Synthetic RNA Silencing of Actinorhodin Biosynthesis in Streptomyces coelicolor A3(2)

We demonstrate the first application of synthetic RNA gene silencers in Streptomyces coelicolor A3(2). Peptide nucleic acid and expressed antisense RNA silencers successfully inhibited actinorhodin production. Synthetic RNA silencing was target-specific and is a new tool for gene regulation and metabolic engineering studies in Streptomyces.Peer reviewe

Evidence for the h_b(1P) meson in the decay Upsilon(3S) --> pi0 h_b(1P)

Using a sample of 122 million Upsilon(3S) events recorded with the BaBar detector at the PEP-II asymmetric-energy e+e- collider at SLAC, we search for the $h_b(1P)$ spin-singlet partner of the P-wave chi_{bJ}(1P) states in the sequential decay Upsilon(3S) --> pi0 h_b(1P), h_b(1P) --> gamma eta_b(1S). We observe an excess of events above background in the distribution of the recoil mass against the pi0 at mass 9902 +/- 4(stat.) +/- 2(syst.) MeV/c^2. The width of the observed signal is consistent with experimental resolution, and its significance is 3.1sigma, including systematic uncertainties. We obtain the value (4.3 +/- 1.1(stat.) +/- 0.9(syst.)) x 10^{-4} for the product branching fraction BF(Upsilon(3S)-->pi0 h_b) x BF(h_b-->gamma eta_b).Comment: 8 pages, 4 postscript figures, submitted to Phys. Rev. D (Rapid Communications

When passive feels active - delusion-proneness alters self-recognition in the moving rubber hand illusion

Psychotic patients have problems with bodily self-recognition such as the experience of self-produced actions (sense of agency) and the perception of the body as their own (sense of ownership). While it has been shown that such impairments in psychotic patients can be explained by hypersalient processing of external sensory input it has also been suggested that they lack normal efference copy in voluntary action. However, it is not known how problems with motor predictions like efference copy contribute to impaired sense of agency and ownership in psychosis or psychosis-related states. We used a rubber hand illusion based on finger movements and measured sense of agency and ownership to compute a bodily self-recognition score in delusion-proneness (indexed by Peters’ Delusion Inventory - PDI). A group of healthy subjects (n=71) experienced active movements (involving motor predictions) or passive movements (lacking motor predictions). We observed a highly significant correlation between delusion-proneness and self-recognition in the passive conditions, while no such effect was observed in the active conditions. This was seen for both ownership and agency scores. The result suggests that delusion-proneness is associated with hypersalient external input in passive conditions, resulting in an abnormal experience of the illusion. We hypothesize that this effect is not present in the active condition because deficient motor predictions counteract hypersalience in psychosis proneness

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Promotion of a healthy lifestyle among 5-year-old overweight children: Health behavior outcomes of the 'Be active, eat right' study

Background: This study evaluates the effects of an intervention performed by youth health care professionals on child health behaviors. The intervention consisted of offering healthy lifestyle counseling to parents of overweight (not obese) 5-year-old children. Effects of the intervention on the child having breakfast, drinking sweet beverages, watching television and playing outside were evaluated. Methods. Data were collected with the 'Be active, eat right' study, a cluster randomized controlled trial among nine youth health care centers in the Netherlands. Parents of overweight children received lifestyle counseling according to the intervention protocol in the intervention condition (n = 349) and usual care in the control condition (n = 288). Parents completed questionnaires regarding demographic characteristics, health behaviors and the home environment at baseline and at 2-year follow-up. Cluster adjusted regression models were applied; interaction terms were explored. Results: The population for analysis consisted of 38.1% boys; mean age 5.8 [sd 0.4] years; mean BMI SDS 1.9 [sd 0.4]. There were no significant differences in the number of minutes of outside play or television viewing a day between children in the intervention and the control condition. Also, the odds ratio for having breakfast daily or drinking two or less glasses of sweet beverages a day showed no significant differences between the two conditions. Additional analyses showed that the odds ratio for drinking less than two glasses of sweet beverages at follow-up compared with baseline was significantly higher for children in both the intervention (p < 0.001) and the control condition (p = 0.029). Conclusions: Comparison of the children in the two conditions showed that the intervention does not contribute to a change in health behaviors. Further studies are needed to investigate opportunities to adjust the intervention protocol, such as integration of elements in the regular well-child visit. The intervention protocol for youth health care may become part of a broader approach to tackle childhood overweight and obesity. Trial registration. Current Controlled Trials ISRCTN04965410

Knowledge brokering between researchers and policymakers in Fiji to develop policies to reduce obesity: a process evaluation

The importance of using research evidence in decision making at the policy level has been increasingly recognized. However, knowledge brokering to engage researchers and policymakers in government and non-government organizations is challenging. This paper describes and evaluates the knowledge exchange processes employed by the Translational Research on Obesity Prevention in Communities (TROPIC) project that was conducted from July 2009 to April 2012 in Fiji. TROPIC aimed to enhance: the evidence-informed decision making skills of policy developers; and awareness and utilization of local and other obesity-related evidence to develop policies that could potentially improve the nation&rsquo;s food and physical activity environments. The specific research question was: Can a knowledge brokering approach advance evidence-informed policy development to improve eating and physical activity environments in Fiji. <br /

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

The Staphylococcus aureus RNome and Its Commitment to Virulence

Staphylococcus aureus is a major human pathogen causing a wide spectrum of nosocomial and community-associated infections with high morbidity and mortality. S. aureus generates a large number of virulence factors whose timing and expression levels are precisely tuned by regulatory proteins and RNAs. The aptitude of bacteria to use RNAs to rapidly modify gene expression, including virulence factors in response to stress or environmental changes, and to survive in a host is an evolving concept. Here, we focus on the recently inventoried S. aureus regulatory RNAs, with emphasis on those with identified functions, two of which are directly involved in pathogenicity

Staphylococcus aureus RNAIII Binds to Two Distant Regions of coa mRNA to Arrest Translation and Promote mRNA Degradation

Staphylococcus aureus RNAIII is the intracellular effector of the quorum sensing system that temporally controls a large number of virulence factors including exoproteins and cell-wall-associated proteins. Staphylocoagulase is one major virulence factor, which promotes clotting of human plasma. Like the major cell surface protein A, the expression of staphylocoagulase is strongly repressed by the quorum sensing system at the post-exponential growth phase. Here we used a combination of approaches in vivo and in vitro to analyze the mechanism used by RNAIII to regulate the expression of staphylocoagulase. Our data show that RNAIII represses the synthesis of the protein through a direct binding with the mRNA. Structure mapping shows that two distant regions of RNAIII interact with coa mRNA and that the mRNA harbors a conserved signature as found in other RNAIII-target mRNAs. The resulting complex is composed of an imperfect duplex masking the Shine-Dalgarno sequence of coa mRNA and of a loop-loop interaction occurring downstream in the coding region. The imperfect duplex is sufficient to prevent the formation of the ribosomal initiation complex and to repress the expression of a reporter gene in vivo. In addition, the double-strand-specific endoribonuclease III cleaves the two regions of the mRNA bound to RNAIII that may contribute to the degradation of the repressed mRNA. This study validates another direct target of RNAIII that plays a role in virulence. It also illustrates the diversity of RNAIII-mRNA topologies and how these multiple RNAIII-mRNA interactions would mediate virulence regulation

Role of calcium channel blocking agents in the prevention of atherosclerosis

Calcium channel blocking agents, although effective and widely used in the symptomatic therapy of hypertension and ischemic heart disease, have an uncertain effect on the development of coronary atherosclerosis, plaque rupture, and postrupture thrombosis. Both nifedipine and nicardipine have been shown to prevent the development of new coronary lesions but not the progression of existing lesions in prospective randomized angiographic studies. Verapamil, in contrast, failed to prevent the development of new coronary lesions and had no significant effect on the progression of existing lesions. Diltiazem, although not studied in patients with coronary atheroscleroses, has been shown to prevent the development of post-transplant coronary vascular disease. Despite the beneficial effects of nifedipine and nicardipine on new coronary lesion development, they have not been shown to reduce the incidence of recurrent ischemic events or mortality in the prospective randomized studies that demonstrated their effect on new coronary lesion development. A relatively new dihydropyridine calcium channel blocking agent, amlodipine, is hypothesized to prevent atherosclerosis due to its calcium channel blocking properties as well as by mechanisms independent of its calcium channel blocking properties. This agent has been selected for evaluation in the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) to explore whether the use of amlodipine over 3 years will reduce the incidence of early atherosclerotic lesions and, possibly, the progression of existing lesions in both the coronary and carotid arterial beds. Amlodipine could play an important future role in the secondary prevention of ischemic heart disease, but further study and a demonstration of a beneficial effect on recurrent ischemic events is required before any final conclusions concerning its effectiveness are reached.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44649/1/10557_2004_Article_BF00878569.pd