Analytical characterization of bioactive N-benzyl-substituted phenethylamines and 5-methoxytryptamines

RationaleSubstances based on the N-(2-methoxybenzyl)phenethylamine template ('NBOMe' derivatives) play an important role in medicinal research but some of these derivatives have also appeared as 'research chemicals' for recreational use which has attracted attention worldwide. A major challenge associated with newly emerging substances includes the lack of analytical data and the ability to correctly identify positional isomers.Methods Six N-benzylphenethylamines based on the 2,5-dimethoxy-4-iodophenethylamine structure ('25I') and twelve substituted N-benzyl-5-methoxytryptamines ('5MT') have been prepared and extensively characterized. Techniques used for characterization were gas chromatography/ion trap mass spectrometry in electron and chemical ionization mode, liquid chromatography/diode array detection (DAD), infrared spectroscopy, electrospray high mass accuracy quadrupole time-of-flight tandem mass spectrometry, and triple quadrupole tandem mass spectrometry.ResultsThe characterization of 18 'NBOMe' compounds provided a comprehensive collection of chromatographic and spectral data. Four groups of three positional isomers, i.e. 25I-NB2OMe, 25I-NB3OMe, 25I-NB4OMe, 25I-NB2B, 25I-NB3B, 25I-NB4B and their 5-methoxytryptamine counterparts, were included and assessed for ability to obtain differentiation. Six meta-substituted N-benzyl derivatives of 5-methoxytryptamine (CF3, F, CH3, Cl, I, SCH3) were also studied.Conclusions The implementation of mass spectral techniques was helpful for the differentiation between isomers, for example, when considering the difference in a number of ion ratios. This was considered beneficial in cases where chromatographic separation was only partially achieved under liquid chromatography (LC) conditions. The use of LC/DAD analysis was also found to be valuable for this particular purpose, which confirmed the integrative value of complementary techniques used in areas related to forensic toxicology

The effect of distance on reaction time in aiming movements

Target distance affects movement duration in aiming tasks but its effect on reaction time (RT) is poorly documented. RT is a function of both preparation and initiation. Experiment 1 pre-cued movement (allowing advanced preparation) and found no influence of distance on RT. Thus, target distance does not affect initiation time. Experiment 2 removed pre-cue information and found that preparing a movement of increased distance lengthens RT. Experiment 3 explored movements to targets of cued size at non-cued distances and found size altered peak speed and movement duration but RT was influenced by distance alone. Thus, amplitude influences preparation time (for reasons other than altered duration) but not initiation time. We hypothesise that the RT distance effect might be due to the increased number of possible trajectories associated with further targets: a hypothesis that can be tested in future experiments

Parameter identification problems in the modelling of cell motility

We present a novel parameter identification algorithm for the estimation of parameters in models of cell motility using imaging data of migrating cells. Two alternative formulations of the objective functional that measures the difference between the computed and observed data are proposed and the parameter identification problem is formulated as a minimisation problem of nonlinear least squares type. A Levenberg–Marquardt based optimisation method is applied to the solution of the minimisation problem and the details of the implementation are discussed. A number of numerical experiments are presented which illustrate the robustness of the algorithm to parameter identification in the presence of large deformations and noisy data and parameter identification in three dimensional models of cell motility. An application to experimental data is also presented in which we seek to identify parameters in a model for the monopolar growth of fission yeast cells using experimental imaging data. Our numerical tests allow us to compare the method with the two different formulations of the objective functional and we conclude that the results with both objective functionals seem to agree

Entomological Surveillance of Behavioural Resilience and Resistance in Residual Malaria Vector Populations.

The most potent malaria vectors rely heavily upon human blood so they are vulnerable to attack with insecticide-treated nets (ITNs) and indoor residual spraying (IRS) within houses. Mosquito taxa that can avoid feeding or resting indoors, or by obtaining blood from animals, mediate a growing proportion of the dwindling transmission that persists as ITNs and IRS are scaled up. Increasing frequency of behavioural evasion traits within persisting residual vector systems usually reflect the successful suppression of the most potent and vulnerable vector taxa by IRS or ITNs, rather than their failure. Many of the commonly observed changes in mosquito behavioural patterns following intervention scale-up may well be explained by modified taxonomic composition and expression of phenotypically plastic behavioural preferences, rather than altered innate preferences of individuals or populations. Detailed review of the contemporary evidence base does not yet provide any clear-cut example of true behavioural resistance and is, therefore, consistent with the hypothesis presented. Caution should be exercised before over-interpreting most existing reports of increased frequency of behavioural traits which enable mosquitoes to evade fatal contact with insecticides: this may simply be the result of suppressing the most behaviourally vulnerable of the vector taxa that constituted the original transmission system. Mosquito taxa which have always exhibited such evasive traits may be more accurately described as behaviourally resilient, rather than resistant. Ongoing national or regional entomological monitoring surveys of physiological susceptibility to insecticides should be supplemented with biologically and epidemiologically meaningfully estimates of malaria vector population dynamics and the behavioural phenotypes that determine intervention impact, in order to design, select, evaluate and optimize the implementation of vector control measures

Using a New Odour-Baited Device to Explore Options for Luring and Killing Outdoor-Biting Malaria Vectors: A Report on Design and Field Evaluation of the Mosquito Landing Box.

Mosquitoes that bite people outdoors can sustain malaria transmission even where effective indoor interventions such as bednets or indoor residual spraying are already widely used. Outdoor tools may therefore complement current indoor measures and improve control. We developed and evaluated a prototype mosquito control device, the 'Mosquito Landing Box' (MLB), which is baited with human odours and treated with mosquitocidal agents. The findings are used to explore technical options and challenges relevant to luring and killing outdoor-biting malaria vectors in endemic settings. Field experiments were conducted in Tanzania to assess if wild host-seeking mosquitoes 1) visited the MLBs, 2) stayed long or left shortly after arrival at the device, 3) visited the devices at times when humans were also outdoors, and 4) could be killed by contaminants applied on the devices. Odours suctioned from volunteer-occupied tents were also evaluated as a potential low-cost bait, by comparing baited and unbaited MLBs. There were significantly more Anopheles arabiensis, An. funestus, Culex and Mansonia mosquitoes visiting baited MLB than unbaited controls (P<=0.028). Increasing sampling frequency from every 120 min to 60 and 30 min led to an increase in vector catches of up to 3.6 fold (P<=0.002), indicating that many mosquitoes visited the device but left shortly afterwards. Outdoor host-seeking activity of malaria vectors peaked between 7:30 and 10:30pm, and between 4:30 and 6:00am, matching durations when locals were also outdoors. Maximum mortality of mosquitoes visiting MLBs sprayed or painted with formulations of candidate mosquitocidal agent (pirimiphos-methyl) was 51%. Odours from volunteer occupied tents attracted significantly more mosquitoes to MLBs than controls (P<0.001). While odour-baited devices such as the MLBs clearly have potential against outdoor-biting mosquitoes in communities where LLINs are used, candidate contaminants must be those that are effective at ultra-low doses even after short contact periods, since important vector species such as An. arabiensis make only brief visits to such devices. Natural human odours suctioned from occupied dwellings could constitute affordable sources of attractants to supplement odour baits for the devices. The killing agents used should be environmentally safe, long lasting, and have different modes of action (other than pyrethroids as used on LLINs), to curb the risk of physiological insecticide resistance

Factors underlying age-related changes in discrete aiming

Age has a clear impact on one’s ability to make accurate goal-directed aiming movements. Older adults seem to plan slower and shorter-ranged initial pulses towards the target, and rely more on sensory feedback to ensure endpoint accuracy. Despite the fact that these age-related changes in manual aiming have been observed consistently, the underlying mechanism remains speculative. In an attempt to isolate four commonly suggested underlying factors, young and older adults were instructed to make discrete aiming movements under varying speed and accuracy constraints. Results showed that older adults were physically able to produce fast primary submovements and that they demonstrated similar movement-programming capacities as young adults. On the other hand, considerable evidence was found supporting a decreased visual feedback-processing efficiency and the implementation of a play-it-safe strategy in older age. In conclusion, a combination of the latter two factors seems to underlie the age-related changes in manual aiming behaviour

How functional programming mattered

In 1989 when functional programming was still considered a niche topic, Hughes wrote a visionary paper arguing convincingly ‘why functional programming matters’. More than two decades have passed. Has functional programming really mattered? Our answer is a resounding ‘Yes!’. Functional programming is now at the forefront of a new generation of programming technologies, and enjoying increasing popularity and influence. In this paper, we review the impact of functional programming, focusing on how it has changed the way we may construct programs, the way we may verify programs, and fundamentally the way we may think about programs

Gene conversion in human rearranged immunoglobulin genes

Over the past 20 years, many DNA sequences have been published suggesting that all or part of the V&lt;sub&gt;H&lt;/sub&gt; segment of a rearranged immunoglobulin gene may be replaced in vivo. Two different mechanisms appear to be operating. One of these is very similar to primary V(D)J recombination, involving the RAG proteins acting upon recombination signal sequences, and this has recently been proven to occur. Other sequences, many of which show partial V&lt;sub&gt;H&lt;/sub&gt; replacements with no addition of untemplated nucleotides at the V&lt;sub&gt;H&lt;/sub&gt;–V&lt;sub&gt;H&lt;/sub&gt; joint, have been proposed to occur by an unusual RAG-mediated recombination with the formation of hybrid (coding-to-signal) joints. These appear to occur in cells already undergoing somatic hypermutation in which, some authors are convinced, RAG genes are silenced. We recently proposed that the latter type of V&lt;sub&gt;H&lt;/sub&gt; replacement might occur by homologous recombination initiated by the activity of AID (activation-induced cytidine deaminase), which is essential for somatic hypermutation and gene conversion. The latter has been observed in other species, but not in human Ig genes, so far. In this paper, we present a new analysis of sequences published as examples of the second type of rearrangement. This not only shows that AID recognition motifs occur in recombination regions but also that some sequences show replacement of central sections by a sequence from another gene, similar to gene conversion in the immunoglobulin genes of other species. These observations support the proposal that this type of rearrangement is likely to be AID-mediated rather than RAG-mediated and is consistent with gene conversion

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Levels of State and Trait Anxiety in Patients Referred to Ophthalmology by Primary Care Clinicians: A Cross Sectional Study

Purpose There is a high level of over-referral from primary eye care leading to significant numbers of people without ocular pathology (false positives) being referred to secondary eye care. The present study used a psychometric instrument to determine whether there is a psychological burden on patients due to referral to secondary eye care, and used Rasch analysis to convert the data from an ordinal to an interval scale. Design Cross sectional study. Participants and Controls 322 participants and 80 control participants. Methods State (i.e. current) and trait (i.e. propensity to) anxiety were measured in a group of patients referred to a hospital eye department in the UK and in a control group who have had a sight test but were not referred. Response category analysis plus infit and outfit Rasch statistics and person separation indices were used to determine the usefulness of individual items and the response categories. Principal components analysis was used to determine dimensionality. Main Outcome Measure Levels of state and trait anxiety measured using the State-Trait Anxiety Inventory. Results State anxiety scores were significantly higher in the patients referred to secondary eye care than the controls (p0.1). Rasch analysis highlighted that the questionnaire results needed to be split into “anxiety-absent” and “anxiety-present” items for both state and trait anxiety, but both subscales showed the same profile of results between patients and controls. Conclusions State anxiety was shown to be higher in patients referred to secondary eye care than the controls, and at similar levels to people with moderate to high perceived susceptibility to breast cancer. This suggests that referral from primary to secondary eye care can result in a significant psychological burden on some patients