text:
Microbit Halo Programmable Expansion Board Tutorial 1.4 Breathing light (download)
The data protocol of the programmable RGB lamp adopts the single-line return-to-zero code communication mode. After the power-on reset, the DIN terminal accepts the data transmitted from the controller. The first 24 bits of data sent by the first pixel are extracted, the data latch is sent to the inside of the pixel. And the remaining data is shaped and amplified by the internal shaping processing circuit, then the output is forwarded to the next cascaded pixel by the DO port.
If the programmable RGB lamp is fully lit, the battery is not enough voltage, it will affect the effect,such as color saturation of RGB lamp is reduced or microphone not work normally.
It is recommended to use the USB data cable to plug in the RGB LED Circular expansion board interface. As shown in the figure below.
2. Learning goals:
In this lesson we will learn how to realize that brightness of lights on the RGB LED Circular from large to small,small to large. And the light will change different color.
3. Programming method:
Online programming:
First,we need to connect the micro:bit to the computer by USB data cable, the computer will pop up a USB flash drive.Then, click on the URL in the USB flash drive: http://microbit.org/ to enter the edit process interface.
Offilne programming:
Open the offline programming software,download address of this software: http://www.microbitgo.com/code.
After creating a new project, you need to load the Neopixel library to program the programmable RGB lights. To load the library, click on 【Advanced】—【Extensions】 — click on 【Neopixel】, and you will see an extra column in the programming interface. As shown in the figure below.
General program diagram:
In this experiment we used an array. We put 7 colors into the array list, click "+" to add the contents of the array, and click"-" to indicate the deletion.
Click on the place shown below to select the color of the RGB lights.
Then, the contents of the array List are taken out one by one. And the effect of the breathing state is executed in the form of the variable color 2.
We need to use the statement shown below. The meaning of this statement is that the variable d is executed from 0 to 4, that is, the code inside is executed 4 times.
As shown in the following figure, it means that the brightness of the RGB lamp is increased from 0 to 100, which realizes the effect of slowly lighting.
As shown in the following figure, it means that the brightness of the RGB lamp is reduced from 100 to 00, which realizes the effect of slowly extinguishing.
4. Download program
We need to make sure that the micro:bit board is connected to the computer. Click the download in the lower left corner as shown below, and select the download path as micro:bit drive letter to download the program.
5. experimental phenomena
after the program is successfully downloaded, you can see that brightness of lights on the RGB LED Circular from large to small, small to large. and the light will change different color.
Microbit Halo Programmable Expansion Board Tutorial
- Last Tutorial>> Microbit Halo Programmable Expansion Board Tutorial 1.3 Light a color randomly
- Next Tutorial>> Microbit Halo Programmable Expansion Board Tutorial 1.5 Sound test


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Mortgage insurance is required with USDA mortgages, but they have the lowest rates. While an fha loan has a mortgage insurance premium of 0.85% of the loan amount. USDA loans have a much lower mip rate of 0.35%.
The APR reflects the mortgage interest rate plus other charges. There are many costs associated with taking out a mortgage. These include; The interest rate, Point(s), Fees, Other Charges. The interest rate is the cost you will pay each year to borrow the money, expressed as a percentage rate.
Average Credit Score For Home Loan Credit score basics explained – This score not only determines whether or not you can get a mortgage loan, car loan, line of credit, or a credit card but also the. account has been open then averages them to determine an average.
USDA Loan Rates and Loan Limits. One of the major appeals of a USDA home loan is how low the interest rate is compared to other zero-down mortgage options. The current average interest rate for a conventional home loan in the U.S. is around 4%. Under the usda rural development direct home loan program, the interest rate is 3.25%.

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WAFA Coach Klavs Rasmussen says their major priority is to maintain their premiership status insisting wining the Ghana premier league title is not their target.
The Sogakope- based club trail leaders Aduana Stars by just a point with a game in hand after 23 games played in the league.
Many have tipped the academy boys to make history this season by winning the Ghana premier league title.
But speaking after his sides 2-0 defeat against Ashgold on Sunday, Klavs Rasmussen says they are not bent on winning the league but to remain in the top flight at the end of the season.
"We are trying to stay in the league so i don't know where you heard this about us wanting to win the league " he told Starr Sports.
"No No No we are going to stay in the league with at 50 points that is our target and not to win the title"he added


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First woman to lead a top-tier U.S. Combat Command
15 February 2018
Gen. Lori Robinson, the U.S. Northern Commander, (pictured right) said in testimony before the Senate Armed Services Committee that North Korea's successful nuclear and missile tests over the past year "represents the most immediate threat to our homeland, and therefore remains NORTHCOM's highest priority." (US Air Force photo by Melanie Rodgers Cox/Released)
The U.S. Air Force general who is in charge of homeland defense told Congress Thursday she is "100 percent" certain she can defend the U.S. against a ballistic missile attack from North Korea.
"I want to assure this committee today that I am confident that I can defend the United States," said Gen. Lori Robinson, the U.S. Northern Commander, in testimony before the Senate Armed Services Committee.
Robinson says North Korea's successful nuclear and missile tests over the past year "represents the most immediate threat to our homeland, and therefore remains NORTHCOM's highest priority."
Robinson is one of the top commanders who would be in the loop to decide how to respond if a missile from North Korea appeared to be heading for the U.S.
While the U.S. interceptors based in Alaska are capable of shooting down a single North Korea missile, Robinson says the U.S. must continue to improve its missile shield as Kim Jong Un builds up his arsenal and could sometime in the future overwhelm the U.S. with multiple missiles or sophisticated decoys.
"He hasn't built up capacity yet," Robinson testified. "While I'm confident that we can defeat this threat today, it is critical that we continue to improve the ballistic missile defense enterprise, with emphasis on the development of improved sensor networks, combined with interceptor capability and capacity and reliability."
Questioned by Nebraska Republican Sen. Deb Fischer about a recent New York Times editorial that called U.S. missiles defenses "a dangerous illusion," Robinson doubled down on her assurance.
"I'm 100 percent confident in my ability to defend the United States of America," Robinson replied. "I think we continue to outpace everybody, and it gives me more and more confidence — continued confidence in our ability to defend the United States."
The Times editorial noted that last month, in a test of a new land-based version of the Navy's ship-based Aegis system, an SM-3 missile failed to intercept a target missile off the coast of Hawaii.
Pentagon officials say the test included some new technology, and while it did not shoot down a target, it provided valuable data as the system is refined.
"You know, one of the things that I say about Kim Jong Un all the time is that he's not afraid to fail in public," Robinson said. "You learn as much from failure as you do from success."
(taken from the Washington Examiner) http://www.washingtonexaminer.com/us-northern-commander-is-100-percent-certain-she-can-defend-america-from-north-korean-missiles/article/2649249


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Medulloblastoma (MB) can arise in the cerebellum due to genetic activation of the Sonic Hedgehog (Shh) signaling pathway. During normal cerebellum development, Shh spurs the proliferation of granule neuron precursors (GNP), the precursor cells of MB. Mutations in the Shh receptor gene patched1 (ptc1+/−) lead to increased MB incidence in humans and mice. MB tumorigenesis in mice heterozygous for ptc1+/− shows distinct steps of progression. Most ptc1+/− mice form clusters of preneoplastic cells on the surface of the mature cerebellum that actively transcribe Shh target genes. In ∼15% of mice, these preneoplastic cells will become fast-growing, lethal tumors. It was previously shown that the loss of function of insulin-like growth factor 2 (igf2) suppresses MB formation in ptc1+/− mice. We found that igf2 is not expressed in preneoplastic lesions but is induced as these lesions progress to more advanced MB tumors. Igf2 is not required for formation of preneoplastic lesions but is necessary for progression to advanced tumors. Exogenous Igf2 protein promoted proliferation of MB precursor cells (GNP) and a MB cell line, PZp53MED. Blocking igf2 signaling inhibited growth of PZp53MED cells, implicating igf2 as a potential clinical target. [Cancer Res 2008;68(21):8788–95]
- hedgehog
- igf2
- medulloblastoma
- patched
- math1
Mutations in the Sonic hedgehog (Shh) signaling pathway that cause constitutive Shh target gene transcription are associated with the formation of many human tumors. Medulloblastoma (MB), the most common malignant brain tumor in children, can arise when such mutations occur in developing cerebellar granule neuron precursors (GNP; ref. 1). Loss of function of the PATCHED1 (PTCH, ptc1 in mice) tumor suppressor gene, which occurs in sporadic and hereditary MB, is the most common of these mutations ( 2, 3). PTCH encodes a 12-transmembrane receptor (Ptc1) for Shh. In the absence of Shh signal, Ptc1 inhibits the downstream transducers of the Shh pathway, preventing activation of target gene transcription by Gli transcription factors. Shh activates target gene transcription by binding to and inhibiting Ptc1. Shh and Ptc1 are therefore antagonists. Ptc1 and gli1 are Shh target genes. Induction of ptc1 and gli1 by Shh creates a negative feedback loop (through Ptc1) that restrains ongoing Shh signaling and a positive feedback loop (through Gli1) that acts as an amplifier of the initial Shh signal. The balance between negatively acting Ptc1 and positively acting Gli proteins determines the functional state of Shh pathway activity ( 4– 7).
In the developing cerebellum, Shh signal produced by Purkinje neurons stimulates proliferation of GNPs in the external germinal layer (EGL) on the surface of the cerebellum ( 8– 10). Shh target genes, such as N-myc and cyclin-D1, become active and promote cell cycle entry ( 11– 13). In mice, expansion of GNPs ceases within 3 weeks after birth, as GNPs migrate to the internal granule cell layer and differentiate to form mature granule neurons ( Fig. 1A ). By the end of this period, the EGL has disappeared.
Mice heterozygous for ptc1 spontaneously form MB and rhabdomyosarcoma (RMS), a tumor derived from muscle ( 14, 15). These tumors exhibit constitutive Shh target gene expression due to reduced Ptc1 activity. Small molecule Shh pathway inhibitors can reduce tumor formation in ptc1+/− mouse models of MB ( 16, 17), demonstrating the dependence of MB cells on Shh target gene expression. Therefore, knowledge of critical Shh target genes or genes that cooperate with the Shh pathway to promote tumorigenesis has potential clinical importance as a step toward identifying drug targets.
Insulin-like growth factor 2 (igf2) is expressed at high levels compared with normal tissue in both MB and RMS in ptc1+/− mice ( 15) and in humans ( 18– 20, 22). Hahn and colleagues ( 21) showed that igf2 is critical for the formation of both MB and RMS in ptc1+/− mice. When ptc1+/− mice are crossed into an igf2-deficient background, they no longer form MB or RMS such as their igf2-wild-type littermates. Igf2 has also been shown to synergize with the Shh pathway to promote MB, as retroviral transfer of Shh and Igf2 expression constructs into postnatal cerebella causes a higher incidence of MB formation than delivery of a Shh expression construct alone ( 23). Igf2 protein can stimulate proliferation of cultured MB cell lines and their precursor cells, GNPs, suggesting a mechanistic basis for the role of igf2 in MB tumorigenesis ( 24).
Important questions remain about the involvement of igf2 in MB. The mechanism of increased igf2 expression in MB and RMS from ptc1+/− mice is not clear. Two independent analyses of igf2 expression from maternal and paternal alleles showed that increased igf2 levels do not result from loss of imprinting in MB or RMS or from gene amplification ( 21, 24). Rather, increased igf2 RNA levels seemed to be induced at a purely transcriptional level. Hahn and colleagues ( 21) proposed that igf2 might be a Shh target gene, overexpressed in ptc1+/− tumors due to constitutive Shh pathway target gene transcription. In support of this hypothesis, the authors showed that compared with ptc1+/+ embryonic day 8.5 embryos, igf2 transcript levels were higher in ptc1+/− embryos and highest in ptc1−/− embryos. C3H/10T1/2 cells transfected with the Shh pathway–activating transcription factor Gli1 have increased igf2 RNA levels after 72 hours ( 25). However, cultured GNPs treated with Shh do not have increased igf2 RNA levels at the 6-hours time point tested ( 24). Therefore, it remains unclear whether constitutive Shh pathway transcriptional activity causes the increased levels of igf2 transcript found in MB.
It is also not clear what role igf2 plays in MB tumorigenesis. Igf2 could contribute to tumor initiation, either as a critical Shh target gene or an independently regulated gene. Alternatively, igf2 could cooperate with the Shh pathway to cause tumor progression at a specific stage of tumorigenesis.
Here, we evaluate igf2 expression at multiple stages of MB tumorigenesis. We also test the requirement for igf2 during early and late stages of tumorigenesis. We show that igf2 is not required for tumor initiation but is required for progression to advanced MB lesions. Modulation of igf2 signaling can regulate proliferation of MB cells in vitro, suggesting that igf2 is important not just for tumor progression but also for tumor maintenance.
Materials and Methods
Mouse strains. Igf2 knockout mice were kindly provided by Dr. Argiris Efstratiadis (Columbia University, New York, NY). Because igf2 is an imprinted gene for which only the paternal gene is expressed, male mice heterozygous for igf2 were mated with ptc1+/− mice (108B2; ref. 14) with or without the Math1-gfp transgene. Math1-gfp mice were kindly provided by Dr. Jane Johnson (University of Texas Southwestern Medical Center, Dallas, TX). Offspring heterozygous for the igf2 knockout allele by PCR, using primers specific for wild-type and mutant igf2 alleles, were effectively igf2 null. Offspring homozygous for the wild-type igf2 allele were considered wild-type.
Math1-gfp ptc1+/− igf2− mice and igf2+ littermates were sacrificed at 3 wk to evaluate for early MB formation. Cerebella were visualized under a fluorescent dissecting microscope for development of green fluorescent protein (GFP)-positive lesions. Adult ptc1+/− igf2− and ptc1+/− igf2+ littermates were assessed for MB formation at 20 to 24 wk by visual inspection of cerebella and X-gal staining, as previously described ( 14).
Microarray analysis. Early and intermediate MB cells were isolated from cerebella of math1-gfp ptc1+/− mice at 3 to 6 wk or 10 to 20 wk, respectively. Tumors were identified by inspection of cerebella for GFP fluorescence. Tumors were dissected and GFP-expressing cells were isolated by fluorescence-activated cell sorting (FACS). Advanced MBs were isolated from symptomatic ptc1+/− mice and tumor cells were purified as previously described ( 10). RNA was isolated using Trizol reagent (Life Technologies). RNA was amplified using Riboamp kit (Arcturus). Probe was reverse transcribed in the presence of aminoallyl-dUTP (Sigma) and subsequently labeled with Cy3 or Cy5 dye (Amersham). Probe made from tumor cell RNA was hybridized to cDNA microarrays produced by the Stanford Microarray Facility. Cy3-labeled tumor cell probes were hybridized against Cy5-labeled probe made from RNA isolated from high-level GFP-expressing GNPs isolated by FACS from the outer EGL of math1-gfp mice. Igf2 transcript level values are displayed relative to outer EGL GNPs. Average values of five independent probes were determined, per experiment.
Quantitative real-time reverse transcription-PCR. Igf2 and gli1 transcript levels were measured by real-time PCR using RNA isolated with Trizol reagent (Life Technologies). Gene expression assays for mouse igf2, gli1, and pgk1 and gapdh were purchased from Applied Biosystems. Igf2 and gli1 transcript levels were normalized to gapdh transcript levels in tumor cell, fibroblast, and PZp53MED cell experiments and to pgk1 transcript levels in GNP cell experiments.
P7 GNPs were isolated and cultured with or without 3 μg/mL Shh for 48 h as previously described ( 10). PZp53MED cells, ptc1+/− fibroblasts, or ptc1+/+ fibroblasts were cultured to confluence in DMEM + 0.5% fetal bovine serum (FBS) in the presence or absence of 10 μmol/L cyclopamine. RNA from ptc1+/+ fibroblasts transfected with cytomegalovirus (CMV) promoter–driven GFP, Gli1, and Gli2 expression constructs was kindly provided by Dr. Anna Penn (Stanford University, Stanford, CA).
In situ hybridization studies. 35S-UTP–labeled probes were made by in vitro transcription, with T3 or T7 RNA polymerase, of linearized plasmids purchased from American Type Culture Collection. Probes were diluted to 5 × 106 cpm/mL final concentration in buffer containing Escherichia coli tRNA and DTT. Frozen tissue was embedded in ornithine carbamyl transferase and cut to 15-μm sections on glass slides. Sections were dried and fixed with 4% paraformaldehyde and dehydrated through ethanol. Before hybridization, sections were treated with Proteinase K, acetylated with acetic anhydride, and dehydrated through ethanol. Hybridization was performed at 60°C to 65°C overnight. Sections were RNase treated and washed with increasing stringencies of SSC with DTT. Slides were dehydrated, dipped in photographic emulsion, incubated for 4 to 14 d, developed, and counterstained with Cresyl violet.
Cell survival assays. P7 GNPs were cultured in Neurobasal medium (Life Technologies) with or without B27 supplement for 48 h. Igf2 protein (R&D systems) was added to a final concentration of 250 ng/mL. Cell titer was determined with CellTiter96 assay (Promega).
Cell proliferation assays. Proliferation of PZp53MED cells in the presence of anti-Igf1R (Anti-IR3; Calbiochem) blocking antibody was assayed by seeding cells at 1 to 2 × 103 cells per well of a 96-well plate in DMEM+0.5% FBS. Antibody or Igf2 protein was diluted in DMEM+0.5% FBS and added to cells 3 h after seeding. Cells were cultured for 48 h, and cell titer was determined by CellTiter96 assay.
For sIgf2R experiments, PZp53MED cells were seeded at 6 × 103 cells per well on coverslips in 24-well plates. The next day, cells were cotransfected in triplicate with 0.5 μg pEYFP-N3 and 1 μg of either pEFBOS-sIgf2R (kindly provided by Dr. Bass Hassan, University of Oxford, Oxford, United Kingdom) or, as a control, 1 μg of pECFP-N2. Twenty-four hours posttransfection, cells were switched to DMEM+0.5% FBS and cultured for an additional 36 h. BrdUrd was added for the final 6 h. Cells were fixed, permeabilized, blocked, and DNase treated as above. Cells were stained with rat anti-BrdUrd antibody (Abcam) at 1:50 dilution. The next day, anti-BrdUrd staining was detected with TRITC-conjugated anti-rat secondary antibody. Percentage of YFP-positive cells that were also BrdUrd positive was calculated for each sample.
Immunoblotting and immunoprecipitation. Cells were grown to confluence in 10-cm plates and then serum starved for 48 h in DMEM+0.5% FBS. Then, cells were treated with 1 μg/mL or 10 μg/mL anti-Igf1R antibody (Calbiochem) and/or 250 ng/mL Igf2 protein (R&D systems), as described above, for 30 min. Protein extracts were prepared in radioimmunoprecipitation assay buffer containing 50 mmol/L Tris, 1% NP40, 0.25% sodium deoxycholate, 150 mmol/L NaCl, 1 mmol/L EDTA, 1 mmol/L DTT, 1 mmol/L phenylmethylsulfonyl fluoride, protease inhibitors (Roche), and phosphatase inhibitors (Calbiochem). Protein samples (30 μg per sample) were resolved by SDS-PAGE, transferred onto polyvinylidene difluoride membranes (Bio-Rad), and then immunoblotted with the following antibodies: anti-Igf1Rβ (Santa Cruz Biotechnology), anti–phospho-Akt (ser473; Cell Signaling), anti-Akt (Cell Signaling), and anti–β-Tubulin (Covance). For determination of Igf1R phosphorylation, 200 μg protein extracts were incubated overnight at 4°C with anti-phosphotyrosine antibody (Upstate) bound to protein G beads (Invitrogen). The immunoprecipitates were washed extensively, eluted in SDS sample buffer, and subjected to Western blotting analysis using an anti-Igf1Rβ antibody (Santa Cruz Biotechnology).
Igf2 transcription increases at a late stage of MB tumorigenesis. To observe developing MBs, we crossed ptc1+/− mice with mice expressing GFP from a Math1 enhancer that is specifically expressed in immature GNPs ( 26). Math1 is a critical regulator of GNP development that is required for the formation of GNPs ( 27). Because Math1 expression is preserved throughout MB tumorigenesis ( 28, 29), tumor cells from multiple stages of MB progression could be readily detected and isolated by virtue of their GFP expression. RNA from these cells was analyzed using cDNA microarrays to identify changes in gene expression that occur at each stage of MB tumorigenesis. We collected three tumor cell populations for this analysis ( Fig. 1A): (a) preneoplastic "early" MB lesions that are present in >85% of 3-week-old mice, the majority of which regress by 6 weeks; (b) intermediate, asymptomatic MB lesions that are present in ∼15% of 10-week-old mice, the majority of which seem to progress to advanced MBs; and (c) advanced, symptomatic MB that occur in ∼15% of mice, with peak incidence at ages ∼20 weeks. For comparison, we used RNA from a purified population of GNPs, the precursor cells of MB, isolated from the EGL of normal postnatal day 7 (P7) cerebella.
We found that igf2 transcript levels are not significantly increased in early MB lesions relative to normal GNPs. Igf2 transcript levels are significantly increased only in intermediate MBs and are even higher in advanced MBs ( Fig. 1B). Only 20% of individually tested early MBs have significantly increased levels relative to normal GNPs, compared with 36% of intermediate and 100% of advanced MBs ( Fig. 1C). To confirm these microarray results, igf2 transcript levels from individual early, intermediate, and advanced MBs were measured by quantitative real-time PCR. Advanced MB samples showed a statistically significant increase (∼20- to 50-fold) in igf2 transcript levels ( Fig. 1D). Igf2 transcript levels were not statistically increased in any of the early or intermediate MBs tested. Increased igf2 transcription seems to be a late event in MB tumorigenesis and is correlated with the critical transition from early and intermediate to advanced MBs.
In situ hybridization of early and advanced MB with a probe specific for igf2 showed absent or low levels of igf2 transcript in early MB but very high levels of transcript in advanced MBs ( Fig. 2A and B ). These data are consistent with our microarray data, confirming that increased igf2 transcription is a late event in MB tumorigenesis. High levels of igf2 transcript were also detected in the meninges of normal cerebella and cerebella containing tumors ( Fig. 2A and B, arrows; Fig. 2C).
Igf2 transcription can be regulated by the Shh pathway. The temporal pattern of igf2 expression during MB tumorigenesis raises the question of how the induction of igf2 expression is regulated. The expression pattern of igf2 is different from what is expected and observed for most Shh target genes. Shh target genes such as ptc1 and gli1 are typically expressed at high levels in GNPs of the outer EGL, which proliferate in response to Shh produced by Purkinje neurons. In situ hybridization studies of developing P7 cerebella show high levels of igf2 transcript in the meninges and low levels in the EGL ( Fig. 2C). Conversely, gli1, a Shh target gene in all tissues, is absent from the meninges but abundantly transcribed in the outer EGL. We conclude that igf2 transcript is minimally produced in areas of Shh target gene transcription in the developing cerebellum.
To further investigate the relationship between Shh pathway activity and igf2 transcription, we examined the effect on igf2 transcript levels of activating or inhibiting the Shh pathway in cultured GNPs and MB cells. Shh-treatment of primary GNP cultures does not increase igf2 transcript levels after 6 hours ( 24). However, treatment of GNPs with Shh for 24 hours increased igf2 transcription relative to untreated controls ( Fig. 3A ). Similarly, treatment of PZp53MED cells, a MB cell line derived from a ptc1+/− p53−/− mouse MB, with the Shh pathway inhibitor, cyclopamine reduced igf2 transcript levels relative to untreated controls ( Fig. 3B). These results show that activation or inhibition of Shh target gene transcription can influence igf2 mRNA levels in cultured MB cells and their precursors.
Igf2 also behaves as a Shh-responsive gene in fibroblasts derived from ptc1+/+ or ptc1+/− embryos. When ptc1+/+ fibroblasts are transfected with Shh target gene–activating transcription factors gli1 or gli2, igf2 transcription is induced >1,500-fold ( Fig. 3C). Ptc1+/− embryos have reduced Ptc1 function and exhibit increased transcription of Shh target genes compared with ptc1+/+ embryos ( 14). Fibroblasts derived from ptc1+/− embryos have a 4-fold higher basal level of igf2 transcription than ptc1+/+ embryonic fibroblasts ( Fig. 3D). Cyclopamine treatment does not change igf2 transcript levels in ptc1+/+ fibroblasts but decreases igf2 transcript levels in ptc1+/− fibroblasts to levels similar to those seen in ptc1+/+ fibroblasts.
In summary, regulation of igf2 by the Shh pathway is complex. Although igf2 is a Shh-responsive gene in some cell types, it seems that igf2 is refractory to induction by Shh in the developing cerebellum and in early MBs that express other Shh target genes.
Igf2 is required for MB tumor progression but not tumor initiation. Hahn and colleagues ( 21) showed that igf2 is required for formation of advanced MBs in ptc1+/− mice, but which stage of tumorigenesis requires igf2 is unknown. Because igf2 transcription is induced during the transition between early and advanced MBs, we tested whether igf2 is required for early MB formation. The low level of igf2 expression in early MBs suggests that early MB formation would not require igf2 to be active within the pretumor cells. However, it is still possible that igf2 might play a role in early MB tumor initiation because paracrine Igf2 signal produced in the neighboring meninges could stimulate GNPs or MB cells during early tumorigenesis. In this way, early lesions might be dependent on igf2, despite their lack of igf2 expression. Late in tumorigenesis, when lesions become too large to subsist on meningeal Igf2 alone, Igf2 produced by the tumor cells themselves may supplement the meningeal source through autocrine signaling.
To distinguish between these possibilities, we crossed Math1-gfp ptc1+/− females with igf2+/− males and analyzed Math1-gfp ptc1+/− offspring that were igf2+/− or igf2+/+. Because igf2 is an imprinted gene, only the paternal allele is expressed, and igf2+/− offspring are effectively igf2 null. We analyzed igf2+/− and igf2+/+ mice for early MB lesions and for MB formation. Consistent with previously reported results ( 21), no advanced MBs were observed in igf2 null offspring, whereas advanced MBs formed as expected in their igf2 wild-type littermates ( Table 1 ). In contrast, formation of early MB lesions occurred even in the absence of igf2. All igf2 wild-type and null offspring developed clusters of preneoplastic cells by ages 3 weeks. These results suggest that igf2 plays a critical role exclusively in the progression to advanced MBs.
Inhibition of igf2 signaling reduces proliferation of MB cells. Igf2 could act at a specific point in the tumor progression decision or as an ongoing promoter of growth. We tested whether igf2 plays a role in maintaining the growth of fully developed MB cells. Proliferative and survival-promoting signals are important for maintaining tumor growth. It was shown previously that Igf2 protein can induce proliferation in GNPs ( 24). Similarly, we find that Igf2 increases the fraction of proliferating GNPs 3-fold ( Fig. 4A ). We also show that Igf2 promotes cell survival of cultured GNPs. If GNPs are cultured in minimal medium, the majority undergoes apoptosis. GNPs cultured in minimal medium with Igf2 alone show enhanced survival similar to GNPs grown in fully supplemented medium ( Fig. 4B).
We tested the effects of augmenting or inhibiting igf2 signaling on cell proliferation of the MB cell line, PZp53MED. Addition of exogenous Igf2 increased proliferation of MB cells in a dose-dependent manner ( Fig. 5A ).
Igf2 ligand acts through the Igf1 receptor (Igf1R), which also can serve as a receptor for Igf1 and Insulin. We used an Igf1R-blocking antibody to inhibit the autocrine activity of endogenously produced Igf2. PZp53MED cells derived from a MB have low basal levels of Igf1R phosphorylation and phosphorylation of Igf pathway target Akt ( Fig. 5B). Phosphorylation of Igf1R and Akt increased dramatically when treated with exogenous Igf2 protein. In contrast, only a minimal increase in phosphorylation was observed in Igf2-treated HELA cell controls. When cells were treated with anti-Igf1R antibody and Igf2, levels of Igf1R and Akt phosphorylation are reduced to levels equal to or below baseline. Treatment of PZp53MED cells with anti-Igf1R antibody can therefore block the effects of even superphysiologic levels of Igf2.
When PZp53MED cells or HELA cell controls were cultured in the presence of anti-Igf1R antibody, PZp53MED cells showed a ∼40% decrease in cell number relative to untreated PZp53MED cells after 48 hours ( Fig. 5C). There was no significant difference in cell number between treated and untreated HELA cells.
Blocking Igf1R can potentially also block the effects of Igf1 and Insulin. To more specifically block the effects of MB cell–produced Igf2, we used a soluble Igf2-Receptor (sIgf2R) construct that has been used previously to block the effects of Igf2 on cells or in vivo tissues ( 30, 31). When sIgf2R is expressed, it is secreted from the cell where it binds and sequesters the Igf2 ligand, blocking its effect. Because sIgf2R specifically binds Igf2, it does not interfere with the actions of insulin, Igf1, or Igf1R. When PZp53MED cells were transfected with sIgf2R, they showed a ∼60% reduction in proliferation, measured by BrdUrd incorporation, relative to CFP-transfected cells ( Fig. 5D). These results indicate that Igf2 is specifically required for MB cell proliferation. In summary, we observe that activation or inhibition of Igf2 signaling can promote or prevent MB cell growth, respectively.
The mechanism of igf2 induction in MB. Here, we present evidence that igf2 is a Shh-responsive gene in cultured GNPs, MB cells, and fibroblasts. It might seem that igf2 is expressed at high levels in MBs because these tumors have increased Shh target gene transcription. However, increased igf2 transcription is not seen until late stages of MB tumorigenesis, although constitutive Shh target gene transcription begins at early stages. Furthermore, increased igf2 transcription is not seen in developing GNPs of the outer EGL in vivo ( Fig. 2B), which respond to Shh signal and express Shh target genes ( 10). Previous studies have indicated that neither genomic imprinting nor gene amplification are the causes of increased igf2 expression ( 21, 24). Rather, increased igf2 transcription seems to be due purely to transcriptional regulation.
One explanation for why igf2 transcription might be induced by Shh in cultured GNPs but not in GNPs or early tumor cells in vivo is that the level of Shh pathway activation achieved in culture may be higher than in vivo. The concentration of Shh protein used in our cultured assays causes maximal activation of Shh target gene transcription ( 10). If igf2 transcription requires very high levels of Shh pathway activity, then perhaps this threshold activity is not achieved until late in tumorigenesis. Alternatively, the presence of some activating factor in the culture medium, or the absence of some inhibitory factor that is present in the intact developing cerebellum may account for the differences in the response of GNPs to Shh in vitro versus in vivo. For example, restrictive chromatin structure or the presence of repressive transcription factors in cells in vivo may not be reproduced when these cells are cultured in vitro.
Another explanation for the pattern of igf2 regulation could be that Shh target gene transcription alone cannot account for increased igf2 transcription in MB. Shh target gene transcription likely plays a role in increased igf2 transcription because igf2 transcript levels are decreased in cultured MB cells treated with the Shh pathway inhibitor cyclopamine, albeit only 2-fold. Another regulator may cooperate with the Shh pathway to induce igf2 transcription.
What might be responsible for the dramatic increase in igf2 transcription that occurs late in MB tumorigenesis? Increased igf2 expression due to altered transcriptional regulation in human tumors is a common finding, and perhaps such a mechanism cooperates with the Shh pathway to cause increased igf2 transcript levels in MB. Igf2 expression is induced by overexpression of the early growth response gene 1 protein in prostate cancer ( 32). Igf2 expression may be induced due to mutation of its flanking regulatory sequences. Changes in the 3′ untranslated region of igf2 are associated with 100- to 1,000-fold increases in igf2 transcript levels in colorectal cancer ( 33). Altered methylation of the igf2 promoter causes increased igf2 transcription in hepatoblastoma ( 34).
PTEN activity can modulate igf2 expression in hepatoma ( 35). Increased PTEN activity leads to decreased igf2 transcription, and decreased PTEN activity causes increased igf2 transcription. Because igf2 signaling antagonizes PTEN activity by activating PI3-K ( 36), increases in Igf2 production may induce progressively increased autotranscription in feed-forward fashion. This hypothesis could explain why Hartmann and colleagues ( 24) did not see induction of igf2 transcription in GNPs treated with Shh alone for 6 hours but did see low-level induction of igf2 transcription in GNPs treated with Shh and Igf2. Shh target gene transcription and Igf2 production, first from the meninges and later from tumor cells themselves, may cooperate to induce igf2 transcription during MB tumorigenesis. A better understanding of the mechanism of increased igf2 expression in MB could yield opportunities to reverse this induction and inhibit the oncogenic effects of Igf2.
Temporal requirement for igf2 in late tumorigenesis. Our results suggest that induction of igf2 transcription is a late event in MB tumorigenesis that occurs as the preneoplastic cells of early MBs acquire a malignant phenotype. The requirement for Igf2 activity arises in late tumorigenesis, as early MB lesion formation occurs in the absence of igf2. These data do not preclude that igf2 may contribute to early tumorigenesis, as high levels of igf2 transcription are observed in the overlying meninges. However, the indispensable role for igf2 in MB formation occurs only in the late malignant conversion of MB and not during tumor initiation. This hypothesis is consistent with the observation that activation of Igf2 signaling alone in the developing cerebellum by retroviral transfer of igf2 is not sufficient to initiate MB formation ( 23).
This temporal pattern suggests a cooperation of autocrine Igf2 and other Shh target genes in MB tumorigenesis. Recent data have supported a cooperative hypothesis for these pathways. If Shh and Igf2 are introduced into neural progenitors by retroviral delivery, the frequency of MB formation is 3-fold greater than with delivery of Shh alone ( 23). The Shh and Igf2 pathways converge to trigger the production of high levels of N-myc protein. The Shh pathway stimulates transcription of N-myc, whereas the Igf pathway leads to stabilization of N-myc protein through Akt-mediated effects on GSK-3β ( 12, 13, 37). Consistent with this hypothesis, retroviral delivery of stabilized N-myc along with Shh also causes a 3-fold increase in MB frequency compared with Shh alone ( 38).
Igf2 might also cooperate with the Shh pathway in MB tumorigenesis by activating cell survival pathways. We show that Igf2 can promote GNP survival under conditions that normally lead to apoptosis. Similarly, the Igf family members, insulin and Igf1, can promote survival in cultured GNPs, likely through activation of the proto-oncogene Akt ( 39).
Igf2 may cooperate with Shh to promote transcription of Shh target genes. Transcription of the Shh target genes, gli1 and cyclinD1, is significantly increased in GNPs cotreated with Shh and Igf2 compared with Shh alone ( 24). Igf2 could increase levels of Shh target transcripts, including, as proposed earlier, igf2 itself, to promote tumor formation.
A model for MB tumorigenesis. Based on our findings, we propose the following model of MB tumorigenesis. Normal GNPs in ptc1+/− mice accumulate one or more mutations that result in constitutive Shh target gene expression. The mutation could inactivate the remaining copy of ptc1, perhaps by methylation ( 16), or affect some other component. Cells with active Shh targets would proliferate and would resist cues to arrest and differentiate, leading to formation of early MBs. Most of these lesions resolve or remain as benign lesions that are noted in most asymptomatic adult ptc1+/− mice. In an ill-fated subset of these mice, the pre-MB cells would undergo additional changes, the most critical being those that cause increased transcription of igf2. Increased autocrine Igf2 production would allow persistence of these lesions and their conversion to a malignant phenotype. Such a further transformation would be consistent with the effects of Igf2 on cell survival and growth. These lesions then progress to form the advanced MB seen in ∼15% of ptc1+/− mice.
Given the apparent requirement of igf2 for progression to advanced MB, it is notable that when igf2 expression is analyzed in independent early MBs ( Fig. 1C), a significant increase in igf2 transcript is observed in ∼20% of lesions. This frequency is similar to the ∼15% of mice that form advanced MB, suggesting that those early MBs that have induced igf2 transcription comprise the subset of lesions that will progress to advanced MB. Failure to induce igf2 transcription would cause these lesions to regress or remain benign. In summary, Igf2 may be an important malignancy associated factor required for the progression to advanced MB, making it an attractive therapeutic target.
Igf2 as a therapeutic target in MB. Strategies for blocking Igf2 signaling for the treatment of human tumors, such as MB, might include inhibition of Igf1R with small molecule inhibitors or receptor-blocking antibodies. Blocking Igf1R offers the advantage of preventing signaling by both Igf1 and Igf2, which stimulate the same signaling cascades. Whether Igf1 contributes to ptc1+/− MB formation is unclear. Increased igf1 expression is noted sporadically in ptc1+/− MBs (data not shown) but at levels much lower than those of igf2. We do not observe substitution for Igf2 by Igf1 in igf2−deficient ptc1+/− mice.
Our work shows the promise of specific targeting of the Igf2 ligand. We used a soluble Igf2R to inhibit MB cell proliferation, which presumably worked by sequestering Igf2. Recently, this same protein, produced from a transgene, was shown to inhibit tumor formation in a mouse model of intestinal adenoma associated with high Igf2 levels ( 31). Neutralizing antibodies specific to Igf2 could also achieve this end. Finally, manipulation of Igf-binding proteins (IgfBP) could block signaling by Igf ligands. For instance, IgfBP-3 can bind to and regulate the mitogenic activities of Igfs and inhibit their antiapoptotic effects ( 40).
Our data show a critical role for Igf2 in the progression and continued growth of MB in ptc1+/− mice. In human MB, dysregulation of the Shh pathway, often through loss of PTCH, is associated with a specific desmoplastic MB histology. Compared with classic MB, desmoplastic MBs have a distinct gene expression profile that includes increased expression of igf2 and Shh target genes ( 41). It is possible that Igf2 could hold similar importance in this class of human MB and that Igf2-directed therapies could provide clinical benefit.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Grant support: National Cancer Institute grant #RO1 CA 088060. R.B. Corcoran and M.T. Barakat were supported by the Stanford Medical Scientist Training Program NIH training grant. T. Bachar Raveh was supported by a Damon Runyan postdoctoral fellowship. M.T. Barakat was also supported by a National Science Foundation graduate research fellowship. E.Y. Lee was supported by the NIH under Ruth L. Kirschstein National Research Service Award (5F32CA117775-03) from the National Cancer Institute. M.P. Scott is an investigator of the Howard Hughes Medical Institute.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank Drs. Argiris Efstratiadis and Jane Johnson for providing mouse strains, Dr. Susan McConnell for an in situ hybridization protocol, Dr. Bass Hassan for the sIgf2R plasmid, Dr. Anna Penn for RNA from Gli1- and Gli2-transfected fibroblasts, Natalia Snarskaya for assistance with microarray and reverse transcription-PCR experiments, and Hermie Manuel for assistance with mouse husbandry.
- Received June 10, 2008.
- Revision received July 24, 2008.
- Accepted August 21, 2008.
- ©2008 American Association for Cancer Research.


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Heterogeneous Beliefs and Quote Transparency in an Order-Driven Market
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This chapter investigates the interrelation between pre-trade quote transparency and stylised properties of order-driven markets populated by traders with heterogeneous beliefs. In a modified version of Chiarella et al. (2009) model we address the ability of the artificial stock market to replicate the empirical phenomena detected in financial markets. Our framework captures negative skewness of stock returns and volatility clustering once book depth is visible to traders. Further simulation analysis reveals that full quote transparency contributes to convergence in traders' actions, while exogenous partial transparency restriction may exacerbate long-range dependencies.
KeywordsAbnormal Return Limit Order Order Book Market Order Artificial Market
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Other external entities: We will share your personal information with the following categories of entities for the purposes of processing your application: the provider of our applicant tracking system and related services, recruitment/staging agencies, background check providers, testing services providers, pre-employment assessment providers, professional service providers, and marketing services providers (to assist us in our candidate recruiting). We enter into contracts with our service providers which ensure they are only permitted to process your personal information for specified purposes and, where required by law, in accordance with our instructions.
We will share your personal data with other parties, including government bodies, where required by law (for example, in relation to right to work and tax disclosures which we are required to make to local governments) or in response to orders or requests from court, regulators, government agencies, parties to a legal proceeding or public authorities.
If all or part of our business or assets are subject to sale, restructuring or refinancing, we may disclose your personal information to prospective buyers or financers, including during a due diligence assessment phase as well as on completion of that process.
If you have consented to us doing so, we also share your personal information with other Vista portfolio companies for the purpose of being considered for other job opportunities in the pooling system. These companies may be based in the US, the EEA, or elsewhere; please consult Vista's website for a full list of all Vista portfolio companies. You can withdraw your consent at any time by contacting us using the details set out below. Withdrawal of your consent will not impact your recruitment decision but will mean that you are unable to be considered for opportunities with other Vista companies. Where this requires us to transfer your personal information outside of the EEA or Australia, please see our section on cross-border transfers below.
Cross-border transfers
If we provide any personal information about you in a way that constitutes a cross-border transfer, we will take appropriate measures as required by law to ensure members of our group and/or our service providers provide an adequate level of protection for your personal information. These measures include entering into European Commission approved standard contractual arrangements with them or ensuring they have signed up to the EU-US Privacy Shield.
You have a right to request a copy of any data transfer agreement under which your personal data is transferred, or to otherwise have access to the safeguards which we use. Any data transfer agreement made available to you may be redacted for reasons of commercial sensitivity. Further details on the steps we take to protect your personal information in these cases are available from us upon request by contacting hr[at]logicmonitor.com.
By providing us with your personal information you acknowledge any such transfer, storage, and use.
How long do we retain your information?
LogicMonitor retains personal information following recruitment exercises to demonstrate, if required, that candidates have not been discriminated against on prohibited grounds and that recruitment exercises are conducted in a fair and transparent way. Personal information belonging to candidates that that ultimately are not employed by us will be retained for no longer than six (6) months from the later of:
- the point at which a rejection decision is made;
- the date at which recruitment decision is communicated to you; or
- the date of our last communication with you regarding your application/recruitment.
If we wish to retain your personal information in our talent network on the basis that a further role or opportunity may arise in the future which we may wish to consider you for, we will ask for your explicit consent to our retaining your personal data for this purpose and for a specified period of time (usually two years).
If you have raised a query, complaint or cause of action in relation to your recruitment process, we will retain your personal information (regardless of any applicable period as set out above) in order to resolve your query or complaint, and/or to establish, exercise and/or defend our legal rights.
What happens if you fail to provide personal information?
As set out above, the provision of most information during the recruitment process is mandatory for continued participation in the process. If you fail to provide information when requested, which is necessary for us to consider your application (such as evidence of qualifications or work history), we will not be able to process your application. For example, if we require references for the role and you fail to provide us with relevant details, we will not be able to take your application further.
Your rights in respect of your personal data?
Under certain circumstances and dependent on applicable law, you may have the right to request that we:
- provide you with a copy of any personal information which we hold about you;
- update any of your personal information which is out of date or incorrect or incomplete;
- delete any personal information which we hold about you if it is no longer necessary in relation to the purposes for which it was collected or processed (or, in some instances, where you have withdrawn your consent or objected to the processing);
- restrict the way that we process your personal information;
- (where our processing of your personal information is based on consent or on being necessary to take steps prior to entering into an employment contract) to obtain a portable copy of your personal information or to request that we provide such a copy to a third party;
- consider any valid objections which you have to our use of your personal information (where we are relying on our legitimate interests (or those of a third party) as the basis for the processing or that the processing is in the public interest);
- (in the limited circumstances where our processing is based on your having provided consent to the collection, processing, and transfer of your personal data for a specific purpose) to withdraw your consent for that specific processing at any time;
- provide a copy of any agreement under which your personal data is transferred outside of the EEA or Australia.
Please contact us by email to privacy[at]logicmonitor.com or by writing to LogicMonitor, 820 State St. Floor 5, Santa Barbara CA 93101 to exercise any of these rights. Alternately you may contact us by phone at +1 (805) 617-3884.
We will consider all such requests and provide our response within the time period stated by applicable law. Please note, however, that certain personal information may be exempt from such requests in certain circumstances, which may include if we need to keep processing your personal information for LogicMonitor's legitimate interests or to comply with a legal obligation. There will be certain circumstances where the right does not apply to you under law, and we will review this when we consider a request.
We may request you provide us with information necessary to confirm your identity and ensure your right to access the information (or to exercise any of your other rights). This is another appropriate security measure to ensure that personal information is not disclosed to any person who has no right to receive it.
We maintain a Data Protection Officer to oversee compliance with this privacy notice. If you have any questions or complaints about this privacy notice or how we handle your personal information, please contact the Data Protection Officer at privacy[at]logicmonitor.com.
You also have the right to make a complaint at any time to your local data protection authority, although we do ask that you try to resolve your issue with us first. In the UK, your local data protection authority is the Information Commissioner's Office (ICO) and in Australia it is the Office of the Australian Information Commissioner.
Review of this Notice
This Intl Applicant Notice was last updated in May 2020.
Any questions regarding this Intl Applicant Notice and our recruiting privacy practices should be sent by email to privacy[at]logicmonitor.com or by writing to LogicMonitor, 820 State St. Floor 5, Santa Barbara CA 93101. Alternately you may contact us by phone at +1 (805) 617-3884.


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We would like to present the hand painted recreation oil on canvas painting of the artwork mentioned in the title. This recreation was finished by Leonid Afremov himself with the help of his best studio artists to do pencil drawing and basic background. This painting comes signed by Leonid Afremov himself on the front and the back. Certificate of authenticity provided. This recreation is made almost identical to the original image that you see online. The only difference is patterns and minor details that give the recreation and original feel.
This piece was created with the same amount of soul and emotion just like the first original painting. This piece was created with oil paint on artistic canvas using unique Afremov technique of a palette knife. The artwork has texture, you can feel the strokes by touching the painting. By purchasing on this site, you are buying directly from Leonid Afremov®. We guarantee your satisfaction and the best customer experience.
This recreation comes in a limited stock. Once the stock has finished, it will disappear from sale on the site and will never be offered again.
To learn more about the concept of recreations please click here https://afremov.com/Recreation-what-is-it.html
To view trademark information please click here https://afremov.com/Trademark.html
about this painting:
When we grow up, at some point or another we have to leave a place where we have spent our childhood and start living independently. While it is one of the most interesting and beautiful periods in life of any person, it can also be quite challenging. Moreover, until you are able to buy yourself a place or house and make a family, you cannot really call just any place where you live home.
Family does not necessarily have to mean marriage. It can be a person that you are in love with, truly close friends that are always there for you or even a dog. Anyway, until you have, you will most likely always feel homesick and willingly come back to your parents' house to spend holidays and vacations.
However, when you finally do have some space that only belongs to you, you should think about what you can do to make it cozier. A nice pretty home is a place where we recharge and rest from the big world's troubles and stresses. So here are some tips on what you can do:
Leonid Afremov is one of the most famous contemporary artists nowadays. However, his original art is completely affordable even for young people.
So, look at this red vase on his new oil painting. It appears giant and majestic. Long yellow flowers in the background are a wonderful contrast to its deep bardic walls. You can also see an elegant goblet and an orange that complement the vase.
Afremov uses a palette knife to apply quick and gentle strokes on canvas. It helps him to smooth the texture of the objects and make them look more three dimensional.
This painting is pretty and bright, so it can be used to decorate any room. It will bring more light and movement in neutral designs or brighten up those that are too gloomy.
Just keep in mind that this artwork is pretty large. So, make sure that all the necessary measurements are done before you purchase it.
We accept payments via Paypal and major credit/debit cards. All transactionsare done through a secure connection which ensures absolute safety.We guarantee the inviolability of your private information. Your personal data is encrypted and not stored anywhere after the payment was completed. We will not share your information with any other third-party site nor company. With us, your personal information remains strictly confidential. After your payment is received, you will get a confirmation email.
To deliver you order, we use UPS and DHLshipping services for shipping around the world. We can send your painting to any location in the world, the only restriction onthe delivery process is Customs legislation of your country.
You will receive an email from the shipping manager with all the details about your purchase within 2 days after your payment.
Shipping is free for Artistic Canvas and Meusuem wrapped paintings to USA, Canada and Mexico.
Shipping is free internationally only for Artistic Canvas paintings.
If you wish to have a gallery wrapped painting to be shipped internationally, it costs $50 extra per every 3 paintings. You need to purchase the shipping separately from the order by this link.
If you shall have any questions or doubts about the delivery process, feel free to contact your delivery manager for more details.
Further information read in shipping policy.


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Luka Modric Wins UEFA's Men's Player Of The Year Award
Luka Modric of Real Madrid and Croatia on Thursday received the accolade of UEFA Player of the Year in Monaco after his Champions League exploits.
"My father always pushed me to fight for my dreams, I owe him a lot for everything," said Modric, whose silky midfield skills helped Real Madrid to a third straight European crown and then propelled Croatia to the World Cup final.
"It's an incredible moment for me, I feel really excited and proud of this great award," said the 32-year-old, who started out at Dinamo Zagreb and then had four years with Tottenham before Real Madrid prised him away six years ago.
Meanwhile, Wolfsburg's Pernille Harder won the women's player of the year award at the star-studded event held in the Grimaldi Forum, Monaco.
13-time European champions Real Madrid swept the individual positional prizes too, with the since-deposed Keylor Navas picking up goalkeeper of the year, captain Sergio Ramos named defender of the year and Modric, who received the overall prize from Uefa president Alexander Ceferin, unsurprisingly winning the midfielder award.
Best Goalkeeper – Keylor Navas
Best Defender – Sergio Ramos
Best Midfielder – Luka Modric
Best Forward – Cristiano Ronaldo pic.twitter.com/wEo4cDtRr2
— 360Nobs.com (@360Nobs) August 30, 2018


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Definitions for "Tool steel"
Hard steel, usually crucible steel, capable of being tempered so as to be suitable for tools.
This term covers a wide range of high-carbon and alloy steels used to make various types of tools. Tool steels are easy to machine before heat-treating but get very hard after that. Grinding and lapping are the only ways to machine tool steels after heat-treating. Common classifications of tool steels are A steels (air hardening) and O steels (oil hardening)
A generic term covering a whole range of both carbon and alloy steels commonly used to make tools. This therefore includes steels used to make cutting tools, press tools, dies, moulds for both plastics and die-casting, hand-tools, in fact any tool used to shape metals or other materials.


text: The call for physician leaders has grown louder with time, as systems face changing cost structures, services, and payment structures. The need for physicians to be engaged in these roles must be part of the discussion around evidence-based management. Delivering care in this new environment will call for skills that are generally not prioritized. Changing the paradigm will require focused and intentional effort… Read more »


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After Ivan Eicher lost his job, he and his wife, Delores, fell several months behind on their house payments. Facing foreclosure, they accepted an offer from a company that promised to help them keep the home where they�d lived for more than 20 years.
Without realizing what they were doing, the couple ended up surrendering ownership of their home.
�It was just a really nice song and dance,� Delores Eicher said.
The Eichers are among the thousands of people who fall each year for offers that promise to help them avoid foreclosure but that leave them with none of the equity they had built up in their property. Their situation matches one of the three common models of foreclosure fraud the National Consumer Law Center has described in a report on the growing problem.
Foreclosures nationwide soared 42 percent in 2006, to 1.26 million, according to RealtyTrac, an Irvine, Calif.-based company that tracks foreclosures. That creates opportunities for fraud, although the number of cases is difficult to determine because they are generally lumped in with other kinds of fraud in crime reports.
The Eichers thought they were taking out a $1,700 loan to help them pay their roughly $4,700 in back mortgage payments. They learned too late they had signed their house over to Mid-America Financial Investment Corp. and agreed to lease their home from Mid-America when they accepted that loan.
Although the couple no longer owned their home, the mortgage remained in their names, so they made their $554 payments on the loan through Mid-America, along with monthly fees of at least $100.
Elizabeth Renuart, a staff lawyer at the National Consumer Law Center who co-authored the report on foreclosure fraud, said such schemes are popular in areas of the country where home values have soared, but any homeowner who has been paying down a mortgage for many years will have significant equity and can become a target.
A second scheme described in the report involves consultants charging high fees to help homeowners out of trouble but never delivering the promised services. A third involves an agreement where a homeowner knowingly signs over their home and agrees to buy it back over time, but the terms of the agreement make it nearly impossible for the homeowner to succeed.
The Eichers became part of a lawsuit against Mid-America in 2001. They eventually won the title to their home back after the Nebraska Supreme Court ruled in 2005 Mid-America had defrauded them and 12 other homeowners in the Omaha area.
Scott Bloemer and Elaina Hollingshead, who run Mid-America, did not respond to The Associated Press� requests for comment. Bloemer and Hollingshead defended their business practices in court and argued the paperwork the Eichers and others signed spelled out what was involved in the deals. But the courts ruled Bloemer�s and Hollingshead�s testimony wasn�t credible.
Renuart said foreclosure rescue agreements can be difficult to decipher � even for a lawyer.
�It�s hard to make heads or tails of these agreements,� she said.
That�s one reason why at least eight states have adopted laws designed to help protect consumers from the questionable practices of some foreclosure consultants. The Nebraska Legislature is considering such legislation this year, based on a law Colorado passed last year.
Most such laws require the agreements to be spelled out in writing, and offer homeowners a chance to cancel the agreements within a few days of signing them.
For most of 2006, Colorado was the state with the highest residential foreclosure rate in the nation, according to RealtyTrac. Colorado had one new foreclosure filing for every 376 households in December.
The Eichers and a dozen other homeowners who sued said they never had a chance to read the Mid-America loan documents before signing them, because Bloemer and Hollingshead rushed them through the process.
One of the other people who successfully sued Mid-America, Steven Starman, said he realizes now he should have read the documents carefully instead of relying on oral explanations.
�I made decisions based on what I was told,� Starman said. �They tell you what you want to hear.�
Renuart and groups that track foreclosures worry many more Americans could fall victim to fraud because the adjustable-rate and interest-only mortgages taken out in recent years will likely contribute to a jump in foreclosures when loan payments increase.
RealtyTrac said 109,652 homes across the nation entered some stage of foreclosure in December, a nearly 9 percent drop from the previous month, but an increase of 35 percent from December 2005. The company reported a national foreclosure rate of one new foreclosure filing for every 1,055 U.S. households.
And the Center for Responsible Lending issued a report in December predicting 2.2 million foreclosures in the coming years among homeowners with so-called sub-prime loans, which are loans offered at rates higher than the prime rate and that are aimed at people with poor credit ratings.


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34 oz Frank Green Reusable Bottle - Cloud
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Gears work with energy, this power tends to make the robot move and operate. Generally they will have batteries inserted on them, there are some that were recently produced that worked with solar power. The gears make the robots move along with the both the torque and the force of the object.
The city has acknowledged that citizens have the suitable to record the actions of police officers. In August, it offered some of its officers with formal education on citizens' rights to record the actions of the police, and it sent an e-mail to the entire police force on the subject. The city has argued these steps will avoid future violations of Sharp's rights, and that this renders Sharp's lawsuit moot. The city has asked that it be dismissed.
But you had been fighting a losing battle. The minute a cool trend is discovered, repackaged, and sold to children at the mall, it is no longer cool. So the kids turn to anything else, and the whole course of action begins all over once again. The superior you get at coolhunting, the more quickly the cycle goes, and the harder it is for everyone to keep up.
If they are asked to think of the word 'nevertheless' for two minutes,120seconds, with no ever permitting any letters at all to enter their imaginations, they cannot comply. A individual from a entirely oral background of course has no such problem. He or she will assume only of the true word, a sequence of sounds, 'nevertheless'. For the genuine word 'nevertheless', the sounded word, can not ever be present all at after, as written words deceptively look to be.
If present trends are anything to go by, the encroachment of computers, robots and 'expert systems' into the workplace puts the Second Law in conflict with the Initial. Robots are particularly fantastic at complying with the orders they are given, and it could be argued that this is 'causing harm' to humans. It really is not physical injury so substantially as financial displacement that is doing the harm.