Structural basis for complement factor H-linked age-related macular degeneration

This is the final version of the article. Available from the publisher via the DOI in this record.Nearly 50 million people worldwide suffer from age-related macular degeneration (AMD), which causes severe loss of central vision. A single-nucleotide polymorphism in the gene for the complement regulator factor H (FH), which causes a Tyr-to-His substitution at position 402, is linked to approximately 50% of attributable risks for AMD. We present the crystal structure of the region of FH containing the polymorphic amino acid His402 in complex with an analogue of the glycosaminoglycans (GAGs) that localize the complement regulator on the cell surface. The structure demonstrates direct coordination of ligand by the disease-associated polymorphic residue, providing a molecular explanation of the genetic observation. This glycan-binding site occupies the center of an extended interaction groove on the regulator's surface, implying multivalent binding of sulfated GAGs. This finding is confirmed by structure-based site-directed mutagenesis, nuclear magnetic resonance-monitored binding experiments performed for both H402 and Y402 variants with this and another model GAG, and analysis of an extended GAG-FH complex.B. Prosser is funded by the Wellcome Trust Structural Biology Training Program (075415/Z/04/Z). S. Johnson and P. Roversi were funded by grants to S.M. Lea from the Medical Research Council (MRC) of the United Kingdom (grants G0400389 and G0400775). D. Uhrin and P.N. Barlow were funded by the Wellcome Trust (078780/ Z/05/Z). S.J. Clark was funded by an MRC Doctoral Training Account (G78/7925), and R.B. Sim and A.J. Day were funded by MRC core funding to the MRC Immunochemistry Unit

Immunogenicity of vaccination against influenza, Streptococcus pneumoniae and Haemophilus influenzae type B in patients with multiple myeloma

Vaccination against influenza and Streptococcus pneumoniae is recommended for elderly and immunocompromised individuals. However, there is little information concerning the efficacy of vaccination in specific groups of patients. In this study, 52 patients underwent vaccination against influenza, S. pneumoniae and Haemophilus influenzae type b (Hib) as they attended hospital outpatient clinics. Serum was analysed prior to vaccination and 4–6 weeks afterwards. Antibody titres against S. pneumoniae and Hib were compared with reference values corresponding to the geometric mean titres of a healthy UK population. For influenza vaccination, haemagglutination inhibition (HI) titres were measured against three inactivated strains; a titre of ≥ 1/40 was considered protective. No patient had protective titres to all three antigens prior to vaccination and 41 patients (85%) had titres < 1/40 to all 3 strains. Post vaccination only 9/48 patients (19%) achieved protective antibody titres. Resistance to S. pneumoniae and response to Pneumovax II was also poor: prevaccination, 45 patients (93%) had suboptimal antibody titres and in 26/43 patients (61%) titres remained low post vaccination. Resistance to Hib and response to vaccination was comparable with the healthy adult UK population. These results question the practice of routine influenza and pneumococcal vaccination in myeloma patients. © 2000 Cancer Research Campaig

Do gender and torus mandibularis affect mandibular cortical index? A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>The interactions between torus and several factors such as age, gender, and dental status have not been studied comprehensively. The purpose of this study was to determine the effect of gender on the mandibular cortical index (MCI) and to investigate a possible association between torus mandibularis (TM) and MCI.</p> <p>Methods</p> <p>The study consisted of 189 consecutive patients referred to Department of Oral Diagnosis and Radiology of Hacettepe University within 30 workdays. Patients who did not have systemic disorders affecting bone density were included; and the age, gender, dental status and existing TM of the patients were recorded. Morphology of the mandibular inferior cortex was determined according to Klemitti's classification on panoramic radiographs.</p> <p>Results</p> <p>MCI was affected by age and gender (<it>P </it>< 0.05). No significant relationship was found between TM and MCI (<it>P </it>> 0.05).</p> <p>Conclusion</p> <p>In the study population, MCI was affected by age and gender. As age increased, semilunar defects could be seen on the cortex of the mandible and MCI values increased. Women appeared to have higher MCI values than men.</p

It’s Not the Left: Ideology and Protest Participation in Old and New Democracies

Multiple studies in political science consistently hold that left-wing ideology renders individuals more prone to protest behavior. However, the familiar association between left-wing ideology and protesting is not empirically corroborated in all democratic nations. Building on existing theoretical principles and applying them to diverse political contexts, this paper sheds light on puzzling variation in protest behavior across new and old democracies. It argues that it is not the left that engenders protest. Instead, we demonstrate that which political camp engages in protest behavior depends on its historical legacies and cultural liberalism. Historical legacies reflect the ideological configuration at democratization. Protesting tends to be more common in the ideological camp that opposed the pre-democratic political order. Simultaneously, it is culturally liberal individuals that more likely embrace protest participation, independent of their left-right identification. These theoretical expectations are supported through survey data analyses, explaining contrasting inter- and intra-regional variation in European democracies

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Collagen-Like Proteins in Pathogenic E. coli Strains

The genome sequences of enterohaemorrhagic E. coli O157:H7 strains show multiple open-reading frames with collagen-like sequences that are absent from the common laboratory strain K-12. These putative collagens are included in prophages embedded in O157:H7 genomes. These prophages carry numerous genes related to strain virulence and have been shown to be inducible and capable of disseminating virulence factors by horizontal gene transfer. We have cloned two collagen-like proteins from E. coli O157:H7 into a laboratory strain and analysed the structure and conformation of the recombinant proteins and several of their constituting domains by a variety of spectroscopic, biophysical, and electron microscopy techniques. We show that these molecules exhibit many of the characteristics of vertebrate collagens, including trimer formation and the presence of a collagen triple helical domain. They also contain a C-terminal trimerization domain, and a trimeric α-helical coiled-coil domain with an unusual amino acid sequence almost completely lacking leucine, valine or isoleucine residues. Intriguingly, these molecules show high thermal stability, with the collagen domain being more stable than those of vertebrate fibrillar collagens, which are much longer and post-translationally modified. Under the electron microscope, collagen-like proteins from E. coli O157:H7 show a dumbbell shape, with two globular domains joined by a hinged stalk. This morphology is consistent with their likely role as trimeric phage side-tail proteins that participate in the attachment of phage particles to E. coli target cells, either directly or through assembly with other phage tail proteins. Thus, collagen-like proteins in enterohaemorrhagic E. coli genomes may have a direct role in the dissemination of virulence-related genes through infection of harmless strains by induced bacteriophages

Turnaround and failure: resource weaknesses and the rise and fall of Jarvis

Research employing the resource-based view (RBV) has overwhelming focused on the upside of resources, namely those that provide benefit to the firm. However, an emerging research stream suggests that the downside of resources, namely resource weaknesses, may be crucial in gaining a greater understanding of the key factors that contribute to firm performance and the ability to turnaround failing companies. We examine the infamous case of Jarvis, a firm that achieved a turnaround, but then experienced catastrophic failure. In so doing we explore the emergence of resource weaknesses, their nature and ability to combine to create a fatal organisational outcome

The Rare Earth Elements: demand, global resources, and challenges for resourcing future generations

The rare earth elements (REE) have attracted much attention in recent years, being viewed as critical metals because of China’s domination of their supply chain. This is despite the fact that REE enrichments are known to exist in a wide range of settings, and have been the subject of much recent exploration. Although the REE are often referred to as a single group, in practice each individual element has a specific set of end-uses, and so demand varies between them. Future demand growth to 2026 is likely to be mainly linked to the use of NdFeB magnets, particularly in hybrid and electric vehicles and wind turbines, and in erbium-doped glass fiber for communications. Supply of lanthanum and cerium is forecast to exceed demand. There are several different types of natural (primary) REE resources, including those formed by high-temperature geological processes (carbonatites, alkaline rocks, vein and skarn deposits) and those formed by low-temperature processes (placers, laterites, bauxites and ion-adsorption clays). In this paper, we consider the balance of the individual REE in each deposit type and how that matches demand, and look at some of the issues associated with developing these deposits. This assessment and overview indicate that while each type of REE deposit has different advantages and disadvantages, light rare earth-enriched ion adsorption types appear to have the best match to future REE needs. Production of REE as by-products from, for example, bauxite or phosphate, is potentially the most rapid way to produce additional REE. There are still significant technical and economic challenges to be overcome to create substantial REE supply chains outside China