A peptide mimic of the chemotaxis inhibitory protein of Staphylococcus aureus: towards the development of novel anti-inflammatory compounds

Complement factor C5a is one of the most powerful pro-inflammatory agents involved in recruitment of leukocytes, activation of phagocytes and other inflammatory responses. C5a triggers inflammatory responses by binding to its G-protein-coupled C5a-receptor (C5aR). Excessive or erroneous activation of the C5aR has been implicated in numerous inflammatory diseases. The C5aR is therefore a key target in the development of specific anti-inflammatory compounds. A very potent natural inhibitor of the C5aR is the 121-residue chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS). Although CHIPS effectively blocks C5aR activation by binding tightly to its extra-cellular N terminus, it is not suitable as a potential anti-inflammatory drug due to its immunogenic properties. As a first step in the development of an improved CHIPS mimic, we designed and synthesized a substantially shorter 50-residue adapted peptide, designated CHOPS. This peptide included all residues important for receptor binding as based on the recent structure of CHIPS in complex with the C5aR N terminus. Using isothermal titration calorimetry we demonstrate that CHOPS has micromolar affinity for a model peptide comprising residues 7–28 of the C5aR N terminus including two O-sulfated tyrosine residues at positions 11 and 14. CD and NMR spectroscopy showed that CHOPS is unstructured free in solution. Upon addition of the doubly sulfated model peptide, however, the NMR and CD spectra reveal the formation of structural elements in CHOPS reminiscent of native CHIPS

Moving from information and collaboration to action: report from the 3rd International Dog Health Workshop, Paris in April 2017

Abstract Background Breed-related health problems in dogs have received increased focus over the last decade. Responsibility for causing and/or solving these problems has been variously directed towards dog breeders and kennel clubs, the veterinary profession, welfare scientists, owners, regulators, insurance companies and the media. In reality, all these stakeholders are likely to share some responsibility and optimal progress on resolving these challenges requires all key stakeholders to work together. The International Partnership for Dogs (IPFD), together with an alternating host organization, holds biennial meetings called the International Dog Health Workshops (IDHW). The Société Centrale Canine (French Kennel Club) hosted the 3rd IDHW, in Paris, in April, 2017. These meetings bring together a wide range of stakeholders in dog health, science and welfare to improve international sharing of information and resources, to provide a forum for ongoing collaboration, and to identify specific needs and actions to improve health, well-being and welfare in dogs. Results The workshop included 140 participants from 23 countries and was structured around six important issues facing those who work to improve dog health. These included individualized breed-specific strategies for health and breeding, extreme conformations, education and communication in relation to antimicrobial resistance, behavior and welfare, genetic testing and population-based evidence. A number of exciting actions were agreed during the meeting. These included setting up working groups to create tools to help breed clubs accelerate the implementation of breed-health strategies, review aspects of extreme conformation and share useful information on behavior. The meeting also heralded the development of an online resource of relevant information describing quality measures for DNA testing. A demand for more and better data and evidence was a recurring message stressed across all themes. Conclusions The meeting confirmed the benefits from inclusion of a diverse range of stakeholders who all play relevant and collaborative parts to improve future canine health. Firm actions were set for progress towards improving breed-related welfare. The next international workshop will be in the UK in 2019 and will be organized by the UK Kennel Club

A novel evolutionary strategy revealed in the Phaeoviruses

Phaeoviruses infect the brown algae, which are major contributors to primary production of coastal waters and estuaries. They exploit a Persistent evolutionary strategy akin to a K- selected life strategy via genome integration and are the only known representatives to do so within the giant algal viruses that are typified by r- selected Acute lytic viruses. In screening the genomes of five species within the filamentous brown algal lineage, here we show an unprecedented diversity of viral gene sequence variants especially amongst the smaller phaeoviral genomes. Moreover, one variant shares features from both the two major sub-groups within the phaeoviruses. These phaeoviruses have exploited the reduction of their giant dsDNA genomes and accompanying loss of DNA proofreading capability, typical of an Acute life strategist, but uniquely retain a Persistent life strategy

Developing a community based psychosocial intervention with older people and third sector workers for anxiety and depression: a qualitative study

Background: One-in-five people in the UK experience anxiety and/or depression in later life. However, anxiety and depression remain poorly detected in older people, particularly in those with chronic physical ill health. In the UK, a stepped care approach, to manage common mental health problems, is advocated which includes service provision from non-statutory organisations (including third/voluntary sector). However, evidence to support such provision, including the most effective interventions, is limited. The qualitative study reported here constitutes the first phase of a feasibility study which aims to assess whether third sector workers can deliver a psychosocial intervention to older people with anxiety and/or depression. The aim of this qualitative study is to explore the views of older people and third sector workers about anxiety and depression among older people in order to refine an intervention to be delivered by third sector workers. Methods: Semi-structured interviews with participants recruited through purposive sampling from third sector groups in North Staffordshire. Interviews were digitally recorded with consent, transcribed and analysed using principles of constant comparison. Results: Nineteen older people and 9 third sector workers were interviewed. Key themes included: multiple forms of loss, mental health as a personal burden to bear, having courage and providing/receiving encouragement, self- worth and the value of group activities, and tensions in existing service provision, including barriers and gaps. Conclusions: The experience of loss was seen as central to feelings of anxiety and depression among community- dwelling older people. This study contributes to the evidence pointing to the scale and severity of mental health needs for some older people which can arise from multiple forms of loss, and which present a significant challenge to health, social care and third sector services. The findings informed development of a psychosocial intervention and training for third sector workers to deliver the intervention

Burden, coping, physical symptoms and psychological morbidity in caregivers of functionally dependent family members

Objectives: this study assessed burden, coping, physical symptoms and psychological morbidity in caregivers of functionally dependent family members. Methods: fifty family caregivers completed self-reported measures of burden, physical symptoms, psychological morbidity and coping strategies. Results: there was a significant negative correlation between coping strategies and the different clinical variables, as well as a significant positive correlation between coping strategies and duration of care. It appears that the stronger bond between caregiver and family member leads to a poorer use of adaptive coping strategies. It also appears that the deterioration of the relationship between them and the lower perceived self-efficacy are more prominente in caregivers of family members with cognitive impairment, indicating that caregivers with family members without cognitive impairment face fewer difficulties. Conclusion: these results emphasize the need for interventions to include coping strategies, since they are important in reducing caregivers’ burden, psychological morbidity and physical symptoms

Do specialty registrars change their attitudes, intentions and behaviour towards reporting incidents following a patient safety course?

<p>Abstract</p> <p>Background</p> <p>Reporting incidents can contribute to safer health care, as an awareness of the weaknesses of a system could be considered as a starting point for improvements. It is believed that patient safety education for specialty registrars could improve their attitudes, intentions and behaviour towards incident reporting. The objective of this study was to examine the effect of a two-day patient safety course on the attitudes, intentions and behaviour concerning the voluntary reporting of incidents by specialty registrars.</p> <p>Methods</p> <p>A patient safety course was designed to increase specialty registrars' knowledge, attitudes and skills in order to recognize and cope with unintended events and unsafe situations at an early stage. Data were collected through an 11-item questionnaire before, immediately after and six months after the course was given.</p> <p>Results</p> <p>The response rate at all three points in time assessed was 100% (n = 33). There were significant changes in incident reporting attitudes and intentions immediately after the course, as well as during follow-up. However, no significant changes were found in incident reporting behaviour.</p> <p>Conclusions</p> <p>It is shown that patient safety education can have long-term positive effects on attitudes towards reporting incidents and the intentions of registrars. However, further efforts need to be undertaken to induce a real change in behaviour.</p

Downsizing a human inflammatory protein to a small molecule with equal potency and functionality

A significant challenge in chemistry is to rationally reproduce the functional potency of a protein in a small molecule, which is cheaper to manufacture, non-immunogenic, and also both stable and bioavailable. Synthetic peptides corresponding to small bioactive protein surfaces do not form stable structures in water and do not exhibit the functional potencies of proteins. Here we describe a novel approach to growing small molecules with protein-like potencies from a functionally important amino acid of a protein. A 77-residue human inflammatory protein (complement C3a) important in innate immunity is rationally transformed to equipotent small molecules, using peptide surrogates that incorporate a turn-inducing heterocycle with correctly positioned hydrogen-bond-accepting atoms. Small molecule agonists (molecular weigh

Immunosenescence and lymphomagenesis

One of the most important determinants of aging-related changes is a complex biological process emerged recently and called \u201cimmunosenescence\u201d. Immunosenescence refers to the inability of an aging immune system to produce an appropriate and effective response to challenge. This immune dysregulation may manifest as increased susceptibility to infection, cancer, autoimmune disease, and vaccine failure. At present, the relationship between immunosenescence and lymphoma in elderly patients is not defined in a satisfactory way. This review presents a brief overview of the interplay between aging, cancer and lymphoma, and the key topic of immunosenescence is addressed in the context of two main lymphoma groups, namely Non Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL). Epstein Barr Virus (EBV) plays a central role in the onset of neoplastic lymphoproliferation associated with immunological changes in aging, although the pathophysiology varies vastly among different disease entities. The interaction between immune dysfunction, immunosenescence and Epstein Barr Virus (EBV) infection appears to differ between NHL and HL, as well as between NHL subtypes

Phylogenetically and spatially close marine sponges harbour divergent bacterial communities

Recent studies have unravelled the diversity of sponge-associated bacteria that may play essential roles in sponge health and metabolism. Nevertheless, our understanding of this microbiota remains limited to a few host species found in restricted geographical localities, and the extent to which the sponge host determines the composition of its own microbiome remains a matter of debate. We address bacterial abundance and diversity of two temperate marine sponges belonging to the Irciniidae family - Sarcotragus spinosulus and Ircinia variabilis – in the Northeast Atlantic. Epifluorescence microscopy revealed that S. spinosulus hosted significantly more prokaryotic cells than I. variabilis and that prokaryotic abundance in both species was about 4 orders of magnitude higher than in seawater. Polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) profiles of S. spinosulus and I. variabilis differed markedly from each other – with higher number of ribotypes observed in S. spinosulus – and from those of seawater. Four PCR-DGGE bands, two specific to S. spinosulus, one specific to I. variabilis, and one present in both sponge species, affiliated with an uncultured sponge-specific phylogenetic cluster in the order Acidimicrobiales (Actinobacteria). Two PCR-DGGE bands present exclusively in S. spinosulus fingerprints affiliated with one sponge-specific phylogenetic cluster in the phylum Chloroflexi and with sponge-derived sequences in the order Chromatiales (Gammaproteobacteria), respectively. One Alphaproteobacteria band specific to S. spinosulus was placed in an uncultured sponge-specific phylogenetic cluster with a close relationship to the genus Rhodovulum. Our results confirm the hypothesized host-specific composition of bacterial communities between phylogenetically and spatially close sponge species in the Irciniidae family, with S. spinosulus displaying higher bacterial community diversity and distinctiveness than I. variabilis. These findings suggest a pivotal host-driven effect on the shape of the marine sponge microbiome, bearing implications to our current understanding of the distribution of microbial genetic resources in the marine realm.This work was financed by the Portuguese Foundation for Science and Technology (FCT - http://www.fct.pt) through the research project PTDC/MAR/101431/2008. CCPH has a PhD fellowship granted by FCT (Grant No. SFRH/BD/60873/2009). JRX’s research is funded by a FCT postdoctoral fellowship (grant no. SFRH/BPD/62946/2009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

An inflammation-based prognostic score (mGPS) predicts cancer survival independent of tumour site: a Glasgow Inflammation Outcome Study

INTRODUCTION: A selective combination of C-reactive protein and albumin (termed the modified Glasgow Prognostic Score, mGPS) has been shown to have prognostic value, independent of tumour stage, in lung, gastrointestinal and renal cancers. It is also of interest that liver function tests such as bilirubin, alkaline phosphatase and gamma-glutamyl transferase, as well as serum calcium, have also been reported to predict cancer survival. The aim of the present study was to examine the relationship between an inflammation-based prognostic score (mGPS), biochemical parameters, tumour site and survival in a large cohort of patients with cancer. METHODS: Patients (n = 21 669) who had an incidental blood sample taken between 2000 and 2006 for C-reactive protein, albumin and calcium (and liver function tests where available) and a diagnosis of cancer were identified. Of this group 9608 patients who had an ongoing malignant process were studied (sampled within 2 years before diagnosis). Also a subgroup of 5397 sampled at the time of diagnosis (sampled within 2 months prior to diagnosis) were examined. Cancers were grouped by tumour site in accordance with International Classification of Diseases 10 (ICD 10). RESULTS: On follow up, there were 6005 (63%) deaths of which 5122 (53%) were cancer deaths. The median time from blood sampling to diagnosis was 1.4 months. Increasing age, male gender and increasing deprivation was associated with a reduced 5-year overall and cancer-specific survival (all P &lt; 0.001). An elevated mGPS, adjusted calcium, bilirubin, alkaline phosphatase, aspartate transaminase, alanine transaminase and gamma-glutamyl transferase were associated with a reduced 5-year overall and cancer-specific survival (independent of age, sex and deprivation in all patients sampled), as well as within the time of diagnosis subgroup (all P &lt; 0.001). An increasing mGPS was predictive of a reduced cancer-specific survival in all cancers (all P &lt; 0.001). CONCLUSION: The results of the present study indicate that the mGPS is a powerful prognostic factor when compared with other biochemical parameters and independent of tumour site in patients with cancer