Contribution of diversity of social participation on the mental health of humanitarian migrants during resettlement.

AIMS: By the end of 2022, an estimated 108.4 million individuals worldwide experienced forced displacement. Identifying modifiable factors associated with the mental illness of refugees is crucial for promoting successful integration and developing effective health policies. This study aims to examine the associations between the changes in the diversity of social participation and psychological distress among refugees throughout the resettlement process, specifically focusing on gender differences. METHODS: Utilizing data from three waves of a longitudinal, nationally representative cohort study conducted in Australia, this study involved 2399 refugees interviewed during Wave 1, 1894 individuals interviewed during Wave 3 and 1881 respondents during Wave 5. At each wave, we assessed psychological distress and 10 types of social participation across 3 distinct dimensions, including social activities, employment and education. The primary analysis employed mixed linear models and time-varying Cox models. Gender-stratified analyses and sensitivity analyses were performed. RESULTS: Refugees engaging in one type or two or more types of social participation, compared with those not engaging in any, consistently had lower psychological distress scores (ß = -0.62 [95% confidence interval (CI), -1.07 to -0.17] for one type of social participation; ß = -0.57 [95% CI, -1.04 to -0.10] for two or more types of social participation) and a reduced risk of experiencing psychological distress (hazard ratio [HR] = 0.81 [95% CI, 0.65-0.99] for one type of social participation; HR = 0.77 [95% CI, 0.61-0.97] for two or more types of social participation) during the resettlement period. When stratifying the results by gender, these associations in the adjusted models only remained significant in male refugees. Moreover, three specific types of social participation, namely sporting activities, leisure activities and current employment status, were most prominently associated with a reduced risk of psychological distress. CONCLUSIONS: The findings of this cohort study suggest that social participation was consistently associated with reduced risks of psychological distress among male refugees during resettlement. These findings highlight the significance of promoting meaningful social participation and interaction may be an effective strategy to improve the mental health of refugees and facilitate their successful integration into society, especially among male refugees.

Childhood Adversity and Adolescent Smartphone Use Across Sexual Orientation and Gender Expression.

Importance: Nonheterosexual and gender-nonconforming (GNC) individuals tend to report adverse childhood experiences (ACEs) more frequently compared with heterosexual and gender-conforming individuals, and individuals who have experienced ACEs, identify as nonheterosexual, or exhibit moderate to high levels of GNC are more prone to engaging in problematic smartphone use (PSU). However, there is limited school-based data among adolescents regarding this matter. Objectives: To explore the associations between ACEs and PSU among adolescents across different sexual orientation and gender expression groups. Design, setting, and participants: Using data from the 2021 School-Based Chinese Adolescents Health Survey, this cross-sectional study includes participants from 288 public high schools across 8 provinces in China. Statistical analysis was performed from October 2023 to February 2024. Exposures: Data on ACEs, sexual orientations, and gender expressions (high, moderate, and low GNC) were collected. Main outcomes and measures: PSU was assessed using the 10-item Smartphone Addiction Scale-Short Version (SAS-SV). Weighted linear, logistic, or Poisson regression models were used. Results: Among the 85 064 adolescents included (mean [SD] age, 14.92 [1.77] years), 42 632 (50.1%) were female, 70 157 (83.2%) identified as Han Chinese, and 14 208 (16.8) identified as other ethnicities (Miao, Hui, Yi, Dai, and other ethnic groups). The prevalence of PSU among participants was 35.4%. Weighted Poisson regression models indicated that the interaction between GNC and ACE was significant (adjusted prevalence ratio [APR], 0.98; 95% CI, 0.97-0.99). Further stratified analysis demonstrated homosexual adolescents who experienced 4 or more ACEs showed a significantly increased prevalence of PSU (APR, 1.79; 95% CI, 1.64-1.96). Similarly, a markedly higher prevalence of PSU was observed among bisexual individuals with 4 or more ACEs (APR, 1.60; 95% CI, 1.41-1.80). Regarding gender expression categories, a significantly higher prevalence of PSU was noted among high GNC adolescents with 4 or more ACEs (APR, 1.78; 95% CI, 1.60-1.98) compared with low GNC adolescents without ACEs. Furthermore, experiencing any 3 ACE categories (abuse, neglect, and household dysfunction) was associated with an increased prevalence of PSU across different sexual orientation and gender expression subgroups. Conclusions and relevance: In this cross-sectional study, the amalgamation of elevated ACE scores with nonheterosexual orientations or GNC identities was significantly associated with increased PSU prevalence. These findings underscore that preventing ACEs may be beneficial in mitigating PSU among adolescents, particularly for nonheterosexual adolescents and those with high levels of GNC.

Associations of recent stressful life events with anxiety symptoms among Chinese adolescents with a consideration of family functioning.

Background: The association between stressful life events (SLEs) and adolescent anxiety symptoms has been extensively studied, but the specific impacts of different SLEs domains remain inconclusive. Moreover, limited research has examined the role of family functioning in these associations.Objective: This study aimed to investigate the associations between various recent SLEs and adolescent anxiety symptoms and explore the role of family functioning.Methods: Data were obtained from the second phase of the Longitudinal Study of Adolescents' Mental and Behavioral Well-being Research in Guangzhou, China. A total of 10,985 students (51.9% boys; mean [SD] age, 15.3 [1.5] years) from forty middle schools participated in the study in 2022 and completed a self-report questionnaire assessing anxiety symptoms, SLEs, and family functioning using the Generalized Anxiety Disorder-7 (GAD-7), Adolescent Self-rating Life Events Checklist (ASLEC; including five subscales: interpersonal stress, academic stress, punishment-related stress, loss-related stress, and adaptation-related stress), and the adapted Chinese version of the Family Assessment Device (FAD), respectively. Linear mixed-effects models were performed and the moderation role of family functioning was also examined.Results: The fully adjusted model revealed that a 1-SD increase in the overall ASLEC score was associated with higher levels of anxiety symptoms (ß = 2.23, 95%CI: 2.15-2.32). Among various SLEs domains, the academic domain shows the most significant association (ß = 2.25, 95%CI: 2.17-2.33). Family functioning exerted an independent protective influence on anxiety symptoms, with each 1-SD increase in FAD scores negatively associated with anxiety symptoms (ß = -2.11, 95%CI: - 2.29 to - 1.93) in the adjusted model. Moreover, family functioning significantly buffered the impacts of overall SLEs and each domain, except for adaptation-related SLEs, on anxiety symptoms.Conclusion: Higher recent SLEs levels were associated with increased anxiety symptoms among adolescents, with academic SLEs showing the greatest association. Positive family functioning had both direct and buffering influences on anxiety symptoms.

Higher levels of recent stressful life events may increase adolescents' anxiety symptoms.Academic stressful life events show the greatest association with anxiety symptoms.Family functioning may be a promising intervention target for adolescent anxiety symptoms.

Association between physical activity and depressive symptoms in adolescents: A prospective cohort study.

It remains uncertain whether a protective association between physical activity and depression exists among adolescents and what the optimal level of physical activity might be. This study aimed to estimate the associations of physical activity levels with depressive symptoms and new-onset depression, while identifying potential modifying factors influencing the relationships. In this cohort study, we initially enrolled 1957 participants at baseline and followed up with 1738 of them after two years. Our analysis focused on data from 1482 students who provided complete information on both physical activity and depressive symptoms. Generalized linear regression and restricted cubic spline regression models were performed. Our adjusted models revealed that engaging in 4-7 h/week of moderate-to-vigorous physical activity (MVPA) at baseline was negatively associated with subsequent depressive symptoms and new-onset depression compared to the non-MVPA group. However, exceeding 7 h/week of MVPA did not provide substantial benefits. Furthermore, drinking and screen time potentially modified the relationship between MVPA and new-onset depression. Our findings suggest that 4-7 h of MVPA per week may be an appropriate level to reduce depressive symptoms in adolescents. Moreover, individual behaviors (e.g., drinking and screen time) warrant heightened attention in interventions targeting the reduction of depression in this population.

Nonconforming gender expression and associated problematic smartphone and internet use among Chinese adolescents.

Background and aims: Gender nonconformity (GNC), which refers to an individual's expression of gender that does not align with the socially prescribed norms for their biological sex, may be associated with adverse behavioral problems, such as problematic smartphone use (PSU) and problematic internet use (PIU). This study examined the associations between GNC and PSU and GNC and PIU among Chinese adolescents. Methods: This cross-sectional study utilized data from the 2021 School-based Chinese Adolescents Health Survey, recruiting 23,054 eligible adolescents aged 11 to 21, with an average age of 14.9 (SD: 1.7) years from 504 classes in 84 public high schools across 7 cities in China. Gender nonconformity, PSU/PIU, and demographics were measured. Mixed-effect linear regression models were performed. Results: Among the participants (51.0% male), 5.3% reported high GNC and 26.9% reported moderate GNC. After adjusting for covariates, high GNC was significantly and positively associated with PSU (Β = 1.11, 95% CI = 0.49-1.72) and PIU severity (Β = 2.16, 95% CI = 1.40-2.93). Stratified analyses indicated that the associations between GNC and PSU differed between males and females, with a significant association observed only among male students (Β = 1.91, 95% CI = 0.97-2.86). Discussion and conclusions: GNC is positively associated with the severity of PSU and PIU among Chinese adolescents, with male gender-nonconforming adolescents being more vulnerable to PSU. These results highlight the importance of implementing education on gender expression diversity in schools to create an inclusive school environment, which may potentially help prevent PSU and PIU among gender-nonconforming adolescents.

Predicting potential global distribution and risk regions for potato cyst nematodes (Globodera rostochiensis and Globodera pallida).

Potato cyst nematodes (PCNs), golden (yellow) cyst nematode (Globodera rostochiensis, gPCN) and pale (white) cyst nematode (G. pallida, pPCN), are important invasive pests in many countries and regions where they can cause significant yield and economic loss for agriculture. Prediction and identification of habitats suitable for PCNs are critical for developing biosecurity strategies, both pre and post border, to maximise the potential for early elimination should an incursion occur. To date, the potential global distribution of PCNs has not been thoroughly studied. Therefore, this study conducted a species distribution model to illustrate the potential global distribution of PCNs and risk regions. In this study, the Maximum Entropy Model (Maxent) associated with the Geographic Information System (GIS) was employed to reveal the potential distribution of the gPCN and pPCN. In addition to bioclimate, soil quality was also included in the model. The global cultivated lands, whether the susceptible hosts were present or not, were used to assess the maximum potential risk regions. The limitation factors for PCNs distribution were also assessed. Results showed that 66% of the global land surface was suitable for gPCN or pPCN or both, and both species can colonise more than 75% of the global cultivated lands. The coldest quarter's mean temperature and precipitation were critical limitations in unsuitable regions. In summary, the global risk maps of PCNs contribute valuable additional information that complements previous national/regional distribution predictions. The results of this distribution research will contribute practical support for decision-makers and practitioners to implement biosecurity strategies from a global perspective, that incorporate prevention or promptly enforce control practices to limit the damage caused by future incursions.

Transfer of neuron-derived α-synuclein to astrocytes induces neuroinflammation and blood-brain barrier damage after methamphetamine exposure: Involving the regulation of nuclear receptor-associated protein 1.

The α-synuclein (α-syn) is involved in methamphetamine (METH)-induced neurotoxicity. Neurons can transfer excessive α-syn to neighboring neurons and glial cells. The effects of α-syn aggregation in astrocytes after METH exposure on the blood-brain barrier (BBB) remains unclear. Our previous study demonstrated that nuclear receptor-related protein 1 (Nurr1), a member of the nuclear receptor family widely expressed in the brain, was involved in the process of METH-induced α-syn accumulated in astrocytes to activate neuroinflammation. The role Nurr1 plays in astrocyte-mediated neuroinflammation, which results in BBB injury induced by METH, remains uncertain. This study found that METH up-regulated α-syn expression in neurons extended to astrocytes, thereby eliciting astrocyte activation, increasing and decreasing IL-1ß, IL-6, TNF-α, and GDNF levels by down-regulating Nurr1 expression, and ultimately damaging the BBB. Specifically, the permeability of BBB to Evans blue and sodium fluorescein (NaF) increased; IgG deposits in the brain parenchyma increased; the Claudin5, Occludin, and PDGFRß levels decreased. Several ultrastructural pathological changes occurred in the BBB, such as abnormal cerebral microvascular diameter, astrocyte end-foot swelling, decreased pericyte coverage, and loss of tight junctions. However, knockout or inhibition of α-syn or astrocyte-specific overexpression of Nurr1 partially alleviated these symptoms and BBB injury. Moreover, the in vitro experiments confirmed that METH increased α-syn level in the primary cultured neurons, which could be further transferred to primary cultured astrocytes, resulting in decreased Nurr1 levels. The decreased Nurr1 levels mediated the increase of IL-1ß, IL-6, and TNF-α, and the decrease of GDNF, thereby changing the permeability to NaF, transendothelial electrical resistance, and Claudin5 and Occludin levels of primary cultured brain microvascular endothelial cells. Based on our findings, we proposed a new mechanism to elucidate METH-induced BBB injury and presented α-syn and Nurr1 as promising drug intervention targets to reduce BBB injury and resulting neurotoxicity in METH abusers.

The Rise and Fall of Physiological Theories of the Control of Human Eating Behavior.

Kuhns was the first to suggest that theories in science do not develop in small increments but rather in major leaps to paradigms that examine the same question through very different perspectives. Theories on the mechanism responsible for control of human food intake fall into Kuhn's description. This article describes how the two major theories of the control of food intake in humans, the Glucostatic Theory, and the Lipostatic Theory, showed initial promise as explanations, but later deteriorated with the slow accumulation experimental data. The locus of theories considered eating behavior as a part of physiological system that regulates the storage of energy on the body. We challenge this fundamental belief with data which suggests that we must be ready to accept a major change in the way we think about eating behavior if we are ever to decrease the prevalence of obesity.

Seasonal and Year-Round Distributions of Bactrocera dorsalis (Hendel) and Its Risk to Temperate Fruits under Climate Change.

Bactrocera dorsalis (Hendel) is an important pest to fruits and vegetables. It can damage more than 300 plant species. The distribution of B. dorsalis has been expanding owing to international trade and other human activities. B. dorsalis occurrence is strongly related to suitable overwintering conditions and distribution areas, but it is unclear where these seasonal and year-round suitable areas are. We used maximum entropy (MaxEnt) to predict the potential seasonal and year-round distribution areas of B. dorsalis. We also projected suitable habitat areas in 2040 and 2060 under global warming scenarios, such as SSP126 and SSP585. These models achieved AUC values of 0.860 and 0.956 for the seasonal and year-round scenarios, respectively, indicating their good prediction capabilities. The precipitation of the wettest month (Bio13) and the mean diurnal temperature range (Bio2) contributed 83.9% to the seasonal distribution prediction model. Bio2 and the minimum temperature of the coldest month (Bio6) provided important information related to the year-round distribution prediction. In future scenarios, the suitable area of B. dorsalis will increase and the range will expand northward. Four important temperate fruits, namely, apples, peaches, pears, and oranges, will be seriously threatened. The information from this study provides a useful reference for implementing improved population management strategies for B. dorsalis.

Aerobic Exercise Improves Methamphetamine-Induced Olfactory Dysfunction Through α-Synuclein Intervention in Male Mice.

Methamphetamine (Meth) is a predominantly abused neurostimulant, and its abuse is often associated with multiple neurological symptoms. Olfaction, the sense of smell, is a highly neurotransmission-dependent physiological process; however, the effect of Meth on olfactory function and its underlying mechanisms remain largely unknown. This study aimed to explore the impact of Meth abuse on the olfactory system and the potential mechanisms. Chronic Meth abuse was induced by daily administration of Meth in male mice for 4 weeks, and we then systematically examined olfactory performance. Behavioral tests found that Meth-treated animals showed increased olfactory threshold, decreased olfactory sensitivity, reduced olfactory-dependent discrimination, and difficulty in seeking buried food. Notably, the increased deposition of α-synuclein (α-syn) in the olfactory bulb was detected. Adeno-associated virus (AAV)-mediated α-syn intervention therapy in the olfactory bulb significantly alleviated Meth-induced olfactory function impairment, and 8 weeks of aerobic exercise showed similar effects through the same principle of α-syn intervention. Notably, exercise-mediated reduction of α-syn inhibited abnormal firing activity and restored the inhibitory synaptic regulation of mitral cells in the olfactory bulb. These findings suggest the involvement of α-syn in the pathogenic mechanisms of Meth-induced olfactory dysfunction and shed light on the possible therapeutic applications of aerobic exercise in Meth-induced olfactory dysfunction.

Microhaplotype and Y-SNP/STR (MY): A novel MPS-based system for genotype pattern recognition in two-person DNA mixtures.

BACKGROUNDS: Y-chromosomal haplotypes based on Y-short tandem repeats (STRs) and Y-single nucleotide polymorphisms/insertion and deletion polymorphisms (SNPs/InDels) are used to characterize paternal lineages of unknown male trace donors. However, Y-chromosomal genetic markers are not currently sufficient for precise individual identification. Microhaplotype (MH), generally < 200 bp on autosomes and consisting of two or more SNPs, was recently introduced in forensic genetics with the development of massive parallel sequencing technology and may facilitate identification and DNA mixture deconvolution. Therefore, combining the two kinds of genetic markers may be beneficial in many forensic scenarios, especially crime scenes with male suspects, such as sexual assault cases. METHODS: In the present study, we developed a novel MPS-based panel, Microhaplotype and Y-SNP/STR (MY), by multiplex PCR and 150-bp paired-end sequencing, including 114 Y-SNPs (twelve dominant Y-DNA haplogroups), 45 Y-STRs (N-1 stutter < 0.09; estimated mutation rate < 5 × 10-3), and 22 MHs (allele coverage ratio > 0.91; pairwise distance > 10 Mb). Additionally, MY system-based genotype pattern recognition (GPR), a regression-based method to identify the genotype pattern for each MH locus, is proposed for two-person DNA mixture deconvolution. We integrated 26 two-person genotype combinations into nine genotype patterns and validated the application range of GPR based on DNA profiles of ten sets of simulated male-male DNA mixtures (1:10-1:2). RESULTS: The effective number of alleles (Ae) ranged from 3.62 to 14.72, with an average of 7.17, in 100 Chinese Guangdong Han individuals. The cumulative discrimination power was 1-5.00 × 10-31, and the cumulative power of exclusion was 1-5.00 × 10-8 and 1-4.85 × 10-12 for duo and trio paternity testing, respectively. Furthermore, the actual mixing ratio-depth of coverage (DoC) ratio (RDoC) regression relationships were established for different genetic markers and genotype patterns. In five overlapping areas, genotype differentiation of the major and minor contributors required likelihood ratio methods. In nonoverlapping areas, the genotype pattern could be recognized by comparing the observed RDoC and RDoC ranges. CONCLUSION: The GPR can be used to deconvolute two-person DNA mixtures (application range: 1:10-1:2) for individual identification.

Icariside II Attenuates Methamphetamine-Induced Neurotoxicity and Behavioral Impairments via Activating the Keap1-Nrf2 Pathway.

Chronic and long-term methamphetamine (METH) abuse is bound to cause damages to multiple organs and systems, especially the central nervous system (CNS). Icariside II (ICS), a type of flavonoid and one of the main active ingredients of the traditional Chinese medicine Epimedium, exhibits a variety of biological and pharmacological properties such as anti-inflammatory, antioxidant, and anticancer activities. However, whether ICS could protect against METH-induced neurotoxicity remains unknown. Based on a chronic METH abuse mouse model, we detected the neurotoxicity after METH exposure and determined the intervention effect of ICS and the potential mechanism of action. Here, we found that METH could trigger neurotoxicity, which was characterized by loss of dopaminergic neurons, depletion of dopamine (DA), activation of glial cells, upregulation of α-synuclein (α-syn), abnormal dendritic spine plasticity, and dysfunction of motor coordination and balance. ICS treatment, however, alleviated the above-mentioned neurotoxicity elicited by METH. Our data also indicated that when ICS combated METH-induced neurotoxicity, it was accompanied by partial correction of the abnormal Kelch 2 like ECH2 associated protein 1 (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) pathway and oxidative stress response. In the presence of ML385, an inhibitor of Nrf2, ICS failed to activate the Nrf2-related protein expression and reduce the oxidative stress response. More importantly, ICS could not attenuate METH-induced dopaminergic neurotoxicity and behavioral damage when the Nrf2 was inhibited, suggesting that the neuroprotective effect of ICS on METH-induced neurotoxicity was dependent on activating the Keap1-Nrf2 pathway. Although further research is needed to dig deeper into the actual molecular targets of ICS, it is undeniable that the current results imply the potential value of ICS to reduce the neurotoxicity of METH abusers.

Local iron deficiency in the substantia nigra directly contributes to hyperlocomotion phenotypes.

Brain iron is precisely regulated, and disrupted brain iron homeostasis is implicated in neuropsychological disease. Mounting evidence connects the iron status of the substantia nigra (SN) with locomotion-related neural symptomatology. Researchers in this field have long speculated that iron deficiency in the SN directly causes the high-locomotion symptoms observed in neuropsychiatric disorders. However, no direct experimental evidence of a causal relationship has been presented. To explore the relationship between iron deficiency in the SN and locomotion-related phenotypes, we stereotaxically injected the well-documented iron chelator, deferiprone (DFP) into the SN of mice to induce regional brain iron deprivation and subsequently performed behavioral tests. Altered expression of iron metabolism-related molecules was detected in the brain regions with interventions, and behavioral changes were observed. Targeted iron chelation effectively decreased the local iron content of the SN. Among the brain regions examined, only DFP injected into the SN resulted in the hyperlocomotion phenotype. Upon SN iron chelation, transferrin receptor (Tfr) expression was found to be upregulated. Conversely, viral vector-mediated SN-Tfr knockdown was sufficient to induce SN iron deficiency and mimic the hyperlocomotion phenotype. All locomotion changes had a significant negative correlation with iron alteration in the SN. Furthermore, SN iron disturbance also contributed to poor sleep efficiency. Thus, SN iron deficiency directly contributed to triggering both hyperlocomotion and sleep disturbances. This study offers a promising research and therapeutic direction for iron-linked neuropsychiatric diseases.

Brain-derived neurotrophic factor upregulates synaptic GluA1 in the amygdala to promote depression in response to psychological stress.

Psychological stress impairs neuronal structure and function and leads to emotional disorders, but the underlying mechanisms have not yet been fully elucidated. The amygdala is closely correlated with emotional regulation. In the present study, we analyzed whether the amygdala plasticity is regulated by psychological stress and explored their regulatory mechanism. We established a mouse psychological stress model using an improved communication box, wherein mice were exposed to chronic fear and avoided physical stress interference. After the 14-day psychological stress paradigm, mice exhibited significantly increased depressive behaviors (decreased sucrose consumption in the sucrose preference test and longer immobility time in the forced swimming test). HPLC, ELISA, and molecular and morphological evidences showed that psychological stress increased the content of glutamate and the expression of glutamatergic neurons, upregulated the content of the stress hormone corticosterone, and activated the CREB/BDNF pathway in the amygdala. Furthermore, psychological stress induced an increased density of dendritic spines and LTD impairment in the amygdala. Importantly, virus-mediated silencing of BDNF in the basolateral amygdala (BLA) nuclei reversed the depression-like behaviors and the increase of synaptic GluA1 and its phosphorylation at Ser831 and Ser845 sites in psychologically stressed mice. This process was likely achieved through mTOR signaling activation. Finally, we treated primary amygdala neurons with corticosterone to mimic psychological stress; corticosterone-induced upregulation of GluA1 was prevented by BDNF and mTOR antagonists. Thus, activation of the CREB/BDNF pathway in the amygdala following psychological stress upregulates synaptic GluA1 via mTOR signaling, which dysregulates synaptic plasticity of the amygdala, eventually promoting depression.

Basolateral Amygdala Serotonin 2C Receptor Regulates Emotional Disorder-Related Symptoms Induced by Chronic Methamphetamine Administration.

Globally, methamphetamine (MA) is the second most abused drug, with psychotic symptoms being one of the most common adverse effects. Emotional disorders induced by MA abuse have been widely reported both in human and animal models; however, the mechanisms underlying such disorders have not yet been fully elucidated. In this study, a chronic MA administration mouse model was utilized to elucidate the serotonergic pathway involved in MA-induced emotional disorders. After 4 weeks of MA administration, the animals exhibited significantly increased depressive and anxious symptoms. Molecular and morphological evidence showed that chronic MA administration reduced the expression of the 5-hydroxytryptamine (5-HT) rate-limiting enzyme, tryptophan hydroxylase 2, in the dorsal raphe and the concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid in the basolateral amygdala (BLA) nuclei. Alterations in both 5-HT and 5-HT receptor levels occurred simultaneously in BLA; quantitative polymerase chain reaction, western blotting, and fluorescence analysis revealed that the expression of the 5-HT2C receptor (5-HT2CR) increased. Neuropharmacology and virus-mediated silencing strategies confirmed that targeting 5-HT2CR reversed the depressive and anxious behaviors induced by chronic MA administration. In the BLA, 5-HT2CR-positive cells co-localized with GABAergic interneurons. The inactivation of 5-HT2CR ameliorated impaired GABAergic inhibition and decreased BLA activation. Thus, herein, for the first time, we report that the abnormal regulation of 5-HT2CR is involved in the manifestation of emotional disorder-like symptoms induced by chronic MA use. Our study suggests that 5-HT2CR in the BLA is a promising clinical target for the treatment of MA-induced emotional disorders.

Systematic Evaluation of a Novel 6-dye Direct and Multiplex PCR-CE-Based InDel Typing System for Forensic Purposes.

Insertion/deletion (InDel) polymorphisms, combined desirable characteristics of both short tandem repeats (STRs) and single nucleotide polymorphisms (SNPs), are considerable potential in the fields of forensic practices and population genetics. However, most commercial InDel kits designed based on non-Asians limited extensive forensic applications in East Asian (EAS) populations. Recently, a novel 6-dye direct and multiplex PCR-CE-based typing system was designed on the basis of genome-wide EAS population data, which could amplify 60 molecular genetic markers, consisting of 57 autosomal InDels (A-InDels), 2 Y-chromosomal InDels (Y-InDels), and Amelogenin in a single PCR reaction and detect by capillary electrophoresis, simultaneously. In the present study, the DNA profiles of 279 unrelated individuals from the Hainan Li group were generated by the novel typing system. In addition, we collected two A-InDel sets to evaluate the forensic performances of the novel system in the 1,000 Genomes Project (1KG) populations and Hainan Li group. For the Universal A-InDel set (UAIS, containing 44 A-InDels) the cumulative power of discrimination (CPD) ranged from 1-1.03 × 10-14 to 1-1.27 × 10-18, and the cumulative power of exclusion (CPE) varied from 0.993634 to 0.999908 in the 1KG populations. For the East Asia-based A-InDel set (EAIS, containing 57 A-InDels) the CPD spanned from 1-1.32 × 10-23 to 1-9.42 × 10-24, and the CPE ranged from 0.999965 to 0.999997. In the Hainan Li group, the average heterozygote (He) was 0.4666 (0.2366-0.5448), and the polymorphism information content (PIC) spanned from 0.2116 to 0.3750 (mean PIC: 0.3563 ± 0.0291). In total, the CPD and CPE of 57 A-InDels were 1-1.32 × 10-23 and 0.999965, respectively. Consequently, the novel 6-dye direct and multiplex PCR-CE-based typing system could be considered as the reliable and robust tool for human identification and intercontinental population differentiation, and supplied additional information for kinship analysis in the 1KG populations and Hainan Li group.

Transfer of pathological α-synuclein from neurons to astrocytes via exosomes causes inflammatory responses after METH exposure.

Methamphetamine (METH) is a highly addictive psychostimulant drug whose abuse can cause many health complications. Our previous studies have shown that METH exposure increases α-synuclein (α-syn) expression. Recently, it was shown that α-syn could be transferred from neurons to astrocytes via exosomes. However, the specific role of astrocytes in α-syn pathology involved in METH neurotoxicity remains unclear. The objective of this study was to determine whether exosomes derived from METH-treated neurons contain pathological α-syn and test the hypothesis that exosomes can transfer pathological α-syn from neurons to astrocytes. To this end, using animal and cell line coculture models, we show that exosomes isolated from METH-treated SH-SY5Y cells contained pathological α-syn. Furthermore, the addition of METH exosomes to the medium of primary cultured astrocytes induced α-syn aggregation and inflammatory responses in astrocytes. Then, we evaluated changes in nuclear receptor related 1 protein (Nurr1) expression and the levels of inflammatory cytokines in primary cultured astrocytes exposed to METH or α-syn. We found that METH or α-syn exposure decreased Nurr1 expression and increased proinflammatory cytokine expression in astrocytes. Our results indicate that α-syn can be transferred from neuronal cells to astrocytes through exosomes. When internalized α-syn accumulated in astrocytes, the cells produced inflammatory responses. Nurr1 may play a crucial role in this process and could be a therapeutic target for inflammatory damage caused by METH.

Role of alpha-synuclein phosphorylation at Serine 129 in methamphetamine-induced neurotoxicity in vitro and in vivo.

The phosphorylation and aggregation of alpha-synuclein (α-Syn) play a key role in methamphetamine (METH)-induced dopaminergic neurotoxicity. The exact mechanism underlying the interaction between METH-induced neurotoxicity and α-Syn was poorly clarified. We aimed to figure out the role of serine 129 phosphorylation (pS129) of α-Syn on its aggregation and neurotoxicity in vitro and in vivo. In this study, we examined pS129 α-Syn expression in vitro and in vivo at the protein phosphorylation and genetic levels and evaluated its effect on METH-induced neurotoxicity. Here, we found that pS129 α-Syn was significantly increased after METH treatment; moreover, the neuronal α-Syn aggregation and apoptosis caused by METH exposure were significantly attenuated after inhibiting α-Syn phosphorylation. We demonstrate that pS129 α-Syn contributes to the aggregation of α-Syn, and that phosphorylated and aggregated forms of α-Syn play an important role in METH-induced neurotoxicity in dopaminergic neurons and SH-SY5Y cells, supporting a potential insight into the treatment of METH-induced neurotoxicity.

Alpha-Synuclein deficiency ameliorates chronic methamphetamine induced neurodegeneration in mice.

The α-Synuclein (α-syn) and tau have synergistic effects on neurodegenerative diseases induced by environmental factors or genetic mutation. Thus, we investigated the role of α-syn and tau in neurodegeneration induced by chronic methamphetamine (METH) exposure (1.0∼20.0 mg/kg/d body weight, for 14 consecutive days). Here, we present a mice model with evidences of α-syn and tau participating in toxicology in chronic METH. METH increased α-syn level in the stratum oriens, pyramidal layer, stratum radiatum and stratum moleculare of hippocampal CA1, CA2 and CA3, polymorph layer of hippocampal dentate gyrus (DG), and substantia nigra (SN). The subcellular locations of the upregulated α-syn were mainly found in mitochondria and axons. The METH upregulated α-syn may directly induce mitochondrial damage, myelin sheath destruction, and synaptic failure. Also, the excess α-syn might indirectly promote tau phosphorylation through tau kinase GSK3ß and CDK5, leading to microtubule depolymerization and eventually fusion deficit of autophagosome and lysosome. In the in vitro experiment, the autophagic vacuoles failed to fuse with the lysosome. The neuropathology induced by both the direct and indirect effects of α-syn could be alleviated by α-syn knockout. Taking together, these results indicate that the α-syn mediates the neurodegenerative process induced by chronic METH and that reducing α-syn might be a potential approach to protect the toxic effects of METH and also be, to a broader view, of therapeutic value in neurodegenerative diseases.

Effect of Parkin on methamphetamine-induced α-synuclein degradation dysfunction in vitro and in vivo.

INTRODUCTION: Methamphetamine (METH) is a psychostimulant drug with complicated neurotoxicity, and abuse of METH is very common. Studies have shown that METH exposure causes alpha-synuclein (α-syn) accumulation. However, the mechanism of α-syn accumulation has not been determined. METHODS: In this study, we established cell and animal models of METH intoxication to evaluate how METH affects α-syn expression. In addition, to explore METH-induced neurotoxicity, we measured the level of Parkin and the phosphorylation levels of α-syn, Polo-like kinase 2 (PLK2), the proteasome activity marker CD3δ, and the apoptosis-related proteins Caspase-3 and PARP. Parkin is a key enzyme in the ubiquitin-proteasome system. In addition, the effect of Parkin on METH-induced neurotoxicity was investigated by overexpressing it in vitro and in vivo. RESULTS: METH exposure increased polyubiquitin and α-syn expression, as did MG132. Furthermore, the level of Parkin and the interaction between Parkin and α-syn decreased after METH exposure. Importantly, the increases in α-syn expression and neurotoxicity were relieved by Parkin overexpression. CONCLUSIONS: By establishing stable cell lines and animal models that overexpress Parkin, we confirmed Parkin as an important factor in METH-induced α-syn degradation dysfunction in vitro and in vivo. Parkin may be a promising target for the treatment of METH-induced neurotoxicity.