A model of the control of cellular regeneration in the intestinal crypt after perturbation based solely on local stem cell regulation

Abstract. The control mechanisms involved in regeneration of murine intestinal crypts after perturbations are presently not well understood. The existence of some feedback signals from the cells on the villus to the cells in the crypt has been suggested. However, some recent experimental data point to the fact that regeneration in the crypt starts very early after perturbation, at a time when the villus cell population has hardly changed. In particular, this early cell proliferative activity is seen specifically at the bottom of the crypt, i.e. in the presumed stem cell zone and furthest from the villus.
The objective of this study was to investigate whether a new concept of regulation operating solely at the stem cell level could explain the present mass of accumulated data on the post-irradiation recovery, which is an extensively studied perturbation from the experimental point of view. In order to check its validity, the new concept was formalized as a mathematical simulation model thus enabling comparison with experimental data. The model describes the cellular development from stem cells to the mature villus cells. As a basic feature it is assumed that the self-maintenance and the cell cycle activity of the stem cells are controlled by the number of these cells in an autoregulatory fashion. The essential features of the experimental data (i.e. the recovery with time and the consistency between different types of measurements) can be very well reproduced by simulations using a range of model parameters. Thus, we conclude that stem cell autoregulation is a valid concept which could replace the villus crypt feedback concept in explaining the early changes after irradiation when the damage primarily affects the crypt. The question of the detailed nature of the control process requires further investigation.     

Genome-Wide Identification of Epigenetic Hotspots Potentially Related to Cardiovascular Risk in Adult Women after a Complicated Pregnancy

Background

The physiological demands of pregnancy on the maternal cardiovascular system can catapult women into a metabolic syndrome that predisposes to atherosclerosis in later life. We sought to identify the nature of the epigenomic changes associated with the increased cardiovascular disease (CVD) risk in adult women following pre-eclampsia.

Findings

We assessed the genome wide epigenetic profile by methyl-C sequencing of monozygotic parous twin sister pairs discordant for a severe variant of pre-eclampsia. In the adult twin sisters at risk for CVD as a consequence of a complicated pregnancy, a set of 12 differentially methylated regions with at least 50% difference in methylation percentage and the same directional change was found to be shared between the affected twin sisters and significantly different compared to their unaffected monozygous sisters.

Conclusion

The current epigenetic marker set will permit targeted analysis of differentially methylated regions potentially related to CVD risk in large cohorts of adult women following complicated pregnancies.     

Role of T-region borders in Agrobacterium host range

The limited host range AB3 strain of Agrobacterium tumefaciens induces tumors by transferring two T-regions, TA and TB. TA is a deleted version of the well-known biotype I octopine TL-region that lacks the iaa and ipt genes, but carries an intact oncogene, gene 6b, and typical left and right border sequences. TB carries two iaa genes that together code for the synthesis of indoleacetic acid. Gene 6b and the iaa gene act synergistically when transferred in a coinoculation experiment. The TA-region of the limited host range isolate Ag57 is related to the TA-region of AB3, but differs from it at several positions. The most significant difference is the absence of the right border region. In spite of this, Ag57 and the exconjugant strain C58C9(pTiAg57) induce normal tumors on Nicotiana rustica and Vitis vinifera. Various experiments indicate that gene 6b of the Ag57 TA-region is active and transferred in spite of the absence of the right border. On N. tabacum, C58C9(pTiAg57) is nononcogenic but becomes oncogenic when the pTiAg57 TA-region is restored by the right TA border sequence of pTiAB3. Thus, the right TA border sequence of the biotype III limited host range strains is required for tumor induction on some hosts, but not on others.     

Vimentin and glial fibrillary acidic protein are codistributed in the same intermediate filament system of malignant glioma cells in vivo

Normal, reactive, and neoplastic astrocytes express two types of intermediate filament (IF) proteins, namely glial fibrillary acidic protein (GFAP) and vimentin. Their submicroscopical distribution in vivo is so far unknown. We therefore investigated four malignant gliomas by electron microscopy, applying postembedding double immunogold labeling. The IF proteins were randomly scattered over the same filament bundles, as in previous experiments on glioma cultures. No clustering or preferential intracytoplasmic location of either IF protein was visible. The demonstration of IF proteins within nuclei gives some support to the suggested intranuclear functions of IF proteins.     

Progesterone attenuates the inhibitory effects of cardiotonic digitalis on pregnenolone production in rat luteal cells

Previous studies have shown that digoxin decreases testosterone secretion in testicular interstitial cells. However, the effect of digoxin on progesterone secretion in luteal cells is unclear. Progesterone is known as an endogenous digoxin-like hormone (EDLH). This study investigates how digitalis affected progesterone production and whether progesterone antagonized the effects of digitalis. Digoxin or digitoxin, but not ouabain, decreased the basal and human chorionic gonadotropin (hCG)-stimulated progesterone secretion as well as the activity of cytochrome P450 side chain cleavage enzyme (P450scc) in luteal cells. 8-Br-cAMP and forskolin did not affect the reduction. Neither the amount of P450scc, the amount of steroidogenic acute regulatory (StAR) protein, nor the activity of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) was affected by digoxin or digitoxin. Moreover, in testicular interstitial and luteal cells, progesterone partially attenuated the reduction of pregnenolone by digoxin or digitoxin and the progesterone antagonist, RU486, blocked this attenuation. These new findings indicated that (1) digoxin or digitoxin inhibited pregnenolone production by decreasing the activity of P450scc enzyme, but not Na(+)-K(+)-ATPase, resulting in a decrease on progesterone secretion in rat luteal cells, and (2) the inhibitory effect on pregnenolone production by digoxin or digitoxin was reversed partially by progesterone. In conclusion, digoxin or digitoxin decreased progesterone production via the inhibition of pregnenolone by decreasing P450scc activity. Progesterone, an EDLH, could antagonize the effects of digoxin or digitoxin in luteal cells.     

Young Children’s Sensitivity to Their Own Ignorance in Informing Others

Prior research suggests that young children selectively inform others depending on others’ knowledge states. Yet, little is known whether children selectively inform others depending on their own knowledge states. To explore this issue, we manipulated 3- to 4-year-old children’s knowledge about the content of a box and assessed the impact on their decisions to inform another person. Moreover, we assessed the presence of uncertainty gestures while they inform another person in light of the suggestions that children''s gestures reflect early developing, perhaps transient, epistemic sensitivity. Finally, we compared children’s performance in the informing context to their explicit verbal judgment of their knowledge states to further confirm the existence of a performance gap between the two tasks. In their decisions to inform, children tend to accurately assess their ignorance, whereas they tend to overestimate their own knowledge states when asked to explicitly report them. Moreover, children display different levels of uncertainty gestures depending on the varying degrees of their informational access. These findings suggest that children’s implicit awareness of their own ignorance may be facilitated in a social, communicative context.