Redox-Mediated Inactivation of the Transcriptional Repressor RcrR is Responsible for Uropathogenic Escherichia coli's Increased Resistance to Reactive Chlorine Species

The ability to overcome stressful environments is critical for pathogen survival in the host. One challenge for bacteria is the exposure to reactive chlorine species (RCS), which are generated by innate immune cells as a critical part of the oxidative burst. Hypochlorous acid (HOCl) is the most potent antimicrobial RCS and is associated with extensive macromolecular damage in the phagocytized pathogen. However, bacteria have evolved defense strategies to alleviate the effects of HOCl-mediated damage. Among these are RCS-sensing transcriptional regulators that control the expression of HOCl-protective genes under non-stress and HOCl stress. Uropathogenic Escherichia coli (UPEC), the major causative agent of urinary tract infections (UTIs), is particularly exposed to infiltrating neutrophils during pathogenesis; however, their responses to and defenses from HOCl are still completely unexplored. Here, we present evidence that UPEC strains tolerate higher levels of HOCl and are better protected from neutrophil-mediated killing compared with other E. coli. Transcriptomic analysis of HOCl-stressed UPEC revealed the upregulation of an operon consisting of three genes, one of which encodes the transcriptional regulator RcrR. We identified RcrR as a HOCl-responsive transcriptional repressor, which, under non-stress conditions, is bound to the operator and represses the expression of its target genes. During HOCl exposure, however, the repressor forms reversible intermolecular disulfide bonds and dissociates from the DNA resulting in the derepression of the operon. Deletion of one of the target genes renders UPEC significantly more susceptible to HOCl and phagocytosis indicating that the HOCl-mediated induction of the regulon plays a major role for UPEC’s HOCl resistance

Smoke rings:towards a comprehensive tobacco free policy for the Olympic Games

Background The tobacco industry has long sought affiliation with major sporting events, including the Olympic Games, for marketing, advertising and promotion purposes. Since 1988, each Olympic Games has adopted a tobacco-free policy. Limited study of the effectiveness of the smoke-free policy has been undertaken to date, with none examining the tobacco industry's involvement with the Olympics or use of the Olympic brand. Methods and Findings A comparison of the contents of Olympic tobacco-free policies from 1988 to 2014 was carried out by searching the websites of the IOC and host NOCs. The specific tobacco control measures adopted for each Games were compiled and compared with measures recommended by the WHO Tobacco Free Sports Initiative and Article 13 of the Framework Convention on Tobacco Control (FCTC). This was supported by semi-structured interviews of key informants involved with the adoption of tobacco-free policies for selected games. To understand the industry's interests in the Olympics, the Legacy Tobacco Documents Library (http://legacy.library.ucsf.edu) was systematically searched between June 2013 and August 2014. Company websites, secondary sources and media reports were also searched to triangulate the above data sources. This paper finds that, while most direct associations between tobacco and the Olympics have been prohibited since 1988, a variety of indirect associations undermine the Olympic tobacco-free policy. This is due to variation in the scope of tobacco-free policies, limited jurisdiction and continued efforts by the industry to be associated with Olympic ideals. Conclusions The paper concludes that, compatible with the IOC's commitment to promoting healthy lifestyles, a comprehensive tobacco-free policy with standardized and binding measures should be adopted by the International Olympic Committee and all national Olympic committees

Ice sheets as a missing source of silica to the polar oceans

Ice sheets play a more important role in the global silicon cycle than previously appreciated. Input of dissolved and amorphous particulate silica into natural waters stimulates the growth of diatoms. Here we measure dissolved and amorphous silica in Greenland Ice Sheet meltwaters and icebergs, demonstrating the potential for high ice sheet export. Our dissolved and amorphous silica flux is 0.20 (0.06-0.79) Tmol year(-1), ∼50% of the input from Arctic rivers. Amorphous silica comprises >95% of this flux and is highly soluble in sea water, as indicated by a significant increase in dissolved silica across a fjord salinity gradient. Retreating palaeo ice sheets were therefore likely responsible for high dissolved and amorphous silica fluxes into the ocean during the last deglaciation, reaching values of ∼5.5 Tmol year(-1), similar to the estimated export from palaeo rivers. These elevated silica fluxes may explain high diatom productivity observed during the last glacial-interglacial period

Targeting Protein-Protein Interactions for Parasite Control

Finding new drug targets for pathogenic infections would be of great utility for humanity, as there is a large need to develop new drugs to fight infections due to the developing resistance and side effects of current treatments. Current drug targets for pathogen infections involve only a single protein. However, proteins rarely act in isolation, and the majority of biological processes occur via interactions with other proteins, so protein-protein interactions (PPIs) offer a realm of unexplored potential drug targets and are thought to be the next-generation of drug targets. Parasitic worms were chosen for this study because they have deleterious effects on human health, livestock, and plants, costing society billions of dollars annually and many sequenced genomes are available. In this study, we present a computational approach that utilizes whole genomes of 6 parasitic and 1 free-living worm species and 2 hosts. The species were placed in orthologous groups, then binned in species-specific ortholgous groups. Proteins that are essential and conserved among species that span a phyla are of greatest value, as they provide foundations for developing broad-control strategies. Two PPI databases were used to find PPIs within the species specific bins. PPIs with unique helminth proteins and helminth proteins with unique features relative to the host, such as indels, were prioritized as drug targets. The PPIs were scored based on RNAi phenotype and homology to the PDB (Protein DataBank). EST data for the various life stages, GO annotation, and druggability were also taken into consideration. Several PPIs emerged from this study as potential drug targets. A few interactions were supported by co-localization of expression in M. incognita (plant parasite) and B. malayi (H. sapiens parasite), which have extremely different modes of parasitism. As more genomes of pathogens are sequenced and PPI databases expanded, this methodology will become increasingly applicable

Mercury exposure, malaria, and serum antinuclear/antinucleolar antibodies in amazon populations in Brazil: a cross-sectional study

BACKGROUND: Mercury is an immunotoxic metal that induces autoimmune disease in rodents. Highly susceptible mouse strains such as SJL/N, A.SW, B10.S (H-2(s)) develop multiple autoimmune manifestations after exposure to inorganic mercury, including lymphoproliferation, elevated levels of autoantibodies, overproduction of IgG and IgE, and circulating immune complexes in kidney and vasculature. A few studies have examined relationships between mercury exposures and adverse immunological reactions in humans, but there is little evidence of mercury-associated autoimmunity in humans. METHODS: To test the immunotoxic effects of mercury in humans, we studied communities in Amazonian Brazil with well-characterized exposures to mercury. Information was collected on diet, mercury exposures, demographic data, and medical history. Antinuclear and antinucleolar autoantibodies (ANA and ANoA) were measured by indirect immunofluorescence. Anti-fibrillarin autoantibodies (AFA) were measured by immunoblotting. RESULTS: In a gold mining site, there was a high prevalence of ANA and ANoA: 40.8% with detectable ANoA at ≥1:10 serum dilution, and 54.1% with detectable ANA (of which 15% had also detectable ANoA). In a riverine town, where the population is exposed to methylmercury by fish consumption, both prevalence and levels of autoantibodies were lower: 18% with detectable ANoA and 10.7% with detectable ANA. In a reference site with lower mercury exposures, both prevalence and levels of autoantibodies were much lower: only 2.0% detectable ANoA, and only 7.1% with detectable ANA. In the gold mining population, we also examined serum for AFA in those subjects with detectable ANoA (≥1:10). There was no evidence for mercury induction of this autoantibody. CONCLUSIONS: This is the first study to report immunologic changes, indicative of autoimmune dysfunction in persons exposed to mercury, which may also reflect interactions with infectious disease and other factors

What can health inequalities researchers learn from an intersectionality perspective?:Understanding social dynamics with an inter-categorical approach

The concept of intersectionality was developed by social scientists seeking to analyse the multiple interacting influences of social location, identity and historical oppression. Despite broad take-up elsewhere, its application in public health remains underdeveloped. We consider how health inequalities research in the United Kingdom has predominantly taken class and later socioeconomic position as its key axis in a manner that tends to overlook other crucial dimensions. We especially focus on international research on ethnicity, gender and caste to argue that an intersectional perspective is relevant for health inequalities research because it compels researchers to move beyond (but not ignore) class and socioeconomic position in analysing the structural determinants of health. Drawing on these theoretical developments, we argue for an inter-categorical conceptualisation of social location that recognises differentiation without reifying social groupings – thus encouraging researchers to focus on social dynamics rather than social categories, recognising that experiences of advantage and disadvantage reflect the exercise of power across social institutions. Such an understanding may help address the historic tendency of health inequalities research to privilege methodological issues and consider different axes of inequality in isolation from one another, encouraging researchers to move beyond micro-level behaviours to consider the structural drivers of inequalities

Efeito do salbutamol liberado através de inalador de pó seco sobre o broncoespasmo induzido por metacolina Effects of salbutamol delivered by dry-powder inhaler on methacholine-induced bronchoconstriction

INTRODUÇÃO: Os beta2-agonistas de curta duração sob a forma de nebulímetro pressurizado são os fármacos utilizados rotineiramente na reversão do broncoespasmo induzido pela metacolina. A administração desses fármacos na forma de pó seco, liberados por inaladores de pó seco pode ser uma alternativa eficaz. OBJETIVO: Avaliar a efetividade e rapidez de ação do salbutamol liberado através de inalador de pó seco pulvinal (Butovent®) na reversão do broncoespasmo induzido por metacolina, comparando-o com o salbutamol liberado por nebulímetro pressurizado. MÉTODO: Foram avaliados prospectivamente 60 pacientes sucessivos com broncoespasmo induzido por metacolina, cuja queda do volume expiratório forçado no primeiro segundo (VEF1) foi de, no mínimo, 20%. Foram randomizados 30 pacientes para receber 200 mcg de salbutamol liberado por nebulímetro pressurizado e 30 pacientes para receber 200 mcg de salbutamol através de inalador de pó seco (pulvinal), na etapa final do teste de broncoprovocação, com o objetivo de reverter o broncoespasmo induzido pela metacolina. Foram avaliados os VEF1 obtidos 1 minuto e 5 minutos após a administração do broncodilatador. RESULTADOS: Os grupos foram pareados por sexo, idade, peso, altura, dose provocativa causadora de queda de 20% no VEF1 (primeiro grupo: 1,3 mg ; segundo grupo: 1,19 mg; p = 0,79) e VEF1 pós-metacolina (primeiro grupo: 2,03 l; segundo grupo: 1,99 l; p = 0,87), sem diferença significativa entre eles. O incremento médio do VEF1 foi de 16,2% (1 minuto) e 22,2% (5 minutos) no primeiro grupo e de 17% (1 minuto) e 23,6% (5 minutos) no segundo grupo, não havendo diferença estatística entre eles (p = 0,8). CONCLUSÕES: Os beta2-agonistas administrados através de inalador de pó seco (pulvinal) apresentam a mesma eficácia broncodilatadora e rapidez de ação que no tradicional método por nebulímetro pressurizado.<br>BACKGROUND: Short-acting beta2 agonists delivered by metered-dose inhaler (MDIs) are the drugs usually used for the reversal of methacholine-induced bronchoconstriction. The b2 agonists that are delivered by dry-powder inhaler (DPI) can be an efficacious option. OBJECTIVE: To evaluate the effectiveness and speed of action of salbutamol delivered by DPI (Pulvinal; Butovent®), in comparison to salbutamol delivered by MDI, in reversing methacholine-induced bronchoconstriction. METHOD: Sixty successive methacholine-induced bronchoconstriction patients who presented a decrease of at least 20% in forced expiratory volume (FEV1) were evaluated prospectively. Of these 60 patients, we randomized 30 (first group) to receive 200 mcg of salbutamol by MDI and 30 (second group) to receive 200 mcg of salbutamol by DPI (Pulvinal). Both drugs were administered with the objective of reversing bronchoconstriction during the final phase of a bronchoprovocation test. The FEV1 values obtained at 1 and 5 minutes after bronchodilator administration were evaluated. RESULTS: The groups were comparable in gender distribution, age, weight, dose level provoking a 20% drop in FEV1 (first group: 1.3 mg; second group: 1.19 mg; p = 0.79) and post-methacholine FEV1 (first group: 2.03 l; second group: 1.99 l; p = 0.87), with no statistically significant differences between the two groups. In the first group (MDI), the mean increase in FEV1 was 16.2% (at 1 minute) and 22.2% (at 5 minutes), and in the second group (DPI) it was 17% (at 1 minute) and 23.6% (at 5 minutes). There was no statistically significant difference between the groups (p = 0.8). CONCLUSION: The beta2-agonists delivered by DPI (Pulvinal) present the same bronchodilator efficacy and speed of action as do those delivered by the more traditional MDI method