Project description:Background: A major challenge in implementing personalized medicine in pediatrics is identifying appropriate drug dosages for children. The majority of drug dosing studies have been based on adult populations, often with modification of the dosing for children based on size and weight. However, the growth and development experienced by children between birth and adulthood represents a dynamically changing biological system, with implications for effective drug dosing, efficacy as well as potential drug toxicity. The purpose of this study was to apply a metabolomics approach to gain preliminary insights into the ontogeny of liver function from newborn to adolescent. Methods: Metabolites were measured in 98 post-mortem pediatric liver samples in two experiments 3 batches of samples, allowing for both technical and biological validation. After extensive quality control, imputation and normalization, non-parametric tests were used to determine which metabolite levels differ between the four age groups (AG) ranging in age from newborn to adolescent (AG1-children <1 year; AG2-children with age between 1 and 6 years; AG3-children with age between 6 and 12 years; AG4-children with age between 12 and 18 years). To identify which metabolites had different concentration levels among the age groups, Kruskal-Wallis and Spearman correlation tests were conducted. Pathway analysis utilized the Gamma Method. Correction for multiple testing was completed using Bonferroni correction. Results: We found 41 metabolites (out of 884) that were biologically validated, and of those 25 were technically replicated, of which 24 were known metabolites. For the majority of these 24 metabolites, concentration levels were significantly lower in newborns than in the other age groups, many of which were long chain fatty acids or involved in pyrimidine or purine metabolism. Additionally, we found two KEGG pathways enriched for association with age: betaine metabolism and alpha linolenic acid and linoleic acid metabolism. Conclusions: Understanding the role that ontogeny of childhood liver plays may aid in determining better drug dosing algorithms for children.

Project description:Background: Cyanobacteria are ecologically significant prokaryotes that can be found in heavy metals contaminated environments. As their photosynthetic machinery imposes high demands for metals, homeostasis of these micronutrients has been extensively considered in cyanobacteria. Recently, most studies have been focused on different habitats using microalgae leads to a remarkable reduction of an array of organic and inorganic nutrients, but what takes place in the extracellular environment when cells are exposed to external supplementation with heavy metals remains largely unknown. Methods: Here, extracellular polymeric substances (EPS) production in strains Nostoc sp. N27P72 and Nostoc sp. FB71 was isolated from different habitats and thenthe results were compared and reported . Result: Cultures of both strains, supplemented separately with either glucose, sucrose, lactose, or maltose showed that production of EPS and cell dry weight were boosted by maltose supplementation. The production of EPS (9.1 ± 0.05 μg/ml) and increase in cell dry weight (1.01 ± 0.06 g/l) were comparatively high in Nostoc sp. N27P72 which was isolated from lime stones.The cultures were evaluated for their ability to remove Cu (II), Cr (III), and Ni (II) in culture media with and without maltose. The crude EPS showed metal adsorption capacity assuming the order Ni (II)> Cu (II)> Cr (III) from the metal-binding experiments .Nickel was preferentially biosorbed with a maximal uptake of 188.8 ± 0.14 mg (g cell dry wt) -1 crude EPS. We found that using maltose as a carbon source can increase the production of EPS, protein, and carbohydrates content and it could be a significant reason for the high ability of metal absorbance. FT-IR spectroscopy revealed that the treatment with Ni can change the functional groups and glycoside linkages in both strains. Results of Gas Chromatography-Mass Spectrometry (GC–MS) were used to determine the biochemical composition of Nostoc sp. N27P72, showed that strong Ni (II) removal capability could be associated with the high silicon containing heterocyclic compound and aromatic diacid compounds content.

Project description:Background: Cyanobacteria are ecologically significant prokaryotes that can be found in heavy metals contaminated environments. As their photosynthetic machinery imposes high demands for metals, homeostasis of these micronutrients has been extensively considered in cyanobacteria. Recently, most studies have been focused on different habitats using microalgae leads to a remarkable reduction of an array of organic and inorganic nutrients, but what takes place in the extracellular environment when cells are exposed to external supplementation with heavy metals remains largely unknown. Methods: Here, extracellular polymeric substances (EPS) production in strains Nostoc sp. N27P72 and Nostoc sp. FB71 was isolated from different habitats and thenthe results were compared and reported . Result: Cultures of both strains, supplemented separately with either glucose, sucrose, lactose, or maltose showed that production of EPS and cell dry weight were boosted by maltose supplementation. The production of EPS (9.1 ± 0.05 μg/ml) and increase in cell dry weight (1.01 ± 0.06 g/l) were comparatively high in Nostoc sp. N27P72 which was isolated from lime stones.The cultures were evaluated for their ability to remove Cu (II), Cr (III), and Ni (II) in culture media with and without maltose. The crude EPS showed metal adsorption capacity assuming the order Ni (II)> Cu (II)> Cr (III) from the metal-binding experiments .Nickel was preferentially biosorbed with a maximal uptake of 188.8 ± 0.14 mg (g cell dry wt) -1 crude EPS. We found that using maltose as a carbon source can increase the production of EPS, protein, and carbohydrates content and it could be a significant reason for the high ability of metal absorbance. FT-IR spectroscopy revealed that the treatment with Ni can change the functional groups and glycoside linkages in both strains. Results of Gas Chromatography-Mass Spectrometry (GC–MS) were used to determine the biochemical composition of Nostoc sp. N27P72, showed that strong Ni (II) removal capability could be associated with the high silicon containing heterocyclic compound and aromatic diacid compounds content. Conclusion: The results of this studyindicatede that strains Nostoc sp. N27P72 can be a good candidate for the commercial production of EPS and might be utilized in bioremediation field as an alternative to synthetic and abiotic flocculants.

Project description:OBJECTIVES:The majority of drug dosing studies are based on adult populations, with modification of the dosing for children based on size and weight. This rudimentary approach for drug dosing children is limited, as biologically a child can differ from an adult in far more aspects than just size and weight. Specifically, understanding the ontogeny of childhood liver development is critical in dosing drugs that are metabolized through the liver, as the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Therefore, we set out to determine pharmacogenes that change over childhood development, followed by a secondary agnostic analysis, assessing changes transcriptome wide. MATERIALS AND METHODS:A total of 47 human liver tissue samples, with between 10 and 13 samples in four age groups spanning childhood development, underwent pair-end sequencing. Kruskal-Wallis and Spearman's rank correlation tests were used to determine the association of gene expression levels with age. Gene set analysis based on the pathways in KEGG utilized the gamma method. Correction for multiple testing was completed using q-values. RESULTS:We found evidence for increased expression of 'very important pharmacogenes', for example, coagulation factor V (F5) (P=6.7×10(-7)), angiotensin I converting enzyme (ACE) (P=6.4×10(-3)), and solute carrier family 22 member 1 (SLC22A1) (P=7.0×10(-5)) over childhood development. In contrast, we observed a significant decrease in expression of two alternative CYP3A7 transcripts (P=1.5×10(-5) and 3.0×10(-5)) over development. The analysis of genome-wide changes detected transcripts in the following genes with significant changes in mRNA expression (P<1×10(-9) with false discovery rate<5×0(-5)): ADCY1, PTPRD, CNDP1, DCAF12L1 and HIP1. Gene set analysis determined ontogeny-related transcriptomic changes in the renin-angiotensin pathway (P<0.002), with lower expression of the pathway, in general, observed in liver samples from younger participants. CONCLUSION:Considering that the renin-angiotensin pathway plays a central role in blood pressure and plasma sodium concentration, and our observation that ACE and PTPRD expression increased over the spectrum of childhood development, this finding could potentially impact the dosing of an entire class of drugs known as ACE-inhibitors in pediatric patients.

Project description:Background/aimsShifts in the gut microbiota and metabolites are interrelated with liver cirrhosis progression and complications. However, causal relationships have not been evaluated comprehensively. Here, we identified complication-dependent gut microbiota and metabolic signatures in patients with liver cirrhosis.MethodsMicrobiome taxonomic profiling was performed on 194 stool samples (52 controls and 142 cirrhosis patients) via V3-V4 16S rRNA sequencing. Next, 51 samples (17 controls and 34 cirrhosis patients) were selected for fecal metabolite profiling via gas chromatography mass spectrometry and liquid chromatography coupled to time-of-flight mass spectrometry. Correlation analyses were performed targeting the gut-microbiota, metabolites, clinical parameters, and presence of complications (varices, ascites, peritonitis, encephalopathy, hepatorenal syndrome, hepatocellular carcinoma, and deceased).ResultsVeillonella bacteria, Ruminococcus gnavus, and Streptococcus pneumoniae are cirrhosis-related microbiotas compared with control group. Bacteroides ovatus, Clostridium symbiosum, Emergencia timonensis, Fusobacterium varium, and Hungatella_uc were associated with complications in the cirrhosis group. The areas under the receiver operating characteristic curve (AUROCs) for the diagnosis of cirrhosis, encephalopathy, hepatorenal syndrome, and deceased were 0.863, 0.733, 0.71, and 0.69, respectively. The AUROCs of mixed microbial species for the diagnosis of cirrhosis and complication were 0.808 and 0.847, respectively. According to the metabolic profile, 5 increased fecal metabolites in patients with cirrhosis were biomarkers (AUROC >0.880) for the diagnosis of cirrhosis and complications. Clinical markers were significantly correlated with the gut microbiota and metabolites.ConclusionCirrhosis-dependent gut microbiota and metabolites present unique signatures that can be used as noninvasive biomarkers for the diagnosis of cirrhosis and its complications.

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Ontogeny related changes in the pediatric liver metabolome (part-II)

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