yet another megabase long enhancer

I like this paper a lot because it’s yet another good example of decoding the functions of non-coding disease variants, and what’s more, it’s a megabase-long looping enhancer!

I’ll never forget, from my college biology class, that crazy drawing of how enhancer elements might work: a piece of DNA, anywhere from introns to intergenic deserts, is bound by some transcription factors, and somehow forms a weird loop like alligator’s jaws all the way to the proximal promoter, where the core transcription regulation occurs.

Given this possible long-range cis regulation, it is not uncommon to see DNA in one gene regulates not this gene, but another gene/genes miles away. And this causes a lot confusions in interpretation of the functions of each of these regulatory sequences, especially when you try to study a disease-associated variant. Continue reading “yet another megabase long enhancer”

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今天我死了。因为头一次在生命里,有一样东西超越了死亡带给我的恐惧。

我的负罪感。

透过空气,我可以注视着我的罪。我看见以往做错的每件事像玫瑰一般一瓣一瓣地被我撕成碎片,漫天飘落了一地。

碎了一地的心。一湖的泪。

我以为我可以作一个局外人。可现在我没法不置身其中,忍受悲剧之火的煎熬。

我以为我的心很重,不能承受世界上多数人的轻。原来我自己才是最轻,最薄,最飘来飘去的没有心。

幸好没有毁了你。只毁了我自己。

我注视着你的眼。清澈。平静。平静到让我恐惧。

我一刻不停的注视着你的眼。是死了心的冷。有无言的控诉。

我闭上眼,也能看见这双眼。黑暗中,也能看见这双眼。

你的眼把我剥的体无完肤。你的眼让我芒刺在背。你的眼直接审判了我。

这是我第一次后悔。

我不信教。我是我自己的信仰。当我开始撕毁我自己的时候,我的信仰也随之倒塌。纵使明天活着,我也只能像虔诚的信徒一般,走上一条自我放逐的道路,背负着对自己的负罪与悔恨不停的苦行,直到终点。

这个原本美丽的Y,现在却像十字架,把我牢牢的钉住。

PAMPs, tyrosine kinases and plant immunity

这篇文章单纯的让我想起了08年我做的第一份研究。

同样的Arabidopsis thaliana, 同样的Pseudomonas syringae, 同样的host-pathogen interaction, 同样的PAMPs。我的工作那么简单,和这篇文章一样简单,直接。

可科研再也没有那么纯粹过;人也是。

那时候每天像白开水一样的过,每天刷试管,洗盘子;看着种子一点点从土里长出绿叶,在温室听广播里泡沫一样的流行音乐边收集种子。下了工时而去水泥球场打球,有时去吃立着的铁盘里盛的披萨。那时候我不认识很多人。那时候我认识很多人。

那时候我喜欢被太阳晒的发痒的皮肤,喜欢楼道水泉里喷出的冰凉到大脑空白的水,喜欢硬的吱嘎吱嘎的单人床,喜欢图书馆高吊的洁白的灯。

那时候我爱音乐;
那时候我爱孤独;
那时候我爱女孩;
那时候我爱忧伤;

是什么改变了我们,我们又改变了什么。

那时的我拒绝改变,拒绝妥协;
那时的我拒绝世俗,拒绝道德;
那时的我拒绝软弱,拒绝将就;
那时的我无情,拒绝了自我。

是什么改变了我们,我们又改变了什么。

那时的我不曾后悔。

single molecule dynamics and two camps in biological research

This paper from Janelia Farm is fucking so cool and nearly flawless to me simply because I can’t understand most part of it.

They are studying transcription factor dynamics and mechanisms of chromatin binding and motif searching. Their raw data were acquired with extremely sophisticated (to me) and state-of-art microscopies. Their conclusions were derived from those raw data based on a series of complicated (to me) mathematical modeling and algorithms.

As my own research also involves molecule tracking and interaction in real time, I’d always dreamed of having one of those multi-focus microscopies they have and it is beyond a dream for me to have someone, applying rigorous computations, to figure out what’s going on in all the movies I’ve captured.

Looking at this work, I’ve never been so perplexed with the vortex of biomedical research that I and many others fall in. On one hand, we have these most careful nature observers who have the very detailed and amazing description of physiology, anatomy, development and disease; On the other hand, we also have these incredible mathematicians, physicists and engineers who take a completely different, very rational and theoretical route to uncover mysteries of biology.

And these two camps seem never be able to reconcile with each other, just like Catholics and Judeo-Christians can’t. I myself fall into the first camp, so I love the way I interact with biology. It’s like telling a story, fitting pieces and pieces together———in a logical manner, but not necessarily stringent, because I believe it’s just totally absurd to seek for absolute accuracy in biology. It loses all the beauty and drama of the nature we study.

But at the same time I’m fully aware of all the ugly bits from this angle of the approach: cherry-picking data, ascertainment bias, ill-designed statistics, and so on and so on. We are too into the little details and forget the general principles; and we are so obsessed with the nature in our eyes in a descriptive way that we couldn’t extract the skeletons and metaphysics of it. This is where the other camp come in. These abstract, cold-blooded mathematicians and computationists. They don’t see colors, they see patterns; they don’t see interactions, they see models; they don’t care about complexities and crosstalks, they care about generalizations and modularities.

That’s why I’m so afraid of them. They have incredible ability to develop new tools and techniques that revolutionize the field. Everything we do is absolutely dependent on their support. They have amazing mind to extract general principles out of messy, daunting experiments. I’m afraid of being useless because I’m not smarter than them and I can’t compete with the robots and software they devise.

As a matter of fact, I’m in a deep deep fear. I genuinely think biological research will be taken over by mathematicians and computer scientists, and the field of biology will become mere applications of physics and engineering.

I don’t know what to do. It’s too late for me to washout my brain to something I never used to and never liked.

My scientific belief has collapsed in front of codes and equations. I don’t see a future of myself.

 

今天得记录下来。今天我的精神家园终于坍塌了。 瓦片碎满一地的声音刺激我的灵魂。我孤单的站在一旁的角落,嗅着尘土飞扬的遗迹,不知所措。

我失去了感官。雨成了冰。我的眼看不见颜色。我的手成了匕首—–锋利和冰凉。

我一直想写一部小说,描述自己的贪婪,软弱,虚伪和人为扭曲的精神世界。但今天我只想用第一人称,赤裸裸的撕开我。

<我端着一碗肥皂水,碗上十字交叉,架着一面镜子和一把剃刀>,把身体和心灵撕开成一条一条。

今天是个重要的日子。我以前评价自己曾在十四岁,和二十岁各长了一岁,之后一直活在<二十岁后>的状态。今天,在我二十五岁零三个月的时候,我又长了一岁。而且这次是立刻认识到,不像之前是后来回想得出结论的。

长大的原因是我发现我一直以来试图搭建的精神的脚手架没有一处不是错的。从一开始就是错的,从根本上都是不应该的。这比白活了还要糟糕一百倍,一千倍。如果白活了可以开始活着,仍是白纸一张;现在我是肯定了又否定,把石头推上去又轰隆隆的滚下来。心中的信仰一念之间全部土崩瓦解,却留下我早已变迁的心境,腐坏的思想,和仍不能止的欲望,纷纷逃脱了本来的禁锢,一下子污染了我灵魂的每一寸。

坍塌的信仰怎样才能修复? 玷污的灵魂怎样才能漂白?
害怕信仰一次次坍塌的心怎样才能重新坚强? 害怕灵魂一次次污染的我怎样才能重整方向?

剃刀是你, 三年后的melpo. 毫不客气的把我解的支离破碎。

我以为我拥有。原来我什么都没有。我一直活在自己精神的孤岛上。而这岛,完全是我自己造的,虚假的,臆想的。早该被当作违章建筑拆的灰都没有。

我以为我不同。原来我没有任何不同。我一直活在人群里的一片真空里,我想超脱他们,到头来确是在模仿他们,重复他们的一切。

everyone is the same.

我以为我有情。原来我只是无情的有情。我以为我付出,原来我一直在索取。我以为我关心,原来我一直在伤心。我以为我是个好人,原来我只是坏人里的好人。我以为我可悲,原来我只是可笑。

我以为我无情。看了你我才知道,原来无情之后是有情,有情之后又会无情。我在第一个无情的时候遇到了有情的你,现在你已经无情了,而我还在有情里挣扎。

im not indifferent anymore.

所以我以为我透彻成熟,原来却只是幼稚的成熟,有情的无情。

如果我们现在重新相遇,我一定会

http://www.xiami.com/widget/0_2083169/singlePlayer.swf

后记:
1. 我只特别欣赏看过点书有点思想的人,所以在沉闷的城市的冬天看到你真是很开心
2. 我一直臆想活在虚幻里。我以前看过一个电影,里面的男主角穿越时空和女主角相爱,后来因为看到了自己身上的一枚现代的硬币而倏的一声回到了现在。你手上的戒指就是那枚硬币。

being an NBA fan

I’m happy to see the two teams that I’d been attached with over the years are finally growing into some prospect since I started watching NBA in 2000.

The Toronto Raptors and the Washinton Wizards.

Going to see a basketball game is such fun. I still remember the times I went to a Raptors’ game on a cozy cool summer night with friends and drinks. I enjoyed sitting upper rows and looking down at the shiny hardwood floor, the giant maple leaf flag and the glowing Raptors’ logo. And of course sometimes when I got lucky, I found myself having a slice of free pizza from pizza-pizza the next day because the Raptor’s won and scored over 100 pts.

I still remember once, after the game, at the entrance of Air Canada Center where the crowd was exiting, I looked up in the sky and saw an eclipse. When the beautiful pale moon was being shadowed, right over the lake, the stadium, the street lights and the people, I couldn’t help but thinking of J D Salinger and I depicted myself as the catcher in this land. I logged the scene and the emotion I had at the time, but from time to time, I can’t resist thinking back of that night over and over again and asked myself:

Where was I ? In the middle of the crowd, under the moon being shadowed, or I was nowhere, no one, no water, no moon ? Should I be there, or should I be somewhere else ? Was all these just my mere imagination ? The voices, the water, the echoes and the moonlight ——- all just illusions and hallucinations, and I was just by myself, totally detached from the scene, just one isolated piece of existence. I was nowhere.

The bottom line is, you don’t need a championship team to become a fan, to enjoy the games and a good time. Some good old days.

with a little help from my friends

This is no doubt the most influential and magnificent sculpture in biomedical sciences. This monument should be erected at the front door of every single research building.

Look at the fine structure. Look at how delicate the paws are. Look at those innocent yet miserable eyes.

There is simply no other art work in biology quite near the level of this one.

gay梦

‘we are observing you.’
‘who invited you?’
‘no one. we invited ourselves.’

这段对话突然深深的印在脑海里,自从一天梦醒后。我好像注视别人的人,不请自来,一厢情愿;也好像在被注视着,只有无言的独白。

这段话发生在这个梦的结尾,是几个坐在椅子上一动不动好像没有灵魂的人对我说的。当时我在客厅里,和一个男人一起。他的妻子在为我们准备晚饭。我兴奋的心跳的很厉害。

多奇怪的梦呵! 后来我一直想搞清楚,我是因为跟男人一起而兴奋,还是因为偷情而兴奋。或者两个都有。

人的一生或许像一滴从天而降的雨。
年轻时恣意妄为,全力成长,前进;
而后放缓脚步,留恋,成熟,依然前进;
最后一大半的时间,像匀速的列车,行驶在单行线上,一路到终点;
偶尔看见窗外倒退的事物,感觉到自我的存在,但已不在乎是否向前,也不想徒劳抓住一切;一切都美好,安静的走向虚无。

brain disease and transposable element

This work

from Chris Walsh’s group is an elegant example linking human genetics, mouse genetics and molecular biology.

The disease of question is polymicrogyria, meaning too many small gyri on the surface of brain grey matter. Key to the design for their success: phenotypic classification. From over 1000 patients with gyri abnormality, they selected specifically those with polymicrogyria restricted to only one part of the cortex. They were able to reconstruct independent pedigrees from these selected patients. And the consanguineous nature of the pedigrees immediately suggest a recessive Mendelian disorder.  Continue reading “brain disease and transposable element”

more on the renilla GFP

I was reading this paper and accidentally came across my new friend, the sea pansy derived GFP. A couple of fusion protein reporters, this time: Npy-hrGFP and POMC-hrGFP. hr here stands for humanized renilla. The researchers who generated these transgenic mice claimed that “the hrGFP expressed from this transgene is more stable and resistant to signal fading compared to other GFP’s”. This is an interesting note and probably true because the eGFP version for both transgenes were available beforehand. A stable signal is definitely important for accurate cell counting, neuronal tracing, optogenetics and all imaging methods.

Just a bit more search on this. Some reports, here and here, claimed that hrGFP is less toxic than regular GFP when expressed in vivo. The evidence is not substantial. And who knows if a humanized version of the aqua GFP is even safer?

历史上的今天:
2012年2月6日 时光倒流七十年