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Most bacterial vaccines work for a subset of bacterial strains or require the modification of the antigen or isolation of the pathogen before vaccine development. Here we report injectable biomaterial vaccines that trigger potent humoral and T-cell responses to bacterial antigens by recruiting, reprogramming and releasing dendritic cells. The vaccines are assembled from regulatorily approved products and consist of a scaffold with absorbed granulocyte-macrophage colony-stimulating factor and CpG-rich oligonucleotides incorporating superparamagnetic microbeads coated with the broad-spectrum opsonin Fc-mannose-binding lectin for the magnetic capture of pathogen-associated molecular patterns from inactivated bacterial-cell-wall lysates. The vaccines protect mice against skin infection with methicillin-resistant Staphylococcus aureus, mice and pigs against septic shock from a lethal Escherichia coli challenge and, when loaded with pathogen-associated molecular patterns isolated from infected animals, uninfected animals against a challenge with different E. coli serotypes. The strong immunogenicity and low incidence of adverse events, a modular manufacturing process, and the use of components compatible with current good manufacturing practice could make this vaccine technology suitable for responding to bacterial pandemics and biothreats.

Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitudinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial isolates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable population sizes within and across humans and that commonly used ‘omics’ survey methods are more reliable when using averages over multiple days of sampling. Variation of gut metabolites within people over time is associated with amino acid levels, and differences across people are associated with differences in bile acids. Finally, we show that genomic diversification can be used to infer eco-evolutionary dynamics and in vivo selection pressures for strains within individuals. The BIO-ML is a unique resource designed to enable hypothesis-driven microbiome research. A comprehensive biobank of bacterial isolates with longitudinal and multi-omics characterization will advance understanding of the diversity and functions of human gut bacteria.

Most bacterial vaccines work for a subset of bacterial strains or require the modification of the antigen or isolation of the pathogen before vaccine development. Here we report injectable biomaterial vaccines that trigger potent humoral and T-cell responses to bacterial antigens by recruiting, reprogramming and releasing dendritic cells. The vaccines are assembled from regulatorily approved products and consist of a scaffold with absorbed granulocyte-macrophage colony-stimulating factor and CpG-rich oligonucleotides incorporating superparamagnetic microbeads coated with the broad-spectrum opsonin Fc-mannose-binding lectin for the magnetic capture of pathogen-associated molecular patterns from inactivated bacterial-cell-wall lysates. The vaccines protect mice against skin infection with methicillin-resistant Staphylococcus aureus, mice and pigs against septic shock from a lethal Escherichia coli challenge and, when loaded with pathogen-associated molecular patterns isolated from infected animals, uninfected animals against a challenge with different E. coli serotypes. The strong immunogenicity and low incidence of adverse events, a modular manufacturing process, and the use of components compatible with current good manufacturing practice could make this vaccine technology suitable for responding to bacterial pandemics and biothreats.

Broad spectrum vaccines could provide a solution to the emergence of antibiotic resistant microbes, pandemics and engineered biothreat agents. Here, we describe a modular vaccine (composite infection vaccine technology (ciVAX)) which can be rapidly assembled and in which 4 of the 5 components are already approved for human use. ciVAX consists of an injectable biomaterial scaffold with factors to recruit and activate dendritic cells (DC) in vivo and microbeads conjugated with the broad-spectrum opsonin Fc-Mannose-binding Lectin (FcMBL) that is pre-bound to polysaccharide-rich cell wall antigens, such as the pathogen-associated molecular patterns (PAMPs) fractions, captured from whole inactivated bacteria. Vaccination of mice and rabbits with ciVAX generates potent humoral and T cell responses to PAMPs isolated from native antibiotic-resistant E. coli and S. aureus, and ciVAX protects mice and pigs against lethal E coli challenge in sepsis and septic shock models. In addition to the efficacy of ciVAX against homologous challenge, PAMPS isolated from an infected animal protects other animals against infection by heterologous challenge using different E. coli serotypes – demonstrating the potential for use of ciVAX in controlling pandemics. The advantage of the ciVAX technology is the strong immunogenicity with limited reactogenicity, the use of inactivated pathogens, and the modular manufacture using cGMP approved products which can be stockpiled ready for the next pandemic.One Sentence SummaryBiomaterial vaccine induces strong immunogenicity, weak reactogenicity, and protects from E. coli sepsis in rodents and pigs, and MRSA skin abscess.

Background People living with HIV have an increased risk of left ventricular diastolic dysfunction ( LVDD ) and heart failure. HIV ‐associated LVDD may reflect both cardiomyocyte and systemic metabolic derangements, but the underlying pathways remain unclear. Methods and Results To explore such pathways, we conducted a pilot study in the Bronx and Brooklyn sites of the WIHS (Women's Interagency HIV Study) who participated in concurrent, but separate, metabolomics and echocardiographic ancillary studies. Liquid chromatography tandem mass spectrometry–based metabolomic profiling was performed on plasma samples from 125 HIV‐infected (43 with LVDD) and 35 HIV‐uninfected women (9 with LVDD). Partial least squares discriminant analysis identified polar metabolites and lipids in the glycerophospholipid‐metabolism and fatty‐acid‐oxidation pathways associated with LVDD . After multivariable adjustment, LVDD was significantly associated with higher concentrations of diacylglycerol 30:0 (odds ratio [ OR ], 1.60, 95% CI [1.01–2.55]); triacylglycerols 46:0 ( OR 1.60 [1.04–2.48]), 48:0 ( OR 1.63 [1.04–2.54]), 48:1 ( OR 1.62 [1.01–2.60]), and 50:0 ( OR 1.61 [1.02–2.53]); acylcarnitine C7 ( OR 1.88 [1.21–2.92]), C9 ( OR 1.99 [1.27–3.13]), and C16 ( OR 1.80 [1.13–2.87]); as well as lower concentrations of phosphocholine ( OR 0.59 [0.38–0.91]). There was no evidence of effect modification of these relationships by HIV status. Conclusions In this pilot study, women with or at risk of HIV with LVDD showed alterations in plasma metabolites in the glycerophospholipid‐metabolism and fatty‐acid‐oxidation pathways. Although these findings require replication, they suggest that improved understanding of metabolic perturbations and their potential modification could offer new approaches to prevent cardiac dysfunction in this high‐risk group.

Unbiased, “nontargeted” metabolite profiling techniques hold considerable promise for biomarker and pathway discovery, in spite of the lack of successful applications to human disease. By integrating nontargeted metabolomics, genetics, and detailed human phenotyping, we identified dimethylguanidino valeric acid (DMGV) as an independent biomarker of CT-defined nonalcoholic fatty liver disease (NAFLD) in the offspring cohort of the Framingham Heart Study (FHS) participants. We verified the relationship between DMGV and early hepatic pathology. Specifically, plasma DMGV levels were correlated with biopsy-proven nonalcoholic steatohepatitis (NASH) in a hospital cohort of individuals undergoing gastric bypass surgery, and DMGV levels fell in parallel with improvements in post-procedure cardiometabolic parameters. Further, baseline DMGV levels independently predicted future diabetes up to 12 years before disease onset in 3 distinct human cohorts. Finally, we provide all metabolite peak data consisting of known and unidentified peaks, genetics, and key metabolic parameters as a publicly available resource for investigations in cardiometabolic diseases.

In the Supplementary Tables 2, 4 and 6 originally published with this Article, the authors mistakenly included sample identifiers in the form of UMCGs rather than UMCG IBDs in the validation cohort; this has now been amended.

Many organizations rely on 360 Feedback to drive their strategic talent agendas. Even when 360 is purposed for development only, organizations are frequently reluctant to limit it to this use. The 360 data represent unique input that informs several talent management processes, from high-potential identification and promotion to performance management and succession planning. When 360 results are extended beyond development only and affect an employee’s status, however, a host of psychometric standards and legal requirements emerge. Highlighted is a series of considerations, beginning with design limitations as a decision-making tool (i.e., assessing performance while supporting development) and including score equivalence (across languages/cultures) and perceived fairness. After providing an overview of the legal framework of human resource decision-making, it is applied to the 360 Feedback process, including disparate impact, adverse impact, validation, and alternative selection procedures. The chapter concludes with recommendations for 360 practices, from design to implementation to use in making talent management decisions.

The inflammatory bowel diseases (IBDs), which include Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial chronic conditions of the gastrointestinal tract. While IBD has been associated with dramatic changes in the gut microbiota, changes in the gut metabolome-the molecular interface between host and microbiota-are less well understood. To address this gap, we performed untargeted metabolomic and shotgun metagenomic profiling of cross-sectional stool samples from discovery (n = 155) and validation (n = 65) cohorts of CD, UC and non-IBD control patients. Metabolomic and metagenomic profiles were broadly correlated with faecal calprotectin levels (a measure of gut inflammation). Across >8,000 measured metabolite features, we identified chemicals and chemical classes that were differentially abundant in IBD, including enrichments for sphingolipids and bile acids, and depletions for triacylglycerols and tetrapyrroles. While > 50% of differentially abundant metabolite features were uncharacterized, many could be assigned putative roles through metabolomic 'guilt by association' (covariation with known metabolites). Differentially abundant species and functions from the metagenomic profiles reflected adaptation to oxidative stress in the IBD gut, and were individually consistent with previous findings. Integrating these data, however, we identified 122 robust associations between differentially abundant species and well-characterized differentially abundant metabolites, indicating possible mechanistic relationships that are perturbed in IBD. Finally, we found that metabolome- and metagenome-based classifiers of IBD status were highly accurate and, like the vast majority of individual trends, generalized well to the independent validation cohort. Our findings thus provide an improved understanding of perturbations of the microbiome-metabolome interface in IBD, including identification of many potential diagnostic and therapeutic targets.

Background Epidemiologic studies suggest a strong link between poor habitual sleep quality and increased cardiovascular disease risk. However, the underlying mechanisms are not entirely clear. Metabolomic profiling may elucidate systemic differences associated with sleep quality that influence cardiometabolic health. Methods We explored cross-sectional associations between sleep quality and plasma metabolites in a nested case–control study of coronary heart disease (CHD) in the Women’s Health Initiative (WHI; n = 1956) and attempted to replicate the results in an independent sample from the Nurses’ Health Study II (NHSII; n = 209). A sleep-quality score (SQS) was derived from self-reported sleep problems asked in both populations. Plasma metabolomics were assayed using LC–MS with 347 known metabolites. General linear regression was used to identify individual metabolites associated with continuous SQS (false-discovery rate Results After adjusting for age, race/ethnicity, body mass index (BMI) and smoking, we identified 69 metabolites associated with SQS in the WHI (59 were lipids). Of these, 16 were replicated in NHSII (15 were lipids), including 6 triglycerides (TAGs), 4 phosphatidylethanolamines (PEs), 3 phosphatidylcholines (PCs), 1 diglyceride (DAG), 1 lysophosphatidylcholine and N6-acetyl-L-lysine (a product of histone acetylation). These metabolites were consistently higher among women with poorer sleep quality. The LASSO selection resulted in a nine-metabolite score (TAGs 45: 1, 48: 1, 50: 4; DAG 32: 1; PEs 36: 4, 38: 5; PCs 30: 1, 40: 6; N6-acetyl-L-lysine), which was positively associated with CHD risk (odds ratio per SD increase in the score: 1.16; 95% confidence interval: 1.05, 1.28; p = 0.0003) in the WHI after adjustment for matching factors and conventional CHD risk factors. Conclusions Differences in lipid metabolites may be an important pathogenic pathway linking poor habitual sleep quality and CHD risk.

Background: Metabolomics has provided new insights into mechanistic knowledge of CVD. However, this approach has limited use for studying arterial disease in high-risk women with and without HIV infection. Methods: Using liquid chromatography-tandem mass spectrometry, we profiled plasma levels of 114 cationic polar and 211 nonpolar lipid metabolites among 411 women (72% HIV+; 60% Black and 31% Hispanic) aged 35-50 from the Women’s Interagency HIV Study. Carotid arterial distensibility, a direct measure of carotid stiffness, was calculated from ultrasound measurements of the right common carotid artery diameter at systole and diastole and brachial artery pulse pressure measured. We performed partial least squares discriminant analysis (PLS-DA) to identify metabolite clusters associated with carotid stiffness (lowest vs. the other 3 quartiles of distensibility index). We used multivariate linear regression models to examine associations of individual metabolites with the distensibility index. Results: PLS-DA identified two major metabolite clusters associated with carotid stiffness. In the lipid metabolite cluster, triacylglycerols (TAGs 52:3, 52:4, 54:4), diacylglycerols (DAGs 36:2, 36:3) and sphingomyelins (16:1, 18:1, 18:2) were associated with decreased distensibility, while lysophosphatidylcholines (18:2, 20:5) were associated with increased distensibility. In the cationic polar metabolite cluster, urate, C4-OH carnitine, C5-DC carnitine, pseudouridine and 1-methyladenosine were associated with decreased distensibility. The associations of TAGs 52:3, 52:4, 54:4 and DAG 36:3 with carotid stiffness remained significant after further adjustment for conventional CVD risk factors ( Table ). No interaction by HIV infection was found. Conclusions: Among women with or at risk of HIV infection from predominantly race-ethnic minority groups, plasma TAGs and DAG of higher carbon number and double bond content are associated with carotid stiffness independent of conventional CVD risk factors.

Age-related macular degeneration (AMD) is the major cause of blindness in developed nations. AMD is characterized by retinal pigmented epithelial (RPE) cell dysfunction and loss of photoreceptor cells. Epidemiologic studies indicate important contributions of dietary patterns to the risk for AMD, but the mechanisms relating diet to disease remain unclear. Here we investigate the effect on AMD of isocaloric diets that differ only in the type of dietary carbohydrate in a wild-type aged-mouse model. The consumption of a high-glycemia (HG) diet resulted in many AMD features (AMDf), including RPE hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degeneration, whereas consumption of the lower-glycemia (LG) diet did not. Critically, switching from the HG to the LG diet late in life arrested or reversed AMDf. LG diets limited the accumulation of advanced glycation end products, long-chain polyunsaturated lipids, and their peroxidation end-products and increased C3-carnitine in retina, plasma, or urine. Untargeted metabolomics revealed microbial cometabolites, particularly serotonin, as protective against AMDf. Gut microbiota were responsive to diet, and we identified microbiota in the Clostridiales order as being associated with AMDf and the HG diet, whereas protection from AMDf was associated with the Bacteroidales order and the LG diet. Network analysis revealed a nexus of metabolites and microbiota that appear to act within a gut–retina axis to protect against diet- and age-induced AMDf. The findings indicate a functional interaction between dietary carbohydrates, the metabolome, including microbial cometabolites, and AMDf. Our studies suggest a simple dietary intervention that may be useful in patients to arrest AMD.

Tumors put in a vulnerable position Cancer cells often display alterations in metabolism that help fuel their growth. Such metabolic “rewiring” may also work against the cancer cells, however, by creating new vulnerabilities that can be exploited therapeutically. A variety of human tumors show changes in methionine metabolism caused by loss of the gene coding for 5-methylthioadenosine phosphorylase (MTAP). Mavrakis et al. and Kryukov et al. found that the loss of MTAP renders cancer cell lines sensitive to growth inhibition by compounds that suppress the activity of a specific arginine methyltransferase called PRMT5. Conceivably, drugs that inhibit PRMT5 activity could be developed into a tailored therapy for MTAP-deficient tumors. Science , this issue pp. 1208 and 1214

Covenant Nation: The Politics of Grace in Early American Literature by Justin M. Scott-Coe Claremont Graduate University: 2012 The argument of this dissertation is that a critical reading of the concept of "covenant" in early American writings is instrumental to understanding the paradoxes in the American political concepts of freedom and equality. Following Slavoj Žižek's theoretical approach to theology, I trace the covenant concept in early American literature from the theological expressions and disputes in Puritan Massachusetts through Jonathan Edwards's Freedom of Will and the essays of Ralph Waldo Emerson, showing how the covenant theology of colonial New England dispersed into more "secular" forms of what may be called an American political theology. The first chapter provides an overview of recent attempts to integrate theology and theory, specifically comparing Jacques Derrida and Žižek to better understand the latter's theology of materialism which relies on as well as informs the Reformed Protestant covenantal dichotomy of grace and works. The second chapter establishes the complicated architecture of the covenant concept within seventeenth-century New England Reformed Protestantism, and uses church membership transcripts along with Ann Hutchinson court trial documents to demonstrate how this inherently unstable theology created unintended slippage between God's grace and mankind's works, resulting in a theological formulation remarkably open to Žižek's analysis of political ideology. The third chapter demonstrates how Jonathan Edwards, through his ingenious counter-argument in Freedom of Will, provides a theoretical foundation for an uneasy but necessary alignment of the covenants of works and grace, releasing the subjunctive potential of grace to operate through history as a predeterminer of meaning and, potentially, freedom. In the last chapter, I argue that Emerson finally converts the covenant from a politically conceptualized theological framework for radical grace into a personal institutionalization of grace itself. Stanley Cavell's exploration of Emerson's "constitution" in light of the covenant motif demonstrates the political (im)possibilities inherent in America's self-conceptions of personal liberty and civic equality. In the end, complexities inherent in the concept of the covenant, especially its creative failure to control the radical nature of "grace," are determinative factors in our contradictory American egalitarian ideals. For Jo, a new beginning