Conformational landscapes of DNA polymerase I and mutator derivatives establish fidelity checkpoints for nucleotide insertion

The fidelity of DNA polymerases depends on conformational changes that promote the rejection of incorrect nucleotides before phosphoryl transfer. Here, we combine single-molecule FRET with the use of DNA polymerase I and various fidelity mutants to highlight mechanisms by which active-site side chains influence the conformational transitions and free-energy landscape that underlie fidelity decisions in DNA synthesis. Ternary complexes of high fidelity derivatives with complementary dNTPs adopt mainly a fully closed conformation, whereas a conformation with a FRET value between those of open and closed is sparsely populated. This intermediate-FRET state, which we attribute to a partially closed conformation, is also predominant in ternary complexes with incorrect nucleotides and, strikingly, in most ternary complexes of low-fidelity derivatives for both correct and incorrect nucleotides. The mutator phenotype of the low-fidelity derivatives correlates well with reduced affinity for complementary dNTPs and highlights the partially closed conformation as a primary checkpoint for nucleotide selection

Interventions to prevent youth violence in Latin America: a systematic review

Objectives: This review aims to summarise evidence on the effectiveness of interventions to prevent youth violence in Latin America. Methods: A systematic search on 13 academic databases was conducted to locate studies evaluating a primary or secondary prevention intervention in Latin America. Studies could use any type of quantitative design to assess outcomes related to youth violence. A search of websites, references and citation searching was also carried out. The quality of each study was assessed. Results: Nine studies were identified. Most documented positive effects of the interventions on the perception of youth violence present in the community/school. Evidence was found of a reduction in homicides and juvenile crimes in three studies, two of which evaluated a community-based intervention. There were mixed results for the self-report of participation on violent acts. The majority of the studies lacked of a rigorous design. Conclusions: Most of the interventions had some promising results, including the reduction of homicides within communities. Community-based programmes were the most consistent regarding an effectiveness to prevent violence. However, the evidence for Latin America is still scarce and relies on non-rigorously designed studies

The impact of measurement errors in the identification of regulatory networks

<p>Abstract</p> <p>Background</p> <p>There are several studies in the literature depicting measurement error in gene expression data and also, several others about regulatory network models. However, only a little fraction describes a combination of measurement error in mathematical regulatory networks and shows how to identify these networks under different rates of noise.</p> <p>Results</p> <p>This article investigates the effects of measurement error on the estimation of the parameters in regulatory networks. Simulation studies indicate that, in both time series (dependent) and non-time series (independent) data, the measurement error strongly affects the estimated parameters of the regulatory network models, biasing them as predicted by the theory. Moreover, when testing the parameters of the regulatory network models, p-values computed by ignoring the measurement error are not reliable, since the rate of false positives are not controlled under the null hypothesis. In order to overcome these problems, we present an improved version of the Ordinary Least Square estimator in independent (regression models) and dependent (autoregressive models) data when the variables are subject to noises. Moreover, measurement error estimation procedures for microarrays are also described. Simulation results also show that both corrected methods perform better than the standard ones (i.e., ignoring measurement error). The proposed methodologies are illustrated using microarray data from lung cancer patients and mouse liver time series data.</p> <p>Conclusions</p> <p>Measurement error dangerously affects the identification of regulatory network models, thus, they must be reduced or taken into account in order to avoid erroneous conclusions. This could be one of the reasons for high biological false positive rates identified in actual regulatory network models.</p

Recognition of depression, anxiety, and alcohol abuse in a Chinese rural sample: a cross-sectional study

Background Under-utilization of mental health services is a global health issue. Recognition of mental disorders, as the first step to seeking help from professional sources, has been well studied in developed countries, yet little is known about the situation in rural areas of developing countries like China. The purpose of the study is to understand the recognition of depression, anxiety, and alcohol abuse and its predictive factors in a Chinese rural sample Methods Face-to-face interviews were conducted on a representative rural adult sample in a cross-sectional study in China (N = 2052). Respondents were presented with three vignettes depicting depression, anxiety and alcohol abuse and asked to label the disorder and its cause to assess their recognition of the three mental disorders. They also completed the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder Scale (GAD-7), and the Alcohol Use Disorders Identification Test (AUDIT) to assess their current mental health status. Results The alcohol abuse vignette was more frequently attributed as a mental problem than the depression vignette and anxiety vignette. The correct labeling rate was 16.1 % in the depression vignette, 15.5 % in the anxiety vignette, and 58.2 % in the alcohol vignette. Higher education is the common and also strongest factor positively predicting the recognition of all three vignettes. Beyond that, being female is an independent predictor of correct recognition of alcohol abuse, while recognition of depression and anxiety were positively predicted by younger age. Conclusions Lower recognition of depression and anxiety as compared to alcohol abuse confirms the importance and need to increase the public’s awareness and knowledge about common mental disorders. Recognition of common mental disorders could be improved through general public campaign and education, while paying attention to the unique predictive factors for each specific disorder and implement targeted intervention

Mental distress, alcohol use and help-seeking among medical and business students: a cross-sectional comparative study

<p>Abstract</p> <p>Background</p> <p>Stress and distress among medical students are thoroughly studied and presumed to be particularly high, but comparative studies including other student groups are rare.</p> <p>Methods</p> <p>A web-based survey was distributed to 500 medical students and 500 business students. We compared levels of study stress (HESI), burnout (OLBI), alcohol habits (AUDIT) and depression (MDI), and analysed their relationship with self-assessed mental health problems by logistic regression, with respect to gender.</p> <p>Results</p> <p>Medical students' response rate was 81.6% and that of business students 69.4%. Business students scored higher on several study stress factors and on disengagement. Depression (OR 0.61, CI₉₅0.37;0.98) and harmful alcohol use (OR 0.55, CI₉₅0.37; 0.75) were both less common among medical students. However, harmful alcohol use was highly prevalent among male students in both groups (medical students 28.0%, business students 35.4%), and among female business students (25.0%). Mental health problems in need of treatment were equally common in both groups; 22.1% and 19.3%, respectively, and was associated with female sex (OR 2.01, CI₉₅1.32;3.04), exhaustion (OR 2.56, CI₉₅1.60;4.10), lower commitment to studies (OR 1.95, CI₉₅1.09;3.51) and financial concerns (OR 1.81 CI₉₅1.18;2.80)</p> <p>Conclusions</p> <p>Medical students may not be more stressed than other high achieving student populations. The more cohesive structure of medical school and a higher awareness of a healthy lifestyle may be beneficial factors.</p

Clinical Psychologists’ Firearm Risk Management Perceptions and Practices

The purpose of this study was to investigate the current perceptions and practices of discussing firearm risk management with patients diagnosed with selected mental health problems. A three-wave survey was mailed to a national random sample of clinical psychologists and 339 responded (62%). The majority (78.5%) believed firearm safety issues were greater among those with mental health problems. However, the majority of clinical psychologists did not have a routine system for identifying patients with access to firearms (78.2%). Additionally, the majority (78.8%) reported they did not routinely chart or keep a record of whether patients owned or had access to firearms. About one-half (51.6%) of the clinical psychologists reported they would initiate firearm safety counseling if the patients were assessed as at risk for self-harm or harm to others. Almost half (46%) of clinical psychologists reported not receiving any information on firearm safety issues. Thus, the findings of this study suggest that a more formal role regarding anticipatory guidance on firearms is needed in the professional training of clinical psychologists

Increased CSF levels of aromatic amino acids in hip fracture patients with delirium suggests higher monoaminergic activity

textabstractBackground: To examine whether delirium in hip fracture patients was associated with changes in the levels of amino acids and/or monoamine metabolites in cerebrospinal fluid (CSF) and serum. Methods: In this prospective cohort study, 77 patients admitted with an acute hip fracture to Oslo University Hospital, Norway, were studied. The concentrations of amino acids in CSF and serum were determined by high performance liquid chromatography. The patients were assessed daily for delirium by the Confusion Assessment Method (pre-operatively and post-operative day 1-5 (all) or until discharge (delirious patients)). Pre-fracture dementia status was decided by an expert panel. Serum was collected pre-operatively and CSF immediately before spinal anesthesia. Results: Fifty-three (71 %) hip fracture patients developed delirium. In hip fracture patients without dementia (n = 39), those with delirium had significantly higher CSF levels of tryptophan (40 % higher), tyrosine (60 % higher), phenylalanine (59 % higher) and the monoamine metabolite 5-hydroxyindoleacetate (23 % higher) compared to those without delirium. The same amino acids were also higher in CSF in delirious patients with dementia (n = 38). The correlations between serum and CSF amino acid levels were poor. Conclusion: Higher CSF levels of monoamine precursors in hip fracture patients with delirium suggest a higher monoaminergic activity in the central nervous system during delirium in this patient group

Outcomes of pediatric patients with therapy-related myeloid neoplasms

Long-term outcomes after allogeneic hematopoietic cell transplantation (HCT) for therapy-related myeloid neoplasms (tMNs) are dismal. There are few multicenter studies defining prognostic factors in pediatric patients with tMNs. We have accumulated the largest cohort of pediatric patients who have undergone HCT for a tMN to perform a multivariate analysis defining factors predictive of long-term survival. Sixty-eight percent of the 401 patients underwent HCT using a myeloablative conditioning (MAC) regimen, but there were no statistically significant differences in the overall survival (OS), event-free survival (EFS), or cumulative incidence of relapse and non-relapse mortality based on the conditioning intensity. Among the recipients of MAC regimens, 38.4% of deaths were from treatment-related causes, especially acute graft versus host disease (GVHD) and end-organ failure, as compared to only 20.9% of deaths in the reduced-intensity conditioning (RIC) cohort. Exposure to total body irradiation (TBI) during conditioning and experiencing grade III/IV acute GVHD was associated with worse OS. In addition, a diagnosis of therapy-related myelodysplastic syndrome and having a structurally complex karyotype at tMN diagnosis were associated with worse EFS. Reduced-toxicity (but not reduced-intensity) regimens might help to decrease relapse while limiting mortality associated with TBI-based HCT conditioning in pediatric patients with tMNs