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Purpose: This study aimed to assess the incidence, potential risk factors and clinical impact of incomplete device endothelialization(IDE) after left atrial appendage closure (LAAC). Methods: A total of 101 consecutive patients with nonvalvular atrial fibrillation (AF) who underwent successful LAAC and received antithrombotic treatment using a standard regimen were prospectively followed up to 6 months after the procedure. The status of device endothelialization and device-related thrombus (DRT) were evaluated using cardiac computed tomography (CT). Major adverse cardio-cerebral events (MACCE) including all-cause death, heart failure(HF) hospitalization, acute ischemic stroke, transient ischemic attack(TIA), peripheral vascular embolism, and major bleeding were recorded. Results: IDE was detected in 65 (64.4%) patients. Patients with IDE or complete device endothelialization (CDE) did not significantly differ with respect to baseline clinical characteristics and interventional procedure features. Multivariate analysis model revealed that persistent AF, left atrial appendage ostial diameter and left atrial size were independent risk factors for IDE. During 6-month follow-up, the incidence of DRT was 4.6% in patients with IDE and 2.8% in those with CDE, respectively (p > 0.05), and the overall rate of MACCE was non-significantly higher in the IDE group (7.7% vs. 2.8%, p = 0.32). Conclusion: IDE is common after LAAC, especially in patients with persistent AF, higher left atrial appendage ostial diameter and left atrial size. IDE confers an increased risk for DRT, but may be not necessarily associated with thromboembolic events and poor clinical outcome, providing careful monitoring and continued antithrombotic therapy are given. [ABSTRACT FROM AUTHOR]

Oral lichen planus (OLP) and oral lichenoid lesion (OLL) are chronic inflammatory diseases involving the oral mucosa. B cells infiltration in OLP and OLL, however, little is known about these cells in OLP and OLL. To analyze the function and infiltrating features of B lymphocytes in OLP and OLL, and to preliminarily evaluate their correlation with clinical outcomes. Tissue samples were collected from OLP, OLL, and healthy mucosa. The phenotypes and amounts of B cells in tissues were analyzed by single-cell sequencing. Their proportion and infiltrating features in tissues were examined by immunohistochemistry and immunofluorescence. With the systemic medication of corticoids, the correlation between B cells infiltrating characteristics and the clinical outcomes were evaluated. A quantified proportion increase of B cells was shown in both OLP and OLL. B cells in OLP demonstrated heightened activation and enhanced regulation in immune response. A cohort of 100 patients with OLP/OLL and 13 healthy controls were examined to investigate the B cells infiltration pattern. B cells were distributed in the superficial layer of lamina propria in 92.9% and 41.9% of OLP and OLL, respectively(P < 0.01); focally distributed in 25.0% and 62.9% of OLP and OLL, respectively(P < 0.01). With the systemic medication of corticoids, the cases with B cell infiltration (B+) in OLP and OLL groups showed a statistically significant reduction in REU scores before and after treatment (P < 0.01). B cells are widely present in OLP and OLL, and B cell infiltration in OLP and OLL are related to the better therapeutic effect of oral corticoids. [ABSTRACT FROM AUTHOR]

Dysregulation of eating behavior can lead to obesity, which affects 10% of the adult population worldwide and accounts for nearly 3 million deaths every year. Despite this burden on society, we currently lack effective pharmacological treatment options to regulate appetite. We used Drosophila melanogaster larvae to develop a high-throughput whole organism screen for drugs that modulate food intake. In a screen of 3630 small molecules, we identified the serotonin (5-hydroxytryptamine or 5-HT) receptor antagonist metitepine as a potent anorectic drug. Using cell-based assays we show that metitepine is an antagonist of all five Drosophila 5-HT receptors. We screened fly mutants for each of these receptors and found that serotonin receptor 5-HT2A is the sole molecular target for feeding inhibition by metitepine. These results highlight the conservation of molecular mechanisms controlling appetite and provide a method for unbiased whole-organism drug screens to identify novel drugs and molecular pathways modulating food intake. [ABSTRACT FROM AUTHOR]

Although the question of to whom a male directs his mating attempts is a critical one in social interactions, little is known about the molecular and cellular mechanisms controlling mammalian sexual preference. Here we report that the neurotransmitter 5-hydroxytryptamine (5-HT) is required for male sexual preference. Wild-type male mice preferred females over males, but males lacking central serotonergic neurons lost sexual preference although they were not generally defective in olfaction or in pheromone sensing. A role for 5-HT was demonstrated by the phenotype of mice lacking tryptophan hydroxylase 2 (Tph2), which is required for the first step of 5-HT synthesis in the brain. Thirty-five minutes after the injection of the intermediate 5-hydroxytryptophan (5-HTP), which circumvented Tph2 to restore 5-HT to the wild-type level, adult Tph2 knockout mice also preferred females over males. These results indicate that 5-HT and serotonergic neurons in the adult brain regulate mammalian sexual preference. [ABSTRACT FROM AUTHOR]

Aggression is an innate behavior that is important for animal survival and evolution. We examined the molecular and cellular mechanisms underlying aggression in Drosophila. Reduction of the neurotransmitter octopamine, the insect equivalent of norepinephrine, decreased aggression in both males and females. Mutants lacking octopamine did not initiate fighting and did not fight other flies, although they still provoked other flies to fight themselves. Mutant males lost to the wild-type males in fighting and in competing for copulation with females. Enhanced octopaminergic signaling increased aggression in socially grouped flies, but not in socially isolated flies. We carried out genetic rescue experiments that revealed the functional importance of neuronal octopamine and identified a small subset of octopaminergic neurons in the suboesophageal ganglion as being important for aggression. [ABSTRACT FROM AUTHOR]

Netrins are prototypical axon guidance cues whose attractive signaling requires the small GTPase Rac1. It remains unclear how Rac1 is regulated in the netrin pathway. DOCK180 is a member of a new family of guanine nucleotide exchange factors for Rho GTPases. Here we provide evidence implicating DOCK180 in netrin signal transduction. Netrin promoted the formation of a protein-protein interaction complex that included DOCK180 and the netrin receptor deleted in colorectal carcinoma (DCC). Inhibition of DOCK180 reduced activation of Rac1 by netrin. Both axon outgrowth and axon attraction induced by netrin were inhibited after DOCK180 knockdown in vertebrate neurons. The in vivo functional role of DOCK180 was demonstrated by its requirement for projection of commissural axons in the neural tube. These findings indicate that netrin stimulation recruits DOCK180 through DCC, which then activates small GTPases, suggesting an essential role for DOCK180 in mediating attractive responses by neurons to netrin-1. [ABSTRACT FROM AUTHOR]

The axon guidance cue netrin is importantly involved in neuronal development. DCC (deleted in colorectal cancer) is a functional receptor for netrin and mediates axon outgrowth and the steering response. Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling. [ABSTRACT FROM AUTHOR]

Although netrins are an important family of neuronal guidance proteins, intracellular mechanisms that mediate netrin function are not well understood. Here we show that netrin-1 induces tyrosine phosphorylation of proteins including focal adhesion kinase (FAK) and the Src family kinase Fyn. Blockers of Src family kinases inhibited FAK phosphorylation and axon outgrowth and attraction by netrin. Dominant-negative FAK and Fyn mutants inhibited the attractive turning response to netrin. Axon outgrowth and attraction induced by netrin-1 were significantly reduced in neurons lacking the FAK gene. Our results show the biochemical and functional links between netrin, a prototypical neuronal guidance cue, and FAK, a central player in intracellular signaling that is crucial for cell migration. [ABSTRACT FROM AUTHOR]

Discusses research on the signalling mechanisms in axon guidance and neuronal migration in the vertebrate nervous system. Implication of several families of extracellular guidance cues for guiding neurons and axons in the nervous system; Movement of neuronal precursor cells during embryonic and postnatal development of the nervous system; Association of guidance cues with responses of axons; Models of axon projection and neuronal migration in vertebrates; Hypothesis used to explain the topographic specificity of retinotectal projection.

Commissural axons cross the ventral midline of the neural tube in a Slit-dependent manner. The underlying molecular mechanisms remain unclear. We found that the deubiquitinating enzyme USP33 interacts with the Robo1 receptor. USP33 was essential for midline crossing by commissural axons and for their response to Slit. Our results reveal a previously unknown role for USP33 in vertebrate commissural axon guidance and in Slit signaling. [ABSTRACT FROM AUTHOR]

Explores the mechanism for the specification of axon formation in young neurons. Determination on the involvement of actin destabilization in axon specification; Suggestion on the effect of local lipid environment in actin network and axon; Possible mechanism for the linkage of axon specification and growth.