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:ObjectivesThe aims of this study are to better understand phenotypic differences between male and female rats during sepsis, to characterise the contribution of the beta1-adrenergic blocker landiolol to septic cardiomyopathy and to determine why landiolol induces divergent effects in males and females.MethodsThe myocardial transcriptional profiles in male and female Wistar rats were assessed after the induction of sepsis by cecal ligation and puncture and addition of landiolol.ResultsOur results showed major differences in the biological processes activated during sepsis in male and female rats. In particular, a significant decrease in processes related to cell organisation, contractile function, ionic transport and phosphoinositide-3-kinase/AKT (PI3K/AKT) signalling was observed only in males. The transcript of ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3 (SERCA3) was sex-differently regulated. In males, landiolol reversed several signalling pathways dysregulated during sepsis. The expression level of genes encoding tubulin alpha 8 (TUBA8) and myosin heavy chain 7B (MYH7) contractile proteins, phosphatase 2 catalytic subunit alpha (PPP2CA), G protein-coupled receptor kinase 5 (GRK5) and A-kinase anchoring protein 6 (AKAP6) returned to their basal levels. In contrast, in females, landiolol had limited effects.ConclusionIn males, landiolol reversed the expression of many genes that were deregulated in sepsis. Conversely, sepsis-induced deregulation of gene expression was less pronounced in females than in males, and was maintained in the landiolol-treated females. These findings highlight important sex-related differences and confirm previous observations on the important benefit of landiolol intake on cardiac function in male rats.
Project description:We compared the myocardial transcriptional profiles in male and female rats after CLP (Cecal ligation and puncture) induction and landiolol administration. This analysis showed major differences between males and females in the biological processes activated during sepsis. In particular, a very significant decrease in processes related to cell organization, contractile function, ionic transport and PI3K-Akt signaling were observed only in males. Regarding the direct regulation of gene expression of the adrenergic pathway, there was no major differences between male and female. Moreover, our results highlighted the large number of signaling pathways dysregulated during sepsis in males that were reversed by landiolol. In particular, the level of expression of the genes encoding the contractile proteins, TUBA8 and MYH7B, the phosphatase PPP2CA, GRK5 and AKAP6 were close to their basal levels in males. In contrast, in females, only few pathways were affected by the action of landiolol. In addition, adrenergic signaling was decreased while genes potentially involved in calcium overload were overexpressed.
Project description:Analysis of CGTH-W-1 follicular thyroid carcinoma cells transcriptome following 48 hrs siRNA-mediated depletion of PROX1. PROX1 is a homeobox transcription factor. PROX1 depletion decreases migratory ability, motility and invasivness and induces profound cytoskeleton changes of CGTH-W-1 cells. Results provide insight into the role of PROX1 in the thyroid cancer. Three biological replicates for a given condition
Project description:To demonstrate that the P. multistriata gene MRP3 is responsible for sex determination, we overexpressed it in a mating type minus strain. The transgenic strain generated displayed sex reversal and behaved like a strain of the opposite mating type. In this study, we compared the gene expression profile of the wild type versus the transformed strain.
Project description:Iron is an essential element that participates in numerous cellular processes. Any disruption of iron homeostasis leads to either iron deficiency or iron overload, which can be detrimental for humans' health, especially in elderly. Each of these changes contributes to the faster development of many neurological disorders or stimulates progression of already present diseases. Age-related cellular and molecular alterations in iron metabolism can also lead to iron dyshomeostasis and deposition. Iron deposits can contribute to the development of inflammation, abnormal protein aggregation, and degeneration in the central nervous system (CNS), leading to the progressive decline in cognitive processes, contributing to pathophysiology of stroke and dysfunctions of body metabolism. Besides, since iron plays an important role in both neuroprotection and neurodegeneration, dietary iron homeostasis should be considered with caution. Recently, there has been increased interest in sex-related differences in iron metabolism and iron homeostasis. These differences have not yet been fully elucidated. In this review we will discuss the latest discoveries in iron metabolism, age-related changes, along with the sex differences in iron content in serum and brain, within the healthy aging population and in neurological disorders such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, and stroke.
Project description:Accumulating metabolomics data is starting to become extremely useful in understanding the ageing process, by providing a snapshot into the metabolic state of tissues and organs, at different ages. Molecular studies of such metabolic variations during "normal" ageing can hence guide lifestyle changes and/or medical interventions aimed at improving healthspan and perhaps even lifespan. In this work, we present MetaboAge, a freely accessible database which hosts ageing-related metabolite changes, occurring in healthy individuals. Data is automatically filtered and then manually curated from scientific articles reporting statistically significant associations of human metabolite variations or correlations with ageing. Up to date, MetaboAge contains 408 metabolites annotated with their biological and chemical information, and more than 1515 ageing-related variations, graphically represented on the website grouped by validation methods, sex and age-groups. The MetaboAge database aims to continually structure the expanding information from the field of metabolomics in relation to ageing, thus making it more accessible for further research in gerontology.
Project description:BackgroundThe objective of the study is to analyse the regions, age and sex differences in the incidence of knee osteoarthritis (KOA).MethodsData were extracted from the global burden of diseases (GBD) 2019 study, including incidence, years lived with disability (YLD), disability-adjusted life-years (DALYs) and risk factors. Estimated annual percentage changes (EAPCs) were calculated to quantify the temporal trends in age standardized rate (ASR) of KOA. Paired t-test, paired Wilcoxon signed-rank test and spearman correlation were performed to analyze the association of sex disparity in KOA and socio-demographic index (SDI).ResultsThere were significant regional differences in the incidence of knee osteoarthritis. In 2019, South Korea had the highest incidence of knee osteoarthritis (474.85,95%UI:413.34-539.64) and Thailand had the highest increase in incidence of knee osteoarthritis (EAPC = 0.56, 95%CI = 0.54-0.58). Notably, higher incidence, YLD and DALYs of knee osteoarthritis were associated with areas with a high socio-demographic index (r = 0.336, p < 0.001; r = 0.324, p < 0.001; r = 0.324, p < 0.001). In terms of age differences, the greatest increase in the incidence of knee osteoarthritis was between the 35-39 and 40-44 age groups. (EAPC = 0.52, 95%CI = 0.40-0.63; 0.47, 95%CI = 0.36-0.58). In addition, there were significant sex differences in the disease burden of knee osteoarthritis (P < 0.001).ConclusionsThe incidence of knee osteoarthritis is significantly different with regions, age and sex.
Project description:We profiled the transcriptomic changes that occur in the Drosophila third antennal segment after silencing the second order olfactory neurons in the antennal lobe with Kir2.1 (EH1). A non-conducting variant of Kir2.1 (Kir2.1-nc or EH2) served as our control.
Project description:BackgroundThe sexual dimorphism represents one of the triggers of the metabolic disparities between the organisms, advising about wild implications in research or diagnostics contexts. Despite the mounting recognition of the importance of sex consideration in the biomedical fields, the identification of male- and female-specific metabolic signatures has not been achieved.Main bodyThis review pointed the focus on the metabolic differences related to the sex, evidenced by metabolomics studies performed on healthy populations, with the leading aim of understanding how the sex influences the baseline metabolome. The main shared signatures and the apparent dissimilarities between males and females were extracted and highlighted from the metabolome of the most commonly analyzed biological fluids, such as serum, plasma, and urine. Furthermore, the influence of age and the significant interactions between sex and age have been taken into account.ConclusionsThe recognition of sex patterns in human metabolomics has been defined in diverse biofluids. The detection of sex- and age-related differences in the metabolome of healthy individuals are helpful for translational applications from the bench to the bedside to set targeted diagnostic and prevention approaches in the context of personalized medicine.