Modeling and Inferring Cleavage Patterns in Proliferating Epithelia

The regulation of cleavage plane orientation is one of the key mechanisms driving epithelial morphogenesis. Still, many aspects of the relationship between local cleavage patterns and tissue-level properties remain poorly understood. Here we develop a topological model that simulates the dynamics of a 2D proliferating epithelium from generation to generation, enabling the exploration of a wide variety of biologically plausible cleavage patterns. We investigate a spectrum of models that incorporate the spatial impact of neighboring cells and the temporal influence of parent cells on the choice of cleavage plane. Our findings show that cleavage patterns generate “signature” equilibrium distributions of polygonal cell shapes. These signatures enable the inference of local cleavage parameters such as neighbor impact, maternal influence, and division symmetry from global observations of the distribution of cell shape. Applying these insights to the proliferating epithelia of five diverse organisms, we find that strong division symmetry and moderate neighbor/maternal influence are required to reproduce the predominance of hexagonal cells and low variability in cell shape seen empirically. Furthermore, we present two distinct cleavage pattern models, one stochastic and one deterministic, that can reproduce the empirical distribution of cell shapes. Although the proliferating epithelia of the five diverse organisms show a highly conserved cell shape distribution, there are multiple plausible cleavage patterns that can generate this distribution, and experimental evidence suggests that indeed plants and fruitflies use distinct division mechanisms.     

The influence of historical landscape change on genetic variation and population structure of a terrestrial salamander (Plethodon cinereus)

Forest loss and fragmentation is expected to shape the genetic structure of amphibian populations and reduce genetic variation. Another factor widely understood to have impacted these same parameters in North America is the range expansion that occurred following glacial retreat at the end of the Pleistocene. The Eastern Red-Backed Salamander (Plethodon cinereus) has been subjected to both processes. In this context, we investigated the historical events that are likely to have shaped genetic variation in this species using a panel of six microsatellite markers screened on individuals sampled across ten localities in northeastern Indiana, USA. We found low genetic diversity across forest patches and minimal differentiation. We expected population structure associated with forest fragmentation to result from genetic drift in isolation but instead found that a balance between gene flow and drift was ~50 times more likely. Ratios of allele number and range (M), and coalescent modeling of population demography suggested the occurrence of marked historic decline in effective population size across the region. Taken together, the data point to a loss of genetic variation which preceded deforestation over the past 200 years. This result indicates an important role for ancient demographic processes in shaping current genetic variation that may make it difficult to detect the effect of recent habitat fragmentation.     

Effect of molecule branching and glycosidic linkage on the degradation of polydextrose by gut microbiota

Polydextrose is a randomly linked complex glucose oligomer that is widely used as a sugar replacer, bulking agent, dietary fiber and prebiotic. Polydextrose is poorly utilized by the host and, during gastrointestinal transit, it is slowly degraded by intestinal microbes, although it is not known which parts of the complex molecule are preferred by the microbes. The microbial degradation of polydextrose was assessed by using a simulated model of colonic fermentation. The degradation products and their glycosidic linkages were measured by combined gas chromatography and mass spectrometry, and compared to those of intact polydextrose. Fermentation resulted in an increase in the relative abundance of non-branched molecules with a concomitant decrease in single-branched glucose molecules and a reduced total number of branching points. A detailed analysis showed a preponderance of 1,6 pyranose linkages. The results of this study demonstrate how intestinal microbes selectively degrade polydextrose, and provide an insight into the preferences of gut microbiota in the presence of different glycosidic linkages.     

Signaling by FGFR2b controls the regenerative capacity of adult mouse incisors

Rodent incisors regenerate throughout the lifetime of the animal owing to the presence of epithelial and mesenchymal stem cells in the proximal region of the tooth. Enamel, the hardest component of the tooth, is continuously deposited by stem cell-derived ameloblasts exclusively on the labial, or outer, surface of the tooth. The epithelial stem cells that are the ameloblast progenitors reside in structures called cervical loops at the base of the incisors. Previous studies have suggested that FGF10, acting mainly through fibroblast growth factor receptor 2b (FGFR2b), is crucial for development of the epithelial stem cell population in mouse incisors. To explore the role of FGFR2b signaling during development and adult life, we used an rtTA transactivator/tetracycline promoter approach that allows inducible and reversible attenuation of FGFR2b signaling. Downregulation of FGFR2b signaling during embryonic stages led to abnormal development of the labial cervical loop and of the inner enamel epithelial layer. In addition, postnatal attenuation of signaling resulted in impaired incisor growth, characterized by failure of enamel formation and degradation of the incisors. At a cellular level, these changes were accompanied by decreased proliferation of the transit-amplifying cells that are progenitors of the ameloblasts. Upon release of the signaling blockade, the incisors resumed growth and reformed an enamel layer, demonstrating that survival of the stem cells was not compromised by transient postnatal attenuation of FGFR2b signaling. Taken together, our results demonstrate that FGFR2b signaling regulates both the establishment of the incisor stem cell niches in the embryo and the regenerative capacity of incisors in the adult.     

The normal and abnormal owl monkey (Aotus sp.) heart: looking at cardiomyopathy changes with echocardiography and electrocardiography

Background Cardiovascular disease, especially cardiomyopathy, was the major cause of death among owl monkeys (Aotus sp.) at a major colony and threatened colony sustainability. For this study, echocardiography (echo) and electrocardiography (ECG) normal values were established, and cardiomyopathy animals identified. Methods Forty‐eight owl monkeys were studied, 30 older than 10 years of age (‘aged’) and 8 of age 5 years (‘young’). Eight aged owl monkeys had cardiomyopathy. Results and Conclusions Aged Aotus had increased left ventricular posterior wall thickness over young animals. Left ventricular diameter and ejection fraction appeared to be the best identifying measurements for cardiomyopathy. There were no differences in the ECG.     

Novel small molecule bradykinin B1 receptor antagonists. Part 1: Benzamides and semicarbazides

The synthesis and SAR of two series of bradykinin B₁ receptor antagonists is described. The benzamide moiety proved to be a suitable replacement for the aryl ester functionality of biaryl based antagonists. In addition, it was found that semicarbazides can effectively replace cyclopropyl amino acids. The compounds with the best overall profile were biaryl semicarbazides which display high antagonistic activity, low Caco-2 efflux and high oral bioavailability in the rat.     

Traumatic brain injury and the effects of diazepam,diltiazem, and MK-801 on GABA-A receptor subunit expression in rat hippocampus

Background  

Excitatory amino acid release and subsequent biochemical cascades following traumatic brain injury (TBI) have been well documented, especially glutamate-related excitotoxicity. The effects of TBI on the essential functions of inhibitory GABA-A receptors, however, are poorly understood.