The role of a disulfide bridge in the stability and folding kinetics of Arabidopsis thaliana cytochrome c6A

Cytochrome c 6A is a eukaryotic member of the Class I cytochrome c family possessing a high structural homology with photosynthetic cytochrome c 6 from cyanobacteria, but structurally and functionally distinct through the presence of a disulfide bond and a heme mid-point redox potential of + 71 mV (vs normal hydrogen electrode). The disulfide bond is part of a loop insertion peptide that forms a cap-like structure on top of the core α-helical fold. We have investigated the contribution of the disulfide bond to thermodynamic stability and (un)folding kinetics in cytochrome c 6A from Arabidopsis thaliana by making comparison with a photosynthetic cytochrome c 6 from Phormidium laminosum and through a mutant in which the Cys residues have been replaced with Ser residues (C67/73S). We find that the disulfide bond makes a significant contribution to overall stability in both the ferric and ferrous heme states. Both cytochromes c 6A and c 6 fold rapidly at neutral pH through an on-pathway intermediate. The unfolding rate for the C67/73S variant is significantly increased indicating that the formation of this region occurs late in the folding pathway. We conclude that the disulfide bridge in cytochrome c 6A acts as a conformational restraint in both the folding intermediate and native state of the protein and that it likely serves a structural rather than a previously proposed catalytic role. © 2011 Elsevier B.V. All rights reserved

Polarimetry and the High-Energy Emission Mechanisms in Quasar Jets. The Case of PKS 1136-135

Since the discovery of kiloparsec-scale X-ray emission from quasar jets, the physical processes responsible for their high-energy emission have been poorly defined. A number of mechanisms are under active debate, including synchrotron radiation, inverse-Comptonized CMB (IC/CMB) emission, and other Comptonization processes. In a number of cases, the optical and X-ray emission of jet regions are inked by a single spectral component, and in those, high- resolution multi-band imaging and polarimetry can be combined to yield a powerful diagnostic of jet emission processes. Here we report on deep imaging photometry of the jet of PKS 1136$-$135 obtained with the {\it Hubble Space Telescope.} We find that several knots are highly polarized in the optical, with fractional polarization $\Pi>30$. When combined with the broadband spectral shape observed in these regions, this is very difficult to explain via IC/CMB models, unless the scattering particles are at the lowest-energy tip of the electron energy distribution, with Lorentz factor $\gamma \sim 1$, and the jet is also very highly beamed ($\delta \geq 20$) and viewed within a few degrees of the line of sight. We discuss both the IC/CMB and synchrotron interpretation of the X-ray emission in the light of this new evidence, presenting new models of the spectral energy distribution and also the matter content of this jet. The high polarizations do not completely rule out the possibility of IC/CMB optical-to-X-ray emission in this jet, but they do strongly disfavor the model. We discuss the implications of this finding, and also the prospects for future work.Comment: 14 pages, 8 figures, ApJ in pres

Optical- & UV-Continuum Morphologies of Compact Radio Source Hosts

We present the first systematic search for UV signatures from radio source-driven AGN feedback in Compact Steep Spectrum (CSS) radio galaxies. Owing to their characteristic sub-galactic jets (1-20 kpc projected linear sizes), CSS hosts are excellent laboratories for probing galaxy scale feedback via jet-triggered star formation. The sample consists of 7 powerful CSS galaxies, and 2 galaxies host to radio sources >20 kpc as control, at low to intermediate redshifts (z<0.6). Our new HST images show extended UV continuum emission in 6/7 CSS galaxies; with 5 CSS hosts exhibiting UV knots co-spatial and aligned along the radio-jet axis. Young (5 M$_\odot$) stellar populations are likely to be the dominant source of the blue excess emission in radio galaxies at these redshifts. Hence, the radio-aligned UV regions could be attributed to jet-induced starbursts. Lower near-UV SFRs compared to other indicators suggests low scattered AGN light contribution to the observed UV. Dust attenuation of UV emission appears unlikely from high internal extinction correction estimates in most sources. Comparison with evolutionary synthesis models shows that our observations are consistent with recent (~1-8 Myr old) star forming activity likely triggered by current or an earlier episode of radio emission, or by a confined radio source that has frustrated growth due to a dense environment. While follow-up spectroscopic and polarized light observations are needed to constrain the activity-related components in the observed UV, the detection of jet-induced star formation is a confirmation of an important prediction of the jet feedback paradigm.Comment: Submitted to Ap

Heritage Quay: What Will You Discover? Transforming the Archives of the University of Huddersfield, Yorkshire, UK

The Heritage Quay project is changing how archive services at the University of Huddersfield are delivered. This article examines how the Staff/Space/Collections dependency model and Customer Service Excellence framework have been used, and what lessons can be drawn for other archives

XMM-NEWTON Detection of X-ray Emission from the Compact Steep Spectrum Radio Galaxy 3C303.1

Using XMM we detect faint unresolved X-ray emission from the Compact Steep Spectrum radio galaxy 3C303.1. We detect a thermal component at kT = 0.8 keV which seems likely to be produced in the ISM of the host galaxy. There is evidence for a second component in the spectrum whose nature is currently ambiguous. Plausible hypotheses for the second component include (1) hot gas shocked by the expansion of the radio source, and (2) Synchrotron self-Compton emission from the southern radio lobe if the magnetic field is below the equipartition value by a factor of about 3.5

A multicentre, randomised, double-blind, single-dose study assessing the efficacy of AMC/DCBA Warm lozenge or AMC/DCBA Cool lozenge in the relief of acute sore throat

<p>Abstract</p> <p>Background</p> <p>Clinically proven over-the-counter (OTC) treatment options are becoming increasingly important in the self-management of acute sore throat. The aim of this study was to determine the analgesic and sensorial benefits of two different amylmetacresol/2,4-dichlorobenzyl alcohol (AMC/DCBA) throat lozenge formulation variants, AMC/DCBA Warm lozenge and AMC/DCBA Cool lozenge, compared with an unflavoured, non-medicated placebo lozenge in the relief of acute sore throat due to upper respiratory tract infections.</p> <p>Methods</p> <p>In this multicentre, randomised, double-blind, single-dose study, 225 adult patients with acute sore throat were randomly assigned to receive either one AMC/DCBA Warm lozenge (n = 77), one AMC/DCBA Cool lozenge (n = 74) or one unflavoured, non-medicated lozenge (matched for size, shape and demulcency; n = 74). After baseline assessments, patients received their assigned lozenge and completed four rating assessments at 11 timepoints from 1 to 120 minutes post dose. Analgesic properties were assessed by comparing severity of throat soreness and sore throat relief ratings. Difficulty in swallowing, throat numbness, functional, sensorial and emotional benefits were also assessed.</p> <p>Results</p> <p>Both the AMC/DCBA Warm and AMC/DCBA Cool lozenge induced significant analgesic, functional, sensorial and emotional effects compared with the unflavoured, non-medicated lozenge. Sore throat relief, improvements in throat soreness and difficulty in swallowing, and throat numbness were observed as early as 1-5 minutes, and lasted up to 2 hours post dose. Sensorial benefits of warming and cooling associated with the AMC/DCBA Warm and AMC/DCBA Cool lozenge, respectively, were experienced soon after first dose, and in the case of the latter, it lasted long after the lozenge had dissolved. Emotional benefits of feeling better, happier, less distracted and less frustrated were reported in those taking either of the AMC/DCBA throat lozenge variants, with no differences in adverse events compared with the unflavoured, non-medicated lozenge.</p> <p>Conclusions</p> <p>AMC/DCBA Warm and AMC/DCBA Cool lozenges are well-tolerated and effective OTC treatment options, offering functional, sensorial and emotional benefits to patients with acute sore throat, over and above that of the rapid efficacy effects provided.</p> <p>Trial registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN00003567">ISRCTN00003567</a></p

GISCOME – Genetics of Ischaemic Stroke Functional Outcome network: A protocol for an international multicentre genetic association study

© 2017, © European Stroke Organisation 2017. Introduction: Genome-wide association studies have identified several novel genetic loci associated with stroke risk, but how genetic factors influence stroke outcome is less studied. The Genetics of Ischaemic Stroke Functional outcome network aims at performing genetic studies of stroke outcome. We here describe the study protocol and methods basis of Genetics of Ischaemic Stroke Functional outcome. Methods: The Genetics of Ischaemic Stroke Functional outcome network has assembled patients from 12 ischaemic stroke projects with genome-wide genotypic and outcome data from the International Stroke Genetics Consortium and the National Institute of Neurological Diseases Stroke Genetics Network initiatives. We have assessed the availability of baseline variables, outcome metrics and time-points for collection of outcome data. Results: We have collected 8831 ischaemic stroke cases with genotypic and outcome data. Modified Rankin score was the outcome metric most readily available. We detected heterogeneity between cohorts for age and initial stroke severity (according to the NIH Stroke Scale), and will take this into account in analyses. We intend to conduct a first phase genome-wide association outcome study on ischaemic stroke cases with data on initial stroke severity and modified Rankin score within 60–190 days. To date, we have assembled 5762 such cases and are currently seeking additional cases meeting these criteria for second phase analyses. Conclusion: Genetics of Ischaemic Stroke Functional outcome is a unique collection of ischaemic stroke cases with detailed genetic and outcome data providing an opportunity for discovery of genetic loci influencing functional outcome. Genetics of Ischaemic Stroke Functional outcome will serve as an exploratory study where the results as well as the methodological observations will provide a basis for future studies on functional outcome. Genetics of Ischaemic Stroke Functional outcome can also be used for candidate gene replication or assessing stroke outcome non-genetic association hypotheses

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

Genome-wide association study of cerebral small vessel disease reveals established and novel loci

Intracerebral haemorrhage and small vessel ischaemic stroke (SVS) are the most acute manifestations of cerebral small vessel disease, with no established preventive approaches beyond hypertension management. Combined genome-wide association study (GWAS) of these two correlated diseases may improve statistical power to detect novel genetic factors for cerebral small vessel disease, elucidating underlying disease mechanisms that may form the basis for future treatments. Because intracerebral haemorrhage location is an adequate surrogate for distinct histopathological variants of cerebral small vessel disease (lobar for cerebral amyloid angiopathy and non-lobar for arteriolosclerosis), we performed GWAS of intracerebral haemorrhage by location in 1813 subjects (755 lobar and 1005 non-lobar) and 1711 stroke-free control subjects. Intracerebral haemorrhage GWAS results by location were meta-analysed with GWAS results for SVS from MEGASTROKE, using 'Multi-Trait Analysis of GWAS' (MTAG) to integrate summary data across traits and generate combined effect estimates. After combining intracerebral haemorrhage and SVS datasets, our sample size included 241 024 participants (6255 intracerebral haemorrhage or SVS cases and 233 058 control subjects). Genome-wide significant associations were observed for non-lobar intracerebral haemorrhage enhanced by SVS with rs2758605 [MTAG P-value (P) = 2.6 x 10(-8)] at 1q22;rs72932727 (P = 1.7 x 10(-8)) at 2q33;and rs9515201 (P = 5.3 x 10(-10)) at 13q34. In the GTEx gene expression library, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1 x 10(-4) in tibial nerve), NBEAL1, FAM117B and CARF (P<2.1 x 10(-7) in arteries) and COL4A2 and COL4A1 (P<0.01 in brain putamen), respectively. Leveraging S-PrediXcan for gene-based association testing with the predicted expression models in tissues related with nerve, artery, and non-lobar brain, we found that experiment-wide significant (P<8.5 x 10(-7)) associations at three genes at 2q33 including NBEAL1, FAM117B and WDR12 and genome-wide significant associations at two genes including ICA1L at 2q33 and ZCCHC14 at 16q24. Brain cell-type specific expression profiling libraries reveal that SEMA4A, SLC25A44 and PMF1 at 1q22 and COL4A1 and COL4A2 at 13q34 were mainly expressed in endothelial cells, while the genes at 2q33 (FAM117B, CARF and NBEAL1) were expressed in various cell types including astrocytes, oligodendrocytes and neurons. Our cross-phenotype genetic study of intracerebral haemorrhage and SVS demonstrates novel genome-wide associations for non-lobar intracerebral haemorrhage at 2q33 and 13q34. Our replication of the 1q22 locus previous seen in traditional GWAS of intracerebral haemorrhage, as well as the rediscovery of 13q34, which had previously been reported in candidate gene studies with other cerebral small vessel disease-related traits strengthens the credibility of applying this novel genome-wide approach across intracerebral haemorrhage and SVS

Rare missense functional variants at COL4A1 and COL4A2 in sporadic intracerebral Hhmorrhage

Objective: To test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH. Methods: We performed sequencing across 559Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in US-based and 1,492 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling. Results: We identified 107 rare nonsynonymous variants in sporadic ICH, of which two missense variants, rs138269346 (COL4A1I110T) and rs201716258 (COL4A2H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the US-based cohort. The minor allele of rs201716258 was also present in Scottish ICH patients, and rs138269346 was observed in two ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with non-lobar ICH risk (P=0.05), but not with lobar ICH (P=0.08), while associations between rs201716258 and ICH subtypes were non-significant (P&gt;0.12). Both variants were considered pathogenic based on minor allele frequency (&lt;0.00035 in EUR), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen). Conclusions: We identified rare missense variants in COL4A1/A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up