Endogenous c-src as a determinant of the tumorigenicity of src oncogenes.

We have compared the tumorigenicity of two src oncogenes, v-src and c-src(527), whose respective protein products pp60v-src and pp60c-src(527) show a different spectrum of amino acid substitutions vis-à-vis the c-src protooncogene-encoded product pp60c-src. Whereas the extent of primary tumor growth induced by c-src(527) was quite similar in the two chicken lines tested, the extent of v-src-induced tumor growth showed a marked line dependence. As examined with a line of chickens that shows immune-mediated regression of v-src-induced tumors, a weaker tumor immunity, as correlated with a greater level of primary tumor growth, resulted from inoculation of c-src(527) DNA than of v-src DNA. These observations indicated that the v-src-specific amino acid substitutions define a major tumor antigenicity. That a separate src-associated antigenicity is also targetable by the tumor immune response followed from the finding that the level of protective immunity against the growth of c-src(527) DNA-induced tumors was augmented under conditions of the prior regression of v-src DNA-induced tumors. As this latter antigenicity may include one or more c-src(527)-encoded peptides that are equivalent to c-src-encoded self peptides, these observations suggest that a host tolerance to pp60c-src can be broken so as to permit a tumor immune response based on recognition of self peptides of pp60c-src(527).

Thermodynamic parameters for the helix-coil transition of oligopeptides: molecular dynamics simulation with the peptide growth method.

The helix-coil transition equilibrium of polypeptides in aqueous solution was studied by molecular dynamics simulation. The peptide growth simulation method was introduced to generate dynamic models of polypeptide chains in a statistical (random) coil or an alpha-helical conformation. The key element of this method is to build up a polypeptide chain during the course of a molecular transformation simulation, successively adding whole amino acid residues to the chain in a predefined conformation state (e.g., alpha-helical or statistical coil). Thus, oligopeptides of the same length and composition, but having different conformations, can be incrementally grown from a common precursor, and their relative conformational free energies can be calculated as the difference between the free energies for growing the individual peptides. This affords a straightforward calculation of the Zimm-Bragg sigma and s parameters for helix initiation and helix growth. The calculated sigma and s parameters for the polyalanine alpha-helix are in reasonable agreement with the experimental measurements. The peptide growth simulation method is an effective way to study quantitatively the thermodynamics of local protein folding.

Failure of programmed cell death and differentiation as causes of tumors: some simple mathematical models.

Most models of tumorigenesis assume that the tumor grows by increased cell division. In these models, it is generally supposed that daughter cells behave as do their parents, and cell numbers have clear potential for exponential growth. We have constructed simple mathematical models of tumorigenesis through failure of programmed cell death (PCD) or differentiation. These models do not assume that descendant cells behave as their parents do. The models predict that exponential growth in cell numbers does sometimes occur, usually when stem cells fail to die or differentiate. At other times, exponential growth does not occur: instead, the number of cells in the population reaches a new, higher equilibrium. This behavior is predicted when fully differentiated cells fail to undergo PCD. When cells of intermediate differentiation fail to die or to differentiate further, the values of growth parameters determine whether growth is exponential or leads to a new equilibrium. The predictions of the model are sensitive to small differences in growth parameters. Failure of PCD and differentiation, leading to a new equilibrium number of cells, may explain many aspects of tumor behavior--for example, early premalignant lesions such as cervical intraepithelial neoplasia, the fact that some tumors very rarely become malignant, the observation of plateaux in the growth of some solid tumors, and, finally, long lag phases of growth until mutations arise that eventually result in exponential growth.

p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts.

Increased expression of wild-type p53 in response to DNA damage arrests cells late in the G1 stage of the cell cycle by stimulating the synthesis of inhibitors of cyclin-dependent kinases, such as p21/WAF1. To study the effects of p53 without the complication of DNA damage, we used tetracycline to regulate its expression in MDAH041 human fibroblasts that lack endogenous p53. When p53 is expressed at a level comparable to that induced by DNA damage in other cells, most MDAH041 cells arrested in G1, but a significant fraction also arrested in G2/M. Cells released from a mimosine block early in S phase stopped predominantly in G2/M in the presence of p53, confirming that p53 can mediate arrest at this stage, as well as in G1. In these cells, there was appreciable induction of p21/WAF1. MDAH041 cells arrested by tetracycline-regulated p53 for as long as 20 days resumed growth when the p53 level was lowered, in striking contrast to the irreversible arrest mediated by DNA damage. Therefore, irreversible arrest must involve processes other than or in addition to the interaction of p53-induced p21/WAF1 with G1 and G2 cyclin-dependent kinases.

Exogenous vascular endothelial growth factor induces malformed and hyperfused vessels during embryonic neovascularization.

Vascular endothelial growth factor (VEGF) is a potent and specific endothelial mitogen that is able to induce angiogenesis in vivo [Leung, D. W., Cachianes, G., Kuang, W.-J., Goeddel, D. V. & Ferrara, N. (1989) Science 246 1306-1309]. To determine if VEGF also influences the behavior of primordial endothelial cells, we used an in vivo vascular assay based on the de novo formation of vessels. Japanese quail embryos injected with nanomolar quantities of the 165-residue form of VEGF at the onset of vasculogenesis exhibited profoundly altered vessel development. In fact, the overall patterning of the vascular network was abnormal in all VEGF-injected embryos. The malformations were attributable to two specific endothelial cell activities: (i) inappropriate neovascularization in normally avascular areas and (ii) the unregulated, excessive fusion of vessels. In the first instance, supernumerary vessels directly linked the inflow channel of the heart to the aortic outflow channel. The second aberrant activity led to the formation of vessels with abnormally large lumens. Ultimately, unregulated vessel fusion generated massive vascular sacs that obliterated the identity of individual vessels. These observations show that exogenous VEGF has an impact on the behavior of primordial endothelial cells engaged in vasculogenesis, and they strongly suggest that endogenous VEGF is important in vascular patterning and regulation of vessel size (lumen formation).

Activation of mammalian retinoid X receptors by the insect growth regulator methoprene.

We report that methoprene and its derivatives can stimulate gene transcription in vertebrates by acting through the retinoic acid-responsive transcription factors, the retinoid X receptors (RXRs). Methoprene is an insect growth regulator in domestic and agricultural use as a pesticide. At least one metabolite of methoprene, methoprene acid, directly binds to RXR and is a transcriptional activator in both insect and mammalian cells. Unlike the endogenous RXR ligand, 9-cis-retinoic acid, this activity is RXR-specific; the methoprene derivatives do not activate the retinoic acid receptor pathway. Methoprene is a juvenile hormone analog that acts to retain juvenile characteristics during insect growth, preventing metamorphosis into an adult, and it has been shown to have ovicidal properties in some insects. Thus, a pesticide that mimics the action of juvenile hormone in insects can also activate a mammalian retinoid-responsive pathway. This finding provides a basis through which the potential bioactivity of substances exposed to the environment may be reexamined and points the way for discovery of new receptor ligands in both insects and vertebrates.

EmotiBlog: a finer-grained and more precise learning of subjectivity expression models

The exponential growth of the subjective information in the framework of the Web 2.0 has led to the need to create Natural Language Processing tools able to analyse and process such data for multiple practical applications. They require training on specifically annotated corpora, whose level of detail must be fine enough to capture the phenomena involved. This paper presents EmotiBlog – a fine-grained annotation scheme for subjectivity. We show the manner in which it is built and demonstrate the benefits it brings to the systems using it for training, through the experiments we carried out on opinion mining and emotion detection. We employ corpora of different textual genres –a set of annotated reported speech extracted from news articles, the set of news titles annotated with polarity and emotion from the SemEval 2007 (Task 14) and ISEAR, a corpus of real-life self-expressed emotion. We also show how the model built from the EmotiBlog annotations can be enhanced with external resources. The results demonstrate that EmotiBlog, through its structure and annotation paradigm, offers high quality training data for systems dealing both with opinion mining, as well as emotion detection.

Europe's growth problem (and what to do about it). Bruegel Policy Brief 2013/03, April 2013

The issue: The European Union's pre-crisis growth performance was disappointing enough, but the performance has been even more dismal since the onset of the crisis. Weak growth is undermining private and public deleveraging,and is fuelling continued banking fragility. Persistently high unemployment is eroding skills, discouraging labour market participation and undermining the EU’s long-term growth potential. Low overall growth is making it much tougher for the hard-hit economies in southern Europe to recover competitiveness and regain control of their public finances. Stagnation would reduce the attractiveness of Europe for investment. Under these conditions, Europe's social models are bound to prove unsustainable. Policy Challenge: The European Union's weak long-term growth potential and unsatisfactory recovery from the crisis represent a major policy challenge. Over and above the structural reform agenda, which vitally important, bold policy action is needed. The priority is to get bank credit going. Banking problems need to be assessed properly and bank resolution and recapitalisation should be pursued. Second, fostering the reallocation of factors to the most productive firms and the sectors that contribute to aggregate rebalancing is vital. Addressing intra-euro area competitiveness divergence is essential to support growth in southern Europe. Third, the speed of fiscal adjustment needs to be appropriate and EU funds should be front loaded to countries in deep recession, while the European Investment Bank should increase investment.

Cities: The Juncker Commission should not miss this key to growth, jobs and the environment. CEPS Commentary, 3 October 2014

Cities, more particularly ‘smart’ cities, could become a catalyst for economic and social development. For this to happen, Europe will need a new type of integrated infrastructure, a new urban governance and policy structure, as well as new finance and business models. Successful smart projects will eventually develop into new business models and companies. While the European Commission cannot mandate or regulate this top down, it has a role to play in nurturing new initiatives to allow Europe the possibility of developing its own Google and Apple.

Is the "Dubai model" a new paradigm for growth and investment strategies for oil-based economies? Case study: Eurasia. ACES Working Papers No. 8, 2008

The first part of the paper addresses the theoretical background of economic growth and competitive advantage models. Although there is a whole set of research on a relationship between foreign direct investments and economic growth, little has been said on foreign direct investments and national competitive advantage with respect to economic growth of oil and gas abundant countries of Middle East and Central Asia. The second part of our paper introduces the framework of the so-called "Dubai Model" in detail and outlines the key components necessary to develop sustainable comparative advantage for the oil-rich economies. The third part proceeds with the methodology employed to measure the success of the "Dubai Model" in the UAE and in application to other regions. The last part brings the results and investigates the degree to which other oil and gas countries in the region (i.e. Saudi Arabia, Kuwait, Qatar, Iran) have adopted the so-called "Dubai Model". It also examines if the Dubai Model is being employed in the Eurasian (Central Asian) oil and gas regions of Kazakhstan, Azerbaijan, Turkmenistan and Uzbekistan. The objective is to gauge if the Eurasian economies are employing the traditional growth strategies of oil-rich non-OECD countries in managing their natural resources or are they adopting the newer non-traditional model of economic growth, such as the "Dubai Model."

Comparing fiscal multipliers across models and countries in Europe. National Bank of Belgium Working Paper No. 278, March 2015

This paper employs fifteen dynamic macroeconomic models maintained within the European System of Central Banks to assess the size of fiscal multipliers in European countries. Using a set of common simulations, we consider transitory and permanent shocks to government expenditures and different taxes. We investigate how the baseline multipliers change when monetary policy is transitorily constrained by the zero nominal interest rate bound, certain crisis-related structural features of the economy such as the share of liquidity-constrained households change, and the endogenous fiscal rule that ensures fiscal sustainability in the long run is specified in terms of labour income taxes instead of lump-sum taxes.

Fetch-limited wave growth in Nootka Sound

Senior thesis written for Oceanography 445

Environmental Enteropathy and Fibroblast Growth Factor 21 are associated with early childhood growth in Bangladesh

Thesis (Ph.D.)--University of Washington, 2016-06

Growth hormone, insulin-like growth factor I and cell proliferation in the mouse blastocyst

The role of growth hormone (GH) in embryonic growth is controversial, yet preimplantation embryos express GH, insulin-like growth factor I (IGF-I) and their receptors. In this study, addition of bovine GH doubled the proportion of two-cell embryos forming blastocysts and increased by about 25% the number of cells in those blastocysts with a concentration-response curve showing maximal activity at 1 pg bovine GH ml(-1), with decreasing activity at higher and lower concentrations. GH increased the number of cells in the trophectoderm by 25%, but did not affect the inner cell mass of blastocysts. Inhibition of cell proliferation by anti-GH antiserum indicated that GH is a potent autocrine or paracrine regulator of the number of trophectoderm cells in vivo. Type 1 IGF receptors (IGF1R) were localized to cytoplasmic vesicles and plasma membrane in the apical domains of uncompacted and compacted eight-cell embryos, but were predominantly apparent in cytoplasmic vesicles of the trophectoderm cells of the blastocyst, similar to GH receptors. Studies using alphaIR3 antiserum which blocks ligand activation of IGF1R, showed that IGF1R participate in the autocrine or paracrine regulation of the number of cells in the inner cell mass by an endogenous IGF-I-IGF1R pathway. However, alphaIR3 did not affect GH stimulation of the number of trophectoderm cells. Therefore, CH does not use secondary actions via embryonic IGF-I to modify the number of blastocyst cells. This result indicates that GH and IGF-I act independently. GH may selectively regulate the number of trophectoderm cells and thus implantation and placental growth. Embryonic GH may act in concert with IGF-I, which stimulates proliferation in the inner cell mass, to optimize blastocyst development.

The role of insulin-like growth factor II and its receptor in mouse preimplantation development

Insulin-like growth factor II (IGF-II) and its receptor, the IGF-II/mannose-6-phosphate (IGF-II/M6P) receptor, are first expressed from the zygotic genome at the two-cell stage of mouse development. However, their role is not clearly defined. Insulin-like growth factor II is believed to mediate growth through the heterologous type 1 IGF and insulin receptors, whereas the IGF-II/M6P receptor is believed to act as a negative regulator of somatic growth by limiting the availability of excess levels of IGF-II. These studies demonstrate that IGF-II does have a role in growth regulation in the early embryo through the IGF-II/M6P receptor. Insulin-like growth factor II stimulated cleavage rate in two-cell embryos in vitro. Moreover, this receptor is required for the glycaemic response of two-cell embryos to IGF-II and for normal progression of early embryos to the blastocyst stage. Improved development of embryos in crowded culture supports the concept of an endogenous embryonic paracrine activity that enhances cell proliferation. These responses indicate that the IGF-II/M6P receptor is functional and likely to participate in such a regulatory circuit. The functional role of IGF-II and its receptor is discussed with reference to regulation of early development.