Monday, November 01, 2004

Mitochondrial mutation linked to blood pressure and cholesterol problems

Mitochondrial mutation linked to blood pressure and cholesterol problems

New Haven, Conn. � Researchers at Yale and Syracuse Universities found the first direct evidence for a mutation in mitochondrial DNA that directly affects blood pressure and cholesterol levels.

It has long been known that several metabolic traits including high cholesterol and hypertension cluster in individuals more frequently than by chance, but the underlying causes were unknown. This study, published early in Science Express on line, suggests that altered mitochondria may account for the clustering as well as the disorders.

"Looking further, this finding raises the possibility that all features of the metabolic syndrome may be attributable to altered mitochondrial function," said Richard P. Lifton, Sterling Professor and Chair of Genetics at Yale and research team leader.

Metabolic syndrome is an emerging problem in industrial societies and. epidemic in the United States. The symptoms include high blood pressure, cholesterol and triglycerides, insulin resistance, obesity, and low HDL. There is independent evidence that altered mitochondrial function plays a role in insulin resistance and high triglyceride level, and the current finding indicates that these other components of metabolic syndrome may also linked to mitochondrial disfunction.

The clear correlation of mutation and disorder in this study was made possible by the evaluation of 142 people in four generations of an affected family. Although family members with each disorder � hypertension, hypercholesterolemia and hypermagnesemia � have the same mitochondrial mutation, the presence of the mutation does not produce all of the symptoms in each individual.

While this study focuses on a rare mutation in mitochondria that provides a clear link to specific disorders, mitochondrial function is known to decline with age in normal people and may be contributing to these common traits in the general population.

Other researchers included Frederick H. Wilson, Ali Hariri, Anita Farhi, Hongyu Zhao, Kitt Falk Petersen, Hakan R. Toka, Carlo Nelson-Williams, Michael Kashgarian, and Gerald I. Schulman at Yale, and Khalid M. Raja and Steven J. Scheinman at Syracuse University. Grants from the National Institutes of Health the Howard Hughes Medical Institute and the American Heart Association supported this research.

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Citation: Science Express (October 21, 2004).

都是粒腺體的錯!?

都是粒腺體的錯!?
  粒線體的突變似乎和代謝疾病息息相關,會導致如高血壓、高膽固醇等心血管疾病危險因子。

  高血壓伴隨了其他心血管危險因子,如血液中高膽固醇和三酸甘油酯含量,以及糖尿病。雖然肥胖的人常會有這些代謝併發症狀,可是體重正常人也會有,所以過重並非主因。

  耶魯大學醫學院的Richard Lifton等人發現了一位血液中鎂離子含量過低的女病人,接著他們發現粒線體中一連串的基因突變是主因。這位女病人的其他親人也有低鎂離子的症狀。追蹤了142個親人,他們大多有低鎂離子、高血壓和高膽固醇的問題。這些症狀都是遺傳自一位母親--粒線體靠母系遺傳把突變傳給了一大票後代。

  把整個粒線體定序了之後,他們發現一個鹼基的變化發生在tRNA的基因中,一個胸腺嘧啶變成了胞嘧啶,結果改變了tRNA的結構而影響了蛋白質合成。

  舊金山加州大學的高血壓專家Theodore Kurtz指出,雖然還不知道為何這個粒腺體突變會造成多種症狀,不過這個發現是非常重要的。之前沒前個心臟病學家把粒腺體原來在高血壓以及其他心血管疾病危險因子上參了一腳,不過這個發現將改變一切。

原學術論文:
Science, Published online 21 October 2004. DOI: 10.1126/science.1102521 Link

The mystery of eye evolution

Darwin's greatest challenge tackled: the mystery of eye evolution

Researchers provide concrete evidence about how the human eye evolved

When Darwin's skeptics attack his theory of evolution, they often focus on the eye. Darwin himself confessed that it was "absurd" to propose that the human eye evolved through spontaneous mutation and natural selection. Scientists at the European Molecular Biology Laboratory (EMBL) have now tackled Darwin's major challenge in an evolutionary study published this week in the journal Science. They have elucidated the evolutionary origin of the human eye.

Researchers in the laboratories of Detlev Arendt and Jochen Wittbrodt have discovered that the light-sensitive cells of our eyes, the rods and cones, are of unexpected evolutionary origin – they come from an ancient population of light-sensitive cells that were initially located in the brain.

"It is not surprising that cells of human eyes come from the brain. We still have light-sensitive cells in our brains today which detect light and influence our daily rhythms of activity," explains Wittbrodt. "Quite possibly, the human eye has originated from light-sensitive cells in the brain. Only later in evolution would such brain cells have relocated into an eye and gained the potential to confer vision."

The scientists discovered that two types of light-sensitive cells existed in our early animal ancestors: rhabdomeric and ciliary. In most animals, rhabdomeric cells became part of the eyes, and ciliary cells remained embedded in the brain. But the evolution of the human eye is peculiar – it is the ciliary cells that were recruited for vision which eventually gave rise to the rods and cones of the retina.

So how did EMBL researchers finally trace the evolution of the eye?

By studying a "living fossil," Platynereis dumerilii, a marine worm that still resembles early ancestors that lived up to 600 million years ago. Arendt had seen pictures of this worm's brain taken by researcher Adriaan Dorresteijn (University of Mainz, Germany). "When I saw these pictures, I noticed that the shape of the cells in the worm's brain resembled the rods and cones in the human eye. I was immediately intrigued by the idea that both of these light-sensitive cells may have the same evolutionary origin."

To test this hypothesis, Arendt and Wittbrodt used a new tool for today's evolutionary biologists – "molecular fingerprints". Such a fingerprint is a unique combination of molecules that is found in a specific cell. He explains that if cells between species have matching molecular fingerprints, then the cells are very likely to share a common ancestor cell.

Scientist Kristin Tessmar-Raible provided the crucial evidence to support Arendt's hypothesis. With the help of EMBL researcher Heidi Snyman, she determined the molecular fingerprint of the cells in the worm's brain. She found an opsin, a light-sensitive molecule, in the worm that strikingly resembled the opsin in the vertebrate rods and cones. "When I saw this vertebrate-type molecule active in the cells of the Playtnereis brain – it was clear that these cells and the vertebrate rods and cones shared a molecular fingerprint. This was concrete evidence of common evolutionary origin. We had finally solved one of the big mysteries in human eye evolution."

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眼睛的起源及演化

眼睛的起源及演化

 各門類動物的眼睛結構大不相同,演化生物學家曾一度認為眼睛是多次起源的,可是一種海生小蟲子的眼睛和人類的相像程度讓生物學家要重新考慮眼睛的起源。

  達爾文在提出天擇說時,就意識到眼睛的演化會是他理論的一大難題。他認為眼睛是經過簡單而不完美的漸進步驟演化而來的,而且幾乎所有科學家也相信複雜的眼睛起源自單細胞的感光受器。

  儘管各種動物的眼睛大小和形狀大不相同,主要還是兩種形式。脊椎動物眼睛中的感光細胞主要是錐細胞和桿細胞,無脊椎動物的則為彈狀細胞(rhabdomeric photoreceptors)。雖然無脊椎動物和脊椎動物都用視蛋白來感光,不過它們的序列大不相同。有些科學家認為眼睛是單次起源的,可是有些卻認為眼睛在無脊椎動物和脊椎動物中至少各自起源一次。

  德國海德堡歐洲分子生物學實驗室的發育生物學家Detlev Arendt和Joachim Wittbrodt等人發現一種海生小蟲子除了視蛋白之外,牠們還含有另外一些和人類極為相似的蛋白質。這個發現意味著脊椎動物和無脊椎動物的眼睛都來自一個共同的祖先,無脊椎動物的感光細胞經過多次變化才變成脊椎動物的。

  他們之所以會漟眼睛起源這渾水,是因為Arendt發現一種五億年中幾乎不變的活化石海生環節動物--岩蟲(Platynereis dumerilii)的眼睛裡有看似錐細胞和桿細胞的感光受器。這類感光細胞只有在少數無脊椎動物中有發現過,例如在扇貝。可是那些觀察主要是基於形態。

  Arendt等人除了形態之外,他們還比較基因和蛋白質。德國Philipps Univ.的Kristin Tessmar-Raible首先試圖找尋岩蟲的無脊椎動物視蛋白基因,可是卻徒勞無功。可是經過徹底的搜尋後,她發現岩蟲的視蛋白和無脊椎動物的有所不同,和脊椎動物的視蛋白比較相像。他們也從岩蟲的基因組中找尋脊椎動物視網膜同源匣蛋白質(homeobox proteins),結果果然在岩蟲腦中找到同源匣蛋白質。

  這個發現讓無脊椎動物和脊椎動物的眼睛萬本歸宗。他們還認為兩個感光竹系統是起源自兩側對稱動物的共同祖先。

  不過美國國家眼睛研究所的Joram Piatigorsky表示,雖然這個發現和眼睛單次起源的想法相符,不過卻並不代表所有動物的眼睛必定演化自一個動物。這還是個尚待解答的演化學問題。

原學術論文:Arendt D., Tessmar-Raible K., Snyman H., Dorresteijn A. & Wittbrodt J. Ciliary photoreceptors with a vertebrate-type opsin in an invertebrate brain. Science, 306. 869 - 871 (2004).

Monday, October 11, 2004

Iron-source preference of Staphylococcus aureus infections.

Iron-source preference of Staphylococcus aureus infections.

Skaar EP, Humayun M, Bae T, DeBord KL, Schneewind O.
Science. 2004 Sep 10;305(5690):1626-8.
Committee on Microbiology, 920 East 58th Street, University of Chicago, Chicago, IL 60637, USA.

Although bacteria use different iron compounds in vitGro, the possibility that microbes distinguish between these iron sources during infection has hitherto not been examined. We applied stable isotope labeling to detect source-specific iron by mass spectrometry and show that Staphylococcus aureus preferentially imports heme iron over transferrin iron. By combining this approach with computational genome analysis, we identified hts (heme transport system), a gene cluster that promotes preferred heme iron import by S. aureus. Heme iron scavenging by means of hts is required for staphylococcal pathogenesis in animal hosts, indicating that heme iron is the preferred iron source during the initiation of infection.

PMID: 15361626 [PubMed - indexed for MEDLINE]

【挑嘴】的金黃葡萄球菌!

【挑嘴】的金黃葡萄球菌!

惡名昭彰的金黃葡萄球菌(Staphylococcus aureus)會導致食物中毒(food poisoning)、腦膜炎(meningitis)、休克等病症。像一般細菌一樣,在葡萄球菌的繁殖過程中,鐵元素攝取也是必要的。

美國芝加哥大學微生物學家Olaf Schneewind與其研究團隊發現:金黃葡萄球菌其實是蠻挑嘴的,它們特別偏好特定來源的鐵元素,尤其血紅素(Hemoglobin)中的鐵元素,更是它們的最愛,此外,鐵元素得取的與否跟病菌的兇猛程度也是息息相關。

紅血球具攜帶血紅素的功能,血紅素內的亞鐵能與氧氣結合,形成氧合血紅素(oxyhemoglobin),這種結合會受酸鹼值、溫度等因素所影響。此外,許多藥物也會使血紅素中的亞鐵轉換成三價的鐵離子,形成高鐵血紅素(methemoglobin),如果血液中含有大量高鐵血紅素,皮膚就會變得藍黑。

在這份刊登於2004年九月份《科學》期刊的研究報告中,研究人員利用同位素標記化合物後,給予金黃葡萄球菌進行攝取,藉以追蹤金黃葡萄球菌的『飲食習慣』。文章中指出:相較於從運鐵蛋白質(transferring)獲得鐵元素,金黃葡萄球菌更偏好從血紅素中取得該項元素。

在得知金黃葡萄球菌選擇鐵元素的特殊喜好後,Olaf Schneewind與其研究團隊進一步分析金黃葡萄球菌的基因組,並辨識出一段與金黃葡萄球菌攝取血紅素內亞鐵離子有關的基因,hts(heme transport system)。接著,研究人員讓hts基因失活,並將這經過基因修飾的金黃葡萄球菌(htsB 和htsC)與正常的金黃葡萄球菌分別感染線蟲(C. elegans)與小鼠。實驗發現:正常金黃葡萄球菌在四十八小時內造成了近80%的線蟲死亡,在受感染的小鼠肝臟、腎臟組織也發現膿瘡出現。相反的,hts基因失活的金黃葡萄球菌則顯得溫和許多,即使四十八小時後,大多數的線蟲的存活狀況仍然相當良好,小鼠的器官也沒有顯著的傷害。

這項研究成果暗示著:透過影響金黃葡萄球菌對鐵元素的攝取能力,可以減弱病菌對宿主所造成的破壞;換句話說,釐清響金黃葡萄球菌的『用鐵』偏好,除了大大有助於藥物研發之外,也可望有益於病菌感染的症狀減緩。

原始論文:
Iron-source preference of Staphylococcus aureus infections. Science. 305:1626 (2004)

DNA barcodes tag species

DNA barcodes tag species

Helen Pearson
Genetic sequence could give an instant biological identification.

Published online: 27 September 2004; doi:10.1038/news040927-2


Wouldn't it be great if every animal had an easy-to-read label, telling you to which species it belonged? Scientists are now one step closer to making this idea a reality, thanks to two studies showing that the DNA sequence of just one gene can tell very closely related species of birds and butterflies apart, and even flag up previously unrecognized ones.

The concept is called DNA barcoding. And if it works, it could find numerous uses. When a foreign ship docks, for example, inspection services could automatically scan ballast water for nasty species that they are keen to keep out. Or researchers in remote locations could use a handheld scanner to get an instant species identification.

At the moment, identifying species is a laborious process, based on characteristics such as the shape of a beak or the colour of a wing. But with DNA barcoding, scientists simply work out 650 letters in the genetic sequence of a single gene, called cytochrome c oxidase I.

This gene tends to vary a lot between species. Proponents of the method believe it is so variable that most different species will have a characteristic code, but many researchers are more sceptical.

Birds and butterflies

To show the system can work, Paul Hebert of the University of Guelph, Canada, and his colleagues read and compared the DNA barcodes from museum specimens of 260 species of North American birds.

They found that birds in different species had very different barcodes, whereas birds within the same species did not. They also support suspicions that some of the birds fall into four new species, they write in the Proceedings of the National Academy of Sciences1.

Working with a different team, Hebert focused on skipper butterflies in the forest of Costa Rica. The group analysed the DNA barcodes of over 480 specimens that had previously been grouped as one species (Astraptes fulgerator).

The barcodes fell into clear groups that suggested the butterflies belonged to ten distinct species. The researchers report in PloS Biology that the result matches known differences in their choice of foods and caterpillars2.

DNA database

Researchers have used the genetic sequences of animals to help work out their evolutionary relationships for over two decades. But they use a variety of different genes, whereas barcoding focuses on just one.

The idea gained credence last year, when Hebert showed that DNA barcodes could tell apart almost 2,000 species3. Now a series of projects around the world is showing that the system works in different animal groups. Supporters ultimately aim to catalogue the DNA barcode of each species, with its name, in a central database.

Daniel Janzen at the University of Pennsylvania, Philadelphia, who collected the butterflies used in the recent study, is enthusiastic about DNA barcodes. To identify a species of caterpillar, he currently has to rear it until it transforms into a butterfly and then send it to an expert taxonomist. A DNA barcode would allow him to classify caterpillars on the spot, he says, and work out the "gazillion species that give taxonomists nightmares".

The system has two other advantages over traditional taxonomy. It can be used to identify species from only a fragment of tissue or shell. And if barcode scanners become available, they could be used by amateurs.

But some researchers have reservations, seeing barcodes as a threat to traditional taxonomy. And even supporters acknowledge that the system will struggle to distinguish species whose genetic sequence is extremely similar, such as ones that have only recently diverged from one another. "We have to be a little bit cynical about where it works and where it doesn't," says ecologist Craig Moritz at the University of California, Berkeley.

Moritz says that, in some cases, it may be necessary to analyse more than one gene to properly identify a species. "There's strong debate about whether one gene fits all," he says.

生命的DNA數位條碼

生命的DNA數位條碼

如果能夠都把動物打上如同貨品上的數位條碼,那麼我們豈不是可以隨時利用掃描器來分辨在野外遇到的動物是屬於哪一種。這個或許已經不是天方夜譚了。

這個構想稱為DNA數位條碼,除了好玩,它還有許多實際的用途。檢疫單位可以利用它來檢測外來生物的侵入。在外的科學家也可以隨時利用手提掃描器來鑑定物種。

迄今,鑑定物種仍是費時費力的,需要依靠許多外在特徵。可是有了DNA數位條碼,科學家只要搞定一個粒線體的基因(COI)的650個字元。這個基因的演化速率較快,因此序列隨著不同物種而異,每個物種都有可能有其獨特的序列。然而還是有科學家對此存疑。

為了排除疑慮,加拿大University of Guelph的動物學家Paul Hebert和洛特菲勒大學的分子生態學家Mark Stoeckle等人比較了博物館中,260種北美鳥類的DNA數位條碼。結果他們發現,不同種的鳥類帶有不同的DNA數位條碼,而且也顯示有些鳥的確是如有些分類學家懷疑般的分屬四個不同種。

和賓州大學的Daniel Janzen等人合作,Hebert等人分析了哥斯達黎加的480個弄蝶樣本,牠們之前被認為是同一種(Astraptes fulgerator)。可是他們的分析結果卻顯示,這些蝴蝶應該分屬十個不同種,而且和牠們選擇的食物息息相關。

科學家雖然早以利用DNA序列來為物種建立親緣關係樹,可是使用的是多種基因,而DNA數位條碼只利用一個。使用DNA數位條碼的想法在去年Hebert證實它可以區分出2千個不同物種時,開始獲得支持。在全世界也有好幾個不同計畫針對不同動物正在進行中,最終的目標是把各各物種的DNA數位條碼都鍵入中央資料庫中。

Janzen對此計畫充滿興趣。以往他只能把毛毛蟲養大成蝴蝶後,再能讓分類學家鑑定種類。DNA數位條碼卻能讓他輕易鑑定成千上萬個令分類學家不眠不休才看得完的物種。這個方法還有一個好處是只需要一小片組織就能做鑑定。如果掃描器面世,門外漢都可輕易使用。

可是還是有科學家對DNA數位條碼保持保留的態度,認為它不能區分出晚近才分化的物種。柏克萊加州大學的生態學家Craig Moritz認為,有些時候還是得使用超過一個基因。

原學術論文:Hebert P. D. N., Penton E. H., Burns J. M., Janze D. H. & Hallwachs W. PNAS (2004). DOI: 10.1073/pnas.0406166101Herbert P. D. N, Stoeckle M. Y., Zemlak T. S. & Francis C. M. PLoS Biol 2, e312 (2004). DOI: 10.1371/journal.pbio.0020312Herbert P. D. N, Ratsingham S. & Dewaard J. R. Proceedings of the Royal Society, B 270, S596-599 (2003).

Researchers devise potent new tools to curb ivory poaching

Researchers devise potent new tools to curb ivory poaching


Despite a long-standing international ban on ivory trade, African elephants continue to be killed in large numbers for their prized tusks. But a team headed by a University of Washington biologist has devised a new means of determining the geographic origin of ivory that could prove a potent tool in slowing elephant poaching and the illegal ivory trade by identifying hot spots where enforcement should be increased.

It is relatively easy to monitor elephant populations with flights over the open savannas of eastern, central and southern Africa, but it is much harder to do the same in the dense forests of central and western Africa. Those forests are where elephants are currently being slaughtered wholesale, said Samuel Wasser, who holds the UW's endowed chair of conservation biology and is director of the Center for Conservation Biology.

"My colleagues working in the forests are saying, 'There are no elephants left here,'" he said. "That's the problem ?in the forest you don't notice the change in population until it's so dramatic that it's almost too late to do anything about it."

Wasser is lead author of a paper describing the new means of determining ivory origins, being published the week of Sept. 27 in the Proceedings of the National Academy of Sciences.

The African elephant population plummeted by 60 percent ?from 1.3 million to just 500,000 ?between 1979 and 1987, largely because of ivory poachers. An international agreement banning ivory trade was enacted in 1989, but still three of the largest ivory seizures have occurred since 2002.

In June 2002, authorities in Singapore seized a shipment of about 6.5 metric tons of ivory bound for the Far East. The shipment included 532 whole tusks, many more than 6 feet long, and 41,000 small carved ivory cylinders about the size of hanko stamps, used for document signatures. The cylinders alone were worth more than $6 million.

The new methods developed by Wasser's team can show generally where such ivory came from, alerting authorities to specific areas where added enforcement is needed to curb poaching.

Wasser and his colleagues extracted DNA from elephant droppings and skin biopsy samples collected from numerous locations in 16 African nations. They used that information to build a DNA-based reference map to assign tusk origin. They noted genetic differences in populations from one location to another, and used a statistical method to extrapolate genetic signatures to fill in gaps between sampled populations.

Matthew Stephens, a UW associate professor of statistics, developed a model allowing the researchers to build genetic profiles for elephant populations from which they do not have genetic samples. The model is weighted toward genetic information obtained from populations nearest those for which information is unavailable.

The method allows a DNA sample to be assigned to a fairly specific location, with a relatively high confidence that the assignment is correct. The study indicated that 50 percent of the samples tested were accurately located within 300 miles and 80 percent were accurate to within less than 600 miles. Accuracy was much greater among forest populations, which are more clearly defined because of terrain.

The new method allows for speedy determination of where a particular ivory sample came from, Wasser said. That is important because there is mounting pressure to lift the 1989 ivory trade ban enacted under the Convention on International Trade in Endangered Species. But many experts believe any legalization of ivory trade will only increase poaching. The new sampling method can help determine quickly whether that is true in time for exemptions to be altered before elephant populations suffer catastrophic damage, he said.

Two years ago, five African nations sought, and three received, an exemption from the ban so that they could conduct one-time ivory sales. Now numerous other countries are considering seeking exemptions, and some hope to obtain permanent exemptions.

"Once the door is cracked open, they try to force it open all the way," Wasser said.

He noted that a number of countries have kept ivory stockpiles since the 1989 ban, and the small central-African nation of Burundi has a stockpile of 80 tons ?despite the fact that it had only one elephant at the time of the ban. Some observers believe ivory has been sold from that stockpile and replenished from poached ivory.

"This method could detect such restocking in the future," Wasser said.

Tracking elephant ivory is just one example of the value of the sampling and statistical method, he said. The same methods can be used to establish the locations from which any endangered species' products originated, to help conservationists find ways to keep those species from extinction.

Wasser and his colleagues have trained narcotics-detection dogs to find the droppings from endangered species over large remote areas. The dogs can track up to 18 species at once at distances greater than a quarter-mile. Such non-invasive techniques can be used to quickly assemble genetic reference maps to apply this technology to other at-risk species.

Besides Wasser and Stephens, authors of the PNAS paper are Andrew Shedlock, formerly of the UW and now at Harvard University; Kenine Comstock and Elaine Ostrander of the Fred Hutchinson Cancer Research Center in Seattle; and Benezeth Mutayoba of Sokoine University of Agriculture in Tanzania.


###The research was supported by the U.S. Fish and Wildlife Service, the Gordon and Betty Moore Foundation, the Bosack Kruger Charitable Trust, the National Institutes of Health, the International Elephant Foundation and the Woodland Park Zoo in Seattle. The entire ivory seizure investigation is being funded by the International Fund for Animal Welfare.

For more information, contact Wasser at 206-543-1669 or wassers@u.washington.eduThe Center for Conservation Biology Web site is http://depts.washington.edu/conserv

A video news release will be available Sept. 27 from the International Fund for Animal Welfare. Contact Chris Cutter at 508-744-2066 or ccutter@ifaw.org

DNA追蹤非法象牙

DNA追蹤非法象牙

保育人士和警方今後可以利用DNA來追蹤非法象牙的來源。

這個遺傳方法的準確度達到500至1000公里的範圍。這個新技術的產生是為了要應對通過網際網路源源不絕地流入美國的非法象牙。發展出此技術的西雅圖華盛頓大學的Samuel Wasser指出,這個方法可以很快地判斷出哪些象牙是非法的。象牙貿易在1989年被瀕臨絕種野生動植物國際貿易公約組織(CITES)禁止,不過現今充許南非的一些象群壯大的地區進行合法的象牙貿易。

他們從非洲16個國家的28個地點取得400頭大象的糞便或組織,粹取出DNA,然後分析各別地區特定基因的分佈頻率。Wesser指出,森林象群較孤立,和草原象群可能分屬不同物種,牠們的DNA也比較獨特。他們幾乎可以百分之百區分出西非和中非的草原和森林象群。在象群雜交的地區,雖然他們沒取樣,可是仍舊可以用原用的樣本外推出當地的基因頻率,準確度也達八成。於是他們可以製作出非洲大象的DNA圖譜。這有助於鑑定出瀕危的森林象群。

到了1989年,非洲象不到十年就從一百卅萬頭減少到只剩六十萬頭。至從象牙貿易在1989年被CITES禁止之後,盜獵者開始對森林象群開刀。CITES雖然利用地面部隊巡查空中看不到的森林大象屍體,不過進行起來不易。在剛果單單去年就有一萬隻象被幹掉,簡直就是大屠殺!根據保育組織TRAFFIC的報告,在美國每週有一千個象牙製品在eBay上拍賣。2002年6月,新加坡警方就起獲到6.5噸的非法象牙走私,包括了532箱滿載的貨櫃,總值超過六百萬美金。

這個方法有助於國際刑事警察組織偵查出非法象牙的來源。可是TRAFFIC的Tom Milliken指出,這個方法還不能解決非法獵殺象牙的問題。在動盪的剛果,有許多饑民獵殺大象是為充饑。如果象牙只是果腹的副產品,那麼餵飽饑民才能治本。

原學術論文:Wasser S. K., et al. Proc. Natl. Acad. Sci, (2004). DOI: 10.1073/pnas.0403170101

Thursday, September 09, 2004

Firefly Compound Lights Up 'Protein Dance' In Living Animals

Firefly Compound Lights Up 'Protein Dance' In Living Animals

St. Louis, July 29, 2004 -- Radiologists at Washington University School of Medicine in St. Louis have developed a first-of-its-kind noninvasive imaging technique that allows them to watch two proteins interacting in live animals.

The technique genetically fuses proteins of interest with carefully cleaved sections of luciferase, the protein fireflies use to create light. When the target proteins interact, the sections of luciferase come together and create light that can be detected outside the body by a highly sensitive camera.

"Instead of looking at a protein by itself, this technique lets us see when two proteins come together and dance," says David Piwnica-Worms, M.D., Ph.D., professor of molecular biology and pharmacology and of radiology. "Those kinds of interactions are very important for many different processes, and they're also key to developing and evaluating new drugs."

Piwnica-Worms and colleagues demonstrated the technique's feasibility on human proteins that interact in the presence of the antibiotic rapamycin. The research appears today in the online edition of the Proceedings of the National Academy of Sciences and will appear in print in the Aug. 17 issue of the journal.

According to Piwnica-Worms, understanding protein interactions has become much more important to biologists in recent years. "We've learned that the human genetic code only has a fraction of the genes we expected, and as a result it's become clear that the context of protein-to-protein interactions significantly affects what proteins can do," he explains. "That's what lets us get away with so few genes -- the same protein can do different things based on when or where it's used." Scientists have studied these interactions previously in cell cultures and in solutions obtained by carefully opening up cells. Luciferase has been used previously to identify the presence of molecules in the cell and in live animals, but this is the first time scientists have used it in the test tube or in live animals to detect the coupling of two proteins by a drug.

The biggest challenge of the project, according to Piwnica-Worms, was determining the best place to split luciferase.

"We were ideally looking for a split version of luciferase that had zero activity when separated but had very high light output when the partner proteins interacted," he explains.

Researchers led by Kathryn E. Luker, Ph.D., a postdoctoral fellow in Piwnica-Worms' lab, first divided luciferase into overlapping halves. They then produced many copies of the halves, and used an enzyme to chomp off varying lengths from the ends of the halves where the split was made. They packed the resulting library of luciferase fragments into phages, viruses that infect bacteria. Scientists allowed the phages to infect bacterial colonies, and then looked for bacteria that glowed.

Of 19,000 bacterial colonies, approximately 120 lit up. The three brightest were further tested to determine which pair of fragments worked best.

In a line of experimental mice, scientists genetically fused one member of the best pair of luciferase fragments onto the protein targeted by rapamycin, attaching the luciferase fragment to the specific portion of the protein where rapamycin establishes its bond. They attached the other luciferase fragment to a protein known through previous research to interact with rapamycin's target protein only in the presence of rapamycin. Using a commercially available instrument known as an in vivo bioluminescence camera, they found they could detect light from the luciferase fragments only when they injected the mice with rapamycin, causing the two proteins to interact. In mutations that disabled rapamycin's ability to bind to the target protein, scientists detected no light even after rapamycin injections.

According to Piwnica-Worms, the series of experiments proved the accuracy and selectivity of the new luciferase-based approach.

Scientists also successfully tested the new technique on two proteins linked to regulation of the cell life cycle. An anti-cancer drug is being developed to block the interaction of these proteins.

"We can now monitor the effects of that drug in live animals using the luciferase technique," says Piwnica-Worms. "It's been an exciting development ?we're already collaborating with several colleagues around campus to use this system to study interactions between seven or eight other important pairs of proteins."

Luker KE, Smith MCP, Luker GD, Gammon ST, Piwnica-Worms H, Piwnica-Worms D. Kinetics of regulated protein-protein interactions revealed with firefly luciferase complementation imaging in cells and living animals. Proceedings of the National Academy of Sciences, Aug. 17, 2004.

親愛的,我看到你磷酸化了!

親愛的,我看到你磷酸化了!

  科學家利用螢火蟲的螢光酵素(luciferase)來顯示分子間運動的狀況。

  生物體中的訊息傳遞路徑(signal pathway)管理著許多重要的功能,細胞週期的進行、新陳代謝等等作用都需要經由訊息傳遞路徑來調控。而在訊息傳遞路徑的調控當中,蛋白質之間的作用扮演了相當重要的角色,磷酸化(phosphorylation)就是一例。

  不過訊息傳遞路徑的運作,會依細胞所處組織環境的不同而有所改變,這是不能在體外實驗中忠實呈現出來的一面。因此有人使用正子斷層攝影(PET)或是生物冷光(bioluminescence)的方式,嘗試以非侵入式的方法,來獲得生物體內蛋白質之間作用的過程。而目前偵測蛋白質之間作用的策略包括了活化或抑制轉譯的步驟、活化訊息傳遞路徑,或是還原被中斷的酵素活性。

  在酵素活性方面,若將單一蛋白質切成兩半,這兩個片段並不會自行組合而產生作用。只有在這兩個片段能夠經由藥物等其他作用而再度團圓時,才會進行正常的酵素功能。但是螢火蟲的螢光酵素受限於其N端部分所發出的藍綠色光(藍綠色光穿透生物體的效果不佳);水母的螢光酵素應用在生物體上的種種限制,所以現有的螢光酵素系統無法完全滿足非侵入式蛋白質作用造影的需求。

  不過最近在美國華盛頓大學的博士後研究員Kathryn E. Luker所領導的研究中,則改進了現有的螢光酵素互補造影系統(luciferase complementation imaging, LCI)。

  他們首先製造出不同重疊長度的螢光酵素N端及C端配對,然後使用細菌來觀察這些配對的作用狀況,選出發光度最強的三對,接著觀察這三對螢光酵素組合在生物體中的表現。

  在老鼠方面的實驗,他們用選用了兩種因為免疫抑制劑rapamycin而作用的蛋白質,一種稱為mTOR(mammalian Target of Rapamycin)的蛋白質,另一個則是FKBP。他們將mTOR上一個跟FKBP-rapamycin複合物親和性很高的區域──FRB──與螢光酵素的N端部分結合;螢光酵素C端部分則與FKBP結合。結果顯示,只有在rapamycin注入老鼠體內時,螢光酵素片段才會結合而發出螢光,另外在細胞中觀察磷酸化相關的反應也得到很好的效果。

  在他們的方法當中,螢光酵素片段在結合時所發出的螢光是背景的1200倍,超過目前現有系統的表現。這使得LCI這個檢測方法的靈敏度大大地提高,也讓偵測一些親和力沒那麼強的蛋白質作用成為可能。這個方法目前正用來進行更多不同蛋白質作用的檢測,不過可預見的是,這個方法將成為一個在藥物篩選上極為有力的工具。


原始論文:
Kathryn E. Luker, et al. Kinetics of regulated protein–protein interactions revealed with firefly luciferase complementation imaging in cells and living animals. PNAS published July 29, 2004, 10.1073/pnas.0404041101.

Could heart drugs treat HIV?

Could heart drugs treat HIV?

David Osumi-Sutherland
Cholesterol-lowering statins may provide an alternative to antiretrovirals.

A study of six AIDS patients has revealed that statins can reduce levels of HIV and boost immune cell numbers. If the results can be repeated in large-scale trials, it's hoped that statins could provide an alternative to standard HIV treatments.

Statins are taken by millions of people to lower cholesterol levels and help protect against heart disease. And studies have shown that cultured cells with low levels of cholesterol in their membranes are less likely to succumb to HIV infection.

So, Carlos Martínez from the Spanish Council for Scientific Research and colleagues decided to study the effects of cholesterol-lowering statin drugs on HIV patients. Their results are reported in the Journal of Experimental Medicine1.

A one-month course of statin treatment caused the virus levels of human patients to drop by up to 20-fold. Levels began to rise when patients stopped taking the drug.

When mice, injected with HIV-infected human cells, were given the drugs, their virus levels fell, in some cases to undetectable levels.

Together, these results suggest that statins may prove useful against HIV in human patients, says Martínez.

Killer virus

HIV suppresses the immune system by infecting and killing the cells of which it consists. Martínez believes that statins prevent the virus from entering healthy cells in the first place.

It is hoped that the drugs could offer an alternative to the standard AIDS treatment, highly active antiretroviral therapy (HAART). This therapy is becoming less effective as drug-resistant HIV strains continue to emerge.

Resistant strains have limited the options for many HIV-infected patients, explains HIV researcher Eric Freed of the HIV Drug Resistance Program at the National Cancer Institute in Frederick, Maryland. "This makes the development of alternative treatments especially urgent."

Statins could also prove safer than antiretrovirals. HAART can trigger serious side-effects, such as liver damage, but statins are relatively free of such problems.

Martínez hopes that statins could also be used preventatively. His study shows that white blood cells taken from patients on statins are less likely to succumb to HIV infection.

Larger clinical trials should be forthcoming, says Martínez. But he cautions that such studies are difficult to set up. It is hard to find HIV-positive patients who are not already taking anti-HIV medication, he points out. One solution may be to concentrate on patients who have already become resistant to the standard treatments.

心臟病藥物能夠治療愛滋病

心臟病藥物能夠治療愛滋病

根據一項針對六位愛滋病患的研究報告,服用statins 類藥物(一種心臟病用藥)能夠降低愛滋病傷害的程度,及增加免疫細胞的數量。如果此結果能再經過大規模的實驗證實,則未來statins將可能會成為愛滋病的另一項替代療法。

世界上有數百萬人服用statins作為降膽固醇藥物,預防心臟病。組織培養顯示若細胞膜上的膽固醇含量低時,細胞較不易受到HIV的侵入感染。所以,西班牙科學研究協會的Carlos Martínez及其同事決定在愛滋病患的身上試驗statins所達到的效用,他們的結果發表在「實驗醫學」期刊(Journal of Experimental Medicine)上。

經過一個月的statins療程後,病患體內的病毒數量降低了20倍之多,一旦停止服藥,病毒量又會開始回升。以注射遭HIV感染之人類細胞的老鼠來進行試驗時,服藥同樣可以降低病毒的數量,某些案例中甚至到了無法偵測的程度。Martínez表示,這些結果共同顯示出statins似乎具有有效抵抗愛滋病的能力。

HIV藉由感染並摧毀免疫細胞的方式來抑制免疫系統,Martínez相信statins阻擋了病毒進入健康細胞的路徑。此藥物為愛滋病的標準療法--雞尾酒療法(Highly active antiretroviral therapy,HAART)提供了替代性的作法,隨著抗藥性HIV病毒株的出現,雞尾酒療法逐漸變得不如從前有效。

愛滋病研究者Eric Freed表示,抗藥性的病毒株已經使得病患沒有太多的治療選擇,這使得替代性療法的發展變得格外緊急。Statins除了具有抗愛滋病的療效,也比其他的抗反轉錄病毒藥物(antiretrovirals)要來的安全。雞尾酒療法會造成嚴重的副作用,例如肝臟受損,statins就沒有這種顧慮。

Martínez希望statins可以作為預防性用途之用,他的研究顯示服用statins的人,其白血球較不易受到愛滋病毒的入侵。Martínez也說大規模的臨床實驗是必須的,但此類的實驗並不易進行。要找到愛滋病檢驗呈陽性反應、又未曾服用任何抗HIV藥物的病患是相當困難,解決之道或許將從已對標準療法產生抗力的病患著手。

RNA Can Now Be Built Into 3-D Arrays

No Longer Just For Biology, RNA Can Now Be Built Into 3-D Arrays

ARLINGTON, Va.?Researchers have coaxed RNA to self-assemble into 3-D arrays, a potential backbone for nanotech scaffolds. These RNA structures can form a wider variety of shapes than double-stranded DNA can and are easier to manipulate than many protein alternatives.

Peixuan Guo of Purdue University and his colleagues report the findings in the August 11, 2004, issue of the journal Nano Letters.

RNA (ribonucleic acid) molecules are best known for implementing the genetic information encoded in DNA (deoxyribonucleic acid). However, instead of using the long molecular strings to carry information, the researchers have achieved new control over RNA and created novel arrays.

By mixing the custom-made RNA strands with other substances, such as magnesium chloride, the researchers were able to get the strands to join into 3-D shapes.

In 1987, Guo discovered that a bacteria-infecting virus possesses a biomolecular nanomotor that requires RNA molecules to function. While determining how RNA works in that motor, he learned to manipulate and control RNA assembly.

Now, Guo and his colleagues have applied that knowledge to building artificial RNA nanostructures, including arge?3-D arrays formed from identical RNA building blocks. Because these arrays extend to several micrometers, far larger than individual RNA strands, they may potentially link nanofabrication with current microfabrication processes.

The researchers hope that the arrays, while still in the earliest stages of development, will one day serve as the scaffolding on which diagnostic chips, tiny sensors, gene delivery vehicles and other nanoscale devices will be mounted or constructed.


From the researchers:

iving systems contain a wide variety of nanomachines and ordered structures, including motors, pumps and valves. Our research is devoted to making these machines function outside their native environment.??Peixuan Guo, Purdue University

e have discovered a particular type of RNA molecule known as pRNA, or packaging RNA, that forms six-unit rings that can drive a tiny but powerful molecular motor.??Peixuan Guo

ur future research will focus on incorporating these nanomachines into nanodevices for such applications as drug or gene delivery, gears for nano-equipment, and intricate arrays and chips for diagnostic devices, sensors and electronics.??Peixuan Guo

his report demonstrates that RNA can be used to form a variety of artificial shapes and that we can assemble these shapes into arrays tens of microns in size. Using RNA tendency to self-assemble, we have built the arrays from many thousands of connected RNA building blocks. The arrays are stable and resistant to a wide range of environmental conditions, such as temperature, salt concentration, and pH.??Peixuan Guo

From experts at NSF:

he discovery of this viral RNA machine is quite remarkable and provides yet another example of the flexibility and versatility of RNA. Dr. Guo is exploiting the properties of RNA in a new and potentially important way.??Patrick Dennis, Program Director for Microbial Genetics at the National Science Foundation and the officer who oversees Dr. Guo award.

強勁的分子發動機─RNA奈米馬達 (nano-motor)

強勁的分子發動機─RNA奈米馬達 (nano-motor)

美國普渡大學研究人員成功地把RNA組成3D陣列 (3D arrays)。

  一般來說,具有遺傳訊息的去氧核糖核酸DNA可以轉譯成核糖核酸RNA,但是RNA分子結構比DNA分子結構具有多樣化的特性,也就是RNA可以形成多樣的結構(諸如:單體monomer、雙合體dimer、三合體trimer、六合體hexamer等等)。

  普渡大學分子病毒學教授Peixuan Guo的研究團隊,早於1987年在phi29病毒裡發現一種特殊的RNA結構,它稱為pRNA(packaging RNA),其pRNA單體(monomer)之間可以互相聯結組合成六合體(hexamer)環狀結構,而這種六合體環狀結構又稱做奈米馬達(nano-motor),它可以用來包裝DNA,把DNA分子送入病毒衣殼(procapsid)裡頭。

  Peixuan Guo等人目前正把奈米馬達的概念應用在設計人工RNA奈米裝置中,他們已經成功地從RNA形成的模塊中建造出3D陣列,並且這些3D陣列更可以延伸至數個微米(micrometers),進而搭起奈米製造(nanofabrication)與微米製造(microfabrication)之間的橋樑。而消息已刊登在2004年八月的《奈米通訊期刊》 (Nano Letters)。

  Peixuan Guo指出,在生物體內具有各式各樣的奈米機器,例如細胞膜上的幫浦(pump)或馬達(motor)等,他們正致力在把這些生物體內的奈米裝置,拿到外界也就是活體外的環境下來表達,正如同上述的RNA六合體環狀結構,就可以用來當成精小但強又有利的奈米馬達。而目前這些RNA的3D陣列還是處於初期研發的階段,他們希望未來能夠把這些3D陣列應用在病理診斷晶片、微小感應器、基因治療使用的基因輸送載體以及電子儀器等研發。

原始論文:Shu D, Moll D, Deng Z, Mao C, and Guo P. 2004. Bottom-up assembly of RNA arrays and superstructures as potential parts in nanotechnology. Nano Letters 4: 1717-1724.

Lotus effect helps light move water

Lotus effect helps light move water

5 August 2004

With the aid of a nanowire-coated surface, researchers at Arizona State University, US, have become the first to move water droplets simply by illuminating them with ultraviolet light. The technique could have applications in microfluidic devices.

Drop by drop
To achieve the result the team deposited silicon nanowires with diameters of 20-50 nm randomly on a silicon surface. Then they coated the wires with a monolayer of photochromic spiropyran molecules. These organic molecules are hydrophobic until illuminated with ultraviolet light. In fact, lotus leaves make use of a similar structure to repel water droplets - they have a very fine surface structure and are coated with hydrophobic wax crystals of around 1 nm in diameter (see Lotus effect shakes off dirt).

A water droplet will move across a surface if its advancing contact angle is lower than the receding contact angle. Shining ultraviolet light with a wavelength of 366 nm onto the spiropyran molecules converted them to their polar hydrophilic form and reduced the contact angle. So you might expect ultraviolet light to cause water droplets to move on any surface coated with spiropyran.

But there's a snag. On a smooth surface the transformation of the spiropyran molecules to their hydrophilic form reduced the contact angle by 12°. That wasn't enough to cause the water droplet to move, however, as the contact angle hysteresis (the difference between advancing and receding contact angles) for the smooth surface was 37° under visible radiation.

On a nanowire surface, in contrast, the contact angle hysteresis was only 17° and the illumination of the spiropyran molecules with UV light reduced the contact angle by 23°, nearly twice as much as for the smooth surface. As a result of both these factors the advancing contact angle became lower than the receding contact angle and the water droplets moved along the surface towards the source of the UV light.

"We have been working on the problem of using light to move microscopic amounts of water around for drug delivery and microanalysis applications," said Tom Picraux of Arizona State. "Our advance came when we realized that if the surface was roughened at the nanoscale, not only would we obtain the 'lotus-leaf effect', but we could also magnify the small change in water repelling controlled by light to a level that can overcome the hysteresis, or the attraction, that causes water to stick even when a drop is pushed along."

The process is also reversible since treating the spiropyran molecules with visible radiation with a wavelength of 450-550 nm caused them to return to their closed hydrophobic form.

Moving water droplets with light avoids the need to use potentially damaging electric fields, air bubbles, which can denature proteins, or microscopic mechanical pumps, which are expensive to make and difficult to repair.

The scientists, who reported their work in Journal of Physical Chemistry B, say their findings also point the way to enhanced fluidic motion and control in electrowetting and thermowetting microfluidic systems.

About the author
Liz Kalaugher is editor of nanotechweb.org.

蓮花效應有助於以光移動水滴

蓮花效應有助於以光移動水滴

 美國亞歷桑那州立大學的科學家藉由將奈米線(nanowire)覆蓋在表面上,首度成功地僅憑紫外光照射就能移動水滴。這項技術未來可望應用在微流(microfluidic)元件上,或許將有助於藥物輸送等應用。

  該研究小組先在矽表面上隨意沉積了直徑20-50奈米的矽奈米線,然後在奈米線上覆蓋單分子層光致色變(photochromic)的spiropyran分子,這種有機分子在照射紫外光之前是拒水性的。事實上,荷葉也是利用類似的效應來趕走水滴──葉面上覆蓋了直徑約1奈米的拒水性蠟質結晶行(參見奈米小辭典蓮花效應)。

  位於表面的水珠如果往前的接觸角(contact angle)大於後退的接觸角,水珠就會向前移動。以波長366奈米的紫外光照射,能讓spiropyran分子轉變成親水性,接觸角因而降低。在平滑表面上,這個降幅為12°,尚不能使水珠移動,因為在光滑表面上,可見光的照射所引起的前後接觸角差值變化(contact angle hysteresis)可達37°。相形之下,在奈米線的表面,接觸角差值變化只有17°,而紫外光造成的降幅為23°,幾乎是光滑平面的兩倍。這兩個因素相加的結果,造成前進的接觸角變大而後退的接觸角變小,於是水珠會朝向紫外光源移動。

  以波長450-550奈米的可見光照射,能使spiropyran分子恢復拒水性,因此上述過程是可逆的。以光來移動分子使科學家得以免除使用電場、氣泡或微機械幫浦,前兩者可能會使樣品變質,後者則既昂貴又不易修理。研究人員表示,這項發現為流體運動的強化及電濕潤(electrowetting)/熱濕潤(thermowetting)微流系統的控制,指出了一個條方向。詳見近期的Journal of Physical Chemistry B。

Saturday, August 21, 2004

Discover Biological Basis For Autism

Carnegie Mellon And University Of Pittsburgh Scientists Discover Biological Basis For Autism

PITTSBURGH -- A team of brain scientists at Carnegie Mellon University and the University of Pittsburgh have made a groundbreaking discovery into the biological basis for autism, a mysterious brain disorder that impairs verbal and non-verbal communications and social interactions.

Using functional magnetic resonance imaging (fMRI) scans, the researchers have found numerous abnormalities in the activity of brains of people with normal IQs who have autism. The new findings indicate a deficiency in the coordination among brain areas. The results converge with previous findings of white matter abnormalities in autism. (White matter consists of the "cables" that connect the various parts of the brain to each other). The new findings led the researchers to propose a new theory of the basis of autism, called underconnectivity theory, which holds that autism is a system-wide brain disorder that limits the coordination and integration among brain areas. This theory helps explain a paradox of autism: Some people with autism have normal or even superior skills in some areas, while many other types of thinking are disordered. The team's study will be published in the August edition of the British journal Brain and is available online at www.brain.oupjournals.org.

In explaining the theory, Marcel Just, one of the study's lead authors and director of Carnegie Mellon's Center for Cognitive Brain Imaging, compared the brain of a normal person to a sports team in which the members cooperate and coordinate their efforts. In an autistic person, though some "players" may be highly skilled, they do not work effectively as a team, thus impairing an autistic's ability to complete broad intellectual tasks. Because this type of coordination is critical to complex thinking and social interaction, a wide range of behaviors are affected in autism.

The research team believes these are the first findings in autism of differences in the brain activation patterns in a cognitive (non-social) task. The study produced two important new findings that help make sense of previous mysteries: The autistic participants had an opposite distribution of activation (compared to the control group) in the brain's two main language areas, known as Broca's and Wernicke's areas. There was also less synchronization of activation among key brain areas in the autistic participants compared to the control group.

To obtain technically acceptable fMRI data from high-functioning autistic participants, the researchers flew in people with autism from all over the eastern United States. High-functioning participants with autism (with IQ scores in the normal range) are rare, accounting for about 10 percent of all people with autism. Using non-invasive fMRIs, the team looked at the brains of 17 people with autism and 17 control subjects as they read and indicated their comprehension of English sentences. In both the healthy brains and in the brains with autism, language functions were carried out by a similar network of brain areas, but in the autism brains the network was less synchronized, and an integrating center in the network, Broca's area, was much less active. However, another center, Wernicke's area, which does the processing of individual words, was more active in the autism brains.

The brain likely adapts to the diminished inter-area communication in autism by developing more independent, free-standing abilities in each brain center. That is, abnormalities in the brain's white matter communication cables could lead to adaptations in the gray matter computing centers. This sometimes translates into enhanced free-standing abilities or superior ability in a localized skill.

These findings provide a new way for scientists and medical researchers to think about the neurological basis of autism, treating it as a distributed system-wide disorder rather than trying to find a localized region or particular place in the brain where autism lives. The theory suggests new research to determine the causes of the underconnectivity and ways to treat it. If underconnectivity is the problem, then a cognitive behavioral therapy might be developed to stimulate the development of connections in these higher order systems, focusing on the emergence of conceptual connections, interpretive language and so on. Eventually, pharmacological or genetic interventions will be developed to stimulate the growth of this circuitry once the developmental neurobiology and genetics of these brain connections are clearly defined by research studies such as these.

The research team is jointly headed by Just, the D.O. Hebb Professor of Psychology at Carnegie Mellon, and Dr. Nancy Minshew, professor of psychiatry and neurology at the University of Pittsburgh School of Medicine and director of its Center for Autism Research. Individuals with High Functioning Autism and Asperger's Syndrome between 10 and 55 years of age who are interested in participating in similar studies can send email to autismrecruiter@upmc.edu or call Nikole Jones at 412-246-5481.

自閉症研究的新視野

自閉症研究的新視野


科學家提出新的理論來解釋自閉症(autism)的成因,認為自閉症可能是源於腦部整合性功能的不足所致。

提到自閉症,最令人印象深刻的莫過於達斯汀霍夫曼(Dustin Hoffman)在雨人(Rain man)一片中所飾演的角色。擁有出色的計算能力,日常生活一絲不苟,但無法與外界溝通,也很難找到一份可以賴以維生的工作。在這樣的狀況下,自閉症患者在某些方面優越的表現,反而為這種病症添上一抹神秘而令人感嘆的色彩。

自閉症的成因至今尚未有定論,父母的管教、染色體的異常、腦部損傷等等原因都有人提出過,但還沒有一個理論可以完整的解釋自閉症患者在某些情況表現優異,卻無法與他人溝通的現象。

美國卡內基梅隆大學(Carnegie Mellon University)與匹茲堡大學(University of Pittsburgh)合作發表了一個新理論:「溝通不良理論」(Underconnectivity theory),為自閉症的研究提供了一個新的視野。

在他們的實驗當中特別找來17位患有自閉症但智商正常的患者,以及17位正常人作為對照組。實驗的方式是測驗受試者對語句的理解力,同時並使用功能性磁振造影(fMRI)來觀察受試者腦部活動的情形。

他們的研究發現,自閉症患者在大腦維尼克區(Wernicke's area)的活動較布羅卡區(Broca's area)來得活躍。維尼克區負責處理的是一個句子當中,個別單字的意義,這可以解釋為何某些自閉症患者有優異的能力來處理個別單字。

而布羅卡區負責的是對句子的理解,由於自閉症患者布羅卡區的活動並不活躍,所以他們在瞭解一些結構複雜的句子時會遭遇到困難。

另一個發現是,自閉症患者腦部的皮質語言系統(cortical language system)中,各皮質區域之間的功能性連結較正常人來得不發達,可以佐證何以自閉症病人無法處理整合性的事件,這也與之前其他研究發現自閉症患者在腦部白質部分有缺陷的情況互相呼應。

同時也發現自閉症患者在腦部枕頂區域(occipitoparietal area)的活動較控制組來得低落,所以自閉症的患者較難想像出一段文字所描述的景象。能夠想像得出文字所描述的內容,就是一種腦部整合性的活動。

根據「溝通不良理論」的解釋,正是因為自閉症患者在腦部整合功能網路上有缺陷,使得他們對數字、文字、或是對某些事件的記憶力有極佳表現,但也使得他們無法順利的同時進行多樣工作,所以沒法與人正常的溝通,也限制了他們在其他整合性工作方面的表現。

藉由「溝通不良理論」就可以解釋自閉症患者一個最大的特徵──孤獨,無法與他人進行正常的社交行為。這是因為社交行為需要腦部極複雜的整合。一個人必須能夠同時解讀他人微妙的表情變化、用句遣詞,配合當下的情境,才能做出相當的應對。不管是對語句的理解或是一般的社交活動,這些複雜的整合性活動對於自閉症患者而言都是一件很困難的事。

可惜在現今這個社會架構當中,無法與人溝通無疑是個嚴重的缺陷,也限制了自閉症患者正常生活的能力。若能真正解開自閉症的成因,就可以設計更適合他們的訓練課程,使他們能融入正常的生活,而且也能發展出更有效治療自閉症的藥物。


原始論文:
Marcel Adam Just, et al. Cortical activation and synchronization during sentence comprehension in high-functioning autism:evidence of underconnectivity. Brain, 127, 1811-1821(2004).

Photon Marathon

Photon Marathon

Somewhere between a light bulb and a laser is an unusual and sometimes puzzling type of light source called a random laser. It emits laser-like light, but in all directions. Now a research team believes they understand one of the mysteries of random lasers: why they can emit blasts of monochromatic light as pure as those of an ordinary laser. As the team reports in the 30 July PRL, their experiments and computer simulations show that each pure pulse begins as a single "lucky" photon that manages to bounce around hundreds of times before escaping.

In a typical laser, the light bounces back and forth inside a reflective cavity containing an amplifying material, such as a laser crystal. The ricocheting photons recruit more photons with each pass through the material and can escape through a partially transmitting mirror to make a beam.

Now imagine taking the crystal out of the cavity and grinding it into a powder, and you have a random laser. Hit it with brief pulses of excitation light, and the powder glows in response. The amplification happens when each photon scatters around many times inside the powder, continually eliciting more photons as it travels on a so-called random walk. When it finally escapes the powder, the light usually contains a spread of wavelengths that is broader than the nearly-single-wavelength output of a normal laser.

But if the amplification is strong enough, a random laser spits out extremely monochromatic light at several wavelengths, light that dominates its broader background emission. These "ultra-narrow" spikes in the spectrum appear at different wavelengths with each pulse and are unpredictable, unlike a normal laser, where the size of the reflecting cavity determines the beam's wavelength. Some researchers have proposed theories to explain this phenomenon, but others have remained unconvinced.

Now Diederik Wiersma of the European Laboratory for Nonlinear Spectroscopy in Florence and the Italian National Institute for the Physics of Matter and his colleagues have come up with an explanation, using results from experiments and computer simulations. The team's random laser consisted of a laser dye dissolved in alcohol along with particles of zinc oxide to scatter photons. When excited with green laser pulses, the mixture emitted the narrow peaks that others had seen.

Computer simulations reproduced the results and led to the explanation, which the researchers call the "lucky photon" effect. Although most photons emerge from their random walks through the liquid after about ten "ricochets," a very few photons walk the photon equivalent of a marathon--from 100 to 1,000 ricochets. In these rare cases, the original photon picks up an enormous number of companion photons of precisely its wavelength--perhaps 1012 of them in the case of a photon that ricochets 500 times.

"Why didn't we think of that before?" Wiersma recalls wondering after he and his colleagues ran the simulations. The random laser problem is deceptively similar to the more common scattering problems physicists look at, in which the medium doesn't amplify. Without amplification, a single photon traveling a marathon path length doesn't make a difference. "Once you understand that it happens, it is quite a natural explanation," says Wiersma.

"For sure, this model explains the random laser effect in some of the systems," agrees Mikhail Noginov of Norfolk State University in Virginia, noting the "good agreement" between the numerical calculations and experimental results. He hopes future experiments will test how broadly the model applies to other types of random lasers.

--Chelsea Wald

幸運光子造就隨機雷射

幸運光子造就隨機雷射

義大利的研究人員相信他們已經找到隨機雷射(random laser)可以發出無方向性但卻具單色性的光源的原因了.

一般雷射的形成是讓光在具有增益介質的共振腔中來回振盪, 透過受激輻射使光強度不斷放大, 並具有同調性及單色性. 但如果把增益介質拿到共振腔外, 並將之磨成粉狀, 則變成一個隨機雷射. 此時若用短脈波光照射激發, 則這粉末將會發光. 如果光子在粉末中被散射很多次, 則會誘發出更多的光子. 最後當光子脫離粉末時, 其波長範圍會比一般的雷射光(幾近單色光)還要寬很多.

然而, 如果更進一步將激發光的強度增強, 隨機雷射所發出的光的波長則會只剩下幾個非常單色的波長. 這些波長的位置會隨著不同的激發脈波而改變, 而且是無法預測的. 不像一般的雷射, 光的波長的位置可由共振腔的寬度來決定. 在此之前也曾有一些研究人員提出理論來解釋這現象, 然而其他的人則尚抱持懷疑的態度.

在2004年7月30的Physical Review Letters中 European Laboratory for Nonlinear Spectroscopy in Florence and the Italian National Institute for the Physics of Matter的Diederik Wiersma及其同僚提出了一個模型, 他們認為, 雖然大部分的光子在增益介質中以隨機步行(random walk)的方式反彈大約十次則會離開物質, 然而有少數的光子卻可在物質中反彈100-1000次, 他們稱這些光子是"幸運的光子". 而這些少數的幸運光子在離開物質時則會伴隨著大量相同波長的同調光子. 估計500次的反彈, 一個光子將會被放大成1012個光子. 他們以實驗及電腦模擬來驗證這個模型, 並得到相當契合的結果.

Norfolk State University in Virginia的Mikhail Noginov表示, 沒錯, 這個模型在某些系統上可以解釋隨機雷射的效應. 然而他更希望能有更多的實驗來測試這個模型的適用範圍.

Hormone levels turn mouse mums fearless

Hormone levels turn mouse mums fearless
05:00 01 August 04
NewScientist.com news service

Mouse mothers become fearless when levels of a particular hormone drop, reveals a new study. This gives mothers the courage to ferociously attack any would-be assailants to their offspring.

In response to scary or stressful situations, the brain secretes corticotropin-releasing hormone (CRH), which triggers a complex cascade of hormones that ready the body for action, such as raising blood sugar levels. It also feeds into the part of the brain which generates feelings of fear and anxiety. Elevated levels of CRH have been linked with symptoms of depression in both rodents and humans.

But lactating females have chronically low levels of CRH in the brain, which is thought to make them generally less anxious. For example, studies in humans show that nursing women are less perturbed, both physiologically and emotionally, by stressful situations.

Stephen Gammie and colleagues at the University of Wisconsin, Madison, US wondered if lowered CRH might also be responsible for a mother’s fearless bravery.

To test their theory, the team injected three different concentrations of CRH or a saline solution into the brains of nursing mothers and then placed a male her nesting cage. Compared to controls, who immediately assaulted the male, mice injected with the two higher doses of CRH showed almost no maternal aggression. Their response was delayed, their attacks less frequent and much shorter.


Stressful jobs

Mothers with the lowest levels of CRH attacked intruding males more than 20 times for the duration of about 45 seconds.

“Low levels of CRH seem to be necessary for maternal protective behaviour. It makes evolutionary sense for mothers to increase aggression because it’s critical for them just to keep the kids alive,” says Gammie. Unbalanced levels of CRH in humans may also be connected with post-partum depression, he says.

For the past few years, pharmaceutical companies have been working to develop CRH receptor blockers, like antalarmin, as a treatment for anxiety disorders, depression and post traumatic stress disorder. The drugs could have a performance-enhancing effect on people with extremely stressful jobs.

“In war, soldiers are under high stress constantly,” says Tracy Bale, who works on CRH and depression at University of Pennsylvania. “In those cases, a CRH blocker might help.”

However, results with animal studies suggest that responses could be highly sex-dependant. And, adds Bale, the dose would be critical because CRH is involved with many other bodily functions, including glucose metabolism. Blocking too much CRH might hinder performance more than it helps.

Journal reference: Behavioral Neuroscience (DOI: 10.1037/0735-7044.118.4.000)
Anna Gosline

賀爾蒙的濃度變化使母親無所畏懼

賀爾蒙的濃度變化使母親無所畏懼

哺乳類雌性動物會不顧任何生命危險地保護自己的子女,研究發現,CRF(Corticotropin-Releasing Factor) 的減少會降低母親的害怕與焦慮,來保護她們的子女。這項研究刊登於最新一期,八月號的Behavoiral Neuroscience。

在生物學上,這種母親不顧一切保護子女的行為,稱為母性侵略行為(maternal aggression)。不過之前很少有研究說明此母性侵略行為背後的生物機制究竟是什麼。美國威斯康辛大學麥迪遜校區的Stephen Gammie說:「我們已經知道,雌性動物在哺乳期時,害怕和焦慮的情緒會減少。也許就是如此,會讓母親們改變其正常行為,將原本只會引起恐懼情緒的刺激,轉變成攻擊的行為,並藉此保護自己的子女。」

為了證實此項假說,Gammie和他的同事便開始研究老鼠的母性侵略行為和腦中CRF的高低有何關聯。CRF是腦內的一種胜肽,可以控制行為。

在母鼠分娩後第六天,研究人員給母鼠注射三種不同劑量的CRF溶液和生理食鹽水(不含CRF)作為控制組。注射的情形是每天一次並連續打四天。然後把母鼠和小鼠放在一起並加入一個公鼠。由於公鼠有時候會去吃小鼠,在正常情形下母鼠會憤怒地去攻擊那些吃小鼠的公鼠。研究的結果發現,當沒有注射和只注射小劑量的CRF時,母鼠們會在45秒內超過20次攻擊公鼠。而中劑量的母鼠則會在八秒內攻擊六次;高劑量的母鼠卻什麼事也不做。

Gammie根據這個結果說明:「降低CRF濃度似乎是形成母性侵略行為的必要條件。」研究人員認為這個結果或許可以解釋為何產後憂鬱症(postpartum depression) 的母親會忽略他們的子女甚至於虐待他們,因為產後憂鬱症可能和高CRF有關。或許將來可以設計阻斷或拮抗CRF接受器的藥物來進一步控制因壓力而引起的焦慮。

原始論文:S.C. Gammie, A. Negron, S. M. Newman, and J. S. Rhodes. Corticotropin-Releasing Factor Inhibits Maternal Aggression in Mice. Behavioral Neuroscience (DOI: 10.1037/0735-7044.118.4.000)

科學解析「盲者善聽」

科學解析「盲者善聽」

盲人音樂家的才華洋溢是一再發生的巧合呢?還是由於專注的凝集呢?加拿大科學家們發現:年幼失明的盲者對於樂音變化的察覺能力確實遠遠強於後天失明者及普通人。

陰符經相傳為黃帝所作,文中曾提到:『盲者善聽,聾者善視;絕利一源,用師十倍;三反晝夜,用師萬倍』。這幾句話的主要意思為:喪失視力之便的盲人,聽力卻往往更為的敏感;屏除聽聞之利的聾者,視覺卻往往尖銳;所以,只要【全神貫注】地成就一件事情,便可以激發出十倍潛能;如果這份專注的功夫更能【持續】上一段時間,那更能產生萬倍的威力。

陰符經中舉了「盲者善聽」與「聾者善視」這兩個例子,但其中又以「盲者善聽」更為令人印象深刻,畢竟從古至今出現了太多才華洋溢的盲人音樂家,例如:Ray Charles 與 Stevie Wonder,他們的音樂作品都曾於二十世紀末風靡一時、專擅一方。

這些「盲者善聽」的偉大成就是純屬巧合呢?還是由於潛能的凝聚呢?加拿大科學家Pascal Belin與其研究團隊發表於2004年七月《自然》期刊(Nature 430:309)的研究成果指出:年幼失明的盲者對於樂音變化的察覺能力確實遠遠強於後天失明者及普通人。

在他們的研究中,將受試者區分為三大群體:第一群為七位年幼(二歲以前)失明盲者,第二群為七位年長(五歲到四十五歲間)後失明者,第三群則為十二位視力正常受試者。接著,研究人員要求這些受試者凝聽一系列由兩個連續且音高不同的樂音組成的音對,並對各音對中樂音的高低變化進行判斷。

實驗中,研究人員將音高差為1/8個八度音(相當於150音分值或1.5個半音),音值(發聲體震動時延續時間的長短)為333毫秒的音對做為參照。通過對參照音對的兩個特徵變量分別進行四次對半遞減,64個實驗音對被分為8組,每組包含8個頻率不同抑揚相異的音對。實驗結果顯示:無論是對稍縱即逝的樂音變化(最短音值:20.8毫秒),還是極其細微的音階波動(1/128個八度音),相較於後天失明或視力正常的受試者,年幼失明的盲者都更能準確地辨析。

Pascal Belin推測:出生時的大腦中負責視覺、聽覺與其他感覺的神經系統都是相互聯繫的,只是在發育的過程中,大腦中各種感官間的聯繫會逐漸消失。然而,如果年幼失明,則這種感官間聯繫現象則會被保留下來,如此一來,大腦中的視覺皮質也可以協助處理聲音信息了。

本文感謝英國牛津大學經濟系劉一沛協助完成。

原始論文:Neuropsychology: pitch discrimination in the early blind. Nature. 2004 Jul 15;430(6997):309.

Thursday, August 12, 2004

Nanoparticles target tumours

Nanoparticles target tumours
29 July 2004

Researchers at Emory University, Georgia Institute of Technology and Cambridge Research & Instrumentation, all in the US, have used semiconductor nanocrystals (or quantum dots) to simultaneously target and image cancerous tumours in mice.

"Although other research groups have used quantum dots to either target or image cells, we believe this is the first time in vivo targeting and imaging has been achieved simultaneously," said Xiaohu Gao of Emory University and Georgia Institute of Technology.

Gao and colleagues used cadmium selenide-zinc sulphide (CdSe-ZnS) core-shell quantum dots with a diameter of 5 nm. They coated the nanoparticles with a protective layer of an ABC triblock copolymer and then a layer of poly (ethylene glycol). The triblock polymer protects the quantum dots from enzymes and other biomolecules and also acts to prevent leakage of toxic cadmium and selenium ions. Finally, they attached the quantum dots to a monoclonal antibody that targets prostate-specific membrane antigen on the prostate tumour cell surfaces.

When the team injected the quantum dots into the circulatory system of mice with solid prostate tumours the dots accumulated selectively at the site of the tumour. The scientists detected the dots by fluorescence imaging. They also tried "passive" targeting of the tumour by injecting quantum dots that weren't conjugated to antibodies. Although the quantum dots accumulated at the tumour sites as they leaked from the porous angiogenic blood vessels that grow in tumours, the process was slower and less efficient than for the quantum dots conjugated to antibodies.

"This is a new class of quantum dot conjugates designed specifically for complex in vivo applications," said Shuming Nie of Emory University and Georgia Institute of Technology. "They are stable over a broad range of pH and salt conditions and maintain their stability even after treatment with hydrochloric acid."

The researchers say they believe this is an important step in the quest to eventually use nanotechnology to target, image and treat cancer, cardiovascular plaques and neurodegenerative disease in humans.

"The larger surface area provided by quantum dots should allow the conjugation of multiple agents, and we envision the development of diagnostic and therapeutic dual-modality quantum dots," said Nie.

The scientists reported their work in Nature Biotechnology.

奈米微粒可標定腫瘤

奈米微粒可標定腫瘤


  美國的艾墨利(Emory)大學、喬治亞理工學院及劍橋儀器研發公司的科學家們,應用半導體奈米微晶(nanocrystals)或稱量子點(quantum dot)技術,已能在老鼠身上標定並觀察到腫瘤的影像。任職於艾墨利大學及喬治亞理工學院的Xiaohu Gao表示,雖然其他研究團隊也曾使用量子點來標定或觀察細胞,但該小組是最先能在活體內同時標定細胞並為其造影。

  Gao和同事們使用硒化鎘(CdSe)為核、硫化鋅(ZnS)為殼、直徑約5奈米的量子點,並在外層包覆ABC三團聯共聚物(triblock copolymer)及聚乙二醇(pol(ethylene glycol))聚合物。這些聚合物保護層可將量子點與酵素及其他生化分子隔離,並可防止具有毒性的鎘(cadmium)及硒(selenium)金屬離子滲出。研究人員最後再將量子點連接上針對攝護腺癌的抗體,使量子點能標定攝護腺癌細胞的表面。

  量子點經由注射進入老鼠體內,透過血液循環選擇性地累積在攝護腺腫瘤部位,科學家藉此偵測到老鼠腫瘤部位的螢光影像。他們也將未包裹抗體的量子點打入老鼠,這些量子點會由腫瘤新生的血管滲出而累積,但過程速度較慢效率也較低。該研究小組表示,這種新型量子點結合技術是特別針對複雜的體內應用而設計,在不同的酸鹼度及鹽類濃度都很穩定,甚至是以鹽酸處理後仍能維持其穩定度。

  科學家相信,應用奈米科技發展運送藥物到腫瘤部位並為腫瘤造影的技術,能幫忙解決人類心血管斑塊阻塞及神經退化性疾病。量子點由於面積較大,可承載多種藥物,科學家期望能據此發展出具有診斷及治療雙效的量子點。詳見近期出刊的Nature Biotechnology。

A nano-polymer a day keeps the microbes away
21 July 2004


Researchers at the University of Freiburg, Germany, have made a nanoparticle-containing polymer network that can act against microscopic organisms in several ways. The material repels bacteria and other microbes, releases a biocide and can also kill the organisms on contact.

"[Our work] demonstrates the potential of making template polymer networks for metal nanoparticles via readily available and relatively cheap starting materials, and might have applications in coatings for medical devices to keep them sterile," Joerg Tiller told nanotechweb.org. "There is also the potential for catalytic or optical applications."

The scientists based their material on the fact that it's possible to form silver nanoparticles within amphiphilically modified poly(ethylene imine) (PEI) derivatives in solution.

"As found in previous work, the approach of coating with silver nanoparticles instead of plain silver was very promising," said Tiller. "However, adhesion of bacteria dramatically changes the microbes' defence system, making them less vulnerable. So we decided to add an additional modification to the coatings: the microbe-repelling polymer poly(ethylene glycol) (PEG)."

To make the material the team copolymerized PEI, derivatized with double bonds, with 2-hydroxyethyl acrylate (HEA). The result was a polymer network containing nanoseparated PEI phases. The material can bind silver ions within these PEI phases as the silver links to the PEI's nitrogen groups. The HEA component, meanwhile, contained a hydroxyl group that can covalently attach to PEG.

"Most significant about our findings is that the silver nanoparticles can be formed within a coating simply by immersing it in aqueous silver nitrate solution, followed by treatment with aqueous ascorbic-acid solution," said Tiller. "Furthermore, the nanoparticle content can be perfectly controlled by the composition of the network."

The team tested the anti-microbial properties of the films by trying to grow Staphylococcus aureus bacteria on them. These bacteria are a major source of nosocomial infections - diseases acquired in hospital. After 12 hours of incubation at 37° C, the silver-loaded polymer networks did not support any bacterial colonies.

In contrast, colonies were visible after 12 hours on polymer networks that didn't contain silver nanoparticles, both on a PEG-modified and an unmodified version. The PEG-modified network supported four to five times fewer colonies than its sister material without PEG. The scientists say that this demonstrates the microbe-repelling properties of the "PEGylated" network.

Silver-loaded polymer networks did support bacterial colonies after longer periods, however. This indicates that the films only inhibited bacterial growth, i.e. that they were bacteriostatic.

The researchers reported their work in Advanced Materials.
About the author
Liz Kalaugher is editor of nanotechweb.org.

可抑菌的奈米織布

可抑菌的奈米織布

  德國科學家研究出一種含奈米微粒的聚合物織布,該材料除了可以驅除細菌或其他微生物,還能釋放殺菌成份,接觸時也能摧毀細菌或微生物的組織。這種材料可以做為維持醫療設備無菌狀態的包被物,同時也具有觸媒及光學上的應用潛力。

  這種材料的製造主要是根據銀奈米微粒可以在聚乙烯亞胺(poly(ethylene imine), PEI)衍生物溶液中形成。弗萊堡(Freiburg)大學的Joerg Tiller指出,先前的研究發現包覆銀奈米微粒比包覆單純銀的織布更有效,然而細菌的吸附會大大強化微生物的防禦系統,因此他們在包覆物中又添加了抗菌的聚甘醇(poly(ethylene glycol), PEG)。

  研究人員將二-羥乙基丙烯酸(2-hydroxyethyl acrylate, HEA)與具雙鍵的PEI衍生物共同聚合,製造出含有PEI相的聚合織布。這種材料能透過PEI的氮基與銀離子結合,HEA則藉由其氫氧基以共價鍵連接PEG。研究人員接著將織布浸入硝酸銀水溶液,再以菸鹼酸(ascorbic-acid)溶液處理,就可以在織布的網狀結構內形成銀奈米微粒。Tiller表示,這項工作證明了可以由便宜又容易取得的材料,製造出含金屬奈米微粒的聚合織布。

  為了測試抗菌效果,研究小組在這種織布上培養金黃葡萄球菌(Staphylococcus aureus),這是醫院內的一種主要感染源,結果發現在37℃下經12小時後,這種載有銀奈米微粒的織布並沒有任何菌落形成,相形之下,未含銀奈米微粒的織布,不論是否添加了PEG,都可觀察到菌落的形成,不過添加PEG的織布上的菌落數量要比未添加者少了四到五倍,顯示出這種聚甘醇烯化(PEGylated)的織布的抗菌特性。詳見近期的Advanced Materials.

Tuesday, August 03, 2004

Revised drug battles leukaemia

Published online: 15 July 2004; doi:10.1038/news040712-13

Revised drug battles leukaemia
Helen Pilcher
Gleevec-resistant patients given fresh hope.

Cancer treatment's 'magic bullet' has had a makeover. Researchers have developed and tested a second-generation version of the leukaemia drug, Gleevec. It is hoped that the newcomer will offer relief to those who have developed resistance to the original drug.

Gleevec was the first cancer drug of its kind - designed specifically to target the molecules that cause chronic myeloid leukaemia (CML), a deadly form of cancer that affects 1 in 100,000 people. Since its approval by the US Food and Drug Administration in 2001, it has become the front-line therapy for CML. But around 20% of patients become resistant to the drug in the early stages of the disease, so other treatments are needed.

The new drug, called BMS-354825, shrinks tumours and prolongs life in mice with a Gleevec-resistant form of CML, researchers report in Science1. Around 80% of treated rodents were still alive one month after their cancer started to develop. Without treatment, all animals died within two weeks.

BMS-354825 also slows the proliferation of cultured bone marrow cells taken from CML patients, regardless of whether they have developed resistance to Gleevec or not.

In theory this means that the drug could work against both drug-resistant and Gleevec-treatable forms of human CML, says Neil Shah from the University of California, Los Angeles, who co-authored the study. But the best treatment regime may involve prescribing Gleevec and BMS-354825 together, he says.

Designer drugs

Gleevec, also known as imatinib, works by binding to and blocking an enzyme that drives the growth of leukaemia cells. Because it targets only the cancer cells, it leaves neighbouring healthy cells unharmed.

The problem is that sometimes genetic mutations occur that cause the enzyme to change shape and prevent the drug from latching on. BMS-354825 is less selective about how it binds to the enzyme, so it can attach even to mutated forms of the protein.

Up to now, 17 resistance-causing mutations have been spotted. The new drug works against 14 of the 15 tested so far. "We're optimistic that the other untested mutations will also be sensitive to the compound," says Shah.

At present, when Gleevec fails, patients hold out for a bone-marrow transplant. But less than a third of patients are eligible, discounted by their age and a lack of tissue-matched donors. Without treatment, the cancer is invariably fatal.

So BMS-354825 is a welcome addition to the CML armoury. Last November, the first human patient began taking the drug as part of a phase I clinical trial. Around 30 CML patients are taking the drug to help assess its safety.

"It's good news for the CML community," says Junia Melo who studies haematology at London's Hammersmith Hospital. But she says it is disappointing that one of the tested mutations is immune. The mutation, known as T315I, is responsible for around one fifth of all drug-resistant CML cases.

改造後的藥物大戰白血病

改造後的藥物大戰白血病

癌症治療的神奇子彈有了新契機。科學家們發展出治療白血病藥物--Gleevec--的第二代,也對它進行了測試。人們希望這個新加入戰場的藥物能給那些對於原先藥物已有抗藥性的患者帶來希望。

慢性骨髓白血病(chronic myeloid leukaemia,CML)是一種致命的癌症,每十萬人中就有一人會罹患此病。Gleevec則是第一個特別針對慢性骨髓白血病所設計的藥物。自從美國食品與藥物管理局(Food and Drug Administration;FDA)在2001年核准後,Gleevec已經變成治療慢性骨髓白血病的前線藥物。但約有20%的病患在發病的早期即對此藥物有抗藥性,因此,其他的治療仍是需要的。

新的藥物被稱為BMS-354825,在罹患慢性骨髓白血病、且具有抗Gleevec藥性的實驗老鼠身上,此藥物能縮小腫瘤以及延長實驗老鼠的生命。在癌症開始發病後,80%接受治療的老鼠仍可以活上一個月以上,而未接受治療的老鼠則會在兩個星期內死去。

不管罹患慢性骨髓白血病的病患對Gleevec有沒有抗藥性,BMS-354825都能讓這些患者的骨髓細胞在培養基中延長生命。

參與這項研究,現任職於加州大學洛杉磯分校的Neil Shah表示,這樣的結果顯示BMS-354825對兩種藥物反應類型的患者都有一定的成效,但是最好的治療方式也許需要Gleevec和BMS-354825同時使用。

Gleevec又稱為imatinib,其機制為結合並阻礙一種會驅使白血病細胞生長的酵素產生作用。Gleevec只會攻擊癌細胞,因此不會使週邊的健康細胞受到傷害。但基因的突變會讓這個酵素改變形狀,使得Gleevec無法和其結合發揮藥效。而BMS-354825對酵素結合上的選擇性比較少,因此對已經改變形狀的酵素蛋白都仍具有結合的能力,所以可以改善病患對於Gleevec有抗藥性的問題。

迄今,17種會造成抗藥性的突變已經被標明了,經試驗其中的15種突變模式後,BMS-354825對之中的14種模式有作用。Shah表示,他們對其餘尚未和此藥物進行測試的突變模式抱持著樂觀的希望。

目前,當病患對Gleevec產生抗藥性後,他們只能寄望於骨髓的移植。但礙於年齡以及缺乏合適的捐贈者,只有少於三分之一的患者能夠進行骨髓移植的手術治療。沒有接受治療的病患勢必會走向死亡。

所以,BMS-354825在廣受歡迎之下,加入了對抗慢性骨髓白血病的生力軍。去年十一月,第一位人類病患在他第一期臨床治療上開始服用此藥物。約有30名病患正在使用BMS-354825,協助研究人員對此藥物的安全性進行評估。

在倫敦Hammersmith醫院進行血液學研究的Junia Melo說,這對慢性骨髓白血病的族群是件好消息,但她也失望地表示,突變模式測試中有一種對BMS-354825已具有免疫的能力了。這個對新藥物具有免疫能力的突變稱為T315I,在對藥物具有抗藥性的慢性骨髓白血病病例之中,大概有五分之一的比例和此種突變有關。


--References:Shah N. P., et al. Science, 305. 399 - 401 (2004).

聖杯化合物在酵素上的應用

聖杯化合物在酵素上的應用

 生命體中,無時無刻都有很多的生理反應在進行著,這些生理反應大多需要酵素的參與才能夠進行,因此若某些酵素不足或是產生缺陷,嚴重地將足以致命,而為了更了解人體中的酵素,在研究上,我們常利用相似的配位子來模擬酵素活性中心周圍的環境,如異核含氮分子來代替組胺酸(histidine),羰酸及酚鹽來代替天門冬胺酸(aspartic acid),硫醇則用來代替半胱胺酸(cysteine)。

  Reinaud 等人設計了聖杯化合物(calixarenes)以三個N-methyl imidazole聚集形成一個洞穴而將金屬鋅置於其中心,來模擬酵素周圍蛋白質的堆疊(圖一)因為蛋白質周圍是有相當多不同的分子以立體構型包圍。而作者合成此錯合物會形成穩定的四配位結構,其中一個配位基為水,但是其可以被很多中性分子所取代如醇類,胺類。
  並很順利的得到配物基被乙醇取代的單晶,藉由其單晶結構發現氫鍵和CH---π作用力均對穩定結構有相當的功效。就其在圖二所示結構來看,鋅是一個四面體結構,和三個imidazole上的氮鍵結,平均距離1.98 Å,乙醇深埋在結構中心,鋅氧鍵長為1.984 Å,略短於Liver Alcohol Dehydrogenase 中鋅氧鍵長2.0 Å,但可歸因於人體酵素有較負的電荷(charge),而其乙醇OH基利用很強的氫鍵(dO-N=2.86 Å)和一個OCH2Im單元鍵結,亞甲基則利用CH---π作用力和苯甲醚的環中心作用,碳至環中心距離為3.67 Å。作者認為可將此作用力視為酵素與基質穩定的要素。

  在本文中另人注意的地方是聖杯化合物和鋅的關係,很類似人體中酵素和基質的關係,所以其鍵長的比較都相當的類似,可請各位到原論文看。而作者稱此化合物為Zn funnel complexes.


論文出處Seneque, O.; Giorgi, M.; Reinaud, O. J. Chem. Soc., Chem. Commum. 2001, 984-985.

Wednesday, July 28, 2004

為什麼癌症會轉移?

為什麼癌症會轉移?

癌細胞的轉移可能是因為喚醒了身體中沈睡的胚胎發育相關轉錄因子所致。


一般來說,癌細胞進行轉移會分為幾個階段:第一個階段稱為侵犯(invasion),這個階段當中癌上皮細胞會鬆開癌細胞之間的連接,使得癌細胞「重獲自由」而能移動到其他地方去。第二個階段稱為內滲(intravasation),癌細胞穿過血管或淋巴管的內皮進入循環系統。第三個階段稱為外滲(extravasation),在這個階段當中,經過循環系統之旅洗禮的倖存者,會穿過微血管的內皮細胞到達新樂土--其他的組織。最後的階段就是這些癌細胞的新大陸移民,在其他組織當中繁衍茁壯形成轉移的惡性腫瘤。

雖然目前已有研究披露出一些與轉移過程相關的基因,不過大部分的研究都是將癌細胞注射入循環系統中,如此便缺少了與侵犯和內滲作用相關的基因研究。而在麻省理工學院的懷德海研究所(Whitehead Institute)當中由Robert Weinberg所領導的研究團隊,則在最近發表與癌症轉移早期相關的研究結果。

首先他們使用當紅的微陣列(microarray)技術來分析會轉移的老鼠乳癌細胞的基因表現,從中他們找到一個重要的轉錄因子:Twist。這個轉錄因子在胚胎發育的某些過程中,肩負著引發細胞移動以及組織重組的任務。而類似的細胞移動以及組織重塑情形在腫瘤轉移的時候也會發生。
他們發現Twist會使由鈣黏附素E(E-cadherin)所調控的的細胞黏附作用失效,以及產生上皮細胞的上皮-間質轉化(Epithelial- Mesenchymal Transition, EMT)。而且被阻斷了Twist表現的癌細胞其轉移的程度會降低,並且在循環系統中的癌細胞數目也有減少的現象。另外在人類乳癌中的侵犯性小葉癌(invasive lobular carcinoma)當中也觀察到Twist抑制了鈣黏附素E的表現。
因此Weinberg等人推測,癌細胞之所以能進行轉移,可能是因為喚醒身體中沈睡已久,負責胚胎早期型態發育的基因,從而啟動相關的程序,因此獲得轉移的可怕能力。

未來在臨床上也許能開發藥物以抑制Twist這類基因的表現,避免腫瘤轉移;又或者可以藉由篩檢這些基因,早期發現腫瘤未來的走向,並給予適當的治療。也許以後癌症不再是那麼令人可怕的洪水猛獸,而會變成另一種慢性病也不一定。

原始論文:
Jing Yang, et al. Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis. Cell(117), 927-939,2004.

Could we defeat the menopause?

News   Published online: 01 July 2004; doi:10.1038/news040628-18

Could we defeat the menopause?

Helen R. Pilcher

Mouse ovaries offer up secret of new egg cells.   From the 20th Annual Meeting of the European Society of Human Reproduction and Embryology, Berlin, Germany
 Cells that are capable of making new eggs have been isolated from adult mouse ovaries. The finding supports an earlier suggestion that mammal ovaries could produce eggs throughout life, and shatters the dogma that women are born with a finite supply.

The researcher involved has even identified a molecule that boosts the activity of these cells and causes mice to develop twice as many egg follicles as normal. If it works in humans, such a chemical could provide a revolutionary treatment for women with a low egg-count, such as cancer survivors or those nearing menopause.

Jonathan Tilly from Harvard Medical School, Boston, who is behind the work, first hinted that adult mice might be able to grow new eggs earlier this year. In Nature, he reported seeing stem cells that were potentially able to develop into eggs within adult mouse ovaries1.

But he was unable to isolate the cells, so critics were not convinced. Now, Tilly has isolated the cells and shown that they display genetic markers that are characteristic of stem cells with the ability to develop into eggs. Although he will not disclose his method, he says he obtained 150 to 200 such cells from a single mouse ovary.

"It's an intriguing story," says Ursula Eichenlaub-Ritter from the University of Beilefeld, Germany, who studies ovarian development. But she cautions that the cells need to be characterized further before the case is proven.

Character building

Tilly has already started characterizing the cells. He has identified a gene in the mice that appears to regulate the stem cells' activity. When he knocked out this gene, the resulting mice had 40% more follicles in their ovaries than normal.

And he has even identified a molecule, which he calls GSA8, that has a similar effect. Tilly will not reveal the identity of GSA8. But he told this week's meeting of the European Society of Human Reproduction and Embryology in Berlin that when he injected it into female mice just before puberty, they ended up with almost double the normal number of follicles.

Tilly suspects that the same kind of mechanism could work in humans. "Why would Mother Nature put all her eggs in one basket when they would just sit there and accumulate DNA-related damage?" he asks. He points out that female flies, fish, birds and now mice all appear to make new eggs throughout life, so it is unlikely that humans would be any different.

原來還有新出廠的卵子?

原來還有新出廠的卵子?

新的研究報告證實小鼠初生之後的卵巢環境仍具有製造新生卵子的能力。

哈佛大學醫學院 Tilly 博士的研究小組於今年初指出成年小鼠的卵巢仍能誘導幹細胞成為新生卵子的潛能(註1),這表示小鼠初生之後 (postnatal) 的卵巢可能在某些條件存在下可以產生新的卵子,而不只是儲存M I卵子與週期催化成熟其中少數為M II卵子。本月 Tilly 等人在 ESHRE (European Society of Human Reproduction & Embryology) 年會發表的報告中表示,他們已進一步地篩選出這些細胞並找出一個遭抑制後能讓成年小鼠卵巢增生 40% 濾泡的基因。同時,他們也發現名為 GSA8 的具相似促濾泡增生效果的分子。

去年賓州大學(U Penn)的 Scholer 博士(現已應聘至德國 Max-Planck 研究院)等人發現利用體外培養小鼠胚幹細胞形成類似卵子的方法(註2,3)。波士頓兒童醫院 Daley 博士所主導的小組亦成功利用體外培養的方式以retinoic acid 等相關物質培養小鼠幹細胞,之後從 embryoid bodies 中生成精子細胞,並利用顯微注射成功使卵子受精(註4)。此次 Tilly 博士發表的結果雖不若上述兩者對不孕治療、複製、基因轉殖等技術以及相關倫理議題造成極大之震撼,但卻讓我們對哺乳動物生殖機轉的一個重要“典範”--初生之後的成熟卵巢“不”再製造新的卵子--有了重新思考的機會。雖然目前仍無證據支持其他哺乳類動物包括人類之成年卵巢亦有促濾泡增生暨產生新卵子的現象,我們期待此研究繼續的延伸及相關領域的突破,諸如卵巢移植/置換與冷凍技術(註5,6),在未來一方面可裨益相對高齡的計劃生育或接受過癌症療程之婦女受孕,另一方面可幫助瞭解更年期現象及開發新的療法幫助更年期前後的婦女。

後記:Tilly 等在 ESHRE 年會發表的報告已刊登於 Obstetrical & Gynecological Survey (註8)。

附註:
1. Johnson, J. et al (2004). Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 428:145.

2. Hubner, K. et al (2003). Derivation of oocytes from mouse embryonic stem cells. Science 300:1251.

3. Dennis, C. (2003) Synthetic sex cells [Review]. Nature 424:364


4. Geijsen, N. et al. (2004) Derivation of embryonic germ cells and male gametes from embryonic stem cells. Nature 427:148

5. Oktay, K. et al. (2004) Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet 363:837.

6. Oktay, K. and Buyuk, E. (2004) Fertility preservation in women undergoing cancer treatment. Lancet 363:1830.
New references updated (July 20, 2004)

7. Greenfeld, C. and Flaws, J.A. (2004) Renewed debate over postnatal oogenesis in the mammalian ovary. BioEssays 26:829

8. Johnson , J. et al (2004). Germline stem cells and follicular renewal in the postnatal mammalian ovary. Obstetrical & Gynecological Survey 59(7):518.

Monday, July 26, 2004

Avian flu grows more virulent

Published online: 29 June 2004; doi:10.1038/news040628-13

Avian flu grows more virulent

Helen R. Pilcher

Virologists urge surveillance of possible outbreaks.  

The bird flu virus is mutating and becoming more dangerous to mammals, say researchers. The discovery reinforces fears that a human pandemic of the disease could yet occur.

Avian flu hit the headlines in 1997 when a strain called H5N1 jumped from chickens to people, killing six people in Hong Kong. Within three days, the country's entire chicken population was slaughtered and the outbreak was controlled.

Since then new strains of virus have emerged, killing a further 14 people. As yet, no strain has been able to jump routinely from person to person. But if a more virulent strain evolves, the fear is that it could trigger widespread outbreaks, potentially affecting millions of people.

Now, genetic and animal studies show that the virus is becoming more menacing to mammals. Immediate action is needed to stem the virus's transmission, says Hualan Chen from Harbin Veterinary Research Institute, China, who was involved in the research.
 'The disease could resurge at any time' 
Marion KoopmansNational Institute of Public Health and the Environment

Sick chickens

Chen and colleagues studied 21 H5N1 flu virus samples taken from apparently healthy ducks, which act as a natural reservoir for the disease, in southern China between 1999 and 2002. The researchers inoculated groups of chickens, mice and ducks with virus samples taken from different years and waited to see which animals became ill. Their results are presented this week in the Proceedings of the National Academy of Sciences1.

As expected, ducks were immune to the virus's effects and the chickens fell sick. However, the mice also became ill, losing weight and the use of their limbs. Crucially, the severity of their illness was linked with the year from which the virus sample was taken. Viruses isolated in 2001 and 2002 made the animals more ill than those isolated earlier on.

The findings hint that some time around 2001, the virus became adept at infecting mammals. Genetic analysis of the same samples reveals that the virus's DNA changed over that time, suggesting that accumulated mutations may have contributed to the increased virulence.

Porcine hosts

Researchers are concerned that a virus that has acquired the ability to infect mice could also infect humans. "The disease could resurge [?] at any time," warns virologist Marion Koopmans from the National Institute of Public Health and the Environment in Bilthoven, the Netherlands. 

The findings highlight the need for improved surveillance to ensure that any future outbreaks are curtailed, she says. Although domestic poultry are easily culled, wild animals are more difficult to contain. "It is impossible to eradicate the natural reservoir," says Koopmans, "so we need to learn to live with it."

Birds may not be the only villains in this story, however. Chen believes that pigs may also play a part. In Asia, chickens and pigs are often kept in close proximity, so the virus may have shuffled back and forth between the two species, picking up mutations and becoming better at infecting mammalian hosts. Humans may then have caught the disease from swine. 

人禽共通的禽流感疫情隨時都可能再度爆發

人禽共通的禽流感疫情隨時都可能再度爆發

 
1997年時,禽流感已因H5N1病毒突變為人禽共通種而在香港造成恐慌,今年又在東南亞如越南和泰國等國家捲土重來,造成24人染病死亡。所幸當時的病毒都還不能人傳人,若像SARS一樣可以在人群間彼此傳染,影響所及,恐怕會造成疫情的嚴重爆發,感染人數可能高達上百萬。

然而,最近卻有一份最新的研究結果顯示,這種情況似乎很有可能在不久的將來發生。中國大陸哈爾濱獸醫學院(Harbin Veterinary Research Institute, China)的研究小組在1999到2002年期間對中國南方健康鴨隻進行採樣,將取得的21份不同年份的H5N1病毒採樣培養於鴨隻、雞隻和老鼠體內,結果一如預期地,鴨隻還是健康,而雞隻則完全得病。但意外的是,他們發現老鼠也得病了,而且病情和病毒的年份有關,感染年份愈新的病毒,造成的病情愈嚴重。進一步分析,更發現到病毒的DNA隨著時間不斷在改變,這表示突變的累積的確可能會造成病毒威脅性的提升,如今病毒的威脅性既然已提高到這種程度,就有可能感染人類,引發比先前更為嚴重的疫情。

在中國南方,畜農通常是將豬隻和鴨隻集中混養,科學家因此推測,由於H5N1病毒對於鴨隻還不至於造成威脅,因此可以在鴨群間不斷增殖突變,甚至隨機性地演化為可以感染人類的種類,但因為是隨機性地,所以過去通常只有零星的病例發生,而且還無法造成人群間傳染;然而,同時由於還沒有充分證據顯示H5N1病毒能造成豬隻感染禽流感,因此,在鴨群間不斷傳播的病毒也可能傳染到豬隻這類哺乳類動物身上,繼續進行不受天擇淘汰影響的突變,等到產生可以感染其它哺乳類動物,甚至是人類的病毒,就有可能再度爆發疫情。如今H5N1病毒可以使老鼠感染禽流感,等於為這項假設提供了間接的證據。雖然科學家還不清楚禽流感病毒是如何突變為可以感染哺乳動物的種類,但顯然一些基因,如HA和PB2,必定涉及這項過程,如1997年時在豬群間流傳甚廣的H3N2病毒就包含有人、豬和禽流感病毒的重組基因片段,這些片段裡都具有如上所述的基因,故可以合理的推測這種情形必然與H5N1病毒感染老鼠的現象息息相關。

因此,科學家不斷呼籲相關單位加強戒備,以確保疫情不會爆發。然而持續突變當中的H5N1病毒是否真能夠在這之前就被人類控制住,似乎沒有人敢斷言。

這項研究結果已刊登於《美國國家科學院期刊》(Proceedings of the National Academy of Sciences, PNAS)上。
原學術論文:Chen, H. et al. The evolution of H5N1 influenza viruses in ducks in southern China. Proceedings of the National Academy of Sciences 101, 10452–10457 (2004)

WHO urges action on bird flu outbreaks

WHO urges action on bird flu outbreaks

Helen Pilcher

Sick poultry raise fears of human pandemic.

 
The World Health Organization has called for a prompt response to curb the spread of avian flu. The announcement follows reports that a potentially lethal virus has re-emerged in birds in Asia.

The last two weeks have seen a spate of outbreaks in Asian poultry, including at least one in China, two in Thailand and three in Vietnam. Tens of thousands of chickens and ducks have been slaughtered to halt the spread of the infection. No humans are thought to have been infected.

The WHO wants Asian countries to step up surveillance of poultry and humans. It is also asking authorities in newly hit countries to make samples of the virus strains that are responsible for the latest cases available to international research teams for study.

"If we can compare the viruses with each other and with those from the earlier outbreaks, we will have a much better picture of what is going on," says Shigeru Omi, head of the WHO's regional office for the Western Pacific. Such studies would confirm whether the virus has mutated into a new strain, and might guide the production of an effective vaccine.

The recent outbreaks show that the virus continues to circulate and that new cases could flare up in future, says Joseph Domenech, chief of the Animal Health Service at the UN Food and Agriculture Organization. "Eradication of the avian flu virus should be considered, at best, a long-term task," he says.

Strong hold

A study published in the Proceedings of the National Academy of Sciences1 says that the virus is becoming more of a threat to human health. And one in Nature2 suggests that it is gaining a stronger foothold among birds in Asia. Over the last six years, the disease has claimed just 23 human lives, although the fear is that a new, more virulent strain could emerge.

"There is no need for public anxiety, but it is vital that the countries affected share what they know with the international community," says Omi.

The affected Asian countries have responded promptly to the recent outbreaks. In China, more than 8,000 birds died or were slaughtered, including all chickens within a three-kilometre radius of the cases. Live poultry trade was suspended in all nearby animal markets.

And as scientists wait to see if the outbreaks have been successfully contained, human trials of a bird-flu vaccine are expected to begin. The biotechnology firms Aventis Pasteur, which has its headquarters in Lyon, France, and California-based Chiron have developed candidate vaccines. These are based on a strain known as H5N1, which was taken from a Vietnamese patient in February 2004.

提防禽流感再度來襲

提防禽流感再度來襲

研究發現在亞洲引起數起恐慌的禽流感病毒在過去幾年內,一直和其他病毒進行基因交換,演化得對人更具威脅力。而且研究也預測禽流感在秋冬季再度來襲的機會很高。

H5N1病毒1997年在香港首度登場就幹掉了大批家禽,還殺死了六個人,逼迫衛生官員下令大量撲殺家禽。香港大學的病毒學家管軼等人自2000年在香港和中國南方的家禽中取樣,以監測H5N1病毒的再度來襲。研究顯示這個病毒起源自野鵝身上的良性病毒。可是當這種病毒到了雞鴨身上,一個輕微的改變就讓它們變得殺傷力極強。

管軼等人分析了各年份來自中國和香港的雞鴨身上的H5N1病毒,並且和來自印尼、泰國和越南在2003~04年疫情中的病毒相比。他們同時也分析了一些被禽流感幹掉的野鳥樣本。結果發現不同年份的H5N1病毒都有HA和NA這兩個來自野鵝病毒的基因,它們還有六個基因來自流感病毒。他們還發現有一株病毒在2002年前是未曾出現的,他們稱之為「基因型Z」,這株病毒之後還成了主流。而中國南方的家鴨似乎是這株病毒起源的溫床。

他們懷疑基因型Z病毒可能能夠在鳥類身上活得更愉快,所以很快地就在東亞的家禽中流行開來。他們也發現來自東南亞的基因型Z病毒,帶有一個特別突變在M2蛋白質上,造成對藥物的抗性。這個突變在其他諸如基因型B、Y和Z+病毒也可見。M2抗性在不同株病毒都可發現,顯然是病毒在感染的動物身上交換基因的結果。事實上人類的感冒病毒H3N2就在中國南方的豬身上發現過,如果H5N1帶原的豬也同時感染了H3N2,則它們就可以快樂地交換基因,而變得對人類更具威脅。

禽流感雖然在過去的六年內,只讓23人死亡,可是殺傷力更強的病毒可能會隨時出現。管軼相信這個病毒是極度危險的,它們的變化之快,可以再度成為全球性流行的死亡疾病。過去兩週內,就有幾起疫情傳出,至少有一起在中國、兩起在泰國、三起在越南。成千上萬隻雞鴨被撲殺以阻止疫情蔓延,所幸無人感染。世界衛生組織(WHO)警告亞洲國家要開始監控疫情。不過如果衛生官員能夠及時發出警訊和採取行動,其實並沒有必要引起恐慌。

原學術論文:Li K. S. et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature, 430, 209 - 213 doi:10.1038/nature02746 (2004).

Tuesday, July 20, 2004

Immune systems evolved more than once

Immune systems evolved more than once
 
Laura Nelson

Primitive fish have advanced protective mechanism.
 
When discussing the attributes that make mammals special, a sophisticated immune response generally comes close to the top of the list. But now it seems that we're not so unique after all.
Researchers have found that fish-like creatures called lampreys have evolved their own system, using building blocks that are completely unrelated to the antibodies found in mammals. The discovery opens up a new world for immunologists, who had previously assumed there was only one way of doing things – ours.

"The result blew my mind," says Chris Amemiya, molecular geneticist at the Benaroya Research Institute in Seattle, and an author of the study. "Now we know there are at least two ways of making the adaptive immune system."
Shifting sequences

There are two types of immune response, innate and adaptive. Both spot and destroy pathogens such as viruses, bacteria and fungi. Innate immunity is inherited, and does not change over an animal's lifetime.

In contrast the adaptive system changes according to the antigens an animal encounters. Specialized genetic sequences shuffle together to generate an almost infinite variety of defence cells, which attack antigens using proteins called antibodies.

A particular antigen triggers the genetic sequence that recognises it to begin copying itself, producing antibodies to fight that antigen.

Scientists believe that the adaptive immune system evolved at around the same time as animals developed jaws, about 400 million years ago. They hoped to find signs of a primitive system in the lamprey. It doesn't have a jaw, but it does show some of the characteristics of an adaptive immune system, such as rejecting skin grafts.

But there was no hint that lampreys made antibodies.

Amemiya's group wondered whether the lamprey might be attacking foreign molecules in some other way. To test the idea, the team injected lamprey larvae with a cocktail of antigen molecules, then compared the genetic sequences of the inoculated animals with untouched ones.
They found that animals exposed to the pathogens produced 13 times more copies of a genetic sequence that generates a pathogen-binding protein that is unrelated to an antibody. "The lamprey has gone for a different basic building block to construct mechanisms to recognize antigens," says Hugh Reyburn, an immunologist at the University of Cambridge, UK. 
 

脊椎動物另類的免疫--八目鰻的適應性免疫

脊椎動物另類的免疫--八目鰻的適應性免疫
 
  一般認為只有高等脊椎動物擁有複雜的適應性免疫系統,可是現在在低等脊椎動物八目鰻的身上也發現了一種前所未知的適應性免疫反應。

  海生八目鰻(Petromyzon marinus)是四億年前直接從原始的脊椎動物演化而來的。牠們是一種活化石,讓我們能瞧見顎和對鰭在演化出來之前,脊椎動物可能長成怎麼個模樣。免疫有兩種,另別為先天免疫(innate immunity)和適應性免疫(adaptive immunity),前者終生不變,後者則會製造出變換無窮的抗體。科學家一般上相信適應性免疫是和顎差不多同時候演化出的,就在約四億年前。因此科學家希望在八目鰻身上瞭解原始的免疫系統。然而六○和七○年代的研究顯示八目鰻有一定程度的適應性免疫,例如牠們對皮膚的移植會排斥。可是八目鰻免疫系統的兵員顯然不是抗體和T細胞,這意味著八目鰻有完全不同於我們的適應性免疫,可是箇中奧妙是迄今仍是個謎。

  為了瞭解八目鰻的免疫系統,美國阿拉巴馬大學的免疫學家Zeev Pancer等人把一個包含大腸桿菌(Escherichia coli)、細菌、線羊紅血球細胞等作成的雞尾酒注射入八目鰻幼體體內。大部分脊椎動物的淋巴球細胞會讓這些抗原給活化,並且協調適應性免疫反應,派出抗體和T細胞來摧毀這個外來入侵物。可是八目鰻的淋色球細胞並不從事協調工作,反而直接去對付這些抗原。八目鰻的淋色球細胞的一個細胞膜表面的多變淋巴球受器取代了抗體來對抗原雞尾酒起反應。這個受器有個高度多變的中段區域,可以重組以針對特定的抗原起免疫反應。
 
  參與研究的Benaroya研究所的分子遺傳學家Chris Amemiya指出,如此一來已知的適應性免疫就有兩種。佛羅里達聖彼得堡All兒童醫院的遺傳學家Gary Litman指出,這個發現對瞭解脊椎動物的免疫系統演化是非常重要的。加拿大多倫多Sunnybrook and Women's學院衛生科學中心的細胞生物學家Jonathan Rast認為,類似的免疫反應搞不好也可以在其他脊椎動物身上找到,甚至還可能是個廣泛存在的免疫反應。

原學術論文:Pancer Z. et al. Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature, 430, 174 - 180, (2004). Article

X-ray evidence points to Japanese cult

X-ray evidence points to Japanese cult
David Cyranoski
 
Forensic work leads to new arrests in 1995 shooting case.   
 
Tokyo - Japanese police arrested three people on Wednesday in connection with the 1995 shooting of the country's top police official. The police identified the suspects using the massive SPring-8 synchrotron, a powerful X-ray beam that can reveal the chemical makeup of tiny samples.

The three are all former members of the Aum Shinrikyo cult, which on 20 March 1995 released sarin nerve gas on the Tokyo subway, killing 12 people. Ten days later Takaji Kunimatsu, then head of the National Police Agency and leader of the investigation into the attack, was shot and critically injured.
 
The key new evidence is reported to have come from analysis of metal traces found on one suspect's clothing. Impurities in this metal are believed to match those in the gun used to shoot Kunimatsu. The police have refused to make any statements, and the name of the scientist leading the new investigation is being withheld to protect his or her safety.

The police wouldn't have a case without SPring-8, says Akito Kakizaki, a physicist at the University of Tokyo. SPring-8, the world's most powerful synchrotron, can analyze samples weighing only trillionths of a gram - which, in criminal evidence, is often all that is available.
This is not SPring-8's first contribution to forensic science. In December 1998, evidence from the synchroton helped convict a woman suspected of killing four people at a festival by putting arsenic in a curry.

Ten milligrams of arsenic found at the suspect's home matched the chemical added to the curry. The synchrotron revealed matching bismuth and antimony impurities in the two samples.
"Conventional methods of analysis would need much more [arsenic]," says the scientist behind that analysis, Izumi Nakai, an analytic chemist at Tokyo University of Science and a member of the American Academy of Forensic Sciences, who is not involved in the current investigation. He thinks the police will use the method more in the future.

Also, synchrotron radiation leaves the sample intact. "We can repeat the experiment many times," says Nakai. "This is extremely important for investigating crimes."
Nakai became involved in the poisoning case through his study of arsenic in hair samples. He is now pushing for synchrotrons to become a staple of forensic science. For example, SPring-8 could identify the glass left behind at a hit-and-run accident or the source of confiscated marijuana, he says.

So far his efforts to get a dedicated synchrotron for forensic science have failed, but he is hopeful. "All countries will begin to use synchrotron energy for forensics," he says.
Only two other synchrotrons could handle samples as small as those in the shooting case: the US Advanced Photon Source at Argonne National Laboratory, Illinois, and the European Synchrotron Radiation Facility in Grenoble France. "With a machine any less powerful it would be difficult," says Kakizaki.

以同步輻射(synchrotron radiation)調查槍擊案!

以同步輻射(synchrotron radiation)調查槍擊案!
 
  同步輻射(synchrotron radiation)的一般應用是在醫學、生命科學、凝態物理、環保、生命科學、材料及冶金科學、及微機械技術研發等,此外可分析射擊殘跡(gunshot residue, GSR)來協助槍擊案調查。

  日本警方近日藉由同步輻射的分析結果,逮捕了三名因涉嫌在1995年暗殺當時的警察廳長官國松孝次(Takaji Kunimatsu)的前奧姆真理教﹙現改名為阿萊夫教﹚的信徒。該名官員所幸最後逃過一劫。

  1995年3月20日,奧姆真理教在東京發動了造成12人死亡,5500多人受傷,14人終身殘疾之駭人聽聞的地鐵沙林毒氣恐怖攻擊。時任日本警察廳長官的國松孝次正是對奧姆真理教調查的主要負責人。

  能逮捕涉案嫌犯的關鍵證據是因為射擊國松孝次槍枝之射擊殘跡的金屬雜質與其中一名嫌犯衣服上採集到的殘跡相吻合。常見的殘餘金屬雜質為鉛(Pb)、鋇(Ba)、及銻(Sb)。這項結論是由可偵測約兆分之一克金屬(part per trillion, ppt)的同步輻射分析所獲得。為了避免報復行動,日本警方拒絕透露分析人員的身份。

  同步輻射(synchrotron radiation):近光速行進的帶電粒子,受到磁場作用而偏轉時,會沿著行進的切線方向發出輻射,即稱之。這種輻射脈波的強度與偏振程度很高,而且為連續光譜。此連續波段電磁波(一般而言所有的電磁波都可稱為光),涵蓋紅外線、可見光、紫外線及X 光,因此可應用於各領域需求。此分析所使用的日本高輝度光科學研究所的SPring-8是現今全球能量最高的同步輻射光源,高達80億電子伏特,可以產生硬X射線光束(台灣擁有的第三代同步輻射為13億電子伏特,但台灣在Spring-8有專屬光束線)。
 
  金屬雜質為特異性較高的射擊殘跡,對嫌犯以及槍枝的連結,頗有助益。常用的GSR 分析有:極譜分析(Polaragraphy)、X光螢光分析(X-ray Fluorescence)、原子吸收光譜分析(Atomic Absorption Spectroscopy)、中子活化光譜分析(Neutron Activation Analysis, NAA)、誘導式耦合電漿原子放射光譜分析(Induced Couple Plasma-Atomic Emission Spectroscopy, ICP-AES)、放射光譜分析(Photoluminescence)、掃瞄式電子顯微鏡X光能譜分析(Scanning Electron Micriscope-Energy Disversive X-rays. SEM-EDX)以及X光繞射分析(X-rays Diffraction)。

  目前只有美國能源部在伊利諾州( Illinois)阿爾貢國家實驗室的先進光子源(US Advanced Photon Source at Argonne National Laboratory)以及在法國格勒諾布爾(Grenoble)的歐洲同步輻射裝置(European Synchrotron Radiation Facility,ESRF),能夠偵測到如此微量的金屬雜質。

  同步輻射屬於非破壞性分析(non-destructive analysis)因此對於寶貴的刑案證物分析上,更具有保存證物的極大優點,可更廣泛應用於各種微物跡證分析。例如協助頗受國人關切的319槍擊案的調查。

Monday, July 19, 2004

US team breaks power density record

US team breaks power density record
5 July 2004

Scientists from the Center for Ultrafast Optical Sciences at the University of Michigan in the US, claim to have generated a laser spot with a power density of 0.85x1022 watts per centimetre squared -- the highest intensity ever recorded. The intense focal spot, which measures 0.8 microns across, was made by optimizing the focusing of pulses from the Center's HERCULES laser system.

HERCULES is a custom-made titanium:sapphire laser that uses chirped pulse amplification (CPA) to generate ultrashort pulses with a power of 45 terawatts (27 femtosecond pulses containing 1.2 joules of energy). The Michigan team used adaptive optics, a well known technique for correcting wave-front distortion, to focus their pulses to the smallest spot possible. Pulses from HERCULES were reflected off a deformable mirror before being focused down by a paraboloid mirror.

The shape of the deformable mirror was adjusted to correct for any distortions in the beam and optimize the focusing. Using the technique the team managed to generate focused intensities of between 0.66 and 0.85x1022 watts per centimetre squared.

"It is the laser wave-front fluctuations that will ultimately limit the focused intensity and its spatial resolution," the team told delegates at the post-deadline session of CLEO 2004 in San Francisco in May. "In our case, HERCULES is remarkably stable. The shot-to-shot fluctuation of wave-front has an rms (root mean square) deviation from its average shape of about 1/20."

Gerard Mourou, the Center's director, invented CPA in the late 1980s as a way to amplify pulses to much higher powers. The technique involves stretching an ultrashort pulse to several nanoseconds so that it can amplified without its peak power damaging the gain medium. After amplification the pulse is recompressed to give a very powerful ultrashort pulse.

Author
Oliver Graydon is Editor of Optics.org and Opto & Laser Europe magazine
 

雷射光束﹕越小越有力

雷射光束﹕越小越有力
 
  美國密西根大學超快光學中心的科學家們﹐利用該中心的高能雷射系統(HERCULES (註): High Energy Repetitive CUos LasEr System)﹐製造出功率密度達8.5x1021 watts/cm2的雷射光束﹐宣稱是至今最高的記錄。

  HERCULES雷射是該中心的科學家們自製的一套鈦: 藍寶石雷射系統, 透過chirped pulse amplification (CPA) 的技術﹐可以產生達45 terawatts (1 tera = 1012)的超短脈衝(在為時27 femtosecond的脈衝裡包含了1.2焦耳的能量)。他們是運用調適光學(adaptive optics) 的原理﹐將HERCULES射出的脈衝則先是經由一可變形的鏡子反射﹐來解決波前扭曲的問題﹐再將其通過一拋物面鏡進行聚焦中﹐以達成將雷射脈衝聚焦到最小尺寸的目的。藉著改變反射鏡的形狀﹐可以用來修正雷射光束中所有的扭曲﹐以使聚焦達到最佳化。而密西根大學的研究小組﹐利用這樣的技術﹐可以使所聚焦的雷射光達到6.6-8.5x1021 watts/cm2的功率密度。
 
  根據研究小組在今年五月份在舊金山所舉行的的CLEO會議所發表的聲明﹐他們認為最終限制聚焦功率以及其空間的解像度的因素﹐就在於雷射光波前的變動。而他們所使用的雷射光源-HERCULES ﹐比較上來說十分地穩定: 其相鄰脈衝之間的波前﹐與平均波形的差別(rms ﹐根均方值)僅有1/20。
 
  此外值得一提的是﹐在這項實驗中所運用的CPA技術﹐乃是由該中心的主任Gerard Mourou在1980年代末期所發明的。這項技術的特點在於將一個超短脈衝在域上延長成數奈秒長進行放大﹐然後再將其壓縮回原來的大小以得到功率密度增加的超短脈衝。

  由於許多需要在高電磁場中進行的實驗(如粒子加速﹑短脈衝x-ray ﹑fast ignition fusion等)﹐都仰賴於高功率密度的(雷射)光源﹐這項實驗的成就﹐可望為從事相關領域的研究人員﹐提供一項有利的工具。

<註>"Hercules"是希臘神話中著名的大力士﹐用來為一高能雷射系統命名﹐可謂名符其實。

Saturday, July 17, 2004

Quantum well energizes nanocrystals

Quantum well energizes nanocrystals
7 July 2004

Semiconductor nanocrystals (or quantum dots) are attractive for use in a number of light-emitting technologies. But there's a snag: it's hard to pump nanocrystals electrically because of their insulating organic capping layers. Now scientists at Los Alamos National Laboratory and Sandia National Laboratories, both in the US, have transferred energy to nanocrystals from epitaxial quantum wells without the need for electrical contacts.
 
 
The non-radiative energy transfer process indirectly injects electron-hole pairs into the nanocrystals. These later recombine, emitting light as a result.
"The high efficiency of energy transfer in combination with the exceptional luminescent properties of nanocrystal quantum dots make hybrid quantum-well/nanocrystal devices feasible as efficient sources of any colour light - or even white light," said Victor Klimov of Los Alamos.
In this study the scientists chose to impart energy to the quantum well by optical pumping so that they could obtain additional information about how that energy then transferred to the nanocrystals. In real-life, however, they say they could also pump the quantum well electrically, in the same way that a common quantum-well light-emitting diode is pumped.
The researchers used a 3 nm InGaN quantum well underneath a monolayer of CdSe/ZnS core/shell nanocrystals. The nanocrystals, which had a core radius of 1.9 nm and a shell thickness of around 0.6 nm, were capped with organic molecules.
Klimov and colleagues pumped the quantum well by shining laser light with a wavelength of 266 nm on the device. The well transferred its energy to the nanocrystals with an efficiency of around 55%. And, according to the researchers, the nanocrystal capping layer did not significantly inhibit the process.
"The transfer of energy is fast enough to compete with exciton [bound electron/hole pair] recombination in the quantum well, and that allows us to 'move' more than 50% of the excitons to adjacent quantum dots," said Klimov. "The recombination of these transferred excitons leads to the emission of light with colour that can be controlled by quantum-dot size."
What's more, the researchers believe they may be able to achieve efficiencies of nearly 100% by improving the quality of the quantum wells to reduce non-radiative losses, and by optimizing the geometry of the nanocrystal/quantum-well structure.
The scientists, who reported their work in Nature, say that the technique could also find a use in nanocrystal-based optical amplifiers and lasers.
About the author
Liz Kalaugher is editor of nanotechweb.org.