A link has been established between prenatal nutrition and the development of metabolic and cardiovascular diseases later in life, a process referred to as developmental programming. It has been ...suggested that the trajectory of development is shifted by alterations in the maternal nutritional state leading to changes in developmental plasticity, in part underpinned by epigenetic changes in gene regulation. However, to date, only candidate gene approaches have been used to assess expression and molecular changes in the offspring of maternally undernourished animals. Furthermore, most work has focused on animals at an age where the programmed phenotype is already manifest and little is known about changes in gene expression in the offspring prior to development of obesity and related metabolic disorders. Gene expression profiles of liver, retroperitoneal white adipose fat, and biceps femoris skeletal muscle tissue from young adult male rats (55 days old) in which nutritional status had been manipulated in utero by maternal undernutrition (UN) were compared to the profiles of offspring of ad libitum fed mothers serving as the control group (AD) (8 offspring/group). The expression profiles were determined using the Illumina RatRef-12 BeadChip. No significant changes in expression were identified for skeletal muscle or white adipose tissue. However, studies of liver tissue showed 249 differentially expressed genes (143 up regulated, 106 down regulated). Although the animals at day 55 have yet to develop obesity they already show biochemical abnormalities and by day 110 express a phenotype characterized by increased adiposity and altered insulin sensitivity. An analysis of pathways affected suggests that intrauterine programming of UN animals to favor fat as an energy source results in mitochondrial dysfunction which initially affects the postnatal hepatic function and subsequently, via the resultant metabolic changes in other organs leads to the evolution of a phenotype similar to that of the metabolic syndrome.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Maternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is ...inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal leptin treatment gives discordant results between males and females. Leptin treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal leptin treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring.
We show by microarray analysis of the female liver transcriptome that both maternal undernutrition and postnatal leptin treatment independently induce a similar thrifty transcriptional programme affecting carbohydrate metabolism, amino acid metabolism and oxidative stress genes. Paradoxically, however, the combination of both stimuli restores a more normal transcriptional environment. This demonstrates that "leptin reversal" is a global phenomenon affecting all genes involved in fetal programming by maternal undernourishment and leptin treatment. The thrifty transcriptional programme was associated with pro-inflammatory markers and downregulation of adaptive immune mediators, particularly MHC class I genes, suggesting a deficit in antigen presentation in these offspring.
We propose a revised model of developmental programming reconciling the male and female observations, in which there are two competing programmes which collectively drive liver transcription. The first element is a thrifty metabolic phenotype induced by early life growth restriction independently of leptin levels. The second is a homeostatic set point calibrated in response to postnatal leptin surge, which is able to over-ride the metabolic programme. This "calibration model" for the postnatal leptin surge, if applicable in humans, may have implications for understanding responses to catch-up growth in infants. Additionally, the identification of an antigen presentation deficit associated with metabolic thriftiness may relate to a previously observed correlation between birth season (a proxy for gestational undernutrition) and infectious disease mortality in rural African communities.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age-related changes in DNA methylation have ...been reported before and may be responsible for aging-induced changes in gene expression, although a causal relationship has yet to be shown. Using genome-wide assays, we analyzed age-induced changes in DNA methylation and their effect on gene expression with and without transient induction with the synthetic transcription modulating agent WY14,643. To demonstrate feasibility of the approach, we isolated peripheral blood mononucleated cells (PBMCs) from five young and five old healthy male volunteers and cultured them with or without WY14,643. Infinium 450K BeadChip and Affymetrix Human Gene 1.1 ST expression array analysis revealed significant differential methylation of at least 5 % (ΔYO > 5 %) at 10,625 CpG sites between young and old subjects, but only a subset of the associated genes were also differentially expressed. Age-related differential methylation of previously reported epigenetic biomarkers of aging including ELOVL2, FHL2, PENK, and KLF14 was confirmed in our study, but these genes did not display an age-related change in gene expression in PBMCs. Bioinformatic analysis revealed that differentially methylated genes that lack an age-related expression change predominantly represent genes involved in carcinogenesis and developmental processes, and expression of most of these genes were silenced in PBMCs. No changes in DNA methylation were found in genes displaying transiently induced changes in gene expression. In conclusion, aging-induced differential methylation often targets developmental genes and occurs mostly without change in gene expression.
This study assesses associations between mothers’ use of relational aggression with their peers and psychological control with their children, and child adjustment in a sample of fifty U.S. mothers ...of elementary and middle school children. Mothers completed surveys assessing their relational aggression and psychological control. Teachers completed surveys assessing children’s externalizing behavior, internalizing symptoms, and relational aggression. Results suggest that mothers who are relationally aggressive with their peers are more likely to be psychologically controlling with their children. Results also showed that relational aggression predicted adjustment problems in youth. Relational aggression was associated with externalizing problems among boys and girls, and with internalizing problems among boys. Few gender differences in mean levels of maternal or child behaviors emerged.
This thesis aims to highlight molecular mechanisms that have been altered by prenatal undernutrition and may be involved in the metabolic syndrome. Two separate studies were conducted both using a ...rat model developed through manipulation of the maternal diet to provoke the key features of the metabolic syndrome in adult offspring. Microarray technology was used to detect changes in gene expression in target tissues between offspring of control (normally fed, AD) and undernourished (UN) mothers to obtain a broader picture of the cellular functions and genetic pathways that may be implicated in the metabolic syndrome. The rst study compared gene expression differences in liver, skeletal muscle, and white adipose tissue between 55 day old male offspring of AD and UN mothers. No significant changes were found in muscle or adipose tissue; however, the differences in the liver suggested the UN animals had been metabolically programmed to favour fat as an energy source. To investigate whether DNA methylation might be responsible for the observed transcriptional changes, pooled liver samples from the rat study were used with the McrBC restriction enzyme assay to determine full, partial, incomplete, or no methylation between AD and UN. Two differentially expressed genes (Zfand2a and Mapk4) showed methylation changes. The same liver samples were hybridised to a miRNA array. Two miRNAs showed a nearly 2-fold upregulation in the UN livers. Both were found to be either directly or indirectly associated with the metabolic syndrome. MiR-335 has been shown to be upregulated in the livers of obese/diabetic mice. By association with miR-27a, miR-451 might be involved in aspects of lipid metabolism in adipose tissue. A second study used microarray to analyse the liver tissues of day 170 female offspring of the same rat model with additional insults (neonatal leptin treatment and post-weaning high-fat (HF) diet). Leptin has been shown to reverse the programming effects of the restricted maternal diet and this study aimed to highlight mechanisms that could be involved in this reversal. The results revealed the importance of the interaction between treatments. Significant gene expression changes were only present when two or more treatments were combined. This study revealed significantly, differentially expressed genes involved in immune function, regulation of the circadian rhythm, and metabolism. These findings provide a number of interesting genes and pathways for further studies and also highlight the need to conduct a thorough study in multiple tissues at different time-points to pinpoint the window of developmental plasticity.
This thesis aims to highlight molecular mechanisms that have been altered by prenatal undernutrition and may be involved in the metabolic syndrome. Two separate studies were conducted both using a ...rat model developed through manipulation of the maternal diet to provoke the key features of the metabolic syndrome in adult offspring. Microarray technology was used to detect changes in gene expression in target tissues between offspring of control (normally fed, AD) and undernourished (UN) mothers to obtain a broader picture of the cellular functions and genetic pathways that may be implicated in the metabolic syndrome. The rst study compared gene expression differences in liver, skeletal muscle, and white adipose tissue between 55 day old male offspring of AD and UN mothers. No significant changes were found in muscle or adipose tissue; however, the differences in the liver suggested the UN animals had been metabolically programmed to favour fat as an energy source. To investigate whether DNA methylation might be responsible for the observed transcriptional changes, pooled liver samples from the rat study were used with the McrBC restriction enzyme assay to determine full, partial, incomplete, or no methylation between AD and UN. Two differentially expressed genes (Zfand2a and Mapk4) showed methylation changes. The same liver samples were hybridised to a miRNA array. Two miRNAs showed a nearly 2-fold upregulation in the UN livers. Both were found to be either directly or indirectly associated with the metabolic syndrome. MiR-335 has been shown to be upregulated in the livers of obese/diabetic mice. By association with miR-27a, miR-451 might be involved in aspects of lipid metabolism in adipose tissue. A second study used microarray to analyse the liver tissues of day 170 female offspring of the same rat model with additional insults (neonatal leptin treatment and post-weaning high-fat (HF) diet). Leptin has been shown to reverse the programming effects of the restricted maternal diet and this study aimed to highlight mechanisms that could be involved in this reversal. The results revealed the importance of the interaction between treatments. Significant gene expression changes were only present when two or more treatments were combined. This study revealed significantly, differentially expressed genes involved in immune function, regulation of the circadian rhythm, and metabolism. These findings provide a number of interesting genes and pathways for further studies and also highlight the need to conduct a thorough study in multiple tissues at different time-points to pinpoint the window of developmental plasticity.
Ambiphilic molecules, which contain a Lewis base and Lewis acid, are of great interest based on their unique ability to activate small molecules. Phosphine boronates are one class of these substrates ...that have interesting catalytic activity. Direct access to these phosphine boronates is described through the iridium‐catalyzed C−H borylation of phosphines. An unconventional cationic iridium catalyst was identified as optimal for a range of phosphines, providing good yields and selectivity across a diverse class of phosphine boronates (isolated as the borane‐protected phosphine). A complimentary catalyst system (quinoline‐based silane ligand with (COD)IrOMe2) was optimal for biphenyl‐based phosphines. Selective polyborylation was also shown providing bis‐ and tris‐borylated phosphines. Deprotection of the phosphine boronate provided free ambiphilic phosphine boronates, which do not have detectable interactions between the phosphorus and boron atoms in solution or the solid state.
Phosphine‐directed C−H borylation: A series of commonly used phosphines undergo iridium‐catalyzed C−H borylation, providing a range of ambiphilic phosphine boronates. The unexpected cationic iridium catalyst overcomes limited reactivity, allowing a large range of phosphines to be selectively functionalized, including selective polyborylation of several phosphines.
We have previously published a technique for objective assessment of freezing of gait (FOG) in Parkinson's disease (PD) from a single shank-mounted accelerometer. Here we extend this approach to ...evaluate the optimal configuration of sensor placement and signal processing parameters using seven sensors attached to the lumbar back, thighs, shanks and feet.
Multi-segmental acceleration data was obtained from 25 PD patients performing 134 timed up and go tasks, and clinical assessment of FOG was performed by two experienced raters from video. Four metrics were used to compare objective and clinical measures; the intraclass correlation coefficient (ICC) for number of FOG episodes and the percent time frozen per trial; and the sensitivity and specificity of FOG detection.
The seven-sensor configuration was the most robust, scoring highly on all measures of performance (ICC number of FOG 0.75; ICC percent time frozen 0.80; sensitivity 84.3%; specificity 78.4%). A simpler single-shank sensor approach provided similar ICC values and exhibited a high sensitivity to FOG events, but specificity was lower at 66.7%. Recordings from the lumbar sensor offered only moderate agreement with the clinical raters in terms of absolute number and duration of FOG events (likely due to musculoskeletal attenuation of lower-limb 'trembling' during FOG), but demonstrated a high sensitivity (86.2%) and specificity (82.4%) when considered as a binary test for the presence/absence of FOG within a single trial.
The seven-sensor approach was the most accurate method for quantifying FOG, and is best suited to demanding research applications. A single shank sensor provided measures comparable to the seven-sensor approach but is relatively straightforward in execution, facilitating clinical use. A single lumbar sensor may provide a simple means of objective FOG detection given the ubiquitous nature of accelerometers in mobile telephones and other belt-worn devices.
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