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Len A.C.L.,University College LondonLondon | Starling S.,University College LondonLondon | Shivkumar M.,University College LondonLondon | Jolly C.,University College LondonLondon
Cell Reports | Year: 2017

HIV-1 spreads between CD4 T cells most efficiently through virus-induced cell-cell contacts. To test whether this process potentiates viral spread by activating signaling pathways, we developed an approach to analyze the phosphoproteome in infected and uninfected mixed-population T cells using differential metabolic labeling and mass spectrometry. We discovered HIV-1-induced activation of signaling networks during viral spread encompassing over 200 cellular proteins. Strikingly, pathways downstream of the T cell receptor were the most significantly activated, despite the absence of canonical antigen-dependent stimulation. The importance of this pathway was demonstrated by the depletion of proteins, and we show that HIV-1 Env-mediated cell-cell contact, the T cell receptor, and the Src kinase Lck were essential for signaling-dependent enhancement of viral dissemination. This study demonstrates that manipulation of signaling at immune cell contacts by HIV-1 is essential for promoting virus replication and defines a paradigm for antigen-independent T cell signaling. © 2017 The Author(s)

Lau W.,University College LondonLondon | Andrew T.,Imperial College London | Maniatis N.,University College LondonLondon
American Journal of Human Genetics | Year: 2017

Interpretation of results from genome-wide association studies for T2D is challenging. Only very few loci have been replicated in African ancestry populations and the identification of the implicated functional genes remain largely undefined. We used genetic maps that capture detailed linkage disequilibrium information in European and African Americans and applied these to large T2D case-control samples in order to estimate locations for putative functional variants in both populations. Replicated T2D locations were tested for evidence of being regulatory hotspots using adipose expression. We validated a sample of our co-location intervals using next generation sequencing and functional annotation, including enhancers, transcription, and chromatin modifications. We identified 111 additional disease-susceptibility locations, 93 of which are cosmopolitan and 18 of which are European specific. We show that many previously known signals are also risk loci in African Americans. The majority of the disease locations appear to confer risk of T2D via the regulation of expression levels for a large number (266) of cis-regulated genes, the majority of which are not the nearest genes to the disease loci. Sequencing three cosmopolitan locations provided candidate functional variants that precisely co-locate with cell-specific chromatin domains and pancreatic islet enhancers. These variants have large effect sizes and are common across populations. Results show that disease-associated loci in different populations, gene expression, and cell-specific regulatory annotation can be effectively integrated by localizing these effects on high-resolution genetic maps. The cis-regulated genes provide insights into the complex molecular pathways involved and can be used as targets for sequencing and functional molecular studies. © 2017

Williamson R.S.,University College London | Williamson R.S.,University College LondonLondon | Williamson R.S.,Massachusetts Eye and Ear Infirmary | Ahrens M.B.,Harvard University | And 4 more authors.
Neuron | Year: 2016

Sensory neurons are customarily characterized by one or more linearly weighted receptive fields describing sensitivity in sensory space and time. We show that in auditory cortical and thalamic neurons, the weight of each receptive field element depends on the pattern of sound falling within a local neighborhood surrounding it in time and frequency. Accounting for this change in effective receptive field with spectrotemporal context improves predictions of both cortical and thalamic responses to stationary complex sounds. Although context dependence varies among neurons and across brain areas, there are strong shared qualitative characteristics. In a spectrotemporally rich soundscape, sound elements modulate neuronal responsiveness more effectively when they coincide with sounds at other frequencies, and less effectively when they are preceded by sounds at similar frequencies. This local-context-driven lability in the representation of complex sounds—a modulation of “input-specific gain” rather than “output gain”—may be a widespread motif in sensory processing. © 2016 The Authors

Auksztulewicz R.,University College LondonLondon | Friston K.,University College LondonLondon
Cortex | Year: 2016

This paper presents a review of theoretical and empirical work on repetition suppression in the context of predictive coding. Predictive coding is a neurobiologically plausible scheme explaining how biological systems might perform perceptual inference and learning. From this perspective, repetition suppression is a manifestation of minimising prediction error through adaptive changes in predictions about the content and precision of sensory inputs. Simulations of artificial neural hierarchies provide a principled way of understanding how repetition suppression – at different time scales – can be explained in terms of inference and learning implemented under predictive coding. This formulation of repetition suppression is supported by results of numerous empirical studies of repetition suppression and its contextual determinants. © 2016 The Authors

Many chemical and biological processes rely on the movement of monovalent cations and an understanding of such processes can therefore only be achieved by characterising the dynamics of the involved ions. It has recently been shown that 15N-ammonium can be used as a proxy for potassium to probe potassium binding in bio-molecules such as DNA quadruplexes and enzymes. Moreover, equations have been derived to describe the time-evolution of 15N-based spin density operator elements of 15NH4 + spin systems. Herein NMR pulse sequences are derived to select specific spin density matrix elements of the 15NH4 + spin system and to measure their longitudinal relaxation in order to characterise the rotational correlation time of the 15NH4 + ion as well as report on chemical exchange events of the 15NH4 + ion. Applications to 15NH4 + in acidic aqueous solutions are used to cross-validate the developed pulse sequence while measurements of spin-relaxation rates of 15NH4 + bound to a 41 kDa domain of the bacterial Hsp70 homologue DnaK are presented to show the general applicability of the derived pulse sequence. The rotational correlation time obtained for 15N-ammonium bound to DnaK is similar to the correlation time that describes the rotation about the threefold axis of a methyl group. The methodology presented here provides, together with the previous theoretical framework, an important step towards characterising the motional properties of cations in macromolecular systems. © 2017 The Author

Deppisch F.F.,University College LondonLondon | Harz J.,University College LondonLondon | Huang W.-C.,University College LondonLondon | Hirsch M.,University of Valencia | Pas H.,TU Dortmund
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2015

Interactions that manifest themselves as lepton number violating processes at low energies in combination with sphaleron transitions typically erase any preexisting baryon asymmetry of the Universe. In this article, we discuss the constraints obtained from an observation of neutrinoless double beta decay in this context. If a new physics mechanism of neutrinoless double beta decay other than the standard light neutrino exchange is observed, typical scenarios of high-scale baryogenesis will be excluded unless the baryon asymmetry is stabilized via some new mechanism. We also sketch how this conclusion can be extended beyond the first lepton generation by incorporating lepton flavor violating processes. © 2015 American Physical Society.

Bocaege E.,French National Center for Scientific Research | Hillson S.,University College LondonLondon
American Journal of Physical Anthropology | Year: 2016

Objectives: The investigation of the record of growth locked in dental enamel provides a unique opportunity to build a comprehensive picture of growth disruption episodes during childhood. This study presents a new methodological basis for the analysis of enamel growth disruptions (enamel hypoplasia) using incremental microstructures of enamel. Methods: A three-dimensional technique based upon use of an Alicona 3D Infinite Focus imaging microscope and software is used to record developmental features in the enamel of human permanent mandibular lateral incisors of one individual from the Neolithic site of Çatalhöyük (Turkey). Using this new technique, perikymata are measured down the longitudinal axis of the crown from the incisal margin to the cervix and perikyma spacing profiles are constructed with this new technique. A mathematical basis for the detection of spacing anomalies, which serve as indicators of enamel hypoplasia is presented based upon these profiles. Results: Three clearly delineated defects were identified visually, then matched and confirmed metrically using the enamel surface and perikyma spacing profiles. Discussion: Human growth has often been used as an indicator of health in past societies because of developmental sensitivity to fluctuations in nutritional status and disease load. Hence, standardization of furrow-form defect identification is of crucial importance for reducing the amount of current subjectivity in the determination of a threshold for the identification of defects among individuals of past populations. The method presented here, which is based on microscopic images of the tooth crown as well as recorded measurements of incremental structures, represents a combined visual-metric approach using LOWESS residuals, and as such provides a substantial advancement to previous methods. It is therefore recommended that additional studies be carried out with this methodology to determine whether this method improves the reliability of enamel defect identification among individuals recovered from bioarchaeological contexts. © 2016 Wiley Periodicals, Inc.

Beard E.,University College LondonLondon | Brown J.,University College LondonLondon | McNeill A.,King's College | Michie S.,University College LondonLondon | West R.,University College LondonLondon
Thorax | Year: 2015

Background: The rise in electronic cigarette use by smokers may be responsible for the decreased use of licensed nicotine products and/or increased overall use of non-tobacco nicotine-containing products. This paper reports findings from the Smoking Toolkit Study (STS) tracking use of electronic cigarettes and licensed nicotine products to address this issue. Methods: Data were obtained from monthly surveys involving 14 502 cigarette smokers in England between March 2011 and November 2014. Smokers were asked about their use of electronic cigarettes and licensed nicotine products. Results: Prevalence of electronic cigarette use increased rapidly from 2.2% (95% CI 1.4% to 3.2%) in quarter 2 of 2011 to 20.8% (95% CI 18.3% to 23.4%) in quarter 3 of 2013, after which there was no change. Prevalence of licensed nicotine product use in smokers remained stable from quarter 2 of 2011 (17.4%, 95% CI 15.3% to 19.8%) to quarter 3 of 2013 (17.9%, 95% CI 15.62% to 20.5%), and thereafter declined steadily to 7.9% (95% CI 6.0% to 10.4%). Prevalence of use of any product was stable to quarter 1 of 2012, after which it increased from 18.5% (95% CI 16.3% to 21.0%) to 33.3% (95% CI 30.4% to 36.3%) in quarter 3 of 2013, and then decreased to 22.7% (95% CI 19.3% to 26.3%). Conclusions: The shapes of trajectories since 2011 suggest that electronic cigarettes are probably not responsible for the decline in use of licensed nicotine products. Electronic cigarettes appear to have increased the total market for use of non-tobacco nicotine-containing products.

Gentsch A.,University College LondonLondon | Panagiotopoulou E.,University College LondonLondon | Fotopoulou A.,University College LondonLondon
Current Biology | Year: 2015

Summary Social touch plays a powerful role in human life, with important physical and mental health benefits in development and adulthood. Touch is central in building the foundations of social interaction, attachment, and cognition [1-5], and early, social touch has unique, beneficial neurophysiological and epigenetic effects [6-9]. The recent discovery of a separate neurophysiological system for affectively laden touch in humans has further kindled scientific interest in the area [10, 11]. Remarkably, however, little is known about what motivates and sustains the human tendency to touch others in a pro-social manner. Given the importance of social touch, we hypothesized that active stroking elicits more sensory pleasure when touching others' skin than when touching one's own skin. In a set of six experiments (total N = 133) we found that healthy participants, mostly tested in pairs to account for any objective differences in skin softness, consistently judged another's skin as feeling softer and smoother than their own skin. We further found that this softness illusion appeared selectively when the touch activated a neurophysiological system for affective touch in the receiver. We conclude that this sensory illusion underlies a novel, bodily mechanism of socio-affective bonding and enhances our motivation to touch others. © 2015 The Authors.

Freyja Olafsdottir H.,University College LondonLondon | Barry C.,University College LondonLondon | Saleem A.B.,University College LondonLondon | Hassabis D.,University College LondonLondon | Spiers H.J.,University College LondonLondon
eLife | Year: 2015

Dominant theories of hippocampal function propose that place cell representations are formed during an animal’s first encounter with a novel environment and are subsequently replayed during off-line states to support consolidation and future behaviour. Here we report that viewing the delivery of food to an unvisited portion of an environment leads to off-line pre-activation of place cells sequences corresponding to that space. Such ‘preplay’ was not observed for an unrewarded but otherwise similar portion of the environment. These results suggest that a hippocampal representation of a visible, yet unexplored environment can be formed if the environment is of motivational relevance to the animal. We hypothesise such goal-biased preplay may support preparation for future experiences in novel environments. © Ólafsdó ttir et al.

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