Clonal analysis of stem cells in differentiation and disease.

Tracking the fate of individual cells and their progeny by clonal analysis has redefined the concept of stem cells and their role in health and disease. The maintenance of cell turnover in adult tissues is achieved by the collective action of populations of stem cells with an equal likelihood of self-renewal or differentiation. Following injury stem cells exhibit striking plasticity, switching from homeostatic behavior in order to repair damaged tissues. The effects of disease states on stem cells are also being uncovered, with new insights into how somatic mutations trigger clonal expansion in early neoplasia.BC and PHJ are supported by a core grant from the Wellcome Trust to the Wellcome Trust Sanger Institute. PHJ acknowledges support from a Cancer Research UK Programme Grant (C609/A17257).This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.ceb.2016.07.00

Cell competition: winning out by losing notch.

Cell competition where 'loser' cells are eliminated by neighbors with higher fitness is a widespread phenomenon in development. However, a growing body of evidence argues cells with somatic mutations compete with their wild type counterparts in the earliest stages of cancer development. Recent studies have begun to shed light on the molecular and cellular mechanisms that alter the competitiveness of cells carrying somatic mutations in adult tissues. Cells with a 'winner' phenotype create clones which may expand into extensive fields of mutant cells within normal appearing epithelium, favoring the accumulation of further genetic alterations and the evolution of cancer. Here we focus on how mutations which disrupt the Notch signaling pathway confer a 'super competitor' status on cells in squamous epithelia and consider the broader implications for cancer evolution.We acknowledge the support of the MRC, the NC3Rs (National Center for the Replacement, Refinement and Reduction of Animals in Research), the Wellcome Trust (Project grant WT090334MA, to PHJ), Cancer Research UK (Program Grant C609/A17257, to PHJ) and a European Union Marie Curie Fellowship (PIEF-LIF-2007-220016, to MPA).This paper was originally published in Cell Cycle (MP Alcolea, PH Jones, Cell Cycle 2015, 14, 9-17

Stability of atoms in intense laser fields

Several mechanisms can impede or even eliminate photoionization or photodissociation of bound quantum systems in an intense laser field. This paper reviews recent laboratory studies of these effects.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87704/2/485_1.pd

Belousov-Zhabotinsky droplet mixing on-chip for chemical computing applications

Without an imposed physical structure, even the most complex chemistries are limited in their ability to process information. For example, the Belousov-Zhabotinsky (BZ) oscillating reaction has been shown to have information procession potential, but only if structure is imposed e.g. using physical barriers or light-sensitive catalysts. Recently, separated BZ droplets in oil have been investigated. Another option for aqueous/oil systems is to add lipid into the oil, which self-assembles into a monolayer at the phase boundary. If the lipid-stabilised droplets are brought into contact, a bilayer is formed, separating the BZ droplets into compartments. This technique is more flexible than other methods of imparting structure, allowing for the creation of droplet arrays inspired by biological neuronal networks

A Step-by-step Guide to the Realisation of Advanced Optical Tweezers

Since the pioneering work of Arthur Ashkin, optical tweezers have become an indispensable tool for contactless manipulation of micro- and nanoparticles. Nowadays optical tweezers are employed in a myriad of applications demonstrating the importance of these tools. While the basic principle of optical tweezers is the use of a strongly focused laser beam to trap and manipulate particles, ever more complex experimental set-ups are required in order to perform novel and challenging experiments. With this article, we provide a detailed step- by-step guide for the construction of advanced optical manipulation systems. First, we explain how to build a single-beam optical tweezers on a home-made microscope and how to calibrate it. Improving on this design, we realize a holographic optical tweezers, which can manipulate independently multiple particles and generate more sophisticated wavefronts such as Laguerre-Gaussian beams. Finally, we explain how to implement a speckle optical tweezers, which permit one to employ random speckle light fields for deterministic optical manipulation.Comment: 29 pages, 7 figure

Hes6 is required for the neurogenic activity of neurogenin and NeuroD.

In the embryonic neural plate, a subset of precursor cells with neurogenic potential differentiates into neurons. This process of primary neurogenesis requires both the specification of cells for neural differentiation, regulated by Notch signaling, and the activity of neurogenic transcription factors such as neurogenin and NeuroD which drive the program of neural gene expression. Here we study the role of Hes6, a member of the hairy enhancer of split family of transcription factors, in primary neurogenesis in Xenopus embryos. Hes6 is an atypical Hes gene in that it is not regulated by Notch signaling and promotes neural differentiation in mouse cell culture models. We show that depletion of Xenopus Hes6 (Xhes6) by morpholino antisense oligonucleotides results in a failure of neural differentiation, a phenotype rescued by both wild type Xhes6 and a Xhes6 mutant unable to bind DNA. However, an Xhes6 mutant that lacks the ability to bind Groucho/TLE transcriptional co-regulators is only partly able to rescue the phenotype. Further analysis reveals that Xhes6 is essential for the induction of neurons by both neurogenin and NeuroD, acting via at least two distinct mechanisms, the inhibition of antineurogenic Xhairy proteins and by interaction with Groucho/TLE family proteins. We conclude Xhes6 is essential for neurogenesis in vivo, acting via multiple mechanisms to relieve inhibition of proneural transcription factor activity within the neural plate

Stem cell patterning and fate in human epidermis

AbstractWithin human epidermis there are two types of proliferating keratinocyte: stem cells, which have high proliferative potential, and transit-amplifying cells, which are destined to undergo terminal differentiation after a few rounds of division. We show that, in vivo, stem cells express higher levels of the α2β1, and α3β1 integrins than transit-amplifying cells and that this can be used both to determine the location of stem cells within the epidermis and to isolate them directly from the tissue. The distribution of stem cells and transit-amplifying cells is not random: patches of integrin-bright and integrin-dull cells have a specific location with respect to the epidermal-dermal junction that varies between body sites and that correlates with the distribution of S phase cells. Stem cell patterning can be recreated in culture, in the absence of dermis, and appears to be subject to autoregulation

Switching roles: the functional plasticity of adult tissue stem cells.

Adult organisms have to adapt to survive, and the same is true for their tissues. Rates and types of cell production must be rapidly and reversibly adjusted to meet tissue demands in response to both local and systemic challenges. Recent work reveals how stem cell (SC) populations meet these requirements by switching between functional states tuned to homoeostasis or regeneration. This plasticity extends to differentiating cells, which are capable of reverting to SCs after injury. The concept of the niche, the micro-environment that sustains and regulates stem cells, is broadening, with a new appreciation of the role of physical factors and hormonal signals. Here, we review different functions of SCs, the cellular mechanisms that underlie them and the signals that bias the fate of SCs as they switch between roles.We thank J. Fowler, J. Frede, P. Greulich, A.M. Klein, K. Murai, B.D. Simons and D.J. Winton for discussions. We acknowledge the support of the Medical Research Council, the Wellcome Trust (Project grant WT090334MA, P.H.J. and PhD studentship Programme in Stem Cell Biology & Medicine, A.W.) and Cancer Research UK (Programme Grant C609/A17257, P.H.J.).This is the author accepted manuscript. The final version is available via EMBO at http://emboj.embopress.org/content/34/9/1164.long#ack-1