Bacterial NLR-related proteins protect against phage.

Bacteria use a wide range of immune pathways to counter phage infection. A subset of these genes shares homology with components of eukaryotic immune systems, suggesting that eukaryotes horizontally acquired certain innate immune genes from bacteria. Here, we show that proteins containing a NACHT module, the central feature of the animal nucleotide-binding domain and leucine-rich repeat containing gene family (NLRs), are found in bacteria and defend against phages. NACHT proteins are widespread in bacteria, provide immunity against both DNA and RNA phages, and display the characteristic C-terminal sensor, central NACHT, and N-terminal effector modules. Some bacterial NACHT proteins have domain architectures similar to the human NLRs that are critical components of inflammasomes. Human disease-associated NLR mutations that cause stimulus-independent activation of the inflammasome also activate bacterial NACHT proteins, supporting a shared signaling mechanism. This work establishes that NACHT module-containing proteins are ancient mediators of innate immunity across the tree of life.

A small molecule that disrupts S. Typhimurium membrane voltage without cell lysis reduces bacterial colonization of mice.

As pathogenic bacteria become increasingly resistant to antibiotics, antimicrobials with mechanisms of action distinct from current clinical antibiotics are needed. Gram-negative bacteria pose a particular problem because they defend themselves against chemicals with a minimally permeable outer membrane and with efflux pumps. During infection, innate immune defense molecules increase bacterial vulnerability to chemicals by permeabilizing the outer membrane and occupying efflux pumps. Therefore, screens for compounds that reduce bacterial colonization of mammalian cells have the potential to reveal unexplored therapeutic avenues. Here we describe a new small molecule, D66, that prevents the survival of a human Gram-negative pathogen in macrophages. D66 inhibits bacterial growth under conditions wherein the bacterial outer membrane or efflux pumps are compromised, but not in standard microbiological media. The compound disrupts voltage across the bacterial inner membrane at concentrations that do not permeabilize the inner membrane or lyse cells. Selection for bacterial clones resistant to D66 activity suggested that outer membrane integrity and efflux are the two major bacterial defense mechanisms against this compound. Treatment of mammalian cells with D66 does not permeabilize the mammalian cell membrane but does cause stress, as revealed by hyperpolarization of mitochondrial membranes. Nevertheless, the compound is tolerated in mice and reduces bacterial tissue load. These data suggest that the inner membrane could be a viable target for anti-Gram-negative antimicrobials, and that disruption of bacterial membrane voltage without lysis is sufficient to enable clearance from the host.

Xanthomonas rydalmerensis sp. nov., a non-pathogenic member of Group 1 Xanthomonas.

Five bacterial isolates were isolated from Fragaria × ananassa in 1976 in Rydalmere, Australia, during routine biosecurity surveillance. Initially, the results of biochemical characterisation indicated that these isolates represented members of the genus Xanthomonas. To determine their species, further analysis was conducted using both phenotypic and genotypic approaches. Phenotypic analysis involved using MALDI-TOF MS and BIOLOG GEN III microplates, which confirmed that the isolates represented members of the genus Xanthomonas but did not allow them to be classified with respect to species. Genome relatedness indices and the results of extensive phylogenetic analysis confirmed that the isolates were members of the genus Xanthomonas and represented a novel species. On the basis the minimal presence of virulence-associated factors typically found in genomes of members of the genus Xanthomonas, we suggest that these isolates are non-pathogenic. This conclusion was supported by the results of a pathogenicity assay. On the basis of these findings, we propose the name Xanthomonas rydalmerensis, with DAR 34855T = ICMP 24941 as the type strain.

A Multilocus Sequence Typing Scheme for Rapid Identification of Xanthomonas citri Based on Whole-Genome Sequencing Data.

Xanthomonas citri is a plant-pathogenic bacterium associated with a diverse range of host plant species. It has undergone substantial reclassification and currently consists of 14 different subspecies or pathovars that are responsible for a wide range of plant diseases. Whole-genome sequencing (WGS) provides a cutting-edge advantage over other diagnostic techniques in epidemiological and evolutionary studies of X. citri because it has a higher discriminatory power and is replicable across laboratories. WGS also allows for the improvement of multilocus sequence typing (MLST) schemes. In this study, we used genome sequences of Xanthomonas isolates from the NCBI RefSeq database to develop a seven-gene MLST scheme that yielded 19 sequence types (STs) that correlated with phylogenetic clades of X. citri subspecies or pathovars. Using this MLST scheme, we examined 2,911 Xanthomonas species assemblies from NCBI GenBank and identified 15 novel STs from 37 isolates that were misclassified in NCBI. In total, we identified 545 X. citri assemblies from GenBank with 95% average nucleotide identity to the X. citri type strain, and all were classified as one of the 34 STs. All MLST classifications correlated with a phylogenetic position inferred from alignments using 92 conserved genes. We observed several instances where strains from different pathovars formed closely related monophyletic clades and shared the same ST, indicating that further investigation of the validity of these pathovars is required. Our MLST scheme described here is a robust tool for rapid classification of X. citri pathovars using WGS and a powerful method for further comprehensive taxonomic revision of X. citri pathovars.

A small molecule that mitigates bacterial infection disrupts Gram-negative cell membranes and is inhibited by cholesterol and neutral lipids.

Infections caused by Gram-negative bacteria are difficult to fight because these pathogens exclude or expel many clinical antibiotics and host defense molecules. However, mammals have evolved a substantial immune arsenal that weakens pathogen defenses, suggesting the feasibility of developing therapies that work in concert with innate immunity to kill Gram-negative bacteria. Using chemical genetics, we recently identified a small molecule, JD1, that kills Salmonella enterica serovar Typhimurium (S. Typhimurium) residing within macrophages. JD1 is not antibacterial in standard microbiological media, but rapidly inhibits growth and curtails bacterial survival under broth conditions that compromise the outer membrane or reduce efflux pump activity. Using a combination of cellular indicators and super resolution microscopy, we found that JD1 damaged bacterial cytoplasmic membranes by increasing fluidity, disrupting barrier function, and causing the formation of membrane distortions. We quantified macrophage cell membrane integrity and mitochondrial membrane potential and found that disruption of eukaryotic cell membranes required approximately 30-fold more JD1 than was needed to kill bacteria in macrophages. Moreover, JD1 preferentially damaged liposomes with compositions similar to E. coli inner membranes versus mammalian cell membranes. Cholesterol, a component of mammalian cell membranes, was protective in the presence of neutral lipids. In mice, intraperitoneal administration of JD1 reduced tissue colonization by S. Typhimurium. These observations indicate that during infection, JD1 gains access to and disrupts the cytoplasmic membrane of Gram-negative bacteria, and that neutral lipids and cholesterol protect mammalian membranes from JD1-mediated damage. Thus, it may be possible to develop therapeutics that exploit host innate immunity to gain access to Gram-negative bacteria and then preferentially damage the bacterial cell membrane over host membranes.

Synthesis and In Vivo Evaluation of a Site-specifically Labeled Radioimmunoconjugate for Dual-Modal (PET/NIRF) Imaging of MT1-MMP in Sarcomas.

Bone sarcomas are devastating primary bone cancers that mostly affect children, young adults, and the elderly. These aggressive tumors are associated with poor survival, and surgery remains the mainstay of treatment. Surgical planning is increasingly informed by positron emission tomography (PET), and tumor margin identification during surgery is aided by near-infrared fluorescence (NIRF) imaging, yet these investigations are confounded by probes that lack specificity for sarcoma biomarkers. We report the development of a dual-modal (PET/NIRF) immunoconjugate ([89Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW) that targets MT1-MMP, a matrix metalloproteinase overexpressed in high-grade sarcomas. [89Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW was synthesized via site-specific chemoenzymatic glycan modification, characterized, and isolated in high specific activity and radiochemical purity. Saturation binding and immunoreactivity assays indicated only minor perturbation of binding properties. A novel mouse model of dedifferentiated chondrosarcoma based on intrafemoral inoculation of HT1080 WT or KO cells (high and low MT1-MMP expression, respectively) was used to evaluate target binding and biodistribution. Fluorescence and Cerenkov luminescence images of [89Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW showed preferential uptake in HT1080 WT tumors. Ex vivo gamma counting revealed that uptake in MT1-MMP-positive tumors was significantly higher than that in control groups. Taken together, [89Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW is a promising dual-modal sarcoma imaging agent for pre-operative surgical planning and intraoperative surgical guidance.

Contextual influences on the within-person association between physical activity and affect in adolescents: an ecological momentary assessment study.

There is limited research on how the context in which moderate-to-vigorous physical activity (MVPA) occurs influences the relationship between physical activity and affect. This study aimed to investigate how the social context and physical environment enhance the relationship between MVPA and affect in daily life. Overall, 119 adolescents (mean age = 14.7 years) provided information about their core affect, physical environment and social context on multiple occasions over a 4-day period using ecological momentary assessment. Additionally, participants' level of MVPA was objectively measured using accelerometers. Level of MVPA was positively associated with energetic arousal, being outdoors was positively associated with valence and energetic arousal, and being with someone else was also positively associated with energetic arousal. Additionally, being outdoors moderated the association between MVPA and tense arousal so that MVPA was only inversely related to tense arousal when outdoors. These findings showed that young people experience more positive valence, greater levels of energetic arousal and less tense arousal when physically active outdoors compared to when indoors and highlight the importance of encouraging young people to participate in physical activity outdoors. Further research is warranted to understand how social contexts may influence the association between MVPA and affect in young people.

A cell-based infection assay identifies efflux pump modulators that reduce bacterial intracellular load.

Bacterial efflux pumps transport small molecules from the cytoplasm or periplasm outside the cell. Efflux pump activity is typically increased in multi-drug resistant (MDR) pathogens; chemicals that inhibit efflux pumps may have potential for antibiotic development. Using an in-cell screen, we identified three efflux pump modulators (EPMs) from a drug diversity library. The screening platform uses macrophages infected with the human Gram-negative pathogen Salmonella enterica (Salmonella) to identify small molecules that prevent bacterial replication or survival within the host environment. A secondary screen for hit compounds that increase the accumulation of an efflux pump substrate, Hoechst 33342, identified three small molecules with activity comparable to the known efflux pump inhibitor PAßN (Phe-Arg ß-naphthylamide). The three putative EPMs demonstrated significant antibacterial activity against Salmonella within primary and cell culture macrophages and within a human epithelial cell line. Unlike traditional antibiotics, the three compounds did not inhibit bacterial growth in standard microbiological media. The three compounds prevented energy-dependent efflux pump activity in Salmonella and bound the AcrB subunit of the AcrAB-TolC efflux system with KDs in the micromolar range. Moreover, the EPMs display antibacterial synergy with antimicrobial peptides, a class of host innate immune defense molecules present in body fluids and cells. The EPMs also had synergistic activity with antibiotics exported by AcrAB-TolC in broth and in macrophages and inhibited efflux pump activity in MDR Gram-negative ESKAPE clinical isolates. Thus, an in-cell screening approach identified EPMs that synergize with innate immunity to kill bacteria and have potential for development as adjuvants to antibiotics.

Genomic Acquisitions in Emerging Populations of Xanthomonas vasicola pv. vasculorum Infecting Corn in the United States and Argentina.

Xanthomonas vasicola pv. vasculorum is an emerging bacterial plant pathogen that causes bacterial leaf streak on corn. First described in South Africa in 1949, reports of this pathogen have greatly increased in the past years in South America and in the United States. The rapid spread of this disease in North and South America may be due to more favorable environmental conditions, susceptible hosts and/or genomic changes that favored the spread. To understand whether genetic mechanisms exist behind the recent spread of X. vasicola pv. vasculorum, we used comparative genomics to identify gene acquisitions in X. vasicola pv. vasculorum genomes from the United States and Argentina. We sequenced 41 genomes of X. vasicola pv. vasculorum and the related sorghum-infecting X. vasicola pv. holcicola and performed comparative analyses against all available X. vasicola genomes. Time-measured phylogenetic analyses showed that X. vasicola pv. vasculorum strains from the United States and Argentina are closely related and arose from two introductions to North and South America. Gene content comparisons identified clusters of genes enriched in corn X. vasicola pv. vasculorum that showed evidence of horizontal transfer including one cluster corresponding to a prophage found in all X. vasicola pv. vasculorum strains from the United States and Argentina as well as in X. vasicola pv. holcicola strains. In this work, we explore the genomes of an emerging phytopathogen population as a first step toward identifying genetic changes associated with the emergence. The acquisitions identified may contain virulence determinants or other factors associated with the spread of X. vasicola pv. vasculorum in North and South America and will be the subject of future work.

Salmonella enterica Requires Lipid Metabolism Genes To Replicate in Proinflammatory Macrophages and Mice.

To survive and replicate during infection, pathogens utilize different carbon and energy sources depending on the nutritional landscape of their host microenvironment. Salmonella enterica serovar Typhimurium is an intracellular bacterial pathogen that occupies diverse cellular niches. While it is clear that Salmonella Typhimurium requires access to glucose during systemic infection, data on the need for lipid metabolism are mixed. We report that Salmonella Typhimurium strains lacking lipid metabolism genes were defective for systemic infection of mice. Bacterial lipid import, ß-oxidation, and glyoxylate shunt genes were required for tissue colonization upon oral or intraperitoneal inoculation. In cultured macrophages, lipid import and ß-oxidation genes were required for bacterial replication and/or survival only when the cell culture medium was supplemented with nonessential amino acids. Removal of glucose from tissue culture medium further enhanced these phenotypes and, in addition, conferred a requirement for glyoxylate shunt genes. We also observed that Salmonella Typhimurium needs lipid metabolism genes in proinflammatory but not anti-inflammatory macrophages. These results suggest that during systemic infection, the Salmonella Typhimurium that relies upon host lipids to replicate is within proinflammatory macrophages that have access to amino acids but not glucose. An improved understanding of the host microenvironments in which pathogens have specific metabolic requirements may facilitate the development of targeted approaches to treatment.

Promoter conservation in HDACs points to functional implications.

BACKGROUND: Histone deacetylases (HDACs) are the proteins responsible for removing the acetyl group from lysine residues of core histones in chromosomes, a crucial component of gene regulation. Eleven known HDACs exist in humans and most other vertebrates. While the basic function of HDACs has been well characterized and new discoveries are still being made, the transcriptional regulation of their corresponding genes is still poorly understood. RESULTS: Here, we conducted a computational analysis of the eleven HDAC promoter sequences in 25 vertebrate species to determine whether transcription factor binding sites (TFBSs) are conserved in HDAC evolution, and if so, whether they provide useful information about HDAC expression and function. Furthermore, we used tissue-specific information of transcription factors to investigate the potential expression patterns of HDACs in different human tissues based on their transcription factor binding sites. We found that the TFBS profiles of most of the HDACs were well conserved in closely related species for all HDAC promoters except HDAC7 and HDAC10. HDAC5 had particularly strong conservation across over half of the species studied, with nearly identical profiles in the primate species. Our comparisons of TFBSs with the tissue specific gene expression profiles of their corresponding TFs showed that most HDACs had the ability to be ubiquitously expressed. A few HDAC promoters exhibited the potential for preferential expression in certain tissues, most notably HDAC11 in gall bladder, while HDAC9 seemed to have less propensity for expression in the nervous system. CONCLUSIONS: In general, we found evolutionary conservation in HDAC promoters that seems to be more prominent for the ubiquitously expressed HDACs. In turn, when conservation did not follow usual phylogeny, human TFBS patterns indicated possible functional relevance. While we found that HDACs appear to uniformly expressed, we confirm that the functional differences in HDACs may be less a matter of location of activity than a question of which proteins and which acetyl groups they may be acting on.

Autophagy Induction by a Small Molecule Inhibits Salmonella Survival in Macrophages and Mice.

Salmonella enterica are natural bacterial pathogens of humans and animals that cause systemic infection or gastroenteritis. During systemic infection, Salmonella generally reside within professional phagocytes, typically macrophages, whereas gastroenteritis is caused by infection of epithelial cells. We are only beginning to understand which host pathways contribute to Salmonella survival in particular cell types. We therefore sought to identify compounds that perturb Salmonella-host interactions using a chemical genetics approach. We found one small molecule, D61, that reduces Salmonella load in cell-line and primary macrophages but has no effect on Salmonella growth in epithelial cells or rich medium. We determined that in macrophages D61 induces LC3II, a marker of the autophagy pathway, and promotes aggregation of LC3II near Salmonella We found that D61 antibacterial activity depends on the VPS34 complex and on ATG5. D61 also reduced Salmonella load in the spleens and livers of infected mice. Lastly, we demonstrate that D61 antibacterial activity in macrophages is synergistic with the antibiotic chloramphenicol, but that this synergy is largely independent of the known autophagy-stimulating activity of chloramphenicol. Thus, a small molecule has anti-bacterial activity specifically in macrophages and mice based on the promotion of bacterial degradation by autophagy.Importance Autophagy is a conserved cellular response to metabolic stress and to invading pathogens. For many pathogens, including Salmonella, autophagy can play a detrimental or beneficial role during infection depending on the cellular context. We combined chemical genetics with single cell analyses and murine infection to dissect host-pathogen interactions. We identified a small molecule that reduces bacterial load in macrophages by increasing autophagic flux. This compound also reduces bacterial colonization of tissues in infected mice. These observations demonstrate the potential therapeutic utility of stimulating autophagy in cells and animals to curb infection.

Carotenoids, fatty acids and disease burden in obese minority adolescents with asthma.

BACKGROUND: Paediatric obesity-related asthma causes high disease burden, is associated with metabolic abnormalities, has few therapeutic options, and disproportionately affects urban minority children. Although poor diet quality is linked to asthma, the association of nutritional status with disease burden among children with obesity-related asthma is not well understood. OBJECTIVE: To quantify nutritional status, defined as concentrations of serum carotenoids and n-3 fatty acids, and its association with pulmonary function and metabolic markers among obese asthmatic children. METHODS: We quantified serum carotenoids and fatty acids in a study cohort of 158 urban minority adolescents including 39 obese asthmatics, 39 healthy weight asthmatics, 38 obese controls and 42 healthy weight controls and compared between the groups. We correlated carotenoid and fatty acid levels with pulmonary function indices and with insulin resistance and dyslipidemia. RESULTS: Mean total carotenoids were lowest in obese asthmatic children (0.41 µg/mL), lower than healthy weight asthmatics (0.52 µg/mL, P < 0.05) and healthy weight controls (0.60 µg/mL, P < 0.001). n-6/n-3 polyunsaturated fatty acid (PUFA) ratio also differed between the groups (P < 0.05). Total carotenoids positively correlated with per cent-predicted FEV1 and inversely correlated with insulin resistance among obese asthmatics only. n-6/n-3 PUFA ratio inversely correlated with per cent-predicted FEV1 in obese asthmatics. CONCLUSIONS & CLINICAL RELEVANCE: Our findings suggest that carotenoids, which are lowest in obese asthmatic children, may have protective effects on metabolic health and pulmonary function among obese asthmatic children. Similarly, n-3 PUFA appear to be protective for pulmonary function.

Tephritid-microbial interactions to enhance fruit fly performance in sterile insect technique programs.

BACKGROUND: The Sterile Insect Technique (SIT) is being applied for the management of economically important pest fruit flies (Diptera: Tephritidae) in a number of countries worldwide. The success and cost effectiveness of SIT depends upon the ability of mass-reared sterilized male insects to successfully copulate with conspecific wild fertile females when released in the field. METHODS: We conducted a critical analysis of the literature about the tephritid gut microbiome including the advancement of methods for the identification and characterization of microbiota, particularly next generation sequencing, the impacts of irradiation (to induce sterility of flies) and fruit fly rearing, and the use of probiotics to manipulate the fruit fly gut microbiota. RESULTS: Domestication, mass-rearing, irradiation and handling, as required in SIT, may change the structure of the fruit flies' gut microbial community compared to that of wild flies under field conditions. Gut microbiota of tephritids are important in their hosts' development, performance and physiology. Knowledge of how mass-rearing and associated changes of the microbial community impact the functional role of the bacteria and host biology is limited. Probiotics offer potential to encourage a gut microbial community that limits pathogens, and improves the quality of fruit flies. CONCLUSIONS: Advances in technologies used to identify and characterize the gut microbiota will continue to expand our understanding of tephritid gut microbial diversity and community composition. Knowledge about the functions of gut microbes will increase through the use of gnotobiotic models, genome sequencing, metagenomics, metatranscriptomics, metabolomics and metaproteomics. The use of probiotics, or manipulation of the gut microbiota, offers significant opportunities to enhance the production of high quality, performing fruit flies in operational SIT programs.

Commensal microbiota modulates larval foraging behaviour, development rate and pupal production in Bactrocera tryoni.

BACKROUND: Commensal microbes can promote survival and growth of developing insects, and have important fitness implications in adulthood. Insect larvae can acquire commensal microbes through two main routes: by vertical acquisition from maternal deposition of microbes on the eggshells and by horizontal acquisition from the environment where the larvae develop. To date, however, little is known about how microbes acquired through these different routes interact to shape insect development. In the present study, we investigated how vertically and horizontally acquired microbiota influence larval foraging behaviour, development time to pupation and pupal production in the Queensland fruit fly ('Qfly'), Bactrocera tryoni. RESULTS: Both vertically and horizontally acquired microbiota were required to maximise pupal production in Qfly. Moreover, larvae exposed to both vertically and horizontally acquired microbiota pupated sooner than those exposed to no microbiota, or only to horizontally acquired microbiota. Larval foraging behaviour was also influenced by both vertically and horizontally acquired microbiota. Larvae from treatments exposed to neither vertically nor horizontally acquired microbiota spent more time overall on foraging patches than did larvae of other treatments, and most notably had greater preference for diets with extreme protein or sugar compositions. CONCLUSION: The integrity of the microbiota early in life is important for larval foraging behaviour, development time to pupation, and pupal production in Qflies. These findings highlight the complexity of microbial relations in this species, and provide insights to the importance of exposure to microbial communities during laboratory- or mass-rearing of tephritid fruit flies.

Diet and irradiation effects on the bacterial community composition and structure in the gut of domesticated teneral and mature Queensland fruit fly, Bactrocera tryoni (Diptera: Tephritidae).

BACKGROUND: Mass-rearing, domestication and gamma irradiation of tephritid fruit flies used in sterile insect technique (SIT) programmes can negatively impact fly quality and performance. Symbiotic bacteria supplied as probiotics to mass-reared fruit flies may help to overcome some of these issues. However, the effects of tephritid ontogeny, sex, diet and irradiation on their microbiota are not well known. RESULTS: We have used next-generation sequencing to characterise the bacterial community composition and structure within Queensland fruit fly, Bactrocera tryoni (Froggatt), by generating 16S rRNA gene amplicon libraries derived from the guts of 58 individual teneral and mature, female and male, sterile and fertile adult flies reared on artificial larval diets in a laboratory or mass-rearing environment, and fed either a full adult diet (i.e. sugar and yeast hydrolysate) or a sugar only adult diet. Overall, the amplicon sequence read volume in tenerals was low and smaller than in mature adult flies. Operational taxonomic units (OTUs), belonging to the families Enterobacteriaceae (8 OTUs) and Acetobacteraceae (1 OTU) were most prevalent. Enterobacteriaceae dominated laboratory-reared tenerals from a colony fed a carrot-based larval diet, while Acetobacteraceae dominated mass-reared tenerals from a production facility colony fed a lucerne chaff based larval diet. As adult flies matured, Enterobacteriaceae became dominant irrespective of larval origin. The inclusion of yeast in the adult diet strengthened this shift away from Acetobacteraceae towards Enterobacteriaceae. Interestingly, irradiation increased 16S rRNA gene sequence read volume. CONCLUSIONS: Our findings suggest that bacterial populations in fruit flies experience significant bottlenecks during metamorphosis. Gut bacteria in teneral flies were less abundant and less diverse, and impacted by colony origin. In contrast, mature adult flies had selectively increased abundances for some gut bacteria, or acquired these bacteria from the adult diet and environment. Furthermore, irradiation augmented bacterial abundance in mature flies. This implies that either some gut bacteria were compensating for damage caused by irradiation or irradiated flies had lost their ability to regulate bacterial load. Our findings suggest that the adult stage prior to sexual maturity may be ideal to target for probiotic manipulation of fly microbiota to increase fly performance in SIT programmes.

Salmonella Meningitis Associated with Monocyte Infiltration in Mice.

In the current study, we examined the ability of Salmonella enterica serovar Typhimurium to infect the central nervous system and cause meningitis following the natural route of infection in mice. C57BL/6J mice are extremely susceptible to systemic infection by Salmonella Typhimurium because of loss-of-function mutations in Nramp1 (SLC11A1), a phagosomal membrane protein that controls iron export from vacuoles and inhibits Salmonella growth in macrophages. Therefore, we assessed the ability of Salmonella to disseminate to the central nervous system (CNS) after oral infection in C57BL/6J mice expressing either wild-type (resistant) or mutant (susceptible) alleles of Nramp1. In both strains, oral infection resulted in focal meningitis and ventriculitis with recruitment of inflammatory monocytes to the CNS. In susceptible Nramp1-/- mice, there was a direct correlation between bacteremia and the number of bacteria in the brain, which was not observed in resistant Nramp1+/+ mice. A small percentage of Nramp1+/+ mice developed severe ataxia, which was associated with high bacterial loads in the CNS as well as clear histopathology of necrotizing vasculitis and hemorrhage in the brain. Thus, Nramp1 is not essential for Salmonella entry into the CNS or neuroinflammation, but may influence the mechanisms of CNS entry as well as the severity of meningitis.

Interventions to improve physical activity among socioeconomically disadvantaged groups: an umbrella review.

BACKGROUND: People from socioeconomically disadvantaged population groups are less likely to be physically active and more likely to experience adverse health outcomes than those who are less disadvantaged. In this umbrella review we examined across all age groups, (1) the effectiveness of interventions to improve physical activity among socioeconomically disadvantaged groups, (2) the characteristics of effective interventions, and (3) directions for future research. METHODS: PubMed/MEDLINE and Scopus were searched up to May 2017 to identify systematic reviews reporting physical activity interventions in socioeconomically disadvantaged populations or sub-groups. Two authors independently conducted study screening and selection, data extraction (one author, with data checked by two others) and assessment of methodological quality using the 'Assessment of Multiple Systematic Reviews' scale. Results were synthesized narratively. RESULTS: Seventeen reviews met our inclusion criteria, with only 5 (30%) reviews being assessed as high quality. Seven (41%) reviews focused on obesity prevention and an additional four focused on multiple behavioural outcomes. For pre school children, parent-focused, group-based interventions were effective in improving physical activity. For children, school-based interventions and policies were effective; few studies focused on adolescents and those that did were generally not effective; for adults, there was mixed evidence of effectiveness but characteristics such as group-based interventions and those that focused on physical activity only were associated with effectiveness. Few studies focused on older adults. Across all ages, interventions that were more intensive tended to be more effective. Most studies reported short-term, rather than longer-term, outcomes and common methodological limitations included high probability of selection bias, low response rates, and high attrition. CONCLUSIONS: Interventions can be successful at improving physical activity among children from socioeconomically disadvantaged groups, with evidence for other age groups weak or inconclusive. More high-quality studies in this population group are needed, which adopt strategies to increase recruitment rates and reduce attrition, report longer term outcomes, and provide adequate intervention details, to allow determination of the characteristics of effective interventions. We recommend that the benefits of physical activity be recognised more broadly than obesity prevention in future studies, as this may have implications for the design and appeal of interventions.

An exploratory analysis of the interactions between social norms and the built environment on cycling for recreation and transport.

BACKGROUND: There is growing evidence of the public health benefits of promoting cycling. The ways that the built environment and perceived social norms independently influence cycling participation is well established. However, whether these factors interact to influence cycling participation has not been examined. Such research is important because understanding the effect of multiple socio-ecological factors and the interactions between them is needed to guide the development of interventions and strategies to increase cycling participation. Therefore, the aim of this study is to explore the interactive effects of the built environment and perceived social norms on transport and recreational cycling. METHODS: Data was collected using a self-administered online questionnaire from 228 office workers in Metropolitan Melbourne, Australia. Measures used in previous research were employed to assess self-reported transport and recreation cycling in the last week, perceptions of neighbourhood built environment, perceived social norms towards cycling, and objective land-use mix, residential density and street connectivity of the suburbs in which participants lived and work. Multiple binary logistic regression analyses were conducted to explore the interactive effects of the built environment and perceived social norms on transport and recreation cycling. All interactive effects were considered significant at p < 0.10. RESULTS: There was a significant interactive effect between the workplace built environment and perceived group norm on transport cycling (p = 0.06). There were no other significant interactive effects observed between components of the built environment and perceived social norms on transport or recreational cycling. CONCLUSIONS: The interactive effect found in this study provides some evidence that the workplace built environment interacts with perceived group norms to influence cycling for transport. Positive perceptions of the workplace built environment, such as showers and secure bike racks, can somewhat compensate for the negative influence of when cycling is considered less of a norm among, family, friend or colleagues. However, the findings of this study did not support that the neighbourhood built environment and perceived social norms interact to influence cycling for recreation or transport. These findings contribute to the knowledge of how multiple factors may reciprocate to influence individual's decision to cycle. More research into the interactive effects of socio-ecological factors is warranted.