Dynamic heterogeneity as a strategy of stem cell self-renewal.

To maintain cycling adult tissue in homeostasis the balance between proliferation and differentiation of stem cells needs to be precisely regulated. To investigate how stem cells achieve perfect self-renewal, emphasis has been placed on models in which stem cells progress sequentially through a one-way proliferative hierarchy. However, investigations of tissue regeneration have revealed a surprising degree of flexibility, with cells normally committed to differentiation able to recover stem cell competence following injury. Here, we investigate whether the reversible transfer of cells between states poised for proliferation or differentiation may provide a viable mechanism for a heterogeneous stem cell population to maintain homeostasis even under normal physiological conditions. By addressing the clonal dynamics, we show that such models of "dynamic heterogeneity" may be equally capable of describing the results of recent lineage tracing assays involving epithelial tissues. Moreover, together with competition for limited niche access, such models may provide a mechanism to render tissue homeostasis robust. In particular, in 2D epithelial layers, we show that the mechanism of dynamic heterogeneity avoids some pathological dependencies that undermine models based on a hierarchical stem/progenitor organization.Engineering and Physical Sciences Research CouncilThis is the author accepted manuscript. It is currently under an indefinite embargo pending publication by the National Academy of Sciences

Single-Bottleneck Approximation for Driven Lattice Gases with Disorder and Open Boundary Conditions

We investigate the effects of disorder on driven lattice gases with open boundaries using the totally asymmetric simple exclusion process as a paradigmatic example. Disorder is realized by randomly distributed defect sites with reduced hopping rate. In contrast to equilibrium, even macroscopic quantities in disordered non-equilibrium systems depend sensitively on the defect sample. We study the current as function of the entry and exit rates and the realization of disorder and find that it is, in leading order, determined by the longest stretch of consecutive defect sites (single-bottleneck approximation, SBA). Using results from extreme value statistics the SBA allows to study ensembles with fixed defect density which gives accurate results, e.g. for the expectation value of the current. Corrections to SBA come from effective interactions of bottlenecks close to the longest one. Defects close to the boundaries can be described by effective boundary rates and lead to shifts of the phase transitions. Finally it is shown that the SBA also works for more complex models. As an example we discuss a model with internal states that has been proposed to describe transport of the kinesin KIF1A.Comment: submitted to J. Stat. Mec

Suitability versus fidelity for rating single-photon guns

The creation of specified quantum states is important for most, if not all, applications in quantum computation and communication. The quality of the state preparation is therefore an essential ingredient in any assessment of a quantum-state gun. We show that the fidelity, under the standard definitions is not sufficient to assess quantum sources, and we propose a new measure of suitability that necessarily depends on the application for the source. We consider the performance of single-photon guns in the context of quantum key distribution (QKD) and linear optical quantum computation. Single-photon sources for QKD need radically different properties than sources for quantum computing. Furthermore, the suitability for single-photon guns is discussed explicitly in terms of experimentally accessible criteria.Comment: 4 pages, 2 figures Revised per referee suggestion

Mutational pathway determines whether drug gradients accelerate evolution of drug-resistant cells

Drug gradients are believed to play an important role in the evolution of bacteria resistant to antibiotics and tumors resistant to anti-cancer drugs. We use a statistical physics model to study the evolution of a population of malignant cells exposed to drug gradients, where drug resistance emerges via a mutational pathway involving multiple mutations. We show that a non-uniform drug distribution has the potential to accelerate the emergence of resistance when the mutational pathway involves a long sequence of mutants with increasing resistance, but if the pathway is short or crosses a fitness valley, the evolution of resistance may actually be slowed down by drug gradients. These predictions can be verified experimentally, and may help to improve strategies for combatting the emergence of resistance.Comment: 6 pages, 3 figures, final version before acceptance to Phys. Rev. Letters. P.G and B.W contributed equally to this wor

Inhibition of EGFR Signaling: All Mutations Are Not Created Equal

Gazdar and Minna discuss the context and implications of a research article that examines the transformation potential and response to inhibitors of specific EGFR mutations found in lung cancer

2015 Update on Acute Adverse Reactions to Gadolinium based Contrast Agents in Cardiovascular MR. Large Multi-National and Multi-Ethnical Population Experience With 37788 Patients From the EuroCMR Registry

Objectives: Specifically we aim to demonstrate that the results of our earlier safety data hold true in this much larger multi-national and multi-ethnical population. Background: We sought to re-evaluate the frequency, manifestations, and severity of acute adverse reactions associated with administration of several gadolinium- based contrast agents during routine CMR on a European level. Methods: Multi-centre, multi-national, and multi-ethnical registry with consecutive enrolment of patients in 57 European centres. Results: During the current observation 37788 doses of Gadolinium based contrast agent were administered to 37788 patients. The mean dose was 24.7 ml (range 5–80 ml), which is equivalent to 0.123 mmol/kg (range 0.01 - 0.3 mmol/kg). Forty-five acute adverse reactions due to contrast administration occurred (0.12 %). Most reactions were classified as mild (43 of 45) according to the American College of Radiology definition. The most frequent complaints following contrast administration were rashes and hives (15 of 45), followed by nausea (10 of 45) and flushes (10 of 45). The event rate ranged from 0.05 % (linear non-ionic agent gadodiamide) to 0.42 % (linear ionic agent gadobenate dimeglumine). Interestingly, we also found different event rates between the three main indications for CMR ranging from 0.05 % (risk stratification in suspected CAD) to 0.22 % (viability in known CAD). Conclusions: The current data indicate that the results of the earlier safety data hold true in this much larger multi-national and multi-ethnical population. Thus, the “off-label” use of Gadolinium based contrast in cardiovascular MR should be regarded as safe concerning the frequency, manifestation and severity of acute events

Chromosomes are predominantly located randomly with respect to each other in interphase human cells

To test quantitatively whether there are systematic chromosome–chromosome associations within human interphase nuclei, interchanges between all possible heterologous pairs of chromosomes were measured with 24-color whole-chromosome painting (multiplex FISH), after damage to interphase lymphocytes by sparsely ionizing radiation in vitro. An excess of interchanges for a specific chromosome pair would indicate spatial proximity between the chromosomes comprising that pair. The experimental design was such that quite small deviations from randomness (extra pairwise interchanges within a group of chromosomes) would be detectable. The only statistically significant chromosome cluster was a group of five chromosomes previously observed to be preferentially located near the center of the nucleus. However, quantitatively, the overall deviation from randomness within the whole genome was small. Thus, whereas some chromosome–chromosome associations are clearly present, at the whole-chromosomal level, the predominant overall pattern appears to be spatially random

Mean field treatment of exclusion processes with random-force disorder

The asymmetric simple exclusion process with random-force disorder is studied within the mean field approximation. The stationary current through a domain with reversed bias is analyzed and the results are found to be in accordance with earlier intuitive assumptions. On the grounds of these results, a phenomenological random barrier model is applied in order to describe quantitatively the coarsening phenomena. Predictions of the theory are compared with numerical results obtained by integrating the mean field evolution equations.Comment: 21 pages, 14 figure