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WASHINGTON - Congress has returned from a seven-week election break to a long list of unfinished business.
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Did you hear the starter's gun on Monday? Neither did I. But Maryland's politicians, blessed with special dog whistle sensitivity, heard the kickoff shot loud and clear. You see, one year from last Monday is Primary Election Day in one-party Maryland, where, in most cases, the primary is more important than November's general election.
How do we know the politicians heard the dog whistle? Well, just look at some of the crazy stunts they're pulling off.
Ken Ulman is defending Howard County residents against the onerous "rain tax," which takes effect next week. At the eleventh hour (June 20) Ulman asked the County Council to lower homeowners' rain tax rates, soften the blow on nonprofits and delay the Rain Tax until December.
But the rain tax Ulman is now watering down (pun intended) is the same rain tax that Ulman, himself, proposed last winter and which the council adopted in March.
What's changed between March and June? Well, the original rain tax was offered by term-limited Howard County Executive Ken Ulman, the new modifications are offered by lieutenant governor candidate Ken Ulman — the same person, but with a newly heightened appreciation for voters' sensitivities.
Perhaps the two Ken Ulmans can meet and reach a rain tax compromise.
Anne Arundel State Del. Steve Schuh is running for county executive. Last Friday he wrote incumbent County Executive Laura Neuman demanding lower county rain tax rates, relief for some taxpayers and delaying the rain tax's collection date. Sound familiar?
Apparently Howard County's political schizophrenia (or amnesia) has lapped the border into neighboring Anne Arundel. You see, county executive candidate Steve Schuh, rain tax opponent, is the same State Del. Steve Schuh who, last year, voted to impose the rain tax on Anne Arundel and nine other counties.
Perhaps the two Steve Schuhs can conference call with the two Ken Ulmans and arrive at a regional rain tax measure.
Montgomery County's "Farm Road" controversy has percolated in the county courts and government for years. The issue revolves around an old gravel road that the residents of a black community, dating back to a freed slave's enclave, used for decades.
But, in 1999, when an adjoining housing development was approved, Farm Road disappeared from county tax maps. This left the black community with no access, no street addresses and devalued homes.
Now, under pressure from county officials, the county planning board is asking the state planning department to restore the road. However, the restoration is stalled by pending lawsuits.
But wait, here comes the Lone Ranger, State Del. Aisha Braveboy, riding to the rescue. Braveboy, chair of the state legislature's Black Caucus, held hearings in Montgomery County this week focusing media attention on the controversy and on herself.
"We need to have a hearing," Braveboy said. "I want to talk about solutions, I want to know what the facts are, ask the tough questions … look for solutions."
There's only one problem, Delegate Braveboy isn't from Montgomery, she's from P.G. A state delegate since 2006, she exhibited no prior interest in Montgomery's Farm Road dispute until she recently decided to run for attorney general. That's why she's looking for headlines in Montgomery. Her pitch is that Montgomery's state lawmakers have only "written letters," failing to solve the matter, a stunning insult to Montgomery's delegation inflicted without objection.
Imagine Montgomery Sen. Brian Frosh, another attorney general candidate, injecting himself into a purely P.G. local matter by holding hearings, in P.G., on the battle over control of the P.G. school system? Believe me, all hell would break loose!
Del. Jon Cardin, another attorney general candidate, tried to make political hay this month by beating up a few rural sheriffs who refuse to enforce the state's new gun control law.
Cardin's Baltimore Sun op-ed piece, "The Lawless Sheriffs of Maryland," gravely opines that elected officials "take an oath to uphold our laws; they do not have the right to pick and choose which laws they like the most." The sheriffs, said Cardin, are guilty of nullification.
Unfortunately, Cardin is equally guilty of picking and choosing his nullification targets.
How about Gov. O'Malley's six-year refusal to restore Maryland's death penalty? How about Maryland's "sanctuary cities" ignoring immigration laws? How about Frederick's refusal to impose a Rain Tax or Montgomery's refusal to comply with state teacher evaluation standards? Or the state's refusal to comply with a sex offender registry court order until a judge threatened contempt?
Are all these election stunts an insult to our intelligence? You bet, but, sadly, an entire year of it lies before us.
Blair Lee is chairman of the board of Lee Development Group in Silver Spring and a regular commentator for WBAL radio. His column appears Fridays in the Business Gazette. His past columns are available at www.gazette.net/blairlee. His email address is firstname.lastname@example.com.


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Weekend Box Office – Oct. 13-15/2006Tuesday, October 17th, 2006
With the debut of The Grudge 2, this weekend, Sony scores it's 12th number one hit for the year. The sequel to the 2004 hit screamed into theaters to the beat of $22 million. It only cost $20 million to make.
The Departed is still going strong dropping a mere 30%, and bringing in $18.7 million to place second. The gangster related film is poised to become Scorsese's highest grossing film ever.
Starring Robin Wiliams, The Man of the Year had a mediocre debut bringing in $12.6 million to take third place. Rounding out the top five releases, Open Season comes in fourth place with $11million, while New Line Cinema's Texas Chainsaw Massacre: The Beginning places fifth with $7.8 million.
Debuting in sixth place, The Marine pulls in $7 million and the other military themed drama The Guardian fell to seventh place with $5.9 million. The critically panned comedy, Employee of the Month comes in eighth with $5.6 million. Costing only $12 million to produce, the comedy has pulled in $19 million for Lionsgate, since it's debut last week.
Cracking the top ten, One Night With the King places ninth with $4.3 million. The Biblical drama starring Peter O'Toole and Omar Shariff opened in just 909 theaters. Jackass: Number 2 places tenth with 3.3 million.
To purchase the posters for the above-mentioned movies just click on the links below:
- The Grudge 2 – $22.0 million
- The Departed – $18.7 million
- Man of the Year – $12.6 million
- Open Season – $11.0 million
- Texas Chainsaw Massacre: The Beginning – $7.8 million
- The Marine – 7.0 million
- The Guardian - $5.9 million
- Employee of the Month – $5.6 million
- One Night With the King – $4.3 million
- Jackass: Number 2 – $3.3 million


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|21 posts found
I rather liked the orignal game other than a few things (way to easy to kill stuff, way to easy to level, game was a total joke diffculty wise, lving speed of combat able jobs was MUCH to fast you skip most of the world), and now square has gone and made it WORSE than it was. I mean how in the hell is it possible to screw up THAT bad? Seen this video and it pretty much did it for me: https://www.youtube.com/watch?v=_N4G854ANo0&feature=g-all-u
Unless the gameplay majorly changes from now till release, I don't think i'll bother resubbing to the game again. If you check the offical ff14 forums people there are as shocked/pissed off as I am. I was actually looking forward to it, but a better ui and prettier graphics won't be enough for me, I was hoping the gameplay would get better but insted they sort of went backwards. The combat in the orignal game was already piss easy, and now it has been made even easier since you now start fights with full tp, well it'll prob be the same as it was for mages, but for anything that has tp based special attacks the game has just become even more of a total joke.
I need to ask how the hell does square screw up this badly? you think they would know better, what with all the wow-clone mmos crashing and burning lately. The game already had a bad reputation, but at least it wasn't called a generic wow clone.. sadly, now thats what the game seems to be, just the newest generic wow clone.
I'll keep checking to see if it changes for the better but to me the most important thing is a mmo is gameplay, and ff14 has somehow managed to have gone backwards on that aspect with the current changes from what I seen so far. I dunno I am just tired of every mmo thinking that copying wow is the way to go lately.
Our only shining hope is the fact this is a alpha video and hopefulyl square is smart enough to listen to their testers/fans this time, and change things, the whole reason ff14 flopedd orignally is because they totally ignored their beta testers and released the game, many testers posted on the beta forums about the gameplay mechanics and their issues and were totally ignored. Thus the game launched and did horribly due to the dev team not listening, then they patched it and changed alot of the aspects of the game and it got alot better, but it was too little too late, the damage was done. I am just completly taken aback at how they could have actually managed to have gone backwards with the game in terms of gameplay.
Also P.S. I find it halarious how comments are disabled on that youtube video, because we all know people would just call it a wow clone since thats bascally what it might become. This is not meant to be a troll post because I actually enjoyed the game when I played it like less than a year ago. I am just extremly worried about what I am seeing/hearing/reading.
Being a pessimist is a win-win pattern of thinking. If you're a pessimist (I'll admit that I am!) you're either:
A. Proven right (if something bad happens)
B. Pleasantly surprised (if something good happens)
Either way, you can't lose! Try it out sometime!
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Novice Member
Joined: 8/13/08
Every MMO that game out after World of Warcraft can be called a World of Warcraft clone. I watched the video and compared with the old FFXIV it's alot better. From the post you made it looks like your after something like the old FFXI, and them days are dead.
Originally posted by xaus
I know *teardrop* those were good times back then. I had ff11 way back when it first came out in north america, good times. I guess I can give it a chance hopefully they can have a free trial I can take a crack at first.
Being a pessimist is a win-win pattern of thinking. If you're a pessimist (I'll admit that I am!) you're either:
A. Proven right (if something bad happens)
B. Pleasantly surprised (if something good happens)
Either way, you can't lose! Try it out sometime!
Hard Core Member
Joined: 4/17/11
Yes, as stated before those who got the game before will get the game for free and a month free most probably.
Funny how different viewpoints work. That gameplay video turned you off of the game, and it actually had the opposite effect for me, in that I'm now more psyched than ever. I love the atmosphere overall, the quests seem like they'll be well done (although bland at times) from this. The combat seems like it could be a little faster, however. The caster in general seemed to not do a ton of damage to those Hoglets, constantly got interrupted mid-cast, and the spells weren't overly exciting to watch. Dragoon seems a bit more exciting to watch, but I expected to be able to fight multiple enemies a little easier rather than just the usual fighting one while doing a bit of AoE damage on occasion, then having to switch to the other one.
I also noticed that they kept in the repairing by crafters, as on the Fang Earrings or whatever, it said to repair you need Goldsmith Lvl. 4. Looks like crafting is gonna be much more useful than many other games, but I may just be jumping the gun. :p
All in all, I'm really looking forward to this game.
Originally posted by drivendawn
This is good to hear, even if it was a 7 day free thing its enough to determine if i wanted to stay or not.
Being a pessimist is a win-win pattern of thinking. If you're a pessimist (I'll admit that I am!) you're either:
A. Proven right (if something bad happens)
B. Pleasantly surprised (if something good happens)
Either way, you can't lose! Try it out sometime!
Originally posted by Aviggin
I watched more of the vid and seen that lv 15 lancer lose over half his hp to 2 lv 11 monsters. If the final game is like that, it might be good cuz the enemies in ff14 when i played were complete pushovers due to their very low hp. He would probally have died if it was a pair of lv 13 or 14 monsters.
Being a pessimist is a win-win pattern of thinking. If you're a pessimist (I'll admit that I am!) you're either:
A. Proven right (if something bad happens)
B. Pleasantly surprised (if something good happens)
Either way, you can't lose! Try it out sometime!
Novice Member
Joined: 10/21/09
Originally posted by Aviggin
Indeed! Game seems to look and play alot better than 1.0. Hopefully they will release footage of Summoner at least and perhaps Blue Mage(wishful thinking).
Hard Core Member
Joined: 1/25/12
I'm only playing the role chosen for me. Who you supposed to be?
Didnt touch FF XIV due to the amount of issues I heard with it. As a FF fan since 1987, and viewing that video in the topic -- I am definitely excited to check this out.
I just hope there is more to the game than just (linear?) questing? If they add other systems to give the game some 'life' I might stay longer than 1 month.
But MMO's track reocord isnt promising....
Originally posted by Siveria
Yeah, I really don't mind it taking a bit of time and making grouping shorten things so people may not thinking of soloing as the "best" option all the time.
I just sorta remember it being advertised that you'll be fighting multiple monsters a lot, and the game was designed around it. Maybe I'm thinking of the wrong game. lol
Still, it's in no way a deal breaker, and is likely a better option in the end.
Originally posted by VaultFairy
Yeah, I wouldn't mind a look at the Summoner myself. Was pretty damn fun in FFXI, and I wonder how many summons will be available and how they'll play...
Novice Member
Joined: 11/10/12
I was a 5 star elite member but my awesomeness was showing and the Mods cant have that
is the.combat the same as wow? what about story? is the party system wow or ffxi ? is the class / job system ffxi or wow ? is the crafting and gathering wow or FF? other then gaining exp for quests in really finding it hard to say this is a WoW clone . It no way is like wow maybe instances raids and exp questing
http://absoluteretribution.enjin.com/ Guild Website and Recruitment link
Novice Member
Joined: 4/04/09
Originally posted by Siveria
And why is XI dead? Its still going. XIV won't change that. Everquest II didn't kill Everquest and they are both still going with content updates too. As for XI, it also has a new expansion coming out. You can always go back, its still there for you :)
Originally posted by Aviggin
The bigger the party size the more mobs will link on the initial pull, in a full party you can sometimes pull 3 or 4 mobs at once, this is normal, you'll hit one and 2-3 others will get a ! too saying they aggroed as well. Sadly alot of the tanks I have seen when I played had no damned clue what they were doing, but its generally better to spread out the aggro a bit anyway, around the melee dd/tank jobs. If your solo you might get up to 1 link depending on what they con to you, if they are a lv or few below you, usually 2 would come at you insted of just the one you hit, it kept it intersting, because it wasn;t guarnteed you'd always get 2. But from what I see in ARR monsters were made stronger, because in 1.0 2 mobs 4 levels lower than me would barely have been able to touch me, yet in one alpha video 2 lv 11 mobs did over half hp to a lv 15 char, so thankfully the mobs aren't total cakewalks now.
Being a pessimist is a win-win pattern of thinking. If you're a pessimist (I'll admit that I am!) you're either:
A. Proven right (if something bad happens)
B. Pleasantly surprised (if something good happens)
Either way, you can't lose! Try it out sometime!
Novice Member
Joined: 4/10/09
Originally posted by dreamsofwar
FFXI is no longer FFXI
Novice Member
Joined: 4/10/09
Originally posted by DarknessReign
I think his issue was with how easy the game appeared
Apprentice Member
Joined: 8/06/08
Actually everything OP said sounds pretty delightful. Now, I'm almost interested.
"Forums aren't for intelligent discussion; they're for blow-hards with unwavering opinions."
Advanced Member
Joined: 12/02/09
Originally posted by darkhalf357x
Bear in mind that XIV has you level all classes/jobs on one character and that the questing won't cover more than a few of them. It works the same as XI did; once a quest is done, it's done, regardless of if you switch jobs. It will actually be impossible to use questing as your entire means of progression after the first few jobs.
We also already know of a fair few systems to give the game variety from housing to chocobo raising and the eventual golden saucer (which will be post-launch). Suffice to say there is a LOT on offer in ARR besides the usual one-dimensional levelling grind.
Apprentice Member
Joined: 12/02/10
Originally posted by Siveria
I rather liked the orignal game other than a few things
Most people didn't.
That is rather an important factor in this issue. I apologise if I am reading you wrong and you are not a member of the "1.0 is right and every other game is wrong!" crowd, but none-the-less I feel the need to get a few things of my chest.
That may be for those that got into it, but it was very hard for everyone else, having to fight the nightmare UI, controls, server lag, combat mechanics, world layout, lack of engine optimisation and quest system on top of all the mobs.
At this point I thought you were being satirical, it was a tedious grind that never ended, and skipping the world? What world? Empty, copy and pasted and therefore uniform, server stressing boredom zones isn't a world. Why do you think they are going to the expense of completely re-designing them?
Seen these? You do know this is basic demo footage of one feature from an ALPHA right? have you seen alpha footage of FFXIV 1.0? (few have and lived to tell the tale, after they died laughing) Seriously, this is just basic combat and questing, industry standard, to ease players who arent part of the FFXIV 1.0 cult of "Tanaka the Martyr".
They can't afford to pursue subs from players like you, there aren't enough who like the asinine design philosophy of 1.0, (how weird is that right?) that's the whole point of re-booting the game, and a large franchise requires mainstream appeal. This isn't an indie project aiming for a niche player base.
Yes I know, and also a bunch of people pointed out what a bunch of elitist cry babies they are. (you should hear what they say about them on the Alpha forums)
What where you looking forward to exactly? Everything we saw was what Yoshida said would be there over a year ago.
Its not about prettier graphics, the previous engine was crap and wouldnt run on a PS3
How is going for more fluid real-time combat backwards from a jarring turn-based camera and NPC/PC lock? Backward would be going into a separate, fixed camera screen after hitting a random invisible spawn, into a turn based, side view to cheesy synth-rock and dramatic camera pans during combat animations. Heck, that sounds more fun and at least would fully exploit turn based strategy better than this half-arsed nonsense.
FFXIV 1.0s combat wasn't just backwards, it was slow and lacked immersion as all you did was trigger combat animations, not actually fight yourself.
All you saw was a couple of low lvl battles against mobs lower than the player, how can you make such an evaluation? Especially as you seem to think 1.0 was too easy already? what is your point of reference? Why not just play Dark Souls if everything is too carebear for you?
All they've screwed up so far is their gameplay trailers. I agree that this is not well presented, but this trailer is not the entire game at launch.
Yes, I am sure they know this, so perhaps it isn't going to be a WoW clone just have the standard elements that a overwhelming majority of people that abandoned the game at launch asked for? Maybe they know what they are doing and it is too soon to jump on the WoW-clone band wagon over a couple of mins of alpha footage? Maybe?
No, it was just the worst mmo ever made, a truly original disaster that cost 10s of millions of dollars, 1 veteran dev his reputation and that of a leading game franchise and its publisher, and required more people to fix it than made it originally.
I can't go into details without breaking the NDA, but Yoshida has managed to make a far, far better engine in less than 2 years than "Tanaka the visionary" managed to in 5. That, due to a vastly better server, UI, npc interaction and quest system you can now appreciate the fundamental parts of the game such as the armoury, crafting and lore that where hidden under the most counter-intuitive design I have seen in 30 yrs of computer gaming.
That bandwagon must be made of chocolate or something...
Well, at least we agree of something.
Backwards from endless leve grinding? sub-titled cutscenes and constant back-tracking across a sprawling empty world? The Link pearl system????? You think FFXIV 1.0 was a step forward from WoW????
There is a reason people copy it (and no one will ever copy FFXIV 1.0) apart from laziness, it's a good design, now many parts can, and should be ignored, but try to re-invent the UI, combat, world and town layout, npc interaction, basic movement etc with no knowledge of what has already been shown to work and you alienate all but the most "unique" tastes.
ARR is not going for just a WoW friendly audience, they have stated many times that there are still features from 1.0 such as leves, crafting, armory, etc remaining, and other parts from FFXI and previous FF games now. All they did was change from leves/behests only to a few quest hubs that you only get to see with your first few classes and combat that doesnt put you in a coma.
They are listening to everyone, the changes from alpha to beta will be extensive, but they are not going to remove user friendly and standard features because of it reminds some people of WoW, (what a shock) or, based on some posts I've read, whiny elitists stuck in the past.
Not quite true. By the time FFXIV 1.0 was in beta it was too late, Tanaka was an arrogant fossil that built the entire game from the very start on the wrong engine designed to run cut-scenes, not render multiple players in the same area, dooming expansions, the PS3 release and any hope of getting people with cheaper PCs to play.
The server code was impossible to work with right to the end, hence the issues with the server shut down event. None of the devs could process so many complaints and demands for features known to work in other mmos as none of them knew of any other mmos. Nothing but a complete scrapping of the game and dev team would have worked in the long run, the testers where wasting their time.
Again, what could they have done? You cant patch away the wrong engine or server tech. Even if they had tried to implement every request, it would have delayed launch by at least a year, and been pointless anyway with no sound foundation.
Not when I played it, engine, server, UI, combat, npc interaction, quests, still shite. Yoshida did add some thing for mid to high lvl players, but if you couldnt get past the flaws they didnt change anything. That's why they didnt bother to get new players in, just keep the old ones sweet. ARR is designed to appeal to those not already in, i.e. not you. Most of the early content won't apply to you anyway.
Again I don't get this phrase "backwards" 1.0 wasn't like anything I have ever played, it wasn't an improvement on WoW or any FF game before. FF7 or 8 had better UI and combat. As did the earlier Square Soft games like Secret of Mana or Chrono Trigger. How is a game built with no knowledge of mmo industry standards, not even of the most well known mmo somehow ahead anything? If this was the case why did it get a unanimous panning from the critics? Is everyone outside the small 1.0 appreciation society missing something?
Comments are disabled on all SquareEnix YouTube videos, it's standard company policy.
That doesn't make you a troll; it simply damaged the credibility of your taste in games.
Even though it was what everyone asked for from the start, and what Yoshida always promised?
The problem is that a lot of those that decry the current changes do not want 1.0 to go away, cannot see the flaws, know very little of other mmos outside of FFXI, and therefore do not know what XIV was/is missing, and react to anything that is remotely like WoW as a unholy blasphemy against their dark Gods of shitty game design. (I am not saying you are one of them, not knowing your gaming background, but their mentality means many criticisms of ARR cannot be taken seriously).
I've been reading posts from the old guard with growing disbelief, and one question keeps popping into my mind.
Are these types of 1.0 fans on crack?
The End.
Novice Member
Joined: 5/07/11
Besides the horrible UI and bad engine/server tech 1.0 had, I agree. I actually liked the retainer system of 1.0 (reminds me of Mabinogi and Ultima Online vendor shopping, two games I'm currently playing on and off). I liked the stamina gauge for battles that existed before Yoshi-P took over. I liked the no required levels for gear, but rather suggested levels that scale the gear based on it and your current level. I liked how you had to get other players (or yourself if you've leveled a crafting class) to repair your gear as they could repair fully rather than the 25% NPC's could before it was changed. And I liked the multiple steps to craft a piece of gear.
I have the XIV collectors edition, the XIV licensed gamepad, and a legacy account - I didn't unsub until after Yoshi-P took over and started changing things, as it began molding the game into something I didn't buy originally. I checked in a few times afterwards, staying for a few days of my subscription and eventually leaving. He added some nice things, like the Materia system, but it seemed all the defining features the game had (whether they were to your liking or not is a different story) and replaced with the same ones you can find in a good majority of MMO's.
I'm going to play 2.0 at launch because of the free month offered, but judging by initial impressions from released videos and answers gave by Yoshi-P in interviews I won't be playing long term.


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text:
- Cell cycle (1)
- Cerebellar ataxia (1)
- Frontotemporal dementia (1)
- Lipid trafficking (1)
- Motor neuron disease (1)
- RNA processing machinery (1)
- Transcriptome (1)
- Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration (2009)
- Background Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD. Methodology/Principal Findings Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of alpha-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. Conclusion Thus, aging Pink1 -/- mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.
- ATXN2-CAG42 sequesters PABPC1 into insolubility and induces FBXW8 in cerebellum of old ataxic knock-in mice (2012)
- Spinocerebellar Ataxia Type 2 (SCA2) is caused by expansion of a polyglutamine encoding triplet repeat in the human ATXN2 gene beyond (CAG)31. This is thought to mediate toxic gain-of-function by protein aggregation and to affect RNA processing, resulting in degenerative processes affecting preferentially cerebellar neurons. As a faithful animal model, we generated a knock-in mouse replacing the single CAG of murine Atxn2 with CAG42, a frequent patient genotype. This expansion size was inherited stably. The mice showed phenotypes with reduced weight and later motor incoordination. Although brain Atxn2 mRNA became elevated, soluble ATXN2 protein levels diminished over time, which might explain partial loss-of-function effects. Deficits in soluble ATXN2 protein correlated with the appearance of insoluble ATXN2, a progressive feature in cerebellum possibly reflecting toxic gains-of-function. Since in vitro ATXN2 overexpression was known to reduce levels of its protein interactor PABPC1, we studied expansion effects on PABPC1. In cortex, PABPC1 transcript and soluble and insoluble protein levels were increased. In the more vulnerable cerebellum, the progressive insolubility of PABPC1 was accompanied by decreased soluble protein levels, with PABPC1 mRNA showing no compensatory increase. The sequestration of PABPC1 into insolubility by ATXN2 function gains was validated in human cell culture. To understand consequences on mRNA processing, transcriptome profiles at medium and old age in three different tissues were studied and demonstrated a selective induction of Fbxw8 in the old cerebellum. Fbxw8 is encoded next to the Atxn2 locus and was shown in vitro to decrease the level of expanded insoluble ATXN2 protein. In conclusion, our data support the concept that expanded ATXN2 undergoes progressive insolubility and affects PABPC1 by a toxic gain-of-function mechanism with tissuespecific effects, which may be partially alleviated by the induction of FBXW8.
- Dysregulated expression of lipid storage and membrane dynamics factors in Tia1 knockout mouse nervous tissue (2014)
- During cell stress, the transcription and translation of immediate early genes are prioritized, while most other messenger RNAs (mRNAs) are stored away in stress granules or degraded in processing bodies (P-bodies). TIA-1 is an mRNA-binding protein that needs to translocate from the nucleus to seed the formation of stress granules in the cytoplasm. Because other stress granule components such as TDP-43, FUS, ATXN2, SMN, MAPT, HNRNPA2B1, and HNRNPA1 are crucial for the motor neuron diseases amyotrophic lateral sclerosis (ALS)/spinal muscular atrophy (SMA) and for the frontotemporal dementia (FTD), here we studied mouse nervous tissue to identify mRNAs with selective dependence on Tia1 deletion. Transcriptome profiling with oligonucleotide microarrays in comparison of spinal cord and cerebellum, together with independent validation in quantitative reverse transcriptase PCR and immunoblots demonstrated several strong and consistent dysregulations. In agreement with previously reported TIA1 knock down effects, cell cycle and apoptosis regulators were affected markedly with expression changes up to +2-fold, exhibiting increased levels for Cdkn1a, Ccnf, and Tprkb vs. decreased levels for Bid and Inca1 transcripts. Novel and surprisingly strong expression alterations were detected for fat storage and membrane trafficking factors, with prominent +3-fold upregulations of Plin4, Wdfy1, Tbc1d24, and Pnpla2 vs. a −2.4-fold downregulation of Cntn4 transcript, encoding an axonal membrane adhesion factor with established haploinsufficiency. In comparison, subtle effects on the RNA processing machinery included up to 1.2-fold upregulations of Dcp1b and Tial1. The effect on lipid dynamics factors is noteworthy, since also the gene deletion of Tardbp (encoding TDP-43) and Atxn2 led to fat metabolism phenotypes in mouse. In conclusion, genetic ablation of the stress granule nucleator TIA-1 has a novel major effect on mRNAs encoding lipid homeostasis factors in the brain, similar to the fasting effect.


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This designer inspired oval cut canary cz vintage style ring is very elegant. The pretty canary cubic zirconia sparkles in it's high setting against the sterling silver accented with gold tones. The detailed antique style band ensures you will get that designer look for less! The center cz in this vintage style sterling silver ring measures 3/8 inch wide and weighs apx. 3 carats. If you looking for a victorian style ring, this vintage style canary cz sterling silver ring is the perfect choice for that special occasion.
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text: Natalie Caula Hauff covers criminal justice and breaking news. She joined The Post and Courier staff in 2012. Before that, she covered general news at ABC News 4 (WCIV-TV) in Charleston for five years. Natalie also worked as a reporter, anchor, and assistant news director for the National Public Radio affiliate, Mid-Florida Public Radio in Gainesville, Florida. She graduated from the University of Florida and is a proud Gator despite the fact that her husband is a Gamecock.