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Fantasy Baseball Live – December 29, 2024Segment 1 – News and Notes1.The Nationals acquired Nathanial Lowe from the Rangers for LHP Robert Garcia. The Rangers then signed Joc Pederson to a 2-year, $37 million contract with an opt-out after the first yeara.First, what did you think of the Nationals' move? Lowe wasn't very good last season but was fairly consistent prior to that.i.For those thinking that Andres Chaparro would get a chance, that appears to not be in the cards.b.The move allows the Rangers to move Jake Burger full-time to first and then park Pederson as the strong-side platoon DH. What do you think of the Rangers lineup?c.Does Robert Garcia get a boost in value with the chance to be the closer in Texas? Or was he your favorite in Washington for saves?2.The Diamondbacks signed Corbin Burnes for 6-years and 210 million.a.Burnes is on a four-year decline in his strikeout rate and only struck out 8.4 per nine last season. Plus, after a stellar first half, he posted a 3.69 ERA in the second half. Are you all in with Burnes in 2025, or do you have some reservations?i.Is he worth an early third-round pick (6th starter off the board)?ii.Are you particularly concerned about his move to the NL West and Arizona?3.The Dodgers re-signed Teoscar Hernandez for three years and $66 million with $23 million deferred. Jeff Passan said it best…the Dodgers are a machine. They get who they want. What do you think?4.The Red Sox signed Walker Buehler to a one-year, $21.05 million contract. He's coming off this second TJS and struggled in 16 starts for the Dodgers last season. He posted a 5.38 ERA, striking out 7.7 per nine.a.Stat line for 2025: IP, K, wins, and ERA5.The Tigers do things that I don't understand. They signed Javier Baez to a huge contract a few years back, and it will turn out to be one of the worst deals in the modern era. Now, they have signed Gleybar Torres to a one-year deal ($15 million). I know people say there are no bad one-year deals, but it clogs up an already full infield. a.Give me the starters in the infield and lose out on playing time.Segment 2 – NL West Fantasy Questions1.Arizona Diamondbacksa.Corbin Carroll will be more like the 2024 first-half player or the 2024 second-half player in 2025?i.Stat line for 2025: HR, SB, and BAb.Jordan Lawlar will take over the shortstop role of ______________ (looking for a date)?c.Is Alek Thomas nothing more than a fourth outfielder or do you think he can develop into something more?d.Justin Martinez had a nice run of closing games in August but didn't save a game after September 3. He's going as the 20th closer off the board. Do you think there is value in this pick?e.Give me a sleeper in the organization (minor or majors)2.Colorado Rockiesa.Brenton Doyle was one of the surprise blow-up players last season. He went 23-30 with a .260 batting average. Give me his stat line for 2025: HR, SB, and BAi.We will see where he is going and if it seems reasonable.b.Nolan Jones cost you a fourth-round pick in 2024. After injuries and poor playing when he was healthy, he will only cost you a 17th-round pick. Am I nuts to think there could be sneaky value here?c.One of your guys last season was Ezequiel Tovar. He popped 26 home runs, stole six bases, but only posted a .295 OBP. He's going as the 12th shortstop off the board. Too rich, or do you like the value here?d.Are there any starting pitchers you are interested in drafting this season?i.Who do you like as the favorite for saves?e.Give me a sleeper in the organization (minor or majors)3.Los Angeles Dodgersa.The Dodgers will win _________ games in 2025?b.Yes or No. Gavin Lux will be the starter at second base for the Dodgers on July 1?i.Stat line: HR, SB, and BAc.Shohei Ohtanii.Hitting Stats: HR, SB, and BAii.Pitching Stats: IP, Wins, Ks, and ERAd.Number of starts by pitcheri.Snell - 24ii.Yamamoto - 25iii.Glasnow - 19iv.Gonsolin - 18v.May - 5vi.Ohtani - 18vii.Sasaki – 18 or 20viii.Bobby Miller – 16ix.Landon Knack – 14x.Emmet Sheehan and Robleski – 15e.Give me a sleeper in the organization (minor or majors)4.San Diego Padresa.Jackson Merrill 2025 Stat Line: HR, SB, BAb.RosterResource has Tirso Ornelas and Eguy Rosario listed as starters. That doesn't stick, does it?c.Do you feel good about a team when you draft Luis Arraez, or do you feel like you screwed up in the draft?d.Michael King was great last season with 13 wins, a 2.95 ERA, and 201 strikeouts in 173.2.e.Give me a sleeper in the organization (minor or majors)5.San Francisco Giantsa.I know this will seem strange, but Jung Hoo Lee is one of my Outfield Targets this season. He's going as the 63rd outfielder. Am I going to be disappointed if I decide to grab him as my fourth or fifth outfielder?b.Is Grant McCray worth a spec pick this season? His ADP is 739.44.c.Tyler Fitzgerald was great last season. In 96 games, he hit 15 home runs and stole 17 bases. Over 162 games, that's a 23 HR, 27 SB guy. Yet, nobody seems to believe as his ADP is 237.87 (16/17 Round).d.Kyle Harrison 2025 stat line: IP, Wins, Ks, ERAe.Give me a sleeper in the organization (minor or majors)6.Who wins the NL West and how many teams make the playoffs?

Fantasy Baseball Live – November 10, 2024 – 3 pmSegment 1 – Where will the Free Agents sign1.Juan Soto (OF, NYY)a.Rich – SFb.Tim - NYM2.Corbin Burnes (RHP, Bal)a.Rich – NYMb.Tim - Det3.Max Fried (LHP, Atl)a.Rich – CHCb.Tim - Bal4.Willy Adames (SS, Mil)a.Rich – SDb.Tim - SF5.Roki Sasaki (RHP, FA)a.Rich – SD if after 1/15 or LAD is before 1/15 b.Tim - SD6.Alex Bregman (3B, Hou)a.Rich – NYYb.Tim - Tor7.Blake Snell (LHP, SF)a.Rich – STLb.Tim - Bos8.Jack Flaherty (RHP, LAD)a.Rich – Bosb.Tim - NYM9.Pete Alonso (1B, NYM)a.Rich – NYYb.Tim - Ari10.Jurickson Profar (OF, SD)a.Rich – LADb.Tim - Mia11.Teoscar Hernandez (OF, LAD)a.Rich – Balb.Tim - LAD12.Anthony Santander (OF, Bal)a.Rich – Seab.Tim - KC13.Ha-Seong Kim (SS, SD)a.Rich – SDb.Tim - SD14.Sean Manaea (LHP, NYM)a.Rich – STLb.Tim - Bal15.Michael Wacha (RHP, KC)a.Rich – KCb.Tim - Det16.Yusei Kikuchi (LHP, Hou)a.Rich – Houb.Tim - Hou17.Nathan Eovaldi (RHP, Tex)a.Rich – Texb.Tim - Tex18.Christian Walker (1B, AZ)a.Rich – Cinb.Tim - Tor19.Gleybar Torres (2B, NYY)a.Rich – SFb.Tim - Sea20.Luis Severino (RHP, NYM)a.Rich – Detb.Tim - LAASegment 2 – Fantasy Baseball Questions of the AL Central – I don't think we get to all of them.1.Chicago White Soxa.Luis Roberts will play for the ________________ on Opening Day. If not the White Sox, will he be moved before the deadline?b.Andrew Vaughn is a Top _______________ first baseman in fantasy baseballi.Over/Under 24 home runsc.Garrett Crochet – 2025 stats - IP, wins, Ks, ERAd.The White Sox won 41 games and lost 121. Over/Under 50 wins in 2025e.Give me a sleeper in the organization (minor or majors)2.Cleveland Guardiansa.Kyle Manzardo is only UT eligible to start the season, but his current NFBC ADP is 355, or he's being taken as the 31st 1B off the board. After Tyler Soderstrom. Interested?i.Give me his ABs, HR, and BAb.Brayan Rocchio is the 39th shortstop off the board with an ADP of 488. Is he nothing more than a waiver wire pickup, or is he a growth stock?c.Jhonkensy Noel is being taken as a fifth outfielder. We will look at players around where he is being taken to see if we like it or not.d.Tanner Bibee was your dark horse for CY Young in 2024. He was good, but not that good. Are you still bullish?i.2025 stats – IP, wins, K's, and ERAe.Give me a sleeper in the organization (minor or majors)

Fantasy Baseball Live – December 3, 2023 @ 3 pmSegment 1 – News and Notes1.Jackson Chourio signs with the Brewers.2.The Mets signed Luis Severino to a one-year deal. The adage is that there is no such thing as a bad one-year deal. However, Severino said he was the worst pitcher in baseball last season, and at the time, he might have been right. What do you think? Good signing by the Mets? He's going off the board as the 137th pitcher (round 32) and is basically free. Will you be taking a flyer?3.The Tigers sign Kenta Maeda to a two-year, $24 million contract. While he continued not to be very durable, he pitched ok with an xERA of 3.77 and a 10 K/9 rate while keeping his walk rate at 2.4 per nine. He's going as the 107th pitcher off the board (round 18). Thoughts?4.The Cardinals continued their youth movement by signing 34-year-old Sonny Gray to a 3-year, $75 million contract. He had a great season in 2023, pitching to a 2.77 ERA and striking out 183 in a robust 184 innings. He's going as the 58th pitcher off the board or the 40th starting pitcher. Solid #3 starter for you, or would you grab him earlier?5.The Reds signed Nick Martinez to a two-year deal (opt-out after the first year). The Reds plan on starting him. His average ADP Is 593, but he's trending up, and it looks like his ADP is #400 in recent drafts. Are you interested in him as a #5/#6 starter if he's a starter?6.Many discussions about Juan Soto with the Yankees appear to be the best fit. However, they are playing hardball and maybe only want to give up Clarke Schmidt and some young prospects for him. How does this all end?Segment 2 – Fantasy Questions of the AL West1.Houston Astrosa.Chas McCormick went 20-19 last season and helped a lot of fantasy managers. His baseballsavant data looks ok. He has an average exit velo, plus speed and a 26% K-Rate.i.Stat line for 2023 – HR, SB, RBI, and BAii.He's being drafted as the 38th outfielder off the board. Does this interest you?b.Jeremy Pena went from 22 home runs in 2022 to 10 last season and is now the 22nd shortstop off the board. Looking at his BaseballSavant page, it's not great. Part of the reason his power dropped is his launch angle dropped from 8.7 degrees to 5.5 degrees. However, he has below-average power, chases too much, and is aggressive at the plate. I dunno; he looks like an average player worthy of his draft selection. Your thoughts?c.Cristian Javier – Stat line for 2024. IP, Wins, Ks, and ERAd.How many wins for the Astros in 2024 – They had 90 in 2023.e.Give me a sleeper in the organization (Minor and/or Major)2.Los Angeles Angelsa.Stat line for Mike Trout – AB, HR, BA, and OBPb.I don't get Nolan Schanuel from a fantasy standpoint. He's a singles hitter. There's no power with exit velos and hard-hit rates in the bottom 10% of the league. He can hit, though. But at first base, how do you make this work? Of course, he's only 21, so you can argue he's going to get stronger, add loft, blah, blah, but I'm not sure I can buy that. Help?c.There's a game called F, Kill, Marry. You are given three women, and you have to F one of them, kill one, and marry the last. Let's do it with the Angels pitching staff.i.Who would you F? Defined as the pitcher you think could blow up this year and be better than anyone thinks.ii.Kill – Defined as the pitcher, you just won't touchiii.Marry – The pitcher you like and would not mind having on your team. d.Percentage chance that the Angels sign Ohtani.e.Give me a sleeper in the organization (Minor and/or Major)This show is part of the Spreaker Prime Network, if you are interested in advertising on this podcast, contact us at https://www.spreaker.com/show/3306394/advertisement

Fantasy Baseball Live – November 26, 2023 @ 3 pmSegment 1 - News and Notes1.The Diamondbacks acquired Eugenio Suarez for RHP Carlos Vargas and Catcher Seby Zavalaa.Suarez brings a 30% K-Rate but has always hit for power. He had back-to-back 31 home run seasons, and then last year, he hit 22. In looking at the data, the exit velos are the same, the launch angle is the same, the K-Rate is the same, and the walk rate is the same. You got it…everything is the same. He's dropped to the 24th third baseman off the board. If you think he can return to 30 home runs, does this give him some value here? Especially if you need power late in the draft.b.Carlos Vargas has a great arm with a fastball that will touch triple-digits, but he has no idea where the ball is going. He's likely a bullpen arm. Seby Zavala came through the White Sox organization and strikes out too much. Not sure he's more than a backup catcher. Thoughts on both players?2.The Cardinals sign two pitchers. Kyle Gibson and Lance Lynn. Both were okay last year with the Orioles and White Sox/Dodgers. Lynn's ADP is 353, and Gibson is 564. Any interest?a.Does this move the needle for the Cardinals?3.We both got excited about the trade that brought Brandon Shewmake to the White Sox. Maybe he would get a shot. What do the White Sox do? Sign Paul DeJong. a.He has one of the worse baseballsavant pages I've seen. 2% rank in exit velo. 15% in hard-hit rate, 5% in whiff, 10% in walks, 37th percentile in speed. It looks like he has good range at short with a poor arm. b.He's only been drafted in four out of the 44 Drafts at the NFBC so far. Maybe that goes up?c.This doesn't appear to be a profile of a Major League full-time regular. Maybe a utility player. What am I missing?Segment 2 – Fantasy Questions of the NL West1.Arizona Diamondbacksa.Alek Thomas is currently living off his great defensive chops. Huge range in center field. He's also a plus runner, ranking in the 87th percentile. There is some solid exit velo, but he beats everything on the ground. He's the 80th outfielder off the board – a number-five outfielder. Is this a growth stock, or would you take a bet on someone else as your fifth outfielder?b.What about Jake McCarthy? There's plus speed but no power. He also beats everything on the ground? Thoughts on McCarthy? Is he a guy you're interested in? His ADP is 490, or the 94th outfielder off the board?i.Can you be a Championship level team with this level of power in centerfield and right?c.Brandon Pfaadt looked great on the biggest stage, and his ADP climbed a little. He's still going as the 87th pitcher off the board – likely the 60th or so starter off the board. Is there value as your fifth pitcher?i.Stat line: IP, wins, Ks, and ERAd.The Diamondbacks won 84 games last season. Does the win total go up or down next season?e.Give me a sleeper in the organization (Minor and/or Major)2.Colorado Rockiesa.Nolan Jones went 20-20 with a .297 average. He's going as the 15th outfielder off the board – pick #58. How many teams of yours will he be on? We will look at other outfielders around the same area.i.Notes: Jones had a .401 BABIP and struck out 30% of the time. There is serious pop with an exit velocity of 90 MPH with a max of 115. There's not a ton of launch.b.Stat line of Ezequiel Tovar – HR, SB, RBI, and BAc.Hunter Goodman (#624) or Brenton Doyle (#541)?d.You have to hold your nose and pick a Rockies starter. Who's it going to be?e.Give me a sleeper in the organization (Minor and/or Major)3.Los Angeles Dodgersa.Gavin Lux stat line: AB, HR, SB and BAb.Are the Dodgers going to battle with Chris Taylor (#429), Gavin Lux, Michael Busch (#546), and Miguel Rojas (#726) hitting at the bottom of the order? We will discuss each (not Lux) and whether they are worth drafting.c.Walker Buhler's stat line: IP, wins, K's, and ERAd.Bobby Miller is going as the #36 pitcher off the board in early NFBC Drafts. That's a #2 starter when you factor in closers. Too high, too low, or just about right?e.Give me a sleeper in the organization (Minor and/or Major)4.San Diego Padresa.Luis Campusano – AB, HR, RBI, and BAb.Manny Machado is going as the #7 third baseman off the board. He's been passed by Gunnar Henderson and Royce Lewis. Solid value in the fifth round, or would you pass him over?c.Yu Darvish had a tough season, pitching to a 4.56 ERA and ending the season on the IL after having bone spurs removed from his pitching elbow. He's fallen to the 15/16 round in 15-team drafts. Any interest?d.2024 will mark AJ Preller's 10th year on the job. He went in big when he first arrived. He quickly sold off almost everyone he traded for when it didn't work. He then drafted and signed high-end Latin player for a few years in what looked like a rebuild. Then, he traded away those prospects for veterans while signing high-priced free agents (Hosmer, Machado, Xander, et. al). They've made the playoffs twice and even got to the NLCS in 2022. However, he's spent a fortune and needs to sell off pieces so the Padres can make payroll. How has he kept his job? e.Give me a sleeper in the organization (Minor and/or Major)5.San Francisco Giantsa.Marco Luciano: Stat line for 2024 – AB, HR, RBI, and BAb.Michael Conforto's bat speed has slowed. He used to light up statcast with his exit velos and hard-hit rates. Now, it's below average – in the 40s for both, with an average launch angle. He's not that old – he turns 31 in March. Could we see a bounce back in 2024, or is he just a 15- to 18-year-old home run guy with some OBP skills now?c.Kyle Harrison: Stat line for 2024 – IP, wins, Ks, and ERAd.Give me a sleeper in the organization (Minor and/or Major)CloseThis show is part of the Spreaker Prime Network, if you are interested in advertising on this podcast, contact us at https://www.spreaker.com/show/3306394/advertisement

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.21.546000v1?rss=1 Authors: Sharninghausen, R., Hwang, J., Dennison, D., Baldridge, R. Abstract: Degrons are the minimal features that target proteins for degradation. In most cases, degrons allow recognition by components of the cytosolic ubiquitin proteasome system. Currently, every degron that has been identified only functions within the cytosol. Using Saccharomyces cerevisiae, we identified the first short linear sequences that function as degrons from the endoplasmic reticulum (ER) lumen. We show that when these degrons are transferred to proteins, they facilitate degradation through the ERAD system at the cytosolic proteasome. These degrons enable degradation of both luminal and integral membrane ER proteins, expanding the types of proteins that can be targeted for degradation both in budding yeast and in mammalian tissue culture. This discovery provides a framework to target proteins for degradation from the previously unreachable ER lumen and enables novel therapeutic approaches that exploit the highly-conserved ERAD system. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.13.536796v1?rss=1 Authors: Lin, L. L., Torres, M., Pederson, B., Wang, H. H., Wei, X., Li, Z. J., Liu, X., Mao, H., Hanzel, M., Govek, E. E., Lu, Y., Wang, H., Zhao, Z., Hatten, M. E., Sun, S. E., Qi, L. Abstract: Despite recent advances in our understanding of the physiological importance of SEL1L-HRD1 endoplasmic reticulum (ER)-associated protein degradation (ERAD) using cell type-specific knockout (KO) mouse models, its relevance and importance in ataxia pathogenesis remain unknown. Here we show that loss of SEL1L-HRD1 ERAD complex interaction or function in Purkinje cells leads to cerebellar ataxia. Both homozygous knock-in (KI) mice carrying SEL1L variant p.Ser658Pro (S658P) and mice with Purkinje cell-specific deletion of SEL1L exhibit early-onset cerebellar ataxia, although disease severity and progression differ between the models. Structure-function analyses reveal that SEL1L S658P variant impairs, not abolishes, ERAD function by attenuating the interaction between SEL1L and HRD1. Proteomic screen of potential endogenous substrates leads to the identification of Astrotactin 1 and 2, two integral membrane proteins involved in neuronal function and development, whose maturation and biogenesis in the ER depend on SEL1L-HRD1 ERAD activity. These data demonstrate the pathophysiological importance of SEL1L-HRD1 interaction and function in the pathogenesis of cerebellar ataxia. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

There's a lot of debate around what is and is not acceptable for Star Citizen, especially with the recent (very) rough launch of Alpha 3.18. Given the feature and backend additions, constant balancing and tweaking, and overall unfinished state, it does feel like an alpha, but with marketing and a timeline that would lead some to believe more, that can be confusing. I'm joined by Youtubers Jack Axton, Dedleader, TenPoundFortyTwo, and Erad to discuss this interesting situation, and set expectations straight for the road ahead! DedLeader: Youtube: https://www.youtube.com/@DedLeader Jack Axton: Youtube: https://www.youtube.com/c/JackAxton Twitter: https://twitter.com/JackAxtonSC TenPoundFortyTwo: https://www.youtube.com/@tenpoundfortytwo Erad*Prime: https://www.youtube.com/@Erad_Prime

This week, please join author Judith Hochman, Editorialist Steven Bradley, and Guest Host Mercedes Carnethon as they discuss the article " Survival After Invasive or Conservative Management of Stable Coronary Disease" and editorial “If the Fates Allow: The Zero-Sum Game of ISCHEMIA-EXTEND.” Dr. Greg Hundley: Welcome everyone to our new year 2023, and we are here on this January 3rd edition of Circulation on the Run. I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Peder Myhre: I am Dr. Peder Myhre, Social Media Editor and doctor at the Akershus University Hospital and University of Oslo. Dr. Greg Hundley: Very nice. Well, welcome listeners and this week's feature, ah, very interesting. You know many times patients with stable coronary artery disease, we're seeing a lot in the literature about an invasive strategy versus a conservative strategy. But what happens long term for these patients? What's their prognosis? Well, more to come in the feature discussion. But first, how about we grab a cup of coffee and we discuss some of the other issues in this session. Peder, would you like to go first? Dr. Peder Myhre: Yes, Greg I would love to and the first paper today is very interesting and relates to one of the most important challenges globally, namely climate changes and extreme temperatures. And in this paper, which comes to us from corresponding author, Barrak Alahmad from Harvard Chan School of Public Health in the United States, together with a large international group of authors, investigated the associations between extreme temperatures and cardiovascular cause-specific mortality in 567 cities in 27 countries from 1979 to 2019. Dr. Greg Hundley: Wow Peder, that is a really large comprehensive study. So, how did they perform this analysis? What did they find? Dr. Peder Myhre: So Greg, the investigators collected city-specific daily ambient temperatures from weather stations and analyzed cause-specific cardiovascular mortality and excess deaths in association with extreme hot and extreme cold temperatures. And in total, the analysis included more than 32 million deaths from any cardiovascular cause, which were subdivided into deaths from ischemic heart disease, stroke, heart failure and arrhythmia and at extreme temperature percentiles. And that is defined as heat above the 99th percentile and as cold below the first percentile were associated with a high risk of dying from any cardiovascular cause, ischemic heart disease, stroke and heart failure as compared to the minimum mortality temperature, which is the temperature associated with least mortality. And Greg, across a range of extreme temperatures, hot days above the 97.5 percentile and cold days below the 2.5 percentile accounted for more than two and more than nine excess deaths for every thousand cardiovascular death respectively. And heart failure was associated with the highest excess death proportions from extreme hot and cold days. So Greg, it seems like extreme temperatures really impact the cardiovascular mortality across the globe. Dr. Greg Hundley: Yeah, beautiful description Peder. And I think what was really exciting about that particular article is you had results from 27 countries. Wow, so really quite a global study and very informative. Dr. Peder Myhre: Yes, indeed very impressive. Dr. Greg Hundley: Well, Peder my next study comes to us from the world of preclinical science. And Peder, these investigators led by Professor Jose Luis de la Pompa from CNIC, evaluated two structural cardiac diseases, left ventricular non-compaction and bicuspid aortic valve. And they wanted to determine if those two conditions were caused by a set of inherited heterozygous gene mutations affecting the notch ligand regulator, Mind bomb-1 and co-segregating genes. Dr. Peder Myhre: Okay Greg, so we are looking at mechanisms for non-compaction and bicuspid aortic valve. What did they find? Dr. Greg Hundley: Right Peder, so whole exome sequencing of the left ventricular non-compaction families identified heterozygous missense mutations in five genes co-segregating with E3 ubiquitin protein ligase-1 Mib-1 as well as left ventricular non-compaction. And corresponding mouse models showed that left ventricular non-compaction or bicuspid aortic valve in a notch-sensitized genetic background. Now, also gene profiling showed that increased cardiomyocyte proliferation and defective morphological and metabolic maturation in mouse hearts and human pluripotent stem cell cardiomyopathy. Biochemistry suggested a direct interaction between notch and some of the identified gene products. And so, these data Peder support a shared genetic basis for left ventricular non-compaction and bicuspid aortic valve with Mib-1 notch playing a crucial role. And thus, identification of heterozygous mutations leading to left ventricular non-compaction or bicuspid aortic valve may allow us to expand the genetic testing panel repertoire for better diagnosis and or risk stratification of both of these conditions, left ventricular non-compaction and bicuspid aortic valve. Dr. Peder Myhre: All right, that is really great and novel linking left ventricular non-compaction to bicuspid aortic valve, really great. And now Greg, we're going to go back to clinical science and we're going to talk about lipoprotein(a) or Lp(a). And as you know, elevated Lp(a) is a common risk factor for cardiovascular disease outcomes with unknown mechanisms. And the authors of this next paper coming to us from corresponding author Olli Raitakari from University of Turku in Finland, examined Lp(a)'s potential role in identifying youths who are at increased risk of developing adult atherosclerotic cardiovascular disease, ASCVD. And they did this by measuring Lp(a) in youths nine to 24 years old and linking that to a diagnosis of ASCVD as adults and also linking it to carotid intermediate thickness in the Young Finns Study. And in addition, these results were validated in the Bogalusa Heart Study. Dr. Greg Hundley: Oh, very nice Peder. So, what did they find? Dr. Peder Myhre: So Greg, those who have been exposed to high Lp(a) levels in youth and that was defined as greater than or equal to 30 milligrams per deciliter, had about two times greater risk of developing adult ASCVD compared to non-exposed individuals. In fact, all the following youth risk factors were independently associated with a higher risk. Lp(a), LD, cholesterol, body mass index and smoking all independently associated with ASCVD. And similar findings were made in the validation cohort who were participants with a high Lp(a) had 2.5 times greater risk of developing adult ASCVD compared to non-exposed individuals. And this also persisted in adjusted models. Now, what about the carotid intermediate thickness? In that analysis, there were no associations detected to youth Lp(a) levels in either of the cohorts. Dr. Greg Hundley: Very nice, Peder. So, great description of the utility of lipoprotein(a) measurements in the youth and for predicting future major cardiovascular events. Well, the next paper goes back to the world of preclinical science. And Peder, cardiac hypertrophy increases demands on protein folding, which causes an accumulation of misfolded proteins in the endoplasmic reticulum. Now, these misfolded proteins can be removed via the adaptive retro-translocation, poly-ubiquitylation and a proteasome mediated degradation process. The endoplasmic reticulum-associated degradation, ERAD, which altogether as a biological process and rate has not been studied in vivo. So, these investigators led by Dr. Christopher Glembotski from University of Arizona College of Medicine, investigated the role of ERAD in a pathophysiological model and they examined the function of the functional initiator of ERAD, VCP-interacting membrane protein and positing that the VCP-interacting membrane protein would be adaptive in pathological cardiac hypertrophy in mice. Dr. Peder Myhre: Thanks Greg. So, we're talking about degradation of the endoplasmatic reticulum and the association to hypertrophy. So, what did these investigators find, Greg? Dr. Greg Hundley: Right, Peder. So, this was really the first study to demonstrate that endoplasmic reticulum-associated protein degradation or ERAD is responsible for degrading and thus, regulating the levels of a cytosolic non-endoplasmic reticular protein. The results reported here describe a new mechanism mediating the pathological growth of the heart, such that in the healthy heart SGK-1 levels are low due to ERAD-mediated degradation. While in the setting of pathology, ERAD-mediated degradation of SGK-1 is disrupted, allowing the pro-growth kinase to accumulate and contribute to pathological cardiac hypertrophy. And so Peder, the clinical relevance of these findings is that the investigators found that a variety of proteins that constitute the ERAD machinery were decreased in both mouse and human heart failure samples while SGK-1 was increased, supporting the possibility that SGK-1 is a contributor to the disease phenotype. And this is notable and that these studies could lead to the development of new therapeutic approaches for managing pathological cardiac hypertrophy and heart failure that target the ERAD to restore efficient SGK-1 degradation. Dr. Peder Myhre: That was an excellent explanation of a very difficult topic. Thank you, Greg. Dr. Greg Hundley: Well, Peder how about we take a look and see what else is in the issue? And now I'll go first. Well, first there's an In Depth by Professor Ntsekhe entitled, "Cardiovascular Disease Among Persons Living with HIV: New Insights into Pathogenesis and Clinical Manifestations within the Global Context." And then, there's a Research Letter by Professor Verma entitled, "Empagliflozin in Black Patients Versus White Patients With Heart Failure: Analysis of EMPEROR results-Pooled." Dr. Peder Myhre: Great Greg and there is an On My Mind by Gabriel Steg entitled, "Do We Need Ischemia Testing to Monitor Asymptomatic Patients With Chronic Coronary Syndromes?" Very timely and interesting. And finally, there is an AHA Update from Michelle Albert, the President of the AHA entitled, "Tackling Adversity and Cardiovascular Health: It is About Time." Dr. Greg Hundley: All right. Well Peder, how about we get onto that feature discussion looking at survival after invasive or conservative management in stable coronary heart disease? Dr. Mercedes Carnethon: Thank you so much for joining us for this episode of Circulation on the Run. I'm Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University, Feinberg School of Medicine. And I'm very excited today to have as a guest, Dr. Judith Hochman, who is going to be discussing the long-awaited findings from the ISCHEMIA-EXTEND trial that are looking at survival after invasive or conservative management of stable coronary disease. Really pleased to have you with us today, Judy to hear about these findings. Dr. Judith Hochman: It's a pleasure to be here. Dr. Mercedes Carnethon: Thank you. So, just to start off, can you tell us about this study? What motivated this long-term follow-up of this particular trial? Dr. Judith Hochman: Yeah, so as I think the viewers or the listeners will recall, we built on a wealth of data from COURAGE and BARI 2D, some of the landmark trials that looked at revascularization versus optimal medical therapy or guideline-directed medical therapy alone. We tested an invasive strategy versus a conservative strategy dating back already to 2012 is when we started. And we had a five component primary outcome, which included cardiovascular death, myocardial infarction or hospitalization for unstable angina, heart failure or resuscitated cardiac arrest. And at the end of 3.2 median years of follow-up, we saw no difference in the primary outcome in that the curves crossed with some excess risk upfront due to periprocedural MI and decreased risk of spontaneous MI long-term. But the net overall timeframe spent free of event was similar between the groups. So, we did observe improved quality of life for the invasive strategy, but in terms of clinical outcomes there was no difference. So, cardiovascular death at the end of that time period was no different between the groups, all-cause mortality was no different, non-cardiovascular death, there was actually an increase in the invasive group, which was somewhat of a mystery. We can get into that a little bit later because I think that becomes important. But 3.2 years meeting and follow-up is relatively short. So, everyone was very interested in what would the long-term outcomes be. So, we had another grant from the National Heart, Lung and Blood Institute to follow these patients long-term. And this is an interim report with seven years of follow-up, a median of 5.7 years. And the bottom line is that all-cause mortality was the same at seven years but for the first time, an invasive strategy resulted in lower cardiovascular mortality, which was very interesting and very exciting except that it was offset, exactly offset by the continued excess that we had previously observed in non-cardiovascular mortality. And that's basically the upshot of what we just reported and why we continue to follow patients and why we're going to continue to follow patients and have a final report in 2026. Dr. Mercedes Carnethon: This is really fantastic work. As you point out, the initial follow-up was fairly short and the findings were so critically important demonstrating that there were subtle differences between the two approaches but that overall, things appeared relatively similar. Did it surprise you? Oh, please correct me. Dr. Judith Hochman: I should point out that because there were less spontaneous MIs during follow-up and spontaneous MIs are associated with a heightened risk of subsequent death more so than the periprocedural MIs, we did hypothesize and we're very interested in longer term cardiovascular and all-cause mortality thinking that those reduced spontaneous MIs in the invasive group would be associated with reduced cardiovascular death and perhaps reduced mortality. As I did indicate, cardiovascular death mortality was reduced but all-cause mortality was the same with a hazard ratio of 1.0. Dr. Mercedes Carnethon: Well, nothing seems more clear than a hazard ratio of 1.0 with those very tight confidence limits so thank you so much. I'm really pleased that our editorialist, Dr. Steve Bradley was also able to join us today because to hear his thoughts about where this fits in the context of what we know can be really insightful. So, I'd really love to turn to you, Dr. Bradley. In your opinion, why was this study question so important and tell us a little bit about how you think the clinical field should use these findings. Dr. Steven Bradley: Absolutely and thanks for having me. I think there were some indication that perhaps the farther we follow the patients out from the original ISCHEMIA trial that we might start to see some evidence of benefit for revascularization. I think Dr. Hochman spoke about the evidence of more of these spontaneous myocardial infarctions that were happening in the non-revascularization arm of the study and an association with worse cardiovascular outcomes in patients that experience spontaneous events. And so, the thoughts might be that over time we would see the benefit of that. And certainly if you parse out cardiovascular versus non- cardiovascular outcomes, we do, we see lower rates of cardiovascular death in the patients who undergo revascularization but it's balanced out by non-cardiovascular death. And so, it becomes a zero sum game for a patient. They want to be alive, it doesn't matter by what mechanism. So, if we have a therapy that doesn't actually prolong their life but it leads to different mechanisms by which they have an outcome, that's important for us to understand. This adds to an already robust evidence-based that ISCHEMIA really did inform and it gives us that long-term trajectory to help us understand for patients what the implications are. I will note that and we've commented in the editorial and this is something that was shown in the original ISCHEMIA trial, that it's not just about mortality for patients, it's important that we help them live better as well. And certainly we know that revascularization is associated with quality of life improvement so that's an important part of the conversation with patients. But again, continuing to refine our understanding of what the implications of revascularization are for mortality is where this study leads us now. Dr. Mercedes Carnethon: Thank you so much. One of the things that I find so impressive about clinical trials of this scale are that you incorporate such a broad audience. I note that 36 countries contributed data to this particular trial. I wonder whether, did you have an opportunity to investigate whether these findings were similar in low and middle income countries as compared with higher income countries? And how would you expect clinicians in low and middle income countries to use this information? Dr. Judith Hochman: That's a great question and yes, the treatment effect was similar across regions, didn't really have any very low income regions but we did have India was in the study and a number of South American countries. And I think it's incredibly important for those countries where there are very limited resources to reassure them, the practitioners and their patients that just because they can't afford an expensive invasive procedure, stenting or bypass, does not mean it's going to cut their life shorter, it's not going to make them survive for a shorter amount of time. Therefore, they can limit the use of scarce resources to the most severely impaired in terms of quality of life, the patients with the most frequent angina. It also became extremely relevant during COVID. Dr. Mercedes Carnethon: Tell me more. Dr. Judith Hochman: Well, elective procedures were shut down during COVID and more publications that cited the ISCHEMIA trial to say that they felt comfortable not being able to do elective stenting in patients with stable ischemic heart disease that would've met the ISCHEMIA trial criteria, which by the way we should add was preserved ejection fraction, we excluded ejection fraction less than 35, patients had to be stable. They could not have had two coronary syndrome within the last few months. They could not have had angina refractory to medical therapy and they could not have had left main disease. So, those are key. There are other exclusion criteria but those are the key exclusion criteria. Dr. Mercedes Carnethon: Thank you for that. And I can really see a corollary and I appreciate the messaging around similar outcomes and preserving resources. And I think certainly even within our own country where we see vast differences in access to intensive medical therapies or tertiary care medical centers who do these procedures on a higher volume, at least we can feel reassured that outcomes may be quite similar as far as mortality. What do you- Dr. Judith Hochman: If they take their guideline-directed medical therapy. Dr. Mercedes Carnethon: Thank you for pointing that out. Dr. Judith Hochman: It's incredibly important. John Curtis' group looked at adherent patients by the modified Morisky score versus non-adherent patients. Non-adherent patients don't have as good a health status as adherent patients. So, just that also adds to a wealth of literature that you have much better outcomes if you actually take your medications. Dr. Mercedes Carnethon: No, I think that's a very good point. What are your thoughts, Steve on what the next steps might be? Dr. Steven Bradley: Well, I know that as was pointed out earlier, there's going to be the opportunity to see additional longer term follow-up beyond this interim analysis. So, it'll be interesting to see what that continues to show us in terms of understanding applications on mortality. I'll pose a question that we posed within our editorial around trying to identify non-fatal outcomes to see if there are any opportunity to capture those non-fatal outcomes to give us an understanding of potential mechanisms for why there is this cardiovascular versus non- cardiovascular mortality difference by treatment arm? Certainly, that may be helpful. Dr. Judith Hochman: Sorry. We're very, very interested in the excess in non-cardiovascular death. So, we are as a result of this interim analysis, revising our case report form, which was very lean, pragmatic because the funding is relatively limited to include especially collection of data around malignancy. Because as we reported before, the non-cardiovascular deaths were largely malignancy and to some extent infection. And what was driving the difference, the excess in non-cardiovascular death as we published in American Heart Journal in the invasive group was excess malignancy. Dr. Mercedes Carnethon: That's really interesting. Dr. Judith Hochman: To our deep surprise and shock, it appeared that the only variable associated with that excess risk was the number of tests or procedures you had that involve radiation. And of course, we're talking about medical doses of radiation. And this short timeframe, three and a half to seven years, which is when the curve started to diverge to three and a half, we filed to seven years is not thought to ... it's thought to be too short a timeframe for exposure to radiation to lead to excess malignancy. So, we have partnered with some radiation experts, we are adding much more details to our case report form, not only in terms of death from malignancy but just the occurrence of malignancy. Did you get malignancy during the course of follow-up? And that's really critically important. We are not adding information about additional myocardial infarctions. We think that the key, if we're going to focus on site burden and how much they can actually collect, is to look at the mechanisms of death and the occurrence of malignancy, whether that leads to death or not, those are our top priorities at this point. Dr. Mercedes Carnethon: I could go on and on, I'm learning so much speaking with the two of you. And again, that really is the primary goal of our podcast to really have an opportunity to extend beyond what's written in the paper and really hear directly from the authors who led the study to hear your thoughts as well as those of the editorialists on where this is going. I really want to thank you both for the time you've spent today to share with our audience of the Circulation on the Run podcast. Dr. Judith Hochman: You're very welcome. Dr. Steven Bradley: My pleasure. Dr. Mercedes Carnethon: I just want to thank all of our listeners for joining us on this really stimulating discussion today on this episode of Circulation on the Run. Please tune in next week where we will have more exciting discussions like this one. Thank you. Dr. Greg Hundley: This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.16.520763v1?rss=1 Authors: Raman, M., Ahlstedt, B. A., Ganji, R., Mukkavalli, S., Paolo, J., Gygi, S. P. Abstract: Endoplasmic reticulum (ER) protein homeostasis (proteostasis) is essential to facilitate proper folding and maturation of proteins in the secretory pathway. Loss of ER proteostasis due to cell stress or mutations in ER proteins can lead to the accumulation of misfolded or aberrant proteins in the ER and triggers the unfolded protein response (UPR). In this study we find that the p97 adaptor UBXN1 is an important negative regulator of the UPR. Loss of UBXN1 significantly sensitizes cells to ER stress and activates canonical UPR signaling pathways. This in turn leads to widespread upregulation of the ER stress transcriptional program. Using comparative, quantitative proteomics we show that deletion of UBXN1 results in a significant enrichment of proteins belonging to ER-quality control processes including those involved in protein folding and import. Notably, we find that loss of UBXN1 does not perturb p97-dependent ER associated degradation (ERAD). Our studies indicate that loss of UBXN1 increases translation in both resting and ER-stressed cells. Surprisingly, this process is independent of p97 function. Taken together, our studies have identified a new role for UBXN1 in repressing translation and maintaining ER proteostasis in a p97 independent manner. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

The party needs to rescue Sihbale and Rose from the Lobo Boys but that meant busting into their base. The 5 of them against a whole base filled with roided out and ERAd individual might not be a good idea but hwat choice do they have? ____________ Socials Twitch - https://twitch.tv/SkyllianRogues Discord - https://discord.gg/HjWKDkB Twitter - https://twitter.com/SkyllianRogues Subscribestar - https://www.subscribestar.com/skyllianrogues Patreon - https://patreon.com/skyllianrogues ___________ Music You can find all music used in our streams here: https://docs.google.com/document/d/11BiOKyieFkoP4ghaIByM7cj16D5ZUFXuWKpbcO2gbI8/edit?usp=sharing

Regulation of cholesterol synthesis is very important: cholesterol is a component of cell membranes and a precursor of steroid hormones and bile acids, yet high levels of cholesterol can be toxic to cells and can contribute to heart disease. Cells in our body obtain cholesterol one of two ways – by taking it up from the bloodstream (via low-density lipoprotein or LDL) or by synthesizing it intracellularly. In Part 1 of his iBioSeminar, Dr. Russell DeBose-Boyd provides an overview of cholesterol regulation with a focus on HMG CoA reductase, the rate-limiting enzyme of cholesterol synthesis. He describes how the effects of statins, drugs prescribed to lower LDL in the blood, are blunted due to the disruption of feedback control of HMG CoA reductase. In the presence of sterols, HMG CoA reductase protein stability is decreased. This sterol-accelerated degradation of HMG CoA reductase is dependent on the enzyme's membrane domain in a process known as ER-associated degradation (ERAD). DeBose-Boyd describes his lab's contributions to a model of HMG CoA reductase ERAD in which polyubiquitination of the enzyme in response to sterols is mediated by two proteins, Insig-1 and Insig-2, leading to its ERAD by the 26S proteasome.

In Part 2 of his talk, DeBose-Boyd introduces a rare genetic disorder known as Schnyder Corneal Dystrophy (SCD). SCD is characterized by accumulation of cholesterol in the corneas of affected individuals, indicating that the genetic defect in SCD may affect cholesterol synthesis. Mutations in the UBIAD1 gene cause SCD – therefore, DeBose-Boyd's lab sought to understand the role of UBIAD1 in regulation of cholesterol metabolism. They found that UBIAD1 acts as a sensor for levels of the metabolite GGpp, which enhances sterol-mediated ERAD of HMG CoA reductase. In the presence of GGpp, UBIAD1 releases HMG CoA reductase, leading to its proteasomal degradation. DeBose-Boyd's lab also discovered a fascinating spatial regulation of UBIAD1, whereby binding of UBIAD1 to GGpp causes UBIAD1 to accumulate in the Golgi apparatus and away from HMG CoA reductase in the ER. Finally, his group found that the SCD-associated mutation N102S in UBIAD1 inhibits the interaction between UBIAD1 and GGpp, such that mutant UBIAD1 is unable to translocate from the ER to the Golgi in the presence of high GGpp.

Regulation of cholesterol synthesis is very important: cholesterol is a component of cell membranes and a precursor of steroid hormones and bile acids, yet high levels of cholesterol can be toxic to cells and can contribute to heart disease. Cells in our body obtain cholesterol one of two ways – by taking it up from the bloodstream (via low-density lipoprotein or LDL) or by synthesizing it intracellularly. In Part 1 of his iBioSeminar, Dr. Russell DeBose-Boyd provides an overview of cholesterol regulation with a focus on HMG CoA reductase, the rate-limiting enzyme of cholesterol synthesis. He describes how the effects of statins, drugs prescribed to lower LDL in the blood, are blunted due to the disruption of feedback control of HMG CoA reductase. In the presence of sterols, HMG CoA reductase protein stability is decreased. This sterol-accelerated degradation of HMG CoA reductase is dependent on the enzyme’s membrane domain in a process known as ER-associated degradation (ERAD). DeBose-Boyd describes his lab’s contributions to a model of HMG CoA reductase ERAD in which polyubiquitination of the enzyme in response to sterols is mediated by two proteins, Insig-1 and Insig-2, leading to its ERAD by the 26S proteasome.

In Part 2 of his talk, DeBose-Boyd introduces a rare genetic disorder known as Schnyder Corneal Dystrophy (SCD). SCD is characterized by accumulation of cholesterol in the corneas of affected individuals, indicating that the genetic defect in SCD may affect cholesterol synthesis. Mutations in the UBIAD1 gene cause SCD – therefore, DeBose-Boyd’s lab sought to understand the role of UBIAD1 in regulation of cholesterol metabolism. They found that UBIAD1 acts as a sensor for levels of the metabolite GGpp, which enhances sterol-mediated ERAD of HMG CoA reductase. In the presence of GGpp, UBIAD1 releases HMG CoA reductase, leading to its proteasomal degradation. DeBose-Boyd’s lab also discovered a fascinating spatial regulation of UBIAD1, whereby binding of UBIAD1 to GGpp causes UBIAD1 to accumulate in the Golgi apparatus and away from HMG CoA reductase in the ER. Finally, his group found that the SCD-associated mutation N102S in UBIAD1 inhibits the interaction between UBIAD1 and GGpp, such that mutant UBIAD1 is unable to translocate from the ER to the Golgi in the presence of high GGpp.

Üsküdar Üniversitesi NPİSTANBUL Beyin Hastanesi AMATEM Koordinatörü Prof. Dr. Nesrin Dilbaz, TGRT HABER’de Özay Erad’ın sunduğu Sağlıklı Hayat programının canlı yayın konuğu oldu. Dilbaz, “İdeal Ebeveyn nasıl olmalı?” konusuna ilişkin değerlendirmelerde bulundu.

Amongst the items in our Programme this morningEamon Curley Chairman of Beef Plan has details of forthcoming meetings at Kanturk Mart and Kenmare Mart.. Michael Gottstein Head of Sheep Dept and K.T. has some important tips on care of lowland and highland ewes and rams. The ICMSA President Mr. Pat McCormack reviews some of the important matters which came to the fore at the recent ICMSA - AGM in Limerick. The results of a recent ploughing match for novices plus arrangements for a charity tractor/ farm machinery drive on to-morrow, Sunday. Richard White, PRO Cork West Ploughing Association has this information for listeners. and Deputy Michael Moynihan, Fianna Fail Chief whip Whip and TD for Cork North-West tells Farm Programme Editor John O'Connor that recent reports of EU trimming regulations being contravened, allegedly, at Irish meat factories has upset farmers and he wants the identity of the factory or factories which reportedly have had twenty-one fines imposed for EU carcase -trimming contraventions. Plus many other items which will be of interest to the farming and wider rural society..including a heifer contract rearing information event at Corrin Mart , Fermoy, on December with high-powered personnel from Teagasc and ERAD. Technical broadcast operations and Podcast production by John Foott at C103 studios, Gouldshill ( aka Goold's Hill) Mallow, County Cork, Ireland. Overall on-air, sound control and supervision and regulation by John Foott. The Farm Talk Programme is kindly sponsored by farmer-owned, and farmer-operated, co-operative venture Dairygold Co-Operative Society Limited.. Farm Talk is researched, edited, produced and presented by John O'Connor. We hope you find our Programme interesting and useful... Thanks for tuning in to Farm Talk...……………… Farm Talk is broadcast twice -weekly. on Saturday morning from 10 am to 11am and on Wednesday evening from 10pm to 11pm See acast.com/privacy for privacy and opt-out information.

Superhjältemaskar, kossor, myror och spädbarn. Dessutom första delen av introspecialaren där vi spelar introlåtar vi älskade eller hatade!

Maurizio Molinari, Institute for Research in Biomedicine, Bellinzona, SWITZERLAND speaks on "ERAD and ERAD tuning: disposal of cargo and of ERAD regulators from the mammalian ER". This seminar has been recorded by ICGEB Trieste

Late mitotic events are chiefly controlled by proteolysis of key regulatory proteins via the ubiquitin-proteasome pathway. In this pathway ubiquitin ligases modify substrates by attachment of ubiquitin (“ubiquitylation”), which usually results in their subsequent degradation by the 26S proteasome. The crucial ubiquitin ligase involved in late mitosis is the anaphase-promoting complex or cyclosome (APC/C). Among the many substrates of the APC/C is the anaphase inhibitor securin, whose destruction leads to activation of separase, which in turn triggers sister chromatid separation by proteolytic cleavage of cohesin. The APC/C also targets cyclin B1, an activating subunit of Cdk1 kinase, whose inactivation is a prerequisite for mitotic exit. The unstable APC/C substrates are often found in association with stable partner proteins. How single subunits of multi-protein complexes are selectively extracted and eventually degraded is largely unknown, but there is increasing evidence that additional factors assist to extract ubiquitin-carrying subunits from stable binding partners. One such factor is vertebrate p97 (Cdc48 in yeast), an abundant and highly conserved member of the AAA-ATPase family. It is involved in such diverse processes as transcriptional regulation, membrane fusion, and ER-associated protein degradation (ERAD). The unifying scheme in these seemingly unrelated functions is that p97 is able to “extract” preferentially ubiquitylated proteins from their environment. Roles of p97 in mitosis have recently emerged: p97 was reported to be required for spindle disassembly and for nuclear envelope reformation during mitotic exit in Xenopus. Furthermore, a genetic interaction between p97, separase and securin, as well as a requirement of p97 for separase stability, were discovered in fission yeast. Given these hints and the importance of ubiquitylation in both mitosis and p97 pathways, this study intended to elucidate additional mitotic roles of p97 in vertebrates. Towards this end, tools to interfere with p97 function in Xenopus egg extracts were developed. These included immunodepletion of the p97 adaptors Npl4, Ufd1 and p47 and addition of recombinant dominant-negative p97-mutants. ERAD, which could be established here for the first time in Xenopus egg extracts, was greatly impaired in the absence of p97 function. However, many aspects of mitosis were found to be unaffected. Importantly, p97’s proposed role in spindle disassembly was clearly falsified within this thesis. Furthermore, p97 was shown to be dispensable for activity and stability of vertebrate separase. Disassembly of the mitotic checkpoint complex, which prevents premature APC/C activation by sequestering its activator Cdc20, did also not require functional p97 despite its dependence on ubiquitylation of Cdc20. However, a novel function of p97 at fertilization was discovered. p97 was found to interact with nucleoplasmin, a histone-binding chaperone that catalyzes the exchange of sperm-specific basic proteins (SBPs) to histones. Indeed, interference with p97 function delayed sperm decondensation in Xenopus egg extracts, thereby confirming a novel role of this AAA-ATPase in sperm chromatin remodelling. In another project the role of securin in human cells was investigated. Human cells lacking securin had been reported to suffer from massive chromosome missegregation, which was in sharp contrast to the mild phenotype of securin knockout mice. In collaboration with the group of M. Speicher it could be demonstrated that chromosome losses in securin-/- cells are transient and give way to a stable segregation pattern after just a few passages. This was despite persisting biochemical defects such as reduced level and activity of separase. These data demonstrate that securin is dispensable for chromosomal stability in human cells.

Die evolutionär stark konservierte AAA-ATPase Cdc48 aus Hefe (p97 in Säugern) ist an einer Vielzahl zellulärer Prozesse beteiligt, unter anderem an homotypischer Membranfusion und Ubiquitin-vermitteltem Proteinabbau. Verschiedene Adaptoren rekrutieren das hexamere Cdc48 an diverse, meist ubiquitinierte Substrate, die unter ATP-Verbrauch aus Proteinkomplexen oder Membranstrukturen herausgezogen werden. Als bekannte Adaptoren wirken das Heterodimer Ufd1-Npl4 und Shp1, deren Bindung an Cdc48 sich wechselseitig ausschließt. Shp1 gehört zur Familie der UBX (“Ubiquitin regulatory X”)-Domänen-Proteine, deren Vertreter bislang weitgehend uncharakterisiert sind. Ziel dieser Arbeit war es, sowohl allgemeine Eigenschaften als auch spezifische zelluläre Funktionen von UBX-Domänen-Proteinen aufzuklären. Für alle sieben UBX-Proteine aus Saccharomyces cerevisiae (Shp1 und Ubx2 bis Ubx7) konnte eine Interaktion mit Cdc48 nachgewiesen werden. Dabei wurde die UBX-Domäne als allgemeines Cdc48-Bindemodul identifiziert. Weiterhin konnte gezeigt werden, dass UBX-Proteine, die eine “Ubiquitin-associated” (UBA)-Domäne enthalten, mit ubiquitinierten Proteinen interagieren. Für die UBA/UBX-Proteine Shp1 und Ubx2 wurde außerdem ein Einfluss auf die Degradation eines Modellsubstrats des Ubiquitin/Proteasom-Systems festgestellt. Darüber hinaus wurde Ubx2 als neue Komponente des ER-assoziierten Proteinabbauweges (ERAD) identifiziert, über den falsch gefaltete Proteine des Endoplasmatischen Retikulums (ER) abgebaut werden. Bevor ERAD-Substrate ubiquitiniert und durch das Proteasom degradiert werden können, müssen sie aus dem ER ins Zytosol retrotransloziert werden. An diesem Prozess ist der Cdc48-Ufd1-Npl4 Komplex entscheidend beteiligt. Das integrale ER-Membranprotein Ubx2 kann gleichzeitig mit Ufd1-Npl4 an Cdc48 binden und rekrutiert Cdc48-Ufd1-Npl4 an ERAD-Substrate und Komponenten der ERAD-Maschinerie, so dass verschiedene für ERAD benötigte Aktivitäten stabil miteinander verbunden werden. Ubx2 wirkt somit als Koadaptor für Cdc48-Ufd1-Npl4 in ERAD und unterstreicht damit die Bedeutung der UBX-Proteine als neue Familie von Kofaktoren im Cdc48-System.

The majority of eukaryotic proteins are degraded by the ubiquitin-proteasome system. In this pathway, cytosolic substrates are first earmarked for degradation by modification with ubiquitin ('ubiquitylation') and subsequently degraded by the 26S pro-teasome, a large protease residing in both the cytosol and the nucleus. ER-resident proteins are similarly degraded but take the route of a specialized pathway coined ER-associated degradation (ERAD). In order to reach the cytosolic ubiquitin/proteasome system, these substrates must first relocate from the ER to the cytosol, possibly with the help of protein conducting membrane channels. Previous work has shown that specific ubiquitin-conjugating enzymes (e.g. Ubc6, Ubc7) and ubiquitin ligases (e.g. Hrd1) con-tribute to ERAD, but how the substrates reach the proteasome remained to be clarified. Besides its function as a quality control system in recognizing and eliminating aberrant proteins, ERAD appears also to play a part in regulatory pathways. This study focuses on the identification of novel components contributing to ERAD. It could be demonstrated that the yeast protein Cdc48 (p97 in mammals), to-gether with its co-factors Ufd1 and Npl4, plays a key role in this process. Cdc48 belongs to the large family of AAA-type ATPases and is believed to function as a chaperone-like enzyme. Previous work has shown that the Cdc48 complex specifically acts on ubiquitylated substrates. This study indicates that the Cdc48 complex takes part in mo-bilization of ERAD substrates from the ER membrane for proteasomal targeting. Fur-thermore, degradation of some ERAD substrates involves the multiubiquitylation factor E4/Ufd2 and proteasome targeting factors of the Rad23 protein family. Another aspect of this work addresses the regulatory functions of ERAD. The fatty acid desaturase Ole1, an integral membrane protein of the ER, was identified as a novel ERAD substrate. Intriguingly, ERAD of Ole1 is specifically regulated since the protein is particularly short lived in the presence of high levels of unsaturated fatty acids, the products of Ole1. Thus, this feedback loop provides an additional mechanism, by which the cell regulates the amount of unsaturated fatty acids. The t-SNARE (syntaxin) protein Ufe1 was characterized as another substrate of ERAD. This protein is required for homotypic membrane fusion of ER vesicles. Notably, Ufe1 degradation is negatively controlled by its binding partner Sly1, a member of the SM (Sec1/Munc18) protein fam-ily. Reciprocal mutations in the Ufe1-Sly1 interaction face result in rapid degradation of Ufe1 by ERAD. Conversely, strong overproduction of Ufe1 was found to be detrimental for cellular growth. These findings suggest that one important function of Sly1 is to con-trol Ufe1 SNARE levels in order to ensure cellular homeostasis. In conclusion, analysis of the degradation of Ole1 and Ufe1 revealed an important contribution of ERAD to es-sential regulatory pathways.