ZipHiC: a novel Bayesian framework to identify enriched interactions and experimental biases in Hi-C data

Motivation Several computational and statistical methods have been developed to analyse data generated through the 3C-based methods, especially the Hi-C. Most of the existing methods do not account for dependency in Hi-C data. Results Here, we present ZipHiC, a novel statistical method to explore Hi-C data focusing on the detection of enriched contacts. ZipHiC implements a Bayesian method based on a hidden Markov random field (HMRF) model and the Approximate Bayesian Computation (ABC) to detect interactions in two-dimensional space based on a Hi-C contact frequency matrix. ZipHiC uses data on the sources of biases related to the contact frequency matrix, allows borrowing information from neighbours using the Potts model and improves computation speed by using the ABC model. In addition to outperforming existing tools on both simulated and real data, our model also provides insights into different sources of biases that affects Hi-C data. We show that some datasets display higher biases from DNA accessibility or Transposable Elements content. Furthermore, our analysis in D. melanogaster showed that approximately half of the detected significant interactions connect promoters with other parts of the genome indicating a functional biological role. Finally, we found that the micro-C datasets display higher biases from DNA accessibility compared to a similar Hi-C experiment, but this can be corrected by ZipHiC

Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM) causes an estimated 180,000 deaths annually, predominantly in sub-Saharan Africa, where most patients receive fluconazole (FLC) monotherapy. While relapse after FLC monotherapy with resistant strains is frequently observed, the mechanisms and impact of emergence of FLC resistance in human CM are poorly understood. Heteroresistance (HetR) - a resistant subpopulation within a susceptible strain - is a recently described phenomenon in Cryptococcus neoformans (Cn) and Cryptococcus gattii (Cg), the significance of which has not previously been studied in humans. METHODS: A cohort of 20 patients with HIV-associated CM in Tanzania was prospectively observed during therapy with either FLC monotherapy or in combination with flucytosine (5FC). Total and resistant subpopulations of Cryptococcus spp. were quantified directly from patient cerebrospinal fluid (CSF). Stored isolates underwent whole genome sequencing and phenotypic characterization. RESULTS: Heteroresistance was detectable in Cryptococcus spp. in the CSF of all patients at baseline (i.e., prior to initiation of therapy). During FLC monotherapy, the proportion of resistant colonies in the CSF increased during the first 2 weeks of treatment. In contrast, no resistant subpopulation was detectable in CSF by day 14 in those receiving a combination of FLC and 5FC. Genomic analysis revealed high rates of aneuploidy in heteroresistant colonies as well as in relapse isolates, with chromosome 1 (Chr1) disomy predominating. This is apparently due to the presence on Chr1 of ERG11, which is the FLC drug target, and AFR1, which encodes a drug efflux pump. In vitro efflux levels positively correlated with the level of heteroresistance. CONCLUSION: Our findings demonstrate for what we believe is the first time the presence and emergence of aneuploidy-driven FLC heteroresistance in human CM, association of efflux levels with heteroresistance, and the successful suppression of heteroresistance with 5FC/FLC combination therapy. FUNDING: This work was supported by the Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z and the Daniel Turnberg Travel Fellowship

Visual attention, EEG alpha power and T7-Fz connectivity are implicated in prosthetic hand control and can be optimized through gaze training

Background Prosthetic hands impose a high cognitive burden on the user that often results in fatigue, frustration and prosthesis rejection. However, efforts to directly measure this burden are sparse and little is known about the mechanisms behind it. There is also a lack of evidence-based training interventions designed to improve prosthesis hand control and reduce the mental effort required to use them. In two experiments, we provide the first direct evaluation of this cognitive burden using measurements of EEG and eye-tracking (Experiment 1), and then explore how a novel visuomotor intervention (gaze training; GT) might alleviate it (Experiment 2). Methods In Experiment 1, able-bodied participants (n = 20) lifted and moved a jar, first using their anatomical hand and then using a myoelectric prosthetic hand simulator. In experiment 2, a GT group (n = 12) and a movement training (MT) group (n = 12) trained with the prosthetic hand simulator over three one hour sessions in a picking up coins task, before returning for retention, delayed retention and transfer tests. The GT group received instruction regarding how to use their eyes effectively, while the MT group received movement-related instruction typical in rehabilitation. Results Experiment 1 revealed that when using the prosthetic hand, participants performed worse, exhibited spatial and temporal disruptions to visual attention, and exhibited a global decrease in EEG alpha power (8-12 Hz), suggesting increased cognitive effort. Experiment 2 showed that GT was the more effective method for expediting prosthesis learning, optimising visual attention, and lowering conscious control – as indexed by reduced T7-Fz connectivity. Whilst the MT group improved performance, they did not reduce hand-focused visual attention and showed increased conscious movement control. The superior benefits of GT transferred to a more complex tea-making task. Conclusions These experiments quantify the visual and cortical mechanisms relating to the cognitive burden experienced during prosthetic hand control. They also evidence the efficacy of a GT intervention that alleviated this burden and promoted better learning and transfer, compared to typical rehabilitation instructions. These findings have theoretical and practical implications for prosthesis rehabilitation, the development of emerging prosthesis technologies and for the general understanding of human-tool interactions

Improved Understanding of the Ball-Pen Probe through Particle-In-Cell Simulations

Ball-pen probes (BPP)have been deployed in the SOL of numerous tokamak experiments and low-temperature magnetised plasmas to make direct measurements of the plasma potential and electron temperature. Despite strong empirical evidence for the success of the BPP it lacks a theoretical underpinning of its collection mechanism. In this paper we investigate the capability of the probe to measure the plasma potential by means of particle-in-cell simulations. The BPP is found to float at a potential offset from the plasma potential by a factor TₑαBPP. By simulating BPPs and Langmuir probes, excellent agreement has been found between the measured electron temperature and the specified source temperature. The transport mechanism for both ions and electrons has been determined.E×B drifts are observed to drive electrons and ions down the tunnel. This mechanism is sensitive to the diameter of the prob

Geroch--Kinnersley--Chitre group for Dilaton--Axion Gravity

Kinnersley--type representation is constructed for the four--dimensional Einstein--Maxwell--dilaton--axion system restricted to space--times possessing two non--null commuting Killing symmetries. New representation essentially uses the matrix--valued $SL(2,R)$ formulation and effectively reduces the construction of the Geroch group to the corresponding problem for the vacuum Einstein equations. An infinite hierarchy of potentials is introduced in terms of $2\times 2$ real symmetric matrices generalizing the scalar hierarchy of Kinnersley--Chitre known for the vacuum Einstein equations.Comment: Published in ``Quantum Field Theory under the Influence of External Conditions'', M. Bordag (Ed.) (Proc. of the International Workshop, Leipzig, Germany, 18--22 September 1995), B.G. Teubner Verlagsgessellschaft, Stuttgart--Leipzig, 1996, pp. 228-23

Determining solar effects in Neptune’s atmosphere

Long-duration observations of Neptune’s brightness in two visible wavelengths provide a disk-averaged estimate of its atmospheric aerosol. Brightness variations were previously associated with the 11-year solar cycle, through solar-modulated mechanisms linked with either ultra-violet (UV) or galactic cosmic ray (GCR) effects on atmospheric particles. Here we use a recently extended brightness dataset (1972-2014), with physically realistic modelling to show that rather than alternatives, UV and GCR are likely to be modulating Neptune’s atmosphere in combination. The importance of GCR is further supported by the response of Neptune's atmosphere to an intermittent 1.5 to 1.9 year periodicity, which occurred preferentially in GCR (not UV) during the mid-1980s. This periodicity was detected both at Earth, and in GCR measured by Voyager 2, then near Neptune. A similar coincident variability in Neptune’s brightness suggests nucleation onto GCR ions. Both GCR and UV mechanisms may occur more rapidly than the subsequent atmospheric particle transport

Moduli Spaces of Cold Holographic Matter

We use holography to study (3+1)-dimensional N=4 supersymmetric Yang-Mills theory with gauge group SU(Nc), in the large-Nc and large-coupling limits, coupled to a single massless (n+1)-dimensional hypermultiplet in the fundamental representation of SU(Nc), with n=3,2,1. In particular, we study zero-temperature states with a nonzero baryon number charge density, which we call holographic matter. We demonstrate that a moduli space of such states exists in these theories, specifically a Higgs branch parameterized by the expectation values of scalar operators bilinear in the hypermultiplet scalars. At a generic point on the Higgs branch, the R-symmetry and gauge group are spontaneously broken to subgroups. Our holographic calculation consists of introducing a single probe Dp-brane into AdS5 times S^5, with p=2n+1=7,5,3, introducing an electric flux of the Dp-brane worldvolume U(1) gauge field, and then obtaining explicit solutions for the worldvolume fields dual to the scalar operators that parameterize the Higgs branch. In all three cases, we can express these solutions as non-singular self-dual U(1) instantons in a four-dimensional space with a metric determined by the electric flux. We speculate on the possibility that the existence of Higgs branches may point the way to a counting of the microstates producing a nonzero entropy in holographic matter. Additionally, we speculate on the possible classification of zero-temperature, nonzero-density states described holographically by probe D-branes with worldvolume electric flux.Comment: 56 pages, 8 PDF images, 4 figure

Imaging cervical cytology with scanning near-field optical microscopy (SNOM) coupled with an IR-FEL

Cervical cancer remains a major cause of morbidity and mortality among women, especially in the developing world. Increased synthesis of proteins, lipids and nucleic acids is a pre-condition for the rapid proliferation of cancer cells. We show that scanning near-field optical microscopy, in combination with an infrared free electron laser (SNOM-IR-FEL), is able to distinguish between normal and squamous low-grade and high-grade dyskaryosis, and between normal and mixed squamous/glandular pre-invasive and adenocarcinoma cervical lesions, at designated wavelengths associated with DNA, Amide I/II and lipids. These findings evidence the promise of the SNOM-IR-FEL technique in obtaining chemical information relevant to the detection of cervical cell abnormalities and cancer diagnosis at spatial resolutions below the diffraction limit (?0.2 \ensuremathμm). We compare these results with analyses following attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy; although this latter approach has been demonstrated to detect underlying cervical atypia missed by conventional cytology, it is limited by a spatial resolution of ~3 \ensuremathμm to 30 \ensuremathμm due to the optical diffraction limit

Evaluation of biospheric components in earth system models using modern and palaeo-observations: The state-of-the-art

PublishedJournal ArticleEarth system models (ESMs) are increasing in complexity by incorporating more processes than their predecessors, making them potentially important tools for studying the evolution of climate and associated biogeochemical cycles. However, their coupled behaviour has only recently been examined in any detail, and has yielded a very wide range of outcomes. For example, coupled climate-carbon cycle models that represent land-use change simulate total land carbon stores at 2100 that vary by as much as 600 Pg C, given the same emissions scenario. This large uncertainty is associated with differences in how key processes are simulated in different models, and illustrates the necessity of determining which models are most realistic using rigorous methods of model evaluation. Here we assess the state-of-the-art in evaluation of ESMs, with a particular emphasis on the simulation of the carbon cycle and associated biospheric processes. We examine some of the new advances and remaining uncertainties relating to (i) modern and palaeodata and (ii) metrics for evaluation. We note that the practice of averaging results from many models is unreliable and no substitute for proper evaluation of individual models. We discuss a range of strategies, such as the inclusion of pre-calibration, combined process-and system-level evaluation, and the use of emergent constraints, that can contribute to the development of more robust evaluation schemes. An increasingly data-rich environment offers more opportunities for model evaluation, but also presents a challenge. Improved knowledge of data uncertainties is still necessary to move the field of ESM evaluation away from a "beauty contest" towards the development of useful constraints on model outcomes. © 2013 Author(s).This paper emerged from the GREENCYCLESII mini-conference “Evaluation of Earth system models using modern and palaeo-observations” held at Clare College, Cambridge, UK, in September 2012. We would like to thank the Marie Curie FP7 Research and Training Network GREENCYCLESII for providing funding which made this meeting possible. Research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7 2007–2013) under grant agreement no. 238366. The work of C. D. Jones was supported by the Joint DECC/Defra Met Office Hadley Centre Climate Programme (GA01101). N. R. Edwards acknowledges support from FP7 grant no. 265170 (ERMITAGE). N. Vázquez Riveiros acknowledges support from the AXA Research Fund and the Newton Trust