Poissonian Cellular Potts Models Reveal Nonequilibrium Kinetics of Cell Sorting.

Cellular Potts models are broadly applied across developmental biology and cancer research. We overcome limitations of the traditional approach, which reinterprets a modified Metropolis sampling as ad hoc dynamics, by introducing a physical timescale through Poissonian kinetics and by applying principles of stochastic thermodynamics to separate thermal and relaxation effects from athermal noise and nonconservative forces. Our method accurately describes cell-sorting dynamics in mouse-embryo development and identifies the distinct contributions of nonequilibrium processes, e.g., cell growth and active fluctuations.

Mechanochemical feedback loops in contact-dependent fate patterning.

To reliably form and maintain structures with specific functions, many multicellular systems evolved to leverage the interplay between biochemical signaling, mechanics, and morphology. We review mechanochemical feedback loops in cases where cell-cell contact-based Notch signaling drives fate decisions, and the corresponding differentiation process leads to contact remodeling. We compare different mechanisms for initial symmetry breaking and subsequent pattern refinement, as well as discuss how patterning outcomes depend on the relationship between biochemical and mechanical timescales. We conclude with an overview of new approaches, including the study of synthetic circuits, and give an outlook on future experimental and theoretical developments toward dissecting and harnessing mechanochemical feedback.

Mechanochemical symmetry breaking during morphogenesis of lateral-line sensory organs.

Actively regulated symmetry breaking, which is ubiquitous in biological cells, underlies phenomena such as directed cellular movement and morphological polarization. Here we investigate how an organ-level polarity pattern emerges through symmetry breaking at the cellular level during the formation of a mechanosensory organ. Combining theory, genetic perturbations, and in vivo imaging, we study the development and regeneration of the fluid-motion sensors in the zebrafish's lateral line. We find that two interacting symmetry-breaking events - one mediated by biochemical signaling and the other by cellular mechanics - give rise to precise rotations of cell pairs, which produce a mirror-symmetric polarity pattern in the receptor organ.

Genetic redundancy strengthens the circadian clock leading to a narrow entrainment range.

Circadian clocks are internal timekeepers present in almost all organisms. Driven by a genetic network of highly conserved structure, they generate self-sustained oscillations that entrain to periodic external signals such as the 24 h light-dark cycle. Vertebrates possess multiple, functionally overlapping homologues of the core clock genes. Furthermore, vertebrate clocks entrain to a range of periods three times as narrow as that of other organisms. We asked whether genetic redundancies play a role in governing entrainment properties and analysed locomotor activity rhythms of genetically modified mice lacking one set of clock homologues. Exposing them to non-24 h light-dark cycles, we found that the mutant mice have a wider entrainment range than the wild types. Spectral analysis furthermore revealed nonlinear phenomena of periodically forced self-sustained oscillators for which the entrainment range relates inversely to oscillator amplitude. Using the forced oscillator model to explain the observed differences in entrainment range between mutant and wild-type mice, we sought to quantify the overall oscillator amplitude of their clocks from the activity rhythms and found that mutant mice have weaker circadian clocks than wild types. Our results suggest that genetic redundancy strengthens the circadian clock leading to a narrow entrainment range in vertebrates.

[Application of radioactive substances in nuclear medicine research: current trends and radiation exposure of study subjects]. / Anwendung radioaktiver Stoffe in der nuklearmedizinischen Forschung: aktuelle Trends und Strahlenexposition der Probanden.

AIM: Analysis of the application of radioactive substances in research in the field of nuclear medicine in human beings and of the resulting radiation exposure to study subjects. METHODS: Assessment of applications for approval submitted in accordance with Paragraph 41 of the Radiation Protection Ordinance, evaluated by the Federal Office for Radiation Protection together with the Federal Institute for Pharmaceuticals and Medical Products, within the period from 1997 to 1999. RESULTS: The focus of the studies on the diagnostic application of radioactive substances in medicine evaluated has, since 1998, shifted from oncological to neurological and psychological aspects, while, at the same time, the number of PET studies increased constantly. The proportion of healthy study subjects included in the diagnostic studies increased from 7 to 22%. The number of therapeutic applications of radioactive substances has, since 1997, undergone a three-fold increase, and in the process of this, the focus of attention lay within the area of radioimmuno-therapy and endovascular brachytherapy. The effective dose was, among up to 49% of the investigated healthy study subjects higher than 5 mSv, and among up to 6% of these subjects was at levels of over 20 mSv. Up to 22% of the patients received, within the scope of diagnostic studies, an effective dose of between 20 and 50 mSv. An exceeding of the 50 mSv limit occurred among up to 3% of the patients. CONCLUSIONS: In spite of the increasing numbers of PET applications, conventional nuclear medicine has maintained its importance in the field of medical research. Further developments in the areas of radiochemistry and molecular biology led to an increase in the importance of radio-immuno therapy. The evaluation of new radiopharmaceuticals and the extension of basic biomedical research, resulted in an increase in the proportion of healthy study subjects included in the studies. The radiation exposure among subjects resulting directly from the studies showed, for the period of evaluation, an overall trend towards reduction.

Assay of ganglioside GM2-N-acetyl-beta-D-galactosaminidase activity in human fibroblasts employing the natural activator protein--diagnosis of variant forms of GM2 gangliosidosis.

The physiological activator protein for the degradation of ganglioside GM2 by hexosaminidase A has been employed to assess the capability of cultured human fibroblast extracts to catalyze this ganglioside. This method permits a more reliable diagnosis of the different variants of GM2 gangliosidoses than the methods hitherto used. These either rely on artificial substrates or, when natural substrates are used, on detergents. Our method avoids a number of possible sources of error introduced by the unphysiological detergents, such as alteration of the isoenzymes' substrate specificity or inactivation of the enzymes. The range of application of the new method is discussed.