If it still says it's invalid, try taking it back to the store you bought it from and exchange it. If they are not willing to do that, contact an EA Game Advisor with proof of purchase ready.You bought the game on DVD and the box was not sealed/it's a used gameUsed games cannot be re-registered. Take it back to where you bought it and get a refund.You bought a key from a key sellerContact the key seller for a replacement. If you bought the game from a unauthorized seller, it's possible that EA blocked the key if they were bought fraudulently by the seller. You're better off to only buy from authorized sellers.You have already registered the game yourself and are trying to reinstall the gameThe game does not need to be registered again. Login in the Origin Client with the Email/PW you first registered the game on and download and install the game from there. The game only needs to be registered once and you won't need the code again after your initial registration. This is true for both the DVD and the download version. You can skip the activation step on reinstalling.Source: -Sims-4/FAQ-Serial-Codes-Game-Activation-and-Download-Issues/td-p/422823...
Sims 4 activation key
Now when I log on to origin then it doesn't show any games in my games and when I want to play the sims 4 it says activation required, but when I type in my product key that I got from my sims 4 book in the CD case, it says that my product key is already in use. So now I cannot play sims.
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The KMS activation is only for 180 days, after 180 days, you need to activate it again , it is troublesome, and if you find a KMS key online , it has as risk of black screen if the key is blocked ! I get the retail server 2019 datacenter product key from the Microsoft partner online store keyingo.com, and it is easier to activate with the retail key, and you wont have any problems in the future too
As Windows 11 will automatically activate if you are connected to the internet, you can confirm your activation status by selecting Start > Settings > System > Activation and looking under Windows.
As Windows 10 will automatically activate if you are connected to the internet, you can confirm your activation status by selecting Start > Settings > Update & Security > Activation and looking under Windows.
Need a new license key to activate RockSim? We can help by looking up your old activation key or creating a new one for you. We can also deactivate your computers if you can no longer do that yourself.
Once you purchase this service for us to look up your old RockSim v9 activation key, please be patient and allow one business day for us to look up your old key. We have to confirm a couple of things:
You can install the software on up to three computers using the single user license key. Alternate key types have differing number of activations. Check under My Account - RockSim keys to see the number of activations allowed and the number in use.
The p21WAF1/Cip1 gene has a key role in cell cycle arrest at the G1 stage by inhibiting CDKs, and was identified as an important transcriptional target of p53 and TGF-β-Smad4 pathways.9, 11, 12, 13, 14, 15 In this study, we showed that the Smad pathway but not the p53 pathway is involved in the zinc-induced apoptosis, in line with other reports.8, 9, 28, 29 Our results demonstrate that zinc induces apoptosis in LNCaP (p53-positive), PC3 (p53-null) cells, indicating that zinc-induced apoptosis is not associated with p53 status, consistent with other studies that zinc leads to IIC9 cell death in a p53-independent manner.41 Furthermore, in our comparative analysis of reporters, p21PΔp53-luc lacking p53-binding sequence, as with p21P-luc or Smad downstream 4*SBE-luc reporter, show significant inductions by zinc, but not the pp53-TA-luc reporter that is only activated by p53, providing evidence that zinc treatment induces p21WAF1/Cip1 transactivation in a Smad-dependent and p53-independent manner.
Smad4 has a central role in TGF-β signaling and is associated with the progression of many tumors. A significantly decreased nuclear Smad4 is always shown in many kinds of cancers, suggesting the inactivation of the Smad pathway.13, 20 Here, we demonstrate the critical roles of Smad4 in zinc-induced apoptosis. Although there are no significant changes for the expression levels in response to zinc treatment, Smad4 exhibits increased binding capacity with phosphorylated Smad2 and PIAS1, significant nuclear translocation, and functionally direct binding to SBE1 and SBE3 regions of the p21WAF1/Cip1 promoter. The knockdown of endogenous Smad4 in LNCaP cells resulted in apparent reduction of cell apoptotic sensitivity to zinc and the attenuation of zinc-induced p21WAF1/Cip1 transactivation and apoptosis in zinc-insensitive cell lines by the overexpression of Smad2/Smad4/PIAS1, suggesting the pivotal mediator roles of Smad4 in the zinc-activated Smad pathway.
In this study, we have identified a novel role of PIAS1 in zinc-induced apoptosis. The PIAS family has been proposed to interact with many transcription factors, acting as a transcriptional co-regulator.21, 22, 23, 24, 25, 26 The substantially reduced expression of PIAS1 is reported to be associated with colon cancer, gastric cancer, and hormone-refractory prostate cancers.27, 28, 29, 30 Previous reports suggested PIAS1 physically interacts with Smad4 and enhances the Smad4-dependent transcriptional activation of TGF-β signaling, whereas PIAS3 preferred to activate Smad3.21, 23 Here, we elucidated that PIAS1 is the only member of the PIAS family involved in zinc-induced Smad4 pathway activation. PIAS1 contains conserved SP-RING zinc-finger ring domains as with other PIAS proteins, but several unique sequences are distinguished from other PIAS numbers. Interestingly, zinc stimulation strongly enhanced the PIAS1 interaction with the Smad2/4 complex, with the disassociation of the original PIAS1/Smad3 complex, suggesting the different roles of PIAS1 in Smad3 and Smad2 regulation. In addition, PIAS1 obviously promotes zinc-induced Smad4 nuclear translocation and dramatically increases Smad4 recruitment on the p21WAF1/Cip1 promoter, to further promote Smad2/4 mediated proliferation inhibition. Moreover, PIAS1 contributes to zinc apoptotic sensitivity in all various cancer cells. All our observations supported that PIAS1, the expression of which is restored by zinc, has essential biological regulatory roles in the zinc-induced cell death.
In Pb-Zn ore flotation, unintentional activation of sphalerite often leads to difficult separation of Pb and Zn minerals, during which grinding plays a key role in unintentional activation. Therefore, the aim of this study was to evaluate the surface component changes of two different mineral particles and to propose the interaction between galena and sphalerite during mixed grinding using time-of-flight secondary ion mass spectrometry (ToF-SIMS). The results show that after mixed grinding of the galena and sphalerite, the Pb content on the sphalerite surface increased with the decrease of Zn and Fe contents on the sphalerite surface. The lead ions from galena were obviously absorbed onto the sphalerite surface, while the zinc and iron ions from sphalerite were not obviously migrated to the galena surface. Principal component analysis (PCA) of a dataset composed of 206 positive ion peaks of galena and sphalerite indicates that the surface components of galena and sphalerite migrated from either side to different degrees. This study successfully identified an important factor for unintentional activation of lead and zinc minerals during flotation: homogenization of surface components of different minerals during grinding.
Breast cancer is second only to lung cancer in cancer-related deaths in women, and the majority of these deaths are caused by metastases. Obtaining a better understanding of migration and invasion, two early steps in metastasis, is critical for the development of treatments that inhibit breast cancer metastasis. In a functional proteomic screen for proteins required for invasion, extracellular heat shock protein 90 alpha (Hsp90alpha) was identified and shown to activate matrix metalloproteinase 2 (MMP-2). The mechanism of MMP-2 activation by Hsp90alpha is unknown. Intracellular Hsp90alpha commonly functions with a complex of co-chaperones, leading to our hypothesis that Hsp90alpha functions similarly outside of the cell. In this study, we show that a complex of co-chaperones outside of breast cancer cells assists Hsp90alpha mediated activation of MMP-2. We demonstrate that the co-chaperones Hsp70, Hop, Hsp40, and p23 are present outside of breast cancer cells and co-immunoprecipitate with Hsp90alpha in vitro and in breast cancer conditioned media. These co-chaperones also increase the association of Hsp90alpha and MMP-2 in vitro. This co-chaperone complex enhances Hsp90alpha-mediated activation of MMP-2 in vitro, while inhibition of Hsp70 in conditioned media reduces this activation and decreases cancer cell migration and invasion. Together, these findings support a model in which MMP-2 activation by an extracellular co-chaperone complex mediated by Hsp90alpha increases breast cancer cell migration and invasion. Our studies provide insight into a novel pathway for MMP-2 activation and suggest Hsp70 as an additional extracellular target for anti-metastatic drug development. 2ff7e9595c
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