ABSTRACT
In drug candidate design, clearance is one of the most crucial pharmacokinetic parameters to consider. Recent advancements in machine learning techniques coupled with the growing accumulation of drug data have paved the way for the construction of computational models to predict drug clearance. However, concerns persist regarding the reliability of data collected from public sources, and a majority of current in silico quantitative structure-property relationship models tend to neglect the influence of molecular chirality. In this study, we meticulously examined human liver microsome (HLM) data from public databases and constructed two distinct data sets with varying HLM data quantity and quality. Two baseline models (RF and DNN) and three chirality-focused GNNs (DMPNN, TetraDMPNN, and ChIRo) were proposed, and their performance on HLM data was evaluated and compared with each other. The TetraDMPNN model, which leverages chirality from 2D structure, exhibited the best performance with a test R2 of 0.639 and a test root-mean-squared error of 0.429. The applicability domain of the model was also defined by using a molecular similarity-based method. Our research indicates that graph neural networks capable of capturing molecular chirality have significant potential for practical application and can deliver superior performance.
Subject(s)
Microsomes, Liver , Neural Networks, Computer , Humans , Microsomes, Liver/metabolism , Stereoisomerism , Quantitative Structure-Activity Relationship , Machine Learning , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/metabolismABSTRACT
Noncovalent interactions between small-molecule drugs and protein targets assume a pivotal role in drug design. Moreover, the design of covalent inhibitors, forming covalent bonds with amino acid residues, requires rational reactivity for their covalent warheads, presenting a key challenge as well. Understanding the intricacies of these interactions provides a more comprehensive understanding of molecular binding mechanisms, thereby guiding the rational design of potent inhibitors. In this study, we adopted the fragment-based drug design approach, introducing a novel methodology to extract noncovalent and covalent fragments according to distinct three-dimensional (3D) interaction modes from noncovalent and covalent compound libraries. Additionally, we systematically replaced existing ligands with rational fragment substitutions, based on the spatial orientation of fragments in 3D space. Furthermore, we adopted a molecular generation approach to create innovative covalent inhibitors. This process resulted in the recombination of a noncovalent compound library and several covalent compound libraries, constructed by two commonly encountered covalent amino acids: cysteine and serine. We utilized noncovalent ligands in KLIFS and covalent ligands in CovBinderInPDB as examples to recombine noncovalent and covalent libraries. These recombined compound libraries cover a substantial portion of the chemical space present in the original compound libraries and exhibit superior performance in terms of molecular scaffold diversity compared to the original compound libraries and other 11 commercial libraries. We also recombined BTK-focused libraries, and 23 compounds within our libraries have been validated by former researchers to possess potential biological activity. The establishment of these compound libraries provides valuable resources for virtual screening of covalent and noncovalent drugs targeting similar molecular targets.
Subject(s)
Drug Design , Ligands , Imaging, Three-DimensionalABSTRACT
Retrosynthesis prediction is crucial in organic synthesis and drug discovery, aiding chemists in designing efficient synthetic routes for target molecules. Data-driven deep retrosynthesis prediction has gained importance due to new algorithms and enhanced computing power. Although existing models show certain predictive power on the USPTO-50K benchmark data set, no one considers the effects of byproducts during the prediction process, which may be due to the lack of byproduct information in the benchmark data set. Here, we propose a novel two-stage retrosynthesis reaction prediction framework based on byproducts called RPBP. First, RPBP predicts the byproduct involved in the reaction based on the product molecule. Then, it handles an end-to-end prediction problem based on the prediction of reactants by product and byproduct. Unlike other methods that first identify the potential reaction center and then predict reactant molecules, RPBP considers additional information from byproducts, such as reaction reagents, conditions, and sites. Interestingly, adding byproducts reduces model learning complexity in natural language processing (NLP). Our RPBP model achieves 54.7% and 66.6% top-1 retrosynthesis prediction accuracy when the reaction class is unknown and known, respectively. It outperforms existing methods for known-class reactions, thanks to the rich chemical information in byproducts. The prediction of four kinase drugs from the literature demonstrates the model's practicality and potential to accelerate drug discovery.
ABSTRACT
OBJECTIVES: Built on the Positive Youth Development (PYD) framework, this study examined how physical activity affected the subjective well-being of adolescents in the multi-ethnic area of southwest China. The mediating role of school connectedness as an external development asset and the moderating role of resilience as an internal development asset were specified and tested within the framework of sport-based PYD. METHODS: A cross-sectional survey of 3143 adolescents (47.2% boys with mean age = 12.88 and SD = 1.68) was conducted in 2020. A structural equation model (SEM) was developed to estimate the direct effect of physical activity, the mediating effect of school connectedness, and the moderating effect of resilience on adolescents' subjective well-being. Multi-group comparison was made to investigate differences and similarities across three parental absence subgroups: (1) both parents present, (2) one parent absent, and (3) both parents absent. RESULTS: As surmised, physical activity, school connectedness, and resilience all positively and significantly affected adolescents' subjective well-being. SEM analyses revealed that school connectedness mediated the effect of physical activity on subjective well-being. Moreover, resilience moderated both the direct and indirect effects of physical activity (through school connectedness) on subjective well-being. Finally, the multi-group comparison revealed a moderating effect of parental absence on the moderated mediation model. LIMITATIONS: This study is a cross-sectional survey, so inference of causal associations among the study variables is impossible. CONCLUSIONS: Healthy lifestyle behaviors, school-supportive settings, and positive individual development assets can enhance the subjective well-being of adolescents in southwest China, especially those whose parents were absent. Physical activity interventions informed by the PYD framework should be incorporated into public health programs designed to foster the physical and mental health of left-behind adolescents in southwest China.
Subject(s)
Exercise , Sports , Male , Humans , Adolescent , Child , Female , Cross-Sectional Studies , China , ParentsABSTRACT
OBJECTIVES: Prior research on the effect of tea consumption on blood pressure (BP) generated inconsistent findings. The objective of this study was to explore the effects of different types of tea consumption on BP. METHODS: We included 76,673 participants aged 30-79 from the baseline data of the China Multi-Ethnic Cohort (CMEC) study. Binary logistic regression was used to analyze the influences of different types of tea consumption on the risk of hypertensive BP. Moreover, multiple linear regression was used to examine the association between tea drinking and BP. RESULTS: Tea consumption was associated with a reduced risk of hypertensive BP by 10% (AOR: 0.90, 95%CI: 0.86-0.94). While dark tea was related to a 1.79-5.31 mmHg reduction in systolic blood pressure (SBP) and a 0.47-1.02 mmHg reduction in diastolic blood pressure (DBP), sweet tea, regardless of the duration, frequency, or amount of consumption, significantly was associated with a reduced SBP by 3.19-7.18 mmHg. Green tea also was associated with a reduced SBP by 1.21-2.98 mmHg. Although scented tea was related to reduced SBP by 1.26-2.48 mmHg, the greatest effect came from the long duration (> 40 years:ß=-2.17 mmHg, 95%CI=-3.47 mmHg --0.87 mmHg), low frequency (1-2 d/w: ß = -2.48 mmHg, 95%CI=-3.76 mmHg--1.20 mmHg), and low amount (≤ 2 g/d: ß=-2.21 mmHg, 95%CI=-3.01 mmHg--1.40 mmHg). Additionally, scented tea was correlated to a decrease in DBP at the frequency of 1-2 d/w (ß=-0.84 mmHg, 95%CI=-1.65 mmHg--0.02 mmHg). Drinking black tea only was associated with lowered SBP. The protective effect of black tea on SBP was characterized by the long-duration (> 15 years, -2.63--5.76 mmHg), high frequency (6-7 d/w, -2.43 mmHg), and medium amount (2.1-4.0 g/d, -3.06 mmHg). CONCLUSION: Tea consumption was associated with lower SBP and a reduced risk of hypertensive BP. The antihypertensive effect varies across types of tea consumed.
Subject(s)
Hypertension , Hypotension , Adult , Humans , Blood Pressure , Hypertension/epidemiology , Hypertension/prevention & control , Hypertension/drug therapy , Antihypertensive Agents/therapeutic use , Tea , China/epidemiologyABSTRACT
BACKGROUND: Few studies have explored the health and development of AIDS orphans using the positive youth development (PYD) framework. Grounded in this framework, the main objective of this study is to examine how internal assets (i.e., resilience) and external assets (i.e., school connectedness, peer support) affect subjective well-being among Yi AIDS orphans in the Liangshan Yi Autonomous Prefecture, Sichuan province, China. METHODS: A cross-sectional survey was conducted by interviewing 571 AIDS orphans and 979 non-orphans of Yi ethnic minority from 5th-10th grades. Structural equation models (SEM) were utilized to identify and estimate the direct and indirect effects of internal and external assets on subjective well-being. RESULTS: The average score of subjective well-being was significantly lower for AIDS orphans than for in non-orphans (P < 0.05). Resilience, school connectedness, peer support (number of friends, caring friends), and self-rated physical health had significant and positive direct effects on subjective well-being. In addition, the effects of school connectedness, and peer support on subjective well-being were mediated by resilience. CONCLUSIONS: Positive individual and school-related contextual assets can bolster subjective well-being among AIDS orphans. The design of health intervention programs for AIDS orphans should incorporate these positive development assets.
Subject(s)
Acquired Immunodeficiency Syndrome , Child, Orphaned , Adolescent , China , Cross-Sectional Studies , Ethnicity , Humans , Minority Groups , SchoolsABSTRACT
BACKGROUND: The Liangshan Yi Autonomous Prefecture is home to the largest population of Yi ethnic minority within mainland China. Due to the high HIV/AIDS epidemic, many Yi children become AIDS orphans who lost one or both parents to AIDS-related causes. This study explored the prevalence and correlates of AIDS orphans' depressive symptom, sleep disorders and their comorbidity. METHODS: A cross-sectional survey was conducted to collect pertinent information from 467 AIDS orphans and 856 non-orphans of Yi ethnic minority. Depressive symptoms were screened by a two-item Patient Health Questionnaire (PHQ-2). The symptoms of insomnia were assessed by the Insomnia Severity Index (ISI), which was complemented by one item from the Pittsburgh Quality Sleep Index (PSQI) to measure the frequency of nightmare. RESULTS: The prevalence of depression (26.8% vs. 20.4%, P = 0.009) and comorbidity of depression, insomnia and nightmare (7.5% vs. 4.3%, P = 0.046) was significantly higher for AIDS orphans than for non-orphans. Risk factors such as ostracization and self-reported poor physical health had stronger effects on depressive symptoms and sleep disorders for AIDS orphans than for non-orphans. On the other hand, peer support, as an important protective factor, was significantly and negatively associated with depressive symptoms and sleep disorders for AIDS orphans. CONCLUSIONS: AIDS orphans of Yi ethnic minority reported higher levels of depressive symptoms and comorbidity of depression and sleep disorders than their non-orphan counterparts. These symptoms were exacerbated by ostracization and self-rated poor physical health but lowered by peer support.
Subject(s)
Acquired Immunodeficiency Syndrome , Child, Orphaned , Sleep Initiation and Maintenance Disorders , Sleep Wake Disorders , Acquired Immunodeficiency Syndrome/complications , Acquired Immunodeficiency Syndrome/epidemiology , Child , China/epidemiology , Cross-Sectional Studies , Depression/diagnosis , Depression/epidemiology , Ethnicity , Humans , Minority Groups , Sleep Initiation and Maintenance Disorders/epidemiology , Sleep Wake Disorders/diagnosis , Sleep Wake Disorders/epidemiologyABSTRACT
Retinoblastoma is the most common intraocular cancer with metastatic potential affecting infants and children. Although chemotherapy is available for retinoblastoma, side effects and drug resistance are frequent. Rpl41, encoding ribosomal protein L41 (RPL41), has been identified as a tumor suppressor gene, and its targeted degradation of activating transcription factor 4 (ATF4) produces an antitumor effect. The goal of the present study is to provide experimental evidence for the clinical application of a small peptide regimen in combination with chemotherapy for the treatment of retinoblastoma and to investigate the mechanism of their combined cytotoxicity. It was observed that treatment with the RPL41 peptide alone decreased the viability, migration, and invasion of retinoblastoma Y79 and Weri-Rb1 cells, in addition to promoting cell apoptosis and cell cycle arrest. Furthermore, RPL41 protein levels showed a significantly decreased trend in retinoblastoma specimens, whereas ATF4 protein levels tended to be increased. Mechanistically, ATF4 degradation as a result of RPL41 peptide treatment was observed in retinoblastoma Y79 and Weri-Rb1 cells. Most important, low-dose administration of the RPL41 peptide significantly enhanced the antitumor effect of carboplatin, and further analysis confirmed their synergistic effect as anti-retinoblastoma therapy, indicating that RPL41 sensitized Y79 and Weri-Rb1 retinoblastoma cells to carboplatin. Thus, our data provide a preclinical rationale for the exploration of the RPL41 peptide as a potential adjuvant to carboplatin treatment in retinoblastoma.
Subject(s)
Activating Transcription Factor 4/metabolism , Antineoplastic Agents/pharmacology , Proteolysis , Retinoblastoma/metabolism , Ribosomal Proteins/metabolism , Apoptosis/drug effects , Carboplatin/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , G1 Phase Cell Cycle Checkpoints/drug effects , Humans , Neoplasm Invasiveness , Peptides/pharmacology , Proteolysis/drug effects , Retinoblastoma/pathologyABSTRACT
BACKGROUND: Depression is common among HIV-infected individuals and may contribute to suboptimal adherence to antiretroviral therapy (ART) and subsequent inability to attain viral load (VL) suppression. We evaluated associations between depression, self-reported adherence, and longitudinal HIV treatment outcomes in US Military HIV Natural History Study (NHS) participants with and without depression. METHODS: Male NHS participants with available ICD-9 data for mental health diagnoses, Center for Epidemiological Studies Depression (CES-D) measures, and self-reported adherence (SRA) were included. ART use was defined as ART initiation between 2006 and 2010, with follow-up through 2015. SRA was defined as taking 95% of ART doses and continuous ART was defined as longitudinal ART use with gaps < 30 days. Continuous VL suppression was defined as maintaining VLs < 200 c/mL on ART. To analyse the association between depression and HIV treatment outcomes, latent class analysis was used to create classes of depression trajectories: low depression (LD), recent onset depression (ROD) and high Depression (HD). RESULTS: Participants had a mean age of 32 (± 8.3) years at HIV diagnosis, and similar proportions were Caucasian (44.3%) or African American (40.8%). Overall, older participants at HIV diagnosis had greater odds of having 95% self-reported adherence (OR 1.06, 95% CI 1.02-1.12), and African Americans had lower odds (OR 0.41, 95% CI 0.22-0.76) compared to Caucasians (OR 1.49, 95% CI 0.52-4.28). However, there was no difference in SRA by depression trajectory. Participants with HD had an increased odds of taking ART continuously (OR 1.75, 95% CI 0.99-3.09), and those with ROD had significantly higher odds of virologic failure (OR 0.58, 95% CI 0.38-0.91). CONCLUSIONS: Although there was no observed association between depression and SRA, participants with ROD had lower odds of attaining the HIV treatment goal of VL suppression. Continued efforts to identify and aggressively manage mental health disorders is important to success along the HIV care continuum.
Subject(s)
HIV Infections , Military Personnel , CD4 Lymphocyte Count , Child , Depression/epidemiology , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/epidemiology , Humans , Male , Medication Adherence , Treatment Outcome , Viral LoadABSTRACT
BACKGROUND: Research suggests that health/safety behaviors (e.g., drinking heavily) and medical behaviors (e.g., donating blood) may be perceived as inherently risky, and further suggests there is substantial variation in the likelihood of engaging in a particular health-related risk behavior across people. Research examining demographic and sociocultural factors related to both health/safety and medical risk-taking is highly limited. Importantly, with very few exceptions the literature examining health risks characterized by potentially hazardous health behaviors (e.g, heavy alcohol use, driving without a seatbelt) is kept separate from the literature examining health risks characterized by potentially beneficial medical behaviors (e.g., donating blood, taking medication). In the interest of health promotion, it is critical for researchers to identify - and describe - individuals who are less inclined to engage in health-harming behaviors while at the same time being more inclined to engage in health-benefiting behaviors. Identifying such a subtype of individuals was the guiding aim for this study. METHOD: A national sample of adults in the United States responded to a survey on sociocultural and demographic correlates of health behaviors. Health-related risk-taking indicators were measured using the items from the health/safety and medical subscales of the DOSPERT-M. Subtypes of risk-takers were identified using latent profile analysis (LPA). Follow-up analyses to describe subtype demographic characteristics were conducted. RESULTS: LPA identified four subtypes of risk-takers, including a subtype (n = 565, 45% of the sample; labeled "divergent") that was comprised of individuals who highly endorsed medical risk-taking (e.g., taking medicine, giving blood) and minimally endorsed health/safety risk-taking (e.g., drinking heavily, unprotected sex). Subsequent analyses suggested that, among other findings, divergent profile members were likely to be married, endorse familial interdependence, and orient toward masculinity rather than femininity. CONCLUSION: By examining potentially modifiable factors related to individuals' inclinations to engage in health protective behaviors, this study is an important step toward improving current health behavior interventions among U.S. adults.
Subject(s)
Automobile Driving , Risk-Taking , Adult , Alcohol Drinking/epidemiology , Female , Health Behavior , Humans , Male , Surveys and Questionnaires , United States/epidemiologyABSTRACT
The purpose of this study is to examine racial/ethnic and gender variations and intersectionality in the knowledge, attitudes, intentions, and behaviors pertaining to substance abuse (SA) and human immunodeficiency virus (HIV)/sexually transmitted disease (STD) prevention among racial/ethnic minority college students (ages 18-24) in South Texas. A total of 535 minority students completed a baseline survey between 2014 and 2016 (N = 535). Results revealed statistically significant (ranging from p < .05 to p < .001) racial/ethnic and gender variations in SA and HIV/STD prevention-related knowledge, attitudes, intentions, and behaviors. However, the significant interaction effects (i.e., intersectionality) were observed only for two of the nine composite variables. That is, although male minority students exhibited lower levels of awareness of sexual risks and safe sex negotiation skills than female minority students, Hispanic male students appeared to fare better in both awareness of sexual risks (p < .01) and safe sex negotiation skills (p < .05) compared to students of other racial/ethnic origin. Implications for prevention and intervention work involving minority college students are discussed.
Subject(s)
HIV Infections , Sexually Transmitted Diseases , Substance-Related Disorders , Adolescent , Adult , Ethnicity , Female , HIV Infections/prevention & control , Health Knowledge, Attitudes, Practice , Hispanic or Latino , Humans , Male , Minority Groups , Sexual Behavior , Substance-Related Disorders/prevention & control , Texas , Young AdultABSTRACT
This study evaluated the relationships between depression trajectories, depression diagnosis and sexual risk behaviors in the US Military HIV Natural History Study. Risk behavior survey data, a coded diagnosis of depression, available Center for Epidemiological Studies Depression measures, and self-reported depressive symptoms (n = 662) were utilized. Latent class analysis created 3 classes of depression trajectories, namely, low depression (LD, n = 378), recent-onset depression (ROD, n = 170), and high depression (HD, n = 114) trajectories. Overall, participants with clinically diagnosed depression were less likely to report often using condoms with new sexual partners in the past 3 months than those who have never been diagnosed with depression (OR 0.15, 95% CI 0.49-2.53). Participants with ROD (OR 0.52, 95% CI 0.28-0.97) and HD (OR 0.48, 95% CI 0.24-0.96) trajectories were less likely to report often using condoms with new sexual partners in the past 3 months than those with LD trajectories. Moreover, those with either ROD (OR 2.13, 95% CI 1.19-3.80) or HD (OR 2.74, 95% CI 1.43-5.24) trajectories were more likely to have had sex with ≥2 new sexual partners in the last 3 months than those with LD trajectories. Continued efforts targeting HIV-infected persons with mental health disorders are warranted to reduce sexual risk behaviors.
Subject(s)
Depressive Disorder/complications , HIV Infections/complications , HIV Infections/psychology , Military Personnel/psychology , Unsafe Sex/psychology , Unsafe Sex/statistics & numerical data , Adult , Cohort Studies , Depressive Disorder/psychology , Female , Health Surveys/statistics & numerical data , Humans , Male , Military Personnel/statistics & numerical data , Prospective Studies , Self Report , United StatesABSTRACT
BACKGROUND: Incidents of patient-initiated workplace violence against health care workers have been a subject of substantial public attention in China. Patient-initiated violence not only represents a risk of harm to health care providers but is also indicative of general tensions between doctors and patients which pose a challenge to improving health system access and quality. This study aims to provide a systematic, national-level characterization of serious workplace violence against health care workers in China. METHODS: This study extracted data from the China Judgment Online System, a comprehensive database of judgment documents. Three key phrases, "criminal case," "health care institution," and "health care worker" were used to search the China Judgment Online System for relevant cases between January 1, 2013, and December 31, 2016. Data extracted from identified cases was used to document the occurrence, the degree of risk, and the factors associated with serious workplace violence. RESULTS: In total, 459 criminal cases involving patient-initiated workplace violence against health care workers in China were reported and processed. The analysis revealed geographic heterogeneity in the occurrence of serious workplace violence, with lower incidence in western provinces compared to central and eastern provinces. Primary hospitals experienced the highest rates of serious workplace violence and emergency departments and doctors were at higher risk compared with other departments and health workers. Perpetrators were primarily male farmers aged 18 to 44 with low levels of education. The most frequently reported reasons of serious patient-initiated workplace violence included perceived medical malpractice by the perpetrator after the death of a patient, death of a patient with no other reason given, failures of the compensation negotiations after the death of a patient, and dissatisfaction with the treatment outcomes. CONCLUSIONS: Serious workplace violence against providers varies across regions and types of health care institutions in China. Perception of low-quality care is the most reported reason for violence. Efforts should be made to improve quality of care in the low-level health institutions and strengthen the doctor-patient communication during the whole course of service.
Subject(s)
Databases, Factual , Health Personnel/statistics & numerical data , Workplace Violence/statistics & numerical data , China , Humans , JudgmentABSTRACT
BACKGROUND: Varicella-zoster virus (VZV) reactivation is common but difficult to predict in HIV-infected persons. OBJECTIVE: Since qualitative VZV antibodies can determine past VZV disease or vaccination, we evaluated whether quantitative VZV antibody levels over time can predict future zoster. STUDY DESIGN: US Military HIV Natural History (NHS) participants with a zoster diagnosis at least 5 years after HIV diagnosis (n = 100) were included. Zoster-negative controls (n = 200) were matched by age, race, gender, and CD4 count at HIV diagnosis. Repository plasma specimens collected at baseline and prior to zoster diagnosis were evaluated using a quantitative anti-VZV ELISA assay. Differences in quantitative VZV levels were analyzed by Wilcoxon Mann-Whitney and Fisher's exact tests. RESULTS: Median CD4 count at HIV diagnosis was similar for cases and controls (535 [IQR 384-666] vs. 523 [IQR 377-690] cells/µL; p = 0.940), but lower for cases at zoster diagnosis (436 [IQR 277-631] vs. 527 [IQR 367-744] cells/µL; p = 0.007). Antiretroviral therapy (ART) use prior to zoster diagnosis was lower for cases (52.0%) compared to controls (64.5%; p = 0.025). Cases had similar mean VZV antibody levels prior to zoster diagnosis compared to controls [2.25 ± 0.85 vs. 2.44 ± 0.96 index value/optical density (OD) ratio; p = 0.151] with no difference in the change in antibody levels over time (0.08 ± 0.71 vs. 0.01 ± 0.94 index value/OD per year; p = 0.276). CONCLUSION: Quantitative VZV antibody levels are stable in HIV-infected persons and do not predict zoster reactivation. Low CD4 count and lack of ART use appear to be better predictors of future zoster diagnosis.
Subject(s)
Antibodies, Viral/immunology , Coinfection , HIV Infections/epidemiology , Herpes Zoster/immunology , Herpes Zoster/virology , Herpesvirus 3, Human/immunology , Virus Activation/immunology , Adult , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , Enzyme-Linked Immunosorbent Assay , Female , HIV Infections/diagnosis , HIV Infections/drug therapy , HIV Infections/immunology , Herpes Zoster/diagnosis , Herpes Zoster/epidemiology , Humans , Male , Viral Load , Young AdultABSTRACT
Does religious involvement (i.e., attendance and salience) mitigate the association between combat casualty exposure and sleep disturbance among US military veterans? To address this question, we analyze cross-sectional survey data from the public-use version of the 2011 Health Related Behaviors Survey of Active Military Personnel. Results from multivariate regression models indicate: (1) Combat casualty exposure was positively associated with sleep disturbance; (2) religious salience both offset and moderated (i.e., buffered) the above association; and (3) religious attendance offset but did not moderate the above association. We discuss study implications and limitations, as well as some avenues for future research.
Subject(s)
Combat Disorders/complications , Military Personnel/psychology , Religion , Sleep Deprivation/complications , Sleep Deprivation/epidemiology , Sleep Wake Disorders/complications , Stress, Psychological/complications , Veterans/psychology , Adaptation, Psychological , Adolescent , Adult , Combat Disorders/epidemiology , Combat Disorders/psychology , Cross-Sectional Studies , Female , Humans , Male , Sleep Deprivation/psychology , Sleep Wake Disorders/epidemiology , United StatesABSTRACT
Purpose: Rupture of lens cataract (RLC) is a hereditary mouse model that shows spontaneous rupture of the lens at the posterior pole at 45-100 days of age. The responsible gene for this phenotype was identified as Dock5, a guanine nucleotide exchange factor for small GTPase Rac1. This study was performed to elucidate the pathway initiating this phenotype. Methods: We examined the RNA expression by microarray in lens epithelial cells (LECs) from wild-type and RLC mice at the pre-rupture age of 21 days. We applied the list of altered genes to an Ingenuity Pathway Analysis (IPA) to predict the pathways that are altered upon dedicator of cytokinesis-5 (Dock5) protein loss. The activation status of the predicted pathways was examined by western blotting in the cultured epithelial cells treated with a Dock5 inhibitor. Results: The highest-scored network was "Antimicrobial Response, Inflammatory Response, Dermatological Diseases and Conditions." In that network, it is predicted that extracellular signal-regulated kinase (Erk) is activated in LECs from RLC mice. Our test confirmed that Erk was more phosphorylated in the LECs at the equator in both Dock5-knockout mice and RLC mice. In an in vitro experiment of the cultured epithelial cells, the inhibition of Dock5 activity significantly induced Erk activation. It was also confirmed that Akt (cellular homolog of murine thymoma virus akt8 oncogene, also called protein kinase B) and nuclear factor-kappa B (NFκB), predicted to be the key molecules in two other high-scoring networks by IPA, were activated upon Dock5 inhibition in the cultured epithelial cells. Conclusions: Dock5 participates in epithelial cell maintenance by regulating gene expression.
Subject(s)
Epithelial Cells/metabolism , Guanine Nucleotide Exchange Factors/physiology , Lens Capsule, Crystalline/metabolism , Lens Diseases/metabolism , Signal Transduction/physiology , Up-Regulation/physiology , Animals , Blotting, Western , Dogs , Electrophoresis, Polyacrylamide Gel , MAP Kinase Signaling System/physiology , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred BALB C , Mice, Knockout , Microarray Analysis , Phosphorylation , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Rupture, Spontaneous , Sequence Deletion , Transcriptional ActivationABSTRACT
A copper nitrate-catalyzed cross-dehydrogenative coupling reaction between N-hydroxyphthalimide (NHPI) and ethers/alkanes has been described. The reaction is accomplished smoothly by using simple and green molecular oxygen as the oxidant, providing an alternative for the efficient synthesis of N-alkoxyphthalimides. In addition, it was found that when tert-butyl ethers were used as substrates, unexpected N-hydroxyimide ester derivatives were obtained in moderate to excellent yields. To further understand this unusual transformation, control experiments were performed and a plausible mechanism was proposed.
ABSTRACT
Youth suicide risks have been on the rise or persistently elevated for decades, and Native American communities are especially vulnerable. This study provides a promising framework for suicide prevention among underserved populations in the U.S., especially Native American communities in states lacking strong suicide prevention supports. Our investigation reports the evaluation results of the Question-Persuade-Refer (QPR) gatekeeper training program, a key component of the SAMHSA-funded Choctaw Youth Resilience Initiative (CYRI) implemented by the Mississippi Band of Choctaw Indians (MBCI). QPR trains adult gatekeepers to identify youth at risk of suicide and refer them to certified mental health service providers. Standardized QPR pre-test and post-test training surveys were administered at in-person trainings delivered to youth-serving MBCI organization leaders and staff. Statistical analyses of all survey items indicate that QPR gatekeeper trainings significantly enhanced the knowledge of prevention practices and risk identification skills for the MBCI trainees. The robust evidence of positive changes revealed in this study suggests that QPR can be an effective suicide prevention program for underserved minority communities, especially Native American populations in rural states where suicide is a persistent and leading cause of mortality.
ABSTRACT
Suicide continues to be a leading cause of mortality for young people. Given persistent intersecting forms of disadvantage, Native American adolescents are especially vulnerable to mental health adversities and other suicide risk factors. The Mississippi Band of Choctaw Indians (MBCI) implemented the Choctaw Youth Resilience Initiative (CYRI), a five-year SAMHSA-funded project that began in 2019. This study uses Choctaw student pre-test/post-test survey data to examine the effectiveness of the Hazelden Lifelines Suicide Prevention Training curriculum for youth. A lagged post-test design was used, whereby post-surveys were administered at least one month after program completion. Several intriguing results were observed. First, the lagged post-test model was subject to some pre-to-post attrition, although such attrition was comparable to a standard pre/post design. Second, analyses of completed surveys using means indicated various beneficial effects associated with the Lifelines curriculum implementation. The greatest benefit of the program was a significant change in student perceptions concerning school readiness in response to a suicidal event. Some opportunities for program improvement were also observed. Our study sheds new light on suicide prevention training programs that can be adapted according to Native American youth culture. Program implementation and evaluation implications are discussed in light of these findings.
ABSTRACT
Fragment-based drug design (FBDD) has emerged as a captivating subject in the realm of computer-aided drug design, enabling the generation of novel molecules through the rearrangement of ring systems within known compounds. The construction of focused fragment library plays a pivotal role in FBDD, necessitating the compilation of all potential bioactive ring systems capable of interacting with a specific target. In our study, we propose a workflow for the development of a focused fragment library and combinatorial compound library. The fragment library comprises seed fragments and collected fragments. The extraction of seed fragments is guided by receptor information, serving as a prerequisite for establishing a focused libraries. Conversely, collected fragments are obtained using the feature graph method, which offers a simplified representation of fragments and strikes a balance between diversity and similarity when categorizing different fragments. The utilization of feature graph facilitates the rational partitioning of chemical space at fragment level, enabling the exploration of desired chemical space and enhancing the efficiency of screening compound library. Analysis demonstrates that our workflow enables the enumeration of a greater number of entirely new potential compounds, thereby aiding in the rational design of drugs.