Structural and signaling mechanisms of TAAR1 enabled preferential agonist design.

Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D3.32 for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.

Causal atlas between inflammatory bowel disease and mental disorders: a bi-directional 2-sample Mendelian randomization study.

Background: The brain-gut axis link has attracted increasing attention, with observational studies suggesting that the relationship between common mental disorders and inflammatory bowel disease (IBD) may run in both directions. However, so far, it is not clear whether there is causality and in which direction. Methods: We conducted a bidirectional 2-sample Mendelian randomization study to investigate the relationship between IBD, including Crohn's disease (CD) and ulcerative colitis (UC), and mental disorders, using summary-level GWAS data. The main analysis was the inverse variance weighted method. IBD (including CD and UC), and nine mental disorders were used as both exposures and outcomes. Results: We found that UC could significantly lead to obsessive-compulsive disorder, attention deficit hyperactivity disorder, and autism spectrum disorder, with odds ratio (OR) of 1.245 (95% confidence intervals [CI]: 1.069-1.450; P=0.008), 1.050 (95%CI: 1.023-1.077; P=2.42×10-4), and 1.041 (95%CI: 1.015-1.068; P=0.002) respectively. In addition, we found that bipolar disorder and schizophrenia could increase the odds of IBD, with OR values of 1.138 (95%CI: 1.084-1.194; P=1.9×10-7), and 1.115 (95%CI: 1.071-1.161; P=1.12×10-7), respectively. Our results also indicate that obsessive-compulsive disorder could lead to IBD, especially for UC, with OR values of 1.091 (95%CI: 1.024-1.162; P=0.009), and 1.124 (95%CI: 1.041-1.214; P=0.004), respectively. Conclusions: Our findings indicate that the brain-gut axis involves the association between IBD, especially UC, and some mental disorders, which guides the targeted prevention, management, and mechanism exploration of these diseases.

Global, regional and national burden of autism spectrum disorder from 1990 to 2019: results from the Global Burden of Disease Study 2019.

AIMS: Autism spectrum disorder (ASD) is a neurodevelopmental condition, with symptoms appearing in the early developmental period. Little is known about its current burden at the global, regional and national levels. This systematic analysis aims to summarise the latest magnitudes and temporal trends of ASD burden, which is essential to facilitate more detailed development of prevention and intervention strategies. METHODS: The data on ASD incidence, prevalence, disability-adjusted life years (DALYs) in 204 countries and territories between 1990 and 2019 came from the Global Burden of Disease Study 2019. The average annual percentage change was calculated to quantify the secular trends in age-standardised rates (ASRs) of ASD burden by region, sex and age. RESULTS: In 2019, there were an estimated 60.38 × 104 [95% uncertainty interval (UI) 50.17-72.01] incident cases of ASD, 283.25 × 105 (95% UI 235.01-338.11) prevalent cases and 43.07 × 105 (95% UI 28.22-62.32) DALYs globally. The ASR of incidence slightly increased by around 0.06% annually over the past three decades, while the ASRs of prevalence and DALYs both remained stable over the past three decades. In 2019, the highest burden of ASD was observed in high-income regions, especially in high-income North America, high-income Asia Pacific and Western Europe, where a significant growth in ASRs was also observed. The ASR of ASD burden in males was around three times that of females, but the gender difference was shrunk with the pronounced increase among females. Of note, among the population aged over 65 years, the burden of ASD presented increasing trends globally. CONCLUSIONS: The global burden of ASD continues to increase and remains a major mental health concern. These substantial heterogeneities in ASD burden worldwide highlight the need for making suitable mental-related policies and providing special social and health services.

Psychological distress, emotion regulation, neuroticism, and sexual relationship on patients with temporary ejaculation failure in vitro fertilization-embryo transfer treatment.

Objective: Temporary ejaculation failure on the oocyte retrieval day might leading interruption of the oocyte retrieval procedure. The present study aims to understand the psychosocial factor that affects men with temporary ejaculation failure (TEF) in Vitro fertilization-embryo transfer (IVF-ET) patients, and thus provide new ideas for optimal clinical treatment. Study design: In a prospective study, the male patients during IVF treatment in a reproductive center of a tertiary hospital in Shandong were divided into two groups, 70 men with TEF and 79 normal controls. General population sociology and clinical disease were investigated, and the Kessler 10 scale, emotion regulation questionnaire, big five inventory questionnaire, and sex subscale of marriage quality were used to assess the psychological distress, emotion regulation, neuroticism, and satisfaction with sexual life. Results: The scores of perceived distress and neuroticism of the TEF group were higher than the non-TEF group (p < 0.001), and cognitive reappraisal and sexual relationship were significantly lower than those in the non-TEF group (p < 0.001). Psychological distress (OR 1.130, p = 0.031) and neuroticism (OR 1.096, p = 0.050) were risk factors for TEF, while cognitive reappraisal (OR 0.883, p = 0.004) and sexual relationship (OR 0.712, p < 0.001) was protective factors. Conclusion: The present study demonstrates that psychosocial factors influence TEF in IVF-ET patients, which provides the basis for the prevention of the occurrence of TEF in a male undergoing IVF-ET.

Global, regional and national burden of anxiety disorders from 1990 to 2019: results from the Global Burden of Disease Study 2019.

AIMS: Anxiety disorders are widespread across the world. A systematic understanding of the disease burden, temporal trend and risk factors of anxiety disorders provides the essential foundation for targeted public policies on mental health at the national, regional, and global levels. METHODS: The estimation of anxiety disorders in the Global Burden of Disease Study 2019 using systematic review was conducted to describe incidence, prevalence and disability-adjusted life years (DALYs) in 204 countries and regions from 1990 to 2019. We calculated the estimated annual percentage change (EAPC) to quantify the temporal trends in anxiety disorders burden by sex, region and age over the past 30 years and analysed the impact of epidemiological and demographic changes on anxiety disorders. RESULTS: Globally, 45.82 [95% uncertainty interval (UI): 37.14, 55.62] million incident cases of anxiety disorders, 301.39 million (95% UI: 252.63, 356.00) prevalent cases and 28.68 (95% UI: 19.86, 39.32) million DALYs were estimated in 2019. Although the overall age-standardised burden rate of anxiety disorders remained stable over the past three decades, the latest absolute number of anxiety disorders increased by 50% from 1990. We observed huge disparities in both age-standardised burden rate and changing trend of anxiety disorders in sex, country and age. In 2019, 7.07% of the global DALYs due to anxiety disorders were attributable to bullying victimisation, mainly among the population aged 5-39 years, and the proportion increased in almost all countries and territories compared with 1990. CONCLUSION: Anxiety disorder is still the most common mental illness in the world and has a striking impact on the global burden of disease. Controlling potential risk factors, such as bullying, establishing effective mental health knowledge dissemination and diversifying intervention strategies adapted to specific characteristics will reduce the burden of anxiety disorders.

Development of the psychosomatic symptom scale (PSSS) and assessment of its reliability and validity in general hospital patients in China.

OBJECTIVES: To develop and verify the Psychosomatic Symptom Scale (PSSS) among psychosomatic patients and the cut-off value of PSSS in distinguishing psychosomatic patients from health controls. METHODS: The PSSS was drafted by an expert workgroup. 996 patients and 366 controls from 14 general hospitals in China were recruited to complete PSSS, Patient Health Questionnaire-15 (PHQ-15) and Symptom Checklist-90 (SCL-90). Student's t-test, Kruskal-Wallis test, Cronbach's α, Spearman's correlation, and confirmatory factor analysis (CFA) were used to verify the PSSS. Receiver operating characteristic (ROC) analyses were used to determine the cut-off value. RESULTS: Cronbach α of PSSS was 0.907. The PSSS was significantly correlated with SCL-90 somatization subscale (r = 0.682, P < 0.001) and PHQ-15 (r = 0.724, P < 0.001). CFA supported the theoretical two-factor structure of the PSSS, with comparative fit index (CFI) = 0.979, Tucker-Lewis index (TLI) = 0.977, root mean square error of approximation (RMSEA) = 0.039 (90% CI: 0.035-0.042), and standardized root mean residual (SRMR) = 0.054. As the sum score of PSSS was significantly higher in female, cut-off values were determined as 11 in females and 10 in males respectively. CONCLUSIONS: The PSSS is a reliable and valid instrument for measuring psychosomatic symptoms.

Chondroblastoma of the patella with pathological fracture in an adolescent: a case report.

BACKGROUND: Chondroblastoma is a rare primary bone tumor of young people that generally occurs in the epiphyseal plate of long bones. To date, only 13 cases of patella with pathological fracture in chondroblastoma have been previously published. CASE PRESENTATION: A 15-year-old male patient presented with acute pain in the left knee after an injury occurred while playing basketball. Plain radiographs and computed tomography showed a pathological fracture of the left patella with an osteolytic lesion (1.5 × 2 × 3 cm). Magnetic resonance imaging revealed an expansile lesion within the patella with a slightly high signal on the T1-weighted image, a high signal on the T2-weighted image and soft tissue swelling in front of the patella. A m99Tc bone scintigraphy revealed moderate uptake. The preoperative diagnosis was chondroblastoma. This patient underwent intralesional meticulous extended curettage, adjuvant high-speed burr, 95% alcohol and electrotome treatment, autogenous iliac crest bone grafting, and internal fixation. A postoperative pathological diagnosis was chondroblastoma. The patient's function was satisfactory, and there was no sign of tumor recurrence. The internal fixator was good, with no loosening or migration observed at the last follow-up at 20 months after surgery. CONCLUSIONS: Rarely, chondroblastoma of the patella can present with acute pain due to pathological fracture. We present the 14th such case in the literature to associate patellar chondroblastoma with pathological fracture. The patient was treated with curettage, inactivation, autogenous bone grafting, and internal fixation. A satisfactory therapeutic effect was obtained. This case may be beneficial to the diagnosis and treatment of chondroblastoma patella.

PDTC Alleviates Depressive Symptoms and Colon Tissue Injury via Inhibiting NO Overproduction in CUMS Rats.

BACKGROUND: The accumulated evidence demonstrates that stress plays an important role in the pathogenesis of depression that is associated with intestinal dysfunctions. However, the mechanisms remain unresolved. METHODS: A total of 40 male Wistar rats were obtained and randomly divided into four equal-sized group: control, PDTC + chronic and unpredictable mild stress (CUMS), FLX + CUMS, and CUMS. Western blotting and qRT-PCR were used to examine the levels of nitric oxide (NO), nuclear factor kappa beta (NF-κB), inducible nitric oxide synthase (iNOS), and iNOS mRNA in spinal cord L1-2 and colon. KEY RESULTS: Chronic and unpredictable mild stress increased the serum CORT level, decreased body weight and sucrose preference, and altered OFT performance, while increased levels of NO, iNOS mRNA, iNOS and NF-κB protein in colon and spinal cord were accompanied by histopathological changes in colon. Pretreatment with an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), reversed these effects. Fluoxetine failed to prevent NO increase in both spinal cord and colon, while the iNOS protein level, although not statistically significantly increased compared to control, was not decreased compared to CUMS. Also, fluoxetine failed to prevent histological changes. CONCLUSION: In conclusion, the NF-κB/iNOS pathway may be involved in the mechanism of CUMS-induced depressive-like behavior and colon tissue injury.

Ginsenoside Rg1 Prevents Chronic Stress-Induced Depression-Like Behaviors and Neuronal Structural Plasticity in Rats.

BACKGROUND/AIMS: Ginsenoside Rg1 has been demonstrated to exhibit neuroprotective effects in various studies. This study aimed to investigate the neuronal mechanisms underlying the neuroprotective and antidepressant-like effects of ginsenoside Rg1 in a rat model of depression. METHODS: Chronic unpredictable mild stress was used to induce depression-like behaviors in rats. Transmission electron microscopy was used to observe neuronal synapses within the basolateral amygdala (BLA). The expression of microRNA (miR)-134 in the BLA was verified by real-time quantitative PCR. Finally, the synaptic plasticity-associated proteins CAMP-response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were detected by immunoblotting. RESULTS: Results showed that chronic stress effectively induced depression-like behaviors in rats, which were associated with significant ultrastructural changes within BLA neurons. Moreover, chronic stress decreased the expression of miR-134 in the BLA, which was accompanied by decreased phosphorylation of CREB and decreased expression of BDNF. Remarkably, chronic administration of ginsenoside Rg1 (40 mg/kg, i.p., 5 weeks) significantly ameliorated the neuronal structural abnormalities and biochemical changes induced by chronic stress, as well as preventing depression-like behaviors in these rats. CONCLUSION: Results suggested that ginsenoside Rg1 may exhibit neuroprotection and antidepressant-like effects by activating the CREB-BDNF system within the BLA in this rat model of depression. Amelioration of depression-like behaviors by ginsenoside Rg1 appears to involve modulation of the synapse-associated factor miR-134 within the BLA. Therefore, these findings demonstrate some of the neuronal mechanisms associated with depression and the therapeutic potential of ginsenoside Rg1 for use in the treatment of depression in clinical trials.

Psychological status of patients with nephrotic syndrome undergoing percutaneous renal biopsy.

BACKGROUND: Nephrotic syndrome (NS) is a common clinical disease with four main clinical manifestations: hypoalbuminemia (<30 g/L), macro-proteinuria (>3.5 g/24 h), edema, and hyperlipidemia. There is a variety of pathological types that are associated with NS. Percutaneous renal biopsy (PRB) plays an important role in clinical practice in that it can be used to establish a histological diagnosis, to provide information for an ultimate NS diagnosis, and subsequent prognosis. Our aim was to observe the psychological status of patients with NS before and after PRB and investigate the factors affecting their psychological status. METHODS: Two hundred and thirty-five patients with NS were enrolled in the present study. We evaluated the psychological status of patients 24 hours before and 6 hours after PRB by using the Symptom Check List-90 and State-Trait Anxiety Inventory. RESULTS: We analyzed the factors affecting the psychological status of the study participants before and after this important NS procedure. Before the PRB procedure was administered, the factorial anxiety and phobic anxiety scores were higher than normal (p < 0.0.5). After PRB, only anxiety was determined to be higher than normal in the somatization score (p < 0.05). In general, there were higher scores among males rather than the female study participants (p < 0.05). Scores of all indices decreased significantly in all patients after PRB (p < 0.05). CONCLUSION: Psychological status was common in patients who underwent PRB and were affected by many factors.

Effects of methylphenidate on attentional set-shifting in a genetic model of attention-deficit/hyperactivity disorder.

BACKGROUND: Although deficits of attentional set-shifting have been reported in individuals with attention deficit/hyperactivity disorder (ADHD), it is rarely examined in animal models. METHODS: This study compared spontaneously hypertensive rats (SHRs; a genetic animal model of ADHD) and Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats (normoactive control strains), on attentional set-shifting task (ASST) performance. Furthermore, the dose-effects of methylphenidate (MPH) on attentional set-shifting of SHR were investigated. In experiment 1, ASST procedures were conducted in SHR, WKY and SD rats of 8 each at the age of 5 weeks. Mean latencies at the initial phase, error types and numbers, and trials to criteria at each stage were recorded. In experiment 2, 24 SHR rats were randomly assigned to 3 groups of 8 each-- MPH-L (lower dose), MPH-H (higher dose), and SHR-vehicle groups. From 3 weeks, they were administered 2.5 mg/kg or 5 mg/kg MPH or saline respectively for 14 consecutive days. All rats were tested in the ASST at the age of 5 weeks. RESULTS: The SHRs generally exhibited poorer performance on ASST than the control WKY and SD rats. Significant strain effects on mean latency [F (2, 21) = 639.636, p < 0.001] and trials to criterion [F (2, 21) = 114.118, p < 0.001] were observed. The SHRs were found to have more perseverative and regressive errors than the control strains (p < 0.001). After MPH treatment, the two MPH treated groups exhibited significantly longer latency and fewer trials to reach criterion than the SHR-vehicle group and the MPH-L group exhibited fewer trials to reach criterion in more stages compared with the MPH-H group. Significant main effects of treatment [F (2, 21) = 52.174, p < 0.001] and error subtype [F (2, 42) = 221.635, p < 0.01] were found. CONCLUSIONS: The SHR may be impaired in discrimination learning, reversal learning and attentional set-shifting. Our study provides evidence that MPH may improve the SHR's performance on attentional set-shifting and lower dose is more effective than higher dose.

Effects of adrenergic agents on stress-induced brain microstructural and immunochemical changes in adult male Wistar rats.

This preliminary study aims to explore how adrenergic agents modulate stress response and affect stress-induced behavioral and brain changes in rodents. A total of 40 adult male Wistar rats were subjected to chronic unpredictable mild stress (CUMS) and randomly divided into five groups. At 30 min before daily stress exposure, the rats were intraperitoneally injected with phentolamine (5mg/kg), noradrenalin (1.0mg/kg), propranolol (10mg/kg), isoproterenol (0.05 mg/kg) or saline, respectively. Another 8 rats served as normal control and received daily saline injection without stress exposure. Open-field behaviors were tested at 1 day after the end of the 21 days of stress exposure. Blood samples were collected for serum corticosterone measurement. Brain sections containing hippocampus were stained with hematoxylin and eosin (H&E) as well as by immunohistochemistry for heat shock protein 70 (hsp70) and nitric oxide synthase type 2 (nos2) analyses. The experimental results demonstrated that repetitive dosing of noradrenalin, phentolamine, and propranolol during chronic stress might region-dependently attenuate stress-induced microstructural and biochemical changes in the hippocampus, although propranolol intensified stress-induced behavioral changes.

Effects of stress in early life on immune functions in rats with asthma and the effects of music therapy.

OBJECTIVE: Although studies have shown that psychological stress has detrimental effects on bronchial asthma, there are few objective data on whether early-life stress, as early postnatal psychosocial environment, has a long-lasting effect on adult asthma and the potential pathophysiologic mechanism. This study aims to examine the effects on immune function and hypothalamic-pituitary-adrenal (HPA) axis responses in adult asthmatic rats that experienced stress in early life and the potential ameliorative effects of music therapy on these parameters. METHODS: Forty male Wistar rat pups were randomly assigned to the asthma group, the adulthood-stressed asthma group, the childhood-stressed asthma group, the music group, and the control group. Restraint stress and Mozart's Sonata K.448 were applied to ovalbumin (OVA)-induced asthmatic rats to establish psychological stress and music therapy models. The levels of serum corticosterone were examined in both childhood after stress and adulthood after OVA challenge. Immune indicators in blood, lung, and brain tissues were measured after the last OVA challenge. RESULTS: Stress in both childhood and adulthood resulted in increases in leukocyte and eosinophil numbers and serum interleukin (IL)-4 levels. The adulthood-stressed group demonstrated increased corticosterone levels after challenge, whereas the childhood-stressed group showed increased corticosterone concentration in childhood but decreased level in adulthood. Central IL-1beta exhibited a similar tendency. Music group rats showed reduced serum IL-4 and corticosterone. CONCLUSIONS: Stress in childhood and adulthood resulted in different HPA axis responsiveness in the exacerbation of markers of asthma. These data provide the first evidence of the long-term normalizing effects of music on asthmatic rats.