Another Microsoft Conspiracy?

I was reading about the Novell acquisition (here) and stumbled upon the fact that Microsoft managed, as part of the disassembly of Novell, to acquire 882 patents that were previously cross-licensed to Microsoft (See http://en.wikipedia.org/wiki/Novell – Agreement with Microsoft). I had always been of the opinion that Microsoft had signed the deal with Novell to neutralize some threat that Microsoft had known about in Novell’s patent portfolio, but that their ulterior motive was to undercut Novell’s reputation in the open source world. Before the deal, Novell and it’s (at the time) recently acquired SUSE Linux were starting to gain momentum. However, within minutes of the deal, people started to distance themselves from Novell – and SUSE linux with it. Dealing with the enemy is usually not regarded well in any community – and I suspect the open source community is a bit more touchy about it than most.

And that makes me wonder how far in advance Microsoft had planned it’s strategy. They were able to neutralize Novell’s patents (which may have some hold on MS Office products) for a period of a few years, and then to make sure that the company itself wouldn’t survive long enough to be a major force against them. Now that Microsoft has actually acquired those patents, it’s not such a far fetched idea.

From the moment Novell signed the Microsoft deal, it’s fate in the open source community was sealed – particularly with Novell hitching many of it’s horses (so to speak) to the SUSE platform – as the deal alienated would-be-adopters of the very technology it was hoping to promote.

So, the open question was: did Microsoft know that this would be the kiss of death for Novell? And was it nothing more than an expensive way to acquire the patents in the long run that it knew it couldn’t get in the short run?

I doubt we’ll ever know, but I’d be very interested in finding out the truth.

Dr. Phillip Sharp – Small RNA biology and cancer

Dr. Sharp from the Koch Institute for Integrative Cancer Research @ MIT.  Visiting scientist – Nobel Prize winner, among many other awards.

Small RNA and cancer biology. How small RNA fits into gene expression of small cells.  Cancer IS a disease of gene regulation.  You can look at cancer and try to understand it in terms of regulation.

With the discovery of RNAi, we began thinking of RNA as a regulatory factor. Something about Pi RNA? (I have no idea what Pi RNA is. – must look this up.)  Now we also have to contend with lincRNA.  Fortunately High Throughput sequencing gives us the tools to investigate this.

MicroRNA pathway overview.  PolII -> miRNA gene -> Drosha produces hairpin -> Export to cytoplasm -> Dicer cuts it -> Argonaut binds and carries to mRNA -> regulation or repression.

Regulation happens for partial complimentation, repression happens when complimentation is perfect.

Dicer is the only enzyme that does the cleavage of hairpins.  Only argonaut2 gives you cleavage of mRNAs.

8-nt Seed region is the most important part for binding.

  1. Most target sites are in seed sites in 3’UTR.
  2. Evidence for miRNA targeting through “centred paired” sites 4-14 or 5-15
  3. Most protein silencing is less than 1.5 fold, but can be synergistic up to 10-fold
  4. Silencing can also happen – most cases mRNA degradation, but sometimes translation
  5. Little evidence of miRNA activity in nucleus. (up for debate)

Sumamry:

  • 87 evolutionary conserved “seed families” of miRNA
  • 1/2 of all genes have no 3′ UTR.
  • 1/2 of all genes have one or more target, average of4.2, 200-500 target mRNAs per family.

UTR complexity: – high, see examples of HMGA2, BIM, CASP2.

Transcription regulatory control – Reprogramming of somatic cells to pluripotency. (Oct4, Sox2, Klf4, cMyc).  TFs are master regulators – control cell state, all other processes are subservient to them.  Discussion of “circuitry of embryonic stem cells”.  The master TF’s for this process also drive miRNAs.

For most cell types, a few types of miRNA dominate.  ES cells have mir-290-295, Embryonic fibroblasts: mir-21 and let-7.  Neural Precursors, let-7.

miRNA circuitry in S cells – incoherent feed forward regulation.   (Nice images of pathways…)  You get strong induction of protein levels, but also tight regulation.  (Strong promoting while also creating strong repression with miRNA.)

So:  Can a decrease in regulation by miRNA promote cancer?  Contend yes.

See Hanahan & Weinberg, 2000.  Great picture of oncogenes and where miRNAs fit in.  eg, Let-7 controls Ras, mir17-92 paired with myc, mir21, mir15 and mir16 control/repress Bcl2.    Etc.

Thus:

  • mir-15a and miR16-1 ->  CLL prostate
  • Mir26-a -> Liver
  • etc etc…. too many others.

How does this work? Kumar and Jacks tested this with a mouse model system: activating Kras, repress p53 (flox), and Dicer(flox) repression.  Does loss of miRNA inhibit activity of tumour?

  • Dicer (+/+)   = 112 days survival
  • Dicer (+/-) = 87 days
  • Dicer (-/-) = 101 days.  (something about heterozygous dicer presence.??)

[This sounds like a very neat experiment, but I’m not following, since I don’t know what cree/flox are.  Must read up on it.]

Dicer null cells retain the ability to form tumours.  miRNA are not essential for growth OR for cancer.

Roll of miRNA regulation:

  1. Stabilise quiescent state
  2. Stabilise differentiated state
  3. Control responses to changes in environment-induction of cell death.

Cells lacking miRNAs are more susceptible to stress.  (FACS data.)  Increase in Caspase3 when miRNA is knocked out, cell death.

Thus, you get more stable on-off transitions, and better stabilisation of expression.

Examples given with a reporting cell line.  Straight line expression becomes hockey stick like when miRNA sites are added.     Thus, suppressing expression at low levels, but not at higher levels.

All of this provides a more sensitive transition – better on-off transitions.  Helps act as a buffer against leaky expression.  You get a more sigmoidal gene expression curve, which significantly helps the cell control it’s states.

BC Cancer Conference report

I spent part of Thursday and most of Friday at the BC Cancer conference held down town Vancouver at the Westin Bayshort.  I’ve gone a few times before, but I don’t recall blogging about it much.  This year, I thought I’d make a concerted effort to take a few notes and write at least one blog entry about it.

Unfortunately, this year was the least useful to me in terms of knowledge transfer. There seemed to have been a significant shift from the previous years’ emphasis on research and knowledge transfer to what appears to be “how to be a better clinician”.  Of course, those of us in research more or less found the event to be a waste of time – in so many ways.  Yes, this post isn’t going to be a glowing recommendation of the conference.

First, it’s incredibly shameful for any conference to have zero wireless support.  No tweets, no blogs, no communication, and not even the ability to access the internet.  The only concession to modern technology was a quiet room with 5 laptops hooked up to the interet.  Unfortunately, they were all equiped with Windows 7 and French keyboards.  No one was able to spend long using them – not because the demand was high, but because the trackpads didn’t work well, and typing was next to impossible.  One woman soundly declared that the 4 emails she’d managed to send in one hour was the least productive hour of her life.

Ok, But on to the conference talks.  There were some amusing points that provided some comic relief.  One of my favourites was a woman who did an entire presentation in comic sans font, which instantly made it hard to focus on her message.  The problem was further compounded by her inability to provide labels on the axes of her graphs.  That was the point at which I pulled out a paper from my bag and worked on something more relevant.

The speaker before her also piqued my funny bone by using the abreviation “FU” on his talk all over the place.  I thought the only place “FU” was acceptable in science talks was for 5FU (a drug called 5 flourouracil.)  However, eventually he explained it was his short form for “follow up”.  Personally, I’d have gone with the full word.

Yes, that was childish humour.  However, there was also humour for those who have a more mature sense of humour.

The best line of the day came after Dr. Sam Apparicio gave his talk on how we’re learning to identify the molecular characteristics of each cancer – and that personalised medicine is only a few years off.  His point was that next-generation sequencing is already here and the only real barrier to getting this to the clinic is our understanding of the mechanisms.    One of the better talks really.

Alas, the speaker who went next started her presentation with a line that was something like “Unlike Dr. Apparicio, I’d like bring this back to the real world.”  She then proceeded to tell us that the only features about breast cancer we should care about are ER/PR/Her2/TP53 statuses.  Way to dismiss some brilliant research with an off handed comment.

It wasn’t long after that talk when we started to get the slide shows that began with the disclosure that the research was sponsored by the drug companies.   Some of it was good work, but I walked out with the distinct impression that pharma sponsored research isn’t all that unbiased.  Go figure.

Another talk that followed in this chain was a great investigation of the despair felt by workers in the post-industrial revolution who become a single cog in the great wheel of progress.  Apparently, this applies to the support staff in cancer centres – and someone decided they shouldn’t just fix the problem, but rather should study it.  Frankly, every single thing they said could have been said about a study in 1850 Scotland about the workers in a shipbuilding plant.

At the end of the day, the failure to recognise history repeating itself was disturbing, but not as much as the conclusion that nurses should be given a greater say in patient treatment.  Frankly, we train oncologists to make difficult decisions based on informed opinion – and everyone should be allowed to input into the project, but at the end of the day, the oncologist is the one with the training. If the nurse wants to direct patient therapy, maybe they should go to school and become an oncologist!  (Did I miss something?)

Then there was the talk I missed on complimentary alternative medicine.  Thank goodness I missed it!  I just heard the end of the questions, which culminated in one of the speakers claiming that if evidence is hard to obtain for alternative medicines, we shouldn’t need to collect it.   Wow.  Who invited this person?

Finally, I spent some time in a sponsored talk which taught me two things: One is that “nonadherance [to a treatment therapy] is a function of your belief of fate over medicine”, which I take to be a pretty damning charge against the claim that faith/religion has no real harm.   The second was that there are people who have no concept of what an addiction is:  Included in the same category were HIV, asthama, gambling and drinking.  Wow… just wow.

Overall, I’d have to say that this conference has gone downhill rapidly – someone has decided to let in the cranks and jokers, and that it’s becoming harder and harder to tell the difference.

If you think that there were no highlights, I’d have to say there were a few really good talks.   Drs. Sam Aparicio and Marco Marra each gave fantastic talks, as did a few others, such as Ian Bosdet and Torsten Nielsen, and the Awards Dinner was one of the highlights of the conference.

However, I’m counting my lucky stars that I won’t be at next years conference.

A few more random amusements:

One of the complimenatary medicine people billed themselves as John Doe, BSc, PhD (c).  I’ve changed the name for obvious reasons, but the hillarity still remains – we think he was trying to impress people with his PhD candidate-ness.  We had a few more suggestions: PhD (a) and PhD (t)  were my two favorite, which indicate you’re almost there (a) or just thinking about doing one (t).  Personally, I think that you should never give yourself a title you don’t have, but I guess that’s not something alternative medicine students would agree with.

And, my own new personal rule: If you need a laser pointer, your slide is just too complicated or you just don’t know how to discuss its contents well.  The corollary is that slides with only three items on it do NOT need you to wave a laser at it.  Really, give the audience some credit for being able to follow what’s on the slide!

Ok, now I’m really done.  With no wifi all week, I was unable to vent all that – and now here it is in one big blob….er blog. (=  Cheers.

A sunny post for a snowy day

Well, things are going better these days.  I now have a policy of not doing things that won’t move me forward on my own work – I haven’t helped out training a new staff member, I haven’t helped someone with a project proposal, and I skipped out on a proposal for a group project for the GSC’s retreat.  However, I finished a poster, wrote my yearly committee meeting report and successfully presented it to my committee.  (Yes, that means I’ll be writing up in January! Yay!).

I guess it’s true – saying No is one of the skills you learn when doing a PhD.

Beyond that, I’ve managed to generate a lot of good leads this week.  Several really good stories have come out of two different projects – and my committee sees the value in following up on it.   That’s a huge improvement on what my committee usually says to me. And all that while getting a significant boost to my productivity.

Did I learn anything this week?  Yeah, I’d say I did.  I learned a lot from another grad student, who helped my with my proposal – she gave me a really good template to follow.  Clearly I owe her a case of beer. (We have a bet going that the first one go graduate wins a case of beer from the other, but I think I owe her one anyhow.)

I also learned a lot about collecting data and presenting it.  I still have lots more to learn, but I’m getting there.  I have a few more months to master this – since my defence is likely to be coming up in the summer.

In any case, it’s time for focus.  The challenges coming at me will be harder than what I’ve faced before, but I’m up for it and looking forward to it…  and all this has put me in a good mood.  Let it snow, it won’t dent my good mood this evening.

Gloomy post for a sunny day.

I spent the day at home so I could quietly work on my poster and my upcoming committee meeting.  That was, in fact, what I did all morning.  By the afternoon, I got caught in several snares of things that need to be urgently debugged.  On the one hand, it’s really great that my software is being used; the more people who use it, the faster we find bugs and the better the software becomes.  On the other hand, I’m busy, and the three hours of debugging modifying code were not exactly welcome interruptions.  My poster is just a skeleton and there are a lot of images left to be done.

Sometimes I wonder if I’d be better off writing “one-off” scripts like other grad students, and not sharing them with the world.  Certainly it would be easier, in that no other grad student I know spends as much time working with the staff to build tools – and they’ll all probably graduate before I do.

On the other hand, it’s just not something I can bring myself to do.  One-off software is just so wrong for so many reasons.

In terms of managing my time better, I’m not sure today was a win, but at least I made progress on all fronts.  I just wish I’d made more.

If there is a lesson to be taken from this, however, it’s that I should have done my code in perl, because then everyone else would be able to fix the bugs they find…  but that would also have been wrong for so many reasons.

Alas, my 9th Grade history teacher, Mr. Neudorf, tried to teach me this lesson. “Going above and beyond the expectations in order to do something well is a bad thing.”  (He gave me a D on an assignment where I clearly did well, just to illustrate his point.) Fortunately, the only lesson I took away from that was that marks aren’t a good measure of anything in particular, and that teachers don’t always have their pupils best interests at heart.

Fortunately, it didn’t dampen my enthusiasm for doing things well – and here I am, still trying to do things well.  If I had only learned what Mr. Neudorf had tried to teach me I’d be that much closer to graduating.  DOH!

Quiet Saturday night.

Ok, I haven’t got much to say this evening. I’ve been feeling under the weather, and I can’t tell if it’s a cold or just allergies.  Either way, I figured I had to post this link, since it amused me that much.  The Intelligent Design Sort. (It came from someone on twitter, but I can no longer remember whom… DOH!)

Otherwise, glad to see the Canucks beat the Leafs. (Which will be nonsense for any non-hockey or non-Canadian person.)  And now, off to walk the dog and go to sleep.

Blogging is hard work…

I’m going to make a concerted effort to get back to blogging, which I’ve said before, but I really mean it this time.  I feel much less self-conscious now that I’m back on my own site.  Part of it is that I feel like I have a smaller audience, part of it is that I feel less like I’m writing an article for peer review – and part of it is just that I feel that I can discuss a wider range of topics here.  Yes, I know that there were no restrictions on the Nature Blogs site, but I just always felt like I should be holding my posts to a higher standard there.

Anyhow, part of what makes blogging so hard is that you’re always striving to put up new ideas or comments, which means that every new idea you have is open to criticism.  Some days that can be pretty hard to accept – we don’t all like being criticised all the time.  (And yes, as a blogger, you pretty much always are.  Thick skins required.)

But, I have to say, I really respect the people who blog all of the time, and do it well.   It’s not easy to be consistently on the top of your game.  There are many good examples of people who can do this – I plan to fill in my blogroll with them over the coming days – as well as plenty of people who just can’t seem to do it at all.  I’m really hoping to push myself into the former category one day.

As an aside, then there are also the people who can consistently blog poorly, hanging it all out proudly despite the criticism, oblivious to how poorly they actually do blog.  Yes, I saw Ray Comfort’s blog tonight.  Wow.  It just amazes me that he can fail to learn anything from his critics, whereas I find myself stressing over every comment, wondering if there’s a lesson I can take from each one.

Anyhow, since leaving Nature Blogs, I’ve been trying to refocus on what I need to do to get my blogging Mojo back.  It seems to me that it is just two things, which I’ve gleaned from other bloggers:

1. write shorter entries.  Blog posts are really daunting when they pass 2000 words, and that tends to de-motivate me.

2. write more often.  I have lots of ideas, but many of them never make it to the blog, because I felt like I needed to write more.

So there we go – less content, but more often.  From now on, I’ll follow the lead of those who have blogged in front of me, and learn from their posts.

And yes, this post is only 457 words.  Ah…  brevity – my new best friend.

Microsoft Fanboi Thread

Ok, I know you’ve been waiting for this.  Here’s a place for the Microsoft Fanboys to rant about how stupid I am.

When I left Nature Blogs, I spent time outlining why I hate Microsoft. Yes, that’s right, I do not like Microsoft or want to have anything to do with them.  They’re a monopoly, repeatedly convicted of abusing that monopoly to the detriment of the consumers around them.

It’s not a speculation, it’s a fact, held up in courts around the world.

In response to “Joe Hammock” – a coward who signed up with a “fastmail.fm” account just to write  a terribly rude comment on my Nature Blog post –  let me reply to get things started:

“You are quitely [sic] frankly the biggest fricken [sic] idiot I’ve ever seen in my entire life”

You lead a sheltered life.

“If you had a clue, you’d know that Microsoft is more altruistic than all the other tech companies combine. Hell, Bill Gates has pleged [sic] half of his wealth to charity. Jesus Christ, do some research before you run off a bunch of lies.”

Oh, I’m well aware that Bill Gates gives up a lot of his wealth to good causes.  I still consider much of it ill-gotten.   Microsoft made most of it’s money on its flag ship products of Windows and Office, both of which have been the focal points of lawsuits for the way that Microsoft has harmed their competitors. (The OS/2 Fiasco as well as WordPerfect come to mind as great examples of how Microsoft lied and cheated on their contracts to gain dominance.)  That Gates now feels he needs to give away 1/2 of his money to make him feel better about how he got it, after retiring from Microsoft, doesn’t make me feel any better about Microsoft as a corporation.

“As for the list of awful things Microsoft has done, would you like for me to reel off the massive list of things that Apple and Google have done?”

Actually, Yes!  I would.  I have never heard of Google abusing it’s monopoly, destroying competitors because it felt like it or engaging in otherwise unethical practices.  I know the standard lines about Google getting in Microsoft’s way, but that’s hardly a crime.  As for Apple, I don’t like their business decisions, but I’m not aware of any that were illegal.

So yes, please do list them! But hold the insults – they’re unnecessary.

“You are clueless and beyond idiotic.”

Thanks!  From you, that’s actually a compliment.

“It’s quite evident that you are nothing more than another pathetic Apple sycophant whose decided to hate Microsoft because of your love of Apple’s overrated products.”

Frankly, your shot is wide of the mark.  I rarely use Apple products, and I find them, for the most part, to be just as poor as Microsoft’s.  I don’t like the lack of interoperability or transparency.  If I’m a fan of anything, it’s GNU/Linux.   So, would you like to tell me why Linux is unethical?

“Did you know that hackers proved at a hacker’s convention that OS X is even less secure than Windows? No, because you’re an idiot.”

Wow.. that’s the best you can do for propaganda?  Common Microsoft Fanboys… man up and at least tell me which convention.  Anyhow, did I mention that I’m not emotionally attached to Apple?  Even if you had evidence, proving that Microsoft is no worse than Apple is hardly going to upset me.  Now, if you can show me how many critical flaws are found in the Microsoft Kernel versus the Linux Kernel, you might be on the right track.  Unfortunately, if you’re following the FUD trail left by Microsoft, their stats compare the Microsoft Windows kernel with the whole Linux ecosystem – hardly a fair comparison.

“God you are pathetic.”‘

I’m an atheist – suck on that.

Ok, have at it, Fanboy, this thread is all yours.

Slow ssh on Ubuntu.

Ok, really, no one is going to be interested in this, but I wanted to put it somewhere I won’t forget.

I’ve been having trouble with ssh sessions taking 2 or 3 minutes to connect and ask for the password – which is intolerable when the computer on the other end has a 2-3 minute time out.  Turns out there’s a very simple solution:

sudo nano /etc/ssh/ssh_config

find the following two lines:

GSSAPIAuthentication yes
GSSAPIDelegateCredentials no

Comment those two lines out, which should look like this:

# GSSAPIAuthentication yes
# GSSAPIDelegateCredentials no

Tada – no more slow ssh!

Science Spam

Periodically I get spam that makes me laugh.  Yes, this is a real company, and yes they do publish anything and everything they can get their hands on – basically they are a custom printing shop, printing your content at great expense to the purchaser.  I have no idea how much they offer to the generator of the content.

Dear Mr. Anthony Peter Fejes,

I am writing on behalf of an international publishing house, LAP Lambert Academic Publishing.

In the course of a research on the University of Waterloo, I came across a reference to your thesis on “Computationally Modeled Properties of BetaTrefoil Proteins”.
We are an international publisher whose aim is to make academic research available to a wider audience.
LAP would be especially interested in publishing your dissertation in the form of a printed book.

Your reply including an e-mail address to which I can send an e-mail with further information in an attachment
will be greatly appreciated.

I am looking forward to hearing from you.
Kind regards,
<Name Redacted>
Acquisition Editor

Why does it make me laugh? The thesis they’re asking about is one I did for my undergraduate Biochemistry degree.

Yeah, I know, my first thesis was a brilliant work of art, but really, computational modeling done over a decade ago using Swiss-Model isn’t going to be earth shattering – and yes, if there is someone out there who wants a copy of my thesis, I can have it printed for you for at Kinkos… if I can find that file.  (It did have awesome pictures, tho!)

And, as far as I’m concerned, one should never combine beta-trefoil proteins and my undergrad thesis with the term “wider audience” – it’s just not going to work out well in the end.