A framework for three-dimensional simulation of morphogenesis

We present COMPUCELL3D, a software framework for three-dimensional simulation of morphogenesis in different organisms. COMPUCELL3D employs biologically relevant models for cell clustering, growth, and interaction with chemical fields. COMPUCELL3D uses design patterns for speed, efficient memory management, extensibility, and flexibility to allow an almost unlimited variety of simulations. We have verified COMPUCELL3D by building a model of growth and skeletal pattern formation in the avian (chicken) limb bud. Binaries and source code are available, along with documentation and input files for sample simulations, at http:// compucell.sourceforge.net.     

Dynamical mechanisms for skeletal pattern formation in the vertebrate limb

We describe a 'reactor-diffusion' mechanism for precartilage condensation based on recent experiments on chondrogenesis in the early vertebrate limb and additional hypotheses. Cellular differentiation of mesenchymal cells into subtypes with different fibroblast growth factor (FGF) receptors occurs in the presence of spatio-temporal variations of FGFs and transforming growth factor-betas (TGF-betas). One class of differentiated cells produces elevated quantities of the extracellular matrix protein fibronectin, which initiates adhesion-mediated preskeletal mesenchymal condensation. The same class of cells also produces an FGF-dependent laterally acting inhibitor that keeps condensations from expanding beyond a critical size. We show that this 'reactor-diffusion' mechanism leads naturally to patterning consistent with skeletal form, and describe simulations of spatio-temporal distribution of these differentiated cell types and the TGF-beta and inhibitor concentrations in the developing limb bud.     

Predictive Model Assessment for Count Data

Summary We discuss tools for the evaluation of probabilistic forecasts and the critique of statistical models for count data. Our proposals include a nonrandomized version of the probability integral transform, marginal calibration diagrams, and proper scoring rules, such as the predictive deviance. In case studies, we critique count regression models for patent data, and assess the predictive performance of Bayesian age‐period‐cohort models for larynx cancer counts in Germany. The toolbox applies in Bayesian or classical and parametric or nonparametric settings and to any type of ordered discrete outcomes.     

Superoxide dismutase 1 modulates expression of transferrin receptor

Copper–zinc superoxide dismutase (SOD1) plays a protective role against the toxicity of superoxide, and studies in Saccharomyces cerevisiae and in Drosophila have suggested an additional role for SOD1 in iron metabolism. We have studied the effect of the modulation of SOD1 levels on iron metabolism in a cultured human glial cell line and in a mouse motoneuronal cell line. We observed that levels of the transferrin receptor and the iron regulatory protein 1 were modulated in response to altered intracellular levels of superoxide dismutase activity, carried either by wild-type SOD1 or by an SOD-active amyotrophic lateral sclerosis (ALS) mutant enzyme, G93A-SOD1, but not by a superoxide dismutase inactive ALS mutant, H46R-SOD1. Ferritin expression was also increased by wild-type SOD1 overexpression, but not by mutant SOD1s. We propose that changes in superoxide levels due to alteration of SOD1 activity affect iron metabolism in glial and neuronal cells from higher eukaryotes and that this may be relevant to diseases of the nervous system.     

In vivo requirement of selenophosphate for selenoprotein synthesis in archaea

Biosynthesis of selenocysteine, the 21st proteinogenic amino acid, occurs bound to a dedicated tRNA in all three domains of life, Bacteria, Eukarya and Archaea, but differences exist between the mechanism employed by bacteria and eukaryotes/archaea. The role of selenophosphate and the enzyme providing it, selenophosphate synthetase, in archaeal selenoprotein synthesis was addressed by mutational analysis. Surprisingly, MMP0904, encoding a homologue of eukaryal selenophosphate synthetase in Methanococcus maripaludis S2, could not be deleted unless selD , encoding selenophosphate synthetase of Escherichia coli , was present in trans , demonstrating that the factor is essential for the organism. In contrast, the homologous gene of M. maripaludis JJ could be readily deleted, obviating the strain's ability to synthesize selenoproteins. Complementing with selD restored selenoprotein synthesis, demonstrating that the deleted gene encodes selenophosphate synthetase and that selenophosphate is the in vivo selenium donor for selenoprotein synthesis of this organism. We also showed that this enzyme is a selenoprotein itself and that M. maripaludis contains another, HesB-like selenoprotein previously only predicted from genome analyses. The data highlight the use of genetic methods in archaea for a causal analysis of their physiology and, by comparing two closely related strains of the same species, illustrate the evolution of the selenium-utilizing trait.     

The 170ms Response to Faces as Measured by MEG (M170) Is Consistently Altered in Congenital Prosopagnosia

Modularity of face processing is still a controversial issue. Congenital prosopagnosia (cPA), a selective and lifelong impairment in familiar face recognition without evidence of an acquired cerebral lesion, offers a unique opportunity to support this fundamental hypothesis. However, in spite of the pronounced behavioural impairment, identification of a functionally relevant neural alteration in congenital prosopagnosia by electrophysiogical methods has not been achieved so far. Here we show that persons with congenital prosopagnosia can be distinguished as a group from unimpaired persons using magnetoencephalography. Early face-selective MEG-responses in the range of 140 to 200ms (the M170) showed prolonged latency and decreased amplitude whereas responses to another category (houses) were indistinguishable between subjects with congenital prosopagnosia and unimpaired controls. Latency and amplitude of face-selective EEG responses (the N170) which were simultaneously recorded were statistically indistinguishable between subjects with cPA and healthy controls which resolves heterogeneous and partly conflicting results from existing studies. The complementary analysis of categorical differences (evoked activity to faces minus evoked activity to houses) revealed that the early part of the 170ms response to faces is altered in subjects with cPA. This finding can be adequately explained in a common framework of holistic and part-based face processing. Whereas a significant brain-behaviour correlation of face recognition performance and the size of the M170 amplitude is found in controls a corresponding correlation is not seen in subjects with cPA. This indicates functional relevance of the alteration found for the 170ms response to faces in cPA and pinpoints the impairment of face processing to early perceptual stages.     

The elementary RNP fiber — not the higher order structure — determines the all-or-none disintegration behaviour of balbiani ring pre-messenger RNP particles upon RNase A treatment

Summary— Balbiani ring premessenger ribonucleoprotein (RNP) particles are built from a 7-nm RNP fiber which is tightly folded into a ring-shaped RNP ribbon. Isolated particles are known to disintegrate in an all-or-none fashion upon RNase A treatment. In the present study we investigated whether this mode of disintegration is dependent on an intact particle structure or is inherent in the 7-nm fiber. When treated at low ionic strength, the Balbiani ring (BR) particles lost their higher order structure and the 7-nm fiber was unpacked, as evidenced by sucrose gradient sedimentation and electron microscopy. When treated with RNase A, unfolded as well as intact particles disintegrated in the all-or-none fashion, with similar kinetics and without apparent intermediates. Proteinase K treatment, however, obliterated this pattern: the protein-free particle RNA degraded progressively. As the typical disintegration pattern of the particles was not altered by unfolding, but was lost by deproteinization, the all-or-none mode of disintegration is likely to be a property of the 7-nm RNP fiber.