Progress in spondylarthritis. Progress in studies of the genetics of ankylosing spondylitis

The advent of high-throughput SNP genotyping methods has advanced research into the genetics of common complex genetic diseases such as ankylosing spondylitis (AS) rapidly in recent times. The identification of associations with the genes IL23R and ERAP1 have been robustly replicated, and advances have been made in studies of the major histocompatibility complex genetics of AS, and of KIR gene variants and the disease. The findings are already being translated into increased understanding of the immunological pathways involved in AS, and raising novel potential therapies. The current studies in AS remain underpowered, and no full genomewide association study has yet been reported in AS; such studies are likely to add to the significant advances that have already been made.

Two monoclonal antibodies to precisely the same epitope of type ii collagen select non-crossreactive phage clones by phage display: Implications for autoimmunity and molecular mimicry

Two monoclonal antibodies (mAb) CB268 and CII-C1 to type II collagen (CII) react with precisely the same conformational epitope constituted by the residues ARGLT on the three chains of the CII triple helix. The antibodies share structural similarity, with most differences in the complementarity determining region 3 of the heavy chain (HCDR3). The fine reactivity of these mAbs was investigated by screening two nonameric phage-displayed random peptide libraries. For each mAb, there were phage clones (phagotopes) that reacted strongly by ELISA only with the selecting mAb, and inhibited binding to CII only for that mAb, not the alternate mAb. Nonetheless, a synthetic peptide RRLPFGSQM corresponding to an insert from a highly reactive CII-C1-selected phagotope, which was unreactive (and non-inhibitory) with CB268, inhibited the reactivity of CB268 with CII. Most phage-displayed peptides contained a motif in the first part of the molecule that consisted of two basic residues adjacent to at least one hydrophobic residue (e.g. RRL or LRR), but the second portion of the peptides differed for the two mAbs. We predict that conserved CDR sequences interact with the basic-basic-hydrophobic motif, whereas non-conserved amino acids in the binding sites (especially HCDR3) interact with unique peptide sequences and limit cross-reactivity. The observation that two mAbs can react identically with a single epitope on one antigen (CII), but show no cross-reactivity when tested against a second (phagotope) indicates that microorganisms could exhibit mimics capable of initiating autoimmunity without this being evident from conventional assays.

VH gene usage in immunoglobulin E responses of seasonal rhinitis patients allergic to grass pollen is oligoclonal and antigen driven

Background: IgE is the pivotal-specific effector molecule of allergic reactions yet it remains unclear whether the elevated production of IgE in atopic individuals is due to superantigen activation of B cell populations, increased antibody class switching to IgE or oligoclonal allergen-driven IgE responses. Objectives: To increase our understanding of the mechanisms driving IgE responses in allergic disease we examined immunoglobulin variable regions of IgE heavy chain transcripts from three patients with seasonal rhinitis due to grass pollen allergy. Methods: Variable domain of heavy chain-epsilon constant domain 1 cDNAs were amplified from peripheral blood using a two-step semi-nested PCR, cloned and sequenced. Results: The VH gene family usage in subject A was broadly based, but there were two clusters of sequences using genes VH 3-9 and 3-11 with unusually low levels of somatic mutations, 0-3%. Subject B repeatedly used VH 1-69 and subject C repeatedly used VH 1-02, 1-46 and 5a genes. Most clones were highly mutated being only 86-95% homologous to their germline VH gene counterparts and somatic mutations were more abundant at the complementarity determining rather than framework regions. Multiple sequence alignment revealed both repeated use of particular VH genes as well as clonal relatedness among clusters of IgE transcripts. Conclusion: In contrast to previous studies we observed no preferred VH gene common to IgE transcripts of the three subjects allergic to grass pollen. Moreover, most of the VH gene characteristics of the IgE transcripts were consistent with oligoclonal antigen-driven IgE responses.

Integration of Geospatial and Built Environment - National Data Policy

Digital technology offers enormous benefits (economic, quality of design and efficiency in use) if adopted to implement integrated ways of representing the physical world in a digital form. When applied across the full extent of the built and natural world, it is referred to as the Digital Built Environment (DBE) and encompasses a wide range of approaches and technology initiatives, all aimed at the same end goal: the development of a virtual world that sufficiently mirrors the real world to form the basis for the smart cities of the present and future, enable efficient infrastructure design and programmed maintenance, and create a new foundation for economic growth and social well-being through evidence-based analysis. The creation of a National Data Policy for the DBE will facilitate the creation of additional high technology industries in Australia; provide Governments, industries and citizens with greater knowledge of the environments they occupy and plan; and offer citizen-driven innovations for the future. Australia has slipped behind other nations in the adoption and execution of Building Information Modelling (BIM) and the principal concern is that the gap is widening. Data driven innovation added $67 billion to the Australian economy in 20131. Strong open data policy equates to $16 billion in new value2. Australian Government initiatives such as the Digital Earth inspired “National Map” offer a platform and pathway to embrace the concept of a “BIM Globe”, while also leveraging unprecedented growth in open source / open data collaboration. Australia must address the challenges by learning from international experiences—most notably the UK and NZ—and mandate the use of BIM across Government, extending the Framework for Spatial Data Foundation to include the Built Environment as a theme and engaging collaboration through a “BIM globe” metaphor. This proposed DBE strategy will modernise the Australian urban planning and the construction industry. It will change the way we develop our cities by fundamentally altering the dynamics and behaviours of the supply chains and unlocking new and more efficient ways of collaborating at all stages of the project life-cycle. There are currently two major modelling approaches that contribute to the challenge of delivering the DBE. Though these collectively encompass many (often competing) approaches or proprietary software systems, all can be categorised as either: a spatial modelling approach, where the focus is generally on representing the elements that make up the world within their geographic context; and a construction modelling approach, where the focus is on models that support the life cycle management of the built environment. These two approaches have tended to evolve independently, addressing two broad industry sectors: the one concerned with understanding and managing global and regional aspects of the world that we inhabit, including disciplines concerned with climate, earth sciences, land ownership, urban and regional planning and infrastructure management; the other is concerned with planning, design, construction and operation of built facilities and includes architectural and engineering design, product manufacturing, construction, facility management and related disciplines (a process/technology commonly known as Building Information Modelling, BIM). The spatial industries have a strong voice in the development of public policy in Australia, while the construction sector, which in 2014 accounted for around 8.5% of Australia’s GDP3, has no single voice and because of its diversity, is struggling to adapt to and take advantage of the opportunity presented by these digital technologies. The experience in the UK over the past few years has demonstrated that government leadership is very effective in stimulating industry adoption of digital technologies by, on the one hand, mandating the use of BIM on public procurement projects while at the same time, providing comparatively modest funding to address the common issues that confront the industry in adopting that way of working across the supply chain. The reported result has been savings of £840m in construction costs in 2013/14 according to UK Cabinet Office figures4. There is worldwide recognition of the value of bringing these two modelling technologies together. Australia has the expertise to exercise leadership in this work, but it requires a commitment by government to recognise the importance of BIM as a companion methodology to the spatial technologies so that these two disciplinary domains can cooperate in the development of data policies and information exchange standards to smooth out common workflows. buildingSMART Australasia, SIBA and their academic partners have initiated this dialogue in Australia and wish to work collaboratively, with government support and leadership, to explore the opportunities open to us as we develop an Australasian Digital Built Environment. As part of that programme, we must develop and implement a strategy to accelerate the adoption of BIM processes across the Australian construction sector while at the same time, developing an integrated approach in concert with the spatial sector that will position Australia at the forefront of international best practice in this area. Australia and New Zealand cannot afford to be on the back foot as we face the challenges of rapid urbanisation and change in the global environment. Although we can identify some exemplary initiatives in this area, particularly in New Zealand in response to the need for more resilient urban development in the face of earthquake threats, there is still much that needs to be done. We are well situated in the Asian region to take a lead in this challenge, but we are at imminent risk of losing the initiative if we do not take action now. Strategic collaboration between Governments, Industry and Academia will create new jobs and wealth, with the potential, for example, to save around 20% on the delivery costs of new built assets, based on recent UK estimates.

Genetics and the pathogenesis of ankylosing spondylitis

Purpose of review The field of genetic research in ankylosing spondylitis (AS) is advancing rapidly. The purpose of this review is to outline recent findings, particularly, in regard to genetic studies of the major histocompatibility complex (MHC) and the non-MHC genes IL23R, ERAP1, and killer cell immunologlobulin-like receptor (KIR) complex, in AS. Recent findings: Convincing evidence has been reported for the existence of further non-B27 MHC genes involved in AS. Strong, replicated association has been reported with IL23R and ERAP1 and AS. The IL23R finding strongly implicates the TH17 lymphocyte system in AS aetiopathogenesis. Suggestive evidence of a role for KIR gene polymorphism in AS exists, but definitive findings are awaited. Summary: The findings suggest that further genome-wide studies in large case-control cohorts are likely to be very productive in this disease. The IL23R findings and subsequent immunological investigations suggest that targeted intervention in the TH17 system is likely to have major therapeutic benefit, as it does in the genetically related diseases, inflammatory bowel disease and psoriasis.

The three-dimensional hydrogen-bonded structures in the ammonium and sodium salt hydrates of 4-aminophenylarsonic acid

The structures of two hydrated salts of 4-aminophenylarsonic acid (p-arsanilic acid), namely ammonium 4-aminophenylarsonate monohydrate, NH4(+)·C6H7AsNO3(-)·H2O, (I), and the one-dimensional coordination polymer catena-poly[[(4-aminophenylarsonato-κO)diaquasodium]-μ-aqua], [Na(C6H7AsNO3)(H2O)3]n, (II), have been determined. In the structure of the ammonium salt, (I), the ammonium cations, arsonate anions and water molecules interact through inter-species N-H...O and arsonate and water O-H...O hydrogen bonds, giving the common two-dimensional layers lying parallel to (010). These layers are extended into three dimensions through bridging hydrogen-bonding interactions involving the para-amine group acting both as a donor and an acceptor. In the structure of the sodium salt, (II), the Na(+) cation is coordinated by five O-atom donors, one from a single monodentate arsonate ligand, two from monodentate water molecules and two from bridging water molecules, giving a very distorted square-pyramidal coordination environment. The water bridges generate one-dimensional chains extending along c and extensive interchain O-H...O and N-H...O hydrogen-bonding interactions link these chains, giving an overall three-dimensional structure. The two structures reported here are the first reported examples of salts of p-arsanilic acid.

Isostructural co-crystals derived from molecules with different supramolecular topologies

In this article, we report the crystal structures of five halogen bonded co-crystals comprising quaternary ammonium cations, halide anions (Cl– and Br–), and one of either 1,2-, 1,3-, or 1,4-diiodotetrafluorobenzene (DITFB). Three of the co-crystals are chemical isomers: 1,4-DITFB[TEA-CH2Cl]Cl, 1,2-DITFB[TEA-CH2Cl]Cl, and 1,3-DITFB[TEA-CH2Cl]Cl (where TEA-CH2Cl is chloromethyltriethylammonium ion). In each structure, the chloride anions link DITFB molecules through halogen bonds to produce 1D chains propagating with (a) linear topology in the structure containing 1,4-DITFB, (b) zigzag topology with 60° angle of propagation in that containing 1,2-DITFB, and (c) 120° angle of propagation with 1,3-DITFB. While the individual chains have highly distinctive and different topologies, they combine through π-stacking of the DITFB molecules to produce remarkably similar overall arrangements of molecules. Structures of 1,4-DITFB[TEA-CH2Br]Br and 1,3-DITFB[TEA-CH2Br]Br are also reported and are isomorphous with their chloro/chloride analogues, further illustrating the robustness of the overall supramolecular architecture. The usual approach to crystal engineering is to make structural changes to molecular components to effect specific changes to the resulting crystal structure. The results reported herein encourage pursuit of a somewhat different approach to crystal engineering. That is, to investigate the possibilities for engineering the same overall arrangement of molecules in crystals while employing molecular components that aggregate with entirely different supramolecular connectivity.

Creating change in government to address the social determinants of health: How can efforts be improved?

Background The evidence base for the impact of social determinants of health has been strengthened considerably in the last decade. Increasingly, the public health field is using this as a foundation for arguments and actions to change government policies. The Health in All Policies (HiAP) approach, alongside recommendations from the 2010 Marmot Review into health inequalities in the UK (which we refer to as the ‘Fairness Agenda’), go beyond advocating for the redesign of individual policies, to shaping the government structures and processes that facilitate the implementation of these policies. In doing so, public health is drawing on recent trends in public policy towards ‘joined up government’, where greater integration is sought between government departments, agencies and actors outside of government. Methods In this paper we provide a meta-synthesis of the empirical public policy research into joined up government, drawing out characteristics associated with successful joined up initiatives. We use this thematic synthesis as a basis for comparing and contrasting emerging public health interventions concerned with joined-up action across government. Results We find that HiAP and the Fairness Agenda exhibit some of the characteristics associated with successful joined up initiatives, however they also utilise ‘change instruments’ that have been found to be ineffective. Moreover, we find that – like many joined up initiatives – there is room for improvement in the alignment between the goals of the interventions and their design. Conclusion Drawing on public policy studies, we recommend a number of strategies to increase the efficacy of current interventions. More broadly, we argue that up-stream interventions need to be ‘fit-for-purpose’, and cannot be easily replicated from one context to the next.

A 2-hour diagnostic protocol for possible cardiac chest pain in the emergency department: A randomized clinical trial

IMPORTANCE Patients with chest pain represent a high health care burden, but it may be possible to identify a patient group with a low short-term risk of adverse cardiac events who are suitable for early discharge. OBJECTIVE To compare the effectiveness of a rapid diagnostic pathway with a standard-care diagnostic pathway for the assessment of patients with possible cardiac chest pain in a usual clinical practice setting. DESIGN, SETTING, AND PARTICIPANTS A single-center, randomized parallel-group trial with blinded outcome assessments was conducted in an academic general and tertiary hospital. Participants included adults with acute chest pain consistent with acute coronary syndrome for whom the attending physician planned further observation and troponin testing. Patient recruitment occurred from October 11, 2010, to July 4, 2012, with a 30-day follow-up. INTERVENTIONS An experimental pathway using an accelerated diagnostic protocol (Thrombolysis in Myocardial Infarction score, 0; electrocardiography; and 0- and 2-hour troponin tests) or a standard-care pathway (troponin test on arrival at hospital, prolonged observation, and a second troponin test 6-12 hours after onset of pain) serving as the control. MAIN OUTCOMES AND MEASURES Discharge from the hospital within 6 hours without a major adverse cardiac event occurring within 30 days. RESULTS Fifty-two of 270 patients in the experimental group were successfully discharged within 6 hours compared with 30 of 272 patients in the control group (19.3% vs 11.0%; odds ratio, 1.92; 95% CI, 1.18-3.13; P = .008). It required 20 hours to discharge the same proportion of patients from the control group as achieved in the experimental group within 6 hours. In the experimental group, 35 additional patients (12.9%) were classified as low risk but admitted to an inpatient ward for cardiac investigation. None of the 35 patients received a diagnosis of acute coronary syndrome after inpatient evaluation. CONCLUSIONS AND RELEVANCE Using the accelerated diagnostic protocol in the experimental pathway almost doubled the proportion of patients with chest pain discharged early. Clinicians could discharge approximately 1 of 5 patients with chest pain to outpatient follow-up monitoring in less than 6 hours. This diagnostic strategy could be easily replicated in other centers because no extra resources are required.

A quantitative metric to identify critical elements within seafood supply networks

A theoretical basis is required for comparing key features and critical elements in wild fisheries and aquaculture supply chains under a changing climate. Here we develop a new quantitative metric that is analogous to indices used to analyse food-webs and identify key species. The Supply Chain Index (SCI) identifies critical elements as those elements with large throughput rates, as well as greater connectivity. The sum of the scores for a supply chain provides a single metric that roughly captures both the resilience and connectedness of a supply chain. Standardised scores can facilitate cross-comparisons both under current conditions as well as under a changing climate. Identification of key elements along the supply chain may assist in informing adaptation strategies to reduce anticipated future risks posed by climate change. The SCI also provides information on the relative stability of different supply chains based on whether there is a fairly even spread in the individual scores of the top few key elements, compared with a more critical dependence on a few key individual supply chain elements. We use as a case study the Australian southern rock lobster Jasus edwardsii fishery, which is challenged by a number of climate change drivers such as impacts on recruitment and growth due to changes in large-scale and local oceanographic features. The SCI identifies airports, processors and Chinese consumers as the key elements in the lobster supply chain that merit attention to enhance stability and potentially enable growth. We also apply the index to an additional four real-world Australian commercial fishery and two aquaculture industry supply chains to highlight the utility of a systematic method for describing supply chains. Overall, our simple methodological approach to empirically-based supply chain research provides an objective method for comparing the resilience of supply chains and highlighting components that may be critical.

Alteration of the C-terminal ligand specificity of the Erbin PDZ domain by allosteric mutational effects

Modulation of protein binding specificity is important for basic biology and for applied science. Here we explore how binding specificity is conveyed in PDZ (postsynaptic density protein-95/discs large/zonula occludens-1) domains, small interaction modules that recognize various proteins by binding to an extended C terminus. Our goal was to engineer variants of the Erbin PDZ domain with altered specificity for the most C-terminal position (position 0) where a Val is strongly preferred by the wild-type domain. We constructed a library of PDZ domains by randomizing residues in direct contact with position 0 and in a loop that is close to but does not contact position 0. We used phage display to select for PDZ variants that bind to 19 peptide ligands differing only at position 0. To verify that each obtained PDZ domain exhibited the correct binding specificity, we selected peptide ligands for each domain. Despite intensive efforts, we were only able to evolve Erbin PDZ domain variants with selectivity for the aliphatic C-terminal side chains Val, Ile and Leu. Interestingly, many PDZ domains with these three distinct specificities contained identical amino acids at positions that directly contact position 0 but differed in the loop that does not contact position 0. Computational modeling of the selected PDZ domains shows how slight conformational changes in the loop region propagate to the binding site and result in different binding specificities. Our results demonstrate that second-sphere residues could be crucial in determining protein binding specificity.

SERS-barcoded colloidal gold NP assemblies as imaging agents for use in biodiagnostics

There is a growing need for new biodiagnostics that combine high throughput with enhanced spatial resolution and sensitivity. Gold nanoparticle (NP) assemblies with sub-10 nm particle spacing have the benefits of improving detection sensitivity via Surface enhanced Raman scattering (SERS) and being of potential use in biomedicine due to their colloidal stability. A promising and versatile approach to form solution-stable NP assemblies involves the use of multi-branched molecular linkers which allows tailoring of the assembly size, hot-spot density and interparticle distance. We have shown that linkers with multiple anchoring end-groups can be successfully employed as a linker to assemble gold NPs into dimers, linear NP chains and clustered NP assemblies. These NP assemblies with diameters of 30-120 nm are stable in solution and perform better as SERS substrates compared with single gold NPs, due to an increased hot-spot density. Thus, tailored gold NP assemblies are potential candidates for use as biomedical imaging agents. We observed that the hot-spot density and in-turn the SERS enhancement is a function of the linker polymer concentration and polymer architecture. New deep Raman techniques like Spatially Offset Raman Spectroscopy (SORS) have emerged that allow detection from beneath diffusely scattering opaque materials, including biological media such as animal tissue. We have been able to demonstrate that the gold NP assemblies could be detected from within both proteinaceous and high lipid containing animal tissue by employing a SORS technique with a backscattered geometry.

Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P combined = 2.76 × 10 -17 and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species. © 2013 Nature America, Inc. All rights reserved.

Fine mapping and replication of genetic risk Loci in primary sclerosing cholangitis

Background and aims. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts eventually leading to biliary cirrhosis. Recent genetic studies in PSC have identified associations at 2q13, 2q35, 3p21, 4q27, 13q31 and suggestive association at 10p15. The aim of this study was to further characterize and refine the genetic architecture of PSC. Methods. We analyzed previously reported associated SNPs at four of these non-HLA loci and 59 SNPs tagging the IL-2/IL-21 (4q27) and IL2RA (10p15) loci in 992 UK PSC cases and 5162 healthy UK controls. Results. The most associated SNPs identified were rs3197999 (3p21 (MST1), p = 1.9 × 10 -6, OR A vs G = 1.28, 95% CI (1.16-1.42)); rs4147359 (10p15 (IL2RA), p = 2.6 × 10 -4, OR A vs G = 1.20, 95% CI (1.09-1.33)) and rs12511287 (4q27 (IL-2/IL-21), p = 3.0 × 10 -4, OR A vs T = 1.21, 95% CI (1.09-1.35)). In addition, we performed a meta-analysis for selected SNPs using published summary statistics from recent studies. We observed genome-wide significance for rs3197999 (3p21 (MST1), P combined = 3.8 × 10 -12) and rs4147359 (10p15 (IL2RA), P combined = 1.5 × 10 -8). Conclusion. We have for the first time confirmed the association of PSC with genetic variants at 10p15 (IL2RA) locus at genome-wide significance and replicated the associations at MST1 and IL-2/IL-21 loci in a large homogeneous UK population. These results strongly implicate the role of IL-2/IL2RA pathway in PSC and provide further confirmation of MST1 association. © Informa Healthcare.

Common variants at 12q14 and 12q24 are associated with hippocampal volume

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10 -7. In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10 -11) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10 -11). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10 -7) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10 -7); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.