Caenorhabditis elegans Cyclin D/CDK4 and Cyclin E/CDK2 Induce Distinct Cell Cycle Re-Entry Programs in Differentiated Muscle Cells

Cell proliferation and differentiation are regulated in a highly coordinated and inverse manner during development and tissue homeostasis. Terminal differentiation usually coincides with cell cycle exit and is thought to engage stable transcriptional repression of cell cycle genes. Here, we examine the robustness of the post-mitotic state, using Caenorhabditis elegans muscle cells as a model. We found that expression of a G1 Cyclin and CDK initiates cell cycle re-entry in muscle cells without interfering with the differentiated state. Cyclin D/CDK4 (CYD-1/CDK-4) expression was sufficient to induce DNA synthesis in muscle cells, in contrast to Cyclin E/CDK2 (CYE-1/CDK-2), which triggered mitotic events. Tissue-specific gene-expression profiling and single molecule FISH experiments revealed that Cyclin D and E kinases activate an extensive and overlapping set of cell cycle genes in muscle, yet failed to induce some key activators of G1/S progression. Surprisingly, CYD-1/CDK-4 also induced an additional set of genes primarily associated with growth and metabolism, which were not activated by CYE-1/CDK-2. Moreover, CYD-1/CDK-4 expression also down-regulated a large number of genes enriched for catabolic functions. These results highlight distinct functions for the two G1 Cyclin/CDK complexes and reveal a previously unknown activity of Cyclin D/CDK-4 in regulating metabolic gene expression. Furthermore, our data demonstrate that many cell cycle genes can still be transcriptionally induced in post-mitotic muscle cells, while maintenance of the post-mitotic state might depend on stable repression of a limited number of critical cell cycle regulators

A preference based measure of complementary feeding quality: Application to the Avon Longitudinal Study of Parents and Children

This paper presents the development of the Complementary Feeding Utility Index (CFUI), a composite index aimed to measure adherence to infant feeding guidelines. Through an axiomatic characterization this paper shows the advantages in using the CFUI are the following: it avoids the use of arbitrary cut-offs, and by converting observed diet preferences into utilities, summing the score is meaningful. In addition, as the CFUI is designed to be scored continuously, it allows the transition from intake of beneficial foods (in low quantities) and intake of detrimental foods (in high quantities) to be more subtle. The paper first describes the rationale being the development of the CFUI and then elaborates on the methodology used to develop the CFUI, including the process of selecting the components. The methodology is applied to data collected from the Avon Longitudinal Study of Parents and Children to show the advantages of the CFUI over traditional diet index approaches. Unlike traditional approaches, the distribution of the CFUI does not peak towards mean value but distributes evenly towards the tails of the distribution.Murthy N. Mittinty, Rebecca K. Golley, Lisa G. Smithers, Laima Brazionis, John W. Lync

Hemolysis-induced gallstones in mice: increased unconjugated bilirubin in hepatic bile predisposes to gallstone formation.

We recently reported that nb/nb mice with hereditary hemolytic anemia spontaneously developed calcium bilirubinate gallstones. We undertook this study to determine whether the differences in gallbladder bile composition were due to altered gallbladder function or hepatic bile composition. Hepatic bile was obtained by cholecystostomy after common bile duct ligation. We found that (a) the hepatic bile of nb/nb mice with or without stones had higher concentrations of unconjugated (p less than 0.001) and total bilirubin (p less than 0.001) but lower concentrations of bile acids (p less than 0.05) than that of control mice; (b) the concentrations of total calcium and hydrogen ion were similar in all groups; (c) nb/nb mice with stones compared with nb/nb mice without stones had higher concentrations of unconjugated (p less than 0.05) and total bilirubin (p less than 0.05); (d) the outputs of unconjugated and total bilirubin of nb/nb mice with or without stones were higher than control mice (p less than 0.001) while bile acid, hydrogen ion, and calcium outputs were similar in all groups; (e) nb/nb mice with stones had higher outputs of unconjugated (p less than 0.005) and total bilirubin (p less than 0.05) than nb/nb mice without stones; (f) in nb/nb mice with stones, but not in those without stones or control mice, unconjugated bilirubin output was associated with bile acid output (p less than 0.001); and (g) unconjugated bilirubin and total bilirubin outputs were significantly correlated in all groups (p less than 0.001). Thus, an increased concentration and amount of unconjugated bilirubin in nb/nb hepatic bile is an essential factor in hemolysis-induced gallstone formation and modification of this abnormal nb/nb hepatic bile within the gallbladder promotes stone formation