Activation of the PERK-CHOP signaling pathway during endoplasmic reticulum stress contributes to olanzapine-induced dyslipidemia.

Olanzapine (OLZ) is a widely prescribed antipsychotic drug with a relatively ideal effect in the treatment of schizophrenia (SCZ). However, its severe metabolic side effects often deteriorate clinical therapeutic compliance and mental rehabilitation. The peripheral mechanism of OLZ-induced metabolic disorders remains abstruse for its muti-target activities. Endoplasmic reticulum (ER) stress is implicated in cellular energy metabolism and the progression of psychiatric disorders. In this study, we investigated the role of ER stress in the development of OLZ-induced dyslipidemia. A cohort of 146 SCZ patients receiving OLZ monotherapy was recruited, and blood samples and clinical data were collected at baseline, and in the 4th week, 12th week, and 24th week of the treatment. This case-control study revealed that OLZ treatment significantly elevated serum levels of endoplasmic reticulum (ER) stress markers GRP78, ATF4, and CHOP in SCZ patients with dyslipidemia. In HepG2 cells, treatment with OLZ (25, 50 µM) dose-dependently enhanced hepatic de novo lipogenesis accompanied by SREBPs activation, and simultaneously triggered ER stress. Inhibition of ER stress by tauroursodeoxycholate (TUDCA) and 4-phenyl butyric acid (4-PBA) attenuated OLZ-induced lipid dysregulation in vitro and in vivo. Moreover, we demonstrated that activation of PERK-CHOP signaling during ER stress was a major contributor to OLZ-triggered abnormal lipid metabolism in the liver, suggesting that PERK could be a potential target for ameliorating the development of OLZ-mediated lipid dysfunction. Taken together, ER stress inhibitors could be a potentially effective intervention against OLZ-induced dyslipidemia in SCZ.

Non-suicidal self-injury and professional psychological help-seeking among Chinese left-behind children: prevalence and influencing factors.

BACKGROUND: Non-suicidal self-injury (NSSI) is a risk factor for suicide. This study aimed to investigate the prevalence of NSSI and professional psychological help-seeking status and influencing factors among left-behind children (LBC) in China. METHODS: We implemented a population-based cross-sectional study in participants aged 10-18 years. Sociodemographic characteristics, NSSI, help-seeking status and coping style were measured by self-reported questionnaires. A total of 16,866 valid questionnaires were collected, including 6096 LBC. Binary logistic regression models were used to analyze the factors influencing NSSI and professional psychological help-seeking. RESULTS: The incidence of NSSI among LBC was 4.6%, significantly higher than that of non-left-behind children (NLBC). This incidence was higher among girls. Moreover, 53.9% of LBC with NSSI did not receive any treatment and only 22.0% sought professional psychological help. LBC often adopt emotion-oriented coping styles, specifically, those with NSSI. LBC with NSSI who seek professional help tend to adopt problem-oriented coping styles. Logistic regression analysis revealed that girls, learning stage, single-parent, remarried families, patience, and emotional venting were risk factors for NSSI in LBC, while problem-solving and social support seeking were protective factors. Moreover, problem-solving was also a predictor for seeking professional psychological help, patience will prevent it. LIMITATIONS: This was an online survey. CONCLUSIONS: The prevalence of NSSI in LBC is high. Gender, grade, family structure, and coping style affect the occurrence of NSSI among LBC. Only a few LBC with NSSI seek professional psychological help, while the coping style will affect the help-seeking behavior.

Nervous Necrosis Virus Coat Protein Mediates Host Translation Shutoff through Nuclear Translocalization and Degradation of Polyadenylate Binding Protein.

Nervous necrosis virus (NNV) belongs to the Betanodavirus genus of the Nodaviridae family and is the main cause of viral nervous necrosis disease in marine fish larvae and juveniles worldwide. The NNV virion contains two positive-sense, single-stranded RNA genomes, which encode RNA-dependent RNA polymerase, coat protein, and B2 protein. Interestingly, NNV infection can shut off host translation in orange-spotted grouper (Epinephelus coioides) brain cells; however, the detailed mechanisms of this action remain unknown. In this study, we discovered that the host translation factor, polyadenylate binding protein (PABP), is a key target during NNV takeover of host translation machinery. Additionally, ectopic expression of NNV coat protein is sufficient to trigger nuclear translocalization and degradation of PABP, followed by translation shutoff. A direct interaction between NNV coat protein and PABP was demonstrated, and this binding requires the NNV coat protein N-terminal shell domain and PABP proline-rich linker region. Notably, we also showed that degradation of PABP during later stages of infection is mediated by the ubiquitin-proteasome pathway. Thus, our study reveals that the NNV coat protein hijacks host PABP, causing its relocalization to the nucleus and promoting its degradation to stimulate host translation shutoff. IMPORTANCE Globally, more than 200 species of aquacultured and wild marine fish are susceptible to NNV infection. Devastating outbreaks of this virus have been responsible for massive economic damage in the aquaculture industry, but the molecular mechanisms by which NNV affects its host remain largely unclear. In this study, we show that NNV hijacks translation in host brain cells, with the viral coat protein binding to host PABP to promote its nuclear translocalization and degradation. This previously unknown mechanism of NNV-induced host translation shutoff greatly enhances the understanding of NNV pathogenesis and provides useful insights and novel tools for development of NNV treatments, such as the use of orange-spotted grouper brain cells as an in vitro model system.

Career choice and influential factors among medical students majoring in psychiatry in China.

BACKGROUND: The undergraduate program of psychiatry has been widely established in recent years to improve the education and recruitment of psychiatrists in China. We aim to investigate the career choice of medical students majoring in psychiatry in China and the influential factors. METHOD: This multicenter study was conducted in 26 medical schools in China from May to October of 2019. Participants included 4610 medical students majoring in psychiatry and 3857 medical students majoring in clinical medicine. Multivariable logistic regression was used to investigate the influential factors of students' choices of psychiatry at matriculation and as a career. RESULTS: 44.08% of psychiatry majored students gave psychiatry as a first choice at matriculation, and 56.67% of them would choose psychiatry as a career, which was in sharp contrast to the proportion of clinical medicine majored students who would choose psychiatry as a career (0.69%). Personal interest (59.61%), suggestions from family members (27.96%), and experiencing mental problems (23.19%) were main reasons for choosing psychiatry major at matriculation. Personal interest (odds ratio [OR] = 2.12, 95% confidence interval [CI] = 1.87-2.40), experiencing a psychiatry clerkship (OR = 1.99, 95% CI = 1.28-3.08), being female (OR = 1.50, 95% CI = 1.30-1.68), experiencing mental problems (OR = 1.33, 95% CI = 1.28-1.56), and suggestions from family members (OR = 1.25, 95% CI = 1.08-1.46) correlated positively with students' choice of psychiatry as career. Students who lacked psychiatry knowledge (OR = 0.49, 95% CI = 0.29-0.85) or chose psychiatry because of lower admission scores (OR = 0.80, 95% CI = 0.63-0.97) were less likely to choose psychiatry as a career. CONCLUSION: More than half of psychiatry majored medical school students planned to choose psychiatry as their career, whereas very few students in the clinic medicine major would make this choice. Increasing students' interest in psychiatry, strengthening psychiatry clerkships, and popularizing psychiatric knowledge are modifiable factors to increase the psychiatry career intention. The extent to which medical students' attitudes toward psychiatry can be changed through medical school education and greater exposure to psychiatry will need further investigation.

DcMYB62, a transcription factor from carrot, enhanced cadmium tolerance of Arabidopsis by inducing the accumulation of carotenoids and hydrogen sulfide.

Cadmium (Cd) is a significant heavy metal contaminant within the environment, carrying a notable level of toxicity that presents a substantial hazard to both plant and human. Carrot (Daucus carota), a significant root vegetable crop globally, have evolved multiple transcriptional regulatory mechanisms to cope with Cd stress, with a crucial involvement of the myeloblastosis (MYB) transcription factor. In this study, the DcMYB62 gene encoding 288 amino acids, localized in the nucleus and demonstrated transcription activation property, was isolated from carrot (cv. 'Kuroda'). There was a positive relationship observed between the levels of DcMYB62 expression and the accumulation patterns of carotenoids in two distinct carrot cultivars. Further investigation revealed that the expression of DcMYB62 improved Cd tolerance of Arabidopsis by increasing seed germination rate, root length, and overall survival rate. The levels of carotenoids in DcMYB62 transgenic Arabidopsis surpassed those in wild type, accompanied by elevated expression levels of 15-cis-phytoene desaturase, zeta-carotene desaturase, and carotenoid isomerase. Meanwhile, the heterologous expression of DcMYB62 promoted the biosynthesis of abscisic acid (ABA) and hydrogen sulfide (H2S), which in turn suppressed the formation of hydrogen peroxide and superoxide anion, while also stimulating stomatal closure. Furthermore, the heterologous expression of DcMYB62 increased the transcription of genes associated with heavy metal resistance in Arabidopsis, notably nicotianamine synthase. Overall, this study contributes to understanding how DcMYB62 promote Cd stress resistance of plants by regulating the biosynthesis pathways of carotenoids, ABA, and H2S, which offers valuable insights into the regulatory mechanism connecting DcMYBs with Cd stress response of carrot.

Hydrogen sulfide alleviates cadmium stress in germinating carrot seeds by promoting the accumulation of proline.

Carrot (Daucus carota L.), a widely cultivated economically vegetable from the Apiaceae family, is grown globally. However, carrots can be adversely impacted by cadmium (Cd) pollution in the soil due to its propensity to accumulate in the fleshy root, thus impeding carrot growth and posing health hazards to consumers. Given the potential of hydrogen sulfide (H2S) to improve plant resistance against Cd stress, we treated germinating carrot seeds with varying concentrations of sodium hydrosulfide (NaHS), aiming to alleviate the toxic impacts of Cd stress on carrot seed germination. The results revealed that carrot seeds treated with a concentration of 0.25 mM NaHS displayed better seed germination-associated characteristics compared to seeds treated with NaHS concentrations of 0.1 mM and 0.5 mM. Further investigation revealed a rise in the expression levels of L-cysteine desulfhydrase and D-cysteine desulfhydrase, along with enhanced activity of L-cysteine desulfhydrase and D-cysteine desulfhydrase among the NaHS treatment group, thereby leading to H2S accumulation. Moreover, NaHS treatment triggered the expression of pyrroline-5-carboxylate synthase and pyrroline-5-carboxylate reductase and promoted the accumulation of endogenous proline, while the contents of soluble sugar and soluble protein increased correspondingly. Interestingly, since the application of exogenous proline did not influence the accumulation of endogenous H2S, suggesting that H2S served as the upstream regulator of proline. Histochemical staining and biochemical indices revealed that NaHS treatment led to elevated antioxidant enzyme activity, alongside a suppression of superoxide anion and hydrogen peroxide generation. Furthermore, high performance liquid chromatography analysis revealed that NaHS treatment reduced Cd2+ uptake, thereby promoting germination rate, seed vitality, and hypocotyl length of carrot seeds under Cd stress. Overall, our findings shed light on the application of NaHS to enhance carrot resistance against Cd stress and lay a foundation for exploring the regulatory role of H2S in plants responding to Cd stress.

Inhibition of PARP1 improves cardiac function after myocardial infarction via up-regulated NLRC5.

The incidence and mortality rate of myocardial infarction are increasing per year in China. The polarization of macrophages towards the classically activated macrophages (M1) phenotype is of utmost importance in the progression of inflammatory stress subsequent to myocardial infarction. Poly (ADP-ribose) polymerase 1(PARP1) is the ubiquitous and best characterized member of the PARP family, which has been reported to support macrophage polarization towards the pro-inflammatory phenotype. Yet, the role of PARP1 in myocardial ischemic injury remains to be elucidated. Here, we demonstrated that a myocardial infarction mouse model induced cardiac damage characterized by cardiac dysfunction and increased PARP1 expression in cardiac macrophages. Inhibition of PARP1 by the PJ34 inhibitors could effectively alleviate M1 macrophage polarization, reduce infarction size, decrease inflammation and rescue the cardiac function post-MI in mice. Mechanistically, the suppression of PARP1 increase NLRC5 gene expression, and thus inhibits the NF-κB pathway, thereby decreasing the production of inflammatory cytokines such as IL-1ß and TNF-α. Inhibition of NLRC5 promote infection by effectively abolishing the influence of this mechanism discussed above. Interestingly, inhibition of NLRC5 promotes cardiac macrophage polarization toward an M1 phenotype but without having major effects on M2 macrophages. Our results demonstrate that inhibition of PARP1 increased NLRC5 gene expression, thereby suppressing M1 polarization, improving cardiac function, decreasing infarct area and attenuating inflammatory injury. The aforementioned findings provide new insights into the proinflammatory mechanisms that drive macrophage polarization following myocardial infarction, thereby introducing novel potential targets for future therapeutic interventions in individuals affected by myocardial infarction.

Effects of resourcefulness on internet game addiction among college students: The mediating role of anxiety and the moderating role of gender.

Introduction: The mechanism of internet game addiction is unclear. Whether anxiety mediates between resourcefulness and internet game addiction and whether gender affect its mediation role have not been studied previously. Methods: A total of 4,889 college students from a college in southwest China were included in this study to complete the investigation, in which three questionnaires were used for evaluation. Results: Pearson's correlation analysis indicated a remarkable negative correlation between resourcefulness with internet game addiction and anxiety, as well as a significant positive correlation between anxiety and this addiction. The structural equation model confirmed the mediation role of anxiety. The multi-group analysis confirmed the moderating role of gender in the mediation model. Discussion: These findings have advanced the results of existing studies, indicating the buffering effect of resourcefulness on internet game addiction and revealing the potential mechanism of this relationship.

Prevalence and Factors Associated With Suicidal Ideation in Medical Students With Migraine.

Background: The association between migraine and suicide ideation has been identified. However, the predictive factors of suicidal ideation are still controversial and whether migraine with aura can serve as an independent associated factor is uncertain. This manuscript studied the association between migraine with aura and suicidal ideation and explored the predictive factors for suicidal ideation. Methods: We surveyed 9,057 medical students and included 579 medical students with migraine into our study population. All students completed the General Situation Questionnaire, the Verified Headache Questionnaire, Hamilton Anxiety Scale (24 items), Hamilton Depression Scale (24 items), 36-item Health Survey Brief (SF-36), Headache Impact Text-6 (HIT-6), Test Anxiety Scale (TAS), and Pittsburgh Sleep Quality Index (PSQI). Suicidal ideation was measured by the Self-rating Idea of Suicide Scale (SIOSS). Results: Out of the 579 migraine medical college students, 562 (age 19.6 ± 1.6; 448 women and 114 men) were included in the final study. The positive rate of suicidal ideation was 13.7%. Compared with students suffering from migraine without aura, those having migraine with aura had higher suicidal ideation (p < 0.015). After adjusting for demographic factors and headache characteristics, migraine with aura was found to be independently associated with suicidal ideation. Other independent associated factors include anxiety, depression, test anxiety, sleep, headache, and quality of life. Among these various factors, high quality of life was found to play a protective role against suicidal ideation. Conclusions: Migraine with aura is independently associated with suicidal ideation. Furthermore, anxiety, depression, text anxiety, poor sleep quality, and headache frequency are associated with suicidal ideation among medical college students with migraine.

Discovery of TAS2R14 Agonists from Platycodon grandiflorum Using Virtual Screening and Affinity Screening Based on a Novel TAS2R14-Functionalized HEMT Sensor Combined with UPLC-MS Analysis.

TAS2R14 is of great potential as a therapeutic target against asthma, and the discovery of TAS2R14 agonists can be very valuable for treating this disease. Herein, we developed a strategy using virtual screening and affinity screening based on a fabricated biosensor combined with UPLC-MS analysis to screen TAS2R14 agonists from Platycodon grandiflorum. By ligand-based virtual screening, 16 best-fit candidates were yielded. A novel TAS2R14-functionalized high-electron-mobility transistor (HEMT) sensor was applied to detect and fish out the potential TAS2R14 agonists from P. grandiflorum extracts. Those components captured by the immobilized TAS2R14 were eluted and characterized on UPLC-QTOF MS. As a result, six potential TAS2R14 agonists were screened out and identified. Among them, platycodin L was confirmed to be a special agonist of TAS2R14 for the first time and had an EC50 of 15.03 ± 1.15 µM via intracellular calcium mobilization assay ( n = 6). The results indicated that the proposed strategy was efficient to discover TAS2R14 agonists from the herb directly.