Cellular metabolic fluxes are determined by enzyme activities and metabolite abundances. Biochemical approaches reveal the impact of specific substrates or regulators on enzyme kinetics, but do not capture the extent to which metabolite and enzyme concentrations vary across physiological states, and therefore how cellular reactions are regulated. We measured enzyme and metabolite concentrations and metabolic fluxes across 25 steady-state yeast cultures. We then assessed the extent to which flux can be explained by a Michaelis-Menten relationship between enzyme, substrate, product, and potential regulator concentrations. This revealed three new instances of cross-pathway regulation, which we biochemically verified. These included inhibition of pyruvate kinase by citrate, which accumulated and thereby curtailed glycolytic outflow in nitrogen-limited yeast. Overall, substrate concentrations were the strongest driver of the net rates of cellular metabolic reactions, with metabolite concentrations collectively having more than double the physiological impact of enzymes.

Obesity is a condition resulting from the interactions of individual biology and environmental factors causing multiple complications. To understand the system's metabolic changes associated with the obesity development and progression, we systematically analyzed the dynamic metabonomic changes induced by a high-fat diet (HFD) in multiple biological matrices of rats using NMR and GC-FID/MS techniques. Clinical chemistry and histopathological data were obtained as complementary information. We found that HFD intakes caused systematic metabolic changes in blood plasma, liver, and urine samples involving multiple metabolic pathways including glycolysis, TCA cycle, and gut microbiota functions together with the metabolisms of fatty acids, amino acids, choline, B-vitamins, purines, and pyrimidines. The HFD-induced metabolic variations were detectable in rat urine a week after HFD intake and showed clear dependence on the intake duration. B-vitamins and gut microbiota played important roles in the obesity development and progression together with changes in TCA cycle intermediates (citrate, α-ketoglutarate, succinate, and fumarate). 83-day HFD intakes caused significant metabolic alterations in rat liver highlighted with the enhancements in lipogenesis, lipid accumulation and lipid oxidation, suppression of glycolysis, up-regulation of gluconeogenesis and glycogenesis together with altered metabolisms of choline, amino acids and nucleotides. HFD intakes reduced the PUFA-to-MUFA ratio in both plasma and liver, indicating the HFD-induced oxidative stress. These findings provided essential biochemistry information about the dynamic metabolic responses to the development and progression of HFD-induced obesity. This study also demonstrated the combined metabonomic analysis of multiple biological matrices as a powerful approach for understanding the molecular basis of pathogenesis and disease progression.

BackgroundAtherogenic index of plasma (AIP) has been reported to be associated with cardiovascular diseases. However no study has yet systematically evaluated the association between AIP and obesity and its advantage in obesity prediction compared with conventional lipid components.MethodsA total of 6465 participants aged over 30 years were included in this study. Blood lipid components including triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were measured, and AIP was calculated as log10(TG/HDL-C). Pearson correlation analyses, multivariable logistic analyses and predictive analyses were used to evaluate the association and discrimination ability between AIP, four conventional lipid profiles and obesity.ResultsSubjects in the higher quartiles of AIP all had a significantly increased risk of obesity compared with those in the lowest quartile (P for trend< 0.01). AIP showed a stronger association with obesity than the conventional lipid components as the pearson coefficient reached up to 0.372 and the adjusted odds ratio was 5.55. Using AIP rather than HDL-C and TG significantly improved risk prediction for obesity (AUC improvement = 0.011, P = 0.011; Continuous net reclassification index = 29.55%, P < 0.01; Category net reclassification index = 6.06%; Integrated discrimination improvement = 0.68%, P < 0.01).ConclusionsHigher AIP level was positively and strongly associated with obesity. AIP is a novel and better biomarker associated with obesity. Controlling the AIP level would be more helpful for the prevention of obesity.

No abstract

Although T-cell checkpoint blockade has revolutionized melanoma therapy, metastatic melanoma in pregnancy remains a challenging area of unmet need. Treatment with anti-PD1 therapy decreases foetal–maternal tolerance and increases the risk of pregnancy loss in animal studies and is considered category D by the Food and Drug Administration. We describe a unique case of conception and pregnancy, with successful maternal and foetal outcomes, in a patient with metastatic melanoma who had received combination anti-CTLA-4 and anti-PD1 therapy. A 32-year-old G0P0 lady, with a 10-year history of infertility of unclear cause, was found to be 7 weeks pregnant after 14 months of nivolumab maintenance therapy, having previously received combination ipilimumab and nivolumab. Nivolumab was ceased upon discovery of pregnancy in the first trimester. The patient had an uneventful pregnancy, followed by spontaneously premature labour, and delivered by caesarean section at 33 weeks’ gestation. The foetus had moderate intrauterine growth restriction, as well as congenital hypothyroidism, which possibly constitutes the first documented case of foetal immune-related adverse event from maternal anti-PD1 exposure. No adverse events were noted in the mother. At 6 months of follow-up postpartum, the mother had a sustained complete response to treatment, and the baby had appropriate weight gain with normal developmental milestones. We summarize and discuss the available literature of immune checkpoint inhibitor exposure in pregnancy, which consists of a total of three case reports.

Schistosomiasis is a parasitic zoonosis caused by small trematode worms called schistosomes, amongst which Schistosoma japonicum (S. japonicum) is endemic in Asia. In order to understand the schistosome-induced changes in the host metabolism so as to facilitate early diagnosis of schistosomiasis, we systematically investigated the dynamic metabolic responses of mice biofluids and liver tissues to S. japonicum infection for five weeks using 1H NMR spectroscopy in conjunction with multivariate data analysis. We were able to detect schistosomiasis at the third week post-infection, which was one week earlier than “gold standard” methods. We found that S. japonicum infection caused significant elevation of urinary 3-ureidopropionate, a uracil catabolic product, and disturbance of lipid metabolism, stimulation of glycolysis, depression of tricarboxylic acid cycle and disruption of gut microbiota regulations. We further found that the changes of 3-ureidopropionate and overall metabolic changes in both urinary and plasma samples were closely correlated with the time-course of disease progression. Furthermore, such changes together with liver tissue metabonome were clearly associated with the worm-burdens. These findings provided more insightful understandings of host biological responses to the infection and demonstrated that metabonomic analysis is potentially useful for early detection of schistosomiasis and comprehension of the mechanistic aspects of disease progression.

Earth‐abundant amorphous nanomaterials with rich structural defects are promising alternative catalysts to noble metals for an efficient electrochemical oxygen evolution reaction; however, their inferior electrical conductivity and poor morphological control during synthesis hamper the full realization of their potency in electrocatalysis. Herein, a rapid surface‐guided synthetic approach is proposed to introduce amorphous and mixed‐metal oxyhydroxide overlayers on ultrathin Ni‐doped MnO2 (NiMnO2) nanosheet arrays via a galvanic replacement mechanism. This method results in a monolithic 3D porous catalyst with a small overpotential of only 232 mV to achieve a current density of 10 mA cm−2 in 1 m KOH, which is much lower than the corresponding value of 307 mV for the NiMnO2 reference sample. Detailed structural and electrochemical characterization reveal that the unique NiMnO2 ultrathin nanosheet arrays do not only provide a large surface area to guide the formation of active amorphous catalyst layers but also ensure the effective charge transport owing to their high electron conductivity, collectively contributing to the greatly improved catalyst activity. It is envisioned that this highly operable surface‐guide synthetic strategy may open up new avenues for the design and fabrication of novel 3D nanoarchitectures integrated with functional amorphous materials for broadened ranges of applications.

Intrauterine growth restriction (IUGR) is not only an underlying factor for stunted postnatal growth and newborn deaths, but also associated with disease prevalence, such as hypertension and diabetes, in both adult humans and animals. To investigate the metabolic status of IUGR, the differences in serum and jejunal tissue metabonome were examined in IUGR and normal weight 21 day old piglets. IUGR piglets had a significantly lower birth weight (785 ± 42 g vs. 1451 ± 124 g), weaned weight (3053 ± 375 g vs. 6489 ± 545 g) and average daily gain (108 ± 16 g vs. 240 ± 21 g) than normal weight piglets (p < 0.05). IUGR piglets also had a shorter villus height and smaller villus height to crypt depth ratio (p < 0.05) in jejunum. An NMR-based metabonomic study found that serum levels of glycoprotein, albumin and threonine were higher in IUGR than in normal weight piglets, while serum levels of HDL, lipids, unsaturated lipids, glycerophosphorylcholine, myo-inositol, citrate, glutamine and tyrosine were lower in IUGR piglets (p < 0.05). In addition, marked changes in jejunal metabolites, including elevated levels of lipids and unsaturated lipids, and decreased levels of valine, alanine, glutamine, glutamate, choline, glycerophosphorylcholine, trimethylamine-N-oxide, scyllo-inositol, lactate, creatine, glucose, galactose, phenylalanine, tyrosine, glutathione, inosine and taurine were observed in IUGR piglets (p < 0.05). These novel findings indicate that IUGR piglets have a distinctive metabolic status compared to normal weight piglets, including changes in lipogenesis, lipid oxidation, energy supply and utilization, amino acid and protein metabolism, and antioxidant ability; these changes could contribute to impaired growth and jejunal function.