The 14-3-3ζ Protein Binds to the Cell Adhesion Molecule L1, Promotes L1 Phosphorylation by CKII and Influences L1-Dependent Neurite Outgrowth

BACKGROUND: The cell adhesion molecule L1 is crucial for mammalian nervous system development. L1 acts as a mediator of signaling events through its intracellular domain, which comprises a putative binding site for 14-3-3 proteins. These regulators of diverse cellular processes are abundant in the brain and preferentially expressed by neurons. In this study, we investigated whether L1 interacts with 14-3-3 proteins, how this interaction is mediated, and whether 14-3-3 proteins influence the function of L1. METHODOLOGY/PRINCIPAL FINDINGS: By immunoprecipitation, we demonstrated that 14-3-3 proteins are associated with L1 in mouse brain. The site of 14-3-3 interaction in the L1 intracellular domain (L1ICD), which was identified by site-directed mutagenesis and direct binding assays, is phosphorylated by casein kinase II (CKII), and CKII phosphorylation of the L1ICD enhances binding of the 14-3-3 zeta isoform (14-3-3ζ). Interestingly, in an in vitro phosphorylation assay, 14-3-3ζ promoted CKII-dependent phosphorylation of the L1ICD. Given that L1 phosphorylation by CKII has been implicated in L1-triggered axonal elongation, we investigated the influence of 14-3-3ζ on L1-dependent neurite outgrowth. We found that expression of a mutated form of 14-3-3ζ, which impairs interactions of 14-3-3ζ with its binding partners, stimulated neurite elongation from cultured rat hippocampal neurons, supporting a functional connection between L1 and 14-3-3ζ. CONCLUSIONS/SIGNIFICANCE: Our results suggest that 14-3-3ζ, a novel direct binding partner of the L1ICD, promotes L1 phosphorylation by CKII in the central nervous system, and regulates neurite outgrowth, an important biological process triggered by L1

Phrenic Nerve Injury During Cryoballoon-Based Pulmonary Vein Isolation: Results of the Worldwide YETI Registry.

BackgroundCryoballoon-based pulmonary vein isolation (PVI) has emerged as an effective treatment for atrial fibrillation. The most frequent complication during cryoballoon-based PVI is phrenic nerve injury (PNI). However, data on PNI are scarce.MethodsThe YETI registry is a retrospective, multicenter, and multinational registry evaluating the incidence, characteristics, prognostic factors for PNI recovery and follow-up data of patients with PNI during cryoballoon-based PVI. Experienced electrophysiological centers were invited to participate. All patients with PNI during CB2 or third (CB3) and fourth-generation cryoballoon (CB4)-based PVI were eligible.ResultsA total of 17 356 patients underwent cryoballoon-based PVI in 33 centers from 10 countries. A total of 731 (4.2%) patients experienced PNI. The mean time to PNI was 127.7±50.4 seconds, and the mean temperature at the time of PNI was -49±8°C. At the end of the procedure, PNI recovered in 394/731 patients (53.9%). Recovery of PNI at 12 months of follow-up was found in 97.0% of patients (682/703, with 28 patients lost to follow-up). A total of 16/703 (2.3%) reported symptomatic PNI. Only 0.06% of the overall population showed symptomatic and permanent PNI. Prognostic factors improving PNI recovery are immediate stop at PNI by double-stop technique and utilization of a bonus-freeze protocol. Age, cryoballoon temperature at PNI, and compound motor action potential amplitude loss >30% were identified as factors decreasing PNI recovery. Based on these parameters, a score was calculated. The YETI score has a numerical value that will directly represent the probability of a specific patient of recovering from PNI within 12 months.ConclusionsThe incidence of PNI during cryoballoon-based PVI was 4.2%. Overall 97% of PNI recovered within 12 months. Symptomatic and permanent PNI is exceedingly rare in patients after cryoballoon-based PVI. The YETI score estimates the prognosis after iatrogenic cryoballoon-derived PNI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03645577. Graphic Abstract: A graphic abstract is available for this article

Expressed emotion in the partners of a non-clinical adult sample: a comparison with relatives of patients with schizophrenia and depression

Background: Expressed emotion (EE) status has been proven to be a good predictor of relapse in schizophrenia and mood disorders. However, EE in schizophrenics and depressed patients was never compared to a healthy control group, and there is no data of healthy and happily married partners (HHP) yet. Method: 80 subjects without a DSM-IV lifetime diagnosis and contented with their partnerships participated in the study. They were compared with a number of samples relatives of schizophrenic and depressed patients from the published literature (N=537) with version of the Camberwell Family Interview (CFI) that was adapted to the use in healthy individuals. Results: HHP made significantly fewer critical comments to their partners than any compared clinical sample of schizophrenic and depressed patients. Furthermore, they were less hostile, less emotional over-involvement, made more positive remarks and showed more warmth than the relatives of the patients’ groups. The women of the HHP expressed significantly more criticism than their partners whereas the male partners made more positive comments. Conclusions: Relatives of clinical groups had significantly higher scores in the EE-Status than HHP. It might seem to be obvious that this can be explained by the stress caused by a psychiatric disease, but this cannot inevitably be inferred from our results. High-EE could also be a behavioural manifestation of a schizophrenia or depression genotype. Further studies, looking at causal relations in particular, are needed. Keywords: Expressed emotion, Camberwell Family Interview, healthy controls, depression, schizophreni