![]() In a pooled CRISPR-Cas9-based screen, we found that CDK2 regulates the abundance of the ASCL1 oncogenic transcription factor. In arrayed chemical screens, we identified novel IMiD-like IKZF1 degraders and Spautin-1, which, unlike the IMiDs, degrades IKZF1 in a cereblon-independent manner. Here, we describe a gain of signal ("up") assay for degraders. Current loss of signal ("down") assays for identifying degraders often exhibit poor signal-to-noise ratios, narrow dynamic ranges, and false positives from compounds that nonspecifically suppress transcription or translation. For example, thalidomide-like drugs (IMiDs) degrade the critical multiple myeloma transcription factors IKZF1 and IKZF3 by recruiting them to the cereblon E3 ubiquitin ligase. Recent studies indicate that some undruggable proteins can be targeted by compounds that can degrade them. Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. 13 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.12 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.11 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. 10 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.9 Departments of Pediatrics and Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.8 Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.7 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.6 Linde Program in Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.5 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.4 Ludwig Cancer Center, Boston, MA 02115, USA.3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.So it’ll be interesting to see how this news is received by those who say, we should be putting our billions of dollars into the technology we know works today and getting off oil and gas ASAP, and then maybe saving life as we know it before we go for these amazing moonshots. In the meantime, there’s all this incredible breakthroughs that are happening with wind and solar and more will go online next five years than went online in the last 20. Bill, maybe you’re more optimistic than I am about how fast this takes. This is for our grandkids probably as a meaningful technology. We have 30 million years of seawater theoretically to feed these machines.īut what Bill was describing there, these 200 lasers aimed at what is essentially a peppercorn of hydrogen, a long way from there to where you can plug in your house to this stuff. We don’t have to drill or mine for fuel anymore because the fuel is seawater. And the appeal of it is you don’t have any nuclear waste, there’s no fallouts, there’s no accidents. So you guys, if this would work, if this is a harbinger, if this is really the beginning of something huge, it would change the world. So, it’s quite a little chin stroke that it’s very close to 80 years later to the day that this breakthrough occurred. And there’s, as far as I know in the reporting the last few days, no one’s mentioned that Enrico Fermiand his colleagues in University of Chicago did the first chain reaction, which led to all the nuclear power plants we have now, on December 2nd, 1942. So this is the first time, by all accounts, they’ve gotten more heat out than they put in. So using lasers they zap this container, this whole rum, this gold thing with the deuterium in it and the lasers create x-rays and the x-rays create constructively interfering shock waves that get the thing to fuse without a giant magnetic bottle and without the gravity of a star. And then if it has two extra neutrons, that’s tritium. And the material would be hydrogen that has an extra neutron, which has this mount marvelous word, deuterium. But for all this time, for 80 years, people have trying to tried to get this idea where you could do it in a controlled fashion using a tiny amount of material. But there’s another amazing thing that happens in nature where you smash tiny, tiny parts of atoms together, protons, and they fuse and convert a tiny amount of their mass into energy, into heat, heat and light. Do you really, or not? So a nuclear weapon can be like we had to terminate World War II, we’re splitting very large atoms apart, gave off tremendous amount of energy.
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