Chinese hamster ovary (CHO) cells transfected to express human beta 2- or beta 3-adrenoceptors (beta 2-CHO and beta 3-CHO cells) were exposed to the beta-adrenoceptor agonist isoprenaline at various concentrations and for differing times. Sustained exposure of the beta 2-CHO but not beta 3-CHO cells to isoprenaline resulted in a time- and concentration-dependent down-regulation of the receptor as measured by a reduction in specific binding of [125I]cyanopindolol. Such maintained exposure of cells expressing either receptor to the agonist produced a marked down-regulation of immunologically detectable levels of the alpha subunit of the stimulatory guanine-nucleotide-binding protein Gs. This effect was specific for Gs because levels of both G12 alpha and Gq alpha/G11 alpha were unaltered by isoprenaline treatment of both beta 2-CHO and beta 3-CHO cells. The effect of isoprenaline on Gs alpha down-regulation was some 30-fold more potent in the beta 2-CHO than in the beta 3-CHO cells. Time courses of isoprenaline-induced down-regulation of Gs alpha were not different, however, in the two cell lines. Isoprenaline treatment of the beta 3-CHO cells produced a desensitization of agonist-mediated regulation of adenylyl cyclase, manifested by a 4-fold reduction in the potency and a 30% reduction in maximal effect of the agonist, whereas desensitization of the beta 2-CHO cells was considerably greater (25-fold reduction in potency and 70% reduction in maximal effect). These results demonstrate that agonist-induced down-regulation of the G-protein which interacts with a receptor can be produced by both beta 2- and beta 3-adrenoceptors. Despite apparent concurrence of down-regulation of receptors and G-proteins in other systems [e.g. Adie, Mullaney, McKenzie and Milligan (1992) Biochem. J. 285, 529-536], agonist-induced receptor down-regulation does not appear to be a prerequisite for down-regulation of the G-protein. Furthermore, the results suggest that agonist-induced down-regulation of a G-protein may be sufficient, in the absence of receptor regulation, to induce some agonist desensitization of effector function.

To the Editor: Recently, Schaefer et al. 1 reported that whole genome sequencing (WGS) of two Cas9-treated, gene-corrected mice and a wild-type control mouse unveiled 1,397 singlenucleotide variations (SNVs) and 117 small insertions and deletions (indels) present commonly in the two Cas9-treated mice "but absent in the uncorrected control" and from a database of mouse SNVs and indels. There was essentially no sequence homology between the on-target site and these SNVs and indel sites, most of which lacked a protospaceradjacent motif (PAM) sequence, suggesting that these variations were both small guide RNA (sgRNA)-independent and Cas9-independent, respectively. Nevertheless, the authors made

Chronic skin inflammation including psoriasis is a multisystem disease, affecting more than 5% of the general population. Here we show that Pellino 1 (Peli1), a signalresponsive ubiquitin E3 ligase, is highly up-regulated in human psoriatic skin lesions and that increased Peli1 expression correlates with the immunopathogenesis of psoriasis-like chronic skin inflammatory disease. Interestingly, Peli1 directly interacts with interferon regulatory factor 4 (IRF4, a transcription factor that plays pivotal roles in proliferation and cytokine production) and induces lysine 63-mediated ubiquitination.Peli1-mediated IRF4 ubiquitination appears to be a common systemic signaling mechanism shared by lesional keratinocytes, dendritic cells, macrophages, and T cells, generating a feedback relationship between keratinocyte and Th17 cell responses.Conversely, inhibition of Peli1 interferes with IRF4 induction and attenuates immunopathogenic signaling in the psoriasis. In summary, Peli1-mediated ubiquitination is a common immunopathogenic intercellular signaling in psoriasis-like chronic skin inflammatory microenvironment. Thus, targeting Peli1 could be used as a potential strategy for psoriasis treatment.

Objective Maumgyeol Basic service is a mental health evaluation and grade scoring software using the 2 channels EEG and photoplethysmogram (PPG). This service is supposed to assess potential at-risk groups with mental illness more easily, rapidly, and reliably. This study aimed to evaluate the clinical implication of the Maumgyeol Basic service. Methods One hundred one healthy controls and 103 patients with a psychiatric disorder were recruited. Psychological evaluation (Mental Health Screening for Depressive Disorders [MHS-D], Mental Health Screening for Anxiety Disorders [MHS-A], cognitive stress response scale [CSRS], 12-item General Health Questionnaire [GHQ-12], Clinical Global Im-pression [CGI]) and digit symbol substitution test (DSST) were applied to all participants. Maumgyeol brain health score and Maumgyeol mind health score were calculated from 2 channel frontal EEG and PPG, respectively. Results Participants were divided into three groups Maumgyeol Risky, Maumgyeol Good, and Maumgyeol Usual. The Maumgyeol mind health scores, but not brain health scores, were significantly lower in the patients group compared to healthy controls. Maumgyeol Risky group showed significantly lower psychological and cognitive ability evaluation scores than Maumgyeol Usual and Good groups. Maumgyel brain health score showed significant correlations with CSRS and DSST. Maumgyeol mind health score showed significant correlations with CGI and DSST. About 20.6% of individuals were classified as the No Insight group, who had mental health problems but were unaware of their illnesses. Conclusion This study suggests that the Maumgyeol Basic service can provide important clinical information about mental health and be used as a meaningful digital mental healthcare monitoring solution to prevent symptom aggravation.

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