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Amitriptyline is a tricyclic antidepressant commonly prescribed for major depressive disorders, as well as depressive symptoms associated with various neurological disorders. A possible correlation between the use of tricyclic antidepressants and the occurrence of Parkinson's disease has been reported, but its underlying mechanism remains unknown. The accumulation of misfolded protein aggregates has been suggested to cause cellular toxicity and has been implicated in the common pathogenesis of neurodegenerative diseases. Here, we examined the effect of amitriptyline on protein clearance and its relevant mechanisms in neuronal cells. Amitriptyline exacerbated the accumulation of abnormal aggregates in both in vitro neuronal cells and in vivo mice brain by interfering with the (1) formation of aggresome-like aggregates and (2) autophagy-mediated clearance of aggregates. Amitriptyline upregulated LC3B-II, but LC3B-II levels did not increase further in the presence of NH4Cl, which suggests that amitriptyline inhibited autophagic flux rather than autophagy induction. Amitriptyline interfered with the fusion of autophagosome and lysosome through the activation of PI3K/Akt/mTOR pathway and Beclin 1 acetylation, and regulated lysosome positioning by increasing the interaction between proteins Arl8, SKIP, and kinesin. To the best of our knowledge, we are the first to demonstrate that amitriptyline interferes with autophagic flux by regulating the autophagosome maturation during autophagy in neuronal cells. The present study could provide neurobiological clue for the possible correlation between the amitriptyline use and the risk of developing neurodegenerative diseases.Lung adenocarcinoma (LUAD) relies on dysregulated gene expression to sustain its infinite growth and progression. Emerging evidence indicates that aberrant transcriptional program results from core transcriptional regulatory circuitry (CRC) which is driven by super-enhancers (SEs). In this study, by integrating profiles of H3K27Ac chromatin immunoprecipitation sequencing (ChIP-seq) from normal adult lung and LUAD cell lines, we revealed that widespread alterations of the super-enhancer were presence during lung carcinogenesis. With SE-based modeling of regulatory circuits and assessments of transcription factor (TF) dependencies, we reconstructed an interconnected transcriptional regulation network formed by three master TFs, including ELF3, EHF, and TGIF1, all of which promoted each other's expression that confirmed by ChIP-qPCR and western blot. Loss-of function assay revealed that each of them is essential for LUAD cells survival, invasion and metastasis. Meanwhile, the rescue assay also illustrated the transacting transcriptional regulatory circuitry. In addition, the mRNA levels of ELF3, EHF, and TGIF1 were differentially expressed in LUAD tumors and peritumoral tissue. IHC of serial sections revealed that high expressions of CRC (ELF3/EHF/TGIF1-High) were closely associated with high proliferative activity in tumor tissue and poor prognosis on patients with LUAD. Finally, we used small molecular inhibitors to perturb the transcriptional circuitry, also exhibited a prominent anti-cancer effect in vitro. Our findings reveal the mechanism of the transcriptional dysregulation and addiction of LUAD.<br /><br /> The ability to perceive and process visuospatial information is a condition for broader neurodevelopment. We examined the association of early visuospatial attention and processing with later neurodevelopmental outcome in very preterm infants.<br /><br /> Visuospatial attention and processing was assessed in 209 children (&lt;30 weeks gestation) using an easy applicable eye tracking-based paradigm at 1 and 2 years. Average reaction times to fixation (RTF) on specific visual stimuli were calculated, representing time needed for overall attention (Cartoon stimuli) and processing (Motion and Form stimuli). Associations between RTFs and various measures of development at 2 years including cognitive and motor development (Bayley Scales of Infant and Toddler Development-Third edition; Bayley-III), language (Lexi test) and behavior (Child Behavior Checklist) were examined.<br /><br /> At 1 year, 100 ms slower Cartoon and Motion RTFs were associated with lower cognitive Bayley-III scores (-4.4 points, 95%CI -7.4; -1.5 and -1.0 points,opmental outcome in preterm children.Early detection of preterm children at risk of adverse neurodevelopment, which allows for more timely interventions.In the fetus and the neonate, altered macrophage function has been implicated not only in inflammatory disorders but also in developmental abnormalities marked by altered onset, interruption, or imbalance of key structural changes. The developmental role of macrophages were first noted nearly a century ago, at about the same time when these cells were being identified as central effectors in phagocytosis and elimination of microbes. Since that time, we have made considerable progress in understanding the diverse roles that these cells play in both physiology and disease. Here, we review the role of fetal and neonatal macrophages in immune surveillance, innate immunity, homeostasis, tissue remodeling, angiogenesis, and repair of damaged tissues. We also discuss the possibility of therapeutic manipulation of the relative abundance and activation status of macrophage subsets in various diseases. This article combines peer-reviewed evidence from our own studies with results of an extensive literature search in the databases PubMed, EMBASE, and Scopus. IMPACT We have reviewed the structure, differentiation, and classification of macrophages in the neonatal period.Neonatal macrophages are derived from embryonic, hepatic, and bone marrow precursors.Macrophages play major roles in tissue homeostasis, innate immunity, inflammation, tissue repair, angiogenesis, and apoptosis of various cellular lineages in various infectious and inflammatory disorders.Macrophages and related inflammatory mediators could be important therapeutic targets in several neonatal diseases.<br /><br /> Preterm birth (PTB) is the leading cause of perinatal morbimortality worldwide. [https://www.selleckchem.com/products/RO4929097.html read more] Genetic and environmental factors could raise PTB risk. The aim of this study was to analyze the contribution of the statistical interaction between genes and vaginal-urinary tract infections (VI-UTI) to the risk of PTB by clinical subtype.<br /><br /> Twenty-four SNPs were genotyped in 18 candidate genes from 352 fetal triads and 106 maternal triads. Statistical interactions were evaluated with conditional logistic regression models based on genotypic transmission/disequilibrium test.<br /><br /> In PTB-idiopathic subtype mothers exposed to UTI, fetal SNPs rs11686474 (FSHR), rs4458044 (CRHR1, allele G), rs883319 (KCNN3), and maternal SNP rs1882435 (COL4A3) showed a nominal significant increment in prematurity risk. In preterm premature rupture of membranes (PPROM), fetal SNP rs2277698 (TIMP2) showed a nominal significant risk increment. In mothers exposed to VI, fetal SNP rs5742612 (IGF1) in PTB-PPROM and maternal SNP rs4458044 (CRHR1, allele C) in spontaneous PTB showed nominal significant increment in prematurity risk.