The degree of microbiome complexity influences the epithelial response to infection

<p>Abstract</p> <p>Background</p> <p>The human microflora is known to be extremely complex, yet most pathogenesis research is conducted in mono-species models of infection. Consequently, it remains unclear whether the level of complexity of a host's indigenous flora can affect the virulence potential of pathogenic species. Furthermore, it remains unclear whether the colonization by commensal species affects a host cell's response to pathogenic species beyond the direct physical saturation of surface receptors, the sequestration of nutrients, the modulation of the physico-chemical environment in the oral cavity, or the production of bacteriocins. Using oral epithelial cells as a model, we hypothesized that the virulence of pathogenic species may vary depending on the complexity of the flora that interacts with host cells.</p> <p>Results</p> <p>This is the first report that determines the global epithelial transcriptional response to co-culture with defined complex microbiota. In our model, human immortalized gingival keratinocytes (HIGK) were infected with mono- and mixed cultures of commensal and pathogenic species. The global transcriptional response of infected cells was validated and confirmed phenotypically. In our model, commensal species were able to modulate the expression of host genes with a broad diversity of physiological functions and antagonize the effect of pathogenic species at the cellular level. Unexpectedly, the inhibitory effect of commensal species was <it>not </it>correlated with its ability to inhibit adhesion or invasion by pathogenic species.</p> <p>Conclusion</p> <p>Studying the global transcriptome of epithelial cells to single and complex microbial challenges offers clues towards a better understanding of how bacteria-bacteria interactions and bacteria-host interactions impact the overall host response. This work provides evidence that the degree of complexity of a mixed microbiota <it>does </it>influence the transcriptional response to infection of host epithelial cells, and challenges the current dogma regarding the <it>potential </it>versus the <it>actual </it>pathogenicity of bacterial species. These findings support the concept that members of the commensal oral flora have evolved cellular mechanisms that directly modulate the host cell's response to pathogenic species and dampen their relative pathogenicity.</p

Vδ2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure.

Vδ2+ γδ T cells are semi-innate T cells that expand markedly following P. falciparum (Pf) infection in naïve adults, but are lost and become dysfunctional among children repeatedly exposed to malaria. The role of these cells in mediating clinical immunity (i.e. protection against symptoms) to malaria remains unclear. We measured Vδ2+ T cell absolute counts at acute and convalescent malaria timepoints (n = 43), and Vδ2+ counts, cellular phenotype, and cytokine production following in vitro stimulation at asymptomatic visits (n = 377), among children aged 6 months to 10 years living in Uganda. Increasing age was associated with diminished in vivo expansion following malaria, and lower Vδ2 absolute counts overall, among children living in a high transmission setting. Microscopic parasitemia and expression of the immunoregulatory markers Tim-3 and CD57 were associated with diminished Vδ2+ T cell pro-inflammatory cytokine production. Higher Vδ2 pro-inflammatory cytokine production was associated with protection from subsequent Pf infection, but also with an increased odds of symptoms once infected. Vδ2+ T cells may play a role in preventing malaria infection in children living in endemic settings; progressive loss and dysfunction of these cells may represent a disease tolerance mechanism that contributes to the development of clinical immunity to malaria

Mechanisms of Copper Ion Mediated Huntington's Disease Progression

Huntington's disease (HD) is caused by a dominant polyglutamine expansion within the N-terminus of huntingtin protein and results in oxidative stress, energetic insufficiency and striatal degeneration. Copper and iron are increased in the striata of HD patients, but the role of these metals in HD pathogenesis is unknown. We found, using inductively-coupled-plasma mass spectroscopy, that elevations of copper and iron found in human HD brain are reiterated in the brains of affected HD transgenic mice. Increased brain copper correlated with decreased levels of the copper export protein, amyloid precursor protein. We hypothesized that increased amounts of copper bound to low affinity sites could contribute to pro-oxidant activities and neurodegeneration. We focused on two proteins: huntingtin, because of its centrality to HD, and lactate dehydrogenase (LDH), because of its documented sensitivity to copper, necessity for normoxic brain energy metabolism and evidence for altered lactate metabolism in HD brain. The first 171 amino acids of wild-type huntingtin, and its glutamine expanded mutant form, interacted with copper, but not iron. N171 reduced Cu(2+) in vitro in a 1∶1 copper∶protein stoichiometry indicating that this fragment is very redox active. Further, copper promoted and metal chelation inhibited aggregation of cell-free huntingtin. We found decreased LDH activity, but not protein, and increased lactate levels in HD transgenic mouse brain. The LDH inhibitor oxamate resulted in neurodegeneration when delivered intra-striatially to healthy mice, indicating that LDH inhibition is relevant to neurodegeneration in HD. Our findings support a role of pro-oxidant copper-protein interactions in HD progression and offer a novel target for pharmacotherapeutics

The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington's disease

<p>Abstract</p> <p>Background</p> <p>Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion within the huntingtin gene. Mutant huntingtin protein misfolds and accumulates within neurons where it mediates its toxic effects. Promoting mutant huntingtin clearance by activating macroautophagy is one approach for treating Huntington's disease (HD). In this study, we evaluated the mTOR kinase inhibitor and macroautophagy promoting drug everolimus in the R6/2 mouse model of HD.</p> <p>Results</p> <p>Everolimus decreased phosphorylation of the mTOR target protein S6 kinase indicating brain penetration. However, everolimus did not activate brain macroautophagy as measured by LC3B Western blot analysis. Everolimus protected against early declines in motor performance; however, we found no evidence for neuroprotection as determined by brain pathology. In muscle but not brain, everolimus significantly decreased soluble mutant huntingtin levels.</p> <p>Conclusions</p> <p>Our data suggests that beneficial behavioral effects of everolimus in R6/2 mice result primarily from effects on muscle. Even though everolimus significantly modulated its target brain S6 kinase, this did not decrease mutant huntingtin levels or provide neuroprotection.</p

The Bottom Line: Investing for Impact on Economic Mobility in the U.S.

There is no greater challenge in the United States today than income inequality. It has been 50 years since the War on Poverty began. We have made progress but not enough. More than 32 million children live in low-income families, and racial and gender gaps persist. For the first time, Americans do not believe life will be better for the next generation. We have both a moral and an economic imperative to fuel social and economic mobility in this country.The Aspen Institute was founded in 1950 as a place to address the critical issues of our time. Today, ensuring that the American dream can be a possibility for all and be passed from one generation to the next is that issue. This commitment is at the heart of the work of many policy programs at the Aspen Institute. Ending the cycle of poverty requires leadership and hard work across all sectors, from nonprofit organizations, philanthropies, and academia to the government and private sector. This report recognizes the importance of learning from all sectors in tackling any challenge. Specifically, it builds on opportunities in the growing impact investment field. The report draws on the lessons from market-based approaches to identify tools and strategies that can help move the needle on family economic security. In this report, you will find the following: Case studies -- An opportunity to go under the hood on deals with the Bank of America, W.K. Kellogg Foundation, Acelero Learning, and others; Point of view essays -- Insights and lessons from leaders in the field; Deals at a glance -- Snapshots of impact investors and what they have learned, including the Kresge Foundation, Living Cities, and the MacArthur Foundation; and Survey results and lessons learned -- Trends among active and emerging players in the U.S. impact investment field and the lessons that can be applied to economic mobility in the U.S. We are pleased to offer this expanded perspective on impact investing in the U.S. and the lessons for investors, philanthropists, and non-profits working to build strong and prosperous families and communities

Pediatricians' weight assessment and obesity management practices

<p>Abstract</p> <p>Background</p> <p>Clinician adherence to obesity screening guidelines from United States health agencies remains suboptimal. This study explored how personal and career demographics influence pediatricians' weight assessment and management practices.</p> <p>Methods</p> <p>A web-based survey was distributed to U.S. pediatricians. Respondents were asked to identify the weight status of photographed children and about their weight assessment and management practices. Associations between career and personal demographic variables and pediatricians' weight perceptions, weight assessment and management practices were evaluated using univariate and multivariate modeling.</p> <p>Results</p> <p>3,633 pediatric medical providers correctly identified the weight status of children at a median rate of 58%. The majority of pediatric clinicians were white, female, and of normal weight status with more than 10 years clinical experience. Experienced pediatric medical providers were less likely than younger colleagues to correctly identify the weight status of pictured children and were also less likely to know and use BMI criteria for assessing weight status. General pediatricians were more likely than subspecialty practitioners to provide diverse interventions for weight management. Non-white and Hispanic general practitioners were more likely than counterparts to consider cultural approaches to weight management.</p> <p>Conclusion</p> <p>Pediatricians' perceptions of children's weight and their weight assessment and management practices are influenced by career and personal characteristics. Objective criteria and clinical guidelines should be uniformly applied by pediatricians to screen for and manage pediatric obesity.</p

Sex Disparity in Cord Blood FoxP3+ CD4 T Regulatory Cells in Infants Exposed to Malaria In Utero.

Sex differences in the immune response and in infectious disease susceptibility have been well described, although the mechanisms underlying these differences remain incompletely understood. We evaluated the frequency of cord blood CD4 T cell subsets in a highly malaria-exposed birth cohort of mother-infant pairs in Uganda by sex. We found that frequencies of cord blood regulatory T cell ([Treg] CD4+CD25+FoxP3+CD127lo/-) differed by infant sex, with significantly lower frequencies of Tregs in female than in male neonates (P = .006). When stratified by in utero malaria exposure status, this difference was observed in the exposed, but not in the unexposed infants

The Impact of Multiple Rounds of Indoor Residual Spraying on Malaria Incidence and Hemoglobin Levels in a High-Transmission Setting.

BACKGROUND: Indoor residual spraying (IRS) is widely used as a vector control measure, although there are conflicting findings of its effectiveness in reducing malaria incidence. The objective of this study was to estimate the effect of multiple IRS rounds on malaria incidence and hemoglobin levels in a cohort of children in rural southeastern Uganda. METHODS: The study was based upon a dynamic cohort of children aged 0.5-10 years enrolled from August 2011 to June 2017 in Nagongera Subcounty. Confirmed malaria infections and hemoglobin levels were recorded over time for each participant. After each of 4 rounds of IRS, malaria incidence, hemoglobin levels, and parasite density were evaluated and compared with pre-IRS levels. Analyses were carried out at the participant level while accounting for repeated measures and clustering by household. RESULTS: Incidence rate ratios comparing post-IRS to pre-IRS incidence rates for age groups 0-3, 3-5, and 5-11 were 0.108 (95% confidence interval [CI], .078-.149), 0.173 (95% CI, .136-.222), and 0.226 (95% CI, .187-.274), respectively. The mean hemoglobin levels significantly increased from 11.01 (pre-IRS) to 12.18 g/dL (post-IRS). CONCLUSIONS: Our study supports the policy recommendation of IRS usage in a stable and perennial transmission area to rapidly reduce malaria transmission