dressing with high biocompatibility.

A highly sensitive electrochemiluminescence immunosensor for h-FABP determination based on self-enhanced luminophore coupled with ultrathin 2D nickel metal-organic framework nanosheets.

In this work, a novel ECL immunosensor based on self-enhanced luminophore and ultrathin 2D nickel MOF nanosheets was fabricated for sensitive and specific detection of h-FABP. Initially, the porous ultrathin Ni-TCPP (Fe) nanosheets with high specific surface area and plentiful active sites were newly synthesized, which could enhance ECL signal of luminol by the superior peroxidase mimics activity towards H2O2 decomposition. Then, PEI and luminol were simultaneously immobilized on Ni-TCPP (Fe) nanosheets to construct self-enhanced solid state luminophore (Ni-TCPP (Fe)-PEI-Lum), possessing desirable stability and high ECL efficiency. Furthermore, poly (indole-5-carboxylic acid) (PICA) worked as substrate with outstanding conductivity and abundant binding sites to improve sensitivity. Under optimal conditions, the designed ECL immunosensor exhibited a wide dynamic range from 100 fg mL-1 to 100 ng mL-1 and a low detection limit of 44.5 fg mL-1. In addition, the ECL immunosensor behaved excellent specificity and was successfully applied to detect target h-FABP protein in complex physiological matrix. Therefore, this work may provide an alternative method for biomarker detection in clinical diagnosis and expand the application potential of 2D MOF nanosheets in ECL technique.

A novel electrochemical biosensor based on peptidoglycan and platinum-nickel-copper nano-cube for rapid detection of Gram-positive bacteria.

A novel non-enzyme electrochemical biosensor for the rapid detection of Gram-positive bacteria has been constructed that relys on a stable and efficient combination between the peptidoglycan layer and platinum-nickel-copper nanocubes (Pt-Ni-Cu NCs). Briefly, bacteria were first captured by a specific antibody. Then, the electrochemical signal materials (Pt-Ni-Cu NCs) were bound to the bacteria peptidoglycan layer using specific structural and surface features. The rapid and sensitive bacterial detection was then achieved using intrinsic electrochemical characteristics and superoxidase-like activity of the Pt-Ni-Cu NCs. Moreover, the nature of peptidoglycan covering the whole bacteria provided the premise for signal amplification. Under optimal conditions, the electrochemical signal variation was proportional to the concentration of bacteria ranging from 1.5 × 102 to 1.5 × 108 CFU/mL with a detection limit of 42 CFU/mL using a working potential of - 0.4 V. This electrochemical biosensor has been successfully applied to detect bacteria concentrations in urine samples, and the recoveries range from 90.4 to 107%. The proposed biosensor could be applied for broad-spectrum detection of Gram-positive bacteria since most Gram-positive bacteria possess a thick peptidoglycan layer. The developed electrochemical biosensing strategy might be used as a potential tool for clinical pathogenic bacteria detection and point-of-care testing (POCT).

Label-free and ultrasensitive electrochemical biosensor for the detection of EBV-related DNA based on AgDNCs@DNA/AgNCs nanocomposites and lambda exonuclease-assisted target recycling.

A label-free and efficient electrochemical biosensor was developed for the ultrasensitive detection of EBV-related DNA by combing AgDNCs@DNA/AgNCs nanocomposites with noncanonical lambda exonuclease (λ exo)-assisted target recycling (LNTR). The conjugates of AgDNCs, DNA/AgNCs and probe DNA (pDNA-AgDNCs@DNA/AgNCs conjugates) worked as not only ideal nanocarriers but also efficient electrochemical tags. LNTR didn't require phosphorylated substrates and could be triggered specifically by target DNA, leading to the recycling use of target DNA and the liberation of plentiful linker probes (LP). Subsequently, the LP hybridized with the capture probes on the electrode and then bond to pDNA-AgDNCs@DNA/AgNCs conjugates, generating a sensitive electric signal directly. What's more, the signal amplification effects of DNA/AgNCs and LNTR were investigated. Under the optimal conditions, the proposed method exhibited a wide linear range of 1 fM to 1 nM and the detection limit down to 0.38 fM. In addition, the developed biosensing method exhibited excellent specificity and was successfully applied to detect target DNA in complex biological matrix. The proposed biosensor without extra bio-labels may provide a promising platform in bioanalysis and biochemical research.

An Enzyme-Free "ON-OFF" Electrochemiluminescence Biosensor for Ultrasensitive Detection of PML/RARα based on Target-Switched DNA Nanotweezer.

Herein, an enzyme-free "ON-OFF" electrochemiluminescence (ECL) biosensor for ultrasensitive detection of fusion gene PML/RARα is constructed based on a simple target-switched DNA nanotweezer as hemin concentration controller. In this biosensor, the hemin concentration is primarily controlled by the conversion of "opened-closed" DNA nanotweezers and low concentration hemin is first used as electrochemically regenerable enhancer. In the absence of the target, the nanotweezers are in an opened state which lead to a low concentration of hemin in the solution, resulting in an enhanced Ru(bpy)32+ ECL signal. In the presence of the target, the closed nanotweezers absorbed onto the surface of electrode can capture the hemin, which achieves a high concentration of hemin and then quenches the ECL signal. The developed method achieves ultrasensitive detection of PML/RARα with a wide linear range from 1 fM to 1 nM and limit of detection as low as 0.125 fM. In addition, the ECL biosensor shows excellent specificity to the other subtypes of PML/RARα (subtype "S", "V"), "PML", and "RARα". Moreover, due to the high designable character of DNA nanotweezer, this method might provide a pragmatic Ru(bpy)32+ ECL platform for ultrasensitive detection of nucleic acid in the future.