Structure, regulation, and function of protein tyrosine phosphatases

The phosphorylation of tyrosyl residues in proteins is an essential aspect of many signal transduction events, including the control of both normal and neoplastic cell growth and proliferation. Since the earliest observations of tyrosine phosphorylation, it has been appreciated that this is a reversible process in which the net level of phosphate in a target substrate reflects the balance between the competing action of kinases and phosphatases. Thus, in cells transformed by temperature-sensitive mutants of Rous sarcoma virus, an elevation in the levels of phosphotyrosine is observed at the permissive temperature, at which the kinase is active; however, if the cells are shifted to the nonpermissive temperature, at which the kinase is inactivated, a rapid dephosphorylation of tyrosyl residues ensues due to the action of protein tyrosine phosphatases (PTPases) (Sefton et al. 1980). The last 10 years has witnessed great progress in the characterization of the protein tyrosine kinases, whereas..

Fund Flows, Manager Changes, and Performance Persistence

Most empirical studies suggest that mutual funds do not persistently outperform an appropriate benchmark in the long run. We analyze this lack of persistence in terms of two equilibrating mechanisms: fund flows and manager changes. Using data on actively managed US equity mutual funds, we find that if neither mechanism is operating, winner funds (top-decile ranked in previous year) continue to significantly outperform loser funds (bottom-decile ranked in previous year) by 4.08 percentage points per annum. However, the difference between previous winner and loser funds declines to zero within one year if the two mechanisms are acting together. Thus, equity mutual fund out- and underperformance are unlikely to persist in well-functioning financial markets

A Poly-algorithmic Approach to Quantifier Elimination

Cylindrical Algebraic Decomposition (CAD) was the first practical means for doing real quantifier elimination (QE), and is still a major method, with many improvements since Collins' original method. Nevertheless, its complexity is inherently doubly exponential in the number of variables. Where applicable, virtual term substitution (VTS) is more effective, turning a QE problem in $n$ variables to one in $n-1$ variables in one application, and so on. Hence there is scope for hybrid methods: doing VTS where possible then using CAD. This paper describes such a poly-algorithmic implementation, based on the second author's Ph.D. thesis. The version of CAD used is based on a new implementation of Lazard's recently-justified method, with some improvements to handle equational constraints

Dual role of splenic mononuclear and polymorphonuclear cells in the outcome of ciprofloxacin treatment of Salmonella enterica infections.

OBJECTIVES: To determine the immune cell populations associated with Salmonella enterica serovar Typhimurium before and after ciprofloxacin treatment using a murine model of systemic infection. The effect of depletion of immune cells associating with Salmonella on treatment outcome was also determined. METHODS: We infected mice with a Salmonella enterica serovar Typhimurium strain expressing GFP and used multicolour flow cytometry to identify splenic immune cell populations associating with GFP-positive Salmonella before and after treatment with ciprofloxacin. This was followed by depletion of different immune cell populations using antibodies and liposomes. RESULTS: Our results identified CD11b+CD11chi/lo (dendritic cells/macrophages) and Ly6G+CD11b+ (neutrophils) leucocytes as the main host cell populations that are associated with Salmonella after ciprofloxacin treatment. We therefore proceeded to test the effects of depletion of such populations during treatment. We show that depletion of Ly6G+CD11b+ populations resulted in an increase in the number of viable bacterial cells in the spleen at the end of ciprofloxacin treatment. Conversely, treatment with clodronate liposomes during antimicrobial treatment, which depleted the CD11b+CD11chi/lo populations, resulted in lower numbers of viable bacteria in the tissues. CONCLUSIONS: Our study identified host cells where Salmonella bacteria persist during ciprofloxacin treatment and revealed a dual and opposing effect of removal of Ly6G+CD11b+ and CD11b+CD11chi/lo host cells on the efficacy of antimicrobial treatment. This suggests a dichotomy in the role of these populations in clearance/persistence of Salmonella during antimicrobial treatment

HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer

Ovarian cancer cells disseminate readily within the peritoneal cavity, which promotes metastasis, and are often resistant to chemotherapy. Ovarian cancer patients tend to present with advanced disease, which also limits treatment options; consequently, new therapies are required. The oncoprotein tyrosine kinase MET, which is the receptor for hepatocyte growth factor (HGF), has been implicated in ovarian tumorigenesis and has been the subject of extensive drug development efforts. Here, we report a novel ligand- and autophosphorylation-independent activation of MET through the nonreceptor tyrosine kinase feline sarcoma-related (FER). We demonstrated that the levels of FER were elevated in ovarian cancer cell lines relative to those in immortalized normal surface epithelial cells and that suppression of FER attenuated the motility and invasive properties of these cancer cells. Furthermore, loss of FER impaired the metastasis of ovarian cancer cells in vivo. Mechanistically, we demonstrated that FER phosphorylated a signaling site in MET: Tyr1349. This enhanced activation of RAC1/PAK1 and promoted a kinase-independent scaffolding function that led to recruitment and phosphorylation of GAB1 and the specific activation of the SHP2-ERK signaling pathway. Overall, this analysis provides new insights into signaling events that underlie metastasis in ovarian cancer cells, consistent with a prometastatic role of FER and highlighting its potential as a novel therapeutic target for metastatic ovarian cancer

The risk assessment of ERTMS-based railway systems from a cyber security perspective: Methodology and lessons learned

The impact that cyber issues might have on the safety and resilience of railway systems has been studied for more than five years by industry specialists and government agencies. This paper presents some of the work done by Adelard in this area, ranging from an analysis of potential vulnerabilities in the ERTMS specifications through to a high-level cyber security risk assessment of a national ERTMS implementation and detailed analysis of particular ERTMS systems on behalf of the GB rail industry. The focus of the paper is on our overall methodology for security-informed safety and hazard analysis. Lessons learned will be presented but of course our detailed results remain proprietary or sensitive and cannot be published

Phytoseiulus persimilis (Acarina: Phytoseiidae) for control of two-spotted mites in a commercial greenhouse

Natural infestations of the two-spotted spider mite were controlled on green house cucumber by early releases of the predatory mite, Phytoseiulus persimilis Athias-Henriot. Later sporadic mite outbreaks severely damaged some plants and required frequent surveys and repeated predator releases in the greenhouse. However, no mite sprays were required and crop yield was satisfactory

Three-dimensional molecular dynamics simulations of void coalescence during dynamic fracture of ductile metals

Void coalescence and interaction in dynamic fracture of ductile metals have been investigated using three-dimensional strain-controlled multi-million atom molecular dynamics simulations of copper. The correlated growth of two voids during the coalescence process leading to fracture is investigated, both in terms of its onset and the ensuing dynamical interactions. Void interactions are quantified through the rate of reduction of the distance between the voids, through the correlated directional growth of the voids, and through correlated shape evolution of the voids. The critical inter-void ligament distance marking the onset of coalescence is shown to be approximately one void radius based on the quantification measurements used, independent of the initial separation distance between the voids and the strain-rate of the expansion of the system. The interaction of the voids is not reflected in the volumetric asymptotic growth rate of the voids, as demonstrated here. Finally, the practice of using a single void and periodic boundary conditions to study coalescence is examined critically and shown to produce results markedly different than the coalescence of a pair of isolated voids.Comment: Accepted for publication in Physical Review