Activation and modulation of recombinant glycine and GABAA receptors by 4-halogenated analogues of propofol

BACKGROUND AND PURPOSE: Glycine receptors are important players in pain perception and movement disorders, and therefore an important therapeutic target. Glycine receptors can be modulated by the intravenous anesthetic propofol (2,6-diisopropylphenol); however, the drug is more potent, by at least one order of magnitude, on GABAA receptors. It has been proposed that halogenation of the propofol molecule generates compounds with selective enhancement of glycinergic modulatory properties. EXPERIMENTAL APPROACH: We synthesized 4-bromopropofol, 4-chloropropofol, and 4-fluoropropofol. The direct activating and modulatory effects of these drugs and propofol were compared on recombinant rat glycine and human GABAA receptors expressed in oocytes. Behavioral effects of the compounds were compared in the tadpole loss-of-righting assay. KEY RESULTS: The concentration-response curves for potentiation of homomeric α1, α2, and α3 glycine receptors were shifted to lower drug concentrations by 2-10-fold for the halogenated compounds. Direct activation by all compounds was minimal with all subtypes of the glycine receptor. The four compounds were essentially equally potent modulators of the α1β3γ2L GABAA receptor with EC50 s between 4 and 7 μM. The EC50 s for loss-of-righting in Xenopus tadpoles, a proxy for loss of consciousness and considered to be mediated by actions on GABAA receptors, ranged from 0.35 to 0.87 μM. Conclusions and Implications We confirm that halogenation of propofol more strongly affects modulation of homomeric glycine receptors than α1β3γ2L GABAA receptors. However, the effective concentrations of all tested halogenated compounds remained lower for GABAA receptors. We infer that 4-bromo-, 4-chloro, or 4-fluoropropofol are not selective homomeric glycine receptor modulators

Search for the rare decay KS0→μ+μ−K_S^0 \to \mu^+ \mu^-

A search for the decay $K_S^0 \to \mu^+ \mu^-$ is performed, based on a data sample of 1.0 fb$^{−1}$ of $pp$ collisions at $\sqrt(s)=7TeV$ collected by the LHCb experiment at the Large Hadron Collider. The observed number of candidates is consistent with the background-only hypothesis, yielding an upper limit of $B(K_S^0 \to \mu^+ \mu^-) < 11(9) × 10^{−9}$ at 95 (90)% confidence level. This limit is a factor of thirty below the previous measurement

Translating with Scarce Resources

Current corpus-based machine translation techniques do not work very well when given scarce linguistic resources. To examine the gap between human and machine translators, we created an experiment in which human beings were asked to translate an unknown language into English on the sole basis of a very small bilingual text. Participants performed quite well, and debriefings revealed a number of valuable strategies. We discuss these strategies and apply some of them to a statistical translation system

Simulation of an SEIR infectious disease model on the dynamic contact network of conference attendees

The spread of infectious diseases crucially depends on the pattern of contacts among individuals. Knowledge of these patterns is thus essential to inform models and computational efforts. Few empirical studies are however available that provide estimates of the number and duration of contacts among social groups. Moreover, their space and time resolution are limited, so that data is not explicit at the person-to-person level, and the dynamical aspect of the contacts is disregarded. Here, we want to assess the role of data-driven dynamic contact patterns among individuals, and in particular of their temporal aspects, in shaping the spread of a simulated epidemic in the population. We consider high resolution data of face-to-face interactions between the attendees of a conference, obtained from the deployment of an infrastructure based on Radio Frequency Identification (RFID) devices that assess mutual face-to-face proximity. The spread of epidemics along these interactions is simulated through an SEIR model, using both the dynamical network of contacts defined by the collected data, and two aggregated versions of such network, in order to assess the role of the data temporal aspects. We show that, on the timescales considered, an aggregated network taking into account the daily duration of contacts is a good approximation to the full resolution network, whereas a homogeneous representation which retains only the topology of the contact network fails in reproducing the size of the epidemic. These results have important implications in understanding the level of detail needed to correctly inform computational models for the study and management of real epidemics

Broad Clade 2 Cross-Reactive Immunity Induced by an Adjuvanted Clade 1 rH5N1 Pandemic Influenza Vaccine

The availability of H5N1 vaccines that can elicit a broad cross-protective immunity against different currently circulating clade 2 H5N1 viruses is a pre-requisite for the development of a successful pre-pandemic vaccination strategy. In this regard, it has recently been shown that adjuvantation of a recombinant clade 1 H5N1 inactivated split-virion vaccine with an oil-in-water emulsion-based adjuvant system also promoted cross-immunity against a recent clade 2 H5N1 isolate (A/Indonesia/5/2005, subclade 2.1). Here we further analyse the cross-protective potential of the vaccine against two other recent clade 2 isolates (A/turkey/Turkey/1/2005 and A/Anhui/1/2005 which are, as defined by WHO, representatives of subclades 2.2 and 2.3 respectively).Two doses of the recombinant A/Vietnam/1194/2004 (H5N1, clade 1) vaccine were administered 21 days apart to volunteers aged 18-60 years. We studied the cross-clade immunogenicity of the lowest antigen dose (3.8 microg haemagglutinin) given with (N = 20) or without adjuvant (N = 20). Immune responses were assessed at 21 days following the first and second vaccine doses and at 6 months following first vaccination. Vaccination with two doses of 3.8 microg of the adjuvanted vaccine induced four-fold neutralising seroconversion rates in 85% of subjects against A/turkey/Turkey/1/2005 (subclade 2.2) and 75% of subjects against A/Anhui/1/2005 (subclade 2.3) recombinant strains. There was no response induced against these strains in the non-adjuvanted group. At 6 months following vaccination, 70% and 60% of subjects retained neutralising antibodies against the recombinant subclade 2.2 and 2.3 strains, respectively and 40% of subjects retained antibodies against the recombinant subclade 2.1 A/Indonesia/5/2005 strain.In addition to antigen dose-sparing, adjuvantation of inactivated split H5N1 vaccine promotes broad and persistent cross-clade immunity which is a pre-requisite for a pre-pandemic vaccine.ClinicalTrials.gov NCT00309634

A 'small-world-like' model for comparing interventions aimed at preventing and controlling influenza pandemics

BACKGROUND: With an influenza pandemic seemingly imminent, we constructed a model simulating the spread of influenza within the community, in order to test the impact of various interventions. METHODS: The model includes an individual level, in which the risk of influenza virus infection and the dynamics of viral shedding are simulated according to age, treatment, and vaccination status; and a community level, in which meetings between individuals are simulated on randomly generated graphs. We used data on real pandemics to calibrate some parameters of the model. The reference scenario assumes no vaccination, no use of antiviral drugs, and no preexisting herd immunity. We explored the impact of interventions such as vaccination, treatment/prophylaxis with neuraminidase inhibitors, quarantine, and closure of schools or workplaces. RESULTS: In the reference scenario, 57% of realizations lead to an explosive outbreak, lasting a mean of 82 days (standard deviation (SD) 12 days) and affecting 46.8% of the population on average. Interventions aimed at reducing the number of meetings, combined with measures reducing individual transmissibility, would be partly effective: coverage of 70% of affected households, with treatment of the index patient, prophylaxis of household contacts, and confinement to home of all household members, would reduce the probability of an outbreak by 52%, and the remaining outbreaks would be limited to 17% of the population (range 0.8%–25%). Reactive vaccination of 70% of the susceptible population would significantly reduce the frequency, size, and mean duration of outbreaks, but the benefit would depend markedly on the interval between identification of the first case and the beginning of mass vaccination. The epidemic would affect 4% of the population if vaccination started immediately, 17% if there was a 14-day delay, and 36% if there was a 28-day delay. Closing schools when the number of infections in the community exceeded 50 would be very effective, limiting the size of outbreaks to 10% of the population (range 0.9%–22%). CONCLUSION: This flexible tool can help to determine the interventions most likely to contain an influenza pandemic. These results support the stockpiling of antiviral drugs and accelerated vaccine development

Design programmes to maximise participant engagement: a predictive study of programme and participant characteristics associated with engagement in paediatric weight management.

BACKGROUND: Approximately 50% of paediatric weight management (WM) programme attendees do not complete their respective programmes. High attrition rates compromise both programme effectiveness and cost-efficiency. Past research has examined pre-intervention participant characteristics associated with programme (non-)completion, however study samples are often small and not representative of multiple demographics. Moreover, the association between programme characteristics and participant engagement is not well known. This study examined participant and programme characteristics associated with engagement in a large, government funded, paediatric WM programme. Engagement was defined as the family's level of participation in the WM programme. METHODS: Secondary data analysis of 2948 participants (Age: 10.44 ± 2.80 years, BMI: 25.99 ± 5.79 kg/m(2), Standardised BMI [BMI SDS]: 2.48 ± 0.87 units, White Ethnicity: 70.52%) was undertaken. Participants attended a MoreLife programme (nationwide WM provider) between 2009 and 2014. Participants were classified into one of five engagement groups: Initiators, Late Dropouts, Low- or High- Sporadic Attenders, or Completers. Five binary multivariable logistic regression models were performed to identify participant (n = 11) and programmatic (n = 6) characteristics associated with an engagement group. Programme completion was classified as ≥70% attendance. RESULTS: Programme characteristics were stronger predictors of programme engagement than participant characteristics; particularly small group size, winter/autumn delivery periods and earlier programme years (proxy for scalability). Conversely, participant characteristics were weak predictors of programme engagement. Predictors varied between engagement groups (e.g. Completers, Initiators, Sporadic Attenders). 47.1% of participants completed the MoreLife programme (mean attendance: 59.4 ± 26.7%, mean BMI SDS change: -0.15 ± 0.22 units), and 21% of those who signed onto the programme did not attend a session. CONCLUSIONS: As WM services scale up, the efficacy and fidelity of programmes may be reduced due to increased demand and lower financial resource. Further, limiting WM programme groups to no more than 20 participants could result in greater engagement. Baseline participant characteristics are poor and inconsistent predictors of programme engagement. Thus, future research should evaluate participant motives, expectations, and barriers to attending a WM programme to enhance our understanding of participant WM engagement. Finally, we suggest that session-by-session attendance is recorded as a minimum requirement to improve reporting transparency and enhance external validity of study findings