IntPred: a structure-based predictor of protein–protein interaction sites

Motivation Protein–protein interactions are vital for protein function with the average protein having between three and ten interacting partners. Knowledge of precise protein– protein interfaces comes from crystal structures deposited in the Protein Data Bank (PDB), but only 50% of structures in the PDB are complexes. There is therefore a need to predict protein–protein interfaces in silico and various methods for this purpose. Here we explore the use of a predictor based on structural features and which exploits random forest machine learning, comparing its performance with a number of popular established methods. Results On an independent test set of obligate and transient complexes, our IntPred predictor performs well (MCC = 0.370, ACC = 0.811, SPEC = 0.916, SENS = 0.411) and compares favourably with other methods. Overall, IntPred ranks second of six methods tested with SPPIDER having slightly better overall performance (MCC = 0.410, ACC = 0.759, SPEC = 0.783, SENS = 0.676), but considerably worse specificity than IntPred. As with SPPIDER, using an independent test set of obligate complexes enhanced performance (MCC = 0.381) while performance is somewhat reduced on a dataset of transient complexes (MCC = 0.303). The trade-off between sensitivity and specificity compared with SPPIDER suggests that the choice of the appropriate tool is application-dependent. Availability and implementation IntPred is implemented in Perl and may be downloaded for local use or run via a web server at www.bioinf.org.uk/intpred/. Supplementary information Supplementary data are available at Bioinformatics online

Evidence for Ubiquitous Collimated Galactic-Scale Outflows along the Star-Forming Sequence at z~0.5

We present an analysis of the MgII 2796, 2803 and FeII 2586, 2600 absorption line profiles in individual spectra of 105 galaxies at 0.3<z<1.4. The galaxies, drawn from redshift surveys of the GOODS fields and the Extended Groth Strip, fully sample the range in star formation rates (SFRs) occupied by the star-forming sequence with stellar masses log M_*/M_sun > 9.5 at 0.3<z<0.7. Using the Doppler shifts of the MgII and FeII absorption lines as tracers of cool gas kinematics, we detect large-scale winds in 66+/-5% of the galaxies. HST/ACS imaging and our spectral analysis indicate that the outflow detection rate depends primarily on galaxy orientation: winds are detected in ~89% of galaxies having inclinations (i) <30 degrees (face-on), while the wind detection rate is only ~45% in objects having i>50 degrees (edge-on). Combined with the comparatively weak dependence of the wind detection rate on intrinsic galaxy properties, this suggests that biconical outflows are ubiquitous in normal, star-forming galaxies at z~0.5. We find that the wind velocity is correlated with host galaxy M_* at 3.4-sigma significance, while the equivalent width of the flow is correlated with host galaxy SFR at 3.5-sigma significance, suggesting that hosts with higher SFR may launch more material into outflows and/or generate a larger velocity spread for the absorbing clouds. Assuming that the gas is launched into dark matter halos with simple, isothermal density profiles, the wind velocities measured for the bulk of the cool material (~200-400 km/s) are sufficient to enable escape from the halo potentials only for the lowest-M_* systems in the sample. However, the outflows typically carry sufficient energy to reach distances of >50 kpc, and may therefore be a viable source of cool material for the massive circumgalactic medium observed around bright galaxies at z~0. [abridged]Comment: Submitted to ApJ. 61 pages, 25 figures, 4 tables, 4 appendices. Uses emulateapj forma

Familial aggregation of migraine and depression: Insights from a large Australian twin sample

Free to read\ud \ud Objectives: This research examined the familial aggregation of migraine, depression, and their co-occurrence.\ud \ud Methods: Diagnoses of migraine and depression were determined in a sample of 5,319 Australian twins. Migraine was diagnosed by either self-report, the ID migraine™ Screener, or International Headache Society (IHS) criteria. Depression was defined by fulfilling either major depressive disorder (MDD) or minor depressive disorder (MiDD) based on the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria. The relative risks (RR) for migraine and depression were estimated in co-twins of twin probands reporting migraine or depression to evaluate their familial aggregation and co-occurrence.\ud \ud Results: An increased RR of both migraine and depression in co-twins of probands with the same trait was observed, with significantly higher estimates within monozygotic (MZ) twin pairs compared to dizygotic (DZ) twin pairs. For cross-trait analysis, the RR for migraine in co-twins of probands reporting depression was 1.36 (95% CI: 1.24–1.48) in MZ pairs and 1.04 (95% CI: 0.95–1.14) in DZ pairs; and the RR for depression in co-twins of probands reporting migraine was 1.26 (95% CI: 1.14–1.38) in MZ pairs and 1.02 (95% CI: 0.94–1.11) in DZ pairs. The RR for strict IHS migraine in co-twins of probands reporting MDD was 2.23 (95% CI: 1.81–2.75) in MZ pairs and 1.55 (95% CI: 1.34–1.79) in DZ pairs; and the RR for MDD in co-twins of probands reporting IHS migraine was 1.35 (95% CI: 1.13–1.62) in MZ pairs and 1.06 (95% CI: 0.93–1.22) in DZ pairs.\ud \ud Conclusions: We observed significant evidence for a genetic contribution to familial aggregation of migraine and depression. Our findings suggest a bi-directional association between migraine and depression, with an increased risk for depression in relatives of probands reporting migraine, and vice versa. However, the observed risk for migraine in relatives of probands reporting depression was considerably higher than the reverse. These results add further support to previous studies suggesting that patients with comorbid migraine and depression are genetically more similar to patients with only depression than patients with only migraine

Shared genetic factors underlie migraine and depression

Free to read\ud \ud Migraine frequently co-occurs with depression. Using a large sample of Australian twin pairs, we aimed to characterize the extent to which shared genetic factors underlie these two disorders. Migraine was classified using three diagnostic measures, including self-reported migraine, the ID migraine screening tool, or migraine without aura (MO) and migraine with aura (MA) based on International Headache Society (IHS) diagnostic criteria. Major depressive disorder (MDD) and minor depressive disorder (MiDD) were classified using the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria. Univariate and bivariate twin models, with and without sex-limitation, were constructed to estimate the univariate and bivariate variance components and genetic correlation for migraine and depression. The univariate heritability of broad migraine (self-reported, ID migraine, or IHS MO/MA) and broad depression (MiDD or MDD) was estimated at 56% (95% confidence interval [CI]: 53-60%) and 42% (95% CI: 37-46%), respectively. A significant additive genetic correlation (r G = 0.36, 95% CI: 0.29-0.43) and bivariate heritability (h 2 = 5.5%, 95% CI: 3.6-7.8%) was observed between broad migraine and depression using the bivariate Cholesky model. Notably, both the bivariate h 2 (13.3%, 95% CI: 7.0-24.5%) and r G (0.51, 95% CI: 0.37-0.69) estimates significantly increased when analyzing the more narrow clinically accepted diagnoses of IHS MO/MA and MDD. Our results indicate that for both broad and narrow definitions, the observed comorbidity between migraine and depression can be explained almost entirely by shared underlying genetically determined disease mechanisms

The Clustering of Massive Halos

The clustering properties of dark matter halos are a firm prediction of modern theories of structure formation. We use two large volume, high-resolution N-body simulations to study how the correlation function of massive dark matter halos depends upon their mass and formation history. We find that halos with the lowest concentrations are presently more clustered than those of higher concentration, the size of the effect increasing with halo mass; this agrees with trends found in studies of lower mass halos. The clustering dependence on other characterizations of the full mass accretion history appears weaker than the effect with concentration. Using the integrated correlation function, marked correlation functions, and a power-law fit to the correlation function, we find evidence that halos which have recently undergone a major merger or a large mass gain have slightly enhanced clustering relative to a randomly chosen population with the same mass distribution.Comment: 10 pages, 8 figures; text improved, references and one figure added; accepted for publication in Ap

Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation.

A variety of diseases lead to degeneration of retinal ganglion cells (RGCs) and their axons within the optic nerve resulting in loss of visual function. Although current therapies may delay RGC loss, they do not restore visual function or completely halt disease progression. Regenerative medicine has recently focused on stem cell therapy for both neuroprotective and regenerative purposes. However, significant problems remain to be addressed, such as the long-term impact of reactive gliosis occurring in the host retina in response to transplanted stem cells. The aim of this work was to investigate retinal glial responses to intravitreally transplanted bone marrow mesenchymal stem cells (BM-MSCs) to help identify factors able to modulate graft-induced reactive gliosis. We found in vivo that intravitreal BM-MSC transplantation is associated with gliosis-mediated retinal folding, upregulation of intermediate filaments, and recruitment of macrophages. These responses were accompanied by significant JAK/STAT3 and MAPK (ERK1/2 and JNK) cascade activation in retinal Muller glia. Lipocalin-2 (Lcn-2) was identified as a potential new indicator of graft-induced reactive gliosis. Pharmacological inhibition of STAT3 in BM-MSC cocultured retinal explants successfully reduced glial fibrillary acidic protein expression in retinal Muller glia and increased BM-MSC retinal engraftment. Inhibition of stem cell-induced reactive gliosis is critical for successful transplantation-based strategies for neuroprotection, replacement, and regeneration of the optic nerve.This work was support by funding from the Biotechnology and Biological Sciences Research Council (BBSRC), the HB Allen Charitable Trust, the Cambridge Eye Trust, the Jukes Glaucoma Research Fund and by Pfizer, Neusentis. We thank Dr. Andras Lakatos from the University of Cambridge (UK) for donating the GFAP-STAT3 CKO mice, Prof. Verdon Taylor from the University of Basel (CH) for the Hes5 GFP+ve mice, Dr. Stefano Pluchino from the University of Cambridge (UK) for donating the mouse neural precursor cell (NPC) line and Prof. Astrid Limb from UCL, London (UK) for the MIO-M1 cell line.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/stem.209

Proteomic Analysis of a Noninvasive Human Model of Acute Inflammation and Its Resolution: The Twenty-one Day Gingivitis Model

The 21-day experimental gingivitis model, an established noninvasive model of inflammation in response to increasing bacterial accumulation in humans, is designed to enable the study of both the induction and resolution of inflammation. Here, we have analyzed gingival crevicular fluid, an oral fluid comprising a serum transudate and tissue exudates, by LC−MS/MS using Fourier transform ion cyclotron resonance mass spectrometry and iTRAQ isobaric mass tags, to establish meta-proteomic profiles of inflammation-induced changes in proteins in healthy young volunteers. Across the course of experimentally induced gingivitis, we identified 16 bacterial and 186 human proteins. Although abundances of the bacterial proteins identified did not vary temporally, Fusobacterium outer membrane proteins were detected. Fusobacterium species have previously been associated with periodontal health or disease. The human proteins identified spanned a wide range of compartments (both extracellular and intracellular) and functions, including serum proteins, proteins displaying antibacterial properties, and proteins with functions associated with cellular transcription, DNA binding, the cytoskeleton, cell adhesion, and cilia. PolySNAP3 clustering software was used in a multilayered analytical approach. Clusters of proteins that associated with changes to the clinical parameters included neuronal and synapse associated proteins

Direct reconstruction of the quintessence potential

We describe an algorithm which directly determines the quintessence potential from observational data, without using an equation of state parametrisation. The strategy is to numerically determine observational quantities as a function of the expansion coefficients of the quintessence potential, which are then constrained using a likelihood approach. We further impose a model selection criterion, the Bayesian Information Criterion, to determine the appropriate level of the potential expansion. In addition to the potential parameters, the present-day quintessence field velocity is kept as a free parameter. Our investigation contains unusual model types, including a scalar field moving on a flat potential, or in an uphill direction, and is general enough to permit oscillating quintessence field models. We apply our method to the `gold' Type Ia supernovae sample of Riess et al. (2004), confirming the pure cosmological constant model as the best description of current supernovae luminosity-redshift data. Our method is optimal for extracting quintessence parameters from future data.Comment: 9 pages RevTeX4 with lots of incorporated figure

Experimental simulation of closed timelike curves

Closed timelike curves are among the most controversial features of modern physics. As legitimate solutions to Einstein's field equations, they allow for time travel, which instinctively seems paradoxical. However, in the quantum regime these paradoxes can be resolved, leaving closed timelike curves consistent with relativity. The study of these systems therefore provides valuable insight into nonlinearities and the emergence of causal structures in quantum mechanics-essential for any formulation of a quantum theory of gravity. Here we experimentally simulate the nonlinear behaviour of a qubit interacting unitarily with an older version of itself, addressing some of the fascinating effects that arise in systems traversing a closed timelike curve. These include perfect discrimination of non-orthogonal states and, most intriguingly, the ability to distinguish nominally equivalent ways of preparing pure quantum states. Finally, we examine the dependence of these effects on the initial qubit state, the form of the unitary interaction and the influence of decoherence