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比克爾語翻譯

最後，此些撰文者們面對了，有關在類似酵母菌的模子生物中，產生大量個體基因及卵白質數據集之任何研究的兩項重大挑戰：若何將此些數據組合成調和的圖？及如何整合此事例中，從酵母菌到人類的跨物種資訊？

Remarkably翻譯社 the maps derived from these two processes were closely related and converged on the same Parkinson’s genes and cellular processes. Whether in a yeast cell or in a neuron翻譯社 alpha synuclein directly interfered with the rate of production of proteins in the cell翻譯社 and the transport of proteins between cellular compartments.

帕金森氏症(PD)及其他“突觸核卵白病”已知，與神經元中的α突觸核卵白毛病折疊有關翻譯透過人類遺傳學的分析，較不清楚的是，此錯誤摺疊若何觸及帕金森氏症中，增多遭牽連的基因數量翻譯

“In the second paper, we created a spatial map of alpha-synuclein, cataloging all the proteins in living neurons that were in close proximity to the protein,” explained Chee Yeun Chung, former Whitehead Institute Senior Research Scientist, who co-led both studies with Khurana.

“Among them were multiple genes known to predispose individuals to Parkinson’s—so we show that various genetic forms of Parkinson’s are directly related to alpha-synuclein. Moreover, the results showed that many effects of alpha-synuclein have been conserved across a billion years of evolution from yeast to human,” said Khurana, former Visiting Scientist at the Whitehead Institute.

目前是美國麻薩諸塞州劍橋市Yumanity Therapeutics生物手藝公司的科學配合開創人兼副總監的Chung強調：「了局，他們首度能在完全腦細胞的心理狀態下，以極微小標准視覺化該卵白質的位置。」

此闡發產生了，正確顯示出α突觸核卵白如何透過明確份子路子，而與其他帕金森氏症的基因有關。Khurana宣稱：「今朝，他們擁探討看似不相幹基因，若何一路激發帕金森氏症及此些基因若何與該疾病中，錯誤摺疊卵白質有關聯的方式。」

To start, they created two ways to systematically map the footprint of alpha-synuclein within living cells. “In the first paper翻譯社 we used powerful and unbiased genetic tools in the simple Baker’s yeast cell to identify 332 genes that impact the toxicity of alpha-synuclein,” explained Vikram Khurana, first and co-corresponding author on the studies.

懷特海德生物醫學研究所前客座科學家，Khurana傳播鼓吹：「其中多個是已知，使個別易得帕金森氏症的基因，是以他們證實，帕金森氏症的各類遺傳情勢，直接與α突觸核蛋白有關。另外，這些研究成績證實了，α突觸核蛋白的諸多感化，在經歷十億年的演化中，從酵母菌到人類一向是守恆的翻譯」

起頭，他們設計了兩種有系統繪製活細胞內α突觸核卵白足跡圖的方式翻譯這兩篇研究的重要暨配合通信撰文人，Vikram Khurana解釋：「第一篇論文中，在麵包酵母細胞樣本中，他們使用了強有力且中庸之道的遺傳東西，來確認332個影響α突觸核蛋白毒性的基因。」

今朝是美國麻薩諸塞州波士頓市布里根婦女病院Ann Romney精神病學疾病中間，及哈佛大學醫學院幹細胞研究所首要查詢拜訪研究員的Khurana宣稱：「這證實了，毛病摺疊的卵白質毒性機理，與其直接交互感化的卵白質有親切聯系關系，並且此些交互感化能诠釋，帕金森氏症分歧遺傳風險因子間的聯系關系性。」

In two studies published in the advance online edition of Cell Systems翻譯社 researchers affiliated with Whitehead Institute and Massachusetts Institute of Technology (MIT) explain how they used a suite of novel biological and computational methods to shed light on the question. 

Parkinson’s disease (PD) and other “synucleinopathies” are known to be linked to the misfolding of alpha-synuclein protein in neurons. Less clear is how this misfolding relates to the growing number of genes implicated in PD through analysis of human genetics.

Finally翻譯社 the authors addressed two major challenges for any study that generates large data-sets of individual genes and proteins in model organisms like yeast: How to assemble the data into coherent maps? And how to integrate information across species翻譯社 in this case from yeast to human?

為了證實他們的研究，此些研究人員從具有分歧帕金森氏症遺傳形式的患者產生了神經元翻譯他們證實，從其闡發圖產生的份子圖，使他們得以確認此些不同情勢帕金森氏症中，共有的異常。

引人注視的是，這些源自上述兩種方式的圖是親切相幹的，且集中於不異帕金森氏症的基因及細胞轉變進程翻譯豈論於酵母細胞或神經元中，α突觸核卵白皆直接干擾此細胞諸蛋白質的產生速度，及細胞分室間的卵白質輸送。

原文網址：http://wi.mit.edu/news/archive/2017/new-clues-basis-parkinson-s-disease-and-other-synucleinopathies

The mapping was achieved without disturbing the native environment of the neuron, by tagging alpha-synuclein with an enzyme—APEX—that allowed proteins less than 10 nanometers away from synuclein to be marked with a trackable fingerprint.

與Khurana配合向導這兩項研究的懷特海德生物醫學研究所，前資深研究科學家Chee Yeun Chung注釋：「在第二篇論文中，他們設計了α突觸核卵白的空間圖，來將活神經元中非常接近該卵白的所有卵白質編入目錄中。」

“As a result, for the first time, we were able to visualize the protein’s location, at minute scale, under physiologic conditions in an intact brain cell,” noted Chung, who is now Scientific Co-founder and Associate Director at Yumanity Therapeutics in Cambridge. 

This analysis produced networks that mapped out how alpha-synuclein is related to other Parkinson’s genes through well-defined molecular pathways. “We now have a system to look at how seemingly unrelated genes come together to cause Parkinson’s and how they are related to the protein that misfolds in this disease,” said Khurana.

懷特海德生物醫學研究所前客座科學家，及麻省理工學院博士後研究員的計較生物學家，今朝是美國伊利諾大學厄巴納-香檳分校計算機科學助理教授，Jian Peng诠釋：「首先，他們必需想出更好的方法，來找出酵母基因的人類對應物，然後必須以成心義的方式，來整理具有人類屬性的基因組。」

藉由使用一種，使距離突觸核卵白不及10奈米的卵白質得以，使用可追蹤酶解圖譜被標志的酵素(APEX)，來標記α突觸核卵白。上述圖的繪製，是在沒有侵擾神經元天然情況下告竣的。

在揭曉於先行網路版《細胞系統》期刊的兩篇研究中，隸屬美國麻省理工學院及懷特海德生物醫學研究所的研究人員們解釋了，他們如何利用一套新的生物暨計較方式，來說明上述問題翻譯

「結果是轉置網(TransposeNet：一套按照從酵母到人類是高度守恆的基因，使用進修演算法的機械來視覺化模式及互動收集，然後作出展望有關，屬人類α突觸核蛋白毒性反映一部門之額外基因的新較量爭論工具。」

翻譯：許東榮

To confirm their work翻譯社 the researchers generated neurons from Parkinson’s patients with different genetic forms of the disease. They showed that the molecular maps generated from their analyses allowed them to identify abnormalities shared among these distinct forms of Parkinson’s.

“It turns out the mechanisms of toxicity of the misfolded protein are closely related to which proteins it directly interacts with, and that these interactions can explain connections between different Parkinson’s genetic risk factors翻譯社” said Khurana翻譯社 now a Principal Investigator within the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital and the Harvard Stem Cell Institute.

Prior to this翻譯社 there was no obvious molecular connection between the genes implicated in these varieties of PD. "We believe these methods could pave the way for developing patient-specific treatments in the future,” Khurana observed.

Enter computational biologist Jian Peng翻譯社 former Visiting Scientist at Whitehead Institute and postdoctoral researcher at MIT. “First, we had to figure out much better methods to find human counterparts of yeast genes, and then we had to arrange the humanized set of genes in a meaningful way,” explained Peng, now Assistant Professor of Computer Sciences at University of Illinois, Urbana-Champaign.

在此之前，在觸及上述各種帕金森氏症的基因間，沒有明明份子關聯性。” Khurana默示：「他們認為，上述方式可能為未來研發特定病患的療法鋪路。」

“The result was TransposeNet, a new suite of computational tools that uses machine learning algorithms to visualize patterns and interaction networks based on genes that are highly conserved from yeast to humans—and then makes predictions about the additional genes that are part of the alpha-synuclein toxicity response in humans.”