A cyclic anaerobic/aerobic bubble column reactor was run for 420 days to study the competition for nitrite between nitrite oxidizing bacteria (NOB) and anaerobic ammonium oxidizing bacteria (Anammox) ...at low temperatures. An anaerobic feeding period with nitrite and ammonium in the influent followed by an aerated period was applied resulting in a biomass specific conversion rate of 0.18 ± 0.02 gN(2) - N · gVSS(-1)· day(-1) when the dissolved oxygen concentration was maintained at 1.0 mgO(2) · L(-1). An increase in white granules was observed in the reactor which were mainly located at the top of the settled sludge bed, whereas red granules were located at the bottom. FISH, activity tests, and qPCR techniques revealed that red biomass was dominated by Anammox bacteria and white granules by NOB. Granules from the top of the sludge bed were smaller and therefore had a higher aerobic volume fraction, a lower density, and consequently a slower settling rate. Sludge was manually removed from the top of the settled sludge bed to selectively remove NOB which resulted in an increased overall biomass specific N-conversion rate of 0.32 ± 0.02 gN(2) - N · gVSS(-1) · day(-1). Biomass segregation in granular sludge reactors gives an extra opportunity to select for specific microbial groups by applying a different SRT for different microbial groups.
Aims
Inflammatory myofibroblastic tumour (IMT) is a rare mesenchymal neoplasm of intermediate malignant potential, occurring at any age and at multiple sites. Epithelioid inflammatory myofibroblastic ...sarcoma (EIMS) is an aggressive subtype of IMT, typically involving the abdomen. Most IMTs harbour kinase gene fusions, especially involving ALK and ROS1, but 20–30% of IMTs show no detectable translocations. The aim of this study is to further delineate clinicopathological and molecular characteristics of abdominal IMT and discover potential new therapeutic targets.
Methods and results
In 20 IMTs, including four EIMS, RNA fusion analysis was performed, followed by multiplex DNA analysis if no ALK or ROS1 fusion was detected. Fourteen IMTs (70.0%) had an ALK translocation and the fusion partner was identified in 11, including a RRBP1::ALK fusion, not previously described in classical (non‐EIMS) IMT. RANBP2::ALK fusion was demonstrated in all EIMS. One IMT had a ROS1 fusion. In all ALK/ROS1 translocation‐negative IMTs mutations or fusions – as yet unreported in primary IMT – were found in genes related to the receptor tyrosine kinase (RTK)/PI3K/AKT pathway. Three of four patients with EIMS died of disease mean survival 8 months (4–15 months), whereas only one of 14 classical IMT patients succumbed to disease mean follow‐up time 52 months (2–204 months); P < 0.01.
Conclusion
This study shows the wide clinical spectrum of abdominal IMTs and affirms the poor prognosis of EIMS, raising discussion about its status as IMT subtype. Furthermore, the newly detected alterations of the RTK/PI3K/AKT pathway expand the molecular landscape of IMTs and provide potential therapeutic targets.
Twenty primary abdominal inflammatory myofibroblastic tumours, including four epithelioid inflammatory myofibroblastic sarcomas, were analysed showing mostly kinase fusions, including a novel RRBP1::ALK fusion and FGFR1 translocation. In kinase fusion‐negative IMTs, we expand the molecular profile to genes related to the RTK/PI3K/AKT pathway, rendering further opportunities for targeted therapy.
In order to determine sensitive periods for induction of neurodevelopmental effects of aluminum (Al), mice were fed either 25 (control) or 1000 (high Al) micrograms Al/g diet (as Al lactate) from ...conception through lactation and litters were fostered either within or between groups at birth. Birth parameters were not influenced by Al intake. Food intake and body weight were 10%-12% lower during lactation in dams fed the high Al diets. Both gestation and lactation high Al exposure led to growth retardation in offspring beginning on day 10 postnatal; combined gestation and lactation exposure led to the biggest weight differential at weaning (23%). For neurobehavioral measures obtained at weaning, forelimb grasp strength was influenced by gestation high Al exposure, whereas negative geotaxis was influenced by lactation exposure, and hindlimb grasp and temperature sensitivity were influenced by both gestation and lactation exposure. Pup liver and brain manganese (Mn) and liver iron (Fe) concentrations at weaning were lower after high Al lactation exposure than in controls. Pup brain and liver Al concentrations were similar among the groups. These data show that mice are susceptible to neurodevelopmental effects of high maternal dietary Al intake during both gestation and lactation, and that high maternal intake can result in altered essential trace element metabolism in the offspring.
A tiered testing strategy has been developed to evaluate the potential for new ingredients, tobacco processes, and technological developments to increase or reduce the biological activity that ...results from burning tobacco. In the manufacture of cigarettes, honey is used as a casing ingredient to impart both aroma and taste. The primary objective of this document is to summarize and interpret chemical and toxicological studies that have been conducted to evaluate the potential impact of honey on the biological activity of either mainstream cigarette smoke or cigarette smoke condensate. As part of ongoing stewardship efforts, cigarettes produced with honey (5% wet weight) as an alternative to invert sugar in tobacco casing material were subjected to extensive evaluation. Principal components of this evaluation were a determination of selected mainstream smoke constituent yields, Ames assay, sister chromatid exchange assay in Chinese hamster ovary cells, a 30-wk dermal tumor promotion evaluation of cigarette smoke condensate in SENCAR mice, and a 13-wk inhalation study of cigarette smoke in Sprague-Dawley rats. Comparative analytical evaluations demonstrated that the substitution of honey for invert sugar as a casing material in cigarettes had no significant impact on mainstream smoke chemistry. In addition, in vitro and in vivo studies demonstrated that cigarettes containing tobacco cased with honey had comparable biological activity to cigarettes containing invert sugar. Collectively, these data demonstrate that the use of honey as an alternative casing material in the manufacture of cigarettes does not alter the potential toxicity of cigarette smoke condensate (CSC) or cigarette smoke; therefore the use of honey as an ingredient added to cigarette tobacco is acceptable from a toxicological perspective.
Information concerning developmental aluminum (Al) toxicity is available from clinical studies and from animal testing. An Al toxicity syndrome including encephalopathy, osteomalacia, and anemia has ...been reported in uremic children receiving dialysis. In addition, some components of the syndrome, particularly osteomalacia, have been reported in nondialyzed uremic children receiving Al-based phosphate binders, nonuremic infants receiving parenteral nutrition with Al-containing fluids, and nonuremic infants given high doses of Al antacids. The number of children in clinical populations that are at risk of Al toxicity is not known and needs to be determined. Work in animal models (rats, mice, and rabbits) demonstrates that Al is distributed transplacentally and is present in milk. Oral Al administration during pregnancy produces a syndrome including growth retardation, delayed ossification, and malformations at doses that also lead to reduced maternal weight gain. The severity of the effects is highly dependent on the form of Al administered. In the postnatal period, reduced pup weight gain and effects on neuromotor development have been described as a result of developmental exposures. The significance of these findings for human health requires better understanding of the amount and bioavailability of Al in food, drinking water, and medications and from sources unique to infants and children such as breast milk, soil ingestion, and medications used specifically by pregnant women and children. We also need a better understanding of the unique biological actions of Al that may occur during developmental periods, and unique aspects of the developing organism that make it more or less susceptible to Al toxicity.
We present a novel approach for the search of dark matter in the DarkSide-50 experiment, relying on Bayesian Networks. This method incorporates the detector response model into the likelihood ...function, explicitly maintaining the connection with the quantity of interest. No assumptions about the linearity of the problem or the shape of the probability distribution functions are required, and there is no need to morph signal and background spectra as a function of nuisance parameters. By expressing the problem in terms of Bayesian Networks, we have developed an inference algorithm based on a Markov Chain Monte Carlo to calculate the posterior probability. A clever description of the detector response model in terms of parametric matrices allows us to study the impact of systematic variations of any parameter on the final results. Our approach not only provides the desired information on the parameter of interest, but also potential constraints on the response model. Our results are consistent with recent published analyses and further refine the parameters of the detector response model.
The biosynthesis of
13Cglycogen from
13Cpyruvate via the gluconeogenic pathway is monitored in surgically removed perfused livers by
13C NMR. The rapid breakdown of
13Cglycogen (glycogenolysis) ...following the addition of 50
pM exogenous glucagon is then monitored in real time using this technique. The concentration-dependent inhibition of glucagon-mediated glycogenolysis is demonstrated for both the peptidyl glucagon antagonist
1 and structurally diverse synthetic glucagon antagonists
2–
7. Perfused livers were obtained from a transgenic mouse strain that exclusively expresses the functional human glucagon receptor, conferring human relevance to the activity observed with these antagonists.
The demonstration of pharmacodynamic efficacy of novel chemical entities represents a formidable challenge in the early exploration of synthetic lead classes. Here, we demonstrate a technique to validate the biological efficacy of novel antagonists of the human glucagon receptor (hGCGR) in the surgically removed perfused liver prior to the optimization of the pharmacokinetic properties of the compounds. The technique involves the direct observation by
13C NMR of the biosynthesis of
13Cglycogen from
13Cpyruvate via the gluconeogenic pathway. The rapid breakdown of
13Cglycogen (glycogenolysis) following the addition of 50
pM exogenous glucagon is then monitored in real time in the perfused liver by
13C NMR. The concentration-dependent inhibition of glucagon-mediated glycogenolysis is demonstrated for both the peptidyl glucagon receptor antagonist
1 and structurally diverse synthetic antagonists
2–
7. Perfused livers were obtained from a transgenic mouse strain that exclusively expresses the functional human glucagon receptor, conferring human relevance to the activity observed with glucagon receptor antagonists. This technique does not provide adequate quantitative precision for the comparative ranking of active compounds, but does afford physiological evidence of efficacy in the early development of a chemical series of antagonists.
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