Universal patterns of stem cell fate in cycling adult tissues

In cycling tissues that exhibit high turnover, tissue maintenance and repair are coordinated by stem cells. But, how frequently stem cells are replaced following differentiation, aging or injury remains unclear. By drawing together the results of recent lineage-tracing studies, we propose that tissue stem cells are routinely lost and replaced in a stochastic manner. We show that stem cell replacement leads to neutral competition between clones, resulting in two characteristic and recurring patterns of clone fate dynamics, which provide a unifying framework for interpreting clone fate data and for measuring rates of stem cell loss and replacement in vivo. Thus, we challenge the concept of the stem cell as an immortal, slow-cycling, asymmetrically dividing cell.A.M.K. is supported by the Engineering and Physical Sciences Research Council fellowship

Extreme value statistics of mutation accumulation in renewing cell populations

The emergence of a predominant phenotype within a cell population is often triggered by the chance accumulation of a sequence of rare genomic DNA mutations within a single cell. For example, tumors may be initiated by a single cell in which multiple mutations cooperate to bypass their natural defense mechanism. The risk of such an event is thus determined by the extremal accumulation of mutations across tissue cells. To address this risk, here we study the statistics of the maximum mutation numbers in a generic, but tested, model of a renewing cell population. By drawing an analogy between the genealogy of a cell population and the theory of branching random walks, we obtain analytical estimates for the probability of exceeding a threshold number of mutations to trigger a proliferative advantage of a cell over its neighbors, and determine how the statistical distribution of maximum mutation numbers scales with age and cell population size.EPSR

Effects of disorder on coexistence and competition between superconducting and insulating states

We study effects of nonmagnetic impurities on the competition between the superconducting and electron-hole pairing. We show that disorder can result in coexistence of these two types of ordering in a uniform state, even when in clean materials they are mutually exclusive.Comment: 11 pages, 6 eps figures; added affiliation; published versio

A Unifying Theory of Branching Morphogenesis

The morphogenesis of branched organs remains a subject of abiding interest. Although much is known about the underlying signaling pathways, it remains unclear how macroscopic features of branched organs, including their size, network topology and spatial patterning, are encoded. Here we show that, in mouse mammary gland, kidney and human prostate, these features can be explained quantitatively within a single unifying framework of branching and annihilating random walks. Based on quantitative analyses of large-scale organ reconstructions and proliferation kinetics measurements, we propose that morphogenesis follows from the proliferative activity of equipotent tips that stochastically branch and randomly explore their environment, but compete neutrally for space, becoming proliferatively inactive when in proximity with neighboring ducts. These results show that complex branched epithelial structures in mammalian tissues develop as a self-organized process, reliant upon a strikingly simple, but generic, rule, without recourse to a rigid and deterministic sequence of genetically programmed events.This work was supported by an ERC consolidator grant (648804), research grants from the Dutch Organization of Scientific Research (NWO; 823.02.017), the Dutch Cancer Society (KWF; HUBR 2009-4621), the Association for International Cancer Research (AICR; 13-0297) (all J.v.R), the Wellcome Trust (110326/Z/15/Z to E.H. and 098357/Z/12/Z to B.D.S.), and equipment grants from the Dutch Organization of Scientific Research (NWO; 175.010.2007.00 and 834.11.002). E.H. is funded by a JRF from Trinity College and acknowledges the Bettencourt-Schueller Young Researcher Prize for support. C.L.G.J.S. is funded by a Boehringer Ingelheim Fonds PhD Fellowship. R.S. was supported by the Norman S. Coplon Extramural Grant. R.H. and M.M. were funded by a Cancer Research UK Clinician Scientist Fellowship (Ref C10169/A12173)

Emergence and universality in the regulation of stem cell fate

The mechanisms that control cell fate behaviour during development, and the factors leading to their dysregulation in disease, remain the subject of interest and debate. Lately, advances in single-cell genomics have shifted emphasis towards the elucidation of molecular regulatory programmes and transcriptional cell states. However, quantitative statistical approaches based on cell lineage tracing data have provided fresh insight into stem and progenitor cell behaviour, questioning the role of cell fate stochasticity, transcriptional heterogeneity and state priming. These investigations, which draw upon conceptual insights from statistical physics and mathematics, provide a novel, generic and rigorous framework to resolve and classify stem cell self-renewal strategies, which heavily constrain, but do not seek to define, underlying molecular mechanistic programmes. Here, using epithelial maintenance as an exemplar, we consider the foundation, conceptual basis, utility and limitations of such quantitative approaches in cell biology.B.D.S. acknowledges the support of the Wellcome Trust (grant number 098357/Z/12/Z) and the core funding to the Gurdon Institute by the Wellcome Trust and Cancer Research UK

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

Impact Factor: outdated artefact or stepping-stone to journal certification?

A review of Garfield's journal impact factor and its specific implementation as the Thomson Reuters Impact Factor reveals several weaknesses in this commonly-used indicator of journal standing. Key limitations include the mismatch between citing and cited documents, the deceptive display of three decimals that belies the real precision, and the absence of confidence intervals. These are minor issues that are easily amended and should be corrected, but more substantive improvements are needed. There are indications that the scientific community seeks and needs better certification of journal procedures to improve the quality of published science. Comprehensive certification of editorial and review procedures could help ensure adequate procedures to detect duplicate and fraudulent submissions.Comment: 25 pages, 12 figures, 6 table

Psychological determinants of whole-body endurance performance

Background: No literature reviews have systematically identified and evaluated research on the psychological determinants of endurance performance, and sport psychology performance-enhancement guidelines for endurance sports are not founded on a systematic appraisal of endurance-specific research. Objective: A systematic literature review was conducted to identify practical psychological interventions that improve endurance performance and to identify additional psychological factors that affect endurance performance. Additional objectives were to evaluate the research practices of included studies, to suggest theoretical and applied implications, and to guide future research. Methods: Electronic databases, forward-citation searches, and manual searches of reference lists were used to locate relevant studies. Peer-reviewed studies were included when they chose an experimental or quasi-experimental research design, a psychological manipulation, endurance performance as the dependent variable, and athletes or physically-active, healthy adults as participants. Results: Consistent support was found for using imagery, self-talk, and goal setting to improve endurance performance, but it is unclear whether learning multiple psychological skills is more beneficial than learning one psychological skill. The results also demonstrated that mental fatigue undermines endurance performance, and verbal encouragement and head-to-head competition can have a beneficial effect. Interventions that influenced perception of effort consistently affected endurance performance. Conclusions: Psychological skills training could benefit an endurance athlete. Researchers are encouraged to compare different practical psychological interventions, to examine the effects of these interventions for athletes in competition, and to include a placebo control condition or an alternative control treatment. Researchers are also encouraged to explore additional psychological factors that could have a negative effect on endurance performance. Future research should include psychological mediating variables and moderating variables. Implications for theoretical explanations of endurance performance and evidence-based practice are described

Publisher's Note: Inhomogeneous Magnetic Phases: A Fulde-Ferrell-Larkin-Ovchinnikov-Like Phase in Sr3Ru2O7 (vol 102, 136404, 2009)

Publisher’s Not

Magnetic analog of the Fulde-Ferrell-Larkin-Ovchinnikov phase in Sr3Ru2O7

The phase diagram of Sr3Ru2O7 contains a metamagnetic transition that bifurcates to enclose an anomalous phase with intriguing properties-a large resistivity with anisotropy that breaks the crystal-lattice symmetry. We propose that this is a magnetic analog of the spatially inhomogeneous superconducting Fulde-Ferrell-Larkin-Ovchinnikov state. Based on a microscopic theory of Stoner magnetism, we derive a Ginzburg-Landau expansion where the magnetization transverse to the applied field can become spatially inhomogeneous. We show that this reproduces the observed phase diagram of Sr3Ru2O7