text:
- Research article
- Open Access
The crosstalk between EGF, IGF, and Insulin cell signaling pathways - computational and experimental analysis
- Rafal Zielinski†1,
- Pawel F Przytycki†2,
- Jie Zheng3,
- David Zhang4,
- Teresa M Przytycka3Email author and
- Jacek Capala1
© Zielinski et al; licensee BioMed Central Ltd. 2009
- Received: 28 September 2008
- Accepted: 4 September 2009
- Published: 4 September 2009
Cellular response to external stimuli requires propagation of corresponding signals through molecular signaling pathways. However, signaling pathways are not isolated information highways, but rather interact in a number of ways forming sophisticated signaling networks. Since defects in signaling pathways are associated with many serious diseases, understanding of the crosstalk between them is fundamental for designing molecularly targeted therapy. Unfortunately, we still lack technology that would allow high throughput detailed measurement of activity of individual signaling molecules and their interactions. This necessitates developing methods to prioritize selection of the molecules such that measuring their activity would be most informative for understanding the crosstalk. Furthermore, absence of the reaction coefficients necessary for detailed modeling of signal propagation raises the question whether simple parameter-free models could provide useful information about such pathways.
We study the combined signaling network of three major pro-survival signaling pathways: E pidermal G rowth F actor R eceptor (EGFR), I nsulin-like G rowth F actor-1 R eceptor (IGF-1R), and I nsulin R eceptor (IR). Our study involves static analysis and dynamic modeling of this network, as well as an experimental verification of the model by measuring the response of selected signaling molecules to differential stimulation of EGF, IGF and insulin receptors. We introduced two novel measures of the importance of a node in the context of such crosstalk. Based on these measures several molecules, namely Erk1/2, Akt1, Jnk, p70S6K, were selected for monitoring in the network simulation and for experimental studies. Our simulation method relies on the Boolean network model combined with stochastic propagation of the signal. Most (although not all) trends suggested by the simulations have been confirmed by experiments.
The simple model implemented in this paper provides a valuable first step in modeling signaling networks. However, to obtain a fully predictive model, a more detailed knowledge regarding parameters of individual interactions might be necessary.
- Epidermal Growth Factor
- Insulin Receptor
- Signaling Network
- Betweenness Centrality
- SKOV3 Cell
Signal transduction is the primary means by which cells respond to external stimuli such as nutrients, hormones, growth factors, and stress. Following the discovery of reversible phosphorylation [1] which provides the fundamental mechanisms of signal propagation, a large spectrum of methods that cells adopt to propagate a signal has been elucidated [2]. The discovery of basic principles of modular organization on the level of signaling domains [3] as well as on the level of whole signaling pathways (as exemplified by the MAP Kinase cascade which is present in multiple copies in eukaryotic organisms added to the understanding of the signaling process. These increasingly more accurate [2, 4] descriptions of signaling mechanisms are accompanied with the reconstruction of ever larger signaling pathways and networks.
Defects in signaling pathways are associated with many serious diseases, in particular cancer [5]. Extensive molecular-level knowledge of signaling mechanisms raised expectation that such defects can be corrected with a therapeutic intervention using either receptor-specific antibodies or low-molecular weight compounds interfering with activation of the signaling molecules. However, individual signaling pathways do not act in isolation, but rather interact with each other, forming complex signaling networks that respond to diverse, often contradictory, stimuli. Such cross-talk can involve components that are common between pathways, as well as positive and negative feedback loops [2]. Furthermore, response to a signal depends on the activation threshold and signal duration [6] adding yet another level of complexity to the system. In consequence, a system level understanding of signaling networks is lagging behind the molecular-level knowledge of its constitutive components, which hinders a systematic approach to drug discovery.
The Epidermal Growth Factor (EGF) signaling pathway is one of the best understood receptor signaling pathways [7]. Members of the EGF receptor (EGFR) family have been shown to be overexpressed in several types of cancers and have been used as main targets for recently developed molecular therapies [8]. However, a significant fraction of cancers has been resistant to the current approach which is based on blocking individual growth factor receptors [9] suggesting that there may be crosstalk between EGF and other pro-survival pathways.
The interplay between the EGF pathway (and EGF plus Insulin) and its antagonist "pro-death" TNF signaling pathway has recently been a focus of a number of computational and experimental studies [10–17].
This work focuses on the signaling network formed by the interaction of three signaling pathways: Epidermal Growth Factor Receptor (EGFR), Insulin-like Growth Factor 1 Receptor (IGF-1R), and Insulin Receptor (IR). All three pathways are pro-survival and have been experimentally linked to cancer. Therefore, it is imperative for the development of successful targeted therapies aimed at these pathways that the crosstalk between them is well understood. In this work, we provide a combined computational and experimental analysis of this crosstalk.
The level of abstraction of a computational approach depends on the prior knowledge of the system and the type of experimental data [18]. We used a multi-level approach. First, we used a high level network model to discover basic properties of the network topology and to identify the nodes of the network that are most likely involved in the crosstalk. Next, we developed fuzzy Boolean network model to predict activities of nodes as functions of combinatorial stimulation of the EGF, IGF, and insulin receptors. That is we assume that each edge passes the signal with a certain probability. Consequently, rather than having binary active/inactive values, each node is active or not with a probability computed using a simulation protocol. In each step of the simulation, the probability of a node being active (i.e. activity level) is computed based on the activity values of its neighbors and the probabilities of transferring the signal along the corresponding edges. In general, different edges can have different probabilities (represented as edge weights); however, in this study we assign them equal values. Note that the method of signal propagation used in our approach is different from Petri net, which has been previously used to analyze signaling pathways [19]. Unlike Petri nets which require two types of nodes ("active" transitions and "passive" places), we use only one type of node. Each node computes the probability of activation using a Boolean function. In contrast, the transition nodes in Petri nets operate by passing units of information (the so called tokens).
The changes in activation of selected nodes following different levels of stimulation of these receptors were also measured experimentally. The experimental results were used to assess if the simple model was able to recover the general trends in the dependence between combinatorial stimulation and the level of activation and to further adjust the parameters of the network.
For this study, EGF, IGF, and insulin pathway information provided by STKE was combined into one signaling network. Our results indicate that, despite its simplicity, the model is able to predict several general patterns of the response and thus is expected to provide a good starting point for investigating signaling networks. To obtain a fully predictive model, a more accurate parameterization is necessary either by acquiring the precise knowledge of kinetic parameters of individual interactions or, given a sufficient number of experimental measurements, by training the model to fit the data.
Results and discussion
Network building and its static analysis
In order to analyze the crosstalk between the three signaling pathways we experimentally monitored the activity of selected signaling molecules as a function of different activity levels of the three receptors. Monitoring of the activity of all molecules in the network would be most informative but, unfortunately, this is not feasible with current technology. This necessitated the development of a method for selection of the most informative set of molecules. An analysis of the topological properties of a biological network provides a good first view of the network as a whole and helps to identify components that play a central role in signal propagation. In the context of biological networks, two such measures attracted particular attention: the degree of the node and the betweenness centrality [24–26]. The degree of a node is the number of edges adjacent to the node, which is the number of interacting partners. The betweenness centrality is the sum over all pairs of nodes of the fraction of the shortest paths that go through a given node. Unfortunately, none of the above measures are directed towards identifying molecules most likely to be affected by the crosstalk between two or more sub-networks, thus they cannot be used to prioritize selection of the molecules such that measuring their activity would be most informative for understanding the crosstalk. Therefore, in this work we introduce two new measurements: network crosstalk and path crosstalk.
The network crosstalk of a node is the difference in the degree of the node in the network containing all considered pathways and the maximum degree of this node in any one individual pathway. A high network crosstalk value implies that a node is a branching node connecting two or more pathways.
The nodes with high network crosstalk correspond to the nodes where the signals from the diverse corresponding starting points are merged together while the nodes with high path crosstalk correspond to signaling molecules that are branching points for several pathways. We observed that the nodes indentified by this method as important for intra-pathway communication correspond to molecules that are assumed to be major crosstalk players in these well studied pathways. Most of these molecules are indicated as important in tumor genesis as well as other pathological states. This suggests that this approach provides a reasonable way of prioritizing experimental measurements for studies of a crosstalk between pathways and shall be useful for studies of less understood pathways.
Computational analysis of networks response to differential receptors stimulation
To analyze the activity of the network in response to various levels of stimulation of the three receptors, we introduced a simple computational model. Similar to the standard representation of signaling pathways, the network is represented as a directed graph with two types of edges: activation edges and inhibition edges. However, the nodes as well as the edges have weights. This modification allows to replace the standard Boolean logic model [27] with fuzzy logic - a generalization of the standard Boolean logic that handles the concept of partial truth. Using such generalization is justified by the fact that the nodes in a signaling network typically represent assemblies of individual molecules each of which could be active or not. Consequently, each node is associated with a weight between 0 and 1 reflecting the level of activation of a given molecule (percentage of active molecules). In an iterative procedure (see Methods section) the activity of each node is updated based on the activities of its neighbors. In contrast to the node weights, the edge weights are not computed but included as a part of the input. The weight of an edge is a value between 0 and 1 representing the probability (efficiency) with which the signal is propagated along this edge. The necessity for modeling such signal loss was discovered by the comparison of the simulation results with edge weights set to one with the experimental results (data not shown). The trends observed for edge weights less than 1.0 had a much better agreement with the experimental results. Consequently, we used 0.8 as the default setting for all edge weights. In the next section we show the results for two different setting of weights. Obviously it is possible, and desirable if supported by a sufficient amount of experimental data, to assign different weights to different edges. However, to avoid any over-fitting in our simulation, we assigned non-default weights only to a small number of edges where such modification could be justified based on literature. We describe these modifications in the experimental validation section.
The results for the remaining molecules with non-zero network crosstalk are given in Additional file 1: Figure S1.
In computational simulation, all selected molecules showed dynamic dependency on the activation levels of at least two receptors. This was also true for all other molecules with non-zero network crosstalk (data not shown) as it would be expected based on the definition of network crosstalk. For Jnk, the dependence on EGFR activation is not very strong except near the point (0,0,0) while the activity of P70S6K is relatively stable for all three parameters (again, except near the point (0,0,0)). For Erk1/2 the strongest influence results from the variability in EGFR activation, while for Akt1 the variability in the activation of any of EGFR or IR has a similar effect which is also quite similar to the effect of IGF-1R.
As demonstrated in Figure 3, ERK1/2 activity was predicted not to depend on IR stimulation (Figure 3A), while EGFR activation was predicted to lead to activation of ERKs. The effect was even more pronounced when the cell was co-stimulated with IGF-1R. However, IGF-1R activation alone was predicted not to contribute to ERK1/2 activity as shown in Figure 3A.
Activation of the other MAPK family kinase JNK was predicted to depend strongly on all three receptors tested. According to simulation, the maximum activation level is observed after saturation of all receptors. EGFR was predicted to have the lowest impact. IR and IGF-1R applied alone at the same conditions activated JNK (Figure 3B).
Simulations of AKT kinase suggested that its activation depends on all tested receptors. Remarkably, efficient activation is achieved by stimulation and co-stimulation of IR and IGF-1R, while saturation of EGFR alone results in AKT activation at a lower extent. However, while activity of AKT increases rapidly with activation of either IGF-1R or EGFR and achieves levels close to the maximal, the saturation of both IGF-1R and EGFR seems necessary to maintain the highest AKT activation level. Under these conditions, IR seems to have the lowest impact (Figure 3C).
Our simulations also suggested a strong response of P70S6K to the activation of the three tested receptors. Even low activation of EGFR, IGF-1R and IR saturates p70S6K activity and further stimulation of receptors has a minimal effect of p70S6K activation (Figure 3D).
As discussed in the next section most (but not all) of these trends were confirmed experimentally.
Experimental validation
Four proteins with non-zero network crosstalk, Erk1/2, Akt1, P70S6K and Jnk, were selected for experimental validation of our simple model and to obtain a set of quantitative data to guide necessary adjustments of the model. All molecules are indicated as important in tumorigenesis as well as other pathological states e.g. diabetes. All of them are well studied and tools for measuring their activation are readily available.
For the experimental study we used SKOV3 cell line. Receptor expression analysis of SKOV3 cells confirmed expression of EGFR, IGF-1R, and IR (data not shown). In order to compare experimental results with our computational results, we next measured the saturation levels of receptors in response to incubation with EGF, IGF and Ins (Additional file 1: Table S1). We also measured the cross-stimulation of IGF-1R and IR by their ligands, so that the corresponding correction could be included into simulation (Additional file 1: Table S1). This set of experiments allowed us to translate ligand dosage into activation level. Five sets of experiments were performed step-wise increasing the receptors activation by 25%. Using Mesoscale Discovery platform plates we measured the response to activation of individual receptors (Additional file 2: Table S1) and their co-stimulation in combination with each other (Additional file 2: Table S3). The results were reported as the percentage of phosphorylation of each examined molecule.
Figure 4 shows all experimental measurements alongside with simulation results after the modifications for Akt1 and Erk1/2 as described above. The computational results are shown for two parameter setting of all remaining edges: (i) all edges not discussed above are set to 0.8, (ii) all activation edges set as in (i), while all inhibition edges set to 0.5. It is clear that, while the slopes of the regression lines are different in both setting of the parameters, the general trend remains the same. Table Additional file 1: Table S1 and Additional file 2: Table S3 provides full list the results of experimental and computational analysis for the first parameter setting.
However, a few discrepancies remained unresolved. For example, while in agreement with simulation results, experimental data showed weak increase in p70S6K activity after stimulation with EGF, no such simulation-predicted increase was obtained experimentally for Ins and IGF. It appears that, in SKOV3 cells, the p70S6K activation is affected only by EGF. Similar inconsistency is observed for Jnk. Interestingly, despite the fact that it is well established that Jnk kinase mainly responds to stress stimuli and inflammatory cytokines, there are reports pointing out induction of Jnk activity after stimulation with growth factors [32, 33]. Such trends are also predicted by our computational model. However, in our experiments, stimulation with different combination of growth factors did not cause increase in T183 and Y185 phosphorylation of Jnk (Additional file 2: Table S2). Again, it is possible that significant overexpression of HER2 causes perturbation in the Jnk activation pathway in a way that is not captured by our model. Additional studies are required in order to resolve these discrepancies.
It is now understood that traditionally defined singling pathways are not functioning in isolation but rather form whole signaling networks involving crosstalk between individual pathways. Can such crosstalk be studied in the absence of high throughput technology that would allow measuring reaction rates, association constants, and other parameters needed to faithfully model a signaling network? We addressed this question on two levels. First, given that we deal with low throughput, labor intensive technologies, we needed to have a measure that would prioritize experimental measurements. To achieve this goal, we developed two measures of involvement of a node in a crosstalk. These measures are based on static, topological properties of the network and are intuitive extensions of centrality measures used to asses essentiality of proteins in protein-protein interaction networks. Subsequently, we used so defined crosstalk measures to facilitate the selection of relevant molecules for computational and experimental evaluation.
The second question that we addressed in this work was whether a simple model that lacks specific data such as abovementioned reaction rates, association constants, etc. can predict activity of a network in response to various levels of stimuli. Consequently, we developed a simple model and tested it on the network constructed by combining EGF, IGF and insulin signaling pathways. Despite its simplicity, the model was in agreement with most experimentally observed trends. It proved to be a valuable tool in the initial investigation of the signaling network in SKOV3 cells. Specifically, the examination of the discrepancy between the expected and obtained results pointed to possible differences between signaling in the studied SKOV3 cells and the available canonical signaling pathways. We confirmed some of these discrepancies through a literature search and subsequently corrected the model.
Intuitively, one can see our model as a simple extension of the standard Boolean-network type of model by adding a stochastic component to it. This view is intuitive but it has not been, until now, confronted with reality. Interestingly, we found that a necessary element of the model is the assumption that the signal is not propagated with 100% efficiency. Without this assumption, the model was unable to correctly predict most of the trends.
Our study indicate, that while crude models, such as the one exercised in this paper, cannot substitute for more precise simulation, they can still provide valuable information on the response of signaling network to stimuli. As more experimental data is being gathered, the parameters of the models will be adjusted to fit the data. It is also possible (and quite likely) that our network is incomplete. However given more data points one can start to employ Bayesian methods to fill the missing edges and improve this aspect of the model.
Experimental procedures
Human ovary carcinoma, SKOV3, cells were cultured in McCoy medium supplemented with FBS to the final concentration of 10% at 37°C in 5% CO2. For every experiment, five 10 cm Petrie Dishes were plated with 2 × 106 cells each to obtain 90% of confluence fifteen hours later. Cells were then starved for 24 hours in McCoy with 0.5% FBS and subsequently stimulated with different combination of EGF, IGF and Ins for 15 min. After the 15-min stimulation the cells were immediately rinsed two times with ice-cold PBS and lysed in complete Mesoscale Discovery (MSD) lyses buffer containing complete mix of proteases and phosphatases inhibitors. After 20 min of incubation cells were sonicated in four 10-second intervals, followed by a cooling step. Finally, the cell lysates were centrifuged at 15000 G for 20 min, aliquoted in small volumes, flash frozen, and stored at -80°C for further analyses. Protein phosphorylation levels were measured using signaling MAPK and Akt1 panel phospho/total assay. EGFR saturation level was determined using EGFR activated/total duplex kit. Saturation of IR and IGF-1R was measured using Insulin signaling phospho/total assay. All assays were purchased from Mesoscale Discovery platform; Gaithersburg, MD and the measurements were carried out according to manufacturer protocols. Each measurement was performed in triplicates. Protein phosphorylation was calculated as the ratio of signal of "phosphorylated" form to it's "total" counterpart" multiplied by factor 100.
Computational procedures
For comparison with experiments we used averaged results of 100 iterations.
The simulation program is currently available on request and a version with enhanced functionality, graphical displays, and appropriate graphical user interface will be shortly publically available as a Cytoscape plugin [35].
This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine, National Cancer Institute, Center for Cancer Research and was funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contracts N01-CO-12400 and N01-CO-12401. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Authors' Affiliations
- Krebs EG, Beavo JA: Phosphorylation-dephosphorylation of enzymes. Annu Rev Biochem. 1979, 48: 923-59. 10.1146/annurev.bi.48.070179.004423View ArticlePubMedGoogle Scholar
- Hunter T: Signaling--2000 and beyond. Cell. 2000, 100 (1): 113-27. 10.1016/S0092-8674(00)81688-8View ArticlePubMedGoogle Scholar
- Pawson T, Nash P: Assembly of Cell Regulatory Systems Through Protein Interaction Domains. Science. 2003, 300 (5618): 445-452. 10.1126/science.1083653View ArticlePubMedGoogle Scholar
- Herskowitz I: MAP kinase pathways in yeast: for mating and more. Cell. 1995, 80 (2): 187-97. 10.1016/0092-8674(95)90402-6View ArticlePubMedGoogle Scholar
- Finkel T, Gutkind JS, : Signal Transduction and Human Disease. Edited by: Hoboken NJ. 2003, Wiley-Liss 488Google Scholar
- Marshall CJ: Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995, 80 (2): 179-85. 10.1016/0092-8674(95)90401-8View ArticlePubMedGoogle Scholar
- Carpenter G: The EGF receptor: a nexus for trafficking and signaling. Bioessays. 2000, 22 (8): 697-707. 10.1002/1521-1878(200008)22:8<697::AID-BIES3>3.0.CO;2-1View ArticlePubMedGoogle Scholar
- Mendelsohn J, Baselga J: Epidermal growth factor receptor targeting in cancer. Semin Oncol. 2006, 33 (4): 369-85. 10.1053/j.seminoncol.2006.04.003View ArticlePubMedGoogle Scholar
- Rubin BP, Duensing A: Mechanisms of resistance to small molecule kinase inhibition in the treatment of solid tumors. Lab Invest. 2006, 86 (10): 981-6. 10.1038/labinvest.3700466View ArticlePubMedGoogle Scholar
- Albeck JG, et al.: Collecting and organizing systematic sets of protein data. Nat Rev Mol Cell Biol. 2006, 7 (11): 803-12. 10.1038/nrm2042View ArticlePubMedGoogle Scholar
- Aldridge BB, et al.: Physicochemical modelling of cell signalling pathways. Nat Cell Biol. 2006, 8 (11): 1195-203. 10.1038/ncb1497View ArticlePubMedGoogle Scholar
- Janes KA, et al.: A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis. Science. 2005, 310 (5754): 1646-53. 10.1126/science.1116598View ArticlePubMedGoogle Scholar
- Janes KA, et al.: A high-throughput quantitative multiplex kinase assay for monitoring information flow in signaling networks: application to sepsis-apoptosis. Mol Cell Proteomics. 2003, 2 (7): 463-73.PubMedGoogle Scholar
- Janes KA, et al.: Cue-signal-response analysis of TNF-induced apoptosis by partial least squares regression of dynamic multivariate data. J Comput Biol. 2004, 11 (4): 544-61. 10.1089/cmb.2004.11.544View ArticlePubMedGoogle Scholar
- Janes KA, Lauffenburger DA: A biological approach to computational models of proteomic networks. Curr Opin Chem Biol. 2006, 10 (1): 73-80. 10.1016/j.cbpa.2005.12.016View ArticlePubMedGoogle Scholar
- Janes KA, et al.: The response of human epithelial cells to TNF involves an inducible autocrine cascade. Cell. 2006, 124 (6): 1225-39. 10.1016/j.cell.2006.01.041View ArticlePubMedGoogle Scholar
- Tasaki S, et al.: Modeling and estimation of dynamic EGFR pathway by data assimilation approach using time series proteomic data. Genome Inform. 2006, 17 (2): 226-38.PubMedGoogle Scholar
- Ideker T, Lauffenburger D: Building with a scaffold: emerging strategies for high- to low-level cellular modeling. Trends Biotechnol. 2003, 21 (6): 255-62. 10.1016/S0167-7799(03)00115-XView ArticlePubMedGoogle Scholar
- Hardy S, Robillard PN: Petri net-based method for the analysis of the dynamics of signal propagation in signaling pathways. Bioinformatics. 2008, 24 (2): 209-17. 10.1093/bioinformatics/btm560View ArticlePubMedGoogle Scholar
- Schlessinger J: Epidermal Growth Factor Receptor Pathway. (Connections Map in the Database of Cell Signaling, as seen 7 June 2008) Sci Signal.Google Scholar
- White MF: IInsulin Signaling Pathway. (Connections Map in the Database of Cell Signaling, as seen 7 June 2008) Sci Signal, Washington DC.Google Scholar
- Lefkowitz RJ, Shenoy SK: IGF-1 Receptor Signaling through beta-Arrestin. (Connections Map in the Database of Cell Signaling, as seen 7 June 2008) Sci Signal, Washington DC.Google Scholar
- Casa AJ, et al.: The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance. Front Biosci. 2008, 13: 3273-87. 10.2741/2925View ArticlePubMedGoogle Scholar
- Batada NN, Hurst LD, Tyers M: Evolutionary and physiological importance of hub proteins. PLoS Comput Biol. 2006, 2 (7): e88- 10.1371/journal.pcbi.0020088PubMed CentralView ArticlePubMedGoogle Scholar
- Jeong H, et al.: The large-scale organization of metabolic networks. Nature. 2000, 407 (6804): 651-4. 10.1038/35036627View ArticlePubMedGoogle Scholar
- Yu H, et al.: The importance of bottlenecks in protein networks: correlation with gene essentiality and expression dynamics. PLoS Comput Biol. 2007, 3 (4): e59- 10.1371/journal.pcbi.0030059PubMed CentralView ArticlePubMedGoogle Scholar
- Thomas R: Boolean formalization of genetic control circuits. J Theor Biol. 1973, 42 (3): 563-85. 10.1016/0022-5193(73)90247-6View ArticlePubMedGoogle Scholar
- Lu Y, et al.: Overexpression of ErbB2 receptor inhibits IGF-I-induced Shc-MAPK signaling pathway in breast cancer cells. Biochem Biophys Res Commun. 2004, 313 (3): 709-15. 10.1016/j.bbrc.2003.12.007View ArticlePubMedGoogle Scholar
- Lefkowitz RJ, Shenoy SK: IGF-1 Receptor Signaling through beta-Arrestin. Sci Signal, (Connections Map in the Database of Cell Signaling, as seen 7 June 2008), Washington DC.Google Scholar
- Girnita L, et al.: Beta-arrestin and Mdm2 mediate IGF-1 receptor-stimulated ERK activation and cell cycle progression. J Biol Chem. 2007, 282 (15): 11329-38. 10.1074/jbc.M611526200View ArticlePubMedGoogle Scholar
- Povsic TJ, Kohout TA, Lefkowitz RJ: Beta-arrestin1 mediates insulin-like growth factor 1 (IGF-1) activation of phosphatidylinositol 3-kinase (PI3K) and anti-apoptosis. J Biol Chem. 2003, 278 (51): 51334-9. 10.1074/jbc.M309968200View ArticlePubMedGoogle Scholar
- Hashimoto A, et al.: Shc regulates epidermal growth factor-induced activation of the JNK signaling pathway. J Biol Chem. 1999, 274 (29): 20139-43. 10.1074/jbc.274.29.20139View ArticlePubMedGoogle Scholar
- Zhang R, et al.: Network model of survival signaling in large granular lymphocyte leukemia. Proc Natl Acad Sci USA. 2008, 105 (42): 16308-13. 10.1073/pnas.0806447105PubMed CentralView ArticlePubMedGoogle Scholar
- Cormen TH, Leiserson CE, Rivest RL: Introduction to algorithms. MIT electrical engineering and computer science series. 1990, xvii: 1028-Cambridge, Mass. New York: MIT Press; McGraw-HillGoogle Scholar
- Shannon P, et al.: Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003, 13 (11): 2498-504. 10.1101/gr.1239303PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


text:
- This page attempts to bring together the various Peel shows that were intended to celebrate special dates in the calendar. The list is limited to programmes where the main preponderance of the music played is themed around that event, connected to it by name, or if a significant musical recording is contained within the show, with a brief summary of the content and links to the respective pages. The birthday and Christmas shows are covered in depth on separate pages.
Index Of Events Celebrated
Birthday (30 August)
See: Birthdays
Boxing Day (26 December)
- 26 December 1983: 'The Rhythm Pals' Boxing Day Bash', hosted by JP and Kid Jensen, 7.30 p.m.-midnight.
Burns Night (25 January)
- 23 January 2003: Burns Night Special, two days early, featuring Scottish songs sung by the Delgados, Belle And Sebastian, and ballboy.
- 22 January 2004: Camera Obscura live from Peel Acres in a Burns Supper special, three days early.
Christmas (25 December)
See: Christmas
New Year's Eve (31 December)
- 31 December 1985: Janice Long and John Peel's New Year's Eve Party, 7.30 p.m.-1 a.m.
- 31 December 1986: 'Janice and John's New Year's Eve Special'. Not listed in The Peel Sessions.
Valentine's Day (14 February)
- 14 February 2002: Appropriately, a session by the Loves live from Maida Vale, and many smoochy tunes.
- Peel made a kind of tradition by playing FSK's version of the Rodgers and Hart song 'My Funny Valentine' and dedicating it to Sheila. Occasions when he did so: 10 February 2000, 14 February 2002, 13 February 2003 and 12 February 2004.

subset: commoncrawl


text:
Hit! Apoorva 13th Day Box Office Collection Total Earning Report :- Apoorva is a 2016 Kannada movie produced and directed by Ravichandran. The movie stars Ravichandran and Apoorva. The movie stars V. Ravichandran and Mysore-based actress Apoorva. The movie will see Vijay Raghavendra and wife playing the role of Ravichandaran's son and daughter-in-law. Actor Sudeep has also done a special role in the movie. People who watching the movie giving good word of mouth and that's cool for the makers.
Apoorva Box Office Collection
Kannada movie Apoorva is doing so good business in India and the reason is movie has good direction with the good acting and that's awesome also I think in upcoming days more people going to attract towards the movie and that's awesome. I think movie can do good business in upcoming days and that's awesome.
Kannada movie Apoorva open up with the good occupancy and collected good bucks for the makers and that's good. People watched the movie in good numbers and still coming out to watch the movie and that's awesome.
13th day Box office collection of the movie-
Movie collected between 2.10 Crore from the first day and 1.80 Crore from the second day and movie collected between 6.20 Crore from the first weekend and that's awesome. Also movie collected between 15.20 Crore from the very first week of release and that's quite good.
I think in upcoming days this movie going to be the goo deal and that's quite interesting and I think in upcoming days this movie going to be the hit. Movie collected between 2.01 Crore from the second weekend and that's quite good. Also I am sure that the movie going to be the good deal in this week too.
Also movie going to collect more than budget from the very second week of release and that's quite good. Movie collected between 25.02 Crore from the second week and that's good.
Movie is good and people loving the chemistry and that's awesome. I think that's why the makers are so good and looking so excited towards the movie and that's awesome.


text:
Monday, February 11, 2013
My prints in PLAKATFABRIKKEN, Copenhagen
9 comments:
If your message is particularly complicated then it may be best to step away now and consider an alternative method of reaching your target audience.Visit our site today and see what we can do for your business.plakat design onlineReplyDelete
Before designing your poster, dine egne t-shirts,egne banner,egne flag,logo,USB stick,banner etc spend time planning ahead,You can get the best tips by visiting our website, Check out please:plakat design onlineReplyDelete
If you'd like to design your own t-shirts, Roller banners, your own logo, own banner, own flag, logo, USB stick, banner,Door etc.why not get started right away with the awesome design related website for getting the best Idea.visit us: design dine egne flag
Roller banners are banners that can be rolled up and down.Designing your Roller banners, your own logo, your own t-shirts, own banner, own flag, logo, USB stick, banner,Door etc,Visit our site today and see what we can do for your Idea's. Check out please: plakat design online
If you want to learn more about how to design your own logo. Learn how to design the best and most effective for your own business Visit our site today and see what we can do for your business.Design dine egne plakatterReplyDelete
For more information on design your own t-shirts, own banner, own flag, logo, USB stick, banner etc, visit www.targethouse.dk.
Here you will find more articles and tips on marketing items as well as a design dine egne t-shirts,egne banner,egne flag,logo,USB stick etc form where you can conveniently
submit your request in one form and get responses from multiple suppliers so that you can find the best price and product for your marketing needs.
Learn how to design your own business logo at: design dine egne flag
Choose a supplier who can deliver a high quality service as this can make or break a campaign.
Ideally the supplier should have detailed knowledge of the USB market, relevant experience and a good reputation. Visit our site today and see what we can do for your business.design dine egne
There are many great ways on how to design your t-shirt,logo,banner, flag,door,windows etc in online.
Some of the instructions are complicated; some are easy and friendly. Just a few clicks in below iinks, you can ge the best idea for your own design.
Here are great ways to design your own Want without sweat and less effort. Check out please:
design dine egne flag
- AnonymousMay 16, 2016 at 12:05 AM
Having a meal three times a day is one of the basic necessities of life. As time in our lives is becoming more and more crucial, small habits like eating and having a proper meal have become a lifestyle decision.ReplyDelete
design dine egne t-shirts


text:
Winzol Info Solutions is a software house that provides excellent and innovative software solutions to the fast growing Information Technology understanding the fast developing Industry Arena. We are full-fledged in developing application software with most modern technologies like ASP.NET, VB.NET, C#, Java, PHP, MS-SQL Server etc. We can integrate with workflow solutions and custom applications as per the requirement of our clients. We use the best and advanced tools and technologies to develop highly advanced and user friendly software products. Winzol Team provides innovative solutions to your existing or new business ambitions to the market flow of the business world.
Our websites are the results of our experience and knowledge. We are specialized in delivering comprehensive, unique and any complex solutions to our valuable customers. You will love our fresh, intuitive designs that cater all the requirements of your organization. We combine our creativity and knowledge with cutting edge designs to make your Web Applications a perfect means of communication to your users. We also provide different e-commerce and e-business applications like Shopping Cart Solutions, Real Estate Portals and Online Trading Portals respectively. Our services include Online Marketing, Search Engine Optimization, Email Marketing, Website Analytics and Website Maintenance etc.
Think about how your website interacts with the users? Does it have the same look and feel on all mobile device platforms? If not, it's the time to re-design your website. Responsive Websites will create a tidal wave in the web industry for the coming decades. The design allows the website to reformat itself depending on the device which it is being accessed on. Our professionals perfectly employ all the recent tools and techniques to make your site consistent across all platforms. We can increase customers for your business by our stunning responsive web solutions. Winzol Info Solutions will design responsive websites that look great on all mobile devices. Being committed, we provide the end result exactly what you expect.
The hot development of Technology made Mobile Application Development - an inevitable factor in this digital world. Nearly 50% of the Smartphone users use their handsets to download mobile apps. At the time, it becomes a necessity to create something different and valuable. By partnering with Winzol Info Solutions, you will get unique and creative mobile applications that satisfy all your objectives and maximize your functionalities. We blend our cutting edge functionality with fresh graphics to deliver stunning apps for your brands. Our team of experienced professionals will always focus to deliver innovative applications in time and always follow all latest updates and maintain highest levels of technical excellence to bring the smile of satisfaction. If you are looking for a Mobile Application Development company which is passionate about the app just like you, contact your pals in Winzol. We are here to support you for your technological requirements!
Winzol Info Solutions is the smart answer for your successful online presence. We successfully managed to help many of our clients to take their business to a higher level by rightly optimizing their websites. We drive clicks to your website with our ultra-modern innovative techniques. Our service will impact your business and give right results in a very faster way. The team comprises of efficient and knowledgeable people who are familiar with all SEO strategies from the evolution itself. Focusing on your vision and mission, we are confident that we can deliver perfect results for you. Trust us! We can make your site on the top of the major Search Engine's results. We keep our promises and so you don't have to worry about your money. Definitely, we can promote your products and services and can reach your goals within a short span of time.
To achieve success in this era, it's necessary to have an E-Commerce solution for your business. If you want to sell your products online, you must seriously think about the stunning features and advantages of making your E-business transactions through Internet. Today, the conventional shopping system has a very tough time as huge chunk of people depend on online shopping carts. At Winzol Info Solutions, we create customized solutions that tailored to the requirements of your business. With the attractive features, we shape your shopping website user friendly, attractive and unique that makes the shopping experience- an unforgettable one. Whatever your business is, whether it's large or small, we can help you to enhance your sale performance and customer satisfaction in a different way. Understanding your business strategy with our experience and right approach, we will convert all the users to buyers and sellers. We provide everything you expect to launch in an online cart and help you to achieve new heights.
Winzol Info Solutions is the pioneers in delivering excellent project services to students and professionals who wish to do their academic or IT projects under the guidelines and support of well experience IT professionals. Our well experienced and dedicated professionals in the IT industry provide exemplary training and tips to ourproject participants. Instead of internal education we also take care to encourage them to enhance their technical skills and experience. As we value your expenditure, we will do our level best to impart quality education. It's a great opportunity for all the students to get professional training that might lead to new career options. No doubt that you will achieve great success in your professional field.


text:
Let me guess, you have been playing The Denver Post crossword and got stuck on the clue ___ Four (the Beatles). Well, you have come to the right place to find the answer to this clue.
While some crosswords are much simpler than others, most require that players have a vast knowledge of the language and possibly even various topics. So while crossword puzzles are seen as a more intelligent game, they can be very frustrating for players to complete and even experienced crossword players need some help occasionally.
When finding the answers to the clues becomes too difficult, there's no shame in looking for them online.
Now you have the answer to your clue. Its time to move on to the next clue. You can browse through the list with all the answers to the The Denver Post crossword of September 6th, 2018. Or you can use the search form below to find the answer (no matter if its The Denver Post Crossword or any other crossword).
|The Denver Post crossword of September 6th, 2018 other clues
|Dinette set item
|Osso buco need
|"Roots" author Haley
|Octopus's octet
|Town on the Thames
|Off one's rocker
|Spritzer ingredient
|Major effect
|Cools one's heels
|Persona non grata, to a striker
|Telecast signal component
|Ready for strumming
|Hurricane Sandy recovery org.
|Lawn-Boy's parent
|Place to use Easy-Off
|Gives approval to
|Admit openly
|It's bid "arrivederci" in song
|3-Down portion
|Fighting tooth and nail
|Apple tablet
|Marx with a Tyrolean hat
|1976 KISS hit with orchestra backing
|Promise "kept" by 17-, 31-, 39- and 55-Across
|Send out
|Lightbulb measures
|Bubbly beverage
|Hardworking Aesopian character
|Be remorseful about
|Beyond repair
|Approach, as for a loan
|Gives a heads-up to
|Like a watch with hands
|Sign of summer
|Skirt style in "Austin Powers" movies
|Recreational sailor's auto attachment
|Hairpin turns, e.g.
|On a grand scale
|Brewery name on an MLB stadium
|Voter's enclosure
|Refuse to grant
|Abrupt turns
|Position in a hierarchy
|Jellyfish attack
|Like comedy that pushes the envelope
|Salt Lake City collegian
|Golden Rule word
|An Andean condor's may exceed 10 feet
|King Kong's kin
|Early automaker Ransom E.
|"Not so fast!"
|Checkroom item
|Comes within reach
|Sleeps under the stars
|What Elmer Fudd did to "wabbits"
|Pooh's feathered friend
|It may have sidewalk seating
|Baylor University city
|Two-toed or three-toed slowpoke
|Name on a rap sheet
|Having great courage
|Paparazzi's prizes
|Backyard barrier
|Guy pals, slangily
|Did some logging
|Leaves the stage
|"Gee, that's swell!"
|It's between batter's boxes
|Many big band instruments
|Intel-gathering mission
|It's verboten to vegans
|Fuji outflow
|O. Henry twist
|Stick with a pin, say
|Wind-up watch parts
|"Battling Bella" of 1970s politics
|Lion, Tiger or Bear
We offer support and help with a wide range of crosswords and are guaranteed to make sure you complete everything; the site is also updated regularly to make sure that all of our answers are correct and to add more crosswords to the ever growing list.__IMAGE__
If there is any problem with the answer, please contact us! We will fix the problem.


text:
- {{listing.bedroomsFormatted}} Beds |
- {{listing.bathroomsFormatted}} Baths |
- {{listing.bathroomsFormatted}} Cars |
- {{listing.category}}
James Paynter
James Paynter
Born and bred in Bayside, James was drawn to real estate by two things – a love of the homes in and around his Bayside suburb and the opportunity to channel his high-energy personality into a high-energy role. It was clearly the right step, with a career spanning more than two decades James has been an agent for all his working life … and is now a director and senior auctioneer of RT Edgar.
Never afraid to take centre-stage, James is renowned for his entertaining auctioneering style. Yet behind the easy banter and relaxed presence, an unflinching determination to draw yet one more bid has built his reputation. For James using goodwill and panache to encourage bidding is just the first step, his technique sharpens to a steely resolve as the auction draws to a close and, if necessary, around the negotiating table after bidding ceases.
Married to Jane and a father to three fast growing boys, Lachlan, Harry and Charlie, James is a serial renovator whose passion for local housing has seen the family move through a variety of styles from pretty Edwardian to cutting edge contemporary. A keen cyclist currently riding most mornings of the week with the Brown Cow Group and a participant in the Portsea and Lorne pier to pub swims, it seems his energy is boundless … and now with his boys set for Haileybury College James" energy is sure to be put to good use in local schools and sporting clubs for many years to come.


text:
By Sue Epstein and Ryan Hutchins/The Star-Ledger
NEW BRUNSWICK — Superior Court Judge Glenn Berman couldn't see how placing Dharun Ravi behind bars for a long term with murderers, robbers and rapists would serve the interest of justice.
"I can't find it within me to remand this gentlemen to a state prison no matter how I hold it unconscionable his conduct was," Berman said today in his New Brunswick courtroom. "I don't believe that fits this case. I believe he has to be punished. He will be."
The judge's comments came as the 20-year-old former Rutgers student appeared in court to say he is ready to go to jail. He is scheduled to surrender Thursday to begin a 30-day term at the Middlesex County jail.
During the hearing today, the judge defended the sentence he handed down last week to Ravi, who was convicted in March of spying on his former roommate, Tyler Clementi, during an intimate encounter, then joking about the 2010 incident in e-mails, text messages and Twitter posts. Clementi, 18, committed suicide several days after the spying incident. Ravi was never charged with causing Clementi's death.
Ravi faced up to 10 years in prison after being found guilty of bias intimidation, invasion of privacy and tampering charges. Berman, however, ordered the jail term, 300 hours of community service, three years of probation, counseling and about $10,000 in fines.
The Middlesex County Prosecutor's Office is appealing the sentence, and the judge said he wanted to "amplify" the reasons for his departure from sentencing guidelines.
Berman acknowledged there was criticism of the sentence, but said it was both consistent and fair, and he noted that there was a difference between bias and hate.
"I don't defend his actions toward Tyler Clementi what so ever. None. Nor does he," the judge said. "But I don't think it was motivated by hatred. And I'll stand on that."
Before Berman made his comments, he asked Middlesex County First Assistant Prosecutor Julia McClure what prison term she expected him to give Ravi.
"I thought the sentencing statutes mandated a 5-year sentence," McClure told Berman in an exchange that turned tense before the two apologized to each other.
Clementi's parents, who have attended every hearing in the case, were not in the courtroom today. Ravi's parents and supporters sat behind the Plainsboro man, who was dressed in a dark suit, pink tie and salmon-colored shirt.
Like he has time and again, the slender computer whiz remained silent throughout the 42-minute hearing except to answer yes or no questions about whether he understands the consequences of heading to jail before he is required to. His term had been stayed because of the appeal. But, Ravi said Tuesday, he wants to get it over with.
Download our
free NJ.com mobile and tablet apps
to keep up with the latest New Jersey news, sports and entertainment.
"It's the only way I can get on with my life," he wrote in a statement, also apologizing for the first time for his "thoughtless, insensitive, immature, stupid and childish choices."
Ravi is now scheduled to surrender Thursday to be processed into the jail in North Brunswick.With good behavior, he could be out in 20 days.
• Dharun Ravi appears in court to begin jail time for Rutgers webcam spying case
• Dharun Ravi: 'I apologize to everyone' affected by my choices
• Editorial: Dharun Ravi apology is overdue, but refreshing
• Dharun Ravi sentence: Middlesex County Prosecutor's office files appeal notice


text:
X-Men Days of Future Past highlighted a disturbing idea: the US Government deploying Drones (Sentinels) to kill US citizens solely on their racial status (Homo Superior, opposed to Homo Sapiens). There would be no crime, no arrest based on probable cause, no right to counsel, or even a trial. Simply killed for their racial status.
Would that be Constitutional?
No, for multiple reasons.
As a preliminary matter, a Court would find a "mutant" is a "person" and a US Citizen under the law. Determining that a Homo Superior is a human being is not as controversial as claiming Orca Whales have their 13th Amendment rights violated at Sea World (an argument that lost in Tilikum v. Sea World Parks & Entm't, Inc., 842 F. Supp. 2d 1259, 1262-1264 (S.D. Cal. 2012).).
A Homo Superior is born like Homo Sapiens, often from other Homo Sapiens. Whether you believe life begins at conception or viability, there is no question that human beings are conceived and born of other humans. Moreover, Homo Sapiens and Homo Superiors can have children together. Human beings cannot cross-bred with other animals (Thank God).
The Constitution would not tolerate human rights being striped of those born of other human beings. Moreover, the very idea someone's child is "not human" because they are Homo Superior has the moral weight of determining humanity by eye color.
There are many historical examples of countries enacting raced-based legislation, imposing nightmarish laws in the past. In the United States, one only needed to have 1/32 African heritage to qualify as a "slave." Courts even took the view that there was a "presumption of law…that a person of African descent is a slave, but that the presumption may be repelled by any evidence tending to show he is free." Lee v. Tapscott, 2 Va. 276, 282 (Va. 1796). Further evidencing horrific legal abominations, Nazi Germany required someone to have 1/16 Jewish heritage to be a "Jew" for Hitler's genocidal war crimes.
Those are two examples from the eighteenth through twentieth centuries etched into my memory from college. The horror of state licensed inhumanity should never be forgotten.
There are far more good laws than bad. The Due Process Clause of the 5th Amendment states that "[N]or shall any person . . . be deprived of life, liberty, or property, without due process of law . . . " The 14th Amendment to the United States Constitution further states:
All persons born or naturalized in the United States, and subject to the jurisdiction thereof, are citizens of the United States and of the State wherein they reside. No State shall make or enforce any law which shall abridge the privileges or immunities of citizens of the United States; nor shall any State deprive any person of life, liberty, or property, without due process of law; nor deny to any person within its jurisdiction the equal protection of the laws.
A Court would be hard pressed to say a "mutant" is not a person under the law without resurrecting the ghosts of Dred Scott and Korematsu. A Judge who would uphold the use of Sentinels would simultaneously channel Chief Justice Taney in saying mutants were not "people" and Korematsu,except instead of interning mutants because of their racial status, to kill them without a trial, regardless whether any crime had been committed. Any such law would be convicting citizens for the crime of being a Homo Superior with an extra-judicial death sentence.
There is no way Congress could authorize the use of Sentinels without triggering "Strict Scrutiny," because it is a race-based law that calls for the execution of US citizens. While the Government could argue there is a compelling government interest in national defense, there is no way they could argue systematically killing citizens without a trial is in the government's interest. Secondly, there is no way any such law would be narrowly tailored, because the Sentinels would systematically kill any mutant. (See, Richmond v. J. A. Croson Co., 488 U.S. 469, 476 (U.S. 1989), for the strict scrutiny test). There would be multiple less restrictive means to carrying out the compelling government interest of national defense without mass murder.
The Constitution further requires the right to a trial and counsel. People in the United States cannot be randomly arrested for no reason, let alone roadside executions by a Drone. There is simply no way the use of Sentinels would be Constitutional because of the extreme denial of Due Process or Equal Protection for Homo Superior citizens.


text:
At the core of the conflict between Gene and Finny is Gene's desire to be more like Finny, or even to become him. Gene's jealousy of Finny corrupts their friendship and leads Gene to "jounce" Finny out of the tree. Some of Gene's jealous feelings toward Finny are casual, such as his desire for Finny's carefree charm. Others are more deeply rooted, so much so that even Gene doesn't understand their origin. For example, Gene finds himself unable to respond when Finny says Gene is his "best pal." A deep-seated sense of envy and rivalry prevents him from reciprocating Finny's pure feelings of friendship. Gene's jealousy of Finny only wanes after Finny's injury destroys the traits about Finny that Gene most envied.
Jealousy ThemeTracker
Jealousy Quotes in A Separate Peace
Unlock explanations and citation info for this and every other A Separate Peace quote.
Plus so much more...Get LitCharts A+


text:
Achillea millefolium 'Paprika' has dark green fern-like foliage and bright red flowers with yellow centers. The flowers are very long lasting and are wonderful for cutting and drying. Deadhead the flowers for re-bloom and cut back to the basil leaf after bloom has finished. 'Paprika' will spread by underground runners and is easily divided making it great for large areas. Yarrow needs good drainage and can take poor to moderate soils, but avoid clay and rich soils. Achillea millefolium 'Paprika' is deer and rabbit resistant, great for border or naturalizing an area. Attracts butterflies!Hardiness Zone: 3, 4, 5, 6, 7, 8, 9
Plant Use: Flowering Perennial
Exposure: Full Sun
Water Requirements: Low to Medium


text:
Do you have a picnic planned for July 4th or will you go see the fireworks? How about a parade? Today's fashion finds are timely and inspired by the upcoming July 4th holiday.
So where can you find these fun fashions for your dolls?
1. Molly's Tap Outfit from American Girl – definitely parade-worthy and now that Molly's retirement has been announced, you will want this in your collection. $32
2. Red White Chevron and Blue by closet4chloe on Etsy. $16
3. 4th of July Flag Tutu and Leotard by Etsy seller ItsSewSusan. $21
4. 4th of July "Betsy Ross" Colonial Style dress by Etsy seller SandRDesignWorks. $43
5. Ships Ahoy by 123MulberryStreet on Etsy (fits 18″ slim body dolls). $26
6. Red Country Star outfit by HarmonyClubDolls. $12.99
7. Red, White and Blue Summer Dress by Etsy seller closet4chloe. $15
8. Black Tank and Tiered Skirt from Liberty Jane. $22
What will your dolls wear for the July 4th festivities? Do you have a favorite outfit that we featured today?


text:
Product Description
Pooja Trendz Hair Accessories -Attractive Medium Size Lotus Style – Plastic-Mixed Color -Hair Clip/Hair Clutcher-3 Pcs.
Type: Lotus Style Medium Size-Plastic-Mixed Colour -Hair Clutcher – Hair Claw suited for Girls/Women.
Total Length of the Hair Clip/Clutcher – Approx 5 Cms.
Width of the Clamp/Clutcher with out expansion of the Clip – Approx 2Cm.
Width of the Clamp/Clutcher with expansion of the Clip – 5Cm
Good Quality Plastic Clips,Designer and Trendy Hair accessories, perfect for all occasions. Ideal for Gift.
It can help you hold your hair conveniently when in hot days, comfortable for wearing.Avoid excessive sweating using the Ponytail holder to make you cool during the hot,humid climatic conditions.
Attractive Medium Size Hair Clip available in the Trendz Market.
Trendy,Tidy Look,Attractive Style,Comfortable and easy to wear. Perfect Match for every dress and every occasion.
These Hair Clutcher – Hair Claw Clip will keep hairstyle in place, and it will add a pop of cute colour to the look, our range of Hair Clutcher – Hair Claw will style your hair with simplicity.
Pack Contains 3 Pcs of Lotus Style-Plastic-Medium Size Mixed Color Hair Clip/Claw/Clutcher as Shown in photo.
Note – Product color may slightly vary due to photographic lighting sources or your monitor settings.


text:
I had a dream, and in the dream
I saw
The evils I had done to others;
How, even though unknowingly,
I'd sinned against my brothers
How Hurt my Dad and Mom would be
By rebellious, wicked words and such;
Neglectful times when they needed me,
And I didn't keep in touch.
And, though I've tried, I knew, that I'd
Caused them many tears,
By thoughtless words and actions
Over many bygone years.
I knew they loved me anyway,
But a gnawing guilt still in my heart did lay.
And then, the Lord cam on the scene--a loving gentle face--
"Peace," He said, You have my word of grace."
Though your sins are great,
They are forgiven,
Forgotten now,
By your Father in heaven.
A wondrous joy flowed over me
To think that Jesus can
Love one such as I--
A wicked, sinful man.
I began to think again,
Of evils done to me.
Words and actions so unkind,
Hurts and neglect,
And I could see,
If God forgives my sin so lovingly and graciously,
Then I can do the same,
To those who have hurt me.
Copyright, 1998, Louise P. Stenson


text:
Increasing First Page Placement Frequency
Search engines have come a very long way in recent years at indexing web pages in response to any possible search that a user enter. The web pages that a search engine, such as Google deems to be most relevant will appear on the first page of search results and the list continues like this, often in the millions, in the order that the search engine decides. As you may know from experience, few of us click past the first page often, so when your website does feature on the very first page, this is a big deal, and we call it first-page placement.
Often, small or medium-sized businesses feel as if they simply cannot compete with the global market leaders out there when it comes to vying for the top spot. While it is true that top companies hold a pretty secure top spot for their relevant keyword choices, this isn't to say that a small business cannot compete.
There are many different ways you can push your web pages up toward the top of the search engine list, you just need to seek innovative ways of competing, so here are a few great yet simple ways to improve your chances.
Think Local
Though you might completely have ignored it, one of the quickest and proven ways to fast track your way toward the top of the search engine results page and to achieve a greater number of first page placements is by being loud and proud about your local area and the areas where your business is based. Many people will search by their area instinctually, but even those that don't are now be guided by locality. You may not be able to compete with Wal-mart with your local foods store, but for "health food store in LA" you might well rank very well.
Find your niche
The first sure way of shortcutting your way to the first page of a search engine, even for the biggest and best companies is by making your business a specialist in its field. By targeting customers in a more particular way you'll be sure to snap up extra visitors who are searching for your niche. You can play around and experiment with this in a variety of ways, especially if you offer a variety of different products or services. For example, if your business is a retailer of sinks then be sure to give special attention to every different type of character and era that you stock. Few will type something as vague or general as "sink" into their browser, far more likely they will enter something more specific along the lines of "classic sink" or "contemporary granite sink" so try to focus more specifically on things like that, you'll appear more relevant to your customer as well as to the search engine.
There are innumerable ways that an expert SEO service can help to push your site higher up in the page rankings, but the most important thing is to deliver high-quality content. Regardless of how a user found their way onto your website, once they're inside you want them to stay, and to return in the future. Oh, and, if possible, to recommend you to their friends too!
No Comments
No comments yet.
RSS feed for comments on this post. TrackBack URI
Leave a comment
You must be logged in to post a comment.


text:
By Sovadhanak Hun
|Samnang, his mother and Commune Focal Point La Phay (in pink)
at the health centre
© UNICEF Cambodia/2015/Hun Sovadhanak
On a dry, hot Tuesday morning in the village of Damnak Sdey in western Battambang Province, 11-year-old Ien Samnang waits outside a health centre. He has come to receive treatment for sores on his legs resulting from a spinal cord injury. His mother and the commune focal point for women and children carry him inside. The mother and son have travelled more than five kilometres from their village for the appointment, which is being provided for free by their commune.
Samnang's parents moved to Battambang in 2001 to work the province's cassava fields, moving from place to place, sometimes even across the border to Thailand. They were barely able to get by.
They continued to live this way after Samnang's birth in 2004. When Samnang was 5 years old, his parents found work for a year in Thailand, enabling them to come back with enough money to buy a small plot of land. Samnang was finally able to enrol in school and began Grade 1 at age 6 in 2010. But due to the migratory nature of his parents' work, he eventually dropped out. Then in 2013, near tragedy struck: Samnang fell from a high building while his parents were working and injured his spine. The boy was referred to a local hospital and then sent to Siem Reap for treatment supported by a local NGO, where an iron rod was attached to his spinal cord to aid recovery.
The rod was removed last April, and luckily Samnang's spinal cord is fine. But he remains weak and must walk slowly in order not to fall. To help, the commune is working with UNICEF partner NGO the Association of Persons Living with Spinal Cord Injuries to follow up on the boy's health; the local health centre is also providing free services.
UNICEF's Seth Koma programme has been supporting Bour commune, where Samnang lives, since 2011, focusing on improving community preschools and the Commune Committee for Women and Children, a consultative committee that ensures women's and children's needs are reflected in local governance. Special attention has been paid to vulnerable children like Samnang.
There are eight villages scattered across the commune, which is about 80 kilometers from the provincial capital. As a newly deforested area, the commune has fertile soil that is good for growing cassava and attracts many Cambodians in search of work. These new residents tend to be among Cambodia's poorest and, as migrant workers, face a host of challenges: children not consistently attending school; inadequate levels of vaccination; poor maternal health and child care; improper water and sanitation; and low levels of birth registration, to name a few.
Under UNICEF guidance and with the assistance of local NGOs, the commune has been delivering essential social services to its most-at-risk community members, especially women and children. Activities include supporting women during delivery at health facilities, equipping community preschools with essential instructional materials, providing water filters for clean drinking water and supplying rice. Over 200 families have been helped. With provincial and district government staff, UNICEF has also been working with the Commune Council to build understanding of the importance of social services and how to implement them.
Samnang's family was identified as vulnerable during social service mapping of Bour. In response, the commune supplied the family with food twice this year, along with a bicycle, books and a uniform so Samnang can go to school. With help from the Commune Committee for Women and Children, the boy enrolled in Grade 2 for the 2015/2016 school year. This vital assistance has not only helped his health, but also brought him back to school.
The parents are overwhelmed with the assistance they have received. "The commune has built a safe community for children with disabilities like my son," Samnang's mother says. "Everybody cares about him and I observed no discrimination at all against him".
|Samnang with his new bicycle, school uniform and
© UNICEF Cambodia/2015/Hun Sovadhanak
Villagers are encouraging of Samnang, teachers enthusiastically welcome him to school and the health centre staff give him close attention and care. The parents will no longer migrate so that they have more time to take care of Samnang. They want to see him finish high school so that he can find a good job.
"When I grow up, I want to be a nurse. I want to care for other people's health," Samnang says with pride.


text:
After few months apple release Apple TV 5 with running tvOS 10.2 Updated version.
PanGu 3.0 jailbreak developers under working for jailbreak apple tv5 with TVos 10.2. Then you can Cydia Install for TVos 10.1, 10.2 and TVos 10.3. After jailbreak apple tv5 now available free applications on tvOS 10.2 cydia store. Once you Jailbreak iOS 10.2 To iOS 10.2.3 you're Apple TV 5, and you will be able to install the Kodi media player to it, which will open up a whole world of possibilities for you! Cydia Download for Apple TV 5 will really modify your life, making the whole thing more enjoyable. It is perhaps one of the most excellent tvOS 10.2 out there, better than those available on any other iOS 10.2 device, Apple TV5 jailbreak for the win!
Download PanGu 3.0 TVos 10.2 jailbreak Tool Here Windows Cydia Install
Download PanGu 3.0 TVos 10.2 jailbreak Tool Here Mac Cydia Install
- Restart the Apple TV5(Settings > General > Restart).
- Restart the Apple TV5 by removing ALL the cables for 30 seconds.
- Restart your router. (Also try removing it's power cord for at least 30 seconds)
- Reset the Apple TV5 (Settings > General > Reset > Reset all settings)
- Restore the Apple TV5 (Settings > General > Reset > Restore)
That is massive, except the news comes through an asterisk: the tvOS 10.2 jailbreak will just work with apple tv5 idevices running tvOS 10.2 otherwise 10.3. If you were updated to tvOS 10.1, 10.2 otherwise several of the innovative betas releases, there is no technique to downgrade back to 10.0 otherwise 10.0.1. Gratefully, there are motionless plenty of fourth generations Apple TV5 accessible in the untamed that come installed through one of the most important two versions of tvOS 10.1, 10.2, 10.
New Apple TV 2017 release date rumours UK
At what time will Apple developers release the next Apple TV 5th generation Apple TV, or Apple TV 5 – in the UK? In addition to what original features, tech specs, UK price with intend change should we expect from the novel 5G Apple TV for 2016 or 2017? The 4th gen Apple TV – the primary Apple TV5 device to agree to users to install applications – was unveiled through Apple developers at the iPhone 6s start on event on 9 September 2015, in addition to went on sale weeks afterward.
Almost a year later, we were looking ahead to the start on of the subsequently, fifth-gen (5G) Apple TV. Certainly, there are already rumors that a next-generation Apple TV5 might arrive in late 2017, even though Apple developers could also be waiting until next year to release a special model to rejoice the Apple TV's 10th anniversary and PanGu 3.0 jailbreak develoepra Waiting for release Cydia Install For Apple TV5 Runnong tvOS 10.1, 10.2 and tvOS 10.3.


text:
ASC Business Experts
Since 1986
ASD Management is one of the nation's oldest and largest privately held ASC management firms, providing personalized service led by our founding/managing partners. Since 1986, we have achieved success in hundreds of ASCs by focusing on what is most essential: managing business and operations, and generating continuous revenue from the market. Our proven practices, strategies and systems have been forged to meet the challenges of today's healthcare.
We partner with physician groups and hospital/physician investors to achieve immediate and long-term profitability. Our expertise in sales generates physician growth and investment. We engineer the turnaround of ASCs to optimize performance that lowers costs, increases revenue and attracts new investors.


text:
Norditech's engineering and technical team is dedicated to delivering the highest quality environmental monitoring systems and services. Our strength as a company is commitment to understanding the specific needs of each client. We are committed to delivering tailored, innovative solutions and services that meet project budgets while satisfying operating licence conditions.
Backed by over 10 years of technical expertise, we offer a full range of air and water quality monitoring services to clients in the public and private sectors including mining, Local Government, transport , water, cement and glass manufacture, and energy generation.
As an Australian owned and operated company, we have an in-depth knowledge of the regulatory issues facing compliance managers in the public, private and industrial arenas. We rely on our expertise to offer clients sound advice on the most efficient ways to maintain regulatory compliance.
Our dedication to providing smart solutions that focus on long-term equipment reliability has earned us a loyal client base that spans the spectrum from small water utilities to major mining operations.
As a company, our strength resides in our ability and commitment to first understand each client's needs. We are committed to delivering tailored, innovative solutions and services that meet project budgets while satisfying operating licence conditions.
When you partner with Norditech, you will benefit from our:
At Norditech, our priority is to deliver the highest possible standards of environmental monitoring services for your long-term project success.
Learn more about our Products, Services, and areas of Expertise.
Contact us about your project by filling out the contact form on this page, or call us at (02) 9622 6327.


text: « 'Cause this ain't Wonderland »If they say life's a dream call this insomnia. Cause this ain't Wonderland it damn sure ain't Narnia. And once you cross the line you can't change your mind. Yeah I'm a monster but I'm no Frankenstein. And quite frankly I've been feeling insane in between my eyes. I really cant explain what I feel inside. If you knew what I was you would run and hide. Many have tried to go into the night cross over the line and come back alive. But that's the price we pay when we living on the other side.


text:
Important advances are being made to understand and predict hurricane activity. On the seasonal time scale, and to a first order, we know that a warm ocean fuels storm genesis, a calm atmosphere allows storms to intensify, and the position and strength of the subtropical high pressure region paves the tracks for storms that do form. The next generation of risk modelers should incorporate this science into their assessments.
We at the Hurricane Climate Institute at Florida State University (FSU) have made important contributions to this science. We have developed techniques for predicting seasonal hurricane activity (Elsner et al. 1998; 1999; Jagger et al. 2001; 2002), have quantified the statistical association between the North Atlantic oscillation (NAO) and hurricane activity (Elsner et al. 2001; Elsner 2003; Elsner and Jagger 2006), and have demonstrated the utility of Bayesian methods for handling incomplete and missing data (Elsner and Bossak 2001; Elsner et al. 2004; Elsner and Jagger 2004). Our approach is to build models from the available data.
Data models help us understand and predict relationships beyond that accessible with statistical descriptions because they provide a safeguard against cherry-picking the evidence. Data models help us unravel the nuances of climate on hurricanes. Standard meteorological procedures like filtering, trend lines, and empirical orthogonal functions are not up to this task. Data models provide us a context that is consistent with the nature of underlying climate processes, similar to the way the laws of physics provide a context for studying meteorology. In short, data modeling is a scientific way to understanding how the climate works given the available evidence. At issue for risk assessment is how extreme coastal hurricane activity is conditional on climate patterns.
The next big improvement in risk modeling will likely come with data models that assess regional hurricane activity using historical data and numerical prediction output. Indeed, we now successfully model hurricane counts (Elsner and Jagger 2006) and hurricane intensities (Jagger and Elsner 2006) in regions along the coastal United States. Moreover we demonstrate statistical skill in predicting the expected annual insured loss conditional on the state of the NAO and Atlantic ocean temperatures (Jagger et al. 2007).
With our help this science is incorporated in risk models from Accurate Environmental Forecasting (AEF). However, more work is needed to add spatial information and regional predictors. Global predictors include leading modes of variability such as the NAO as well as variables that track the El Nino. Regional predictors like sea temperatures in the Gulf of Mexico and the Caribbean Sea, surface air pressures over Bermuda, and rainfall/soil moisture indicators over eastern North America and western Europe should be considered.
As a consequence of incomplete data and the existence of alternative scientific theories (e.g., climate change versus natural variability), probabilistic risk assessment requires some degree of expert judgment. One approach is to use Bayesian statistics another is to use expert opinion in formal elicitation. Elicitation is practiced in analyzing earthquakes and other geological hazards. Although the physics of climate is better understood than certain geological processes, there remains a sufficient lack of understanding with regard to hurricane risk to cause divergence among researchers.
Formal methods are available for eliciting expert judgment. One method involves a panel of experts who debate and explain the merits of evidence and argument. This approach is based on the assumption that group judgments can improve the validity of forecasts. In any case, the procedures will provide information about the relative risk that is agreeable to the panel. This is done by Risk Management Solutions (RMS) resulting in updates to their hurricane risk assessments that reflects, to some degree, expert opinions about future hurricane activity.
To improve these efforts evidence models should be used to ensure that the experts give credible witness to the data. For example, it is inconsistent for an expert to believe that the most likely number of U.S. hurricanes over the next 5 years will be 10 while at the same time believing there is a 40% chance that the number will be less than 3. The data simply do not conform to this type of distribution.
Averaging expert opinion will not necessarily give a consistent estimate of the hurricane rate either and the method does not account for the uncertainty inherent in the numbers provided by the experts. Moreover, there is some agreement on increased hurricane activity over the basin as a whole for the next few years, but much less agreement on what that means for citizens living along the U.S. coast. This differential in uncertainty also needs to be quantified and incorporated.
As mentioned, a data model can help. One model is to assume that each of the N-year totals from the experts is Poisson with a parameter equal to rate times N. This generates separate estimates for each expert. Another model is to assume that the observed counts have a negative binomial distribution. More work is needed, but future risk models will certainly benefit by utilizing the latest hurricane climate science.
Disclosure: I acknowledge discussions with Thomas H. Jagger on this topic. My financial support comes from the U.S. National Science Foundation and the Risk Prediction Institute of the Bermuda Institute of Ocean Sciences. These opinions are mine and do not necessarily reflect those of the funding agencies. I worked previously under contract with AEF. Currently I have no financial interest in a risk modeling or insurance company.
Wednesday, January 10, 2007
Better risk models
Posted by James Elsner at 9:31 AM No comments:
Labels: climate, hurricanes, NAO, risk models
Thursday, January 04, 2007
Comparing hurricane return levels using historical and geological records
Hurricane return levels estimated using historical and geological information are quantitatively compared for Lake Shelby, Alabama. The minimum return level of overwash events recorded in sediment cores is estimated using a modern analogue (Hurricane Ivan of 2004) to be 54 m/s (105 kt) for a return period of 318 years based on 11 events over 3500 years. The expected return level of rare hurricanes in the observed records (1851-2005) at this location and for this return period is estimated using a parametric statistical model and a maximum likelihood procedure to be 73 m/s (141 kt) with a lower bound on the 95% confidence interval of 64 m/s (124 kt). Results are not significantly different if data are taken from the shorter 1880-2005 period. Thus the estimated sensitivity of Lake Shelby to overwash events is consistent with the historical record given the model. In fact, assuming the past is similar to the present the sensitivity of the site to overwash events as estimated from the model is likely more accurately set at 64 m/s. Read more.
Posted by James Elsner at 11:47 AM 6 comments:
Labels: climate, hurricanes, paleotempestology, return period
Subscribe to: Posts (Atom)


text:
Maranatha Ministries
God has the whole world in His hands.
He is shaping, and controlling the ultimate destiny of our world--recent political events, and even . . . the world economy. Have you ever heard of the mark of the beast (how about Antichrist, or "666")?
Ever wonder what significance all of this has in our day of digital communication, and the world wide web? If already familiar with Bible prophecy, what about the "midnight cry" of Matthew's gospel? Jesus said that half of the "virgins" in this prophecy (Matthew 25:1-10) will be truly left behind. What does this mean to the evangelical church, today?
When is the "rapture"??
What does this mean to the evangelical church, in America?? What "changes" may we expect, now that America is turning down a socialist road?
Hi, my name is Frank Chisholm, and I can understand your shock and surprise. Today, many are starting to re-examine the Bible. The shrug of the shoulder, and "maybe Christ will return, someday" response of many--may be too shallow for you, as you as it was for me, as I started to dig into these things, years ago. Like the noble-minded Bereans (Acts 17:11) you too, feel the need check the prophetic Scriptures for yourself.
Praise God! For, when first starting to see these things, several decades ago-- I would continually hope and pray that others would pick up on the urgency of these themes, which are so obvious in light of the Word (especially, as they continue to be fulfilled)!
So, go ahead, bookmark this page--so that after these matters continue to come to pass . . .
you will know where to return, for further explanation, and encouragement.
Yes, this is true--and Jesus is coming again!
Yet, where may we also find America in Bible prophecy
--from an evangelical perspective??
With the US as the last, remaining, super power upon earth, seeing ourselves in Bible prophecy causes our whole view of world events to start to "change" (one word of caution it's not all pretty. This is the Bible, after all)!
So, will all of human economy simply continue to go "poof" ( )?
Perhaps it would be better to consider first things first, and consider: What is it that really matters most in life?
Is it money?
Is it prestige? --A new car?
· When someone dies, will they live again?
· Why is the Bible so important?
· What on earth is "sin"??
· Why Jesus?
Having considered these questions, you may feel more comfortable to go on to others. It is my earnest desire that as you consider these issues for yourself, you will come to the same conclusion that millions of others have, and grab hold of the Deliverer sent down to earth, two millennia ago–to a little town in the same land where human history, as we know it, will soon end.
For when he returns . . . nothing else will matter.
And behold, I come quickly, and my reward is with me . . .
Revelation 22:12
Amen. Even come quickly, Lord Jesus.
Will we live again?
This is one of the very oldest questions penned in Holy Writ (by Job) and yet it appears near the center of the Book, allowing the Bible to be arranged in a manner that gives us a panorama of the human experience that starts at creation (in Genesis) and reaches to Malachi (the closing prophet of the Old Testament). That first Testament was sealed in blood, marked by sacrifices--not the least of which were those executed for personal atonement, when requesting that God pass over them in the coming judgment (Passover). The second (or new) Testament was sealed with the blood of Messiah: More on this later. Our present question is:
If a man die, shall he live again? (Job 14:14)
Will we? Will we live again? This question absolutely demands an answer. Some religions side step the issue by saying that we enter a new state of consciousness, or that we come back in some other form (like reincarnation). In such cases "life" after death denies the significance of who we are now. We are only transitional beings: evolving to ultimate fulfillment. It does make it easier to accept the presence of evil in the world, since a (supposedly) higher form of life will someday solve all of our problems--Yet this view of the universe which (perhaps unconsciously) sees all things evolving with God as an extension of man, is based upon human hopes, fears, and just plain pride--since even God is seen as just one step ahead of us. This is NOT the view of the Holy Bible.
The Bible, a historical book (verifiable by archeological research) is a record of God's dealing with humanity. Its account of creation was written by someone who communed personally with God in a supernatural, and observable, way while an entire nation that sat encamped at the base of a mountain (Mt. Sinai). Humans, the Bible tells us, were created in God's image. "Male and female created He them; and blessed them, and called their name Adam, in the day when they were create" (Gen. 5:2).
God is eternal, without beginning or end.
Man was created in God's image and designed to live forever.
While Humanism posits that matter is eternal, and that something (somehow) sprang from nothing in the past (by laws not now present within nature). Scripture states plainly, and up front that "the things which are seen are temporary, but the things which are not seen are eternal" (II Cor. 4:18). While no one has ever seen something made out of nothing, the Bible is a record of those who have seen God act supernaturally within our universe.
(Seen in the above context, it takes more faith to believe in evolution, than in God . . .).
When Job asks, therefore, if a man will live again, he is asking if a person may somehow regain his (or her) first condition, and live as God originally intended, when first created.
Why the Bible?
The Bible, although incredibly lofty--because its message transcends life and death--is nonetheless quite down to earth. For this reason it survives translation quite well and, as long as it is translated accurately, retains its power in any language.
This power is so direct as to be at once wonderful, and astounding (demanding obedience, in other words). When the God of the Bible declares a consequence of disobedience, that consequence is real and absolute.
"The wages of sin is death"
When volunteering to break the curse that fell upon us, the result was just as absolute:
"the gift of God is eternal life. . ." (Romans 6:23a)
Why Sin?
As stated above, God made man in his image, and after his likeness (Gen. 1:26). This being the case, and realizing that God never intended that we be as powerful as He is, nor as glorious (to out-shine Him -- Isa. 42:8) we are moved to ask ourselves, "How are we like God, exactly?"
We are most like God in our essential nature: God has mandated that we be moral creatures. In other words, although we may deny it, we can naturally distinguish right from wrong. Violating this essential nature will bring great anguish and sorrow. Animals may become crazed and wreak havoc: dogs, and wild cats, may become rabid. However, when humans go bad (really bad) they may threaten all that exists around them--even to the point of genocide. Man has the capacity to be very good . . . and very bad. This is because we are created in God's image. Validating this mandate brings great comfort and relief (even in the face of great tragedy)--violating it, can bring unspeakable horror.
The God of the Bible is holy. Remove the holiness and righteousness of God from the Bible and you have spiritualism at best (and witchcraft at worst). "Be ye holy for I am holy," the Lord demands (I Peter 1:16, Lev. 20:7). What is it to be holy?
To be holy is to be completely good. Further, being good requires more than mere innocence.
Consider two young ladies coming to your house to apply for a baby-sitting job. One is good, and the other innocent. Which do you hire?
Obviously, you hire the one who is good. To be good, one must be able to avoid (or resist) doing wrong. Within the moral sphere this is especially vital. It is not enough to be an innocent judge!
I didn't know (that it was a bribe)!
I didn't see!
No one told me!
No, a good jurist knows how to resist temptation, and how to correct the wrong, and evil. A person who is good cannot be neutral towards evil. We may not be able to correct it, directly, but it does displease us. Where evil exists, it offends the righteous.
This ability to be morally upright (good) however, is one of the most difficult attributes to achieve! How many moral decisions there are to be made within a single day! How many opportunities there are, to falter, and mess up!
In the mercy of God, His original plan included demanding only one act of obedience: refusing to eat from the tree of the knowledge of good and evil. Note the name of the tree, the tree of the knowledge of good and evil (Gen. 2:17 emphasis mine). So long as they obeyed God in this one demand, no other moral choices were necessary. They only had to "know" one thing: not to eat from that tree!
In God s economy, an arch-enemy (the Devil, or Adversary - I Peter 5:8) was allowed to present our original parents with a counter-proposal: to become like (independent) gods. You know the story: Adam and Eve took the bait, but without weighing the consequences of being like a god (Gen. 3:5)--having to make all of the moral decisions, for themselves--while being held accountable.
And failing the "God test" enforces . . . mortality.
for there is no difference:
For all have sinned, and come short of the glory of God
. . .
the wages of sin is death,
Romans 3:22b,23, 6:23a
Now, humankind, which was given dominion over this world (Gen. 1:26,27)--in a manner similar to God's dominion over the heavens and the rest of the universe--is blinded by sin: like a defective auto, with damaged brakes ravaging the Interstate (awaiting a recall). Now, instead of being a thing of beauty, beautifying the road we travel, humankind is broken on the inside; regularly ravaging what was once a Paradise (Isa. 24:5,6). Death is our recall.
it is appointed unto men once to die, but after this the judgment:
. . . .
For it is written, As I live, saith the Lord, every knee shall bow to me,
and every tongue shall confess to God.
So then every one of us shall give account of himself to God.
Heb. 9:27, Romans 14:11,12
Because God cannot lie, and His word (which brought the Universe into being) cannot be broken, we must all give account of ourselves before God, after we leave this present world. However, it may be possible that at the bar of justice, Another may take our place, and satisfy the righteous heart of God. This was the reason for the Old Testament pattern of offering an animal as a sacrificial substitute for human sin. However, because animals are not made in the image of God, such sacrifices were only symbolic, and not truly effective (before God, in eternity --Hebrews 10:1).
Why Jesus?
Now we come to the gospel (the really good news). God has made it possible, through the death of his only begotten Son, Jesus Christ--to be truly forgiven for our sins: even those we have inherited from Adam.
Such an accomplishment may only be completed by God, and although there are many ways to look at this question (the most extensive of which is found in the apostle Paul's letter to the Romans, in the New Testament)--An abbreviated view might look at the matter mathematically, in this way.
The Bible describes God as eternal and infinite, while man is finite and temporal. Infinity is a number without limit, or end. Infinity divided by a thousand still equals infinity. This number cannot be exhausted.
Now consider justice as an equation, or set of scales, where an offense on one side must be satisfied, or paid for in full, by an act on the other side of the scales. In other words, if a man steals a car, or takes merchandise from his neighbor, restitution might involve returning the stolen goods (with a surcharge. In the Scriptures, stealing something as valuable as a man´s ox required multiple reimbursement, "he shall restore five oxen for an ox, and four sheep for a sheep" (Ex. 22:1). Certainly, crime did not pay within such a society!)
- Moral sins, which violated the basic nature/dignity of our original humanity made in the image of God, were capital offenses.
He that smiteth a man, so that he die, shall be surely put to death.
. . . .
And he that smiteth his father, or his mother, shall be surely put to death.
And he that stealeth a man, and selleth him, or if he be found in his hand, he shall surely be put to death.
And he that curseth his father, or his mother, shall surely be put to death.
. . . .
whosoever lieth with a beast shall surely be put to death.
Ex. 21:12,15-17,19
And the man that committeth adultery with another man's wife, even he that committeth adultery with his neighbour's wife, the adulterer and the adulteress shall surely be put to death.
Lev. 20:10
And, of course, Jesus Christ stated that looking at a woman in the wrong way may accomplish the same moral trespass as the act itself (Matt. 5:28).
How can we escape?
The payment for sin is costly!
In years gone by, when we understood the basic value of human life, we might understand the practice of putting a dog to sleep for biting a man or a woman. If the same offence were committed to another mongrel, the animal might simply be slapped, and let go. Offensive actions directed towards a man or woman, however, warranted putting the animal to sleep. Why is this?
The dog had offended against one higher than himself. It paid for it with its life.
How do we pay back an offence against God?
He is infinite, and eternal. I am finite, and mortal. Justice served would require not only that I die once but do so again, and again, and again . . . . (this is essentially what Hell is).
In other words, it is not enough to simply have a perfect man pay for my sins. He must be equal to God, as well.
There is no one, in the entire Universe fitting this description except God Himself! (If you have trouble accepting the idea of the Trinity, please see the flyer provided here, or go to OneSecondcoming a more detailed explanation.
All of Christ's activity was foreshadowed in the Old Covenant (Old Testament). The sacrifice of God's only Son is certainly no exception. Do you remember the testing of Abraham when he was told to offer his son as a sacrifice (Genesis 22)? In that case Abraham told Isaac, "God will provide himself a lamb for a burnt offering:" (Gen. 22: 5). Yes, He did. God provided a ram in the thicket, for a temporary satisfaction of sin (vs. 13) but then offered His own Son for us all (John 3:16)!
For when we were yet without strength, in due time Christ died for the ungodly.
For scarcely for a righteous man will one die: yet peradventure for a good man some would even dare to die.
But God commendeth his love toward us, in that, while we were yet sinners, Christ died for us.
Romans 5:6-8
This is the BIG DEAL about Jesus Christ! He sealed the New Testament with His own blood. As the apostle Paul said to the church elders:
"Therefore take heed to yourselves and to all the flock, among which the Holy Spirit has made you overseers, to shepherd the church of God which He purchased with His own blood."
Acts 20:28 nkjv
He is the only One capable of paying the price for our sins. You say, "It's too simple to just believe in Jesus, and be saved! All those murderers and prostitutes, they can be saved in the same way!"
Yes, you are right. That's exactly what Jesus said--to the religious hypocrites of His day, while walking the earth. He noted that they will get into Heaven faster than the, so called, "righteous" people.
Do you know why? Because many are still taking the bait that the Devil offered to Adam and Eve. They still want to "be as gods" in their own right. They still want to have their own righteousness, instead of simply trusting God for it. You see, that's what Adam would have had to do, if he were to avoid the temptation: He'd have had to believe the Lord, over his own pride and self conceit, to refuse the devil's temptation.
For the same reason, today, many will still go to Hell--because they want to "have it their way" instead of the Lord's.
However, if you can humble yourself. If you can bring yourself to bow the knee to this wonderful God who not only loves you, but was willing to pay the price for your wayward heart, so that you may regain Paradise and eternal life with Him--beyond this present troubled world (and within it, through His precious Holy Spirit)--you may do so, right now. Please bow your head (or get on your knees) right now and ask Him into your heart.
Yes, sin is a serious matter--as serious as death itself. And God's solution is no less serious: the death of the Creator, Himself, the Lord Jesus Christ (John 1:1-3). How shall we escape, if we seek to bypass such an offer??!
"For God so loved the world that He gave His only begotten Son, that whoever believes in Him should not perish but have everlasting life.
"For God did not send His Son into the world to condemn the world, but that the world through Him might be saved.
"He who believes in Him is not condemned; but he who does not believe is condemned already, because he has not believed in the name of the only begotten Son of God."
John 3:16-18 nkj
The door of salvation is open today. Walk through it, and choose Life! Choose Jesus Christ!
Welcome | Reading : Room | Born Again? | Flyers | What's New? | email