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BACKGROUND: Treatment with Ivacaftor provides a significant clinical benefit in people with cystic fibrosis (PWCF) with the class III G551D-CFTR mutation. This study determined the effect of CFTR modulation with ivacaftor on the lung microbiota in PWCF.METHODS: Using both extended-culture and culture-independent molecular methods, we analysed the lower airway microbiota of 14 PWCF, prior to commencing ivacaftor treatment and at the last available visit within the following year. We determined total bacterial and Pseudomonas aeruginosa densities by both culture and qPCR, assessed ecological parameters and community structure and compared these with biomarkers of inflammation and clinical outcomes.RESULTS: Significant improvement in FEV1, BMI, sweat chloride and levels of circulating inflammatory biomarkers were observed POST-ivacaftor treatment. Extended-culture demonstrated a higher density of strict anaerobic bacteria (p = 0.024), richness (p = 1.59*10-4) and diversity (p = 0.003) POST-treatment. No significant difference in fold change was observed by qPCR for either total bacterial 16S rRNA copy number or P. aeruginosa density for oprL copy number with treatment. Culture-independent (MiSeq) analysis revealed a significant increase in richness (p = 0.03) and a trend towards increased diversity (p = 0.07). Moreover, improvement in lung function, richness and diversity displayed an inverse correlation with the main markers of inflammation (p < 0.05).CONCLUSIONS: Following treatment with ivacaftor, significant improvements in clinical parameters were seen. Despite modest changes in overall microbial community composition, there was a shift towards a bacterial ecology associated with less severe CF lung disease. Furthermore, a significant correlation was observed between richness and diversity and levels of circulating inflammatory markers.

This repeated-measures case series describes the changes in cardiorespiratory fitness, body composition and systemic inflammation in 4 well-trained athletes pre- and post-completion of an unsupported transatlantic rowing race. The acute effects of endurance exercise have been well described previously, but the enduring consequences of ultra-endurance on the cardiorespiratory, metabolic and immune systems are largely unknown. This study explores these physiological adaptations following 2 weeks of recovery. Cardiorespiratory fitness testing, body composition analysis, and blood sampling for inflammatory cytokines were recorded immediately before race departure and repeated 14 days following race completion. Mean VO2max (ml/kg/min) was similar pre- (48.2±2.8) and post-race (46.7±1.5). Heart rate responses were equivalent at incremental workloads. Mean blood lactate (mmol/L) was higher at low to moderate power outputs and lower at maximal effort (14.6±1.85 vs. 13.1±2.5). Percentage body fat (17.7 ± 7.9 vs. 16.2±7.4) was analogous to pre-race analysis. Low-grade inflammation persisted, indicated by an increase in IL-1β (69%), IL-8 (10%), TNF-α (8%), IL-6 (5.4%), and C-reactive protein (22.4%). VO2max and heart rate responses were similar pre- and post-race, but sub-maximal efficiency measures of cardiorespiratory fitness were consistent with persistent fatigue. Body composition had returned to baseline but low-grade systemic inflammation persisted. Persistent pro-inflammatory cytokinaemia is known to exert deleterious consequences on immune, metabolic, and psychological function. Adequate recovery is necessary to re-establish inflammatory homeostasis, and the results of this study may inform these decisions.

In this paper, we analyse the effect of the introduction of macroprudential limits on loan-to-value ratios on the borrowing behaviour of first-time-home-buyers in Ireland. Observing lending activity pre- and post- the unanticipated introduction of the regulations in 2015, we estimate the direct effect of the regulations on first-time-buyer leverage and house purchasing decisions. We exploit a unique provision in the macroprudential framework, that places different loan-to-value limits on properties above and below a fixed house price (€ 220,000), to determine the causal effect of the macroprudential measures on this group of borrowers. We find that LTVs fell by approximately 1.4 percentage points after the measures, with larger reductions recorded for high income borrowers. We also find that borrowers increased their downpayments in response to the regulations, with no change in the house price paid. However, findings differ across the income distribution, indicating the impact of wealth constraints on borrower behaviour. This research reinforces the importance of using granular data to understand the impact of loan-to-value regulations.

Pirfenidone is a novel anti-fibrotic agent in idiopathic pulmonary fibrosis with proven clinical benefit. Better human tissue models to demonstrate the immunomodulatory and anti-fibrotic effect of pirfenidone are required. The purpose of the study was to use transbronchial lung cryobiopsy (TBLC), a novel technique which provides substantial tissue samples, and a large panel of biomarkers to temporally assess disease activity and response to pirfenidone therapy. Thirteen patients with confirmed idiopathic pulmonary fibrosis (IPF) underwent full physiological and radiological assessment at diagnosis and after 6-month pirfenidone therapy. They underwent assessment for a wide range of potential serum and bronchoalveolar lavage biomarkers of disease activity. Finally, they underwent TBLC before and after treatment. Tissue samples were assessed for numbers of fibroblast foci, for Ki-67, a marker of tissue proliferation and caspase-3, a marker of tissue apoptosis. All patients completed treatment and investigations without significant incident. There was no significant fall in number of fibroblast foci per unit tissue volume after treatment (pre-treatment: 0.14/mm2 vs. post-treatment 0.08/mm2, p = 0.1). Likewise, there was no significant change in other markers of tissue proliferation, Ki-67 or Caspase-3 with pirfenidone treatment. We found an increase in three bronchoalveolar lavage angiogenesis cytokines, Placental Growth Factor, Vascular Endothelial Growth Factor-A, and basic Fibroblast Growth Factor, two anti-inflammatory cytokines Interleukin-10 and Interleukin-4 and Surfactant Protein-D. TBLC offers a unique opportunity to potentially assess the course of disease activity and response to novel anti-fibrotic activity in IPF.

Objective: Patients (F508del/F508del or F508del/MF) with severe CF (ppFEV1

Background: Medical professionals are aware that patients continue to use the internet as a medical information source. With the advent of government campaigns to increase awareness of data privacy and information sources, we investigate how the landscape of internet postings has changed for CF and how this could affect patients seeking online medical information. Methods: Key phrases relating to CF were identified by a CF multidisciplinary team and entered in Google Alerts with prospective tracking for 6 months in 2015. Alerts were also created for 3 non-orphan lung diseases (asthma, chronic obstructive pulmonary disease and lung fibrosis). These steps were repeated again in 2019 and the data compared. Results: In 2015, Asthma received the highest mean number of alerts per day (31.7), followed by CF (16.1), then COPD (14.6), and Lung Fibrosis (5.1). This changed in 2019 where CF was the highest with 19.5, followed by Asthma (11.5), COPD (10.3), and Lung Fibrosis (7.4). In both years, the USA generated (56%) the highest number of alerts for CF. There was an increased number of blocked articles in 2019 (540). In 2015, News (58%) was the most common category for CF alerts, but this changed to Financial/Marketing (35%) in 2019. In 2015 there was a small number of Social Media alerts recorded for all lung conditions;however, in 2019, there were none for the comparative lung conditions and only 3 for CF. Alert frequency for CF-related terms also increased in 2019. Conclusion: The landscape for internet postings for CF has changed. CF is now more commonly reported than other lung conditions and the ‘business of CF’ is now more frequently reported online while content from the general public has decreased (or is private). Medical professionals need to remain vigilant and increase awareness of information-dilution by monetary based media. A limitation of this study is that it predated the COVID-19 pandemic and it is suggested that future works revisit this at an appropriate time.

The substantial role played by greater credit provision in the international house price boom between 1995 and 2007 has lead to an increase in the use of macro-prudential measures as a means of preventing future credit bubbles. Calibration of these measures can prove difficult, however, given the relative ‘newness’ of the macro-prudential field and the limited experience with the use of these measures. Micro-loan level data can contribute to this debate by providing detail on how these measures tend to evolve across different buyer types and at different points in the business cycle. This paper uses a sample of 400,000 loans to assess the evolution of mortgage credit conditions across borrower groups in Ireland during the 2000s. The Irish case is particularly interesting given the severity of its housing boom and bust during this period. Furthermore, controlling for demand-side factors, we use the granular loan level data to provide estimates of an index of mortgage credit availability over the same period for the Irish mortgage market.

International audience

The greater use of microeconomic and survey based data in addressing key financial stability related questions is a natural outcome of the recent financial crisis. Amongst other benefits, the use of such data enables a more precise understanding of the differing attitudes and responses of individual agents such as households to financial shocks. However, some difficulties can arise with the use, in particular, of survey data in this regard. In this paper we calculate measurement error in the house prices “recalled” by a representative sample of mortgaged Irish households and illustrate the degree of attenuation bias consequently introduced into estimates of housing wealth effects, when recall as opposed to actual house prices are used.

Background We have recently shown that human epididymis protein 4 (HE4) levels correlate with the severity of cystic fibrosis (CF) lung disease. However, there are no data on how HE4 levels alter in patients receiving CFTR modulating therapy. Methods In this retrospective clinical study, 3 independent CF patient cohorts (US-American: 29, Australian: 12 and Irish: 19 cases) were enrolled carrying at least one Class III CFTR CF-causing mutation (p.Gly551Asp) and being treated with CFTR potentiator ivacaftor. Plasma HE4 was measured by immunoassay before treatment (baseline) and 1–6 months after commencement of ivacaftor, and were correlated with FEV1 (% predicted), sweat chloride, C-reactive protein (CRP) and body mass index (BMI). Results After 1 month of therapy, HE4 levels were significantly lower than at baseline and remained decreased up to 6 months. A significant inverse correlation between absolute and delta values of HE4 and FEV1 (r = −0.5376; P Conclusions This study shows that plasma HE4 levels inversely correlate with lung function improvement in CF patients receiving ivacaftor. Overall, this potential biomarker may be of value for routine clinical and laboratory follow-up of CFTR modulating therapy.

peer-reviewed Background Overweight and metabolic problems now add to the burden of illness in patients with Inflammatory Bowel Disease. We aimed to determine if a program of aerobic and resistance exercise could safely achieve body composition changes in patients with Inflammatory Bowel Disease. Methods A randomized, cross-over trial of eight weeks combined aerobic and resistance training on body composition assessed by Dual Energy X-ray Absorptiometry was performed. Patients in clinical remission and physically inactive with a mean age of 25 ± 6.5 years and Body Mass Index of 28.9 ± 3.8 were recruited from a dedicated Inflammatory Bowel Disease clinic. Serum cytokines were quantified, and microbiota assessed using metagenomic sequencing. Results Improved physical fitness was demonstrated in the exercise group by increases in median estimated VO2max (Baseline: 43.41mls/kg/min; post-intervention: 46.01mls/kg/min; p = 0.03). Improvement in body composition was achieved by the intervention group (n = 13) with a median decrease of 2.1% body fat compared with a non-exercising group (n = 7) (0.1% increase; p = 0.022). Lean tissue mass increased by a median of 1.59 kg and fat mass decreased by a median of 1.52 kg in the exercising group. No patients experienced a deterioration in disease activity scores during the exercise intervention. No clinically significant alterations in the α- and β-diversity of gut microbiota and associated metabolic pathways were evident. Conclusions Moderate-intensity combined aerobic and resistance training is safe in physically unfit patients with quiescent Inflammatory Bowel Disease and can quickly achieve favourable body compositional changes without adverse effects. Trial registration The study was registered at ClinicalTrials.gov; Trial number: NCT02463916 .

We have recently shown that human epididymis protein 4 (HE4) levels correlate with the severity of cystic fibrosis (CF) lung disease. However, there are no data on how HE4 levels alter in patients receiving CFTR modulating therapy.In this retrospective clinical study, 3 independent CF patient cohorts (US-American: 29, Australian: 12 and Irish: 19 cases) were enrolled carrying at least one Class III CFTR CF-causing mutation (p.Gly551Asp) and being treated with CFTR potentiator ivacaftor. Plasma HE4 was measured by immunoassay before treatment (baseline) and 1-6 months after commencement of ivacaftor, and were correlated with FEVAfter 1 month of therapy, HE4 levels were significantly lower than at baseline and remained decreased up to 6 months. A significant inverse correlation between absolute and delta values of HE4 and FEVThis study shows that plasma HE4 levels inversely correlate with lung function improvement in CF patients receiving ivacaftor. Overall, this potential biomarker may be of value for routine clinical and laboratory follow-up of CFTR modulating therapy.

Using a unique combination of regulatory and survey microdata, we examine the importance of the life cycle theory of consumption in estimating housing wealth effects for the Irish mortgage market. Since the recent financial crisis, this market has experienced substantial house price declines and negative equity. Thus, house price expectations are likely to be important in influencing housing wealth effects. We find a positive correlation between consumption and changes in housing wealth among our sample of mortgaged Irish households. Furthermore, we find that this positive association only exists when housing wealth changes are perceived to be of a permanent nature.

Stenotrophomonas maltophilia encodes proteins related to the Rax proteins of Xanthomonas oryzae, which are required for the synthesis and secretion of the Ax21 protein. Here we show that Ax21 acts as a cell-cell signal to regulate a diverse range of functions, including virulence, in this nosocomial pathogen.

Multiday endurance sports expose athletes to multiple physical stressors. Little is known about the athletes’ physiological responses to these stressors. A detailed understanding of the serological changes that occur during competition may improve the treatment of athletes suffering from illness or injury. This prospective, observational study aimed to characterize serological changes in AR athletes across multiday competition. Athletes underwent venipuncture at the start, midpoint, and end of a 5‐day, multidiscipline event. A variety of serological and inflammatory factors was measured and then analyzed to describe their changes over the course of the race. A total of 27 AR athletes (29.6% female, 70.4% male) met inclusion criteria out of 33 recruited initially. The mean age was 37.7 (IQR 32.5, 41). The median race time for athletes was 133 hours (IQR 123, 142). Serum creatinine, sodium, and potassium tended to remain stable as the race progressed. Conversely, serological measures, including hemoglobin, interleukin‐6, and C‐reactive protein levels, tended to change substantially during the race. Participants demonstrated the ability to maintain homeostasis, despite significant physiological threat. Renal function, electrolyte balance, and hormonal profiles were stable. However, a pro‐inflammatory response and decrease in red cell availability were evident by the midpoint of the race.

Xanthomonas citri subsp. citri (Xcc) is the causal agent of citrus canker. Biofilm formation on citrus leaves plays an important role in epiphytic survival of Xcc. Biofilm formation is affected by transposon insertion in XAC3733, which encodes a transcriptional activator of the NtrC family, not linked to a gene encoding a sensor protein, thus could be considered as an 'orphan' regulator whose function is poorly understood in Xanthomonas spp. Here we show that mutation of XAC3733 (named xbmR) resulted in impaired structural development of the Xcc biofilm, loss of chemotaxis and reduced virulence in grapefruit plants. All defective phenotypes were restored to wild-type levels by the introduction of PA2567 from Pseudomonas aeruginosa, which encodes a phosphodiesterase active in the degradation of cyclic diguanosine monophosphate (c-di-GMP). A knockout of xbmR led to a substantial downregulation of fliA that encodes a σ(28) transcription factor, as well as fliC and XAC0350 which are potential member of the σ(28) regulon. XAC0350 encodes an HD-GYP domain c-di-GMP phosphodiesterase. These findings suggest that XbmR is a key regulator of flagellar-dependent motility and chemotaxis exerting its action through a regulatory pathway that involves FliA and c-di-GMP.

Cystic Fibrosis (CF) and its treatment result in an altered gut microbiota composition compared to non-CF controls. However, the impact of this on gut microbiota functionality has not been extensively characterised. Our aim was to conduct a proof-of-principle study to investigate if measurable changes in gut microbiota functionality occur in adult CF patients compared to controls. Metagenomic DNA was extracted from faecal samples from six CF patients and six non-CF controls and shotgun metagenomic sequencing was performed on the MiSeq platform. Metabolomic analysis using gas chromatography-mass spectrometry was conducted on faecal water. The gut microbiota of the CF group was significantly different compared to the non-CF controls, with significantly increased Firmicutes and decreased Bacteroidetes. Functionality was altered, with higher pathway abundances and gene families involved in lipid (e.g. PWY 6284 unsaturated fatty acid biosynthesis (p = 0.016)) and xenobiotic metabolism (e.g. PWY-5430 meta-cleavage pathway of aromatic compounds (p = 0.004)) in CF patients compared to the controls. Significant differences in metabolites occurred between the two groups. This proof-of-principle study demonstrates that measurable changes in gut microbiota functionality occur in CF patients compared to controls. Larger studies are thus needed to interrogate this further.

Objectives: IPF is a progressive fibro-proliferative lung disease that causes destruction of lung architecture. Pirfenidone is the first licensed therapy for IPF. The aim of this prospective study is to characterise specific molecular and cellular mechanisms of patient response to Pirfenidone. We also wished to evaluate cryoprobe assisted transbronchial lung biopsy …

Objectives: IPF is a progressive fibro-proliferative lung disease that causes destruction of lung architecture. Pirfenidone is the first licensed therapy for IPF. The aim of this prospective study is to characterise specific molecular and cellular mechanisms of patient response to Pirfenidone. Methods: 13 IPF patients (mean age 68 years, 69% male) with a diagnosis confirmed at regional MDT with cryoprobe assisted transbronchial lung biopsies, were recruited and commenced on Pirfenidone at standard doses. MSD multiplex ELISA plates measured distinct panels of cytokines for vascular injury, angiogenesis, inflammation, chemokine function and fibrogensis in plasma and BAL pre-and post- 6 months of Pirfenidone. Additional ELISA assays measured TGF-β, MMP-7 and SP-D. Immunohistochemical analysis of cryoprobe assisted transbronchial lung biopsy tissue for markers of proliferation Ki67, apoptosis Caspace 3 and TGF-β were also carried out pre- and post-treatment. Results: Expression of pro-inflammatory cytokines (IL-4, IL-8, IL-10, IL-12, IL-13 and TNF-α) increased in BAL but not plasma over 6 months (P 2 . This was not altered by Pirfenidone treatment. Conclusion: The findings underscore the value of unravelling the molecular mechanisms regulating Pirfenidone efficacy in the search for clinical biomarkers of IPF disease.

In Burkholderia cenocepacia, the second messenger cyclic diguanosine monophosphate (c-di-GMP) has previously been shown to positively regulate biofilm formation and the expression of cellulose and type-I fimbriae genes through binding to the transcriptional regulator Bcam1349. Here, we provide evidence that cellulose and type-I fimbriae are not involved in B. cenocepacia biofilm formation in flow chambers, and we identify a novel Bcam1349/c-di-GMP-regulated exopolysaccharide gene cluster which is essential for B. cenocepacia biofilm formation. Overproduction of Bcam1349 in trans promotes wrinkly colony morphology, pellicle, and biofilm formation in B. cenocepacia. A screen for transposon mutants unable to respond to the overproduction of Bcam1349 led to the identification of a 12-gene cluster, Bcam1330-Bcam1341, the products of which appear to be involved in the production of a putative biofilm matrix exopolysaccharide and to be essential for flow-chamber biofilm formation. We demonstrate that Bcam1349 binds to the promoter region of genes in the Bcam1330-Bcam1341 cluster and that this binding is enhanced by the presence of c-di-GMP. Furthermore, we demonstrate that overproduction of both c-di-GMP and Bcam1349 leads to increased transcription of these genes, indicating that c-di-GMP and Bcam1349 functions together in regulating exopolysaccharide production from the Bcam1330-Bcam1341 gene cluster. Our results suggest that the product encoded by the Bcam1330-Bcam1341 gene cluster is a major exopolysaccharide that provides structural stability to the biofilms formed by B. cenocepacia, and that its production is regulated by c-di-GMP through binding to and promotion of the activity of the transcriptional regulator Bcam1349.

RpfG is a member of a class of wide spread bacterial two-component regulators with an HD-GYP cyclic di-GMP phosphodiesterase domain. In the plant pathogen Xanthomonas campestris, RpfG together with the sensor kinase RpfC regulates multiple factors as a response to the cell-to-cell Diffusible Signalling Factor (DSF). A dynamic physical interaction of RpfG with two diguanylate cyclase (GGDEF) domain proteins controls motility. Here we show that, contrary to expectation, regulation of motility by the GGDEF domain proteins does not depend upon their cyclic di-GMP synthetic activity. Furthermore we show that the complex of RpfG and GGDEF domain proteins recruits a specific PilZ domain 'adaptor' protein, and this complex then interacts with the pilus motor proteins PilU and PiIT. The results support a model in which DSF signalling influences motility through the highly regulated dynamic interaction of proteins that affect pilus action. A specific motif that we identify to be required for HD-GYP domain interaction is conserved in a number of GGDEF domain proteins, suggesting that regulation via interdomain interactions is of broad relevance.

Stenotrophomonas maltophilia encodes proteins related to the Rax proteins of Xanthomonas oryzae , which are required for the synthesis and secretion of the Ax21 protein. Here we show that Ax21 acts as a cell-cell signal to regulate a diverse range of functions, including virulence, in this nosocomial pathogen.

Burkholderia cenocepacia is an opportunistic human pathogen that uses cis-2-dodecenoic acid (BDSF) as a quorum-sensing signal to control expression of virulence factors. BDSF is a signal molecule of the diffusible signal factor (DSF) family that was first described in the plant pathogen Xanthomonas campestris. The mechanism of perception of this signal and the range of functions regulated in B. cenocepacia are, however, unknown. A screen for transposon mutants unable to respond to exogenous signal identified BCAM0227 as a potential BDSF sensor. BCAM0227 is a histidine sensor kinase with an input domain unrelated to that of RpfC, the DSF sensor found in xanthomonads. Transcriptome profiling established the scope of the BDSF regulon and demonstrated that the sensor controls expression of a subset of these genes. A chimeric sensor kinase in which the input domain of BCAM0227 replaced the input domain of RpfC was active in BDSF signal perception when expressed in X. campestris. Mutation of BCAM0227 gave rise to reduced cytotoxicity to Chinese hamster ovary cells and reduced virulence to Wax moth larvae and in the agar-bead mouse model of pulmonary infection. The findings identify BCAM0227 as a novel BDSF sensor and a potential target for interference in virulence-related signalling in B. cenocepacia.

Cyclic-di-GMP [bis-(3′-5′)-cyclic diguanosine monophosphate] controls a wide range of functions in eubacteria, yet little is known about the underlying regulatory mechanisms. In the plant pathogen Xanthomonas campestris, expression of a subset of virulence genes is regulated by c-di-GMP and also by the CAP (catabolite activation protein)-like protein XcCLP, a global regulator in the CRP/FNR superfamily. Here, we report structural and functional insights into the interplay between XcCLP and c-di-GMP in regulation of gene expression. XcCLP bound target promoter DNA with submicromolar affinity in the absence of any ligand. This DNA-binding capability was abrogated by c-di-GMP, which bound to XcCLP with micromolar affinity. The crystal structure of XcCLP showed that the protein adopted an intrinsically active conformation for DNA binding. Alteration of residues of XcCLP implicated in c-di-GMP binding through modeling studies caused a substantial reduction in binding affinity for the nucleotide and rendered DNA binding by these variant proteins insensitive to inhibition by c-di-GMP. Together, these findings reveal the structural mechanism behind a novel class of c-di-GMP effector proteins in the CRP/FNR superfamily and indicate that XcCLP regulates bacterial virulence gene expression in a manner negatively controlled by the c-di-GMP concentrations.

Ireland’s exceptional economic growth in recent years has led to an influx of immigrants. Given the favourable economic climate into which these immigrants are arriving, it is interesting to ask how their earnings and welfare dependence compare with the native population. To the extent that strong economic growth produces good labour market opportunities for immigrants, earnings disadvantages may be lessened and any tendency towards welfare dependence may be reduced. Data from a nationally representative sample drawn in 2004 are used to assess the earnings of immigrants in Ireland relative to the native population and also the rate of welfare receipt across the two groups. Immigrants are found to earn 18 percent less than natives, controlling for education and years of work experience. However, this single figure hides differences across immigrants from English-speaking and non-English speaking countries. We also find evidence of a wage gap for immigrants with third level educations, relative to comparable natives. On average, immigrants are half as likely to have been in receipt of social welfare payments in the previous twelve months relative to natives. A difference in welfare participation remains when we control for the higher education attainment of immigrants.

Many pathogenic bacteria use cell–cell signaling systems involving the synthesis and perception of diffusible signal molecules to control virulence as a response to cell density or confinement to niches. Bacteria produce signals of diverse structural classes. Signal molecules of the diffusible signal factor (DSF) family are cis-2-unsaturated fatty acids. The paradigm is cis-11-methyl-2-dodecenoic acid from Xanthomonas campestris pv. campestris (Xcc), which controls virulence in this plant pathogen. Although DSF synthesis was thought to be restricted to the xanthomonads, it is now known that structurally related molecules are produced by the unrelated bacteria Burkholderia cenocepacia and Pseudomonas aeruginosa. Furthermore, signaling involving these DSF family members contributes to bacterial virulence, formation of biofilms and antibiotic tolerance in these important human pathogens. Here we review the recent advances in understanding DSF signaling and its regulatory role in different bacteria. These advances include the description of the pathway/mechanism of DSF biosynthesis, identification of novel DSF synthases and new members of the DSF family, the demonstration of a diversity of DSF sensors to include proteins with a Per-Arnt-Sim (PAS) domain and the description of some of the signal transduction mechanisms that impinge on virulence factor expression. In addition, we address the role of DSF family signals in interspecies signaling that modulates the behavior of other microorganisms. Finally, we consider a number of recently reported approaches for the control of bacterial virulence through the modulation of DSF signaling.

The study evaluates the effectiveness of a sibling support programme (Sibshops) involving three disability agencies in Cork, Ireland. Qualitative and quantitative data were obtained using semi-structured interviews and the Piers-Harris Children’s Self-Concept Scale with siblings, together with parent feedback. Results from the Piers-Harris showed that there was no significant increase in sibling self-esteem following attendance at the Sibshops. However, the interviews revealed that the majority of siblings enjoyed and benefited from the Sibshops. Parents reported satisfaction with the Sibshops and felt that their children had benefited. Reflections on the experience of working on an interagency basis are outlined. Recommendations are made regarding further research and development in the organization of Sibshops and in staffing and staff training.

Cyclic guanosine 3′,5′-monophosphate (cyclic GMP) is a second messenger whose role in bacterial signalling is poorly understood. A genetic screen in the plant pathogen Xanthomonas campestris (Xcc) identified that XC_0250, which encodes a protein with a class III nucleotidyl cyclase domain, is required for cyclic GMP synthesis. Purified XC_0250 was active in cyclic GMP synthesis in vitro. The linked gene XC_0249 encodes a protein with a cyclic mononucleotide-binding (cNMP) domain and a GGDEF diguanylate cyclase domain. The activity of XC_0249 in cyclic di-GMP synthesis was enhanced by addition of cyclic GMP. The isolated cNMP domain of XC_0249 bound cyclic GMP and a structure–function analysis, directed by determination of the crystal structure of the holo-complex, demonstrated the site of cyclic GMP binding that modulates cyclic di-GMP synthesis. Mutation of either XC_0250 or XC_0249 led to a reduced virulence to plants and reduced biofilm formation in vitro. These findings describe a regulatory pathway in which cyclic GMP regulates virulence and biofilm formation through interaction with a novel effector that directly links cyclic GMP and cyclic di-GMP signalling.

A role for the HD-GYP domain in c-di-GMP hydrolysis was then proposed based on examination of the distribution and numbers of GGDEF, EAL, and HD-GYP domains encoded by different bacterial genomes, coupled with the known activities of other members of the HD superfamily of enzymes as metal-dependent hydrolases. This chapter reviews the current understanding of the HD-GYP domain in c-di-GMP signaling. In particular, it discusses (i) the identification of the HD-GYP domain and bioinformatic prediction as a novel c-di-GMP PDE, (ii) the experimental evidence implicating the HD-GYP domain in c-di-GMP degradation, (iii) the biological role of the HD-GYP domain protein RpfG in signal transduction in Xcc, (iv) regulatory interplay between RpfG and other c-di-GMP signaling proteins in Xcc, and (v) emerging information on the role of HD-GYP domain proteins in other bacteria. A role for HD-GYP in c-di-GMP hydrolysis was proposed based on an examination of the distribution and numbers of GGDEF, EAL, and HD-GYP domains encoded by different bacterial genomes, where several genomes encode proteins with the GGDEF and HD-GYP domains but no EAL domain. These findings illustrate two aspects of HD-GYP domain proteins that are consonant with our understanding of the diverse roles of GGDEF and EAL domain proteins. The first is that different HD-GYP domain proteins appear to have distinct regulatory roles.

The aim of this paper is twofold. First, we present an up-to-date assessment of the differences across euro area countries in the distributions of various measures of debt conditional on household characteristics. We consider three different outcomes: the probability of holding debt, the amount of debt held and, in the case of secured debt, the interest rate paid on the main mortgage. Second, we examine the role of legal and economic institutions in accounting for these differences. We use data from the first wave of a new survey of household finances, the Household Finance and Consumption Survey, to achieve these aims. We find that the patterns of secured and unsecured debt outcomes vary markedly across countries. Among all the institutions considered the length of asset repossession periods best accounts for the features of the distribution of secured debt. In countries with longer repossession periods, the fraction of people who borrow is smaller, the youngest group of households borrow lower amounts (conditional on borrowing), and the mortgage interest rates paid by low-income households are higher. Regulatory loan-to-value ratios, the taxation of mortgages and the prevalence of interest-only or fixed rate mortgages deliver less robust results. JEL Classification: D14, G21, G28, K35

A distinguishing feature of the period preceding the 2007/08 financial crisis was the sizeable increase in private sector debt observed across many countries. A key component of household liabilities is mortgage debt and with many countries experiencing persistent increases in house prices from the mid-1990s onwards, a marked increase in this aspect of household leverage was observed. While aggregate statistics across countries confirm reductions in personal debt levels in recent years, relatively few sources of micro data are available to examine the nature of the deleveraging process at the household level. In this paper, using a unique combination of regulatory and survey data, we examine deleveraging amongst a representative sample of mortgaged Irish households. In particular, we examine the characteristics of households presently reducing their debt levels and empirically assess whether the subsequent balance sheet adjustments have implications for key economic decisions. Our analysis suggests that, typically, it is those households who can deleverage, who do, and furthermore the decision to deleverage has negative implications for household consumption.

We report enthalpies of solution of formamide, N,N-dimethylformamide,N,N-dimethylacetamide, acetic acid, methyl acetate, and acetonitrile in water +dimethylsulfoxide mixed solvents. These, along with literature data for additional solutes,are analyzed in terms of the extended coordination model of solvation. We alsoanalyze infrared data for several of these solutes. These analyses show thatN,N-dimethylformamide and N,N-dimethylacetamide are preferentially hydrated,while the other solutes appear to be preferentially solvated by dimethylsulfoxide.In all cases, the extent of preferential solvation is relatively small. It is also foundthat the degrees of preferential solvation recovered from analyses of the enthalpydata correspond closely to those recovered from the infrared data, although thelatter refer only to the polar chromophores on the solute molecules. It is foundthat the extent to which the solutes disrupt the solvent-solvent interactions variessystematically with the area of the nonpolar surfaces of the solute molecules.

Xanthomonas citri subsp. citri (Xcc) is the causal agent of citrus canker. Biofilm formation on citrus leaves plays an important role in epiphytic survival of Xcc. Biofilm formation is affected by transposon insertion in XAC3733, which encodes a transcriptional activator of the NtrC family, not linked to a gene encoding a sensor protein, thus could be considered as an 'orphan' regulator whose function is poorly understood in Xanthomonas spp. Here we show that mutation of XAC3733 (named xbmR) resulted in impaired structural development of the Xcc biofilm, loss of chemotaxis and reduced virulence in grapefruit plants. All defective phenotypes were restored to wild-type levels by the introduction of PA2567 from Pseudomonas aeruginosa, which encodes a phosphodiesterase active in the degradation of cyclic diguanosine monophosphate (c-di-GMP). A knockout of xbmR led to a substantial downregulation of fliA that encodes a σ(28) transcription factor, as well as fliC and XAC0350 which are potential member of the σ(28) regulon. XAC0350 encodes an HD-GYP domain c-di-GMP phosphodiesterase. These findings suggest that XbmR is a key regulator of flagellar-dependent motility and chemotaxis exerting its action through a regulatory pathway that involves FliA and c-di-GMP.