Systematic review of allelic exchange experiments aimed at identifying mutations that confer drug resistance in Mycobacterium tuberculosis

First published online: September 20, 2013BACKGROUND: Improving our understanding of the relationship between the genotype and the drug resistance phenotype of Mycobacterium tuberculosis will aid the development of more accurate molecular diagnostics for drug-resistant tuberculosis. Studies that use direct genetic manipulation to identify the mutations that cause M. tuberculosis drug resistance are superior to associational studies in elucidating an individual mutation's contribution to the drug resistance phenotype. METHODS: We systematically reviewed the literature for publications reporting allelic exchange experiments in any of the resistance-associated M. tuberculosis genes. We included studies that introduced single point mutations using specialized linkage transduction or site-directed/in vitro mutagenesis and documented a change in the resistance phenotype. RESULTS: We summarize evidence supporting the causal relationship of 54 different mutations in eight genes (katG, inhA, kasA, embB, embC, rpoB, gyrA and gyrB) and one intergenic region (furA-katG) with resistance to isoniazid, the rifamycins, ethambutol and fluoroquinolones. We observed a significant role for the strain genomic background in modulating the resistance phenotype of 21 of these mutations and found examples of where the same drug resistance mutations caused varying levels of resistance to different members of the same drug class. CONCLUSIONS: This systematic review highlights those mutations that have been shown to causally change phenotypic resistance in M. tuberculosis and brings attention to a notable lack of allelic exchange data for several of the genes known to be associated with drug resistance.This work was supported by the Portuguese Foundation for Science and Technology (FCT) (SFRH/BD/33902/2009 to H. N.-G.), the National Institutes of Health/Fogarty International Center (1K01 TW009213 to K.R.J.), departmental funds of the pulmonary division of Massachusetts General Hospital to M. R. F. and the National Institutes of Health/NIAID (U19 A1076217 to M.B.M.)

NMR and NQR Fluctuation Effects in Layered Superconductors

We study the effect of thermal fluctuations of the s-wave order parameter of a quasi two dimensional superconductor on the nuclear spin relaxation rate near the transition temperature Tc. We consider both the effects of the amplitude fluctuations and the Berezinskii-Kosterlitz-Thouless (BKT) phase fluctuations in weakly coupled layered superconductors. In the treatment of the amplitude fluctuations we employ the Gaussian approximation and evaluate the longitudinal relaxation rate 1/T1 for a clean s-wave superconductor, with and without pair breaking effects, using the static pair fluctuation propagator D. The increase in 1/T1 due to pair breaking in D is overcompensated by the decrease arising from the single particle Green's functions. The result is a strong effect on 1/T1 for even a small amount of pair breaking. The phase fluctuations are described in terms of dynamical BKT excitations in the form of pancake vortex-antivortex (VA) pairs. We calculate the effect of the magnetic field fluctuations caused by the translational motion of VA excitations on 1/T1 and on the transverse relaxation rate 1/T2 on both sides of the BKT transitation temperature T(BKT)<Tc. The results for the NQR relaxation rates depend strongly on the diffusion constant that governs the motion of free and bound vortices as well as the annihilation of VA pairs. We discuss the relaxation rates for real multilayer systems where the diffusion constant can be small and thus increase the lifetime of a VA pair, leading to an enhancement of the rates. We also discuss in some detail the experimental feasibility of observing the effects of amplitude fluctuations in layered s-wave superconductors such as the dichalcogenides and the effects of phase fluctuations in s- or d-wave superconductors such as the layered cuprates.Comment: 38 pages, 12 figure

BIRD - A Microsatellite for Hot Spot Detection

The BIRD mission of the German Aerospace Centre shall demonstrate the scientific and technological value and the technical and programmatic feasibility of a remote sensing small satellite mission under low budget constraints. The payload -a new generation of cooled infrared detectors- is adapted to the mission objective - the investigation of hot spots caused by forest fires or volcanic activities completed by the diagnosis of vegetation conditions and changes. BIRD -the Bispectral Infra-Red Detector- is a three-axis stabilised spacecraft within a volume of 0.21 m3 and a mass of 88 kg. In flight configuration with one fixed and two deployed solar panels, providing 40 W average and 200 W peak power, the spacecraft dimensions are 620x 1600x 620 mm3 • Although compatible to several launchers due to the highly compact design, the launch is scheduled for mid 2000 as a piggy-back payload. To fit in this time scale a modular design was chosen for parallel development, manufacturing and integration of all functional segments. The article gives an overview of the mission objectives and some of the main design aspects as well as shows the status of work of the space segment

Growth and yield of mixed versus pure stands of Scots pine (Pinus sylvestris L. ) and European beech (Fagus sylvatica L.) analysed along a productivity gradient through Europe

Mixing of complementary tree species may increase stand productivity, mitigate the effects of drought and other risks, and pave the way to forest production systems which may be more resource-use efficient and stable in the face of climate change. However, systematic empirical studies on mixing effects are still missing for many commercially important and widespread species combinations. Here we studied the growth of Scots pine (Pinus sylvestris L.) and European beech (Fagus sylvatica L.) in mixed versus pure stands on 32 triplets located along a productivity gradient through Europe, reaching from Sweden to Bulgaria and from Spain to the Ukraine. Stand inventory and taking increment cores on the mainly 60-80 year-old trees and 0.02-1.55 ha sized, fully stocked plots provided insight how species mixing modifies the structure, dynamics and productivity compared with neighbouring pure stands. In mixture standing volume (+12 %), stand density (+20 %), basal area growth (+12 %), and stand volume growth (+8 %) were higher than the weighted mean of the neighbouring pure stands. Scots pine and European beech contributed rather equally to the overyielding and overdensity. In mixed stands mean diameter (+20 %) and height (+6 %) of Scots pine was ahead, while both diameter and height growth of European beech were behind (−8 %). The overyielding and overdensity were independent of the site index, the stand growth and yield, and climatic variables despite the wide variation in precipitation (520-1175 mm year−1), mean annual temperature (6-10.5 °C), and the drought index by de Martonne (28-61 mm °C−1) on the sites. Therefore, this species combination is potentially useful for increasing productivity across a wide range of site and climatic conditions. Given the significant overyielding of stand basal area growth but the absence of any relationship with site index and climatic variables, we hypothesize that the overyielding and overdensity results from several different types of interactions (light-, water-, and nutrient-related) that are all important in different circumstances. We discuss the relevance of the results for ecological theory and for the ongoing silvicultural transition from pure to mixed stands and their adaptation to climate change.The networking in this study has been sup-ported by COST Action FP1206 EuMIXFOR. All contributors thanktheir national funding institutions to establish, measure, and analysedata from the triplets. The first author also thanks the BayerischenStaatsforsten (BaySF) for supporting the establishment of the plots,the Bavarian State Ministry for Nutrition, Agriculture, and Forestryfor permanent support of the project W 07 ‘‘Long-term experimentalplots for forest growth and yield research’’ (# 7831-22209-2013) andthe German Science Foundation for providing the funds for the pro-jects PR 292/12-1 ‘‘Tree and stand-level growth reactions on droughtin mixed versus pure forests of Norway spruce and European beech’’.Thanks are also due to Ulrich Kern for the graphical artwork, and totwo anonymous reviewers for their constructive criticism

The neural correlates of reinforcement sensitivity theory: a systematic review of the (f)MRI literature

Objectives: Reinforcement Sensitivity Theory (RST) is a theory of motivation, emotion and learning, that has been translated into an account of personality. RST proposes neural structures that form the basis of systems responsible for reward (BAS), punishment (FFFS) and conflict processing (BIS). This systematic review collated studies examining psychometric measures of RST alongside structural and function MRI data to (i) examine how psychometric RST is associated with the proposed neural topologies of RST, (ii) identify any common associations between psychometric RST and other brain regions, and (iii) provide recommendations for advancing the current literature base. Methods: Initial search terms identified 10952 papers. After processing, 39 papers that investigated the association between RST scales and neural functioning in healthy adult samples were included in this review. Results: There was general support for associations between the BAS and the structure/activity of the pre-frontal cortex and ventral striatum with some additional findings for the ventral pallidum and ventral tegmental area. There was also some support for associations between BIS/FFFS and structure/activity of frontal regions, cingulate cortices and the amygdala. Conclusions: Overall, psychometric correlates of RST were associated with activity in proposed neural circuitry, with the most consistent support being found for the BAS; however, psychometric and experimental limitations still hamper the differentiation of the BIS and FFFS systems in their activation of deeper brain networks. Future studies need to include revised RST scales that separate the BIS and FFFS and implement more rigorous tasks that allow for the examination of each system both independently and codependently

Effects of system- and media-driven immersive capabilities on presence and affective experience

Virtual reality (VR) is receiving widespread attention as a delivery tool for exposure therapies. The advantage offered by VR over traditional technology is a greater sense of presence and immersion, which magnifies user effects and enhances the effectiveness of exposure-based interventions. The current study systematically examined the basic factors involved in generating presence in VR as compared to standard technology, namely (1) system-driven factors that are exclusive to VR devices while controlling general factors such as field of view and image quality; (2) media-driven factors of the virtual environment eliciting motivational salience through different levels of arousal and valence (relaxing, exciting and fear evoking stimuli); and (3) the effects of presence on magnifying affective response. Participants (N = 14) watched 3 different emotionally salient videos (1 × fear evoking, 1 × relaxing and 1 × exciting) in both viewing modes (VR and Projector). Subjective scores of user experience were collected as well as objective EEG markers of presence (frontal alpha power, theta/beta ratio). Subjective and objective presence was significantly greater in the VR condition. There was no difference in subjective or objective presence for stimulus type, suggesting presence is not moderated by arousal, but may be reliant on activation of motivational systems. Finally, presence did not magnify feelings of relaxation or excitement, but did significantly magnify users’ experience of fear when viewing fear evoking stimuli. This is in line with previous literature showing strong links between presence and generation of fear, which is vital in the efficacy of exposure therapies

The mental health benefits of community helping during crisis: coordinated helping, community identification and sense of unity during the COVID-19 pandemic

Communities are vital sources of support during crisis, providing collective contexts for shared identity and solidarity that predict supportive, prosocial responses. The COVID-19 pandemic has presented a global health crisis capable of exerting a heavy toll on the mental health of community members while inducing unwelcome levels of social disconnection. Simultaneously, lockdown restrictions have forced vulnerable community members to depend upon the support of fellow residents. Fortunately, voluntary helping can be beneficial to the well-being of the helper as well as the recipient, offering beneficial collective solutions. Using insights from social identity approaches to volunteering and disaster responses, this study explored whether the opportunity to engage in helping fellow community members may be both unifying and beneficial for those engaging in coordinated community helping. Survey data collected in the UK during June 2020 showed that coordinated community helping predicted the psychological bonding of community members by building a sense of community identification and unity during the pandemic, which predicted increased well-being and reduced depression and anxiety. Implications for the promotion and support of voluntary helping initiatives in the context of longer-term responses to the COVID-19 pandemic are provided. Please refer to the Supplementary Material section to find this article’s Community and Social Impact Statement

Enhancing biofeedback-driven self-guided virtual reality exposure therapy through arousal detection from multimodal data using machine learning

Virtual reality exposure therapy (VRET) is a novel intervention technique that allows individuals to experience anxiety-evoking stimuli in a safe environment, recognise specific triggers and gradually increase their exposure to perceived threats. Public-speaking anxiety (PSA) is a prevalent form of social anxiety, characterised by stressful arousal and anxiety generated when presenting to an audience. In self-guided VRET, participants can gradually increase their tolerance to exposure and reduce anxiety-induced arousal and PSA over time. However, creating such a VR environment and determining physiological indices of anxiety-induced arousal or distress is an open challenge. Environment modelling, character creation and animation, psychological state determination and the use of machine learning (ML) models for anxiety or stress detection are equally important, and multi-disciplinary expertise is required. In this work, we have explored a series of ML models with publicly available data sets (using electroencephalogram and heart rate variability) to predict arousal states. If we can detect anxiety-induced arousal, we can trigger calming activities to allow individuals to cope with and overcome distress. Here, we discuss the means of effective selection of ML models and parameters in arousal detection. We propose a pipeline to overcome the model selection problem with different parameter settings in the context of virtual reality exposure therapy. This pipeline can be extended to other domains of interest where arousal detection is crucial. Finally, we have implemented a biofeedback framework for VRET where we successfully provided feedback as a form of heart rate and brain laterality index from our acquired multimodal data for psychological intervention to overcome anxiety

Beneficial effects on subjective mood and brain function of biophilic quality in university environments shown in virtual reality

Beneficial effects on subjective mood and brain function of biophilic quality in university environments shown in virtual reality. ABSTRACT Biophilic designs incorporate nature-based features into built environments. Raised theta activity is reported in biophilic environments. Virtual Reality allows greater control of experimental parameters than in-field studies. Participants provided subjective reports and underwent an electroencephalography assessment as they viewed interior spaces that varied (0 no features to 3 most features) in biophilic quality. Mood improved with biophilic quality. Theta power increased with biophilic quality for levels 1-3. Paradoxically, however, theta was also high in the condition devoid of biophilic features (Level 0). Findings suggest that the benefit of biophilic environments on mood is paralleled by alterations in theta

Species mixing reduces drought susceptibility of Scots pine (Pinus sylvestris L.) and oak (Quercus robur L., Quercus petraea (Matt.) Liebl.) – Site water supply and fertility modify the mixing effect

Tree species mixing has been widely promoted as a promising silvicultural tool for reducing drought stress. However, so far only a limited number of species combinations have been studied in detail, revealing inconsistent results. In this study, we analysed the effect of mixing Scots pine and oak (pedunculate oak and sessile oak) trees on their drought response along a comprehensive ecological gradient across Europe. The objective was to improve our knowledge of general drought response patterns of two fundamental European tree species in mixed versus monospecific stands. We focused on three null hypotheses: () tree drought response does not differ between Scots pine and oak, () tree drought response of Scots pine and oak is not affected by stand composition (mixture versus monoculture) and () tree drought response of Scots pine and oak in mixtures and monocultures is not modified by tree size or site conditions. To test the hypotheses, we analysed increment cores of Scots pine and oak, sampled in mixed and monospecific stands, covering a wide range of site conditions. We investigated resistance (the ability to maintain growth levels during drought), recovery (the ability to restore a level of growth after drought) and resilience (the capacity to recover to pre-drought growth levels), involving site-specific drought events that occurred between 1976 and 2015. In monocultures, oak showed a higher resistance and resilience than Scots pine, while recovery was lower. Scots pine in mixed stands exhibited a higher resistance, but also a lower recovery compared with Scots pine in monocultures. Mixing increased the resistance and resilience of oak. Ecological factors such as tree size, site water supply and site fertility were found to have significant effects on the drought response. In the case of Scots pine, resistance was increased by tree size, while recovery was lowered. Resistance of oak increased with site water supply. The observed mixing effect on the tree drought response of Scots pine and oak was in some cases modified by the site conditions studied. Positive mixing effects in terms of resistance and resilience of oak increased with site water supply, while the opposite was found regarding recovery. In contrast, site fertility lessened the positive mixing effect on the resistance of Scots pine. We hypothesise that the observed positive mixing effects under drought mainly result from water- and/or light-related species interactions that improve resource availability and uptake according to temporal and spatial variations in environmental conditions.This work was supported by the European Union as part of the ERA-Net SUMFOREST project REFORM – Mixed species forest management. Lowering risk, increasing resilience (2816ERA02S, PCIN2017-026) and the Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 778322. All contributors thank their national funding institutions for supporting the establishment, mensuration and analysis of the studied triplets. The first author wants to thank the German Federal Ministry of Food and Agriculture (BMEL) for financial support through the Federal Office for Agriculture and Food (BLE) (grant number 2816ERA02S), as well as the Bayerische Staatsforsten (BaySF) and Landesbetrieb Forst Brandenburg for providing suitable research sites. Research on the Lithuanian triplets (LT 1, LT 2) was made possible by the national funding institution Research Council of Lithuania (LMTLT) (agreement number S-SUMFOREST-17-1). The French site FR 1 belongs to the OPTMix experimental site (https://optmix.irstea.fr), which is supported annually by Ecofor, Allenvi, and the French national research infrastructure ANAEE-F. A special thank is due to Peter Biber for supporting the statistical analysis