Cocrystal structure of a class-I preQ1 riboswitch reveals a pseudoknot recognizing an essential hypermodified nucleobase

Riboswitches are mRNA domains that bind metabolites and modulate gene expression in cis. We report cocrystal structures of a remarkably compact riboswitch (34 nucleotides suffice for ligand recognition) from Bacillus subtilis selective for the essential nucleobase preQ1 (7-aminomethyl-7-deazaguanine). These reveal a previously unrecognized pseudoknot fold, and suggest a conserved gene-regulatory mechanism whereby ligand binding promotes sequestration of an RNA segment that otherwise assembles into a transcriptional anti-terminator

Fission Hindrance in Hot Nuclei

The role of dynamics in fission has attracted much interest since the discovery of this process over fifty years ago. However, the study of the dynamical aspects of fission was for many years hampered by the lack of suitable experimental observables against which theoretical calculations could be tested. For example, it was found that the total kinetic energy release in fission can be described equally well by very different dissipation mechanisms, namely the wall formula, that is based on the collisions of the nucleons with the moving wall of the system, as well as a bulk viscosity of the nuclear matter. Although early theoretical work suggested that the fission process may be described as a diffusion process over the fission barrier, this was largely forgotten because of the success of a purely statistical model which instead of enumerating the ultimate final states of the process argues that the fission rate is determined at the {open_quote}transition state{close_quote} as the system traverses the fission saddle point. It was therefore significant when Gavron showed that the transition state model was unable to describe the number of neutrons emitted prior to scission at high excitation energy in reactions of {sup 16}O+{sup 142}Nd. Subsequent experimental work using different methods to measure the fission dissipation/viscosity has confirmed these initial observations. It was therefore very surprising when Moretto in recent publications concluded that their analysis of fission excitation functions obtained with a and {alpha} and {sup 3}He induced projectiles was perfectly in accord with the transition state model and left no room for fission viscosity. In this paper we`ll show that Moretto`s analysis is flawed by assuming first chance fission only (in direct contradiction to the experimental observation of pre-scission neutron emission in heavy-ion induced fission), and reveal why the systematics presented by Moretto looked so convincing despite these flaws

A primary care, multi-disciplinary disease management program for opioid-treated patients with chronic non-cancer pain and a high burden of psychiatric comorbidity

BACKGROUND: Chronic non-cancer pain is a common problem that is often accompanied by psychiatric comorbidity and disability. The effectiveness of a multi-disciplinary pain management program was tested in a 3 month before and after trial. METHODS: Providers in an academic general medicine clinic referred patients with chronic non-cancer pain for participation in a program that combined the skills of internists, clinical pharmacists, and a psychiatrist. Patients were either receiving opioids or being considered for opioid therapy. The intervention consisted of structured clinical assessments, monthly follow-up, pain contracts, medication titration, and psychiatric consultation. Pain, mood, and function were assessed at baseline and 3 months using the Brief Pain Inventory (BPI), the Center for Epidemiological Studies-Depression Scale scale (CESD) and the Pain Disability Index (PDI). Patients were monitored for substance misuse. RESULTS: Eighty-five patients were enrolled. Mean age was 51 years, 60% were male, 78% were Caucasian, and 93% were receiving opioids. Baseline average pain was 6.5 on an 11 point scale. The average CESD score was 24.0, and the mean PDI score was 47.0. Sixty-three patients (73%) completed 3 month follow-up. Fifteen withdrew from the program after identification of substance misuse. Among those completing 3 month follow-up, the average pain score improved to 5.5 (p = 0.003). The mean PDI score improved to 39.3 (p < 0.001). Mean CESD score was reduced to 18.0 (p < 0.001), and the proportion of depressed patients fell from 79% to 54% (p = 0.003). Substance misuse was identified in 27 patients (32%). CONCLUSIONS: A primary care disease management program improved pain, depression, and disability scores over three months in a cohort of opioid-treated patients with chronic non-cancer pain. Substance misuse and depression were common, and many patients who had substance misuse identified left the program when they were no longer prescribed opioids. Effective care of patients with chronic pain should include rigorous assessment and treatment of these comorbid disorders and intensive efforts to insure follow up

Development and evaluation of a youth mental health community awareness campaign – The Compass Strategy

BACKGROUND: Early detection and treatment of mental disorders in adolescents and young adults can lead to better health outcomes. Mental health literacy is a key to early recognition and help seeking. Whilst a number of population health initiatives have attempted to improve mental health literacy, none to date have specifically targeted young people nor have they applied the rigorous standards of population health models now accepted as best practice in other health areas. This paper describes the outcomes from the application of a health promotion model to the development, implementation and evaluation of a community awareness campaign designed to improve mental health literacy and early help seeking amongst young people. METHOD: The Compass Strategy was implemented in the western metropolitan Melbourne and Barwon regions of Victoria, Australia. The Precede-Proceed Model guided the population assessment, campaign strategy development and evaluation. The campaign included the use of multimedia, a website, and an information telephone service. Multiple levels of evaluation were conducted. This included a cross-sectional telephone survey of mental health literacy undertaken before and after 14 months of the campaign using a quasi-experimental design. Randomly selected independent samples of 600 young people aged 12–25 years from the experimental region and another 600 from a comparison region were interviewed at each time point. A series of binary logistic regression analyses were used to measure the association between a range of campaign outcome variables and the predictor variables of region and time. RESULTS: The program was judged to have an impact on the following variables, as indicated by significant region-by-time interaction effects (p < 0.05): awareness of mental health campaigns, self-identified depression, help for depression sought in the previous year, correct estimate of prevalence of mental health problems, increased awareness of suicide risk, and a reduction in perceived barriers to help seeking. These effects may be underestimated because media distribution error resulted in a small amount of print material "leaking" into the comparison region. CONCLUSION: We believe this is the first study to apply the rigorous standards of a health promotion model including the use of a control region to a mental health population intervention. The program achieved many of its aims despite the relatively short duration and moderate intensity of the campaign

Effects of the Training Dataset Characteristics on the Performance of Nine Species Distribution Models: Application to Diabrotica virgifera virgifera

Many distribution models developed to predict the presence/absence of invasive alien species need to be fitted to a training dataset before practical use. The training dataset is characterized by the number of recorded presences/absences and by their geographical locations. The aim of this paper is to study the effect of the training dataset characteristics on model performance and to compare the relative importance of three factors influencing model predictive capability; size of training dataset, stage of the biological invasion, and choice of input variables. Nine models were assessed for their ability to predict the distribution of the western corn rootworm, Diabrotica virgifera virgifera, a major pest of corn in North America that has recently invaded Europe. Twenty-six training datasets of various sizes (from 10 to 428 presence records) corresponding to two different stages of invasion (1955 and 1980) and three sets of input bioclimatic variables (19 variables, six variables selected using information on insect biology, and three linear combinations of 19 variables derived from Principal Component Analysis) were considered. The models were fitted to each training dataset in turn and their performance was assessed using independent data from North America and Europe. The models were ranked according to the area under the Receiver Operating Characteristic curve and the likelihood ratio. Model performance was highly sensitive to the geographical area used for calibration; most of the models performed poorly when fitted to a restricted area corresponding to an early stage of the invasion. Our results also showed that Principal Component Analysis was useful in reducing the number of model input variables for the models that performed poorly with 19 input variables. DOMAIN, Environmental Distance, MAXENT, and Envelope Score were the most accurate models but all the models tested in this study led to a substantial rate of mis-classification

Increased Membrane Cholesterol in Lymphocytes Diverts T-Cells toward an Inflammatory Response

Cell signaling for T-cell growth, differentiation, and apoptosis is initiated in the cholesterol-rich microdomains of the plasma membrane known as lipid rafts. Herein, we investigated whether enrichment of membrane cholesterol in lipid rafts affects antigen-specific CD4 T-helper cell functions. Enrichment of membrane cholesterol by 40–50% following squalene administration in mice was paralleled by an increased number of resting CD4 T helper cells in periphery. We also observed sensitization of the Th1 differentiation machinery through co-localization of IL-2Rα, IL-4Rα, and IL-12Rβ2 subunits with GM1 positive lipid rafts, and increased STAT-4 and STAT-5 phosphorylation following membrane cholesterol enrichment. Antigen stimulation or CD3/CD28 polyclonal stimulation of membrane cholesterol-enriched, resting CD4 T-cells followed a path of Th1 differentiation, which was more vigorous in the presence of increased IL-12 secretion by APCs enriched in membrane cholesterol. Enrichment of membrane cholesterol in antigen-specific, autoimmune Th1 cells fostered their organ-specific reactivity, as confirmed in an autoimmune mouse model for diabetes. However, membrane cholesterol enrichment in CD4+ Foxp3+ T-reg cells did not alter their suppressogenic function. These findings revealed a differential regulatory effect of membrane cholesterol on the function of CD4 T-cell subsets. This first suggests that membrane cholesterol could be a new therapeutic target to modulate the immune functions, and second that increased membrane cholesterol in various physiopathological conditions may bias the immune system toward an inflammatory Th1 type response