Metabolic profiles of six African cultivars of cassava (Manihot esculenta Crantz) highlight bottlenecks of root yield

Open Access Article; Published online: 17 Jan 2020Cassava is an important staple crop in sub‐Saharan Africa, due to its high productivity even on nutrient poor soils. The metabolic characteristics underlying this high productivity are poorly understood including the mode of photosynthesis, reasons for the high rate of photosynthesis, the extent of source/sink limitation, the impact of environment, and the extent of variation between cultivars. Six commercial African cassava cultivars were grown in a greenhouse in Erlangen, Germany, and in the field in Ibadan, Nigeria. Source leaves, sink leaves, stems and storage roots were harvested during storage root bulking and analyzed for sugars, organic acids, amino acids, phosphorylated intermediates, minerals, starch, protein, activities of enzymes in central metabolism and yield traits. High ratios of RuBisCO:phosphoenolpyruvate carboxylase activity support a C3 mode of photosynthesis. The high rate of photosynthesis is likely to be attributed to high activities of enzymes in the Calvin–Benson cycle and pathways for sucrose and starch synthesis. Nevertheless, source limitation is indicated because root yield traits correlated with metabolic traits in leaves rather than in the stem or storage roots. This situation was especially so in greenhouse‐grown plants, where irradiance will have been low. In the field, plants produced more storage roots. This was associated with higher AGPase activity and lower sucrose in the roots, indicating that feedforward loops enhanced sink capacity in the high light and low nitrogen environment in the field. Overall, these results indicated that carbon assimilation rate, the K battery, root starch synthesis, trehalose, and chlorogenic acid accumulation are potential target traits for genetic improvement

Hsp90 middle domain phosphorylation initiates a complex conformational program to recruit the ATPase-stimulating cochaperone Aha1

Complex conformational dynamics are essential for function of the dimeric molecular cha- perone heat shock protein 90 (Hsp90), including transient, ATP-biased N-domain dimer- ization that is necessary to attain ATPase competence. The intrinsic, but weak, ATP hydrolyzing activity of human Hsp90 is markedly enhanced by the co-chaperone Aha1. However, the cellular concentration of Aha1 is substoichiometric relative to Hsp90. Here we report that initial recruitment of this cochaperone to Hsp90 is markedly enhanced by phosphorylation of a highly conserved tyrosine (Y313 in Hsp90α) in the Hsp90 middle domain. Importantly, phosphomimetic mutation of Y313 promotes formation of a transient complex in which both N- and C-domains of Aha1 bind to distinct surfaces of the middle domains of opposing Hsp90 protomers prior to ATP-directed N-domain dimerization. Thus, Y313 represents a phosphorylation-sensitive conformational switch, engaged early after client loading, that affects both local and long-range conformational dynamics to facilitate initial recruitment of Aha1 to Hsp90

Erratum to: Assessment of predictive performance in incomplete data by combining internal validation and multiple imputation

Abstract Background Missing values are a frequent issue in human studies. In many situations, multiple imputation (MI) is an appropriate missing data handling strategy, whereby missing values are imputed multiple times, the analysis is performed in every imputed data set, and the obtained estimates are pooled. If the aim is to estimate (added) predictive performance measures, such as (change in) the area under the receiver-operating characteristic curve (AUC), internal validation strategies become desirable in order to correct for optimism. It is not fully understood how internal validation should be combined with multiple imputation. Methods In a comprehensive simulation study and in a real data set based on blood markers as predictors for mortality, we compare three combination strategies: Val-MI, internal validation followed by MI on the training and test parts separately, MI-Val, MI on the full data set followed by internal validation, and MI(-y)-Val, MI on the full data set omitting the outcome followed by internal validation. Different validation strategies, including bootstrap und cross-validation, different (added) performance measures, and various data characteristics are considered, and the strategies are evaluated with regard to bias and mean squared error of the obtained performance estimates. In addition, we elaborate on the number of resamples and imputations to be used, and adopt a strategy for confidence interval construction to incomplete data. Results Internal validation is essential in order to avoid optimism, with the bootstrap 0.632+ estimate representing a reliable method to correct for optimism. While estimates obtained by MI-Val are optimistically biased, those obtained by MI(-y)-Val tend to be pessimistic in the presence of a true underlying effect. Val-MI provides largely unbiased estimates, with a slight pessimistic bias with increasing true effect size, number of covariates and decreasing sample size. In Val-MI, accuracy of the estimate is more strongly improved by increasing the number of bootstrap draws rather than the number of imputations. With a simple integrated approach, valid confidence intervals for performance estimates can be obtained. Conclusions When prognostic models are developed on incomplete data, Val-MI represents a valid strategy to obtain estimates of predictive performance measures

Effect of serum 25-hydroxyvitamin D on risk for type 2 diabetes may be partially mediated by subclinical inflammation: results from the MONICA/KORA Augsburg study

OBJECTIVE: To assess the association between serum 25-hydroxyvitamin D (25-OHD) and incident type 2 diabetes and to determine whether the association is mediated by subclinical inflammation. RESEARCH DESIGN AND METHODS: Using a case-cohort design, baseline levels of 25-OHD were measured in 416 case subjects with incident type 2 diabetes and 1,267 noncase subjects selected from a source population of 7,936 middle-aged participants in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) study. RESULTS: A significant inverse association was observed between serum 25-OHD and incident type 2 diabetes after adjustment for diabetes risk factors and season. The hazard ratio (HR) and 95% CI comparing tertile extremes was 0.63 (0.44–0.90) (P(trend) = 0.010). Further adjustment for C-reactive protein, interleukin-6, soluble intercellular adhesion molecule-1, and interferon-γ–inducible protein-10 attenuated this association by 16% (HR 0.73 [0.50–1.05], P = 0.090). CONCLUSIONS: Vitamin D status is inversely related to type 2 diabetes risk and our data suggest that this association may be partially mediated by subclinical inflammation

Hippurate as a metabolomic marker of gut microbiome diversity: Modulation by diet and relationship to metabolic syndrome

Reduced gut microbiome diversity is associated with multiple disorders including metabolic syndrome (MetS) features, though metabolomic markers have not been investigated. Our objective was to identify blood metabolite markers of gut microbiome diversity, and explore their relationship with dietary intake and MetS. We examined associations between Shannon diversity and 292 metabolites profiled by the untargeted metabolomics provider Metabolon Inc. in 1529 females from TwinsUK using linear regressions adjusting for confounders and multiple testing (Bonferroni: P < 1.71 × 10-4). We replicated the top results in an independent sample of 420 individuals as well as discordant identical twin pairs and explored associations with self-reported intakes of 20 food groups. Longitudinal changes in circulating levels of the top metabolite, were examined for their association with food intake at baseline and with MetS at endpoint. Five metabolites were associated with microbiome diversity and replicated in the independent sample. Higher intakes of fruit and whole grains were associated with higher levels of hippurate cross-sectionally and longitudinally. An increasing hippurate trend was associated with reduced odds of having MetS (OR: 0.795[0.082]; P = 0.026). These data add further weight to the key role of the microbiome as a potential mediator of the impact of dietary intake on metabolic status and health

Detection of stable community structures within gut microbiota co-occurrence networks from different human populations

Microbes in the gut microbiome form sub-communities based on shared niche specialisations and specific interactions between individual taxa. The inter-microbial relationships that define these communities can be inferred from the co-occurrence of taxa across multiple samples. Here, we present an approach to identify comparable communities within different gut microbiota co-occurrence networks, and demonstrate its use by comparing the gut microbiota community structures of three geographically diverse populations. We combine gut microbiota profiles from 2,764 British, 1,023 Dutch, and 639 Israeli individuals, derive co-occurrence networks between their operational taxonomic units, and detect comparable communities within them. Comparing populations we find that community structure is significantly more similar between datasets than expected by chance. Mapping communities across the datasets, we also show that communities can have similar associations to host phenotypes in different populations. This study shows that the community structure within the gut microbiota is stable across populations, and describes a novel approach that facilitates comparative community-centric microbiome analyses

Circulating glucuronic acid predicts healthspan and longevity in humans and mice

Glucuronic acid is a metabolite of glucose that is involved in the detoxification of xenobiotic compounds and the structure/remodeling of the extracellular matrix. We report for the first time that circulating glucuronic acid is a robust biomarker of mortality that is conserved across species. We find that glucuronic acid levels are significant predictors of all-cause mortality in three population-based cohorts from different countries with 420 years of follow-up (HR=1.44, p=2.9x10(-6) in the discovery cohort; HR=1.13, p=0.032 and HR=1.25, p=0.017, respectively in the replication cohorts), as well as in a longitudinal study of genetically heterogenous mice (HR=1.29, p=0.018). Additionally, we find that glucuronic acid levels increase with age and predict future healthspan-related outcomes. Together, these results demonstrate glucuronic acid as a robust biomarker of longevity and healthspan

Metabolomic profiling identifies novel associations with Electrolyte and Acid-Base Homeostatic patterns

Electrolytes have a crucial role in maintaining health and their serum levels are homeostatically maintained within a narrow range by multiple pathways involving the kidneys. Here we use metabolomics profiling (592 fasting serum metabolites) to identify molecular markers and pathways associated with serum electrolyte levels in two independent population-based cohorts. We included 1523 adults from TwinsUK not on blood pressure-lowering therapy and without renal impairment to look for metabolites associated with chloride, sodium, potassium and bicarbonate by running linear mixed models adjusting for covariates and multiple comparisons. For each electrolyte, we further performed pathway enrichment analysis (PAGE algorithm). Results were replicated in an independent cohort. Chloride, potassium, bicarbonate and sodium associated with 10, 58, 36 and 17 metabolites respectively (each P < 2.1 x 10(-5)), mainly lipids. Of all the electrolytes, serum potassium showed the most significant associations with individual fatty acid metabolites and specific enrichment of fatty acid pathways. In contrast, serum sodium and bicarbonate showed associations predominantly with amino-acid related species. In the first study to examine systematically associations between serum electrolytes and small circulating molecules, we identified novel metabolites and metabolic pathways associated with serum electrolyte levels. The role of these metabolic pathways on electrolyte homeostasis merits further studies

Transforming Growth Factor-β1 and Incident Type 2 Diabetes: Results from the MONICA/KORA case-cohort study, 1984–2002

Subclinical inflammation leads to insulin resistance and beta-cell dysfunction. This study aimed to assess whether levels of circulating transforming growth factor-beta1 (TGF-beta1)-a central, mainly immunosuppressive, and anti-inflammatory cytokine-were associated with incident type 2 diabetes. RESEARCH DESIGN AND METHODS: We measured serum levels of TGF-beta1 from 460 individuals with and 1,474 individuals without incident type 2 diabetes in a prospective case-cohort study within the population-based MONICA (MONItoring of Trends and Determinants in CArdiovascular Disease)/KORA (Cooperative Health Research in the Region of Augsburg) cohort. RESULTS: Elevated TGF-beta1 concentrations were associated with higher, not lower, risk for type 2 diabetes (age-, sex-, and survey-adjusted hazard ratios [95% CI] for increasing TGF-beta1 tertiles: 1.0, 1.08 [0.83-1.42], and 1.41 [1.08-1.83]; P(for) (trend) = 0.012). Adjustment for BMI and metabolic and lifestyle factors had virtually no impact on the effect size. CONCLUSIONS: Elevated serum concentrations of the cytokine TGF-beta1 indicate an increased risk for type 2 diabetes. TGF-beta1 may be upregulated to counterbalance metabolic and immunological disturbances preceding type 2 diabetes

Effects of statins on the immunoglobulin G glycome

Background Statins are among the most widely prescribed medications worldwide and usually many individuals involved in clinical and population studies are on statin therapy. Immunoglobulin G (IgG) glycosylation has been associated with numerous cardiometabolic risk factors. Methods The aim of this study was to investigate the possible association of statin use with N-glycosylation of IgG. The association was analyzed in two large population cohorts (TwinsUK and KORA) using hydrophilic interaction liquid chromatography (HILIC-UPLC) in the TwinsUK cohort and reverse phase liquid chromatography coupled with electrospray mass spectrometry (LC-ESI-MS) in the KORA cohort. Afterwards we investigated the same association for only one statin (rosuvastatin) in a subset of individuals from the randomized double-blind placebo-controlled JUPITER study using LC-ESI-MS for IgG glycome and HILIC-UPLC for total plasma N-glycome. Results In the TwinsUK population, the use of statins was associated with higher levels of core-fucosylated biantennary glycan structure with bisecting N-acetylglucosamine (FA2B) and lower levels of core-fucosylated biantennary digalactosylated monosialylated glycan structure (FA2G2S1). The association between statin use and FA2B was replicated in the KORA cohort. In the JUPITER trial we found no statistically significant differences between the randomly allocated placebo and rosuvastatin groups. Conclusions In the TwinsUK and KORA cohorts, statin use was associated with a small increase of pro-inflammatory IgG glycan, although this finding was not confirmed in a subset of participants from the JUPITER trial. General significance Even if the association between IgG N-glycome and statins exists, it is not large enough to pose a problem for glycomic studies