Tyrosine-specific MAPK phosphatases and the control of ERK signaling in PC12 cells

BACKGROUND: Spatio-temporal control of extracellular signal-regulated kinase (ERK) activity, a critical determinant of the cell's response to growth factors, requires timely dephosphorylation of its regulatory tyrosine and/or threonine residue by MAPK phosphatases. We studied the physiological role of kinase interaction motif (KIM)-containing protein tyrosine phosphatases (PTPs) in the control of EGF- and NGF-induced ERK activity in neuroendocrine PC12 cells. RESULTS: We found a single KIM-containing PTP to be endogenously expressed in rat PC12 cells: the transmembrane PTPRR isoform termed PCPTP1. Protein knock-down of PCPTP1, or fourfold overexpression of its mouse orthologue, PTPBR7, left EGF- and NGF-induced ERK1/2 activity in PC12 cells unaltered. Ectopic expression of cytosolic PTPRR isoforms, however, resulted in reduced EGF-induced ERK1/2 activity, an effect that was dependent on the phosphatase activity and the KIM-domain of these PTPs. CONCLUSION: The finding that robust changes in tyrosine-specific MAPK phosphatase expression levels have minor effects on temporal ERK1/2 activity control in PC12 cells suggests that dual-specificity MAPK phosphatases may act as major regulators of growth factor-induced ERK1/2 signaling in these cells

Evolutionary Algorithms with Self-adjusting Asymmetric Mutation

Evolutionary Algorithms (EAs) and other randomized search heuristics are often considered as unbiased algorithms that are invariant with respect to different transformations of the underlying search space. However, if a certain amount of domain knowledge is available the use of biased search operators in EAs becomes viable. We consider a simple (1+1) EA for binary search spaces and analyze an asymmetric mutation operator that can treat zero- and one-bits differently. This operator extends previous work by Jansen and Sudholt (ECJ 18(1), 2010) by allowing the operator asymmetry to vary according to the success rate of the algorithm. Using a self-adjusting scheme that learns an appropriate degree of asymmetry, we show improved runtime results on the class of functions OneMax$_a$ describing the number of matching bits with a fixed target $a\in\{0,1\}^n$.Comment: 16 pages. An extended abstract of this paper will be published in the proceedings of PPSN 202

Lattice QCD without topology barriers

As the continuum limit is approached, lattice QCD simulations tend to get trapped in the topological charge sectors of field space and may consequently give biased results in practice. We propose to bypass this problem by imposing open (Neumann) boundary conditions on the gauge field in the time direction. The topological charge can then flow in and out of the lattice, while many properties of the theory (the hadron spectrum, for example) are not affected. Extensive simulations of the SU(3) gauge theory, using the HMC and the closely related SMD algorithm, confirm the absence of topology barriers if these boundary conditions are chosen. Moreover, the calculated autocorrelation times are found to scale approximately like the square of the inverse lattice spacing, thus supporting the conjecture that the HMC algorithm is in the universality class of the Langevin equation.Comment: Plain TeX source, 26 pages, 4 figures include

Non-renormalizability of the HMC algorithm

In lattice field theory, renormalizable simulation algorithms are attractive, because their scaling behaviour as a function of the lattice spacing is predictable. Algorithms implementing the Langevin equation, for example, are known to be renormalizable if the simulated theory is. In this paper we show that the situation is different in the case of the molecular-dynamics evolution on which the HMC algorithm is based. More precisely, studying the phi^4 theory, we find that the hyperbolic character of the molecular-dynamics equations leads to non-local (and thus non-removable) ultraviolet singularities already at one-loop order of perturbation theory.Comment: Plain TeX source, 23 pages, 3 figures included; v2: typos corrected, agrees with published versio

Clinical significance of the nuclear receptor co-regulator DC-SCRIPT in breast cancer: an independent retrospective validation study

Contains fulltext : 88921.pdf (publisher's version ) (Open Access

Quantification of crypt and stem cell evolution in the normal and neoplastic human colon.

Human intestinal stem cell and crypt dynamics remain poorly characterized because transgenic lineage-tracing methods are impractical in humans. Here, we have circumvented this problem by quantitatively using somatic mtDNA mutations to trace clonal lineages. By analyzing clonal imprints on the walls of colonic crypts, we show that human intestinal stem cells conform to one-dimensional neutral drift dynamics with a "functional" stem cell number of five to six in both normal patients and individuals with familial adenomatous polyposis (germline APC(-/+)). Furthermore, we show that, in adenomatous crypts (APC(-/-)), there is a proportionate increase in both functional stem cell number and the loss/replacement rate. Finally, by analyzing fields of mtDNA mutant crypts, we show that a normal colon crypt divides around once every 30-40 years, and the division rate is increased in adenomas by at least an order of magnitude. These data provide in vivo quantification of human intestinal stem cell and crypt dynamics.This study was supported by Cancer Research UK (to A.-M.B. and N.A.W.), the Medical Research Council (to B.C. and S.A.C.M.), the Engineering and Physical Sciences Research Council (to A.G.F.), Microsoft Research (to A.G.F.), the National Institute for Health Research University College London Hospitals Biomedical Research Centre (to M.R.J.), the Dutch Cancer Research Foundation (to M.J.), the Wellcome Trust (to B.D.S.), and Higher Education Funding Council for England (to T.A.G.)

The continuum limit of the static-light meson spectrum

We investigate the continuum limit of the low lying static-light meson spectrum using Wilson twisted mass lattice QCD with N_f = 2 dynamical quark flavours. We consider three values of the lattice spacing a ~ 0.051 fm, 0.064 fm, 0.080 fm and various values of the pion mass in the range 280 MeV < m_PS < 640 MeV. We present results in the continuum limit for light cloud angular momentum j = 1/2, 3/2, 5/2 and for parity P = +, -. We extrapolate our results to physical quark masses, make predictions regarding the spectrum of B and B_s mesons and compare with available experimental results.Comment: 18 pages, 3 figure

Farmer perceptions and responses to soil degradation in Swaziland

Soil degradation is globally concerning due to its adverse effects on the environment and agricultural production. Much of Swaziland is at risk from degradation. This paper assesses farmer perceptions and responses to soil degradation in 2002 and 2014, focusing on two land uses that underpin rural livelihoods: arable land and rangeland areas. It uses repeat household surveys and semi-structured interviews, in two case study chiefdoms in the country’s middleveld (KaBhudla and Engcayini) in the first longitudinal study of its kind. We find that observations of land degradation are perceived mainly through changes in land productivity, with chemical degradation occurring predominantly on arable land and physical degradation and erosion mainly in rangeland areas. Changes in rainfall are particularly important in determining responses. While perceptions of the causes and impacts of degradation largely concur with the scientific literature, responses were constrained by poor land availability, shorter and more unpredictable cropping seasons because of changing rains and low awareness, access to or knowledge of agricultural inputs. We suggest that sustainable arable land management can be enhanced through improved access to alternative sources of water, use of management practices that retain soil and moisture and greater access to agricultural inputs and capacity building to ensure their appropriate use. We suggest collaborative management for settlement planning that integrates soil conservation and livestock management strategies such as controlled stocking levels and rotational grazing could improve land quality in rangeland areas. Together, these approaches can help land users to better manage change