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Thus, substrate NH hydrogen bonds may help define the substrate orientation by optimally positioning ESCRT-III side chains with respect to their binding pockets ( Figure 3E ). It is also consistent with other recent models ( Gates et al. 2017; Monroe et al. 2017; Puchades et al. 2017; Ripstein et al. 2017 ), albeit with additional molecular details. We envision that the enzyme proceeds by transitioning of subunit configurations around the hexameric ring, such that one step represents transitioning of subunits F, A, B, C, D, E to the configurations of subunits A, B, C, D, E, F ( Figure 4A, Figure 4—video 1 ). Each step comprises concomitant changes in subunit interfaces at each end of the Vps4 A-E helix. At the leading end, binding of ATP allows subunit F to pack against subunit A and thereby bind the next two residues of the substrate. At the lagging end, hydrolysis of ATP and subsequent phosphate release destabilizes the interface and drives subunit E to the transitioning configuration, thereby opening the nucleotide binding site to allow exchange of ADP by ATP. In this manner, the equivalent dipeptide-binding sites formed at the interfaces of subunits A-E track with their bound dipeptides along the pore as subunits transition from the lagging end to the leading end of the helix. W206 and M207 residues of the six Vps4 subunits are shown, with the peptide passing through the Vps4 hexamer. The peptide model was constructed by changing the side chains to leucine without adjusting the main chain, and building out in the N and C directions by overlapping copies of the peptide model. The proposed mechanism envisions that Vps4 progresses through states A to E while bound to successive dipeptides of its substrate. Subsequent ATP binding allows subunit F to pack against subunit A, bind to the next dipeptide of ESCRT-III, and assume the subunit A configuration. ( BC ) Conservation of helical pore loop structure in AAA ATPases. This is because subunit E will disengage from substrate as it moves toward the F configuration while the F subunit is moving toward the substrate-binding A configuration. It also explains the importance of the pore loop residues and the integral role of the class I and II pockets, because once a substrate residue binds at the top of the Vps4 helix it does not substantially change conformation until released at the bottom of the helical conveyor belt. These proteins are hexameric protein translocases, whose conserved pore loops emanate from equivalent structural elements, although their N-terminal domains are variable and only Vps4 has a ? domain.

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But what happened first, the death of the sons or the father's death. I don't think he had the heart to burn his brother, but his policy has been to burn the bodies. I had assumed he'd sail all the way up North and go after Jon. But, Walder Frey has quite a few sons so the poison killed off the rest of them. A very interesting appearance for a potential reunion. If it were under different circumstances, Sansa's advice might have some merit, but her approach was wrong. The only Northen family who stayed loyal was House Mormont. The lord and lady, being impressionable children, need the support of the new king to solidify their claims to continue as houses. Jon can wield considerable influence over those houses now. Sansa's trying to play by the old rules despite KNOWING what's coming for them (unlike Cersei, who has no clue). If the situation gets bad enough, he could off her. MESSAGE! I will forever love and miss you. y sweet Prince. I think the only other wolf alive is Jon's and this one wasn't white. However, in the first episode of season seven, the newly named King in the North could heed a bit of advice that all of us need from time to time as leaders -- lessons that we'll all see play out in the near future. As leaders, we often assume that the best advice comes from people with the biggest titles -- experts in industries or practices. Dismissing the opinions of people who may not fully understand your work can lead to failure. And, research from the Great Work Study reveals that 90 percent of award winning work projects include employees who patiently remain involved with the work from start to finish -- measuring the impact the work makes on the recipient of that work until the final product is loved. As leaders it's important to understand that although we may not be leading large armies, people look to us every day see if their efforts and results at work are valued and appreciated.

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But HDMI and USB-A are still far too widely used to have been removed completely, and neither are likely to fade away anytime soon regardless of how Apple configures their laptops. Re-adding HDMI and at least one USB-A port would reduce or eliminate many people’s dongle needs, which I bet would dramatically improve their satisfaction. SD cards are more widely used than ever in photography, video, audio, and other specialized equipment, and they provide excellent options for fast, reliable storage expansion and data transfer. And they’re going to be around for a while — Wi-Fi and cables don’t or can’t replace most current uses in practice. There’s no shame in that — Apple should just recognize this, learn from it, and move on. If we can’t have that yet, the ideal setup is Touch ID without the Touch Bar. We’d retain the Secure Enclave’s protection for the camera and microphones, and hopefully get the iMac Pro’s boot protection, too. USB-C PD is the reason I didn’t include battery life in this list — occasional needs for extended battery life can be achieved with inexpensive USB-C PD batteries. These weren’t superfluous — they served important, useful functions, and their removal made real-world usability worse for small, unnecessary gains. MagSafe 2 wasn’t universally loved because it detached with too little vertical pressure when used on laps, couches, or beds, but maybe it could be moved to a splitting module along the cable, a few inches from the laptop end, like the original Xbox’s controller cables. It’s already a specialized, dedicated power-only cable in practice (high-wattage USB PD support, but no Thunderbolt, and limited to USB 2. speeds). Third-party cables could still work — Apple’s could just be nicer. And with all-SSD storage, quad-core i7 processors, and a healthy amount of RAM all standard, every configuration was fast, capable, and pleasant to use. In exchange for those removals, we got substantial reductions in thickness and weight, and a huge new battery. Everything else about this machine was an upgrade: thinner, lighter, faster, better battery life, quieter fans, better speakers, better microphones, a second Thunderbolt port, and a convenient new HDMI port. The crowd-pleasing design was neither fanatically loved nor widely despised. It quietly and reliably did its job, as all great tools should, and nobody ever really had to think about it. It provided ample room for multitouch gestures, but without being too large or close to the keyboard, so people’s fingers wouldn’t inadvertently brush against it while typing. The SD-card slot could also serve as inexpensive storage expansion.

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