EEG biomarkers of behavioral inhibition in patients with depression who committed violent offenses: a Go/NoGo ERP study.

Understanding the neurobiological correlates of behavioral inhibition in patients with depression who committed violent offenses could contribute to the prediction and prevention of violence. The present study recruited 29 depressed patients with violent offenses (VD group), 27 depressed patients without violent behavior (NVD group), and 28 healthy controls (HC group) to complete a visual Go/NoGo task, during which their responses and electroencephalography were simultaneously recorded using an event-related potentiometer. The results showed that the VD group made more commission errors and responded more slowly relative to the NVD and HC groups. The P3 amplitude of the VD group was reduced in the frontal and central brain regions compared to the HC group and increased in the parietal regions compared to the NVD group. In comparison to Go stimuli, NoGo stimuli induced longer P3 latencies in frontal regions in both the VD and NVD groups; however, this difference was not statistically significant in the HC group. These results provide electrophysical evidence of behavioral inhibition deficits in patients with depression, especially in those with violent behaviors. The reduced P3 amplitude in the frontal-central regions, increased P3 amplitude in the parietal regions, and increased NoGo P3 latency may be potential electrophysiological features that can predict violent behavior in patients with depression.

MicroRNA-503-5p protects streptozotocin-induced erectile dysfunction in diabetic rats by downregulating SYDE2.

Plentiful studies have clarified miRNAs take on a key role in the sexual dysfunction of diabetic rats. This study aimed to figure out microRNA (miR)-503-5p/SYDE2 axis' latent mechanisms in streptozotocin-induced diabetic rat sexual dysfunction. A model of erectile dysfunction (ED) in diabetic rats was established by injecting streptozotocin. MiR-503-5p and SYDE2 in ED rats were altered by injection of miR-503-5p mimic or si/oe-SYDE2. The targeting link between miR-503-5p and SYDE2 was testified. ICP/MAP value was tested by pressure sensor; Penile capillary abundance was assessed; Penile cGMP and AGEs were detected; penile smooth muscle cell apoptosis was assessed; MiR-503-5p and SYDE2 were tested. In streptozotocin-induced ED rats, miR-503-5p was reduced and SYDE2 was elevated. Elevating miR-503-5p or silencing of SYDE2 can enhance penile erection rate, ICP/MAP value, capillary abundance, and cGMP but reduce AGEs and penile smooth muscle cell apoptosis rate in ED rats. Strengthening SYDE2 with elevating miR-503-5p turned around the accelerating effect of elevated miR-503-5p on penile erection in ED rats. SYDE2 was a downstream target gene of miR-503-5p. MiR-503-5p protects streptozotocin-induced sexual dysfunction in diabetic rats by targeting SYDE2.

Characterization of loss of chromosome Y in peripheral blood cells in male Han Chinese patients with schizophrenia.

BACKGROUND: Schizophrenia (SCZ) has a global prevalence of 1% and increases the risk of mortality, reducing life expectancy. There is growing evidence that the risk of this disorder is higher in males than in females and it tends to develop in early adulthood. The Y chromosome is thought to be involved in biological processes other than sex determination and spermatogenesis. Studies have shown that loss of chromosome Y (LOY) in peripheral blood cells is associated with a variety of diseases (including cancer) and increased all-cause mortality. An analysis of the relationship between LOY and schizophrenia is warranted. METHODS: A total of 442 Chinese males (271 patients with schizophrenia vs. 171 controls) were included in this study. The copy numbers of the Y and X chromosomes were detected by positive droplets targeting the amelogenin gene (AMEL) on the Y chromosome and X chromosome (AMELY and AMELX, respectively), using droplet digital PCR (ddPCR). The LOY percentage was defined as the difference between the concentration of AMELX and the concentration of AMELY divided by the concentration of AMELX, denoted as (X - Y)/X. RESULTS: In the Han Chinese population, the LOY percentage was higher in the schizophrenia group than in the control group (p < 0.05), although there was no significant difference in the presence of LOY between the two groups. A strong correlation was found between the average of the disease duration and the average of the LOY percentage (R2 = 0.506, p = 0.032). The logistic regression analysis implied that the risk of LOY increases by 0.058 and 0.057 per year according to age at onset and duration of disease, respectively (ponset = 0.013, pduration = 0.017). CONCLUSIONS: In the Han Chinese population, the LOY percentage of the disease group was significantly different from that of the control group. The age of onset and duration of schizophrenia might be risk factors for LOY in peripheral blood cells. A larger sample size and expanded clinical information are needed for more in-depth and specific analyses.

Research on interpersonal violence in schizophrenia: based on different victim types.

BACKGROUND: Schizophrenia is one of the most common severe mental disorders associated with an increased risk of violence. The present study compares the demographical, clinical, and criminological characteristics of the patients with schizophrenia who committed different types of violence to relatives, acquaintances, or strangers. METHOD: Archives of the violent offenders with schizophrenia referred to forensic psychiatric assessments from January 2015 to December 2019 in the West China Forensic Medicine Assessment Center in China were analyzed. The demographic information, mental illness history, and criminological characteristics of the offenders were collected. The clinical symptoms, previous violent behaviors, and social deficits were also evaluated. One-way ANOVA, Kruskal-Wallis test, Chi-square test, and logistic regression analysis were enrolled to do the statistical analysis. RESULTS: The study enrolled 332 cases: 165 cases (49.7%) in the acquaintance victim group (AV), 96 cases (28.9%) in the relative victim group (RV), and 71 cases (21.4%) in the stranger victim group (SV). The multinomial logistic regression analysis revealed that older patients were less likely to attack relatives (OR = 0.966, 95% CI = 0.944-0.990; p = 0.005), and strangers, (OR = 0.971, 95% CI = 0.944-0.998; p = 0.034). Patients who lived with others were more inclined to attack relatives (OR = 15.057, 95% CI = 3.508-64.628; p < 0.001). Additionally, employed patients were more likely to attack strangers (OR = 2.034, 95% CI = 1.036-3.994; p = 0.039). The regression equation did not include psychiatric symptoms. For RV and AV victims, the risk of death was higher compared to that of SV victims (OR = 13.778, p < 0.001; OR = 2.663, p = 0.014). CONCLUSION: In the interpersonal violence cases committed by schizophrenia patients, the victim type correlates with demographic characteristics of offenders such as living situation, age, and employment status, but not with the psychiatric symptoms. The majority of victims were acquaintances and relatives, and the relative victims having more severe injuries. In order to decrease interpersonal violence, especially violent crimes, more people, especially family members and neighbors, should be educated about symptoms of schizophrenia, the ways to communicate with the patients, and the methods for crisis management.

Adolescent mobile phone addiction during the COVID-19 pandemic predicts subsequent suicide risk: a two-wave longitudinal study.

Both the rate of mobile phone addiction and suicidality among adolescents have increased during the pandemic lockdown. However, the relationship between mobile phone addiction and suicide risk and the underlying psychological mechanisms remains unknown. This study examined the associations between mobile phone addiction in adolescents during the first month of lockdown and the suicide risk in the subsequent five months. A two-wave short-term longitudinal web-based survey was conducted on 1609 senior high school students (mean age = 16.53 years, SD = 0.97 years; 63.5% female). At Time 1 (T1), the severity of mobile phone addiction and basic demographic information was collected from Feb 24 to 28, 2020 in Sichuan Province, China (at the pandemic's peak). Five months later, between July 11 and July 23 (Time 2, T2), mobile phone addiction, daytime sleepiness, depression, and suicidality were measured within the past five months. The regression analysis revealed that mobile phone addiction during quarantine directly predicted suicidality within the next five months, even after controlling for the effect of depression and daytime sleepiness. Meanwhile, mobile phone addiction at T1 also indirectly predicted suicidality at T2, with depression and daytime sleepiness mediating this association. Programs targeting improvement of daytime sleepiness and depressive symptoms may be particularly effective in reducing suicide risk among adolescents with mobile phone addiction.

Tibetan Y-STR trait in the eleven regions of the Qinghai-Tibet Plateau.

Y-Chromosomal short-tandem repeats (Y-STRs) could provide highly valuable information for forensic investigation and demographic studies. However, there is still no systematic Y-STR information on Tibetan as obtained from different regions of the broad Qinghai-Tibet Plateau. In this study, an analysis was conducted on 585 male individuals, classed into 3 different dialect branches as Ü-Tsang, Amdo, and Khams and originating from 11 scattered regions of the Qinghai-Tibet Plateau. The gene diversity values of the 41 Y-STRs in Tibetan ranged from 0.3636 to 0.9322. Additionally, a total of 563 distinct haplotypes were obtained with an overall haplotype diversity of 0.9999 and a discrimination capacity of 0.9624. As suggested by the inter-population diversity analysis, there were two main separated clades of Tibetan subgroups. The visualization of pairwise genetic distances between 11 Tibetan subgroups and 59 reference populations using cladogram revealed the distribution of various populations, which was basically consistent with the patterns of geographic origin and linguistic affinity.

Association study between genetic variants and the risk of schizophrenia in the Chinese population based on GWAS-implicated 6p21.3-23.1 human genome region: a case-control study.

BACKGROUND: Schizophrenia is a polygenic disease; however, the specific risk genetic variants of schizophrenia are still largely unknown. Single nucleotide polymorphism (SNP) is important genetic factor for the susceptibility of schizophrenia. Investigating individual candidate gene contributing to disease risk remains important. METHODS: In a case-control study, five SNPs located in 6p21.3-p23.1 including rs2021722 in human leukocyte antigen (HLA) locus and rs107822, rs383711, rs439205 and rs421446 within the upstream of microRNA-219a-1 were genotyped in 454 schizophrenia patients and 445 healthy controls to investigate the possible association between the loci and schizophrenia in a Han Chinese population. RESULTS: Our results showed significant associations between the rs2021722 and schizophrenia in allele (A vs. G: adjusted OR = 1.661, 95%CI = 1.196-2.308), co-dominant (AG vs. GG: OR = 1.760, 95%CI = 1.234-2.510) and dominant genetic model (AG + AA vs. GG: OR = 1.756, 95%CI = 1.237-2.492), respectively. Haplotype analysis showed that TGGT and CAAC were protective factor for schizophrenia compared with TAAC haplotype (OR = 0.324, 95% CI = 0.157-0.672; OR = 0.423, 95% CI = 0.199-0.900). CONCLUSIONS: These findings indicate that rs2021722 in HLA locus might be involved in pathogenesis of schizophrenia and that genotypes AG and allele A of the locus are risk factors for schizophrenia in the Han Chinese population, confirming the association between immune system and schizophrenia.

[Sperm mitochondrial DNA and male infertility: An update].

Sperm mitochondrial DNA (mtDNA) damage is closely related with male infertility. Lacking for the protection by histone and DNA-binding protein, sperm mtDNA is prone to the attack by reactive oxygen species (ROS) and, without an effective repair system of mtDNA, ROS-induced changes in mtDNA may damage the synthesis of mtDNA encoding proteins and affect the function of mitochondria, which may be an important genetic factor for male infertility. Related studies should focus on finding the causes of sperm mtDNA damage and its relationship with male infertility.

Activity of quinolone CP-115,955 against bacterial and human type II topoisomerases is mediated by different interactions.

CP-115,955 is a quinolone with a 4-hydroxyphenyl at C7 that displays high activity against both bacterial and human type II topoisomerases. To determine the basis for quinolone cross-reactivity between bacterial and human enzymes, the activity of CP-115,955 and a series of related quinolones and quinazolinediones against Bacillus anthracis topoisomerase IV and human topoisomerase IIα was analyzed. Results indicate that the activity of CP-115,955 against the bacterial and human enzymes is mediated by different interactions. On the basis of the decreased activity of quinazolinediones against wild-type and resistant mutant topoisomerase IV and the low activity of quinolones against resistant mutant enzymes, it appears that the primary interaction of CP-115,955 with the bacterial system is mediated through the C3/C4 keto acid and the water-metal ion bridge. In contrast, the drug interacts with the human enzyme primarily through the C7 4-hydroxyphenyl ring and has no requirement for a substituent at C8 in order to attain high activity. Despite the fact that the human type II enzyme is unable to utilize the water-metal ion bridge, quinolones in the CP-115,955 series display higher activity against topoisomerase IIα in vitro and in cultured human cells than the corresponding quinazolinediones. Thus, quinolones may be a viable platform for the development of novel drugs with anticancer potential.

Fear of COVID-19, prolonged smartphone use, sleep disturbances, and depression in the time of COVID-19: A nation-wide survey.

Background: The COVID-19 pandemic has had a wide range of behavioral and psychological effects on the general population. This study examined the relationship between fear of COVID-19, daily smartphone use, sleep disturbance, and depression in the general population during the early stage of COVID-19. Methods: An online nation-wide survey was conducted from March 20 to April 10, 2020. Sociodemographic information, including age, gender, educational attainment, vocation, and duration of self-isolation, was collected; fear of COVID-19 and other objective exposures, daily hours of smartphone use, night sleep duration, sleep disturbance, and depressive symptoms were measured with structured questions and PHQ-9. There were 1,280 questionnaires in total, and 1,250 valid questionnaires remained. Results: The prevalence of sleep disturbance and depression were found to be 13.1 and 10.7%, respectively. Feelings of extreme fear, longer smartphone use, difficulty initiating sleep, and early morning awakening were significant risk factors for depression. Daily hours of smartphone use, difficulty initiating sleep, and early morning awakening partially mediated the association between feeling extremely scared of the pandemic and depression. Conclusion: Psychological interventions in a major public health crisis should focus more on the subjective perception of pandemic fear. At the same time, daily smartphone use and sleep disturbances could serve as targets for monitoring and intervention for depression during a pandemic.

Migration, Schizophrenia, and Crime: A Study From a Forensic Psychiatric Sample.

Background: The association between mental health problems and crime in immigrants has attracted recent academic interest, with results suggesting that there were possible interactions between immigration, schizophrenia, and criminal behavior. However, very few studies have examined these interactions, especially in developing countries that have mass internal immigration. Therefore, this study sought to identify the associations between the sociodemographic, clinical, and criminal factors in migrants and non-migrants with schizophrenia who had been involved in criminal activities in China. Methods: Forensic archives of suspects who had been referred for criminal responsibility assessments in the Sichuan West China Forensic Center from January 2015 to December 2019 were reviewed. The sociodemographic, and criminal activity information of the suspects were extracted, while the clinical and social function were measured by the Brief Psychiatric Rating Scale (BPRS) and Social Disability Screening Schedule (SDSS) based on the archives. A Chi-squared test, a T-test, a Mann-Whitney U test, and Multinomial logistic regression were employed for the statistical analysis. Results: A total of 552 patients were reviewed and evaluated, 17.2% (n = 95) of which were migrants. The migrant patient group was younger than the non-migrant patient group. The BPRS and SDSS scores for the migrant patient group were lower than for the non-migrant patient group. The migrant patient group had more work experience and more had been employed at the time of the crime than the non-migrant patient group. The unemployed migrant patients were more likely to commit a property-related crime. Conclusions: Compared to the non-migrant schizophrenia patient group, the migrant patient group had less severe psychiatric symptoms and less social function impairments. Employment was an important factor in preventing criminality in patients with schizophrenia, especially for migrant patients. Vocational rehabilitation focuses on developing appropriate employment that can significantly assist in schizophrenia patient recovery, which in turn could reduce their chances of committing crime. Besides, reducing other obstacles to stigma, housing and health insurance would also be beneficial to crime reduction.

Neurological Symptoms and Their Associations With Inflammatory Biomarkers in the Chronic Phase Following Traumatic Brain Injuries.

Background: The underlying biological mechanisms for neurological symptoms following a traumatic brain injury (TBI) remain poorly understood. This study investigated the associations between serum inflammatory biomarkers and neurological symptoms in the chronic phase following moderate to severe TBI. Methods: The serum interleukin [IL]-1ß, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, and the tumor necrosis factor [TNF]-α in 72 TBI patients 6 months to 2 years post injury were measured. Neurological symptoms including depression, chronic headache, sleep disturbance, irritability, anxiety, and global neurological disability was assessed. The associations between the biomarkers and the neurological symptoms were assessed using correlation and regression analysis. Results: It was found that the most common post-injury symptom was sleep disturbance (84.7%), followed by chronic headaches (59.7%), irritability (55.6%), and depression (54.2%). TNF-α was a protective factor for chronic headache (OR = 0.473, 95% CI = 0.235-0.952). IL-6 was positively associated with sleep disturbance (r = 0.274, p = 0.021), while IL-5 and IL-12p70 were negatively associated with the degree of global neurological disability (r = -0.325, p = 0.006; r = -0.319, p = 0.007). Conclusion: This study provides preliminary evidence for the association between chronic inflammation with neurological symptoms following a TBI, which suggests that anti-inflammatory could be a potential target for post-TBI neurological rehabilitation. Further research with larger sample sizes and more related biomarkers are still needed, however, to elucidate the inflammatory mechanisms for this association.

Evaluation of association between methylenetetrahydrofolate reductase and azoospermia: A meta-analysis.

BACKGROUND: Infertility affects childbearing age couples all over the world. One of the important reasons for infertility is genetic factors. Our study evaluated the association between methylenetetrahydrofolate reductase (MTHFR) and azoospermia. METHODS: Multiple databases like MEDLINE, EMBASE, Cochrane library, and China journal full-text database were used to search for relevant studies, and full-text articles involved in the evaluation of MTHFR and azoospermia. The results were evaluated using STATA 12.0. Heterogeneity analysis, sensitivity analysis, and bias analysis were also performed on the data. RESULTS: Thirteen related studies eventually met the inclusion criteria. Significant association between C677T polymorphism and azoospermia (relative risk [RR] = 0.94 [0.90, 0.99], I2 = 60.9%, P = .002), and between A1298C polymorphism and azoospermia (RR = 0.98 [0.94, 1.02], I2 = 56.3%, P = .011) was observed. Meanwhile, in subgroup analysis, Caucasians had higher risk than Mongolians in association between MTHFR and azoospermia. CONCLUSION: There was association between MTHFR polymorphism and azoospermia. Caucasian populations had higher risk than Mongolian populations in association between MTHFR and azoospermia.

ESTAT3 Inhibitor AG-490 Inhibits the Growth of Prostate Cancer by miR-503-5p Both In Vivo and In Vitro.

OBJECTIVE: To explore the effect and the related mechanism of STAT3 inhibitor AG-490 on inhibiting the proliferation of prostate cancer cells. METHODS: PC3 cells and DU145 cells were cultured stably and treated with AG-490 to detect the changes in the activity of PC3 cells and DU145 cells. Thirty 6-8 weeks male BALB/c nude mouse were randomly divided into a control group, a DMSO group, and an AG-490 group to detect differences in various indexes . RESULTS: The overexpression of miR-503-5p depends on the activation of STAT3. After treatment with AG-490, The proliferation and invasion of PC3 cells and DU145 cells and the expression of miR-503-5p were all reduced. Luciferase reporter assay demonstrated that the target proteins of miR-503-5p include PDCD4, TIMP-3, and PTEN. After treatment with AG-490, the expression of PDCD4, TIMP-3, and PTEN in cells was significantly up-regulated. IL-6-induced overexpression of miR-503-5p and restored the expression of STAT3, demonstrating the correlation between STAT3 and miR-503-5p. AG-490 can inhibit tumor growth and induce tumor cell apoptosis in the PC3 BALB/c nude mouse xenograft model. Western blotting and immunohistochemical staining showed that the expression levels of STAT3, Ki67, Bcl-2 and MMP-2 in the AG-490 group were significantly reduced, and the expression of PDCD4, TIMP-3 and PTEN increased. CONCLUSION: AG-490 can inhibit the growth of prostate cancer cells in a miR-503-5p-dependent manner by targeting STAT3. AG-490 is expected to become a new candidate drug for the treatment of prostate cancer.

The Symptoms and Medications of Patients with Inflammatory Bowel Disease in Hubei Province after COVID-19 Epidemic.

OBJECTIVES: The COVID-19 epidemic triggered by coronavirus SARS-CoV-2 is rapidly spreading around the globe. This study is aimed at finding out the suspected or confirmed SARS-CoV-2 infection in patients with inflammatory bowel disease (IBD) in Hubei province, China. We also investigated symptoms, medications, life quality, and psychological issues of IBD patients under the ongoing pandemic. METHODS: We conducted a self-reported questionnaire survey via an online survey platform. SARS-CoV-2 infection-related data was collected from IBD patients. The status quo of medications and symptoms of the subjects were investigated. Life quality, depression, and anxiety were measured by clinical questionnaires and rated on scoring systems. RESULTS: A total of 204 IBD patients from Hubei province were included in this study. No suspected or confirmed SARS-CoV-2 infection case was found in this study. As a result of city shutdown, two-thirds of the patients (138/204) in our series reported difficulty in accessing medicines and nearly half of them (73/138) had to discontinue medications. Apart from gastrointestinal symptoms, systemic symptoms were common while respiratory symptoms were rare in the cohort. Though their quality of life was not significantly lowered, depression and anxiety were problems that seriously affected them during the COVID-19 epidemic. CONCLUSIONS: Inaccessibility to medications is a serious problem for IBD patients after city shutdown. Efforts have to be made to address the problems of drug withdrawal and psychological issues that IBD patients suffer from during the COVID-19 outbreak.

Comparative study of forensic psychiatric system between China and America.

Laws and regulations about the forensic psychiatric systems in China and America were compared, and suggestions for improving the forensic psychiatric system of China were provided. There are many differences regarding the role of the forensic psychiatrist, the initiation of the assessment and the admission of expert opinion because of elements in the legal systems in China and America. The Chinese system has the advantages of objectivity, cost saving and high efficiency; but it has deficiencies in procedural justice and the admission of expert opinion. China can persist with the current system while taking measures to give more rights to the litigants to participate in their assessment, and while improving the quality and utility of the expert opinion; however, this review article will compare broadly the two systems without addressing human rights issues or procedural justice issues, nor will it presume to address the entirety of Chinese systems. In addition, China is developing its legal system for dealing with the mentally ill defendant in situations involving the criminal justice system and civil commitment. Although China enacted new laws regarding the mandatory treatment for the mentally ill, both in criminal and civil systems, there remain many aspects to be improved, including but not limited to a system of review of the decision to detain a patient on psychiatric grounds, and the need for provisions in the laws preventing indefinite detention. From this viewpoint, America's laws and regulations are instructive for us, in matters such as the method of dealing with the mentally ill defendant who is "incompetent to stand trial", "not guilty only by reason of insanity" or "guilty but mentally ill". The conditional release of the committed mentally ill person and the special programs in the forensic security hospital are all worthy of study by China in order to manage the mentally ill offender and to reduce the recidivism rate.

Genetic variants in the promoters of let-7 family are associated with an increased risk of major depressive disorder.

BACKGROUND: Let-7 family plays a critical role in the pathogenesis of major depressive disorder (MDD). Genetic polymorphisms in the promoters of miRNA may influence individual׳s susceptibility to diseases. The purpose of this study was to investigate the association between rs10877887 and rs13293512 polymorphisms in the promoters of let-7 family and the risk of MDD. METHOD: Polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing assays were used to analyze the rs10877887 and rs13293512 polymorphisms in 237 MDD patients and 296 controls. RESULTS: We found that the rs10877887 CC genotype was associated with an increased risk of MDD (CC vs. TT: OR=1.73, 95% CI, 1.04-2.86, P=0.03, and CC vs. TT/TC: OR=1.74, 95% CI, 1.08-2.80, P=0.02, respectively). Similarly increased risk was also observed for the rs13293512 (CC vs. TT: OR=1.83, 95% CI, 1.12-2.99, P=0.015; CC vs. TT/TC: OR=1.84, 95% CI, 1.20-2.81, P=0.005; and C vs. T: OR=1.32, 95% CI, 1.03-1.68, P=0.03, respectively). Stratification analysis showed that patients with the rs13293512 TC and CC genotypes had a 2.29 and 2.56-fold increased risk of MDD recurrence after treatment (TC vs. TT: 95% CI, 1.23-4.25, P=0.008; CC vs. TT: 95% CI, 1.25-5.23, P=0.009, respectively). LIMITATIONS: Relatively small sample size and hospital-based study design may influence the results. CONCLUSIONS: Our findings suggest that the rs10877887 and rs13293512 polymorphisms may be related to the development of MDD.

An exploratory study of using polygraph to detect deception in patients with traumatic brain injury.

To investigate the accuracy of the polygraph when used on patients with traumatic brain injury (TBI) and to analyze the factors influencing accuracy to enable provision of some field data for expert witnesses. Sixty patients with TBI (experimental group) and sixty normal individuals (control group) were tested by the polygraph with a Stimulation Test; responses of skin conductance, respiration, and finger pulse were recorded. The intelligence quotient of the experimental participants was measured and the factors influencing the accuracy of the polygraph test were analyzed. According to the computer automatic scoring, the overall accuracy was 76.7% for the control group; the accuracy of skin conductance, respiration, and finger pulse was 76.7, 35, and 18.7%, respectively, whereas for the experimental group, the overall accuracy was 56.7%. The accuracy of skin conductance, respiration, and finger pulse was 55.6, 23.3, and 25%, respectively. There was a significant difference in the overall accuracy between the two groups (P=0.020). According to the examiner's manual scoring, the overall accuracy was 86.7% for the control group and 61.7% for the experimental group (χ=9.786, P=0.002). The difference in accuracy obtained from the examiner and the computer was not significant. In the experimental group, the intelligence quotient of participants who had the right outcome was 63.2±10.9 and it was 55.3±9.5 for those who had the wrong outcome; this difference was significant (t=2.68, P=0.010).The accuracy of a polygraph test is much lower when it is used on patients with TBI compared with that of normal individuals. In actual application, full communication with the examinees should take place and their comprehension of the protocol should be evaluated. If participants can understand and co-operate with the test, the outcome can be considered reliable; if not, the outcome should not be relied on.

Overcoming target-mediated quinolone resistance in topoisomerase IV by introducing metal-ion-independent drug-enzyme interactions.

Quinolones, which target gyrase and topoisomerase IV, are the most widely prescribed antibacterials worldwide. Unfortunately, their use is threatened by the increasing prevalence of target-mediated drug resistance. Greater than 90% of mutations that confer quinolone resistance act by disrupting enzyme-drug interactions coordinated by a critical water-metal ion bridge. Quinazolinediones are quinolone-like drugs but lack the skeletal features necessary to support the bridge interaction. These compounds are of clinical interest, however, because they retain activity against the most common quinolone resistance mutations. We utilized a chemical biology approach to determine how quinazolinediones overcome quinolone resistance in Bacillus anthracis topoisomerase IV. Quinazolinediones that retain activity against quinolone-resistant topoisomerase IV do so primarily by establishing novel interactions through the C7 substituent, rather than the drug skeleton. Because some quinolones are highly active against human topoisomerase IIα, we also determined how clinically relevant quinolones discriminate between the bacterial and human enzymes. Clinically relevant quinolones display poor activity against topoisomerase IIα because the human enzyme cannot support drug interactions mediated by the water-metal ion bridge. However, the inclusion of substituents that allow quinazolinediones to overcome topoisomerase IV-mediated quinolone resistance can cause cross-reactivity against topoisomerase IIα. Therefore, a major challenge in designing drugs that overcome quinolone resistance lies in the ability to identify substituents that mediate strong interactions with the bacterial, but not the human, enzymes. On the basis of our understanding of quinolone-enzyme interactions, we have identified three compounds that display high activity against quinolone-resistant B. anthracis topoisomerase IV but low activity against human topoisomerase IIα.

Gefitinib analogue V1801 induces apoptosis of T790M EGFR-harboring lung cancer cells by up-regulation of the BH-3 only protein Noxa.

Treatment of non-small cell lung cancer (NSCLC) with drugs targeting the epidermal growth factor receptor (EGFR), e.g., gefitinib and erlotinib, will eventually fail because of the development of secondary mutations such as T790M in EGFR. Strategies to overcome this resistance are therefore an urgent need. In this study, we synthesized a dozen of novel gefitinib analogues and evaluated their effects on L858R/T790M-EGFR harboring NSCLC cells, and reported that one of these gefitinib mimetics, N-(2-bromo-5-(trifluoromethyl) phenyl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine (hereafter, V1801), triggered apoptosis of the NSCLC cells and overcame gefitinib-resistance in mice inoculated with NCI-H1975 cells. Though V1801 only moderately inhibited EGFR kinase activity, it markedly induced the expression of the BH3-only protein Noxa, and Noxa silencing significantly reduced V1801-induced apoptosis of NCI-H1975 cells. It is showed that V1801 interfered with the expression of the transcription factor c-Myc and the extracellular signal regulated kinase (Erk) pathway. V1801 in combination with proteasome inhibitor bortezomib exerted enhanced cytotoxicity in NCI-H1975 cells possibly due to potentiated induction of Noxa expression. These data indicate that gefinitib analogues with weak EGFR inhibitory activity may overcome drug-resistance via activation of BH-3 only pro-apoptotic proteins, and V1801 may have therapeutic potentials for NSCLC.