RanGTPase : a candidate for myc-mediated cancer progression

Background Ras-related nuclear protein (Ran) is required for cancer cell survival in vitro and human cancer progression, but the molecular mechanisms are largely unknown. Methods We investigated the effect of the v-myc myelocytomatosis viral oncogene homolog (Myc) on Ran expression by Western blot, chromatin immunoprecipitation, and luciferase reporter assays and the effects of Myc and Ran expression in cancer cells by soft-agar, cell adhesion, and invasion assays. The correlation between Myc and Ran and the association with patient survival were investigated in 14 independent patient cohorts (n = 2430) and analyzed with Spearman's rank correlation and Kaplan-Meier plots coupled with Wilcoxon-Gehan tests, respectively. All statistical tests were two-sided. Results Myc binds to the upstream sequence of Ran and transactivates Ran promoter activity. Overexpression of Myc upregulates Ran expression, whereas knockdown of Myc downregulates Ran expression. Myc or Ran overexpression in breast cancer cells is associated with cancer progression and metastasis. Knockdown of Ran reverses the effect induced by Myc overexpression in breast cancer cells. In clinical data, a positive association between Myc and Ran expression was revealed in 288 breast cancer and 102 lung cancer specimens. Moreover, Ran expression levels differentiate better or poorer survival in Myc overexpressing breast (χ2 = 24.1; relative risk [RR] = 9.1, 95% confidence interval [CI] = 3.3 to 24.7, P <. 001) and lung (χ2 = 6.04; RR = 2.8, 95% CI = 1.2 to 6.3; P =. 01) cancer cohorts. Conclusions Our results suggest that Ran is required for and is a potential therapeutic target of Myc-driven cancer progression in both breast and lung cancers. © 2013 The Author.

Targeting amino acid transport in metastatic castration-resistant prostate cancer : effects on cell cycle, cell growth, and tumor development

Background L-type amino acid transporters (LATs) uptake neutral amino acids including L-leucine into cells, stimulating mammalian target of rapamycin complex 1 signaling and protein synthesis. LAT1 and LAT3 are overexpressed at different stages of prostate cancer, and they are responsible for increasing nutrients and stimulating cell growth. Methods We examined LAT3 protein expression in human prostate cancer tissue microarrays. LAT function was inhibited using a leucine analog (BCH) in androgen-dependent and -independent environments, with gene expression analyzed by microarray. A PC-3 xenograft mouse model was used to study the effects of inhibiting LAT1 and LAT3 expression. Results were analyzed with the Mann-Whitney U or Fisher exact tests. All statistical tests were two-sided. Results LAT3 protein was expressed at all stages of prostate cancer, with a statistically significant decrease in expression after 4–7 months of neoadjuvant hormone therapy (4–7 month mean = 1.571; 95% confidence interval = 1.155 to 1.987 vs 0 month = 2.098; 95% confidence interval = 1.962 to 2.235; P = .0187). Inhibition of LAT function led to activating transcription factor 4–mediated upregulation of amino acid transporters including ASCT1, ASCT2, and 4F2hc, all of which were also regulated via the androgen receptor. LAT inhibition suppressed M-phase cell cycle genes regulated by E2F family transcription factors including critical castration-resistant prostate cancer regulatory genes UBE2C, CDC20, and CDK1. In silico analysis of BCH-downregulated genes showed that 90.9% are statistically significantly upregulated in metastatic castration-resistant prostate cancer. Finally, LAT1 or LAT3 knockdown in xenografts inhibited tumor growth, cell cycle progression, and spontaneous metastasis in vivo. Conclusion Inhibition of LAT transporters may provide a novel therapeutic target in metastatic castration-resistant prostate cancer, via suppression of mammalian target of rapamycin complex 1 activity and M-phase cell cycle genes.

Exact parametric confidence intervals for Bland-Altman limits of agreement

Purpose The previous literature on Bland-Altman analysis only describes approximate methods for calculating confidence intervals for 95% Limits of Agreement (LoAs). This paper describes exact methods for calculating such confidence intervals, based on the assumption that differences in measurement pairs are normally distributed. Methods Two basic situations are considered for calculating LoA confidence intervals: the first where LoAs are considered individually (i.e. using one-sided tolerance factors for a normal distribution); and the second, where LoAs are considered as a pair (i.e. using two-sided tolerance factors for a normal distribution). Equations underlying the calculation of exact confidence limits are briefly outlined. Results To assist in determining confidence intervals for LoAs (considered individually and as a pair) tables of coefficients have been included for degrees of freedom between 1 and 1000. Numerical examples, showing the use of the tables for calculating confidence limits for Bland-Altman LoAs, have been provided. Conclusions Exact confidence intervals for LoAs can differ considerably from Bland and Altman’s approximate method, especially for sample sizes that are not large. There are better, more precise methods for calculating confidence intervals for LoAs than Bland and Altman’s approximate method, although even an approximate calculation of confidence intervals for LoAs is likely to be better than none at all. Reporting confidence limits for LoAs considered as a pair is appropriate for most situations, however there may be circumstances where it is appropriate to report confidence limits for LoAs considered individually.

Dominant negative ATM mutations in breast cancer families

BACKGROUND: The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10-6T-->G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case-control series of breast cancer families and multiple-case breast cancer families. METHODS: Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10-6T-->G ATM mutations, as were index patients from 76 non-BRCA1/2 multiple-case breast cancer families. Linkage and penetrance were analyzed. ATM protein expression and kinase activity were analyzed in lymphoblastoid cell lines from mutation carriers. All statistical tests were two-sided. RESULTS: In case and control subjects unselected for family history of breast cancer, one case patient had the T7271G mutation, and none had the IVS10-6T-->G mutation. In three multiple-case families, one of these two mutations segregated with breast cancer. The estimated average penetrance of the mutations was 60% (95% confidence interval [CI] = 32% to 90%) to age 70 years, equivalent to a 15.7-fold (95% CI = 6.4-fold to 38.0-fold) increased relative risk compared with that of the general population. Expression and activity analyses of ATM in heterozygous cell lines indicated that both mutations are dominant negative. CONCLUSION: At least two ATM mutations are associated with a sufficiently high risk of breast cancer to be found in multiple-case breast cancer families. Full mutation analysis of the ATM gene in such families could help clarify the role of ATM in breast cancer susceptibility.

Essays on Labor Market Frictions, Technological Change and Macroeconomic Fluctuations

The dissertation consists of an introductory chapter and three essays that apply search-matching theory to study the interaction of labor market frictions, technological change and macroeconomic fluctuations. The first essay studies the impact of capital-embodied growth on equilibrium unemployment by extending a vintage capital/search model to incorporate vintage human capital. In addition to the capital obsolescence (or creative destruction) effect that tends to raise unemployment, vintage human capital introduces a skill obsolescence effect of faster growth that has the opposite sign. Faster skill obsolescence reduces the value of unemployment, hence wages and leads to more job creation and less job destruction, unambiguously reducing unemployment. The second essay studies the effect of skill biased technological change on skill mismatch and the allocation of workers and firms in the labor market. By allowing workers to invest in education, we extend a matching model with two-sided heterogeneity to incorporate an endogenous distribution of high and low skill workers. We consider various possibilities for the cost of acquiring skills and show that while unemployment increases in most scenarios, the effect on the distribution of vacancy and worker types varies according to the structure of skill costs. When the model is extended to incorporate endogenous labor market participation, we show that the unemployment rate becomes less informative of the state of the labor market as the participation margin absorbs employment effects. The third essay studies the effects of labor taxes on equilibrium labor market outcomes and macroeconomic dynamics in a New Keynesian model with matching frictions. Three policy instruments are considered: a marginal tax and a tax subsidy to produce tax progression schemes, and a replacement ratio to account for variability in outside options. In equilibrium, the marginal tax rate and replacement ratio dampen economic activity whereas tax subsidies boost the economy. The marginal tax rate and replacement ratio amplify shock responses whereas employment subsidies weaken them. The tax instruments affect the degree to which the wage absorbs shocks. We show that increasing tax progression when taxation is initially progressive is harmful for steady state employment and output, and amplifies the sensitivity of macroeconomic variables to shocks. When taxation is initially proportional, increasing progression is beneficial for output and employment and dampens shock responses.

L-p Wiener-Tauberian theorems for M(2)

We prove two sided and one sided analogues of the Wiener-Tauberian theorem for the Euclidean motion group, M(2).

Essays on Platforms: Business Strategies, Regulation and Policy in Telecommunications, Media and Technology Industries

The growth of the information economy has been stellar in the last decade. General-purpose technologies such as the computer and the Internet have promoted productivity growth in a large number of industries. The effect on telecommunications, media and technology industries has been particularly strong. These industries include mobile telecommunications, printing and publishing, broadcasting, software, hardware and Internet services. There have been large structural changes, which have led to new questions on business strategies, regulation and policy. This thesis focuses on four such questions and answers them by extending the theoretical literature on platforms. The questions (with short answers) are: (i) Do we need to regulate how Internet service providers discriminate between content providers? (Yes.) (ii) What are the welfare effects of allowing consumers to pay to remove advertisements from advertisement-supported products?(Ambiguous, but those watching ads are worse off.) (iii) Why are some markets characterized by open platforms, extendable by third parties, and some by closed platforms, which are not extendable? (It is a trade-off between intensified competition for consumers and benefits from third parties) (iv) Do private platform providers allow third parties to access their platform when it is socially desirable? (No.)

Persistent passive hopping and juggling is possible even with plastic collisions

We describe simple one-dimensional models of passive (no energy input, no control), generally dissipative, vertical hopping and one-ball juggling. The central observation is that internal passive system motions can conspire to eliminate collisions in these systems. For hopping, two point masses are connected by a spring and the lower mass has inelastic collisions with the ground. For juggling, a lower point-mass hand is connected by a spring to the ground and an upper point-mass ball is caught with an inelastic collision and then re-thrown into gravitational free flight. The two systems have identical dynamics. Despite inelastic collisions between non-zero masses, these systems have special symmetric energy-conserving periodic motions where the collision is at zero relative velocity. Additionally, these special periodic motions have a non-zero sized, one-sided region of attraction on the higher-energy side. For either very large or very small mass ratios, the one-sided region of attraction is large. These results persist for mildly non-linear springs and non-constant gravity. Although non-collisional damping destroys the periodic motions, small energy injection makes the periodic motions stable, with a two-sided region of attraction. The existence of such special energy conserving solutions for hopping and juggling points to possibly useful strategies for both animals and robots. The lossless motions are demonstrated with a table-top experiment.

Spiral-Wave Dynamics in a Mathematical Model of Human Ventricular Tissue with Myocytes and Fibroblasts

Cardiac fibroblasts, when coupled functionally with myocytes, can modulate the electrophysiological properties of cardiac tissue. We present systematic numerical studies of such modulation of electrophysiological properties in mathematical models for (a) single myocyte-fibroblast (MF) units and (b) two-dimensional (2D) arrays of such units; our models build on earlier ones and allow for zero-, one-, and two-sided MF couplings. Our studies of MF units elucidate the dependence of the action-potential (AP) morphology on parameters such as E-f, the fibroblast resting-membrane potential, the fibroblast conductance G(f), and the MF gap-junctional coupling G(gap). Furthermore, we find that our MF composite can show autorhythmic and oscillatory behaviors in addition to an excitable response. Our 2D studies use (a) both homogeneous and inhomogeneous distributions of fibroblasts, (b) various ranges for parameters such as G(gap), G(f), and E-f, and (c) intercellular couplings that can be zero-sided, one-sided, and two-sided connections of fibroblasts with myocytes. We show, in particular, that the plane-wave conduction velocity CV decreases as a function of G(gap), for zero-sided and one-sided couplings; however, for two-sided coupling, CV decreases initially and then increases as a function of G(gap), and, eventually, we observe that conduction failure occurs for low values of G(gap). In our homogeneous studies, we find that the rotation speed and stability of a spiral wave can be controlled either by controlling G(gap) or E-f. Our studies with fibroblast inhomogeneities show that a spiral wave can get anchored to a local fibroblast inhomogeneity. We also study the efficacy of a low-amplitude control scheme, which has been suggested for the control of spiral-wave turbulence in mathematical models for cardiac tissue, in our MF model both with and without heterogeneities.

Marangoni-Benard instability with the exchange of evaporation at liquid-vapour interface

A new two-sided model rather than the one-sided model in previous works is put forward. The linear instability analysis is performed on the Marangoni-Benard convection in the two-layer system with an evaporation interface. We define a new evaporation Biot number which is different from that in the one-sided model, and obtain the curves of critical Marangoni number versus wavenumber. The influence of evaporation velocity and Biot number on the system is discussed and a new phenomenon uninterpreted before is now explained from our numerical results.

Influence of Evaporation on Marangoni-Benard Instability

Evaporative convection and instability give rise to both scientific and technological interests. Practically, a number of the industrial applications such as thin-film evaporators, boiling technologies and heat pipes concern with the evaporation process of which through the vapor-liquid interface the heat and mass transfer occur. From a physical viewpoint, one of interesting questions is the mechanisms of convection instability in thin-liquid layers induced by the coupling of evaporation phenomenon and Marangoni effect at the mass exchanged interface. Classical theories, including Rayleigh’s and Pearson’s, have only successfully explained convection in a liquid layer heated from below without evaporation. However these theories are unable to explain the convection in an evaporating thin layer, especially liquid layer is cooled from below. In present paper, a new two-sided model is put forward rather than the one-sided model in previous works. In previous works, the vapor is treated as passive gas and dynamics of vapor has been ignored. In this case, the vapor liquid system can be described by one-sided model. In our two-sided model, the dynamics of vapor should be considered. Linear instability analysis of the Marangoni-Bénard convection in the two-layer system with an evaporation interface is performed. We define a new evaporating Biot number which is different from the Biot number in one-sided model and obtain the curves of critical Marangoni number versus wave number. In our theoretical results, the Biot number and the evaporating velocity play a major role in the stability of the vapor-liquid system.

Invariant-free deduction systems for temporal logic

In this thesis we propose a new approach to deduction methods for temporal logic. Our proposal is based on an inductive definition of eventualities that is different from the usual one. On the basis of this non-customary inductive definition for eventualities, we first provide dual systems of tableaux and sequents for Propositional Linear-time Temporal Logic (PLTL). Then, we adapt the deductive approach introduced by means of these dual tableau and sequent systems to the resolution framework and we present a clausal temporal resolution method for PLTL. Finally, we make use of this new clausal temporal resolution method for establishing logical foundations for declarative temporal logic programming languages. The key element in the deduction systems for temporal logic is to deal with eventualities and hidden invariants that may prevent the fulfillment of eventualities. Different ways of addressing this issue can be found in the works on deduction systems for temporal logic. Traditional tableau systems for temporal logic generate an auxiliary graph in a first pass.Then, in a second pass, unsatisfiable nodes are pruned. In particular, the second pass must check whether the eventualities are fulfilled. The one-pass tableau calculus introduced by S. Schwendimann requires an additional handling of information in order to detect cyclic branches that contain unfulfilled eventualities. Regarding traditional sequent calculi for temporal logic, the issue of eventualities and hidden invariants is tackled by making use of a kind of inference rules (mainly, invariant-based rules or infinitary rules) that complicates their automation. A remarkable consequence of using either a two-pass approach based on auxiliary graphs or aone-pass approach that requires an additional handling of information in the tableau framework, and either invariant-based rules or infinitary rules in the sequent framework, is that temporal logic fails to carry out the classical correspondence between tableaux and sequents. In this thesis, we first provide a one-pass tableau method TTM that instead of a graph obtains a cyclic tree to decide whether a set of PLTL-formulas is satisfiable. In TTM tableaux are classical-like. For unsatisfiable sets of formulas, TTM produces tableaux whose leaves contain a formula and its negation. In the case of satisfiable sets of formulas, TTM builds tableaux where each fully expanded open branch characterizes a collection of models for the set of formulas in the root. The tableau method TTM is complete and yields a decision procedure for PLTL. This tableau method is directly associated to a one-sided sequent calculus called TTC. Since TTM is free from all the structural rules that hinder the mechanization of deduction, e.g. weakening and contraction, then the resulting sequent calculus TTC is also free from this kind of structural rules. In particular, TTC is free of any kind of cut, including invariant-based cut. From the deduction system TTC, we obtain a two-sided sequent calculus GTC that preserves all these good freeness properties and is finitary, sound and complete for PLTL. Therefore, we show that the classical correspondence between tableaux and sequent calculi can be extended to temporal logic. The most fruitful approach in the literature on resolution methods for temporal logic, which was started with the seminal paper of M. Fisher, deals with PLTL and requires to generate invariants for performing resolution on eventualities. In this thesis, we present a new approach to resolution for PLTL. The main novelty of our approach is that we do not generate invariants for performing resolution on eventualities. Our method is based on the dual methods of tableaux and sequents for PLTL mentioned above. Our resolution method involves translation into a clausal normal form that is a direct extension of classical CNF. We first show that any PLTL-formula can be transformed into this clausal normal form. Then, we present our temporal resolution method, called TRS-resolution, that extends classical propositional resolution. Finally, we prove that TRS-resolution is sound and complete. In fact, it finishes for any input formula deciding its satisfiability, hence it gives rise to a new decision procedure for PLTL. In the field of temporal logic programming, the declarative proposals that provide a completeness result do not allow eventualities, whereas the proposals that follow the imperative future approach either restrict the use of eventualities or deal with them by calculating an upper bound based on the small model property for PLTL. In the latter, when the length of a derivation reaches the upper bound, the derivation is given up and backtracking is used to try another possible derivation. In this thesis we present a declarative propositional temporal logic programming language, called TeDiLog, that is a combination of the temporal and disjunctive paradigms in Logic Programming. We establish the logical foundations of our proposal by formally defining operational and logical semantics for TeDiLog and by proving their equivalence. Since TeDiLog is, syntactically, a sublanguage of PLTL, the logical semantics of TeDiLog is supported by PLTL logical consequence. The operational semantics of TeDiLog is based on TRS-resolution. TeDiLog allows both eventualities and always-formulas to occur in clause heads and also in clause bodies. To the best of our knowledge, TeDiLog is the first declarative temporal logic programming language that achieves this high degree of expressiveness. Since the tableau method presented in this thesis is able to detect that the fulfillment of an eventuality is prevented by a hidden invariant without checking for it by means of an extra process, since our finitary sequent calculi do not include invariant-based rules and since our resolution method dispenses with invariant generation, we say that our deduction methods are invariant-free.

Instabilities of a liquid film flowing down an inclined porous plane

The problem of a film flowing down an inclined porous layer is considered. The fully developed basic flow is driven by gravitation. A careful linear instability analysis is carried out. We use Darcy's law to describe the porous layer and solve the coupling equations of the fluid and the porous medium rather than the decoupled equations of the one-sided model used in previous works. The eigenvalue problem is solved by means of a Chebyshev collocation method. We compare the instability of the two-sided model with the results of the one-sided model. The result reveals a porous mode instability which is completely neglected in previous works. For a falling film on an inclined porous plane there are three instability modes, i.e., the surface mode, the shear mode, and the porous mode. We also study the influences of the depth ratio d, the Darcy number delta, and the Beavers-Joseph coefficient alpha(BJ) on the instability of the system.

A kinetic theory description for external spherical flows with arbitrary Knudsen number by a moment method

The Maxwell integral equations of transfer are applied to a series of problems involving flows of arbitrary density gases about spheres. As suggested by Lees a two sided Maxwellian-like weighting function containing a number of free parameters is utilized and a sufficient number of partial differential moment equations is used to determine these parameters. Maxwell's inverse fifth-power force law is used to simplify the evaluation of the collision integrals appearing in the moment equations. All flow quantities are then determined by integration of the weighting function which results from the solution of the differential moment system. Three problems are treated: the heat-flux from a slightly heated sphere at rest in an infinite gas; the velocity field and drag of a slowly moving sphere in an unbounded space; the velocity field and drag torque on a slowly rotating sphere. Solutions to the third problem are found to both first and second-order in surface Mach number with the secondary centrifugal fan motion being of particular interest. Singular aspects of the moment method are encountered in the last two problems and an asymptotic study of these difficulties leads to a formal criterion for a "well posed" moment system. The previously unanswered question of just how many moments must be used in a specific problem is now clarified to a great extent.