照片因為這個月的空間限制傳到第四天的一半

要到11月才能在上傳了…= =”

遊記稍後在補上囉~:P (意思就是不要太期待會是什麼時候XD)

這次去玩得滿有心得的

我們住了Legian的Courtyard hotel、Nusa Dua的Conrad

去Seminyak的Samaya還有Uluwatu的Bvlgari吃晚飯

還去了有名的Nikko、Jari Menari和Conrad的Jiwa spa按摩

在GENEVA的handycraft center買手工藝小東西

跟上一次去是滿截然不同的感覺

有要去的人可以來討論一下行程~:P

Dr. Moon是我去年在美國的老闆，這是他剛發表在雜誌上的自傳性文章，講述他發現與研究Wnt pathway的起源與過程。 我覺得這種科學家的故事給我滿大的啟發，尤其是最後一段關於我們對基礎科學研究的態度，更是發人深省。在這邊與大家分享，強烈建議大家用心慢慢看完。:P

WNTer wonderland

A developmental signal involved in tissue regeneration could be a target for cancer and Alzheimer therapies.

By Randall Moon

Oringin: TheScientist http://www.the-scientist.com/2008/3/1/34/1/

Development. Disease. Regeneration. Aging. The Wnt/β-catenin signaling cascade has provided enough surprises and insight to fill my career many times over. It all started with a hunch. Like many newly minted assistant professors, I was working on too many things at once, and I didn't want to abandon any of them. I couldn't resist trying just one more. During Christmas break in 1988, I stole back to the laboratory while most of my students were home for the holidays, and I injected scores of tadpole embryos with the RNA of a gene called INT-1 that had piqued my interest.

It was one of those goofball experiments that you never expect to work. A friend of mine, Andy McMahon at the Roche Institute (and now at Harvard University) had been struggling to knock out the INT-1 gene in mice where it was known to cause mammary tumors. We wondered what would happen in the reverse situation - if we overexpressed the gene. We hypothesized that since the gene was expressed in the nervous system, then perhaps the embryos would develop with neural defects. I certainly wasn't expecting to come back the next day to find a hundred tadpoles with two heads.

The forked spines of these embryos reminded me of a famous experiment that every developmental biologist knows by heart. In the 1920s, German Nobel laureate Hans Spemann transplanted sections of one embryo into another, creating a secondary embryonic axis and thus a double headed tadpole. He called the transplanted section the organizing center. What was remarkable was that it looked as if I had replicated the effect with a single gene - the INT-1 oncogene.

It was clear that something really important had fallen into my lap. That very day I euthanized all the meandering projects in the lab (except for those that grad students depended on to finish their PhDs), and focused everyone on INT-1. Working closely with McMahon, we repeated and developed the finding. We eventually put together a manuscript describing the axis-inducing activity for INT-1 in vertebrate development. It was featured on the cover of Cell¹ and the experiments were quickly repeated by many people in the field, either out of a sense of disbelief or just because they were so easy and exciting to do.

Today INT-1 is called WNT-1. Researchers realized that INT-1 and the Wingless gene in fruit flies were the same, so they combined the names to WNT. In fact, an entire family of 19 Wnt glycoproteins has now been identified in mammals alone. Each of these glycoproteins is expressed in spatially and temporally restricted patterns in embryos and adults. We now know that the Wnts are secreted factors that activate multiple signaling pathways in cells by binding to receptors known as the Frizzled receptors, as well as to other transmembrane proteins.

In the 20 years that followed that first experiment, others and I have tried to understand how Wnt operates. We have learned that the normal roles of Wnt signaling include control of cell proliferation, differentiation, and movements in a variety of contexts. We have discovered a tremendous amount about the mechanisms by which these Wnt pathways work, and what happens when they fail. Wnt signaling is altered in cancer, bone density diseases, familial exudative vitreoretinopathy (a retinal disease), inflammatory bowel disease, and other conditions. This raises the possibility of new therapeutics, and indeed a number of large and small companies now work on Wnt signaling as a target for therapies in a range of diseases.

We and others used a range of model organisms to tease out the mechanisms by which Wnt pathways operate. It isn't difficult to determine the genes that were originally discovered in Drosophila: Fruit fly geneticists have a penchant for wacky names. The rest of us provided the gravitas!

The first connections were made in the 1990's, when other researchers worked out that the Wnt pathway in Drosophila activates the function of the cytoplasmic protein called Dishevelled. Dishevelled functions upstream of Armadillo, which is called β-catenin in vertebrates. It was not clear how the product of the Shaggy gene (called Glycogen Synthetase Kinase-3, or just GSK-3, in vertebrates) worked; it was operating downstream of Dishevelled and upstream of Armadillo. Roel Nusse found that the Wnt receptor in flies was Frizzled, and a few months later (darn those slow reviewers!) we showed that this was also true for vertebrate Frizzled proteins. This gave us an outline of the pathway starting with a ligand, the Wnts, the receptors, the Frizzleds, and some of the cytoplasmic components that transduced the signal.

More connections started to appear. Kimelman, a wonderful colleague at the University of Washington, and I thought that the GSK-3 and β-catenin proteins might interact to activate the Wnt pathway. Sure enough, when we injected frog eggs with β-catenin RNA, the double-headed phenotype reappeared. However, it was blocked by coinjection of GSK-3 RNA, suggesting that the genes were working antagonistically in vertebrates as they do in flies. The question was: How was this working?

Kimelman and I suspected that GSK-3 might directly phosphorylate β-catenin to alter its function. To test this we mutated the site on β-catenin that we thought was most likely to be phosphorylated by GSK-3. Not only was this β-catenin not phosphorylated at normal endogenous levels, but it also accumulated to very high levels, first in the cytoplasm and subsequently in the nucleus. Nuclear accumulation resulted in a kind of hyperactive induction of the two-headed phenotype in frogs. ² I believe that the publication of this work was a key paper for the field, for three reasons: It showed directly that GSK-3 phosphorylates β-catenin, that this phosphorylation regulates posttranslational stability, and that the Wnt pathway controls the accumulation of β-catenin in the nucleus.

The first inkling that GSK-3-mediated phosphorylation might be relevant to medicine and not just frogs came from papers in Science and elsewhere showing that these same phosphorylation sites were often mutated in cancers such as melanoma. We realized that modulators of the Wnt pathways might have an important therapeutic application, and we immediately started to think about experiments that could demonstrate this in animals.

Courtesy of Cristi Stoick-Cooper
Day 1	Day 2	Day 3

That simple experiment convinced us that small molecules targeting Wnt and other signaling pathways could help patients. ³ Patients with various types of cancer undergo radiation or chemotherapy, followed by transplantation with bone-marrow stem cells or cord blood to replace the immune cells that were killed by the treatment along with the cancer cells. However, there aren't many stem cells in cord blood; in fact, when patients receive stem cells from two cords, their chances of survival increase greatly. Could GSK-3 blockers increase the efficiency of cord blood transplants, conserving this key resource?

This idea, and the broader notion that developmental signaling pathways such as Wnts, Hedgehog, and Notch might be greatly untapped sources for therapies, led to the formation of Fate Therapeutics. Four colleagues and I started the company, with timely backing and great scientific insight from four venture capital companies lead by Arch Venture Capital in Seattle and Polaris based in Boston. One major goal is to discover drugs that regulate endogenous and transplanted stem and progenitor cells, as well as drugs that reprogram cells to adopt other fates. The company was launched in 2007, and is off to a great start with a pipeline of products in development and testing.

Cristi Stoick-Cooper, then a graduate student, took the project on and in an elegant series of experiments showed that the Wnt/ β-catenin pathway is central to regeneration in zebra-fish tails. ⁴ With help from Gilbert Weidinger, then a postdoc, she found that blocking Wnt signaling through β-catenin completely blocked regeneration. Conversely, enhancing β-catenin signaling enhanced regeneration. Another postdoc, Hitoshi Yokayama, found that hind limb regeneration in frog tadpoles also required Wnt signaling through β-catenin. Thus, Wnt signaling is necessary for regeneration, raising new possibilities for therapies in mammals.

Of course, mammals have at best, a limited capacity to regrow limbs. Certain organs, such as the liver, do have some regenerative properties. We studied liver regeneration in mice and found that Wnt signaling through β-catenin was activated. These were exciting findings, among the first to show that Wnt signaling was key to control of tissue regeneration in mammals.

The finding raised the possibility that the converse might also be true: If Wnts served a positive role in regenerative processes, might Wnt signaling be reduced in some degenerative diseases? The literature gave hints that Wnt signaling might be important in Alzheimer's disease. For example, GSK-3 activity levels are elevated in patients, but this was not tied to a definite genetic connection. A highly motivated Chilean postdoc, Giancarlo de Ferrari, decided to look for this missing link. ⁵

Aside from Frizzled, Wnt sometimes uses a coreceptor called LRP6 to initiate its signaling pathway. Giancarlo showed that a statistically significant number of patients with Alzheimer's disease had a single amino-acid change in the LRP6 protein. In some cells this change reduced its signaling ability as we had hypothesized.

An interesting follow-up to this is that lithium chloride, an approved drug used to treat patients with bipolar disorder, inhibits GSK-3. As described above, the consequence of GSK-3 inhibition is activation of β-catenin. Could an increase in β-catenin by lithium treatment help protect neurons of patients predisposed to Alzheimer's? De Ferrari had some evidence to support this in rats from his PhD work. Nicely enough, recent data from other labs support this happening in humans. So I am hopeful that understanding Wnt signaling or at least GSK-3 inhibition might contribute to therapies for some patients with this horrible disease. We are working on drugs that might help the lithium to work better and at lower doses than are needed at present.

For many, developmental biology - a field that often studies early development of fruit flies, worms, mice, sea urchins, fish, and frogs - seems like it should be on the top-ten list of stupid things on which to spend federal funds. However, many biotech companies, including Fate Therapeutics, are emerging, aiming to find ways to harness Wnt and other early developmental pathways for useful drugs. It looks like the investment by the National Institutes of Health in this field is going to pay off.

I can only hope that politicians, and the public, begin to understand the importance of investing in basic research at nonfluctuating levels, which would encourage students to invest decades of their lives in training, so that the basic research of today will have major impact on therapies in the future. Certainly no one foresaw that studying flies and two-headed frogs would save lives, but we and others are convinced that this will happen, and we are dedicating our careers to making it a reality.

我只能期盼政客與社會大眾開始了解基礎科學研究的重要性，並且儘可能的資助基礎科學研究。如此一來才能夠鼓勵青年學子們投資十數年青春來訓練自己 (大學到研究所)，進而貢獻一己之力於科學研究。也才能使得今日的基礎研究成果，能夠成為未來人類對抗疾病的工具。 沒人會知道以往研究果蠅與青蛙發育的成果，竟能在今日成為對抗疾病、挽救人類性命的知識；但是我們從事科學研究的人卻從不曾懷疑，更進而投入我們的一生讓這一切可以成真。

Randall Moon is a Howard Hughes Medical Institute investigator at the University of Washington and director of the Institute for Stem Cell and Regenerative Medicine.

引述

「台獨自慰派」開始抓狂了！

 

http://news.chinatimes.com/2007Cti/2007Cti-News/2007Cti-News-Content/0,4521,130501+132007072600849,00.html#
【中時電子報主筆俞雨霖/特稿】

 

      實在不知道台灣的政治為什麼會墮落到今天這種地步，那麼殘酷、卑鄙又齷齪，有良知的人即使有心也是無力，只有聽任撒旦繼續蠱惑台灣的人心。如今「台獨基本自慰派」又開始抓狂了，為了確保「台獨自慰」政權的延續，他們勢必會將最極端的手段搬出來，現在他們已開始牛刀小試，他們的做法絕不會只限於當前的口水戰，而是「割喉」。

 

      最按耐不住的是陳水扁，他最近公開吹起了族群鬥爭的號角，想再一次將台灣社會徹底撕裂。陳水扁公開宣示，二○○八年總統大選，對兩千三百萬人民來講，是面臨十字路口重要抉擇的關鍵時刻，要抉擇台灣到底要走「台灣主體意識」的正確路線？還是要走「大中國主義意識」形態投降的路線？明年不只是選總統，也是「台灣主體路線」與「大中國主義路線」的選擇，是「相信台灣、看好台灣」對上「否定台灣、唱衰台灣」的一個競爭。

 

      的確，對「台獨基本自慰派」而言，七個多月後預定舉行的台灣總統大選，將是決定他們命運的三合一的「生死存亡之戰」：一是陳水扁家族的生死存亡之戰；二是民進黨政權的生死存亡之戰；三是「台獨基本自慰派」的生死存亡之戰。千萬不要懷疑「台獨基本自慰派」的殺傷力、破壞力與割喉的決心。

 

      一旦失去政權就失去一切，「台獨基本自慰派」比誰都清楚這個道理。「台獨基本自慰派」如果失去了他們現在暫時擁有的「台獨小朝廷」，他們就無法再立足於台灣，他們一旦無法立足於台灣，他們就將一無所有。試想想，在過去，「台獨基本自慰派」還可以假民主、本土之名，騙取台灣善良民眾的支持，高舉反抗國民黨威權統治的道德正當性，而如今，「台獨基本自慰派」在統治台灣七年後，台灣民眾看到的是一個「只會閉門自慰」，無能又失德的統治小集團，這個集團比過去他們曾嚴辭批判的國民黨更墮落、更腐敗不知多少倍，只要他們失去了政權，他們真的連「台獨自慰」的舞台都將喪失。

 

     「台獨基本自慰派」真的開始抓狂了，因為他們極度恐懼將一無所有，他們的恐懼是對的，他們一定會一無所有，這是他們對台灣這塊土地、對台灣善良人民七年來作惡多端的業報。但是「台獨基本自慰派」不會自動退出統治舞台的，為了保有他們的「小朝廷」，不要懷疑，他們什麼事都幹的出來。狗急都會跳牆，更何況「台獨基本自慰派」現在是又急、又驚、又懼，他們太擔心失去政權了，用他們自己的話語：「外來政權要復辟了」、「台灣本土政權要失敗了」。

 

      說真的，「台獨基本自慰派」的抓狂程度，目前還只停留在「初級階段」，仍屬於小打小鬧的文鬥階段，善良的台灣民眾現在絕對不要大驚小怪，否則會被「台獨自慰派」訕笑沒有見識。短期內，他們推出的做法，頂多只是為「台獨自慰」「warm up」(熱身)一下而已，但這個階段很快就會過去，一旦「台獨基本自慰派」發現他們就要失去政權、徹底喪失「自慰」舞台時，那麼他們大打大鬧、搏命演出的戲碼就要登場了。

 

      將「台獨基本自慰派」近半年來的做法歸納起來，應可以很清晰的呈現出「台獨基本自慰派」在割喉「初級階段」的三個策略：

 

      一是以國民黨的候選人馬英九、蕭萬長為目標。全面打擊馬英九，同時將馬英九拉下馬，是民進黨認為最便宜的行動，只要馬英九無法參選，國民黨將難以推出足以打敗民進黨候選人的強棒，如此民進黨就可以高枕無憂躺著選。馬英九的特別費案就是民進黨操作的「刺馬」最佳利器。馬英九案起訴書的誇張指控，以及近來曝光的侯寬仁檢察官的證人筆錄記錄不實的風波，深入觀察，應該是「台獨基本自慰派」最典型的抓狂表現。至於「台獨基本自慰派」對馬英九的各種抹黑、對馬英九副手蕭萬長的「請鬼拿藥單」的指控，基本上只是「割喉戰」中的一碟小菜。這樣的小菜在未來七個多月，還會不停的端上桌來。

 

      二是以挑釁中國大陸為目標。「台獨基本自慰派」的年度「自慰」代表作─「以台灣名義加入聯合國」的申請案及「以台灣名義加入聯合國」的公投案，目標並不在可行性，而是在試圖透過挑釁中共的「一中底線」，激怒中共領導人，並操作兩岸緊張關係，激化台灣一般民眾對中共的不滿，強化台灣民眾歷史的悲情意識，並將這些不滿轉嫁國民黨，進而產生對「台獨基本自慰派」的同情。

 

      三是以台灣一般民眾為目標。可以分成三類。一類是深綠選民與淺綠選民。一類是中間選民。一類是低政治意識選民。對於泛綠選民，「台獨基本自慰派」的做法一以貫之，激化族群意識與「仇中意識」，將這些深綠與淺綠選票最大程度的催出來；對於中間選民，則要持續抹黑國民黨與蔣介石，強化他們的「歷史記憶」，讓中間選民不會因厭惡民進黨而轉向支持國民黨。當前全面「去中國化」、「去蔣化」即為他們的主要做法；對於低政治意識選民，「台獨自慰派」則用「實惠」來催出這些選票，說白一點就是撒錢。做法包括提高老人年金、增加基層補助款綁樁、對特地人群直接補助等等不一而足，甚至大赦罪犯也屬其中之一。

 

      但是，外界若認為「台獨基本自慰派」只會操作這些缺乏新意的老把戲，那就大錯特錯了，也太低估了這些人的選舉陰謀創意能力。隨著二○○八年大選選情加劇，為了讓「台獨自慰」政權繼續下去，大打大鬧的手法必然層出不窮。雖然，目前仍難以預測未來台灣選舉可能出現的事端，但二○○四年「兩顆子彈」的驚奇經驗，可以提供外界更多的想像空間。

 

      可以很肯定的說，在必須勝選的極端壓力下，「台獨基本自慰派」一定會抓狂進而發狂，並採取任何最極端的手段，操作的範圍應該設定在「選不贏，就不准選」的終極目標。而這就不能排除「兩顆子彈」的暗殺事件重演，差別只在「兩顆子彈」會射向誰；甚至也不能排除「台獨基本自慰派」挑起台灣社會動盪，甚至兩岸軍事衝突，導致選舉暫停，讓「台獨自慰」政權能一時茍延殘喘下去。總之，「台獨基本自慰派」一定會不擇手段，終究這群人的素質決定了他們的行為。