Simple rules for a “simple” nervous system? Molecular and biomathematical approaches to enteric nervous system formation and malformation

We review morphogenesis of the enteric nervous system from migratory neural crest cells, and defects of this process such as Hirschsprung disease, centering on cell motility and assembly, and cell adhesion and extracellular matrix molecules, along with cell proliferation and growth factors. We then review continuum and agent-based (cellular automata) models with rules of cell movement and logistical proliferation. Both movement and proliferation at the individual cell level are modeled with stochastic components from which stereotyped outcomes emerge at the population level. These models reproduced the wave-like colonization of the intestine by enteric neural crest cells, and several new properties emerged, such as colonization by frontal expansion, which were later confirmed biologically. These models predict a surprising level of clonal heterogeneity both in terms of number and distribution of daughter cells. Biologically, migrating cells form stable chains made up of unstable cells, but this is not seen in the initial model. We outline additional rules for cell differentiation into neurons, axon extension, cell-axon and cell–cell adhesions, chemotaxis and repulsion which can reproduce chain migration. After the migration stage, the cells re-arrange as a network of ganglia. Changes in cell adhesion molecules parallel this, and we describe additional rules based on Steinberg's Differential Adhesion Hypothesis, reflecting changing levels of adhesion in neural crest cells and neurons. This was able to reproduce enteric ganglionation in a model. Mouse mutants with disturbances of enteric nervous system morphogenesis are discussed, and these suggest future refinement of the models. The modeling suggests a relatively simple set of cell behavioral rules could account for complex patterns of morphogenesis. The model has allowed the proposal that Hirschsprung disease is mostly an enteric neural crest cell proliferation defect, not a defect of cell migration. In addition, the model suggests an explanations for zonal and skip segment variants of Hirschsprung disease, and also gives a novel stochastic explanation for the observed discordancy of Hirschsprung disease in identical twins.     

Regional variability of aquatic pattern in braided reaches (example of the French Rhône basin)

We analysed, at a regional scale, the braiding pattern and the structure of the water channel habitats of 53 braided reaches located in the Rhône hydrographical district (France), in relation to three control factors: (i) spatial location along the network (i.e. slope, altitude), (ii) hydrological conditions and (iii) morphological conditions. This research is based on aerial orthophotos belonging to the French National Geographic Institute (IGN) taken between 2002 and 2006. We defined a regional typology of braided reaches based on the distribution of the variables listed above, and identified five hydro-geographical types of braided reaches. Following this regional classification, we compared the pattern of braided reaches by testing several parameters, which describe the physical characters of water channel habitats (such as braided index, channel sinuosity, or aquatic habitat diversity). We found that discharge appears to be less relevant than sediment supply or groundwater level in structuring the braided geometry and the channel habitat pattern in natural braided rivers at a regional scale. We discussed the importance of local factors, such as the position of the groundwater table and the width of the active channel, for explaining the intensity of the braided pattern. There are numerous cases where the discharge is very low but the braided index high. These findings support management and conservation recommendations of braided rivers for implementing the European Water Framework Directive (2000).     

α-Catenin and Vinculin Cooperate to Promote High E-cadherin-based Adhesion Strength

Maintaining cell cohesiveness within tissues requires that intercellular adhesions develop sufficient strength to support traction forces applied by myosin motors and by neighboring cells. Cadherins are transmembrane receptors that mediate intercellular adhesion. The cadherin cytoplasmic domain recruits several partners, including catenins and vinculin, at sites of cell-cell adhesion. Our study used force measurements to address the role of αE-catenin and vinculin in the regulation of the strength of E-cadherin-based adhesion. αE-catenin-deficient cells display only weak aggregation and fail to strengthen intercellular adhesion over time, a process rescued by the expression of αE-catenin or chimeric E-cadherin·αE-catenins, including a chimera lacking the αE-catenin dimerization domain. Interestingly, an αE-catenin mutant lacking the modulation and actin-binding domains restores cadherin-dependent cell-cell contacts but cannot strengthen intercellular adhesion. The expression of αE-catenin mutated in its vinculin-binding site is defective in its ability to rescue cadherin-based adhesion strength in cells lacking αE-catenin. Vinculin depletion or the overexpression of the αE-catenin modulation domain strongly decreases E-cadherin-mediated adhesion strength. This supports the notion that both molecules are required for intercellular contact maturation. Furthermore, stretching of cell doublets increases vinculin recruitment and α18 anti-αE-catenin conformational epitope immunostaining at cell-cell contacts. Taken together, our results indicate that αE-catenin and vinculin cooperatively support intercellular adhesion strengthening, probably via a mechanoresponsive link between the E-cadherin·β-catenin complexes and the underlying actin cytoskeleton.     

Life history of the individuals buried in the St. Benedict Cemetery (Prague, 15th–18th Centuries): Insights from 14C dating and stable isotope (δ13C, δ15N, δ18O) analysis

Funerary practices and bioarchaeological (sex and age) data suggest that a mortality crisis linked to an epidemic episode occurred during the fifth phase of the St. Benedict cemetery in Prague (Czech Republic). To identify this mass mortality episode, we reconstructed individual life histories (dietary and mobility factors), assessed the population's biological homogeneity, and proposed a new chronology through stable isotope analysis (δ¹³C, δ¹⁸O and δ¹⁵N) and direct radiocarbon dating. Stable isotope analysis was conducted on the bone and tooth enamel (collagen and carbonate) of 19 individuals from three multiple graves (MG) and 12 individuals from individual graves (IG). The δ¹⁵N values of collagen and the difference between the δ¹³C values of collagen and bone carbonate could indicate that the IG individuals had a richer protein diet than the MG individuals or different food resources. The human bone and enamel carbonate and δ¹⁸O values suggest that the majority of individuals from MG and all individuals from IG spent most of their lives outside of the Bohemian region. Variations in δ¹⁸O values also indicate that all individuals experienced residential mobility during their lives. The stable isotope results, biological (age and sex) data and eight ¹⁴C dates clearly differentiate the MG and IG groups. The present work provides evidence for the reuse of the St. Benedict cemetery to bury soldiers despite the funeral protest ban (1635 AD). The Siege of Prague (1742 AD) by French‐Bavarian‐Saxon armies is identified as the cause of the St. Benedict mass mortality event. Am J Phys Anthropol 151:202–214, 2013. © 2013 Wiley Periodicals, Inc.     

Characterization of the Effect of the Mitochondrial Protein Hint2 on Intracellular Ca dynamics

Hint2, one of the five members of the superfamily of the histidine triad AMP-lysine hydrolase proteins, is expressed in mitochondria of various cell types. In human adrenocarcinoma cells, Hint2 modulates Ca²⁺ handling by mitochondria. As Hint2 is highly expressed in hepatocytes, we investigated if this protein affects Ca²⁺ dynamics in this cell type. We found that in hepatocytes isolated from Hint2^−/− mice, the frequency of Ca²⁺ oscillations induced by 1 μM noradrenaline was 150% higher than in the wild-type. Using spectrophotometry, we analyzed the rates of Ca²⁺ pumping in suspensions of mitochondria prepared from hepatocytes of either wild-type or Hint2^−/− mice; we found that Hint2 accelerates Ca²⁺ pumping into mitochondria. We then resorted to computational modeling to elucidate the possible molecular target of Hint2 that could explain both observations. On the basis of a detailed model for mitochondrial metabolism proposed in another study, we identified the respiratory chain as the most probable target of Hint2. We then used the model to predict that the absence of Hint2 leads to a premature opening of the mitochondrial permeability transition pore in response to repetitive additions of Ca²⁺ in suspensions of mitochondria. This prediction was then confirmed experimentally.     

Peach palm (Bactris gasipaes) in tropical Latin America: implications for biodiversity conservation, natural resource management and human nutrition

Peach palm (Bactris gasipaes) is a multi-purpose palm tree native to tropical Latin America, which is predominantly cultivated by smallholders in agroforestry systems. The fruits are rich in starch and contribute importantly to food security and the cash income of farmers who cultivate them. Complex value chains have emerged that link producers to consumers, but irregular product quality and market chain inequalities undermine the economic well-being of producers and retailers. Peach palm is genetically diverse, but screening for traits of commercial and nutritional interest is required to enhance the use of its genetic resources. Alliances between public organizations and private enterprises are needed to realize the potential for processing novel products from peach palm, especially in the pharmaceutical and cosmetic sectors. The diverse challenges that emerge at different stages of production, processing and marketing require participatory research that directly involves stakeholders from the beginning.     

Molecular diagnosis of Pneumocystis pneumonia

The detection of Pneumocystis DNA in clinical specimens by using PCR assays is leading to important advances in Pneumocystis pneumonia (PcP) clinical diagnosis, therapy and epidemiology. Highly sensitive and specific PCR tools improved the clinical diagnosis of PcP allowing an accurate, early diagnosis of Pneumocystis infection, which should lead to a decreased duration from onset of symptoms to treatment, a period with recognized impact on prognosis. This aspect has marked importance in HIV-negative immunocompromised patients, who develop often PcP with lower parasite rates than AIDS patients. The specific amplification of selected polymorphous sequences of Pneumocystis jirovecii genome, especially of internal transcribed spacer regions of the nuclear rRNA operon, has led to the identification of specific parasite genotypes which might be associated with PcP severity. Moreover, multi-locus genotyping revealed to be a useful tool to explore person-to-person transmission. Furthermore, PCR was recently used for detecting P. jirovecii dihydropteroate synthase gene mutations, which are apparently associated with sulfa drug resistance. PCR assays detected Pneumocystis-DNA in bronchoalveolar lavage fluid or biopsy specimens, but also in oropharyngeal washings obtained by rinsing of the mouth. This non-invasive procedure may reach 90%-sensitivity and has been used for monitoring the response to treatment in AIDS patients and for typing Pneumocystis isolates.     

The interstitial system of the trigeminal spinal tract projects to the red nucleus in mice

We studied projections from the interstitial system of the spinal trigeminal tract (InSy-S5T) to the red nucleus of the mouse with retrograde tracers (fluorogold and latex microbeads impregnated with rhodamine and fluorescein). Injections in the magnocellular part of the red nucleus caused labeling of cells in the rostral, intermediate, and caudal paratrigeminal nucleus (Pa5), dorsal paramarginal nucleus (PaMD), insular trigemeo-lateral cuneate nucleus (I5CuL), and the trigeminal extension of the parvocellular reticular formation (5RPC). All projections were bilateral, but contralateral projections were stronger. The number of retrogradely labeled cells in the InSy-S5T in 3-, 6-, and 12-month-old mice was similar. Injections restricted to the parvocellular red nucleus did not label the nuclei of the InSy-S5T. This projection from the InSy-S5T to the red nucleus may mediate modulation of the facial muscles by pain and other sensory information.