S-maltoheptaose targets syndecan-bound effectors to reduce smoking-related neutrophilic inflammation.

Cigarette smoke induces injury and neutrophilic inflammation in the airways of smokers. The stability and activity of inflammatory effectors, IL8 and neutrophil elastase (NE), can be prolonged by binding to airway heparan sulfate (HS)/syndecan-1, posing risk for developing chronic obstructive pulmonary disease(COPD). We hypothesize that antagonizing HS/syndecan-1 binding of the inflammatory effectors could reduce smoking-related neutrophil-mediated airway inflammation. Analysis of bronchoalveolar lavage fluid(BALF) of COPD patients found both total and unopposed NE levels to be significantly higher among smokers with COPD than non-COPD subjects. Similar NE burden was observed in smoke-exposed rats compared to sham air controls. We chose sulfated-maltoheptaose(SM), a heparin-mimetic, to antagonize HS/sydecan-1 binding of the inflammatory mediators in airway fluids and lung tissues of the smoke-exposed rat model. Airway treatment with SM resulted in displacement of CINC-1 and NE from complexation with bronchio-epithelial HS/syndecan-1, dissipating the chemokine gradient for neutrophil flux across to the bronchial lumen. Following SM displacement of NE from shed HS/syndecan-1 in bronchial fluids, NE became accessible to inhibition by α1-antitrypsin endogenous in test samples. The antagonistic actions of SM against syndecan-1 binding of NE and CINC-1 in smoke-exposed airways suggest new therapeutic opportunities for modulating airway inflammation in smokers with SM delivery.published_or_final_versio

The Importance of Self-Management in the Context of Personalized Care in COPD

Despite current guidelines and decades of evidence on the benefits of a self-management approach, self-management of COPD remains relatively under-utilized in clinical care compared with other chronic diseases. However, self-management interventions can play a valuable role in supporting people with COPD to respond to changing symptoms, and thereby make appropriate decisions regarding the management of their own chronic condition. In this review, we discuss the history and evolution of the concept of self-management, assess current multidisciplinary support programs and clinical interactions designed to optimize self-management, and reflect on how effective these are in terms of clinical and humanistic outcomes. We also evaluate the mechanisms for encouraging change from protocol-based care towards a more personalized care approach, and discuss the role of digital self-management interventions and the importance of addressing health inequalities in COPD treatment, which have been accelerated by the COVID-19 pandemic. Reflecting on the importance of self-management in the context of symptom monitoring and provision of educational support, including information from patient organizations and charities, we discuss the ideal components of a self-management plan for COPD and provide six key recommendations for its implementation: 1) better education for healthcare professionals on disease management and consultation skills; 2) new targets and priorities for patient-focused outcomes; 3) skills gap audits to identify barriers to self-management; 4) best practice sharing within primary care networks and ongoing professional development; 5) enhanced initial consultations to establish optimal self-management from the outset; and 6) negotiation and sharing of self-management plans at the point of diagnosis

Variability in the immunogenicity of inactivated seasonal influenza vaccine in children due to age and recent previous influenza vaccination

Poster Session: VaccinesBackground: Annual receipt of trivalent inactivated influenza (TIV) vaccination is recommended for school-age children in some countries. However, there is little data on the variability of the immunogenicity of influenza vaccination in children and how this is affected by their age and recent influenza vaccination history. Materials and Methods: We used data on children in a Hong Kong community-based study who were randomized to receive TIV before the 2009-2010 influenza season. Antibody titers against seasonal and pandemic A(H1N1), seasonal A(H3N2), and two B influenza viruses (B/Brisbane and B/Florida) were measured by hemagglutination inhibition immediately before and 1 month after vaccination (Cowling et al. Clin Infect Dis. 2012). Multivariate regression models were fitted in a Bayesian framework to characterize the distribution of changes in antibody titers following vaccination and update previous findings by considering the correlation between virus strains (Ng et al. Pediatr Infect Dis J. 2013). Results: In 452 subjects, statistically significant rises in the geometric means of all antibody titers were observed, with those against the virus strains included in the TIV rising by geometric means of 7.95 to 13.36; those against pandemic A(H1N1) and B/Florida rose by 1.47 and 4.21, respectively. Geometric standard deviations were between 3.76 and 8.41 around the geometric means, with pandemic A(H1N1) showing the least variability in rises. The most closely correlated titer increases were those for the two influenza B viruses, while increases in pandemic A(H1N1) titers were unrelated to any other titer. Being vaccinated in either of the two previous years significantly reduced the increase in seasonal A(H1N1) and A(H3N2) antibody titers, while among children not vaccinated in the previous 2 years, those aged > 9 years experienced significantly higher increases in the influenza B titers than those aged 6-8 years. Conclusions: Increases in antibody titers following vaccination can vary depending on age and vaccination history. Results from our study suggest that humoral antibody response to TIV may be lower in children receiving repeated vaccination, but receipt of TIV induced seroprotection in most subjects.published_or_final_versio

GEN1 from a thermophilic fungus is functionally closely similar to non-eukaryotic junction-resolving enzymes

AbstractProcessing of Holliday junctions is essential in recombination. We have identified the gene for the junction-resolving enzyme GEN1 from the thermophilic fungus Chaetomium thermophilum and expressed the N-terminal 487-amino-acid section. The protein is a nuclease that is highly selective for four-way DNA junctions, cleaving 1nt 3′ to the point of strand exchange on two strands symmetrically disposed about a diagonal axis. CtGEN1 binds to DNA junctions as a discrete homodimer with nanomolar affinity. Analysis of the kinetics of cruciform cleavage shows that cleavage of the second strand occurs an order of magnitude faster than the first cleavage so as to generate a productive resolution event. All these properties are closely similar to those described for bacterial, phage and mitochondrial junction-resolving enzymes. CtGEN1 is also similar in properties to the human enzyme but lacks the problems with aggregation that currently prevent detailed analysis of the latter protein. CtGEN1 is thus an excellent enzyme with which to engage in biophysical and structural analysis of eukaryotic GEN1

Infant feeding bottle design, growth and behaviour: results from a randomised trial

BACKGROUND: Whether the design of an anti-vacuum infant feeding bottle influences infant milk intake, growth or behavior is unknown, and was the subject of this randomized trial. METHODS: SUBJECTS: 63 (36 male) healthy, exclusively formula-fed term infants. INTERVENTION: Randomisation to use Bottle A (n = 31), one-way air valve: Philips Avent) versus Bottle B (n = 32), internal venting system: Dr Browns). 74 breast-fed reference infants were recruited, with randomisation (n = 24) to bottle A (n = 11) or B (n = 13) if bottle-feeding was subsequently introduced. Randomisation: stratified by gender and parity; computer-based telephone randomisation by independent clinical trials unit. SETTING: Infant home. PRIMARY OUTCOME MEASURE: infant weight gain to 4 weeks. SECONDARY OUTCOMES: (i) milk intake (ii) infant behaviour measured at 2 weeks (validated 3-day diary); (iii) risk of infection; (iv) continuation of breastfeeding following introduction of mixed feeding. RESULTS: Number analysed for primary outcome: Bottle A n = 29, Bottle B n = 25. PRIMARY OUTCOME: There was no significant difference in weight gain between randomised groups (0-4 weeks Bottle A 0.74 (SD 1.2) SDS versus bottle B 0.51 (0.39), mean difference 0.23 (95% CI -0.31 to 0.77). SECONDARY OUTCOMES: Infants using bottle A had significantly less reported fussing (mean 46 versus 74 minutes/day, p < 0.05) than those using bottle B. There was no significant difference in any other outcome measure. Breast-fed reference group: There were no significant differences in primary or secondary outcomes between breast-fed and formula fed infants. The likelyhood of breastfeeding at 3 months was not significantly different in infants subsequently randomised to bottle A or B. CONCLUSION: Bottle design may have short-term effects on infant behaviour which merit further investigation. No significant effects were seen on milk intake or growth; confidence in these findings is limited by the small sample size and this needs confirmation in a larger study. TRIAL REGISTRATION: Clinical Trials.gov NCT00325208

Crystal Structure of a Eukaryotic GEN1 Resolving Enzyme Bound to DNA

SummaryWe present the crystal structure of the junction-resolving enzyme GEN1 bound to DNA at 2.5 Å resolution. The structure of the GEN1 protein reveals it to have an elaborated FEN-XPG family fold that is modified for its role in four-way junction resolution. The functional unit in the crystal is a monomer of active GEN1 bound to the product of resolution cleavage, with an extensive DNA binding interface for both helical arms. Within the crystal lattice, a GEN1 dimer interface juxtaposes two products, whereby they can be reconnected into a four-way junction, the structure of which agrees with that determined in solution. The reconnection requires some opening of the DNA structure at the center, in agreement with permanganate probing and 2-aminopurine fluorescence. The structure shows that a relaxation of the DNA structure accompanies cleavage, suggesting how second-strand cleavage is accelerated to ensure productive resolution of the junction

Limited contribution of permafrost carbon to methane release from thawing peatlands

Models predict that thaw of permafrost soils at northern high-latitudes will release tens of billions of tonnes of carbon (C) to the atmosphere by 21001-3. The effect on the Earth's climate depends strongly on the proportion of this C which is released as the more powerful greenhouse gas methane (CH4), rather than carbon dioxide (CO2)1,4; even if CH4 emissions represent just 2% of the C release, they would contribute approximately one quarter of the climate forcing5. In northern peatlands, thaw of ice-rich permafrost causes surface subsidence (thermokarst) and water-logging6, exposing substantial stores (10s of kg C m-2, ref. 7) of previously-frozen organic matter to anaerobic conditions, and generating ideal conditions for permafrost-derived CH4 release. Here we show that, contrary to expectations, although substantial CH4 fluxes (>20 g CH4 m 2 yr-1) were recorded from thawing peatlands in northern Canada, only a small amount was derived from previously-frozen C (<2 g CH4 m-2 yr-1). Instead, fluxes were driven by anaerobic decomposition of recent C inputs. We conclude that thaw-induced changes in surface wetness and wetland area, rather than the anaerobic decomposition of previously-frozen C, may determine the effect of permafrost thaw on CH4 emissions from northern peatlands

The Interstellar Environment of our Galaxy

We review the current knowledge and understanding of the interstellar medium of our galaxy. We first present each of the three basic constituents - ordinary matter, cosmic rays, and magnetic fields - of the interstellar medium, laying emphasis on their physical and chemical properties inferred from a broad range of observations. We then position the different interstellar constituents, both with respect to each other and with respect to stars, within the general galactic ecosystem.Comment: 39 pages, 12 figures (including 3 figures in 2 parts

The effects of government construction projects abandonment: stakeholders' perspective

The construction industry of every country drives economic growth as it serves as the foundation for other sectors’ growth and as such, the need to manage projects in this sector cannot be overemphasised. However, in developing countries, some of these projects fail through abandonment but researchers have not paid attention to the effects that these abandoned construction projects have on stakeholders associated with such projects. This study, therefore, investigates the effects of abandonment on key stakeholders associated with such projects. Using sequential data collection approach through focused group discussions, questionnaire and an in-depth semi-structured interview, twenty-six (26) effects of construction projects abandonment on stakeholders are identified. The top ten most important effects are: unemployment, bad image for the government, government sector underdevelopment, slow economic growth, financial institutions lose confidence in the state, discourages investment, loss of revenue by state, pollution, loss of properties and loss of revenue by the citizens. The effects were grouped into four main themes and the most important effects are the economic, social, political and psychological respectively. The findings also suggest that some of these effects are direct whilst others are indirect; and they are cyclical in nature