Efficacy of computational predictions of the functional effect of idiosyncratic pharmacogenetic variants

BACKGROUND: Pharmacogenetic variation is important to drug responses through diverse and complex mechanisms. Predictions of the functional impact of missense pharmacogenetic variants primarily rely on the degree of sequence conservation between species as a primary discriminator. However, idiosyncratic or off-target drug-variant interactions sometimes involve effects that are peripheral or accessory to the central systems in which a gene functions. Given the importance of sequence conservation to functional prediction tools—these idiosyncratic pharmacogenetic variants may violate the assumptions of predictive software commonly used to infer their effect. METHODS: Here we exhaustively assess the effectiveness of eleven missense mutation functional inference tools on all known pharmacogenetic missense variants contained in the Pharmacogenomics Knowledgebase (PharmGKB) repository. We categorize PharmGKB entries into sub-classes to catalog likely off-target interactions, such that we may compare predictions across different variant annotations. RESULTS: As previously demonstrated, functional inference tools perform variably across the complete set of PharmGKB variants, with large numbers of variants incorrectly classified as ‘benign’. However, we find substantial differences amongst PharmGKB variant sub-classes, particularly in variants known to cause off-target, type B adverse drug reactions, that are largely unrelated to the main pharmacological action of the drug. Specifically, variants associated with off-target effects (hence referred to as off-target variants) were most often incorrectly classified as ‘benign’. These results highlight the importance of understanding the underlying mechanism of pharmacogenetic variants and how variants associated with off-target effects will ultimately require new predictive algorithms. CONCLUSION: In this work we demonstrate that functional inference tools perform poorly on pharmacogenetic variants, particularly on subsets enriched for variants causing off-target, type B adverse drug reactions. We describe how to identify variants associated with off-target effects within PharmGKB in order to generate a training set of variants that is needed to develop new algorithms specifically for this class of variant. Development of such tools will lead to more accurate functional predictions and pave the way for the increased wide-spread adoption of pharmacogenetics in clinical practice

An imaging neutron/gamma-ray spectrometer

We present the test results of a neutron/gamma-ray imaging spectrometer for the identification and location of radioactive and special nuclear materials. Radioactive materials that could be fashioned into a radiation dispersal device typically emit gamma rays, while fissile materials such as uranium and plutonium emit both neutrons and gamma rays via spontaneous or induced fission. The simultaneous detection of neutrons and gamma rays is a clear indication of the presence of fissile material. The instrument works as a double-scatter telescope, requiring a neutron or gamma ray to undergo an interaction in two detectors to be considered a valid event. While this requirement reduces the detector efficiency, it yields information about the direction and energy of the incident particle, which is then used to reconstruct an image of the emitting source. Because of this imaging capability background events can be rejected, decreasing the number of events required for high confidence detection and thereby greatly improving its sensitivity. The instrument is optimized for the detection of neutrons with energies from 1-20 MeV and gamma rays from 0.4 to 10 MeV. Images and energy spectra for neutron and gamma rays are reported for several sources including depleted uranium and plutonium. In addition, the effect of neutron source shielding is investigated

Non-antibiotic selection systems for soybean somatic embryos: the lysine analog aminoethyl-cysteine as a selection agent

<p>Abstract</p> <p>Background</p> <p>In soybean somatic embryo transformation, the standard selection agent currently used is hygromycin. It may be preferable to avoid use of antibiotic resistance genes in foods. The objective of these experiments was to develop a selection system for producing transgenic soybean somatic embryos without the use of antibiotics such as hygromycin.</p> <p>Results</p> <p>When tested against different alternate selection agents our studies show that 0.16 μg/mL glufosinate, 40 mg/L isopropylamine-glyphosate, 0.5 mg/mL (S-(2 aminoethyl)-L-cysteine) (AEC) and the acetolactate synthase (ALS) inhibitors Exceed^®and Synchrony^®both at 150 μg/mL inhibited soybean somatic embryo growth. Even at the concentration of 2 mg/mL, lysine+threonine (LT) were poor selection agents. The use of AEC may be preferable since it is a natural compound. Unlike the plant enzyme, dihydrodipicolinate synthase (DHPS) from <it>E. coli </it>is not feed-back inhibited by physiological concentrations of lysine. The <it>dapA </it>gene which codes for <it>E. coli </it>DHPS was expressed in soybean somatic embryos under the control of the CaMV 35S promoter. Following introduction of the construct into embryogenic tissue of soybean, transgenic events were recovered by incubating the tissue in liquid medium containing AEC at a concentration of 5 mM. Only transgenic soybeans were able to grow at this concentration of AEC; no escapes were observed.</p> <p>Conclusion</p> <p>Genetically engineered soybeans expressing a lysine insensitive DHPS gene can be selected with the non-antibiotic selection agent AEC. We also report here the inhibitory effects of glufosinate, (isopropylamine-glyphosate) (Roundup^®), AEC and the ALS inhibitors Exceed^®and Synchrony^®against different tissues of soybean</p

Traversable wormholes: Some simple examples

Building on the work of Morris, Thorne, and Yurtsever, some particularly simple examples of traversable wormholes are exhibited. These examples are notable both because the analysis is not limited to spherically symmetric cases, and because it is possible to in some sense minimize the use of exotic matter. In particular, it is possible for a traveller to traverse such a wormhole without passing through a region of exotic matter. As in previous analyses, the weak energy condition is violated in these traversable wormholes.Comment: Pre-arXiv article from 1989; 7 pages, no figures. (Uploaded to arXiv to help researchers with limited library facilities.

A method for continuous239Pu determinations in Arctic and Antarctic ice cores

Atmospheric nuclear weapons testing (NWT) resulted in the injection of plutonium (Pu) into the atmosphere and subsequent global deposition. We present a new method for continuous semi-quantitative measurement of 239Pu in ice cores, which was used to develop annual records of fallout from NWT in ten ice cores from Greenland and Antarctica. The 239Pu was measured directly using an Inductively Coupled Plasma – Sector Field Mass Spectrometer, thereby reducing analysis time and increasing depth-resolution with respect to previous methods. To validate this method, we compared our one year averaged results to published 239Pu records and other records of NWT. The 239Pu profiles from four Arctic ice cores reflected global trends in NWT and were in agreement with discrete Pu profiles from lower latitude ice cores. The 239Pu measurements in the Antarctic ice cores tracked low latitude NWT, consistent with previously published discrete records from Antarctica. Advantages of the continuous 239Pu measurement method are (1) reduced sample preparation and analysis time; (2) no requirement for additional ice samples for NWT fallout determinations; (3) measurements are exactly co-registered with all other chemical, elemental, isotopic, and gas measurements from the continuous analytical system; and (4) the long half-life means the 239Pu record is stable through time

A self-consistent hybrid Comptonization model for broad-band spectra of accreting supermassive black holes

The nature of the broad-band spectra of supermassive accreting black holes in active galactic nuclei (AGNs) is still unknown. The hard X-ray spectra of Seyferts as well as of Galactic stellar-mass black holes (GBHs) are well represented by thermal Comptonization, but the origin of the seed photons is less certain. The MeV tails observed in GBHs provide evidence in favour of non-thermal electron tails and it is possible that such electrons are also present in the X-ray emitting regions of AGNs. Using simulations with the kinetic code that self-consistently models electron and photon distributions, we find that the power-law-like X-ray spectra in AGNs can be explained in terms of the synchrotron self-Compton radiation of hybrid thermal/non-thermal electrons, similarly to the hard/low state of GBHs. Under a very broad range of parameters the model predicts a rather narrow distribution of photon spectral slopes consistent with that observed from LINERs and Seyferts at luminosities less than 3 per cent of the Eddington luminosity. The entire infrared to X-ray spectrum of these objects can be described in terms of our model, suggesting a tight correlation between the two energy bands. We show that the recently found correlation between slope and the Eddington ratio at higher luminosities can be described by the increasing fraction of disc photons in the emitting region, which may be associated with the decreasing inner radius of the optically thick accretion disc. The increasing flux of soft photons is also responsible for the transformation of the electron distribution from nearly thermal to almost completely non-thermal. The softer X-ray spectra observed in narrow-line Seyfert galaxies may correspond to non-thermal Comptonization of the disc photons, predicting that no cutoff should be observed up to MeV energies in these sources, similarly to the soft-state GBHs.Comment: MNRAS publishe

Sympatric seals, satellite tracking and protected areas : habitat-based distribution estimates for conservation and management

Analysis was funded by the UK Government Department for Business, Energy and Industrial Strategy (BEIS; OESEA-16-76/OESEA-17-78) with support from the Natural Environment Research Council (NERC; INSITE Phase II NE/T010614/1 EcoSTAR), EU INTERREG (MarPAMM), and the Scottish Government (MMSS/002/15). DJFR’s contribution was funded by NERC National Capability Funding (NE/R015007/1). WJG was supported by INSITE Phase I (MAPS). Telemetry tags and their deployment were funded in the UK by BEIS (and previous incarnations), NERC, Marine Scotland, Scottish Government, NatureScot, SMRU, SMRU Instrumentation Group, Marine Current Turbines, Ørsted, the Met Office, the Zoological Society of London (ZSL), the Crown Estate, Highlands & Islands Enterprise, Moray Firth Renewables Limited (MORL), Beatrice Offshore Windfarm Limited (BOWL), SITA Trust, BBC Wildlife Fund and the Hampshire & Isle of Wight Wildlife Trust. Tags and their deployment in Ireland were funded by Inland Fisheries Ireland, the Department of Communications, Marine and Natural Resources, the Higher Education Authority of Ireland, the National Geographic Society, the Department of Agriculture, Food and the Marine, and the National Parks and Wildlife Service. UK aerial surveys conducted by SMRU were funded by NERC (NE/R015007/1), NatureScot, the Department for Agriculture, Environment and Rural Affairs (Northern Ireland), Marine Current Turbines, Marine Scotland, Natural England, and Scottish Power. Aerial surveys in Ireland were funded by the Department for Tourism, Culture, Arts, Gaeltacht, Sport and Media.Marine predator populations are crucial to the structure and functioning of ecosystems. Like many predator taxa, pinnipeds face an increasingly complex array of natural and anthropogenic threats. Understanding the relationship between at-sea processes and trends in abundance at land-based monitoring sites requires robust estimates of at-sea distribution, often on multi-region scales. Such an understanding is critical for effective conservation management, but estimates are often limited in spatial extent by spatial coverage of animal-borne tracking data. Grey (Halichoerus grypus) and harbour seals (Phoca vitulina) are sympatric predators in North Atlantic shelf seas. The United Kingdom (UK) and Ireland represents an important population centre for both species, and Special Areas of Conservation (SACs) are designated for their monitoring and protection. Here we use an extensive high-resolution GPS tracking dataset, unprecedented in both size (114 grey and 239 harbour seals) and spatial coverage, to model habitat preference and generate at-sea distribution estimates for the entire UK and Ireland populations of both species. We found regional differences in environmental drivers of distribution for both species which likely relate to regional variation in diet and population trends. Moreover, we provide SAC-specific estimates of at-sea distribution for use in marine spatial planning, demonstrating that hotspots of at-sea density in UK and Ireland-wide maps cannot always be apportioned to the nearest SAC. We show that for grey seals, colonial capital breeders, there is a mismatch between SACs (where impacts are likely to be detected) and areas where impacts are most likely to occur (at sea). We highlight an urgent need for further research to elucidate the links between at-sea distribution during the foraging season and population trends observed in SACs. More generally, we highlight that the potential for such a disconnect needs to be considered when designating and managing protected sites, particularly for species that aggregate to breed and exhibit partial migration (e.g. grey seals), or spatial variation in migration strategies. We demonstrate the use of strategic tracking efforts to predict distribution across multiple regions, but caution that such efforts should be mindful of the potential for differences in species-environment relationships despite similar accessible habitats.Publisher PDFPeer reviewe

D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.2018-05-0

Broad-band spectra of Cyg X-1 and correlations between spectral characteristics

We present the results of spectral analysis of 42 simultaneous broad-band Ginga--OSSE and RXTE--OSSE observations of Cyg X-1 carried out in 1991 and 1996--1999. The hardest spectra in our sample in the energy range from 3 to \~1000 keV can be well described by thermal Comptonization model with reflection from the cold disc, while the rest of the spectra are more complex and require an additional component below 10 keV. We consider a number of physically realistic models to describe the shape of the E<10 keV excess. The additional soft component can result from thermal Comptonization by electrons with a low Compton parameter, or can be a part of a nonthermal, power-law like emission extending above 1 MeV. We study correlations between parameters obtained from the spectral fits with different models. We confirm a general correlation between the photon index $\Gamma$ and the amplitude of reflection R. We find that simple phenomenological models (like power-law plus Compton reflection) applied to the narrow band (3--20 keV) data overestimated the values of R and $\Gamma$, although the simple models did rank correctly the spectra according to R and $\Gamma$. The dynamic corona model provides a satisfactory description of the observed correlation, while the hot inner disc models have problems in reproducing it quantitatively. We do not find significant correlation between the electron temperature and other spectral parameters, while the optical depth of the hot medium seems to decrease when the spectrum becomes softer. It is also shown that spectral parameters are well correlated with the timing characteristics of the source.Comment: 17 pages, 11 figures, accepted to MNRAS. Changes to v2: added N_H notes, improved discussion on timing, new calibration use