Rationale
Malondialdehyde, one of the peroxidation products of polyunsaturated fatty acids, has been widely reported as an oxidative stress biomarker in many diseases. However, malondialdehyde is ...inherently unstable in biological matrices, which renders its measurement unreliable with all the reported analytical methods. To find an alternative oxidative stress biomarker, we envisioned that N‐(2‐carboxyethyl)proline, a modified conjugate of malondialdehyde and proline, could be a stable candidate for this purpose.
Methods
The proposed compound was chemically synthesized, and liquid chromatography–mass spectrometry methods were developed and used to search for the compound in human biological samples.
Results
An endogenous metabolite in human feces and urine samples was found to match the synthetic N‐(2‐carboxyethyl)proline by chromatographic retention and the fragmentation pattern of its molecular ion.
Conclusion
The results confirmed that N‐(2‐carboxyethyl)proline was a new metabolite in human feces and urine samples. In addition, our results demonstrated a case of successful identification of true unknown metabolite by knowledge‐based hypothesis of possible metabolites followed by experimental confirmation with a synthetic standard.
Optimal Trend Inflation Adam, Klaus; Weber, Henning
The American economic review,
02/2019, Letnik:
109, Številka:
2
Journal Article
Recenzirano
Sticky price models featuring heterogeneous firms and systematic firm-level productivity trends deliver radically different predictions for the optimal inflation rate than their popular ...homogenous-firm counterparts: (i) the optimal steady-state inflation rate generically differs from zero and (ii) inflation optimally responds to productivity disturbances. We show this by aggregating a heterogeneous-firm model with sticky prices in closed form. Using firm-level data from the US Census Bureau, we estimate the historically optimal inflation path for the US economy: the optimal inflation rate ranges between 1 percent and 3 percent per year and displays a downward trend over the period 1977–2015.
Insulin resistance is a risk factor for type 2 diabetes and cardiovascular disease progression. Current diagnostic tests, such as glycemic indicators, have limitations in the early detection of ...insulin resistant individuals. We searched for novel biomarkers identifying these at-risk subjects.
Using mass spectrometry, non-targeted biochemical profiling was conducted in a cohort of 399 nondiabetic subjects representing a broad spectrum of insulin sensitivity and glucose tolerance (based on the hyperinsulinemic euglycemic clamp and oral glucose tolerance testing, respectively).
Random forest statistical analysis selected alpha-hydroxybutyrate (alpha-HB) as the top-ranked biochemical for separating insulin resistant (lower third of the clamp-derived M(FFM) = 33 12 micromol x min(-1) x kg(FFM) (-1), median interquartile range, n = 140) from insulin sensitive subjects (M(FFM) = 66 23 micromol x min(-1) x kg(FFM) (-1)) with a 76% accuracy. By targeted isotope dilution assay, plasma alpha-HB concentrations were reciprocally related to M(FFM); and by partition analysis, an alpha-HB value of 5 microg/ml was found to best separate insulin resistant from insulin sensitive subjects. alpha-HB also separated subjects with normal glucose tolerance from those with impaired fasting glycemia or impaired glucose tolerance independently of, and in an additive fashion to, insulin resistance. These associations were also independent of sex, age and BMI. Other metabolites from this global analysis that significantly correlated to insulin sensitivity included certain organic acid, amino acid, lysophospholipid, acylcarnitine and fatty acid species. Several metabolites are intermediates related to alpha-HB metabolism and biosynthesis.
alpha-hydroxybutyrate is an early marker for both insulin resistance and impaired glucose regulation. The underlying biochemical mechanisms may involve increased lipid oxidation and oxidative stress.
We show that unexpected price-level movements generate sizable wealth redistribution in the Euro Area (EA), using sectoral accounts and newly available data from the Household Finance and Consumption ...Survey. The EA as a whole is a net loser of unexpected price-level decreases, with Italy, Greece, Portugal, and Spain losing most in per capita terms, and Belgium and Malta being net winners. Governments are net losers of deflation, while the household (HH) sector is a net winner in the EA as a whole. HHs in Belgium, Ireland, Malta, and Germany experience the biggest per capita gains, while HHs in Finland and Spain turn out to be net losers. Considerable heterogeneity exists also within the HH sector: relatively young middle class HHs are net losers of deflation, while older and richer HHs are winners. As a result, wealth inequality in the EA increases with unexpected deflation, although in some countries (Austria, Germany, and Malta) inequality decreases due to the presence of relatively few young borrowing HHs. We document that HHs' inflation exposure varies systematically across countries, with HHs in high-inflation EA countries holding systematically lower nominal exposures.
The relevance of cysteine metabolism in cancer has gained considerable interest in recent years, largely focusing on its role in generating the antioxidant glutathione. Through metabolomic profiling ...using a combination of high-throughput liquid and gas chromatography-based mass spectrometry on a total of 69 patient-derived glioma specimens, this report documents the discovery of a parallel pathway involving cysteine catabolism that results in the accumulation of cysteine sulfinic acid (CSA) in glioblastoma. These studies identified CSA to rank as one of the top metabolites differentiating glioblastoma from low-grade glioma. There was strong intratumoral concordance of CSA levels with expression of its biosynthetic enzyme cysteine dioxygenase 1 (CDO1). Studies designed to determine the biologic consequence of this metabolic pathway identified its capacity to inhibit oxidative phosphorylation in glioblastoma cells, which was determined by decreased cellular respiration, decreased ATP production, and increased mitochondrial membrane potential following pathway activation. CSA-induced attenuation of oxidative phosphorylation was attributed to inhibition of the regulatory enzyme pyruvate dehydrogenase. Studies performed in vivo abrogating the CDO1/CSA axis using a lentiviral-mediated short hairpin RNA approach resulted in significant tumor growth inhibition in a glioblastoma mouse model, supporting the potential for this metabolic pathway to serve as a therapeutic target. Collectively, we identified a novel, targetable metabolic pathway involving cysteine catabolism contributing to the growth of aggressive high-grade gliomas. These findings serve as a framework for future investigations designed to more comprehensively determine the clinical application of this metabolic pathway and its contributory role in tumorigenesis.
Metabolomic screening of fasting plasma from nondiabetic subjects identified α-hydroxybutyrate (α-HB) and linoleoyl-glycerophosphocholine (L-GPC) as joint markers of insulin resistance (IR) and ...glucose intolerance. To test the predictivity of α-HB and L-GPC for incident dysglycemia, α-HB and L-GPC measurements were obtained in two observational cohorts, comprising 1,261 nondiabetic participants from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) study and 2,580 from the Botnia Prospective Study, with 3-year and 9.5-year follow-up data, respectively. In both cohorts, α-HB was a positive correlate and L-GPC a negative correlate of insulin sensitivity, with α-HB reciprocally related to indices of β-cell function derived from the oral glucose tolerance test (OGTT). In follow-up, α-HB was a positive predictor (adjusted odds ratios 1.25 95% CI 1.00-1.60 and 1.26 1.07-1.48, respectively, for each standard deviation of predictor), and L-GPC was a negative predictor (0.64 0.48-0.85 and 0.67 0.54-0.84) of dysglycemia (RISC) or type 2 diabetes (Botnia), independent of familial diabetes, sex, age, BMI, and fasting glucose. Corresponding areas under the receiver operating characteristic curve were 0.791 (RISC) and 0.783 (Botnia), similar in accuracy when substituting α-HB and L-GPC with 2-h OGTT glucose concentrations. When their activity was examined, α-HB inhibited and L-GPC stimulated glucose-induced insulin release in INS-1e cells. α-HB and L-GPC are independent predictors of worsening glucose tolerance, physiologically consistent with a joint signature of IR and β-cell dysfunction.
An LC–MS/MS‐based bioanalytical method has been developed to measure the concentration of L‐threonate at its endogenous level in human plasma. Following isotope dilution and protein precipitation, ...the samples were acetylated and chromatographed under reversed‐phase conditions for baseline separation of the derivatized L‐threonate and its stereoisomer D‐erythronate. The method was assessed by a fit‐for‐purpose validation with a calibration range from 100 to 10,000 ng/mL. The intra‐run coefficients of variation (CVs) were <3.6% and the inter‐run CV was 3.2% for the QC samples at endogenous level. At the lower limit of quantitation, the intra‐run CV was 6.1% and the average inaccuracy was −1.4%. This method provides an efficient and reliable quantitation of L‐threonate and could be useful to certain biomarker investigators.
Ignoring the existence of the zero lower bound on nominal interest rates one considerably understates the value of monetary commitment in New Keynesian models. A stochastic forward-looking model with ...an occasionally binding lower bound, calibrated to the U.S. economy, suggests that low values for the natural rate of interest lead to sizeable output losses and deflation under discretionary monetary policy. The fall in output and deflation are much larger than in the case with policy commitment and do not show up at all if the model abstracts from the existence of the lower bound. The welfare losses of discretionary policy increase even further when inflation is partly determined by lagged inflation in the Phillips curve. These results emerge because private sector expectations and the discretionary policy response to these expectations reinforce each other and cause the lower bound to be reached much earlier than under commitment.
We study the distributional consequences of housing price, bond price and equity price increases for Euro Area households using data from the Household Finance and Consumption Survey (HFCS). The ...capital gains from bond price and equity price increases turn out to be concentrated among relatively few households, while the median household strongly benefits from housing price increases. The capital gains from bond price increases (relative to household net wealth) do not correlate with household net wealth (or income). Bond price increases thus leave net wealth inequality largely unchanged. In contrast, equity price increases largely benefit the top end of the net wealth (and income) distribution, thus amplify net wealth inequality. Housing price increases display a hump shaped pattern over the net wealth distribution, with the poorest and richest households benefitting least, but there exists considerable heterogeneity across Euro Area countries. The ECB's OMT announcements over the summer of 2012 had quantitatively similar distributional implications as an unexpected loosening of the policy rate by about 175 basis points.
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