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Messenger information.
Author: anon
Date: 06-06-04 00:15
Dan, I used to work over at Hotmail, which also maintains the MSN/Windows Messenger network. I wish to remain anonymous, just because. :P
What Microsoft tells you about getting your own logs is quite true. They don't provide details to *anyone* without a court order. That includes the FBI and state or county police departments. The only exclusion applied (but still required a letterhead for verification purposes) was in the case of physical harm (suicide, death threats, rape, etc.), which resulted in a call to Legal regardless of the hour (day or night).
As far as what the Messenger network actually logs, none of us really know -- yes, even those who maintained the servers and kept things flowing aren't sure what was logged. Messenger is one of those "gray area" things, even inside of Microsoft. But, I can tell you that connection logs (but NOT conversational logs) are likely kept, due to some of the equipment used for the service.
I'll be placing a small donation to you regardless. Hopefully enough members of the BSD community will come forth and help you get a replacement, if not something better.
Best of luck in the future!
Reply To This Message
Re: Messenger information.
Date: 06-06-04 00:57
anon wrote:
> What Microsoft tells you about getting your own logs is quite
> true. They don't provide details to *anyone* without a court
> order.
The irony of this situation is that I'm asking for my own logs. My logs for my account.
I find it quite depressing and sad when I think that my laptop is out there being used and there's information in a log at MSN which might help us catch the thief. That leaves me a sense of complete powerlessness.
Sure, here, take my laptop, there's no way we can catch you..... Even if you do use my accounts without my permission. Go for it. You have MSN's blessing.
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Re: Messenger information.
Date: 07-06-04 02:24
I have been an avid reader of your site for quite some time now. I have followed your track record of misfortune - from losing your job to losing your laptop, to exploding NICs and nonfunctional parts. But this stubbornness from M$ has to be most annoying.
I don't have any idea to share with you on how to proceed, other than to convey my best wishes.
Just so you know, I have learned much from your experiences with FreeBSD. I have lived through working with 2.2.7-release, then 3.5.1-release, then almost all the 4.x- and the 5.x-releases. It is encouraging to know that someone somewhere out there has at one point banged his head against the wall and lived through what I am living through right now.
Best wishes, and keep those entries coming.
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Re: Messenger information.
b. s. duser
Date: 08-06-04 05:16
Really it can't be that hard to get a court order. Ask, and you shall receive. Worth a try.
Don't just think about the past logs, which may or may not get lost. The perpetrator will no doubt connect again and again.
Looking forward to hearing how it works out if you manage to get the IP addresses!
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Re: Messenger information.
Author: truant
Date: 08-06-04 12:26
Hey, I was sitting here the other day at one of my machines, the *only* one that even has an MSN account setup on it, and I'm the ONLY one who knows the password. When... all of a sudden it kicks me off and says... 'someone else has signed into this msn account' --- I tripped out, ran to hotmail.com or where ever and change my password...... anyway, long and short of the story, no-one actually signed into my account... I just got that message for some weird reason... that would've been in May of this year (05) -- I've never seen that happen in my 6 or so years of having this account - just thought I'd let ya know.
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Re: Messenger information.
David Eriksson
Date: 16-06-04 11:46
You wrote that you don't want to buy off ebay, but maybe if IBM is the seller?
Anyway, good luck getting back the laptop or getting a new one!
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Re: Messenger information.
Author: anon
Date: 17-06-04 18:05
Wishful thinking, but if you could use another account and attempt to 'trick' them into accepting a file, or video/voice connection, I *believe* that Messenger would create a direct connection to the other user. You would then be able to do a netstat and see the connected addresses. Unfortunately, this is not a very probable solution.
Best of luck in your recovery efforts.
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Re: Messenger information.
Date: 17-06-04 18:08
Many have noted this. Unfortunately, they were only on once. At least I think they were on. MSN refuses to confirm or deny whether or not my account was used from an IP other than my home (which has a static IP).
I have also not had a response to my registered letter.
Reply To This Message
Re: Messenger information.
Author: Graham
Date: 28-06-04 09:15
I empathise with your situation but wonder why you use M$N in the
first place (sorry if this is obvious elsewhere)
I personally avoid anything M$ unless I absolutley have to get involved
in my work as a support tech.
If it wasnt for that I would blacklist all their sites / services altogether,
particularly in light of your situ :(
I am sure there are others sharing my feelings.
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Re: Messenger information.
Author: Dan (Monday USENIX)
Date: 28-06-04 12:17
Graham wrote:
> Dan,
> I empathise with your situation but wonder why you use M$N in
> the
> first place (sorry if this is obvious elsewhere)
I'm using MSN Messenger to communicate with people. I find it odd that I need to justify that.
Reply To This Message
Re: Messenger information.
Author: Graham
Date: 28-06-04 22:32
ICQ, Yahoo Messenger, Yahoo Chat, Trillian, Internet Relay Chat . . . .
Email ?
Theres alot of alternatives - still its up to you :)
Reply To This Message
Re: Messenger information.
Author: Dan (USENIX)
Date: 29-06-04 04:13
Graham wrote:
> ICQ, Yahoo Messenger, Yahoo Chat, Trillian, Internet Relay Chat
> . . . .
> Email ?
I use some of those as well. I think you are missing the point. I feel no need to justify this.
> Theres alot of alternatives - still its up to you :)
No, it's also up to the people I wish to communicate with.
Reply To This Message
Re: Messenger information.
Author: Graham
Date: 29-06-04 10:04
You are right, you dont need to justify anything - you have a great site
and have enabled Phorum which is a great way of communicating too.
I try and convince people I want to communicate with to use a method
which I believe to be safer / more efficient etc.
As its a two way thing then yes, its up to both parties.
Your point : Lack of M$ action on your behalf
Mine : Stop using their software or accept the in-adequacy
Sorry about your laptop BTW - mine was removed from a college
classroom whilst I popped out to get some notes :(
Reply To This Message
Re: Messenger information.
Author: Dan (USENIX)
Date: 29-06-04 12:11
Graham wrote:
> Your point : Lack of M$ action on your behalf
> Mine : Stop using their software or accept the in-adequacy
The above quoted statements are indicative of a strong anti-MS feeling. I do not share those views.
I use and have used MS software since Windows 2.11. I am a firm believer in using the right tool for the job, whatever that job may happen to be.
My frustration at being unable to extract information from MSN with regards to this incident could just as easily be directed at the owners of
"ICQ, Yahoo Messenger, Yahoo Chat, Trillian, Internet Relay Chat . . . .". Should that have been the case, I would not have abandoned that communication tool either.
I get the idea that you would not be making similar comments if the incident had occurred with ICQ. You do not like MS. Please do not use this forum to attempt to spread your philosophy.
Thank you
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Re: Messenger information.
Fred Stone
Date: 02-07-04 14:53
Sorry about your loss dude. But really you shouldn't feel so left out in the cold by MSN. I say this having been robbed at knife point in Houston, had my car stolen in LA, my house broken into in Dallas, attacked in the subway in NYC and various other things that some of the more pleasant folks in our society have visited upon me.
In every one of these instances the police would only pay lip service to the crime. Even when I knew who the perp was and where they could be found. The police really have an attitude about this kind of stuff. I guess they see so much of it they just become jaded to it all.
It really is a pisser though when I'm stopped by the cops for going 50 MPH in a 45 MPH zone. They seem to be able to find out anything they want to here but ask them to go and arrest the guy who stole my refrigerator, well unless I produce a video tape showing the crime in progress and personally bring the perp into the station, the cops may as well not exist.
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Re: Messenger information.
Kevin B
Date: 14-07-04 14:47
> In every one of these instances the police would only pay lip service to the crime.
> well unless I produce a video tape showing the crime in progress and personally bring the perp into the station, the cops may as well not exist.
How true. I was tazed (aka stun-gunned) at the gas station where I worked in a failed robbery attempt. I say failed because the guy paniced when I did not go down -- I guess he didn't expect someone who wouldn't panic when electrocuted. We had video, finger-prints, and a license plate number. As well as visual confirmation on the color and make of the car from the police themselves... who saw the car before I was robbed and thought it looked suspicious.
They never arrested the guy. Never. They did fingerprint me and my company demanded a drug-test because I had been injured on the job. I have lost so much faith in the police.
Then, when there is a computer error and my license ACCIDENTALLY gets suspended without telling me... the pigs want to toss me in jail for a couple of days until I can get a judge to believe my insurance company.
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Re: Messenger information.
Author: raymond
Date: 22-08-04 00:32
what about setting up a email from batch to send it self once a week to your email to a server that you have some rights to with some logs of connection and or ping your connection batch or Task Scheduler as it static connection
Reply To This Message
Re: Messenger information.
Date: 31-08-04 14:29
What i would do is create another MSN account and use Miranda IM to connect to MSN instead of the Microsoft client. Then you would add the address the thief is using on your contact list and turn on protocol logging in Miranda. If he logs in again, you should immediately see his ip adress in the logs when the plugin downloads the avatar pic.
P.S. You can download the latest build of Miranda IM at: http://miranda-icq.sourceforge.net/alpha
Only the latest builds allow logging so be sure to install a nightly.
Reply To This Message
Re: Messenger information.
Date: 31-08-04 14:30
P.S.S. Oh, be sure to enable Avatar support in the MSN plugin options once installed..
Reply To This Message
Re: Messenger information.
Date: 22-09-04 15:10
I have read about your laptop please have a look at our site we have a new product which is brilliant for protection and if you would have had this it would of not have gone missing in the first place .... please look at our site www.secureitsafe.com you can use this safe anywhere i promise also tell your boss you and your colleagues need one!!!!!!!!!! looking forward to your comments
Kind regards
Reply To This Message
Date: 13-10-04 04:20
Hi Dan,
I wondered if you could tell me for how long MSN keeps logs of their last IP ?
(please send a link to my email address with your reply..tahnk you.)
my email is soniared2002 .at. hotmail.com
Reply To This Message
Re: Messenger information.
Ted Mittelstaedt
Date: 23-01-05 09:04
Hi Dan,
Two comments I will make on your logging incident.
I work at an ISP. back in 1999, we got our first (and only, so far)
subpoena from the FBI asking for records. Unfortunately, at that
time we only were keeping detail records of dialup calls for 3 months and
the subpoena wanted them back 6 months previously so we couldn't
help the FBI.
Immediately following that I changed log settings on everything
to hold detail records for a -minimum- of ONE YEAR. At that time this
was somewhat of a burden as large disk drives were still rather
expensive, not to mention you need a lot of CPU power to read
through a years worth of radius detail records, even if they are in a
mysql database as ours our. Fortunately today this isn't an issue.
I think you should push the cops to get a subpoena for those
records. I'm sure your going to get a lot of bullcrap from people
claiming that they purged the records, etc. but the simple facts of
the matter are that with storage as cheap as it is, and people as
litigious as they are today, it's obvious to me that MSN has
records that extend back for probably many years.
As you say you have a right to those records. Of course MSN is
going to try to stall you because the flappers that isolate you from
the people that do the real work, don't want to spend the money on
the labor to get them. But, MSN has put an attractive nuis.. I mean public
service up on the Internet and they have a responsibility to the
public to assist in criminal investigations that involve that. I can
certainly tell you that if the ISP I work at was running Messenger
you would have had your records already. Not every company
views providing data to assist a criminal investigation as a
nuisance. For damn sure I would much rather be digging out old
logs to catch a thief than helping Grandma Moses yet once again
to figure out how to send e-mail in her weekly time-wasting
phone support call.
And as for my second comment I'm going to say it anyway even
though you don't want to hear it - there's a lot of alternatives to
MSN Messenger. I have never used it in the past and certainly
would not use it in the future, and I have never suffered from doing
so. Although I will admit I am biased - because MSN directly competes
against my employer who pays me and therefore enables me to
buy food. Paying money to competitors of your employer is pretty
self-defeating in my book. You might keep this in mind next time
you feel the need to make a comment along the lines of the
right tool for the job.
Reply To This Message
Re: Messenger information.
Shawn Pinet
Date: 03-02-05 08:25
As an aside, you might want to look into other applications that communicate with the internet in this case. In my case I've helped in a few cases with distributed.net where we've had PC's and/or laptops get stolen and we've got the IP's logged of the clients as they connect, and once the person had that information they could contact the ISP (etc. etc.)
I've been reading your site for years, so if I can help, it's worth it. :)
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text: Kosmor :: View topic - Prespective date for Tournament??? Imprint Search Log in Legal Memberlist Profile Prespective date for Tournament??? Goto page 1, 2, 3, 4, 5, 6 Next Kosmor Forum Index -> Kosmor Tournaments View previous topic :: View next topic Author Message e1567Guest Posted: Sun Dec 05, 2004 18:44 Post subject: Prespective date for Tournament??? This question is for the moderators: I know that prensently no one really has an idea when this tournament will start so I would like to ask the mods directly. I am going out of town soon and will be away from a computer for 3 weeks and I would be throughly dissapointed if I couldn't enter the tournament. But if I know ahead of time I'm sure I can find a library or somthing. So is there a possibility that the tournament will be in December or at the beginning of January. Thank you for you time. Back to top TriacGuest Posted: Sun Dec 05, 2004 18:50 Post subject: the tournament will start if kosmor have 500 user Back to top e1567Guest Posted: Sun Dec 05, 2004 19:00 Post subject: thanks for the reply but I wanted the mod to answer because if you followed the other thread it was said they were mostly waiting for the new server so like I said I would like a mod to answer to clarify. Back to top TadrGuest Posted: Mon Dec 06, 2004 00:29 Post subject: An answer from the mod Maelstroem wrote: We will start the first international tournament, when there are 500 Users... Back to top e1567Guest Posted: Mon Dec 06, 2004 01:44 Post subject: ok well then is that just 500 pro users or not. Like I said I would like an answer from a mod not a quote from a mod. Thank you though Back to top ZayNGuest Posted: Mon Dec 06, 2004 05:42 Post subject: 500 pro users? maelstroem would be happy, when everyone in this game is a pro user no, of course, when there are 500 players, equal if he/she ist pro user or not. Back to top e1567Guest Posted: Mon Dec 06, 2004 13:18 Post subject: well thankyou for you guess but I as i have said 3 times so far I would like to hear this from a mod. And possibly an answer to my other question. Back to top MerthosGuest Posted: Mon Dec 06, 2004 13:20 Post subject: Oh come one, Maelstroem has a lot of better things to do than to give you the same answer as we do. Back to top e1567Guest Posted: Tue Dec 07, 2004 13:07 Post subject: This question is withdrawn since the residing mod doesn't know and I don't want to bug maelstrom about such a trivial thing. Back to top MaelstroemCommanderJoined: 30 Jan 2004Posts: 432Location: Munich, Germany Posted: Wed Dec 22, 2004 14:59 Post subject: No problem bugging. I had a lot to do in the last days, but it is getting a bit better To start a .com tournament we first have to install the new server. After doing some serious security stuff necessary (like upgrading phpBB) and introducing the delete-protection for users, we will work on improved tournaments among other things. It will take some time though, but i would say within 3 months from now, there should be a fair chance to see a .com tournament. Bye, Maelstroem_________________Commander Maelstroem in the house Nemesis Back to top alphabravoMajorJoined: 15 Feb 2004Posts: 827Location: UK Posted: Wed Dec 22, 2004 16:20 Post subject: YAY... there will be a tourni it will be almost 3 months just another thing... is pro-user supposed to cost more in .com?_________________Major alphabravo in the house Thalgados-Sissyhood Back to top Templar_scumGuest Posted: Fri Mar 04, 2005 15:43 Post subject: How will a tourni work with 10 minuite 10 days, the person who plays the longest wins Back to top alphabravoMajorJoined: 15 Feb 2004Posts: 827Location: UK Posted: Fri Mar 04, 2005 18:27 Post subject: touri is soon and each "day" lasts 10 minutes, and the whole thing lasts a few hours_________________Major alphabravo in the house Thalgados-Sissyhood Back to top Templar_scumGuest Posted: Sat Mar 19, 2005 04:43 Post subject: So its an excuse to miss school/work Back to top fernGuest Posted: Sat Mar 19, 2005 04:57 Post subject: great! Coltz, it will most likely be german midday, so you MIGHT be out of school Probably a weekend any way Back to top Display posts from previous: All Posts1 Day7 Days2 Weeks1 Month3 Months6 Months1 Year Oldest FirstNewest First Kosmor Forum Index -> Kosmor Tournaments All times are GMT - 6 HoursGoto page 1, 2, 3, 4, 5, 6 Next Page 1 of 6 Jump to: Select a forum Information----------------NewsGalactic News Community----------------Kosmor TalkKosmor TradeKosmor TournamentsKosmor RPG Support/Feedback----------------Questions and AnswersFeedback / suggestions for improvementBug-Reports You cannot post new topics in this forumYou cannot reply to topics in this forumYou cannot edit your posts in this forumYou cannot delete your posts in this forumYou cannot vote in polls in this forum Powered by phpBB © 2001, 2002 phpBB Group


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Download PDF of MacArthur Fellows FAQs.
The MacArthur Fellowship
What is the MacArthur Fellowship?
The MacArthur Fellowship is a five-year grant to individuals who show exceptional creativity in their work and the prospect for still more in the future. The Fellowship is designed to provide recipients with the flexibility to pursue their own artistic, intellectual, and professional activities in the absence of specific obligations or reporting requirements. There are no limits on age or area of activity. Individuals cannot apply for this award; they must be nominated.
What are the selection criteria?
The selection decisions focus primarily on exceptional creativity, as demonstrated through a track record of significant achievement, and manifest promise for important future advances. Emphasis is placed on nominees for whom our support would relieve limitations that inhibit them from pursuing their most innovative ideas. The MacArthur Fellowship is not a lifetime achievement award; we are looking for individuals on the precipice of great discovery or a game-changing idea. Recipients must also be citizens or residents of the United States and must not hold elective office or advanced positions in government as defined by statute.
What do the recipients receive?
The stipend for the MacArthur Fellowship is currently set at $625,000, paid in quarterly installments over five years.
Why are no strings attached?
The MacArthur Fellowship is designed to provide seed money for intellectual, social, and artistic endeavors. We believe that highly motivated, self-directed, and talented people are in the best position to decide how to allocate their time and resources. By adopting a "no strings attached" policy, we provide the maximum freedom for the recipients to follow their creative vision, whether it is moving forward with their current activities, expanding the scope of their work, or embarking in entirely new directions. There are no restrictions on how the money can be spent, and we impose no reporting obligations.
What fields are generally represented among the recipients?
We consider creative people applying their talents across the widest possible range of activities, rather than a pre-determined set of fields. Some expand traditional disciplines in unexpected ways, others synthesize ideas from apparently disparate fields, still others undertake endeavors that defy easy classification. Our recipients have included scientists, historians, poets and novelists, artists and composers, and people working in public service, but many work outside of conventional disciplinary categories. Search Fellows by area of focus.
How does the program define "creativity"?
Creativity comprises the drive and ability to make something new or to connect the seemingly unconnected in significant ways so as to enrich our understanding of ourselves, our communities, the world, and the universe that we inhabit. Creativity can take many forms: asking questions that open onto fields of inquiry as yet unexplored; developing innovative solutions to perplexing problems; inventing novel methods, tools, or art forms; fusing ideas from different disciplines into wholly new constructions; producing works that broaden the horizons of the imagination.
Why does the Fellows Program recognize only individuals?
The Fellows Program emphasizes individual creativity because the discoveries, actions, and ideas that shape our society often begin with the path-breaking efforts of individuals. We are looking for individuals engaged in the thinking and practice that inspires new query, engagement, or behavior.
What do you know about the impact of the Fellows Program?
In 2012, a review of the Fellows Program was conducted as part of the Foundation's routine review of its grantmaking programs. In addition to increasing the capacity of individual recipients to pursue creative ideas and projects, the review found that the Fellowship inspires members of the general public to pursue their own personal creative activities and to think about how they can use their own skills and ideas to make the world a better place. By highlighting the remarkable breadth and diversity of creativity exhibited by some people, the MacArthur Fellows Program indirectly acknowledges the value and efforts of many others who apply their creative energies to the common benefit. Read a full summary of the findings.
How do Fellows spend their stipend?
Because the Fellowship is "no strings attached," Fellows are not required to report how they spend the stipend, and the Foundation does not ask. However, we do know anecdotally that Fellows use the money in a variety of ways. Some uses are expected, such as undertaking research for which traditional sources of funding are unavailable; taking time off from teaching or performing to focus on research or creating new works; and building an organization to support their work. Other uses are less expected but no less important, such as facilitating a successful leadership transition in their current organization and beginning a new enterprise; securing the long-term health of their organization (for example, salaries for members of a dance company); funding scholarships or grants for young people in their field; or receiving training in an entirely new field. We know that, in some cases, Fellows use the funds for purposes that may appear unconnected to their work (for example, retirement savings or child care) but that, in fact, allow the Fellows to focus on their work and take advantage of new opportunities in a way that was not possible before due to financial or other constraints.
Is this the same thing as the "genius grant"? Why does the program not use the term "genius" regarding its Fellows?
Journalists and others sometimes use "genius grant" as a shorthand reference for the MacArthur Fellowship. We avoid using the term "genius" to describe MacArthur Fellows because it connotes a singular characteristic of intellectual prowess. The people we seek to support express many other important qualities: ability to transcend traditional boundaries, willingness to take risks, persistence in the face of personal and conceptual obstacles, capacity to synthesize disparate ideas and approaches.
The Nomination Process
How are candidates brought to MacArthur's attention?
So that we can expand our search for creative people as widely as possible while keeping the number of nominations manageable, we limit our consideration only to those who have been nominated by someone from our constantly changing pool of invited external nominators. Applications or unsolicited nominations are not accepted.
Who are the nominators?
In order to gather fresh perspectives, we invite throughout the year new nominators across the spectrum of human activity; they serve confidentially for terms of several months. Nominators are identified for their expertise and familiarity with exceptionally creative people in their respective areas of focus. We maintain a large and ever-growing list of potential nominators who have been recommended to us from many sources: Foundation board members, Selection Committee members, past nominators, and various experts across the country. We also identify people who are recognized leaders in their fields and whose work naturally exposes them to a wide variety of interesting and creative people.
How do nominators nominate?
Nominators write a letter to the program director, usually a page or two, describing the person they are nominating and their reasons for doing so. These letters focus on the quality and creativity of the nominees and their work, and on the likely benefits of the award to the recipient. We ask them to suggest the names of others who can provide independent evaluations of their nominees. Nominators may submit any number of nominations they please.
How many nominations are received during the course of a year? How long does it take for a nomination to move through the selection process?
We receive approximately 2000 nominations per year. The shortest possible interval from nomination to award is about nine months, but it normally takes more than a year, sometimes several. We often consider nominees over a period of years; individuals nominated during one particular year are not under consideration for that year alone.
Do some people know that they have been nominated?
Occasionally nominees do find out, but not from us. We specifically ask nominators and evaluators not to contact the nominee or others regarding the nomination. Since individuals can't apply for the Fellowship or promote themselves as candidates, and because many more are nominated than will receive a fellowship, it is best for individuals to remain unaware of their nomination.
The Selection Process
What is the Selection Committee?
The Selection Committee consists of approximately 12 people who serve confidentially and are chosen for their breadth of experience, excellent judgment, and curiosity. In identifying members for the committee, we look for depth of interest in at least one major field, broad familiarity with other major fields, and, above all, an enthusiasm for creative ideas and important issues within and outside of their areas of expertise. Committee members bring experiences from many different perspectives — the arts, humanities, social sciences, biological and physical sciences, the professions, business, and public service — but individual members do not speak on behalf of a particular discipline. Because the committee works as a group, the decision on each nomination represents a collective judgment drawn from a wide range of insightful and discerning perspectives. At the end of each review cycle, some members rotate off the committee.
What information does the Selection Committee use to make its recommendations?
Prior to review, each nomination is assigned to one of the program's senior staff. Staff members draw from the nominator's letter, experience with nominations in similar areas, and independent investigation to prepare a file for the Selection Committee. The file is composed of letters of evaluation from experts in the nominee's field and samples of the nominee's work that exemplify their creativity, such as articles, books, slides, films, and audio or video recordings. It may also contain reviews of those works and reports about the nominee published by others.
What is the selection process?
Having reviewed the background materials collected, the Selection Committee meets to discuss the nominations against the selection criteria. If the nomination appears promising, selectors will work with staff to develop a strategy for further investigation. Other nominations are deferred pending additional work forthcoming from the nominee. For still other nominations, a consensus develops that further consideration is not warranted. At the final meeting for each review cycle, the Selection Committee identifies the most outstanding nominations, representing a spectrum of creative activity, for recommendation to the Board of Directors for that year's MacArthur Fellowships. Nominations that do not advance within a particular review cycle are retained for possible subsequent reconsideration. View a diagram of the entire process, from nomination to selection, below.
Why all the confidentiality?
All of the participants in the selection process — nominators, evaluators, and selectors — serve anonymously, and we keep their communications confidential. Anonymity protects them from being inundated with unsolicited requests. In addition, our experience shows that people readily provide frank impressions if they have an assurance that their responses will not be disseminated beyond the program staff and Selection Committee.
The Board of Directors
What role does the Board of Directors play in the MacArthur Fellows Program?
The Board of Directors established the MacArthur Fellows Program and is ultimately responsible for its overall policies and procedures. Throughout the selection cycle, the Board is kept apprised of Selection Committee progress. At the end of the cycle, the Board receives for its consideration and approval the committee's formal recommendations for MacArthur Fellowships. In addition, the Board of Directors authorizes the invitation of members of the Selection Committee who have been recommended by the program's staff.
The Announcement
How are recipients notified of the Fellowship, and what are their responses?
Generally, the director of the program calls the new Fellows just prior to the announcement each year, and we confirm the award with a letter. Fellows' responses are just what one might imagine — amazement, gratitude, and sometimes incredulity.
How many people receive the fellowship and when are they announced?
Typically, between 20 and 25 recipients are selected each year, and a public announcement is made in early Fall. Neither the number of recipients nor the timing of the announcement is fixed. Search Fellows by year ›
Program History and Background
Who were John D. and Catherine T. MacArthur?
John MacArthur was a businessman whose funds created the Foundation; Catherine was his second wife and a member of the boards of many of the firms he owned. John MacArthur was the sole owner of Bankers Life & Casualty Company, a Chicago-based firm he purchased in the 1930s. He had numerous real estate holdings in New York and Florida, and other businesses and real estate all over the country. He created the Foundation in 1970. It began operations upon his death in 1978. He selected Board members to run the Foundation but did not provide guidelines for them to follow. More about the MacArthurs ›
Why is the Foundation interested in issues relating to individuals and creativity? Whose idea was the Fellows Program?
The late William T. Kirby, a member of the Board from its beginning, brought to the Board's attention at one of its first meetings, in August 1978, an article entitled "Of Venture Research" by Dr. George Burch [American Heart Journal, December 1976]. Dr. Burch argued that money should be set aside to allow truly creative individuals the free time to be alone and think. He wrote, "There is a need for granting agencies to seek out investigators who are genuinely interested in research and exploration of the unknown to advance knowledge for the sake of knowledge." He argued, "Recipients should be left alone without the annoyances and distractions imposed by grant applications, reviewing committees, and pressure to publish." This article became the focal point of early discussions about the program.
The Burch article, and others like it, prompted John MacArthur's son, J. Roderick MacArthur, who was also a member of the Foundation's Board, to propose the formation of the MacArthur Fellows Program. He, along with other Board members, met with representatives of other foundations and with scientists, humanists, and others to test this innovative idea. There were meetings held in Chicago, New York, and elsewhere, all devoted to exploring the idea, shaping it, testing it, and seeing how it might develop into a program.
The Board envisioned a program that would: (a) identify creative individuals with extraordinary promise for significant accomplishment; (b) select these individuals from across a broad range of fields and professions; (c) give them enough money to live decently, so that they would not be required to take other work; (d) pay out this money over a long enough time period to allow them the freedom to set their own agenda; and (e) leave them alone to work on whatever they might choose, without any strings attached to the use of the funds or any reporting requirements.


text:
- Method
- Open Access
m:Explorer: multinomial regression models reveal positive and negative regulators of longevity in yeast quiescence
© Reimand et al.; licensee BioMed Central Ltd. 2012
- Received: 24 February 2012
- Accepted: 29 May 2012
- Published: 21 June 2012
We developed m:Explorer for identifying process-specific transcription factors (TFs) from multiple genome-wide sources, including transcriptome, DNA-binding and chromatin data. m:Explorer robustly outperforms similar techniques in finding cell cycle TFs in Saccharomyces cerevisiae. We predicted and experimentally tested regulators of quiescence (G0), a model of ageing, over a six-week time-course. We validated nine of top-12 predictions as novel G0 TFs, including Δmga2, Δcst6, Δbas1 with higher viability and G0-essential TFs Tup1, Swi3. Pathway analysis associates longevity to reduced growth, reprogrammed metabolism and cell wall remodeling. m:Explorer (http://biit.cs.ut.ee/mexplorer/) is instrumental in interrogating eukaryotic regulatory systems using heterogeneous data.
- Transcription Factor Binding Site
- Area Under Curve
- Nucleosome Occupancy
- Transcription Factor Target
- Diauxic Shift
Eukaryotic transcriptional regulation is a core cellular process that governs the expression of genes. Understanding gene expression is crucial in explaining complex biological processes including development, disease and cancer. Transcription factors (TF) are key proteins that activate or repress transcription by binding sequence-specifically to DNA in promoter regions of target genes. Mapping such regulatory networks and TF functions is therefore an important goal of current biomedical research. In complex vertebrate organisms like human, this task is hindered by enormous genomic space, numerous cell types, and distinct experimental procedures with data that is often unsuitable for direct comparison. The relatively simple unicellular model organism budding yeast (S. cerevisiae) serves as a platform for regulatory genomics. Multiple types of global-scale data of yeast gene regulation are available to date, including microarrays with TF deletion (ΔTF) strains [1, 2], predictions of TF binding sites (TFBS) [3–5], and measurements of chromatin state such as nucleosome positioning [6]. These data appear to be complete, however the agreement between transcript expression and TF binding events remains modest [2, 7]. While part of this controversy can be attributed to experimental and statistical noise, we may still lack significant details regarding the biological relationships among such heterogeneous information. Consequently high-throughput data constitute less reliable evidence and much functional knowledge is extracted from careful and expensive focused studies. Most TFs and their exact roles in cellular processes remain poorly understood. Therefore biologically meaningful computational analysis is an important challenge in deciphering cellular regulatory networks.
Computational prediction of TF function from gene expression and DNA binding data is an active area of research. Numerous algorithms have been published elsewhere, albeit few have been validated experimentally. Earliest approaches focused on a specific class of data and used alternative types of evidence for computational validation. For instance, microarray clustering followed by DNA motif discovery in gene promoters helped establish the genome-scale link between mRNA expression profiles and TF binding [8, 9]. Similarly, analysis of cell cycle expression patterns of TF-bound genes led to recovery of cell cycle TFs [10]. More recent methods use statistical modeling to integrate multiple types of evidence. For example, ARACNE extracts transcriptional networks from numeric microarray data using mutual information [11], and MARINA is a down-stream method that identifies master regulators of these networks through association tests with TF binding target genes [12]. The SAMBA biclustering algorithm studies matrices of regulators and target genes, and highlights regulatory relationships between genes and TFs that co-occur in clusters [13]. The linear regression method REDUCE integrates numeric microarray data, DNA sequence and TF affinity matrices by modeling the linear relationship between gene expression levels and TF-DNA interactions [14]. The GeneClass algorithm additionally integrates information about gene function, as it constructs decision trees of discrete microarray profiles and TF binding sites to select predictors of process-specific genes [15]. While this method provides direct modeling of gene function, TFs and gene expression data are studied as independent predictors. Notably, none of the above methods take advantage of recent ΔTF microarrays that reveal regulator target genes [1, 2]. Nested effects models are designed to extract regulatory networks from perturbation data [16], although integration of TFBS and gene annotations is not supported. Nucleosome positioning measurements also remain unexplored in all above approaches. In summary, additional computational efforts are required for meaningful integration of versatile biological data.
Here we propose a method m:Explorer that uses multinomial logistic regression models to predict process-specific transcription factors. We aim to provide the following improvements in comparison to earlier methods. First, our method allows simultaneous analysis of four classes of data: (i) gene expression data, including perturbation screens, (ii) TF binding sites, (iii) chromatin state in gene promoters, and (iv) functional gene classification. The model is based on the assumption that TF target genes from perturbation screens and TF binding assays are equally informative about TF process specificity. Second, we reduce noise by including only high-confidence regulatory relationships, and do not assume linear relationships between regulators and target genes. Third, we integrate detailed information to better reflect underlying biology: multiple subprocesses may be studied in a single model, and chromatin state data are incorporated into TF binding site analysis. TF target genes with simultaneous evidence from gene expression and TFBS data are highlighted separately. Fourth, our analysis is robust to highly redundant biological networks, as statistical independence is not required. We use univariate models to study all TFs independently and avoid over-fitting that is characteristic to many model-based approaches. This is statistically valid under the assumption that a complex model may be understood by examining its components.
To test our method, we compiled a comprehensive dataset covering most TFs of the budding yeast. We benchmarked m:Explorer in a well-studied biological system and establish its improved performance in comparison to several similar methods. Then we used the tool to discover regulators of quiescence (G0, stationary phase), a cellular resting state that serves as a model of chronological ageing. Experimental validations of our predictions revealed nine TFs with significant impact on G0 viability. Besides demonstrating the applicability of our computational method, these findings are of great potential interest to yeast biologists and researchers of G0-related processes like ageing, development and cancer.
m:Explorer - multinomial logistic regression for inferring process-specific gene regulation
The first stage of our analysis involves data preprocessing and discretization in which high-confidence TF target genes are identified from multiple sources (Figure 1A). We assumed that genes responding to TF perturbation are likely targets of the regulator. We previously analyzed a large collection of ΔTF microarrays, extracted genes with significant up or down-regulation (moderated t-test, FDR p ≤ 0.05), and assigned these to perturbed regulators (Step 1, methods described in [2]). We also followed the assumption that TF binding in promoters is likely to indicate regulation of downstream genes, and binding sites in low nucleosome occupancy regions are more likely targets of TFs. We collected TF-DNA interactions from multiple datasets and classified genes as TF-bound if at least one dataset showed significant binding in 600 bp promoters (Step 2). We further categorized our TFBS collection into nucleosome-depleted TFBS (onesided t-test, FDR p ≤ 0.05) and sites with no nucleosome depletion. Next we integrated TF target genes into a genome-wide matrix, by assigning non-related genes to a baseline class and creating extra classes for genes with multiple evidence (Steps 3, 5).
Besides regulatory targets of transcription factors, our method requires a list of process-specific genes for which potential regulators are predicted. These may originate from literature, additional microarray datasets, pathway databases or biomedical ontologies. Several non-overlapping lists of genes may be provided to integrate further information about sub-process specificity, sample treatment or differential expression. These genes are organized similarly to TF targets (Steps 4, 5).
where ν corresponds to degrees of freedom and reflects number of model parameters. To predict all regulators to a process of interest, we test all TFs independently, correct for multiple testing and find TFs with significant chi-square p-values (Benjamini-Yekutieli FDR, p ≤ 0.05).
In summary, m:Explorer uses the multinomial regression framework to associate process genes with TF regulatory targets from TFBS maps, gene expression patterns and nucleosome positioning data. Our method finds candidate TFs whose targets are especially informative of process genes, and thus may regulate their expression.
Yeast TF dataset with perturbation targets, DNA binding sites and nucleosome positioning
We used m:Explorer to study transcriptional regulation and TF function in yeast, as it has the widest collection of relevant genome-wide evidence. First we compiled a dataset of 285 regulators that contains carefully selected target genes for nearly all yeast TFs from microarrays, DNA-binding assays and nucleosome positioning measurements. Statistically significant target genes from regulator deletion experiments originate from our recent reanalysis [2] of an earlier study [1]. High-confidence TFBS targets were assembled from earlier chromatin immunoprecipitation (ChIP) assays by Harbison et al. [3], in silico TFBS predictions [4, 17], and recent refinements with protein-binding microarrays by Zhu et al. [5]. The data were further processed with in vivo nucleosome positioning measurements [6] to distinguish binding sites where lower nucleosome occupancy reflects open chromatin structure.
In conclusion, the yeast TF dataset is a useful resource for studying gene regulation.
High-confidence recovery of cell cycle regulators
First we tested m:Explorer in a well-defined biological context. Cell cycle is a thoroughly described regulatory system with four consecutive phases: gap-1 (G1), synthesis (S), gap-2 (G2) and mitosis (M). Some of the earliest microarray experiments identified cell cycle-regulated yeast genes [18, 19], and a computational analysis organized these into phase-specific groups [20]. Several focused studies have investigated the roles of individual cell cycle TFs [21–25], and a genome-wide experiment outlined the underlying regulatory network in its interconnected, circular nature [26]. Altogether, the core cell cycle network comprises nine transcriptional regulators (Swi4, Swi6, Mbp1, Ndd1, Fkh1, Fkh2, Swi5, Ace2, Mcm1, Additional file 1, Table s1).
Our method reveals additional details about cell cycle regulation. First, as we model all cell cycle phases in one run, relative TF phase activities can be quantified through regression coefficients (Figure 3B). For instance Swi4, Swi6 and Mbp1 make up the G1-S specific TF complexes MBF and SBF [21], and m:Explorer correctly highlights the phases with the strongest signal of regulatory activity. Second, we can assess the relative contribution of different kinds of regulatory evidence, and show that combined TFBS and ΔTF evidence are most informative of cell cycle regulation (Figure 3C). Third, simultaneous analysis of multiple sub-processes in a single multinomial model is advantageous to separate logistic models for each related subprocess, since the latter approach is more prone to false positive predictions (Additional file 1, Figure s1). We performed m:Explorer analysis for four cell cycle phases and two checkpoints separately and recovered all cell cycle TFs found by the multinomial model, however also retrieved a large number (28) of additional false positive TFs not associated to cell cycle. Despite the above, analysis of sub-processes showed that m:Explorer is applicable to relatively small gene lists, for instance Mcm1 and Yox1 are correctly recovered as regulators of M-phase through only 55 informative genes.
Summary of comparison with similar methods
ΔTF expression
Gene function
Univariate multinomial regression
Multivariate multinomial regression
Decision tree
Kolmogorov Smirnov test
Mutual information
Fisher's exact test
Univariate linear regression
Multivariate linear regression
In conclusion, the cell cycle analysis showed that our approach successfully recovers a well-characterized regulatory system from multiple lines of high-throughput data. m:Explorer greatly outperformed several similar methods and showed robustness to incomplete data.
Computational prediction of TFs for quiescence entry and maintenance
Next, we applied m:Explorer in a less familiar biological context to create experimentally verifiable hypotheses about TF function. We focused on the transcriptional mechanisms that govern cell quiescence (G0, reviewed by Gray [32] and Kaeberlein [33]). G0 is a cellular resting state with no proliferation, silenced genomes, reduced metabolism and translation, and greater stress resistance. Studying G0 has proven difficult and related regulatory programs remain elusive.
Here we studied two public microarray datasets and executed m:Explorer in two independent rounds. First, we retrieved 207 diauxic shift genes in three distinct subgroups of early, transient and late expression from the dataset by Radonjic et al. [35]. Second, we used 594 genes and 676 genes characteristic of quiescent and non-quiescent cells from the study by Aragon et al. [36] (Figure 4B). We identified 29 and 82 statistically significant candidate TFs in the two runs, log-transformed the scores and produced a final list of 97 G0 regulators (Figure 4C). A large number of regulators is expected, as G0 entry is thought to comprise large-scale cellular reprogramming [35]. Several top-ranking TFs have high scores in both m:Explorer predictions. This ranking is not an artifact of the overlap between diauxic shift and quiescence genes. Although the two lists comprise a considerable number of common genes (n = 62, p = 0.0005, Fisher's exact test), these were not sufficient for predicting a similar collection of G0 TFs, as m:Explorer analysis with the 62 genes only provided in a single significant TF (Mga2, p = 0.0005, LR test from m:Explorer).
In summary, the result of this analysis is an inclusive, prioritized list of candidate G0 TFs that serves as a resource for hypothesis generation and experimental testing.
Experimental validation reveals super-wildtype and essential G 0 TFs
All tested strains showed significant deviances from background viability at different stages of the quiescence time-course (Figure 5A). The deletion strains of Bas1, Sds3, cst6, Mga2, and Spt10 show consistently greater viability in G0, indicating that their normal presence in wildtype cells suppresses viability and hastens cell ageing (Figure 5C). We refer to these knockout phenotypes as super-wildtypes (WT+). In particular, Δbas1 strains are on average 1.7-4.5 times more viable than wildtype in weeks 3-6 of quiescence (all FDR p ≤ 10−4, LR test from error model). The transcription factor Bas1 is involved in the regulation of amino acid and nucleic acid metabolic pathways [37], and cst6 is related to chromosome stability and non-optimal carbon source regulation [38, 39]. Spt10 and Sds3 are chromatin modifiers involved in genome silencing [40, 41], and Mga2 regulates fatty acid metabolism, transcriptional silencing and response to low oxygen [42–44]. Deletion of Sds3 of the Sin3-Rpd3 histone deacetylase complex has been associated to increased chronological cell ageing [45].
The deletion strains Δtup1, Δswi3, Δhaa1 are significantly less viable than wildtype in quiescence (Figure 5A). In particular, Δtup1 and Δswi3 strains become inviable in later stages of G0 (viability ≤ 0.005) and can be considered essential for survival in this cell state (Figure 5D). Two further strains Δspt20 and Δsnf2 are less viable in early quiescence, while Δsin3 shows later deviations. With the exceptions of Sin3 and Haa1, corresponding null mutants are previously known for decreased or absent respiratory growth. Tup1 is a general inhibitor of transcription that establishes repressive chromatin structure [46]. Other factors are also involved in regulation of chromatin, transcription and genome stability, such as Swi3 and Snf2 of the SWI-SNF complex [47], Sin3 of Sin3-Rpd3 complex [48] and Spt20 of the SAGA complex [49]. While the factors have not been specifically described in the context of quiescence, disruption of their global functions is likely to affect this cellular state. Besides the above, the reduced G0 viability of Δ haa1 potentially relates to its role in regulating cell wall proteins [50].
Before entering quiescence, most tested TF strains have similar viability to wildtype strains, suggesting that their function in regulating viability is specific to G0 (Figure 5B). During exponential growth at seven hours after inoculation, only three strains including the positive control Δ ard1 are significantly less viable. Ard1 encodes an N-terminal acetyltransferase subunit that guides genome silencing, and Δard1 fails to enter G0 as observed previously [51]. In contrast, the other positive control Δmip1 is as viable as wildtype in exponential phase, and more viable in post-diauxic phase. Mip1 encodes a mitochondrial DNA polymerase subunit required for cell respiration [52], and Δmip1 loses viability in a similar manner to Δ tup1 (Figure 5E). Curiously, Δspt10 is less viable in exponential growth phase and early quiescence, while its viability exceeds wildtype after week three of our time-course. The negative control strains Δgal3 and Δpdr3 expectedly show no major deviations from wildtype viability (Figure 5F). The TFs are related to alternative carbon metabolism and drug resistance, respectively [53, 54], and show non-significant scores in m:Explorer predictions of G0 TFs. Finally, our glycerol growth assays confirm the respiratory properties of tested strains (Additional file 1, Table s3) and mostly agree with previous studies [55, 56]. However, in contrast to those reports, our data indicate that Δcst6 is viable on glycerol and indeed displays increased G0 viability.
According to our knowledge, most of our predicted TFs are not recognized as quiescence regulators. However previous functional evidence refers to processes important in quiescence, and hence lends confidence to our experimental observations. Besides uncovering novel regulators of viability in G0, our experiments show that m:Explorer provides biologically meaningful prediction of regulator function.
Functional enrichment analysis explains roles of G 0 TFs
To gain insight into G0 gene regulation of validated TFs, we performed a functional enrichment analysis of their G0 target genes. We focused on quiescence genes defined by Aragon et al. [36] and identified the subset of genes that were bound by at least one WT+ TF or showed differential gene expression in at least one WT+ ΔTF microarray [2]. Target genes were then scored by product of differential expression p-values across all WT+ ΔTF microarrays and ranked such that genes with most dramatic transcriptional changes were prioritized. The target gene list for viability-deficient TF strains was complied in a similar fashion. We expect that ΔTF differential expression is informative of regulatory relationships in quiescence. The strains underlying microarray profiling are genetically identical to the strains in our G0 experiments, although the former assays were performed with exponentially growing cells. Intersection of known quiescence genes with target genes of validated G0 TFs, and subsequent prioritization according to differential expression, is therefore likely to highlight high-confidence TF targets and functional relationships. To investigate this in detail, we then used the ordered gene list analysis of g:Profiler [57] to study the functional importance of significance-ranked target genes of WT+ and viability-deficient TFs.
Taken together, the above results associate to known mechanisms of quiescence and provide clues of the regulatory programs of predicted G0 TFs. Inhibition of growth through down-regulation of ribosome genes has been linked to increased replicative lifespan [58]. Efficient cell wall remodeling and response to increased oxidative stress are essential prerequisites of quiescence entry and survival [32]. Expectedly, increased viability appears to correlate with reduced metabolism, as related genes show opposite expression patterns in corresponding strains. Further discussion on G0 TFs and related pathways can be found below.
Function of G 0 regulators
It is tempting to speculate about the role of identified quiescence TFs in modulating quiescence signalling, as links between the factors and global G0-related pathways are apparent in our dataset. Our findings of WT+ regulators are especially intriguing, since their normal presence in wildtype cells reduces viability in quiescence and causes increased chronological ageing. From the perspective of evolutionary maintenance, WT+ regulators should engage in significant cellular functions that compensate for such negative properties.
As an example of G0 regulation, protein kinase A (PKA) mediates nutritional signals to the cell and is known as an inhibitor of quiescence [32]. Its primary regulatory subunit Bcy1 acts as an inhibitor of the pathway, and mutations in Bcy1 cause viability loss and death in G0 [59, 60]. This double negative regulatory mechanism provides a potential explanation to observed viability phenotypes. In our TF dataset, Δmga2 has significantly higher levels of Bcy1, potentially allowing more starving cells to pass into quiescence. The G0-essential Tup1 and Swi3 knockout strains have depleted levels of Bcy1 and as a possible consequence, we observe reduction and loss of viability. As another example, protein kinase C (PKC) guides cell wall remodeling in response to starvation and its activity is required for G0 entry [61]. The cell wall biosynthesis enzyme Gsc2 is a downstream target of PKC [62] and part of the gene expression signature of quiescent cells [36]. In ΔTF microarrays, Δmga2 and Δcst6 strains have elevated levels of Gsc2, while Δswi3 and Δtup1 show inhibition of PKC upstream of Gsc2 (Additional file 1, Figure s5). Other genes with known function in G0 appear to be regulated by WT+ and viability-deficient TFs. Notably, the conserved superoxide dismutase (SOD) genes are responsible for neutralizing oxidative damage of mitochondrial respiration. In yeast, SOD genes are required for G0 survival and extend chronological lifespan when over-expressed [63, 64]. Induced levels of Sod2 expression in Δcst6 may explain our observations of increased G0 viability.
Several confirmed G0 TFs are also associated to mammalian gene regulation.Cst6 carries the DNA-binding domain of CREB, an extensively studied TF that regulates a variety of processes, including cell survival and proliferation, cellular metabolism, and synaptic plasticity of long-term memory [65]. Bas1 is homologous to the MYB TF that regulates stem and progenitor cells and appears as an oncogene in multiple tumour types [66]. Chromatin modifier complexes Swi/Snf, Sin3/Rpd3 and SAGA are also broadly conserved, for instance Swi3 homolog SMARCC1 is involved in versatile functions, including neural stem cell renewal and differentiation [67]. As the yeast quiescence model associates to hallmark cancer properties of cell cycle control, proliferation and differentiation, further analysis of our Findings may reveal intriguing links to cancer biology.
Applicability and validity of m:Explorer
Here we present the robust computational method m:Explorer for predicting functions of gene regulators from high-throughput data. We applied a model that probabilistically accounts for multiple types of regulatory signals and functional gene annotations. To take advantage of abundant genome-wide data and powerful experimental approaches, we present a case study for predicting transcription factors (TF) in the unicellular budding yeast. However, our method is not restricted to yeast and even not to these classes of data and regulators, being easily scalable to more complex regulatory systems of vertebrate organisms. Our method is also applicable to data such as protein-protein and genetic interactions that are categorical in nature. As shown here, m:Explorer is particularly useful in investigating sparse, high-confidence sets of data that may be controversial and not entirely comparable. For instance, we envisage large-scale characterization of human pathways in the context of heterogeneous tumours, utilizing sequence mutations, gene expression and chromatin modification data that are collected in cancer genomics projects.
In our model benchmarks, we demonstrate the advantage of univariate multinomial models in m:Explorer over similar multivariate models (AUC = 0.83 vs AUC = 0.67 for recovering cell cycle TFs). Briefly, the former models treat each TF independently in process gene classification, while the latter models include a non redundant collection of TFs as predictors. However, TF redundancy is an inherent property of robust biological networks that have evolved through gene and genome duplication [68]. In our case, the core cell cycle system involves three pairs of homologous TFs (Swi4 and Swi6; Fkh1 and Fkh2; Ace2 and Swi5) that have strikingly similar TFBS and expression patterns. Due to redundancy, such TFs are not treated as significant predictors in the multivariate setting. This is evident in our simulations: none of the tested multivariate models included both TFs of homologous pairs as significant predictors.
This analysis provides multiple lines of evidence to establish m:Explorer among other methods with similar goals. First, we carried out a highly detailed reconstruction of the known cell cycle regulatory system and proved the validity of our approach through existing knowledge. Second, we repeated the same analysis using eight alternative computational methods and random samples of input data, and provided quantitative proof to the robustness and better performance of our method. Third, we predicted regulators to the enigmatic cellular state of quiescence and validated our top-ranking candidate TFs in follow-up experiments. Nine of twelve tested TFs were confirmed to have consistent and significant G0 viability deviations in gene knockout screens, while the remaining three factors showed differences in subsections of our time-course. Thus we proved a high success rate given our relatively simple experimental assays. Besides demonstrating the biological validity of our method, our findings reveal novel, previously unrecognized regulators of quiescence.
m:Explorer web server and data availability
m:Explorer is available as an R package on our web site [69] and elsewhere. The yeast TF dataset may prove to be a useful resource for the community and is also provided. We have established a web server at [69], allowing online prediction of regulator function using the yeast TF dataset.
m:Explorer is a generally applicable method for inferring transcription factor function from heterogeneous high-throughput datasets. Our approach outperforms similar state-of-the art tools in recovering regulatory relationships in a well-studied eukaryotic system. Furthermore, the algorithm helps explore uncharacterized regulatory networks and propose valuable hypotheses for detailed assays. Our case study of quiescence G0and subsequent experimental validations revealed nine novel regulators that enhance or reduce cellular longevity, providing insights to investigators of this cryptic cellular state. In conclusion, our computational and experimental analyses provide strong support to the validity and usefulness of m:Explorer.
Materials and methods
Data processing
The yeast transcription factor dataset of 6253 genes and 285 transcription factors was compiled from gene expression, TF binding and nucleosome positioning data. Perturbation microarrays for 269 regulators were originally produced by Hu et al. [1], while our recently reanalyzed dataset [2] was used here for discretized, high-confidence values of up- and down-regulation (moderated t-test, FDR p ≤ 0.05). Further details on microarray preprocessing are available in the related publication [2]. TF binding site data for 178 TFs were compiled from multiple datasets of ChIP-chip [3], protein-binding microarrays [5] and computational predictions [4, 17], using custom filtering and significance cutoffs proposed by the authors. Each promoter of 600 bp was considered to be bound by a TF if at least one binding site occurred in the dataset, and the TFBS was considered nucleosome-depleted (NDTFBS) if nucleosome occupancy [6] at the site was considerably below normalized genome-wide average (t-test, FDR p ≤ 0.05). Finally, gene expression and TF binding targets for each regulator were integrated and split into eight classes (up, down, TFBS, NDTFBS, up+TFBS, down+TFBS, up+NDTFBS, down+NDTFBS). All other genes except TF targets were assigned to the baseline class (not regulated).
Process-specific gene lists originate from previous high-throughput gene expression experiments. 600 cell cycle specific genes were retrieved from the tiling array experiment by Granovskaia et al. [27] and split into six sublists (G1, S, G2, G2/M, M, M/G1) according to authors' instructions. Three classes of diauxic shift genes (early, transient and late expression) originate from the G0 time series [35], and genes specific to quiescent and non-quiescent cell cultures were first mapped in the analysis by Aragon et al. [36].
Computational methods
m:Explorer is based on univariate multinomial regression and implements the functionality of the R NNET package [70] for model fitting. We use a list of process-specific genes as categorical model response, and TF target genes as predictors. Briefly, m:Explorer compares two models: the null intercept-only model classifies process gene through their frequency, and the alternative univariate model additionally incorporates TF regulatory targets as predictors. We apply the log likelihood ratio test with null and alternative models to decide if TF target genes are significantly informative of process-related genes. Detailed description of the model is available in Additional file 1.
Yeast cell cycle TFs were predicted from a single structured gene list and directly ranked according to log p-values from m:Explorer. G0 TFs were predicted in two independent m:Explorer runs using genes from two datasets. TF p-values from LR tests were log-transformed, scaled to unit range and summed across the two runs to create unbiased composite scores for final ranking. Unit-scaled positive regression coefficients were used to assess the relative phase specificity of cell cycle TFs, since these indicate over-represented regulatory targets in contrast to baseline genes. Relative contribution of regulatory evidence was computed in a similar way.
Linear regression was used to assess the significance of mutant strain viability deviations from control and wildtype strains. With viability as model response v, three types of variance were included as model predictors for assessing each mutant/time-point combination across all related replicas, as the alternative model H1 : v ~ i + c + b + m. The above reflect global variance i, variance of negative controls c, variance between two batches of independent time-courses b, and additional variance of the tested strain m. Significance of viability deviation was assessed with a LR test, similarly to the m:Explorer algorithm. Specifically, the null model comprised only global variance, negative control variance and batch variance as H0 : v ~ i + c + b, and null and alternative models were compared using the chi-square distribution. Resulting p-values were corrected for multiple testing with FDR.
where g denotes the number of genes in a particular set, C indicates cell cycle genes, T indicates TF targets, c shows genes unrelated to cell cycle, t shows genes not regulated by the particular TF, and n = g CT +g Ct +g cT +g ct reflects the number of all yeast genes. As Fisher's test does not support large contingency tables of multi-level variables, different types of TF regulatory targets were treated as the first category and non-regulated genes were assigned to second category, and cell cycle phase-specific genes were similarly merged into a bivariate discrete variable. A similar analysis was carried out to compare the overlap between diauxic shift genes and quiescence genes, using the set of all yeast genes as statistical background.
Gene Ontology (GO) and pathway enrichment analysis for G0 TFs was carried out with with g:Profiler software [57]. We defined two ranked gene lists: G0 genes [36] that were differentially expressed in WT+ TF knockout strains (Mga2, Cst6, Sds3, Spt10, Bas1), and G0 genes that were differentially expressed in viability-deficient TF strains (Swi3, Sin3, Snf2, Spt20, Tup1, Haa1), according to TF knockout microarrays [2]. The gene lists were ordered according to statistical significance in TF knockout data [2], computed as products of p-values across WT+ and RD strains for every gene. We used the ordered enrichment analysis of g:Profiler to find GO functions and pathways in ranked gene lists and applied statistical filtering to find significant enrichments (FDR p ≤ 0.05).
given that there are N genes in total and K of which are part of the functional category. As ordered enrichment analysis assumes that genes with stronger signals are ranked first, it consequently tests different subsets of the top list and returns the portion of top genes with the strongest p-value for a particular functional category [71]. Resulting G0 functional categories were grouped into three classes: enriched G0 categories associating to WT+ TF targets, categories of viability-deficient TF targets, and categories with statistical enrichment in both groups of targets. Enrichment p-values were corrected for multiple testing with the FDR procedure. To rank the third class of common functional categories, we multiplied corresponding p-values of WT+ target genes and viability-deficient TF target genes. After functional enrichment analysis, redundant categories whose genes formed a subset of some other category were removed. To quantify each GO category and function, we also counted up-regulated and down-regulated G0 genes across all related TF strains.
Experimental procedures
Regulator knockout strains were selected as 12 top-ranking candidates from m:Explorer results. S. cerevisiae deletion strains originate from the EUROSCARF deletion collection in the BY4741 strain (MATa his3Δ1 leu2Δ0 met15Δ0 ura3Δ0). Liquid cultures were grown in triplicate at 30°C with aeration in YPD (1% yeast extract, 2% peptone, 2% glucose) for 28 days and subsequently shifted to room temperature without aeration. Viability measurements of the six-week time-course were taken in eight time-points: 7h after colony initiation, 48h after colony initiation, followed by six weekly measurements on days 7, 14, 21, 28, 35 and 42. Two independent batches involved distinct sets of tested strains, while wildtypes and controls were covered in both batches. A shorter, independent time-course covered the first three days of growth and involved viability measurements at 7h, 11h, 24h, 48h, and 72h. Cell density was measured at 600 nm. Colony forming units (CFU/ml) were determined by plating cells on YPD agar and counting colonies after three days of growth at 30°C. Culture viability was determined by dividing CFU/ml with total cell number per milliliter in corresponding culture (OD600 units ×107). Growth on glycerol was determined by streaking strains onto YPG plates (1% yeast extract, 2% peptone, 3% glycerol, 2% agar). Glucose concentration was determined by measuring NADPH production in hexokinase and glucose-6-phosphate dehydrogenase coupled reactions provided by Roche.
We are grateful to Gary Bader, Richard Bourgon, John Marioni, Gabriella Rustici, and Annabel Todd for their valuable advice, and to Tambet Arak for his work on the m:Explorer website. JR would like to acknowledge financial support from IKTDK, EXCS, ENFIN, EITSA, Marie Curie Biostar, the Ustus Agur Foundation, and the Artur Lind Foundation. Computational resources were provided by the University of Tartu HPC Centre.
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teardrop earrings - moss and champagne sparkle
These lovely teardrop shapes are the most popular in my range - and I've doubled the sparkle! They are made of brass that has been darkened to an antique finish. They hang from oxidized brass ear hooks - but I can attach them to darkened sterling silver hooks for an extra $7
The teardrop is 18mm x 13mm and is made by under laying sparling ombre dipped paper underneath clear glass. . They are then set into the brass teardrop.
The last picture on the model is for size reference only as it does display this pair of earrings.


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Re: VS 2003 Crashing - ViEmu 2.0 - on Up Scrolling
First, let me say - I love your software - I use it daily and its a lifesaver.
I have experienced 3 VS crashes in the last 2 days - this occurs when I am moving Upward in the document (I belive I was using the K key).
And as any dev knows, when you have a number of FooBar.vb* files active and VS crashes - its not a pretty site
The whole VS locks up - I get a Not Responding on the Title bar and I have to shut it down.
I am running on a XP SP2 (fully patched) , .NET 1.1 , VS 2003 system
I was in VB code (*if that matters at all)


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Secret Commands: Whispers from the robo to a collared bunny. that way the robo can give secret orders or messages to different bunnies.
Spectator match: a match where every player bunny is randomly assigned a spectator as a "friend" while the bunny is playing normally he will rely on his "friend" to mislead the robo giving the player a better position. since the robo doesn't know whose spectator is whose "friend" the amount of misinformation will skyrocket. (possible addition: anytime the robo is subverted the spectators are re-randomized in order to leave the new robo with no knowledge, also maybe allowing the spectator to see his own bunnie's name in order to track them down quickly)
really small changes: update the in game chat to scroll when you go past the bar. change the item spawned when robo kills right after dropping. we still need something to be there but the idea of scrap appearing doesn't seem to make sense because logically it doesn't seem like that is what would show up. maybe make it like gravestones or like a casket signifying that because he didn't wait long enough the bunny hitched a ride with the same ship that is carrying his body off.
Nerf Pink Bush: Pink Bush OP must be nerfed