Solidarity through National Pride: The Future of Catholic Politics in the 21st Century

This paper raises the Pragmatist concepts of solidarity and national pride, as espoused by American philosophers such as John Dewey and Richard Rorty, as potential means for Catholics in Western democratic nations to approach the current political issues facing them in the 21st century. Though Dewey and Rorty were neither politicians nor Catholics (being liberal thinkers trained in philosophy), their views on solidarity and patriotism in modern liberal democracies provide useful roadmaps for Catholics in Europe and the Anglosphere to navigate our present period of polarised and highly partisan politics, potentially reaching a ‘sensible centre’ akin to the American Catholic political tradition since the 1930s. This centrism relies on this Pragmatist solidarity through a shared hope of a pluralistic society constantly improved upon for the benefit of future generations. Catholics can only achieve this solidarity and hope if they feel, in the spirit of Rorty, a deep sense of national pride for their country. This type of national pride is not reactionary in nature, but advocates a politics of pluralism rather than identity, democratic nationalism rather than amorphous internationalism, and active engagement in the public square to implement an achievable political programme of action which is hopeful and borne out of a collective imagination for a better future for their countries

Diversity of the parB and repA genes of the Burkholderia cepacia complex and their utility for rapid identification of Burkholderia cenocepacia

Background: Burkholderia cenocepacia is the most prominent species of the B. cepacia complex (Bcc), a group of nine closely related and difficult to identify bacteria that cause serious infections in patients with cystic fibrosis. Despite its clinical relevance, identification of B. cenocepacia as a single species is unavailable, as it splits by a widely used recA gene-based PCR identification method into discrete phylogenetic subgroups IIIA, IIIB, IIIC and IIID. With the aim of identifying gene targets suitable for unified detection of B. cenocepacia strains, we examined sequence polymorphisms in the repA and parB genes. These essential genes are involved in the replication and partitioning of bacterial replicons, hence we also had the opportunity for the first time to investigate the evolution of the multireplicon (three chromosome) structure of Bcc genomes. Results: Alignment of the repA and parB genes from publicly available Bcc genome sequences enabled the design of primers for their amplification and sequence analysis. Multilocus sequencing typing, a highly discriminatory method for Bcc species and strain discrimination, was used to select strains of unique sequence types (STs) that spanned the known Bcc genetic diversity. Sequence datasets of repA (83 isolates, 67 STs) and parB (120 isolates, 95 STs) genes from the second chromosome were aligned and examined phylogenetically to identify polymorphisms suitable for identification of B. cenocepacia. In contrast to parB, the Bcc repA sequences demonstrated distinct clustering of B. cenocepacia from other species, which enabled the design a species-specific multiplex PCR. The novel single-reaction B. cenocepacia detection method was tested on a panel of 142 different Bcc strains (142 STs) and distinguished recA groups IIIA, IIIB and IIID, from all other Bcc members with 100% sensitivity and 93% specificity. Conclusion: The repA-based multiplex PCR is a useful aid to the rapid identification of the most clinically relevant B. cenocepacia recA subgroups IIIA, IIIB and IIID. Phylogenetic analysis of repA and parB genes demonstrated that acquisition of the second and third replicons of Bcc genomes occurred prior to their differentiation into discrete species and that the sharing of replicons across species had not occurred

DNA methylation in fibrosis

Fibrosis is characterised by an exuberant wound healing response and the major cell type responsible is the myofibroblast. The myofibroblast is typified by excessive ECM production and contractile activity and is demarcated by alpha-smooth muscle actin expression. What has recently come to light is that the activation of the fibroblast to myofibroblast may be under epigenetic control, specifically methylation. Methylation of DNA is a conserved mechanism to precisely regulate gene expression in a specific context. Hypermethylation leads to gene repression and hypomethylation results in gene induction. Methylation abnormalities have recently been uncovered in fibrosis, both organ specific and widespread fibrosis. The fact that these methylation changes are rapid and reversible lends themselves amenable to therapeutic intervention. This review considers the role of methylation in fibrosis and the activation of the myofibroblasts and how this could be targeted for fibrosis. Fibrosis is of course currently intractable to therapeutics and is a leading cause of morbidity and mortality and is an urgent unmet clinical need

Evaluation of salivary sirtuin 2 as a novel biomarker for periodontitis

PhD ThesisSIRT2 is an NAD-dependent histone deacetylase (HDAC) that is involved in the regulation of gene expression and protein function. This study aimed to evaluate SIRT2 as a salivary biomarker for periodontitis and investigate any association between SIRT2 and the inflammatory processes relevant to periodontitis. Immune responses were investigated in vitro using THP1 monocytes differentiated into macrophages using phorbol 12-myristate 13-acetate (PMA) and stimulated with TLR2 or TLR4 agonists. Analysis using qPCR and western blotting showed there were no significant changes to SIRT2 mRNA or intracellular protein expression respectively after stimulation with TLR agonists. Secreted SIRT2 levels measured by ELISA were significantly elevated after stimulation with TLR2 agonists but not after stimulation with TLR4 agonists. TLR agonists had no effect on SIRT2 deacetylation activity in macrophages. Inhibition experiments in macrophages showed that SIRT2 regulates secretion of TNFα, IL-6, IL-8, and IL-1β as measured by ELISA. Multiple regression analysis (ANCOVA) showed that SIRT2 was significantly elevated in periodontitis when accounting for the influence of age but SIRT2 levels did not correlate with clinical measurements of periodontitis such as bleeding on probing and pocket depth. Receiver operating characteristic (ROC) curve analysis showed that salivary SIRT2 could detect periodontitis with a high degree of sensitivity and specificity (AUC 89%). In summary, SIRT2 levels accurately represent the presence of periodontitis, but do not correlate with clinical measures of periodontitis, which may limit its utility as a diagnostic biomarker. We have demonstrated a novel TLR2-mediated pathway of SIRT2 secretion from THP1-derived macrophages which may explain the elevated levels of SIRT2 present in the saliva of patients with periodontitis but will require further investigation. We have also shown that SIRT2 mediates the secretion of pro-inflammatory cytokines after stimulation with TLR agonists which may be of relevance to the pathogenesis of periodontitis

Nod1 signaling overcomes resistance of S. pneumoniae to opsonophagocytic killing

Airway infection by the Gram-positive pathogen Streptococcus pneumoniae (Sp) leads to recruitment of neutrophils but limited bacterial killing by these cells. Co-colonization by Sp and a Gram-negative species, Haemophilus influenzae (Hi), provides sufficient stimulus to induce neutrophil and complement-mediated clearance of Sp from the mucosal surface in a murine model. Products from Hi, but not Sp, also promote killing of Sp by ex vivo neutrophil-enriched peritoneal exudate cells. Here we identify the stimulus from Hi as its peptidoglycan. Enhancement of opsonophagocytic killing was facilitated by signaling through nucleotide-binding oligomerization domain-1 (Nod1), which is involved in recognition of γ-D-glutamyl-meso-diaminopimelic acid (meso-DAP) contained in cell walls of Hi but not Sp. Neutrophils from mice treated with Hi or compounds containing meso-DAP, including synthetic peptidoglycan fragments, showed increased Sp killing in a Nod1-dependent manner. Moreover, Nod1-/- mice showed reduced Hi-induced clearance of Sp during co-colonization. These observations offer insight into mechanisms of microbial competition and demonstrate the importance of Nod1 in neutrophil-mediated clearance of bacteria in vivo

Multilocus sequence typing of Cronobacter sakazakii and Cronobacter malonaticus reveals stable clonal structures with clinical significance which do not correlate with biotypes

Background: The Cronobacter genus (Enterobacter sakazakii) has come to prominence due to its association with infant infections, and the ingestion of contaminated reconstituted infant formula. C. sakazakii and C. malonaticus are closely related, and are defined according their biotype. Due to the ubiquitous nature of the organism, and the high severity of infection for the immunocompromised, a multilocus sequence typing (MLST) scheme has been developed for the fast and reliable identification and discrimination of C. sakazakii and C. malonaticus strains. It was applied to 60 strains of C. sakazakii and 16 strains of C. malonaticus, including the index strains used to define the biotypes. The strains were from clinical and non-clinical sources between 1951 and 2008 in USA, Canada, Europe, New Zealand and the Far East. Results: This scheme uses 7 loci; atpD, fusA, glnS, gltB, gyrB, infB, and pps. There were 12 sequence types (ST) identified in C. sakazakii, and 3 in C. malonaticus. A third (22/60) of C. sakazakii strains were in ST4, which had almost equal numbers of clinical and infant formula isolates from 1951 to 2008. ST8 may represent a particularly virulent grouping of C. sakazakii as 7/8 strains were clinical in origin which had been isolated between 1977 - 2006, from four countries. C. malonaticus divided into three STs. The previous Cronobacter biotyping scheme did not clearly correspond with STs nor with species. Conclusion: In conclusion, MLST is a more robust means of identifying and discriminating between C. sakazakii and C. malonaticus than biotyping. The MLST database for these organisms is available online at http://pubmlst.org/cronobacter

Touching proteins with virtual bare hands : visualizing protein–drug complexes and their dynamics in self-made virtual reality using gaming hardware

The ability to precisely visualize the atomic geometry of the interactions between a drug and its protein target in structural models is critical in predicting the correct modifications in previously identified inhibitors to create more effective next generation drugs. It is currently common practice among medicinal chemists while attempting the above to access the information contained in three-dimensional structures by using two-dimensional projections, which can preclude disclosure of useful features. A more accessible and intuitive visualization of the three-dimensional configuration of the atomic geometry in the models can be achieved through the implementation of immersive virtual reality (VR). While bespoke commercial VR suites are available, in this work, we present a freely available software pipeline for visualising protein structures through VR. New consumer hardware, such as the HTC Vive and the Oculus Rift utilized in this study, are available at reasonable prices. As an instructive example, we have combined VR visualization with fast algorithms for simulating intramolecular motions of protein flexibility, in an effort to further improve structure-led drug design by exposing molecular interactions that might be hidden in the less informative static models. This is a paradigmatic test case scenario for many similar applications in computer-aided molecular studies and design

AMR policy dialogue : driving innovative solutions for antimicrobial discovery

Antimicrobial resistance (AMR) is a global strategic priority and sits within the UK Government’s National Risk Register. By 2050, AMR is predicted to cause 10 million deaths, more than cancer. In 2019 alone, there were an estimated 4.95 million deaths associated with bacterial AMR. Although global pharmaceutical research and development (R&D) spend continues to increase year on year, research into antimicrobial drug discovery is not currently an attractive commercial investment. This has had two major consequences: an ongoing decline of human capital for R&D in this field, and a decline over the longer term in availability of therapeutically effective antibiotics and other antimicrobial agents. Concerted and coordinated efforts are needed to translate high-level policy commitments into strategic actions for long-term funding and support for the R&D of new antimicrobials

Investigating bacteriophages targeting the opportunistic pathogen Acinetobacter baumannii

The multi-drug resistance of the opportunistic pathogen Acinetobacter baumannii is of growing concern, with many clinical isolates proving to be resistant to last resort as well as front line antibiotic treatments. The use of bacteriophages is an attractive alternative to controlling and treating this emerging nosocomial pathogen. In this study, we have investigated bacteriophages collected from hospital wastewater in Thailand and we have explored their activity against clinical isolates of A. baumannii. Bacteriophage vB_AbaM_PhT2 showed 28% host range against 150 multidrug resistant (MDR) isolates and whole genome sequencing did not detect any known virulence factors or antibiotic resistance genes. Purified vB_AbaM_PhT2 samples had endotoxin levels below those recommended for preclinical trials and were not shown to be directly cytotoxic to human cell lines in vitro. The treatment of human brain and bladder cell lines grown in the presence of A. baumannii with this bacteriophage released significantly less lactate dehydrogenase compared to samples with no bacteriophage treatment, indicating that vB_AbaM_PhT2 can protect from A. baumannii induced cellular damage. Our results have also indicated that there is synergy between this bacteriophage and the end line antibiotic colistin. We therefore propose bacteriophage vB_AbaM_PhT2 as a good candidate for future research and for its potential development into a surface antimicrobial for use in hospitals. View Full-Tex