Long-read sequencing unveils novel somatic variants and methylation patterns in the genetic information system of early lung cancer.

Lung cancer poses a global health challenge, necessitating advanced diagnostics for improved outcomes. Intensive efforts are ongoing to pinpoint early detection biomarkers, such as genomic variations and DNA methylation, to elevate diagnostic precision. We conducted long-read sequencing on cancerous and adjacent non-cancerous tissues from a patient with lung adenocarcinoma. We identified somatic structural variations (SVs) specific to lung cancer by integrating data from various SV calling methods and differentially methylated regions (DMRs) that were distinct between these two tissue samples, revealing a unique methylation pattern associated with lung cancer. This study discovered over 40,000 somatic SVs and over 180,000 DMRs linked to lung cancer. We identified approximately 700 genes of significant relevance through comprehensive analysis, including genes intricately associated with many lung cancers, such as NOTCH1, SMOC2, CSMD2, and others. Furthermore, we observed that somatic SVs and DMRs were substantially enriched in several pathways, such as axon guidance signaling pathways, which suggests a comprehensive multi-omics impact on lung cancer progression across various biological investigation levels. These datasets can potentially serve as biomarkers for early lung cancer detection and may hold significant value in clinical diagnosis and treatment applications.

Dihydroartemisinin Protects Mice from CUMS-induced Depression-like Behaviors by Regulating Gut Microbes.

Depression is one of the most common forms of psychopathology, which is associated with gut microbiota dysfunction. Dihydroartemisinin (DHA) has been shown to regulate gut microbiota and ameliorate neuropathies, but whether it can be used to treat depression remains unclear. Our study found that DHA treatment raised the preference for sugar water in chronic unpredictable mild stress (CUMS)-induced mice and reduced the immobility time in open field, forced swimming and tail suspension experiments, and promoted doublecortin expression. Additionally, DHA up-regulated the diversity and richness of intestinal microbiota in depression-like mice, and restored the abnormal abundance of microbiota induced by CUMS, such as Turicibacter, Lachnospiraceae, Erysipelotrichaceae, Erysipelatoclostridium, Eubacterium, Psychrobacter, Atopostipes, Ileibacterium, Coriobacteriacea, Alistipes, Roseburia, Rikenella, Eggerthellaceae, Ruminococcus, Tyzzerella, and Clostridia. Furthermore, KEGG pathway analysis revealed that gut microbiota involved in the process of depression may be related to glucose metabolism, energy absorption and transport, and AMPK signaling pathway. These results indicated that DHA may play a protective role in CUMS-induced depression by mediating gut-microbiome.

Inhibition of ferroptosis alleviates chronic unpredictable mild stress-induced depression in mice via tsRNA-3029b.

Depression is a common mental illness. Ferroptosis is a form of cell death that may be responsible for neurological disease, but the role of ferroptosis in depression remains unclear. tRNA-derived small RNA (tsRNA) is an emerging non-coding small RNA, making it an important medium for studying neurological diseases. Chronic unpredictable mild stress (CUMS) was used to construct the depression model in mice, which was treated with ferrostatin-1 (Fer-1). Classical behavioral test, immunofluorescence and small RNA sequencing were used to detect depression-like behaviors, neuronal proliferation and the expression profile of tsRNAs in mice, respectively. The primary neuronal cell damage model was constructed by corticosterone (CORT), and the function of key tsRNA was investigated by quantitative real-time PCR, western blot and CCK-8 assays. Here, Fer-1 reduced the depression-like behavior of CUMS-induced mice and promoted neuronal growth. In addition, CUMS caused the disorder of tsRNA expression profile in hippocampal tissues of mice, and Fer-1 alleviated the abnormal tsRNA expression, among which tsRNA-3029b was an effective target. In vitro experiments manifested that ROS accumulation and decreased expression of SLC7A11 and GPX4 were found in CORT-induced depression-like cell model, suggesting that ferroptosis was involved in neuronal injury. However, inhibition of tsRNA-3029b suppressed neuronal cell ferroptosis and facilitated neuronal regeneration. In conclusion, Fer-1 showed an antidepressant effect in CUMS-induced mice and alleviated the abnormal expression profile of tsRNA. tsRNA-3029b was a key target in depression, and silencing of tsRNA-3029b reduced the occurrence of ferroptosis and protected neurons from injury, which may provide novel target for the treatment of depression.

Validation and application of the Chinese version of the Columbia-Suicide Severity Rating Scale: Suicidality and cognitive deficits in patients with major depressive disorder.

BACKGROUND: Depression is a significant risk factor for death by suicide. Additionally, patients with depression who have neurocognitive dysfunction are at a higher risk of exhibiting suicidal behaviors. We aimed to validate the Chinese version of the Columbia Suicide Severity Rating Scale (C-SSRS) and then employ it to examine the association between suicidality and cognitive deficits in patients with Major Depressive Disorder (MDD). METHODS: Data from 456 patients with MDD who underwent baseline assessment and 3-month follow-up were used for psychometric validation of the C-SSRS. 430 patients were divided into a mild cognitive impairment group (N = 390) and a severe cognitive impairment group (N = 40) using cluster analysis and compared with healthy controls. The relationship between C-SSRS scores and the degree of cognitive impairment was analyzed. RESULTS: 1) The Chinese version of C-SSRS demonstrated good internal consistency (Cronbach's alpha = 0.884/0.842), convergent and divergent validity. 2) The severity of suicidal ideation (SI), the intensity of SI, and the lifetime history of suicide attempts were significant independent predictors of short-term suicide attempts. 3) Higher worst-point lifetime SI severity and intensity scores in patients with MDD were significantly associated with severe cognitive impairment. LIMITATIONS: The analysis of cognition and suicide was based on cross-sectional studies. Hence, changes in SI and cognitive function over time could not be analyzed. CONCLUSIONS: The Chinese C-SSRS is a reliable and valid assessment tool for suicidal ideation and behavior in patients with depression. Suicidal ideation in patients with MDD is associated with cognitive dysfunction. These findings provide a reference for suicide prevention in patients with depression.

Magnetic resonance imaging for evaluation of bowel inflammation and disease activity in Crohn's disease: A systematic review and meta-analysis / Imágenes por resonancia magnética para la evaluación de la inflamación intestinal y la actividad de la enfermedad en la enfermedad de Crohn: una revisión sistemática y un metaanálisis

Background: The aim of this systematic review and meta-analysis was to determine the performance of magnetic resonance imaging (MRI) in the diagnosis of bowel inflammation and disease activity in Crohn's disease (CD). Methods: MEDLINE, Embase and Web of Science databases of biomedical literature were systematically searched to identify studies that investigated the diagnostic accuracy of MRI in diagnosing bowel inflammation and disease activity in CD by comparing it with reference standards. Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality. The summary sensitivity and specificity were estimated using the bivariate model, and hierarchical summary receiver operating characteristic (HSROC) parameters were calculated and plotted. Results: Of 5492 citations of interest, 34 articles contained the diagnostic accuracy data. Of these, results for the small bowel and the colorectum were reported separately in 19 studies and jointly by 21 studies. The meta-analytic summary sensitivity and specificity under the bivariate model were 90.9% (95% CI, 85.8%–94.2%) and 90.2% (95% CI, 81.9%–95.0%), respectively. The sensitivities and specificities of individual studies ranged from 55% to 100% and 51% to 100%, respectively. Substantial heterogeneity was observed in both sensitivity (I2=84.9%) and specificity (I2=78.8%). The HSROC curve also showed considerable heterogeneity between studies. Conclusion: Although the meta-analytic summary accuracy of MRI was high for the diagnosis of bowel inflammation in CD, the summary estimates might be unreliable due to the presence of high heterogeneity.(AU)

Antecedentes: El objetivo de esta revisión sistemática y metaanálisis fue determinar el rendimiento de la resonancia magnética nuclear (RM) en el diagnóstico de la inflamación intestinal y la actividad de la enfermedad en la enfermedad de Crohn (EC). Métodos: Se realizaron búsquedas sistemáticas en las bases de datos de literatura biomédica de MEDLINE, Embase y Web of Science para identificar estudios que investigaran la precisión diagnóstica de la RM en el diagnóstico de la inflamación intestinal y la actividad de la enfermedad en la EC comparándola con estándares de referencia. Evaluación de la calidad de los estudios de precisión diagnóstica: se utilizó la herramienta 2 para evaluar la calidad del estudio. La sensibilidad y la especificidad resumidas se estimaron mediante el modelo bivariado, y se calcularon y trazaron los parámetros de características operativas del receptor resumidas jerárquicas (HSROC). Resultados: De 5.492 citas de interés, 34 artículos contenían datos de precisión diagnóstica. De estos, los resultados para el intestino delgado y el colorrectal se informaron por separado en 19 estudios y en forma conjunta en 21 estudios. La sensibilidad y la especificidad del resumen metanalítico bajo el modelo bivariado fueron del 90,9% (IC del 95%, 85,8%-94,2%) y el 90,2% (IC del 95%, 81,9%-95,0%), respectivamente. Las sensibilidades y especificidades de los estudios individuales variaron del 55 al 100% y del 51 al 100%, respectivamente. Se observó heterogeneidad sustancial tanto en la sensibilidad (I2=84,9%) como en la especificidad (I2=78,8%). La curva HSROC también mostró una considerable heterogeneidad entre los estudios. Conclusión: Aunque la precisión del resumen metaanalítico de la RM fue alta para el diagnóstico de inflamación intestinal en la EC, las estimaciones del resumen pueden no ser confiables debido a la presencia de una gran heterogeneidad.(AU)

Association of adenosine triphosphate-related genes to major depression and suicidal behavior: Cognition as a potential mediator.

BACKGROUND: Soluble epoxide hydrolase (sEH, encoded by EPHX2) and P2X2 (a subtype of ATP receptors) may mediate the antidepressant-like effects of ATP. We sought to determine whether polymorphisms and mRNA expression of EPHX2 and P2X2 are associated with depression and suicidal behavior and how cognition may mediate such associations. METHOD: We examined 83 single nucleotide polymorphisms (SNPs) of EPHX2 and P2X2. Subjects were MDD suicide attempters (N = 143), MDD non-suicide attempters (N = 248), and healthy volunteers (HV, N = 110). Data on demographics, depression severity, and suicide attempts were collected. Participants completed a set of cognitive tasks. Polymorphisms were genotyped using MALDI-TOF MS within the MassARRAY system. The expression of mRNA was measured using real-time polymerase chain reaction (RT-PCR). RESULTS: Cognitive function was a significant mediator (p = 0.006) of the genetic effect on depression. Allele C of rs202059124 was associated with depression risk (OR = 11.57, 95%CI: 2.33-209.87, p = 0.0181). A significant relationship was found between P2X2 mRNA expression and depression (OR = 0.68, 95%CI: 0.49-0.94, p = 0.0199). One haploblock (rs9331942 and rs2279590) was associated with suicide attempts: subjects with haplotype GC (frequency = 19.8 %, p = 0.017) and AT (frequency = 35.2 %, p < 0.001) had a lower rate of suicide attempts. CONCLUSIONS: Our results confirmed that cognitive impairment plays a role in the effect of rs9331949 on depression. Moreover, we confirmed a relationship between P2X2, EPHX2, and MDD in humans and presented preliminary haplotype-based evidence that implicates EPHX2 in suicide. LIMITATIONS: The main limitation of this study is the limited sample size. More comprehensive and multi-domain cognition tasks and different assessment measures are required in further study.

Efficacy and safety of non-prostanoid prostacyclin receptor agonist for pulmonary hypertension: A meta-analysis.

BACKGROUND: Oral non-prostanoid prostacyclin receptor agonists therapies have been recommended for pulmonary arterial hypertension in many countries. OBJECTIVE: We aimed to evaluate the specific impact of non-prostanoid prostacyclin receptor agonists on pulmonary hypertension and to explore the influence of study characteristics on results. METHODS: PubMed, Embase, and ClinicalTrials.gov were systematically searched from inception to July 12, 2022. Randomized controlled trials comparing non-prostanoid prostacyclin receptor agonists administration with placebo for treating pulmonary hypertension were included. Two researchers independently selected eligible studies, assessed the bias risk and extracted related data. RevMan5.1 was used for performing the statistical analysis and the assessment of bias risk of the enrolled studies. PROSPERO registered number CRD42022304172. RESULTS: Seven trials involving 1727 patients were included. Pooled analyses indicated non-prostanoid prostacyclin receptor agonists significantly reduced clinical worsening events (risk ratio [RR], 0.63; 95% confidence interval [CI], 0.54 to 0.74), increased 6-min walk distance (mean difference [MD], 10 m; 95% CI, 3-17 m), decreased pulmonary vascular resistance (MD, -121 dyn s/cm5; 95% CI, -172 to -69 dyn s/cm5) and increased cardiac index (MD, 0.38 L/min/m2; 95% CI, 0.26-0.50 L/min/m2) compared with the control. No significant differences in all-cause mortality (RR, 0.86; 95% CI, 0.26 to 2.78), NYHA/WHO functional class (RR, 1.16; 95% CI, 0.61 to 2.18), mean pulmonary artery pressure (MD, -0.88 mmHg; 95% CI, -2.20 to 0.44 mmHg), right atrial pressure (MD, 0.66 mmHg; 95% CI, -0.59 to 1.90 mmHg) and total adverse events (RR, 1.05; 95% CI, 0.99 to 1.10) were found between non-prostanoid prostacyclin receptor agonists group and control group. CONCLUSION: Non-prostanoid prostacyclin receptor agonists treatment exerted benefits on clinical worsening, pulmonary vascular resistance, and cardiac index in pulmonary hypertension patients, without increasing the incidence of total adverse events.

Magnetic resonance imaging for evaluation of bowel inflammation and disease activity in Crohn's disease: A systematic review and meta-analysis.

BACKGROUND: The aim of this systematic review and meta-analysis was to determine the performance of magnetic resonance imaging (MRI) in the diagnosis of bowel inflammation and disease activity in Crohn's disease (CD). METHODS: MEDLINE, Embase and Web of Science databases of biomedical literature were systematically searched to identify studies that investigated the diagnostic accuracy of MRI in diagnosing bowel inflammation and disease activity in CD by comparing it with reference standards. Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality. The summary sensitivity and specificity were estimated using the bivariate model, and hierarchical summary receiver operating characteristic (HSROC) parameters were calculated and plotted. RESULTS: Of 5492 citations of interest, 34 articles contained the diagnostic accuracy data. Of these, results for the small bowel and the colorectum were reported separately in 19 studies and jointly by 21 studies. The meta-analytic summary sensitivity and specificity under the bivariate model were 90.9% (95% CI, 85.8%-94.2%) and 90.2% (95% CI, 81.9%-95.0%), respectively. The sensitivities and specificities of individual studies ranged from 55% to 100% and 51% to 100%, respectively. Substantial heterogeneity was observed in both sensitivity (I2=84.9%) and specificity (I2=78.8%). The HSROC curve also showed considerable heterogeneity between studies. CONCLUSION: Although the meta-analytic summary accuracy of MRI was high for the diagnosis of bowel inflammation in CD, the summary estimates might be unreliable due to the presence of high heterogeneity.

ECoalVis: Visual Analysis of Control Strategies in Coal-fired Power Plants.

Improving the efficiency of coal-fired power plants has numerous benefits. The control strategy is one of the major factors affecting such efficiency. However, due to the complex and dynamic environment inside the power plants, it is hard to extract and evaluate control strategies and their cascading impact across massive sensors. Existing manual and data-driven approaches cannot well support the analysis of control strategies because these approaches are time-consuming and do not scale with the complexity of the power plant systems. Three challenges were identified: a) interactive extraction of control strategies from large-scale dynamic sensor data, b) intuitive visual representation of cascading impact among the sensors in a complex power plant system, and c) time-lag-aware analysis of the impact of control strategies on electricity generation efficiency. By collaborating with energy domain experts, we addressed these challenges with ECoalVis, a novel interactive system for experts to visually analyze the control strategies of coal-fired power plants extracted from historical sensor data. The effectiveness of the proposed system is evaluated with two usage scenarios on a real-world historical dataset and received positive feedback from experts.

[Retracted] IL­33 attenuates cardiac remodeling following myocardial infarction via inhibition of the p38 MAPK and NF­κB pathways.

An interested reader of an article published in the journal Circulation Research [Krishnamurthy P, Rajasingh J, Lambers E, Qin G, Losordo DW and Kishore R: L­10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR. Circ Res 104: e9­18, 2008] drew to our attention that data featured in their paper had appeared subsequently in the abovementioned article by Yin et al in Molecular Medicine Reports in 2014. Specifically, Fig. 1 in the Mol Med Rep paper included the same histograms as those featured in Fig. 2 in the Circ Res paper; Fig. 2 in the Mol Med Rep paper contained data derived from Fig. 1 in the Circ Res paper; and Figs. 3­5 in both papers shared a substantial amount of the same data. Following an internal investigation, the Journal was able to confirm that this accusation of plagiarism was well­founded. On those grounds, the Editor of Molecular Medicine Reports has decided to retract this paper. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor deeply regrets the grievance that this matter has caused to the authors of the previously published article, and also any inconvenience caused to the readership of the Journal.

Thematic trends and knowledge structure on cognitive behavior therapy for insomnia: A bibliometric and visualization analysis.

Objective: To find publications trend about cognitive behavior therapy for insomnia (CBTI) using bibliometric and visualization analysis. In this study, the authors sought to identify the publication trends of peer-reviewed articles about CBTI. Materials and methods: Analyses were focused on the past 18 years from 2004 to 2021. All searches were performed on the Web of Science Core Collection database. The search was repeated to include structural cognitive behavior therapy for insomnia. Quantitative analysis was assessed using the bibliometric tool. Visualization analysis was carried out using VOSviewer. Results: In the 736 articles reviewed, the number of publications has been increasing every year for the past 18 years. Behavioral sleep medicine and sleep were the most active journals published on CBTI. The United States and Canada had the highest scientific publications in the field. Morin CM and Espie CA were the most active authors. The study type mostly observed were randomized controlled trials, meta-analyses, and epidemiological. Publications on digital-based cognitive behavior therapy and accessibility to primary care settings represent the future trends of research on CBTI. Conclusion: Possible explanations for CBTI publication trends were discussed, including the emergence of the evidence-based therapy, feasibility, and scalability. Potential CBTI publications trends in the future and clinical implications were also discussed.

Can cognition help predict suicide risk in patients with major depressive disorder? A machine learning study.

BACKGROUND: Previous studies suggest that deficits in cognition may increase the risk of suicide. Our study aims to develop a machine learning (ML) algorithm-based suicide risk prediction model using cognition in patients with major depressive disorder (MDD). METHODS: Participants comprised 52 depressed suicide attempters (DSA) and 61 depressed non-suicide attempters (DNS), and 98 healthy controls (HC). All participants were required to complete a series of questionnaires, the Suicide Stroop Task (SST) and the Iowa Gambling Task (IGT). The performance in IGT was analyzed using repeated measures ANOVA. ML with extreme gradient boosting (XGBoost) classification algorithm and locally explanatory techniques assessed performance and relative importance of characteristics for predicting suicide attempts. Prediction performances were compared with the area under the curve (AUC), decision curve analysis (DCA), and net reclassification improvement (NRI). RESULTS: DSA and DNS preferred to select the card from disadvantageous decks (decks "A" + "B") under risky situation (p = 0.023) and showed a significantly poorer learning effect during the IGT (F = 2.331, p = 0.019) compared with HC. Performance of XGBoost model based on demographic and clinical characteristics was compared with that of the model created after adding cognition data (AUC, 0.779 vs. 0.819, p > 0.05). The net benefit of model was improved and cognition resulted in continuous reclassification improvement with NRI of 5.3%. Several clinical dimensions were significant predictors in the XGBoost classification algorithm. LIMITATIONS: A limited sample size and failure to include sufficient suicide risk factors in the predictive model. CONCLUSION: This study demonstrate that cognitive deficits may serve as an important risk factor to predict suicide attempts in patients with MDD. Combined with other demographic characteristics and attributes drawn from clinical questionnaires, cognitive function can improve the predictive effectiveness of the ML model. Additionally, explanatory ML models can help clinicians detect specific risk factors for each suicide attempter within MDD patients. These findings may be helpful for clinicians to detect those at high risk of suicide attempts quickly and accurately, and help them make proactive treatment decisions.

Influence of the GABA Receptor Subunit Gene Polymorphism and Childhood Sexual Abuse on Processing Speed in Major Depression and Suicide Attempt.

Background: Suicide is moderately heritable and also more common in those who report childhood abuse. Previously, it was found that allele A of GABRG2 (GABA A receptor subunit gamma2) polymorphism rs211034 was protective in a suicide attempt (SA). Hence, it was proposed that rs211034 may interact with childhood trauma to influence cognitive deficits related to SA or depression risk. Genetic variants may predict the benefits of certain cognitive treatments. Methods: A total of 52 individuals who had attempted suicide, 59 individuals with major depressive disorder (MDD) or bipolar depression who had not previously attempted suicide, and 90 healthy volunteers were subjected to the modified Suicide Stroop task and were clinically assessed using the Childhood Trauma Questionnaire (CTQ) and Hamilton Depression Scale-24 items (HAMD-24). rs211034 was genotyped using Sanger sequencing. Results: After correcting for covariates, depressed participants displayed longer reaction times for all emotional conditions, including suicide-related words, compared with healthy controls. Depressed suicide attempters displayed longer reaction times for negative words than depressed non-attempters. Depressed non-attempters displayed higher interference scores for negative words compared with healthy controls. There was an interaction between rs211034 risk allele and the effects of reported childhood sexual abuse (CSA) on reaction time for all emotional words and suicide-related words. Carriers of the rs211034 risk allele A exhibited shorter reaction times, but the protective effects of this allele were eliminated in those exposed to reported CSA. Conclusion: Only limited results were found regarding effects of a past suicide attempt on response times to emotional and suicide-related words, but there was an overall effect of major depression on slower response time. Protective genetic effects of the rs211034 A allele on this slowing were eliminated in those with a history of sexual abuse during childhood. Further research is needed to better characterize the mechanisms underlying the effects of childhood trauma on these genetic effects.

Hyperpolarized 3 helium MRI measured apparent diffusion coefficient and its correlations with pulmonary functions tests in patients with chronic obstructive pulmonary disease: A meta-analysis.

BACKGROUND: This study evaluates role of hyperpolarized 3 helium (3 He) MRI measured apparent diffusion coefficient (ADC) in examining pulmonary function of chronic obstructive pulmonary disease (COPD) patients. METHODS: After literature search in electronic databases, studies were selected by following precise eligibility criteria. Meta-analyses were performed to estimate mean difference in ADC between COPD patients and healthy individuals and to seek correlations between lung ADC and pulmonary function. Metaregression analyses were performed to seek relationships between ADC and age, gender, BMI, cigarette pack-years, and pulmonary function tests. RESULTS: Twenty-five studies (622 COPD patients and 469 healthy controls) were included. Lung ADC was 0.402 (95% confidence interval [CI]: 0.374, 0.429) in COPD patients and 0.228 (95% CI: 0.205, 0.252) in healthy individuals (mean difference 0.160 [95% CI: 0.127, 0.193]; p < 0.001). In metaregression, age (coefficient: 0.006; p = 0.004), pack-years (coefficient: 0.005; p = 0.018), forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio (coefficient: -1.815; p = 0.007), percent predicted diffusion capacity of carbon monoxide (DLCO) (coefficient: -0.004; p = 0.008), and percent predicted inspiratory capacity (coefficient: -0.004; p = 0.012) were significantly associated with ADC in COPD patients. In meta-analysis of correlation coefficients, ADC was significantly correlated with FEV1 (r = -0.62; p < 0.00001), FEV1/FVC (r = -0.80; p < 0.00001), DLCO (r = -0.85; p < 0.00001), functional residual capacity (r = 0.71; p < 0.00001), reserve volume (r = 0.53; p = 0.0001), and emphysema index (r = 0.89; p < 0.00001). CONCLUSION: Hyperpolarized 3 He MRI measured ADC was higher in COPD patients than in healthy individuals and was inversely associated with FEV1, FEV1/FVC, DLCO, and inspiratory capacity.

Down-regulated long non-coding RNA RMST ameliorates dopaminergic neuron damage in Parkinson's disease rats via regulation of TLR/NF-κB signaling pathway.

OBJECTIVE: Current treatment and prognosis of Parkinson's disease (PD) are not ideal. This study explored the mechanism of long non-coding RNA (lncRNA) rhabdomyosarcoma 2-associated transcript (RMST) in dopaminergic (DA) neuron damage in PD rats. METHODS: PD rats were modeled and injected with RMST silence or overexpression vectors to figure out its roles in oxidative stress, the apoptosis of DA neurons in brain substantia nigra (SN), and neurobehavioral activities of PD rats. Tyrosine hydroxylase (TH), synaptophysin (SYN), glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule (Iba-1) in SN were detected. RMST and Toll-like receptor (TLR)/nuclear factor kappa B (NF-κB) pathway-related factors were detected. RESULTS: RMST expression in brain SN of rats, TLR2, TLR4 expression in neurons and NF-κB expression in cell nucleus were increased. Silenced RMST improved the neurobehavioral activities, depressed oxidative stress and neuronal apoptosis, increased TH and SYN expression, and reduced the activation degree of glial cells in SN and the inflammatory response via reducing GFAP and Iba-1. Moreover, reduced RMST reduced TLR2 and TLR4 expression in neurons and NF-κB expression in cell nucleus in PD rats. CONCLUSION: Inhibited RMST attenuates DA neuron damage in PD rats, which may be implicated with TLR/NF-κB signaling pathway.

Curcumin slows the progression of Alzheimer's disease by modulating mitochondrial stress responses via JMJD3-H3K27me3-BDNF axis.

Disturbance of mitochondrial proteins by amyloid beta-protein (Aß) that associates with mitochondrial stress responses (MSR) is one of the pathological mechanisms of Alzheimer's disease (AD). This study tried to explore whether the axis of Jumonji domain-containing protein 3 (JMJD3)-trimethylated lysine 27 on histone H3 (H3K27me3)-brain derived neurotrophic factor (BDNF) is involved in the regulation of MSR which in turn intervenes in the process of AD, and whether curcumin (CUR) has a protective role against AD by influencing this axis, aiming to provide insights into AD treatment. AD mouse models presented a significant aggregation of Aß, with conspicuous pathological changes in brain tissues and an increase in neuronal apoptosis. Moreover, the mRNA and protein levels of JMJD3 and BDNF were down-regulated, H3K27me3 methylation levels were increased, and the MSR markers (ClpP, HSP6, HSP-60, and ATFS-1) showed abnormal alterations. In in-vitro cellular models of AD, up-regulation of either JMJD3 or BDNF up-regulated BDNF levels, down-regulated H3K27me3 methylation levels, mitigated abnormalities of MSR markers and Aß aggregation, and increased cell proliferation and inhibited apoptosis. JMJD3 was confirmed to regulate Aß and MSR via BDNF. In addition, CUR was confirmed to modulate JMJD3-H3K27me3-BDNF axis. Furthermore, moderate and high doses of CUR could improve the morphology and histopathology of the brain, inhibit Aß aggregation and cell apoptosis, and maintain MSR balance at least partly by modulating the JMJD3-H3K27me3-BDNF axis. To sum up, moderate and high doses of CUR regulate the progression of AD via MSR JMJD3-H3K27me3-BDNF axis.

Relationship between suicide rate and antidepressant prescription: An ecological study in the People's Republic of China.

OBJECTIVES: The objective of this study was to estimate the features of suicide rate and its association with antidepressant prescriptions during the past decade in China. METHODS: Official data on suicides were obtained and stratified by four age groups, gender, urban/rural areas, and regions (East, Central, and West). The annual antidepressant prescriptions were expressed in pills per 100 persons calculated as the volume of prescriptions divided by the total population. Negative binomial regression was carried out to examine the association between suicide and other variables. RESULTS: Suicide rates in each stratum typically decreased from 2008 to 2015, while annual antidepressant prescriptions were generally increased by the year. The suicide rate increased with age and was greater in adult males than in females; higher in the central area and greater in rural than in urban areas. Suicide rates are negatively associated with antidepressant prescriptions including selective serotonin reuptake inhibitors (Incidence rate ratio [IRR] 0.983, 95% confidence interval [CI] 0.983-0.983), serotonin-norepinephrine reuptake inhibitors (IRR 0.951, 95% CI 0.951-0.951), tricyclic antidepressant (IRR 0.925, 95% CI 0.925-0.925) and total antidepressants (IRR 0.990, 95% CI 0.990-0.990) during 2008-2012. CONCLUSION: Suicide varied among different studied stratum. Suicide rates are negatively associated with antidepressant prescriptions.

Up-regulated microRNA-218-5p ameliorates the damage of dopaminergic neurons in rats with Parkinson's disease via suppression of LASP1.

OBJECTIVE: Parkinson's disease (PD) is a frequent degenerative disease of the nervous system with undefined pathogenesis. This study explored the protective effect of microRNA (miR)-218-5p on dopaminergic neuron injury in substantia nigra (SN) of rats with PD through the regulation of LIM and SH3 domain protein 1 (LASP1). METHODS: The PD rat model was established by fixed point injection of 6-hydroxydopamine into the rats. The PD rats were injected with miR-218-5p overexpressed recombinant adeno-associated virus (rAAV) or LASP1 silenced rAAV to explore their roles in dopaminergic neurons in SN of rats with PD. The changes in pathological structure of SN were observed and the expression of tyrosine hydroxylase (TH) and deacetylvindoline acetyltransferase (DAT), the dopaminergic neuron apoptosis and oxidative stress factor in the SN were detected. The expression of miR-218-5p, LASP1, Bcl-2 and Bax in SN was detected. The targeting relationship between miR-218-5p and LASP1 was confirmed. RESULTS: Declined miR-218-5p and overexpressed LASP1 existed in the brain SN of PD rats. Up-regulated miR-218-5p or inhibited LASP1 improved the pathological damage of dopaminergic neurons and increased the number of TH and DAT positive cells in brain SN of PD rats. Furthermore, elevated miR-218-5p or depressed LASP1 inhibited the apoptosis, and oxidative stress of dopaminergic neurons in brain SN of PD rats. In addition, increased miR-218-5p repressed the expression of LASP1 in the brain SN of PD rats. LASP1 was proven to be a direct target of miR-218-5p. CONCLUSION: The study highlights that up-regulated miR-218-5p could improve the damage of dopaminergic neurons in PD rats, which was related to the inhibition of LASP1.

miR129-1 regulates protein phosphatase 1D protein expression under hypoxic conditions in non-small cell lung cancer cells harboring a TP53 mutation.

Protein phosphatase 1D (PPM1D), which functions as an oncogene, is a known target of the tumor suppressor p53 and is involved in p53-regulated genomic surveillance mechanisms. PPM1D dephosphorylates both p53 and its ubiquitin ligase mouse double minute 2 homolog, as well as the RNA-binding protein (RBM)38, which turns RBM38 from an inducer to inhibitor of TP53 translation. In addition, RBM38 induces PPM1D translation. Hence, the PPM1D-RBM38-p53 axis is important in maintaining genomic integrity and is often altered during tumorigenesis. TP53, which encodes p53, is deleted or mutated in >50% of cancer types, including lung cancer. Mutant p53 has been revealed to complex with hypoxia-inducible factor 1α (HIF1α) and upregulate transcription of pro-metastatic genes. However, the mechanism underlying the action of the PPM1D-RBM38-p53 axis in the context of mutant p53 under normoxic and hypoxic conditions is yet to be elucidated. In the present study, using non-small cell lung cancer (NSCLC) cell lines harboring wild-type (A549 cells) or hot-spot mutant (NCI-H1770 and R249WΔ-TP53-A549 cells) TP53, it was demonstrated that in cells harboring mutant p53, RBM38 was not the primary regulator of PPM1D translation under hypoxic conditions. Knockdown of RBM38 in TP53 mutant cells did not affect the PPM1D protein expression under hypoxic conditions. Instead, in NCI-H1770 cells maintained under normoxic conditions, PPM1D was revealed as a target of micro RNA (miR)-129-1-3p, a known tumor suppressor in lung cancer. Hypoxia resulted in the downregulation of miR-129-1-3p expression, and thus, in the downregulation of PPM1D messenger RNA (mRNA) translation. In NCI-H1770 cells grown under hypoxic conditions, the transient transfection of miR-129-1-3p mimic, and not control mimic, repressed the expression of a reporter containing wild-type, but not miR-129-1-3p binding mutant, of the PPM1D 3'-untranslated region (UTR). Analysis of NSCLC cell lines from the Broad Institute Cancer Cell Encyclopedia and patients with NSCLC from The Cancer Genome Atlas dataset revealed significant co-occurrence of PPM1D/RBM38 and PPM1D/HIF1A mutations. However, there was no significant difference in the overall survival of patients with NSCLC with or without genomic alterations in TP53, RBM38, PPM1D and HIF1A. In summary, the current study demonstrated hypoxia-dependent miR-129-1-3p-mediated regulation of PPM1D protein expression in NSCLC cell line harboring mutant TP53.