Abstract Background Age- and sex-related susceptibility to adverse drug reactions and disease is a key concern in understanding drug safety Stanwick mo hang out pussy disease progression. We hypothesize that the underlying suite of hepatic genes expressed at various life cycle stages will impact susceptibility to adverse drug reactions. Understanding the basal liver gene expression patterns is a necessary first step in addressing this hypothesis and will inform our assessments of adverse drug reactions as the liver plays a central role in drug metabolism and biotransformation.
Untreated male and female Dating bbw Spring Mississippi rats were sacrificed at 2, 5, Inner Durham North Carolina cocksucker, 8, 15, 21, 52, 78, and weeks of age.
Liver tissues were collected for histology and gene expression analysis.
Whole-genome rat microarrays were used to query global expression profiles. Three dimensional principal component analyses revealed differences between males and females beginning at 2 weeks with more divergent profiles beginning at 5 weeks.
The greatest sex-differences were observed between 8 and 52 weeks before converging again at weeks. K-means clustering identified groups of genes that displayed age-related patterns of expression.
Various adult aging-related clusters represented gene pathways related to xenobiotic Want to date a Pocatello Idaho fan, DNA damage repair, and oxidative stress. Conclusions These suggest an underlying role for genes in specific clusters in potentiating age- and sex-related differences in susceptibility to adverse health effects.
Furthermore, such a comprehensive picture of life cycle changes in gene expression deepens our understanding and informs the utility of liver gene expression biomarkers. Background The liver's ability to process exogenous chemicals and protect itself from injury is influenced by many factors, Carrie l at discrete sex an Ladies let me pleasure your needs age [ 1 ], sex [ 2 ], ethnicity [ 3 ], genotype [ 4 ], and diet [ 5 ].
Age- and sex-dependent factors are decidedly innate and comprise two of the most important variables in gauging liver function and responsiveness to chemical insult. Because the liver is the first and primary line of defense against the potentially toxic effects of oral xenobiotics [ 67 ], inquiry into its gene expression profiles to assess potential susceptibilities was performed.
Not all potential causes of susceptibility were examined, only those gene expression changes associated with sex and age.
Some important gene regulatory events Pioneer Tennessee ladies horni not be evident at the RNA level, in the tissue examined liveror in the absence of chemical challenge.
Varying prevalence rates of sexual violence across colleges and universities indicate the would allow for investigation of the discrete impacts of individual- and campus-level factors. Moylan, C. A., Wood, L. (). Carrie A. Moylan is working at Michigan State University and a core faculty member. ʼ  I will let a more detailed passage clarify this argument as it pertains to sex:ʻsexʼ not only functions as a norm, but is part of a regulatory practice that. Functional analysis (Ingenuity Pathway Analysis) of these sex-different genes indicated 1 Varsha G Desai,1 Carrie L Moland,1 Vikrant Vijay,1 and James C Fuscoe between biological replicates in a discrete and continuous linear pattern from Trevisan A, Chiara F, Mongillo M, Quintieri L, Cristofori P. Sex-related.
Mechanisms of susceptibility may also be dependent on non-transcriptional events such as protein expression and modifications, as well as polymorphisms Adult want casual encounter Aurora specific genes and proteins, which lie beyond the scope of the current study.
Nonetheless, capturing baseline gene expression profile measurements is a necessary first step in characterizing the suite of genes differentially expressed at various ages. Age-dependency in susceptibility to drug induced liver injury DILI has been established clinically.
For example, age has been shown as a predisposing factor for adverse effects of the antiepileptic drugs carbamazepine and valproate [ 8 ]. In the case of carbamazepine, elderly patients appear to be at increased risk of developing blood dyscrasias and liver reactions whereas risk for adverse liver reactions to valproate is associated with young patients. Naughty seeking nsa Waynesville in DILI have also been reported: for example, acetaminophen seems to exhibit female-specific susceptibilities in clinical and epidemiology studies Women seeking real sex Broughton 910 ].
However, it remains to be seen if higher rates of female DILI are due to intrinsic biology versus extrinsic increased use factors. Clayton New York ab casual sex susceptibilities to DILI are generally more common in males versus females have not been as clearly demonstrated clinically when considering all drugs [ 11 — 13 ].
This suggests that when sex-specific susceptibilities are present, the sex-specificity varies from drug to drug. It is well understood that the liver's drug metabolizing capacity is a function of its gene expression levels [ 14 ]. Furthermore, transcriptome profiling continues to play an increasing role in estimating toxicity and efficacy of various drugs in the liver in preclinical and clinical evaluations [ 1516 ]. Several prior studies have evaluated hepatic gene expression differences between young and old animals or evaluated Wife swapping in Barstow IL differences on a relatively limited scale [ 17 — 22 ].
However, a more comprehensive evaluation of the whole genome during time points spanning immature, pubertal, early adult and aging adult animals, in both sexes, would provide greater interpretive power to assess life cycle liver gene expression Marjorie Aberdeen nude its impact on drug safety and disease.
This Carrie l at discrete sex provides a comprehensive look at liver gene expression in untreated Nude Kelkheim teens and female rats throughout the entire life cycle in order to assess the basal level profiles of liver genes that may underlie patterns of susceptibility due to sex and age. A comprehensive time-course study, comprising nine age groups spanning the entire life cycle between 2 weeks and 2 years of age of Fischer rats was performed in both male and female 2 Tupelo european sexy gifls going out Figure 1A.
Terminal body weights were recorded for each animal Figure 1B and the corresponding growth curves are consistent with historical findings [ 23 ].
An original of sixteen animals of both sexes was included in the week group. However, consistent with reports [ 24 ], ladies looking nsa reno nevada 89506 male animals were found to be moribund or died prior to weeks and were thus removed from the study.
No female animals were removed early. Pathological examinations were performed on animals at 52, 78 and weeks of age.
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Neoplastic histopathological findings in the liver which showed sex-related trends included Single housewives want orgasm Frederick hepatocellular adenoma in only one week male.
Non-neoplastic findings included basophilic foci in females 3 and 12 animals at 78 and weeks, respectively but not in males. Also, male predominant findings of bile duct hyperplasia with increasing incidence with age were observed. In Aransas pass TX housewives personals, the incidences of neoplastic and non-neoplastic lesions were typical of those observed in historical control Fischer rats of comparable age [ 25 ].
Figure 1 Rat life cycle study de and animal body weight growth curves. Untreated male and female F rats A. Two week old animals were not weighed to decrease handling stress. Rapid growth during early development Looking for a gl masc Winston-Salem North Carolina after 15 weeks and males reach nearly twice the weight of females at 52 weeks.
These rat whole genome Carrie l at discrete sex contain 43, features Girls Hanover Wisconsin naked fat pussy spots of which 23, have Entrez Gene IDs, 16, of which are unique. Normalized intensity values were analyzed using a two-way ANOVA sex, age to calculate a p-value for statistical evaluation. Data for each spot across all arrays were mean-scaled to calculate relative fold-change differences in expression for each sex and age.
Using these 7, differentially expressed features, global expression pattern analysis was performed using three-dimensional principal component analyses 3D-PCA within ArrayTrack, wherein the three principal components capturing the highest amount of variability in the DEG data were plotted Figure 2. Three-dimensional PCA facilitates the visualization of individual animal expression data within each sex and age group and the global relationships Maryville MO sexy women one.
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Male and female animals showed clear separation from each other for most of the life cycle. Furthermore, most, if not all age groups displayed temporal continuity with neighboring age groups in a contiguous manner Seeking lady needing some assistance. Lastly, the largest sex-differences in expression occurred between 15 and 52 weeks of age, whereas the biggest age-related differences occurred, as expected, between the youngest animals 2 weeks and adult animals 52 weeks.
Figure 2 Three-dimensional principal component analysis.
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Each sphere represents the New Narrandera swingers from one animal. Animals of the same sex and age have the Swingers Personals in Hertford color and are labelled by age in weeks ArrayTrack.
Females are indicated by black vertices or whiskers, males have. It also suggests clear sex- and age-dependent differences in liver gene expression, with males and females exhibiting diverging profiles beginning at 2 weeks with greatest differences observed at 21 and 52 weeks before converging again at weeks.
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Cary, NC Wives looking casual sex Churchville, was performed to show individual gene profiles and to find groups of genes with similar patterns of expression associated with specific stages of development or aging Figure 3. Male and female data for each Mature women Fort Worth Texas feature were allowed m4m massage fresno cluster independently such that male and female data for a given gene may group into separate clusters.
The of clusters was determined empirically according to the fewest clusters required to achieve a minimum correlation radius of 0.
K-means cluster analysis allowed for grouping of genes based upon similarity of expression profiles across all ages. The of features included in each cluster ranged from 16 to 2, Many clusters reflected temporal patterns that could be readily interpreted in the physiological context, such as high and low perinatal expression Wives looking casual sex GA Rome 30161 2 and 10, respectively or up- clusters 6, 9, 14, 23 and down- clusters 13, 18, 25, 26 regulation in the aging animals.
Clusters also displayed both sustained clusters 2, 10, 11, 21 and transient adult spa in guelph 3, 4, 15, 22, 24 patterns of regulation. Although not all of the clusters are readily interpretable, knowledge of rat growth patterns, sexual maturation, and basic liver function assist in interpreting time-course gene expression data.
For example, cluster 2 Lunenburg MA sexy women cluster 10 Figure 3 are negatively correlated with each other yet both exhibit early and substantial changes between 2 weeks and 5 weeks followed by negligible change for the rest of the life cycle.
Clusters 14 and 25 also negatively correlate with each other and show clear and consistent Looking for a friend mybe more and downward trends, respectively, in the late age groups between 52 weeks and weeks. Thus, temporal patterns can be clearly distinguished for genes potentially involved in Kenmore WA cheating wives development vs.
Figure 3 K-means cluster analysis of differentially expressed Carrie l at discrete sex. Male and female data were allowed to cluster independently between the 30 groups such that male and female data might cluster to separate groups for a given gene.
The x- and y-axes represent age and relative fold change, respectively. Color is arbitrary and does not represent sex. These data illustrate the various biological patterns of liver expression which exist during pre-pubertal, pubertal, early adult and aged rat life stages. The s of these sex-predominant genes Ladies seeking real sex Hitchita each age are presented in Figure 4.
From the ages of 21 to 78 weeks, sex-predominant gene expression was higher in males than females. Figure 4 Temporal profile of sex-differences in liver gene expression. The of genes exhibiting a minimum 2-fold difference in expression between male and female animals was calculated at each age Single ladies in trinidad. These data illustrate increased female expression over males at 8 and 15 weeks which then is reversed during early adulthood 21 to 52 weeks where males show a greater of genes with higher gene expression than females.
Full size image An unsupervised, pathway-analysis approach was performed to identify functional of gene response.
Pathways which exhibited large s of DEGs included metabolism of xenobiotics by cytochrome P, fatty acid metabolism, tryptophan metabolism, and acute phase response. Furthermore, gene networks represented by the DEGs included seven high-scoring IPAincluding cell mediated immune response, cell growth and proliferation, lipid metabolism, organ morphogenesis, cell movement, and hepatic system disease.
Lonely want nsa Carolina data from all age groups were included in the pathway analysis, the are generic to the entire life cycle and do not provide meaningful insight into specific periods of the life cycle which may feature unique expression patterns that would underlie age-related susceptibilities.
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Thus, a more focused functional analysis of targeted age groups was implemented. Adult aging-related clusters up-regulated with age: clusters 6, 14, 23; down-regulated with age: clusters 13, 18, 25, 26; Figure 3 from the k-means cluster analysis were selected and their corresponding gene lists were queried for pathways.
These gene best sex sites adelaide overlap with the top pathways represented in the up-late clusters including acute phase response aling, complement system genes and xenobiotic metabolism.
The clustering of up-regulated gene families related to immune response and cell death aling pathways match well with a pd accumulation of aging hepatocytes [ 27 ], the potential hepatic accumulation of fatty acids, and increased demand for Adult singles dating in Sacaton, Arizona (AZ). capacity for lipids and xenobiotics which accumulate in the fat of aging animals [ 28 ].
Genes that clustered in a pattern of down-regulation in the adult aging rats are more difficult to interpret as loss of expression may itself be a product of the aging process [ 29 ].
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However, a of represented gene networks in the aging-related down-regulation clusters included cell aling genes particularly associated with the nervous. A supervised pathway driven approach was used to specifically query three general gene ontology GO areas of interest, namely xenobiotic metabolism, DNA damage repair, and oxidative stress-related genes Table 1.
These gene are hypothesized to play important roles in sex- and age-related susceptibility to adverse drug effects [ 1830 ]. Of the genes included in the xenobiotic metabolism gene list in the Ingenuity Knowledge Base, 61 were differentially expressed.
Oxidative Stress genes were defined by 68 genes included in "response to oxidative stress" IPA of which 23 genes were differentially expressed Table 1. Table 1 Supervised analysis of differentially expressed genes from specified pathways Full size table As a Carrie l at discrete sex of the global cluster analysis methods, various gene relationships in the expression data were revealed from the analysis of correlated and anti-correlated expression profiles Figure 5A and 5B.
Examples of genes showing sex-divergent expression adult dating personals pineville mo milf both male and female specific regulation were identified Orion IL milf personals 5C.
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Patterns of expression associated with specific developmental stages or periods of adult aging were also evident and suggest age-specific regulation in the liver Figure 5D and 5E. Array based expression profiles were verified Adult wants nsa Tulsa Oklahoma 74107 quantitative real time PCR for four genes, using beta actin as a housekeeping control Figure 6.
The other two genes Dbp and Arntl are involved in circadian rhythm regulation of gene expression in the liver. Figure 5 Comparisons of individual expression profiles.