Paths reunited: initiation of the classical and lectin pathways of complement activation

Understanding the structural organisation and mode of action of the initiating complex of the classical pathway of complement activation (C1) has been a central goal in complement biology since its isolation almost 50 years ago. Nevertheless, knowledge is still incomplete, especially with regard to the interactions between its subcomponents C1q, C1r and C1s that trigger activation upon binding to a microbial target. Recent studies have provided new insights into these interactions, and have revealed unexpected parallels with initiating complexes of the lectin pathway of complement: MBL–MASP and ficolin–MASP. Here, we develop and expand these concepts and delineate their implications towards the key aspects of complement activation via the classical and lectin pathways

Determination of positron annihilation lifetime spectroscopy instrument timing resolution function and source terms using standard samples

The extraction of material positron lifetime components from positron annihilation lifetime spectroscopy measurements, performed using conventional unmoderated radionuclide positron sources, requires accurate knowledge of both the spectrometer instrument timing resolution function (IRF) and annihilation events extrinsic to the material, the source correction terms. Here we report the results from study of spectrometer performance made using two reference samples, high purity polycrystalline aluminium, and stainless steel supplied by the National Metrology Institute of Japan (NMIJ RM 5607-a). Both prepared with directly deposited 22NaCl positron sources. The IRFs obtained by fitting spectra from both reference samples were monitored with time to evaluate spectrometer stability and to compare methods of IRF determination. Using the aluminium IRFs the analysis of spectra from the NMIJ stainless steel reference samples yielded a single lifetime component with value 106.9(9) ps

Lucy Hutchinson and the Business of Memoirs

Until comparatively recently, Lucy Hutchinson’s Memoirs were read as a personal and private document, and, even though their significance as a primary historical source is now increasingly recognized, it is still generally assumed that they were conceived solely for circulation within her own family. Their true business, however, is with public affairs and posterity. Like the many other late seventeenth-century memoirs, they anticipate a posthumous readership, to whom they present an apologetic, justificatory, and highly partisan, account of the recent past, participating in a literary contest for the master narrative of seventeenth-century history. This argument is pursued through a comparative analysis of the Memoirs and other examples of its curious hybrid genre, part autobiography, part historiography, taking up their compositional and publishing history, their implied readership, and Hutchinson’s binary categorization of historical agents as ‘children of light and of darkness’. Unusually, Hutchinson does not identify these with the Civil War antagonists. The former, embodied in the idealized Christian gentleman John Hutchinson, fail in their ‘just defence of English liberties’ because of those on the Parliamentarian, Puritan, and republican side who betray the Good Old Cause as the Israelites betrayed Moses after their liberation. This is Hutchinson’s witness to posterity.Output Status: Forthcoming/Available Onlin

Anomalous thermal expansion in 1D transition-metal cyanides: what makes the novel trimetallic cyanide Cu1/3Ag1/3Au1/3CN behave differently?

The structural dynamics of a quasi-one-dimensional (1D) mixed-metal cyanide, Cu1/3Ag1/3Au1/3CN, with intriguing thermal properties is explored. All the current known related compounds with straight-chain structures, such as group 11 cyanides CuCN, AgCN, AuCN and bimetallic cyanides MxM’1-xCN (M, M’ = Cu, Ag, Au), exhibit 1D negative thermal expansion (NTE) along the chains and positive thermal expansion (PTE) perpendicular to them. Cu1/3Ag1/3Au1/3CN exhibits similar PTE perpendicular to the chains, however PTE, rather than NTE, is also observed along the chains. In order to understand the origin of this unexpected behavior, inelastic neutron scattering (INS) measurements were carried out, underpinned by lattice-dynamical density-functional-theory (DFT) calculations. Synchrotron-based pair-distribution-function (PDF) analysis and 13C solid-state nuclear-magnetic-resonance (SSNMR) measurements were also performed to build an input structural model for the lattice dynamical study. The results indicate that transverse motions of the metal ions are responsible for the PTE perpendicular to the chains, as is the case for the related group 11 cyanides. However NTE along the chain due to the tension effect of these transverse motions is not observed. As there are different metal-to-cyanide bond lengths in Cu1/3Ag1/3Au1/3CN, the metals in neighboring chains cannot all be truly co-planar in a straight-chain model. For this system, DFT-based phonon calculations predict small PTE along the chain due to low-energy chain-slipping modes induced by a bond-rotation effect on the weak metallophilic bonds. However the observed PTE is greater than that predicted with the straight-chain model. Small bends in the chain to accommodate truly co-planar metals provide an alternative explanation for thermal behavior. These would mitigate the tension effect induced by the transverse motions of the metals and, as temperature increases and the chains move further apart, a straightening could occur resulting in the observed PTE. This hypothesis is further supported by unusual evolution in the phonon spectra, which suggest small changes in local symmetry with temperature

The Power Spectrum of the PSC Redshift Survey

We measure the redshift-space power spectrum P(k) for the recently completed IRAS Point Source Catalogue (PSC) redshift survey, which contains 14500 galaxies over 84% of the sky with 60 micron flux >= 0.6 Jansky. Comparison with simulations shows that our estimated errors on P(k) are realistic, and that systematic errors due to the finite survey volume are small for wavenumbers k >~ 0.03 h Mpc^-1. At large scales our power spectrum is intermediate between those of the earlier QDOT and 1.2 Jansky surveys, but with considerably smaller error bars; it falls slightly more steeply to smaller scales. We have fitted families of CDM-like models using the Peacock-Dodds formula for non-linear evolution; the results are somewhat sensitive to the assumed small-scale velocity dispersion \sigma_V. Assuming a realistic \sigma_V \approx 300 km/s yields a shape parameter \Gamma ~ 0.25 and normalisation b \sigma_8 ~ 0.75; if \sigma_V is as high as 600 km/s then \Gamma = 0.5 is only marginally excluded. There is little evidence for any `preferred scale' in the power spectrum or non-Gaussian behaviour in the distribution of large-scale power.Comment: Latex, uses mn.sty, 14 pages including 11 Postscript figures. Accepted by MNRA

x509-free access to WLCG resources

Access to WLCG resources is authenticated using an x509 and PKI infrastructure. Even though HEP users have always been exposed to certificates directly, the development of modern Web Applications by the LHC experiments calls for simplified authentication processes keeping the underlying software unmodified. In this work we will show a solution with the goal of providing access to WLCG resources using the user's home organisations credentials, without the need for user-acquired x509 certificates. In particular, we focus on identity providers within eduGAIN, which interconnects research and education organisations worldwide, and enables the trustworthy exchange of identity-related information. eduGAIN has been integrated at CERN in the SSO infrastructure so that users can authenticate without the need of a CERN account. This solution achieves x509-free access to Grid resources with the help of two services: STS and an online CA. The STS (Security Token Service) allows credential translation from the SAML2 format used by Identity Federations to the VOMS-enabled x509 used by most of the Grid. The IOTA CA (Identifier-Only Trust Assurance Certification Authority) is responsible for the automatic issuing of short-lived x509 certificates. The IOTA CA deployed at CERN has been accepted by EUGridPMA as the CERN LCG IOTA CA, included in the IGTF trust anchor distribution and installed by the sites in WLCG. We will also describe the first pilot projects which are integrating the solution.Peer reviewe

The Neutrophil-Lymphocyte Ratio and Locoregional Melanoma: A Multicentre Cohort Study

Objectives The neutrophil–lymphocyte ratio (NLR) is an inflammatory biomarker which is useful in cancer prognostication. We aimed to investigate the differences in baseline NLR between patients with localised and metastatic cutaneous melanoma and how this biomarker changed over time with the recurrence of disease. Methods This multicentre cohort study describes patients treated for Stage I–III cutaneous melanoma over 10 years. The baseline NLR was measured immediately prior to surgery and again at the time of discharge or disease recurrence. The odds ratios (OR) for sentinel node involvement are estimated using mixed-effects logistic regression. The risk of recurrence is estimated using multivariable Cox regression. Results Overall 1489 individuals were included. The mean baseline NLR was higher in patients with palpable nodal disease compared to those with microscopic nodal or localised disease (2.8 versus 2.4 and 2.3, respectively; p < 0.001). A baseline NLR ≥ 2.3 was associated with 30% higher odds of microscopic metastatic melanoma in the sentinel lymph node [adjusted OR 1.3 (95% CI 1.3, 1.3)]. Following surgery, 253 patients (18.7%) developed recurrent melanoma during surveillance although there was no statistically significant association between the baseline NLR and the risk of recurrence [adjusted HR 0.9 (0.7, 1.1)]. Conclusion The NLR is associated with the volume of melanoma at presentation and may predict occult sentinel lymph metastases. Further prospective work is required to investigate how NLR may be modelled against other clinicopathological variables to predict outcomes and to understand the temporal changes in NLR following surgery for melanoma

The Wnt receptor Ryk is required for Wnt5a-mediated axon guidance on the contralateral side of the corpus callosum

Ryk (receptor related to tyrosine kinase) has been shown to be a novel Wnt receptor in both Caenorhabditis elegans and Drosophila melanogaster. Recently, Ryk-Wnt interactions were shown to guide corticospinal axons down the embryonic mouse spinal cord. Here we show that, in Ryk-deficient mice, cortical axons project aberrantly across the major forebrain commissure, the corpus callosum. Many mouse mutants have been described in which loss-of-function mutations result in the inability of callosal axons to cross the midline, thereby forming Probst bundles on the ipsilateral side. In contrast, loss of Ryk does not interfere with the ability of callosal axons to cross the midline but impedes their escape from the midline into the contralateral side. Therefore, Ryk(-/-) mice display a novel callosal guidance phenotype. We also show that Wnt5a acts as a chemorepulsive ligand for Ryk, driving callosal axons toward the contralateral hemisphere after crossing the midline. In addition, whereas callosal axons do cross the midline in Ryk(-/-) embryos, they are defasciculated on the ipsilateral side, indicating that Ryk also promotes fasciculation of axons before midline crossing. In summary, this study expands the emerging role for Wnts in axon guidance and identifies Ryk as a key guidance receptor in the establishment of the corpus callosum. Our analysis of Ryk function further advances our understanding of the molecular mechanisms underlying the formation of this important commissure