Amyloid precursor protein and its interacting proteins in neurodevelopment.

Amyloid precursor protein (APP) is a key molecule in the pathogenesis of Alzheimer's disease (AD) as the pathogenic amyloid-ß peptide is derived from it. Two closely related APP family proteins (APPs) have also been identified in mammals. Current knowledge, including genetic analyses of gain- and loss-of-function mutants, highlights the importance of APPs in various physiological functions. Notably, APPs consist of multiple extracellular and intracellular protein-binding regions/domains. Protein-protein interactions are crucial for many cellular processes. In past decades, many APPs interactors have been identified which assist the revelation of the putative roles of APPs. Importantly, some of these interactors have been shown to influence several APPs-mediated neuronal processes which are found defective in AD and other neurodegenerative disorders. Studying APPs-interactor complexes would not only advance our understanding of the physiological roles of APPs but also provide further insights into the association of these processes to neurodegeneration, which may lead to the development of novel therapies. In this mini-review, we summarize the roles of APPs-interactor complexes in neurodevelopmental processes including neurogenesis, neurite outgrowth, axonal guidance and synaptogenesis.

[Correlation between drug-induced liver injury in rats caused by Xianling Gubao oral preparation and extraction process].

In light of the liver injury risk associated with the oral administration of Xianlin Gubao oral preparation, this study compared the differences in liver injury induced by two different extraction processes in rats and explored the correlation between hepatotoxicity and extraction process from the perspective of the differences in the content of the relevant components. Thirty male Sprague-Dawley(SD) rats were randomly divided into a normal group, tablet extract groups of different doses, and capsule extract groups of different doses, with 6 rats in each group. Each group received continuous oral administration for 4 weeks. The assessment of liver injury caused by different extracts was conducted by examining rat body weight, liver function blood biochemical indicators, liver coefficient, and liver pathological changes. In addition, a high-performance liquid chromatography(HPLC) method was established to simultaneously determine the content of icariin, baohuoside I, and bakuchiol in the extracts to compare the differences in the content of these three components under the two extraction processes. The results showed that both extracts caused liver injury in rats. Compared with the normal group, the tablet extract groups, at the studied dose, led to slow growth in body weight, a significant increase in triglyceride levels(P<0.05), a significant decrease in liver-to-brain ratio(P<0.05), and the appearance of hepatic steatosis. The capsule extract groups, at the studied dose, resulted in slow growth in body weight, a significant increase in aspartate aminotransferase levels(P<0.05), a significant decrease in body weight, liver weight, and liver-to-brain ratio(P<0.05), and the presence of hepatic steatosis and inflammatory cell infiltration. In comparison, the capsule extraction process had a higher risk of liver injury. Furthermore, based on the completion of the liquid chromatography method, the content of icariin and baohuoside Ⅰ in the capsule extract groups was 0.83 and 0.81 times that in the tablet extract groups, respectively, while the bakuchiol content in the capsule extract group was 29.80 times that in the tablet extract groups, suggesting that the higher risk of liver injury associated with the capsule extraction process may be due to its higher bakuchiol content. In summary, the differences in rat liver injury caused by the two extracts are closely related to the extraction process. This should be taken into consideration in the formulation production and clinical application.

Insulin stimulates atypical protein kinase C-mediated phosphorylation of the neuronal adaptor FE65 to potentiate neurite outgrowth by activating ARF6-Rac1 signaling.

Neurite outgrowth is a fundamental process in neurons that produces extensions and, consequently, neural connectivity. Neurite damage and atrophy are observed in various brain injuries and disorders. Understanding the intrinsic pathways of neurite outgrowth is essential for developing strategies to stimulate neurite regeneration. Insulin is a pivotal hormone in the regulation of glucose homeostasis. There is increasing evidence for the neurotrophic functions of insulin, including the induction of neurite outgrowth. However, the associated mechanism remains elusive. Here, we demonstrate that insulin potentiates neurite outgrowth mediated by the small GTPases ADP-ribosylation factor 6 (ARF6) and Ras-related C3 botulinum toxin substrate 1 (Rac1) through the neuronal adaptor FE65. Moreover, insulin enhances atypical protein kinase Cι/λ (PKCι/λ) activation and FE65 phosphorylation at serine 459 (S459) in neurons and mouse brains. In vitro and cellular assays show that PKCι/λ phosphorylated FE65 at S459. Consistently, insulin potentiates FE65 S459 phosphorylation only in the presence of PKCι/λ. Phosphomimetic studies show that an FE65 S459E mutant potently activates ARF6, Rac1, and neurite outgrowth. Notably, this phosphomimetic mutation enhances the FE65-ARF6 interaction, a process that promotes ARF6-Rac1-mediated neurite outgrowth. Likewise, insulin treatment and PKCι/λ overexpression potentiate the FE65-ARF6 interaction. Conversely, PKCι/λ knockdown suppresses the stimulatory effect of FE65 on ARF6-Rac1-mediated neurite outgrowth. The effect of insulin on neurite outgrowth is also markedly attenuated in PKCι/λ knockdown neurons, in the presence and absence of FE65. Our findings reveal a novel mechanism linking insulin with ARF6-Rac1-dependent neurite extension through the PKCι/λ-mediated phosphorylation of FE65.

ARNO is recruited by the neuronal adaptor FE65 to potentiate ARF6-mediated neurite outgrowth.

ADP-ribosylation factor 6 (ARF6) is a small GTPase that has a variety of neuronal functions including stimulating neurite outgrowth, a crucial process for the establishment and maintenance of neural connectivity. As impaired and atrophic neurites are often observed in various brain injuries and neurological diseases, understanding the intrinsic pathways that stimulate neurite outgrowth may provide insights into developing strategies to trigger the reconnection of injured neurons. The neuronal adaptor FE65 has been shown to interact with ARF6 and potentiate ARF6-mediated neurite outgrowth. However, the precise mechanism that FE65 activates ARF6 remains unclear, as FE65 does not possess a guanine nucleotide exchange factor (GEF) domain/function. Here, we show that FE65 interacts with the ARF6 GEF, namely the ARF nucleotide-binding site opener (ARNO). Moreover, a complex consisting of ARNO, ARF6 and FE65 is detected. Notably, FE65 potentiates the stimulatory effect of ARNO on ARF6-mediated neurite outgrowth, and the effect of FE65 is abrogated by an FE65 mutation that disrupts FE65-ARNO interaction. Additionally, the intramolecular interaction for mediating the autoinhibited conformation of ARNO is attenuated by FE65. Moreover, FE65 potentiates the effects of wild-type ARNO, but not the monomeric mutant, suggesting an association between FE65 and ARNO dimerization. Collectively, we demonstrate that FE65 binds to and activates ARNO and, consequently, potentiates ARF6-mediated neurite outgrowth.

Split and combine simulation extrapolation algorithm to correct geocoding coarsening of built environment exposures.

A major challenge in studies relating built environment features to health is measurement error in exposure due to geocoding errors. Faulty geocodes in built environment data introduce errors to exposure assessments that may induce bias in the corresponding health effect estimates. In this study, we examine the distribution of the measurement error in measures constructed from point-referenced exposures, quantify the extent of bias in exposure effect estimates due to geocode coarsening, and extend the simulation extrapolation (SIMEX) method to correct the bias. The motivating example focuses on the association between children's body mass index and exposure to the junk food environment, represented by the number of junk food outlets within a buffer area near their schools. We show, algebraically and through simulation studies, that coarsening of food outlet coordinates results in exposure measurement errors that have heterogeneous variance and nonzero mean, and that the resulting bias in the health effect can be away from the null. The proposed SC-SIMEX procedure accommodates the nonstandard measurement error distribution, without requiring external data, and provides the best bias correction compared to other SIMEX approaches.

Covid-19 pandemic and lockdown impacts: A description in a longitudinal study of bipolar disorder.

OBJECTIVES: To investigate the impact of the SAR-Cov-2 pandemic and lockdown on individuals with bipolar disorder in comparison to healthy controls. METHODS: A longitudinal study of 560 participants including 147 healthy controls was conducted between April 30 and May 30, 2020 during a state-wide lockdown. Bi-weekly measures included the Coronavirus Impact Scale, the Pittsburg Sleep Quality Index, the Patient Health Questionnaire, 9-item, and the Generalized Anxiety Disorder scale, 7-item. Generalized estimating equations method was used to examine the longitudinal change of the measures within the lockdown and the change from pre-pandemic period to pandemic period. RESULTS: All participants reported an impact of lockdown. Individuals with bipolar disorder reported greater impact from the stay-at-home orders with disruptions in routines, income/employment, social support and pandemic related stress. While these measures improved over time, healthy controls recovered quicker and with greater magnitude than persons with bipolar disorder. Comparing mood symptom severity measures in mid-March through May 2020 to the same time window in 2015-2019 (pre- verses post-pandemic), there were no significant differences among individuals with bipolar disorder, whereas healthy controls showed a significant, albeit transient, increase in mood symptoms. CONCLUSION: Everyone was impacted by the SARs-CoV pandemic; however, those with bipolar disorder experienced more life impacting changes from the stay-at-home orders vs healthy controls. These disruptions improved over time but much more slowly than healthy controls. Pre- vs post-pandemic comparisons show a modest but significant increase in mood severity in the healthy controls which was not observed in those with bipolar disorder.