insight cdc
下面，我将用我自己的方式来解释insight cdc的问题，希望我的回答能够对大家有所帮助。让我们开始讨论一下insight cdc的话题。
1.英美文学名词解释()
2.暗黑破坏神用符文组成最实用的装备是什么？要哪些符文？
3.求一首英文歌曲的名字
4.什么是内质网相关降解（ERAD）？国自然开始了，研究一下！
英美文学名词解释()
situation. The use of this technique gave the story a circular form wherein one event was the center, with various points of view radiating from it. The multiple points of view technique makes the reader recognize the difficulty of arriving at a true judgment.
95. Myth: A story, often about immortals and sometimes connected with religious rituals, that is intended to give meaning to the mysteries of the world. Myths make it possible for people to understand and deal with things that they cannot control and often cannot see. A body of related myths that is accepted by a people is known as its mythology. A mythology tells a people what it is most concerned about.
96. Narration: Like description, narration is a part of conversation and writing. Narration is the major technique used in expository writing. Such as autobiography. Successful narration must grow out of good observation, to-the-point selection from observation, and clear arrangement of details in logical sequence, which is usually chronological. Narration gives an exact picture of things as they occur.
97. Narrative poem: A poem that tells a story. One kind of narrative poem is the epic, a long poem that sets forth the heroic ideals of a particular society.
98. Narrator: One who narrates, or tells, a story. A story may be told by a first-person narrator, someone who is either a major or minor character in the story. Or a story may be told by a third-person narrator, someone who is not in the story at all. The word narrator can also refer to a character in a drama who guides the audience through the play, often commenting on the action and sometimes participating in it.
99. Naturalism: An extreme form of realism. Naturalistic writers usually depict the sordid side of life and show characters who are severely, if not hopelessly, limited by their environment or heredity.
100. Neoclassicism: A revival in the 17th agogo of order, balance, and harmony in literature.
101. Nonet: the nine-line stanza. Spenserian stanza: ababbcbcc.
102. Nonfiction: It refers to any prose narrative that tells about things as the actually happened or that presents factual information about something. The purpose of this kind of writing is to give a presumably accurate accounting of a person’s life. Writers of nonfiction use the major forms of discourse: description (an impression of the subject); narration (the telling of the story); exposition (explanatory information); persuasion (an argument to influence people’s thinking). Forms: autobiography, biography, essay, story, editorial, letters to the editor found in newspaper, diary, journal, travel literature.
103. Novel: A book-length fictional prose narrative, having may characters and often a complex plot.
104. Octava: the eight-line stanza. 2 quatrains/ 2 triplets + 1 couplet.
105. Ode: A complex and often lengthy lyric poem, written in a dignified formal style on some lofty or serious subject. Odes are often written for a special occasion, to honor a person or a season or to commemorate an event.
106. Onomatopoeia: The use of a word whose sound in some degree imitates or suggests its meaning.
107. Oxymoron: a figure of speech that combines opposite or contradictory ideas or terms. An oxymoron suggests a paradox, but it does so very briefly, usually in two or three words.
108. Paradox: A statement that reveals a kind of truth, although it seems at first to be self-contradictory and untrue.
109. Parallelism: (a figure of speech) The use of phrases, clauses, or sentences that are similar or complementary in structure or in meaning. Parallelism is a form of repetition.
110. Parody: The humorous imitation of a work of literature, art, or music. A parody often achieves its humorous effect through the use of exaggeration or mockery. In literature, parody can be make of a plot, a character, a writing style, or a sentiment or theme.
111. Pastoral: A type of poem that deals in an idealized way with shepherds and rustic life.
112. Pathos: The quality in a work of literature or art that arouses the reader’s feelings of pity, sorrow, or compassion for a character. The term is usually used to refer to situations in which innocent characters suffer through no fault of their own.
113. Persuasion: It’s the type of speaking or writing that is intended to make its audience adopt a certain opinion or perform an action or do both. Persuasion is one of the major forms of discourse.
114. Pictorialism: It’s an important poetic device characterized by efforts to achieve striking visual effects. Among its features are irregularity of line, contrast or enchantment of light, color and image. Other means of pictorialism include personification, juxtaposition and the matching of colors with verbs of action.
115. Plot: Plot is the first and most obvious quality of a story. It is the sequence of events or actions in a short story, novel, play, or narrative poem. For the reader, the plot is the underlying pattern in a work of fiction, the structural element that gives it unity and order. For the writer, the plot is the guiding principle of selection and arrangement. Conflict, a struggle of some kind, is the most important element of plot. Each event in the plot is related to the conflict, the struggle that the main character undergoes. Conflict may be external or internal, and there may be more than one form of conflict in a work. As the plot advances, we learn how the conflict is resolved. Action is generally introduced by the exposition, information essential to understanding the situation. The action rises to a crisis, or climax. This movement is called the rising action. The falling action, which follows the crisis, shows a reversal of fortune for the protagonist. The denouement or resolution is the moment when the conflict ends and the outcome of the action is clear.
116. Poetry: The most distinctive characteristic of poetry is form and music. Poetry is concerned with not only what is said but how it is said. Poetry evokes emotions rather than express facts. Poetry means having a poetic experience. Imagination is also an essential quality of poetry. Poetry often leads us to new perceptions, new feelings and experiences of which we have not previously been aware.
117. Point of view: The vantage point from which a narrative is told. There are two basic points of view: first-person and third-person. In the first-person point of view, the story is told by one of the characters in his or her own words. The first-person point of view is limited. In the third-person point of view, the narrator is not a character in the story. The narrator may be an omniscient. On the other hand, the third-person narrator might tell a story from the point of view of only one character in the story.
118. Pre-Romanticism: It originated among the conservative groups of men and letters as a reaction against Enlightenment and found its most manifest expression in the “Gothic novel”. The term arising from the fact that the greater part of such romances were devoted to the medieval times.
119. Protagonist: The central character of a drama, novel, short story, or narrative poem. The protagonist is the character on whom the action centers and with whom the reader sympathizes most. Usually the protagonist strives against an opposing force, or antagonist , to accomplish something.
120. Psalm: A song or lyric poem in praise of God.
121. Psychological Realism: It is the realistic writing that probes deeply into the complexities of characters’ thoughts and motivations. Henry James is considered the founder of psychological realism. His novel The Ambassadors is considered to be a masterpiece of psychological realism.
122. Pun: The use of a word or phrase to suggest tow or more meaning at the same time. Puns are generally humorous.
123. Quatrain: Usually a stanza or poem of four lines. A quatrain may also be any group of four lines unified by a rhyme scheme. Quatrains usually follow an abab, abba, or abcb rhyme scheme.
124. Quintain: the five-line stanza.
125. Realism: The attempt in literature and art to represent life as it really is, without sentimentalizing or idealizing it. Realistic writing often depicts the everyday life and speech of ordinary people. This has led, sometimes, to an emphasis on sordid details.
126. Refrain: 叠句: A word phrase, line or group of lines repeated regularly in a poem, usually at the end of each stanza. Refrains are often used in ballads and narrative poems to create a songlike rhythm and to help build suspense. Refrains can also serve to emphasize a particular idea.
127. Renaissance: The term originally indicated a revival of classical (Greek and Roman) arts and sciences after the dark ages of medieval obscurantism.
128. Rhyme: It’s one of the three basic elements of traditional poetry. It is the repetition of sounds in two or more words or phrases that appear close to each other in a poem. If the rhyme occurs at the ends of lines, it is called end rhyme. If the rhyme occurs within a line, it is called internal rhyme. Approximate rhyme is rhyme in which only the final consonant sounds of the words are identical. A rhyme scheme is the pattern of rhymes in a poem. Interlocking rhyme is a rhyme scheme in which an unrhymed line in one stanza rhymes with a line in the following stanza. Interlocking rhyme occurs in an Italian verse form called terza rima.
129. Rhythm: It is one of the three basic elements of traditional poetry. It is the arrangement of stressed and unstressed syllables into a pattern. Rhythm often gives a poem a distinct musical quality. Poets also use rhythm to echo meaning.
130. Romance: Any imagination literature that is set in an idealized world and that deals with a heroic adventures and battles between good characters and villains or monsters.
131. Romanticism: A movement that flourished in literature, philosophy, music, and art in Western culture during most of the 19th century, beginnigogom.
132. Satire: A kind of writing that holds up to ridicule or contempt the weaknesses and wrongdoings of individuals, groups, institutions, or humanity in general. The aim of satirists is to set a moral standard for society, and they attempt to persuade the reader to see their point of view through the force of laughter.
133. Scansion诗的韵律分析: The analysis of verse in terms of meter.
134. Sentimentalism: Sentimentalism came into being as a result of a bitter discontent on the part of certain enlighteners in social reality.
135. Septet: the seven-line stanza. Chaucerian stanza: ababbcc.
136. Sestet: the six-line stanza. 3couplets/ a quatrain + a couplet/ 2 triplets.
137. Setting: The time and place in which the events in a short story, novel, play or narrative poem occur. Setting can give us information, vital to plot and theme. Often, setting and character will reveal each other.
138. Short Story: A short story is a brief prose fiction, usually one that can be read in a single sitting. It generally contains the six major elements of fiction—characterization, setting, theme, plot, point of view, and style.
139. Simile: (a figure of speech) A comparison make between two things through the use of a specific word of comparison, such as like, as than, or resembles. The comparison must be between two essentially unlike things.
140. Skaz: It’s a Russian word used to designate a type of first person narration that has the characteristics of the spoken rather than the written word. In this kind of novel, the narrator is a character who refers to himself as “I” and addresses the reader as “you”. He or she uses vocabulary and syntax characteristic of colloquial speech, and appears to be relating the story spontaneously rather than delivering a carefully constructed and polished written account.
141. Soliloquy: In drama, an extended speech delivered by a character alone onstage. The character reveals his or her innermost thoughts and feelings directly to the audience, as if thinking aloud.
142. Song: A short lyric poem with distinct musical qualities, normally written to be set to music. In expresses a simple but intense emotion.
143. Sonnet: A fourteen-line lyric poem, usually written in rhymed iambic pentameter. A sonnet generally expresses a single theme or idea.
144. Speech: It was defined by Aristotle as the faculty of observing all the available means of persuasion.
145. Spenserian stanza: A nine-line stanza with the following rhyme scheme: ababbabcc. The first eight lines are written in iambic pentameter. The ninth line is written in iambic hexameter and is called an alexandrine.
146. Spondee扬扬: It consists of two stressed syllables.
147. Sprung Rhythm: A term created by the poet Gerard Manley Hopkins to designate a variable kind of poetic meter in which a stressed syllable may be combined with any number of unstressed syllables. Poems with sprung rhythm have an irregular meter and are meant to sound like natural speech.
148. Stanza: It’s a structural division of a poem, consisting of a series of verse lines which usually comprise a recurring pattern of meter and thyme.
149. Stereotype: A commonplace type or character that appears so often in literature that his or her nature is immediately familiar to the reader. Stereotypes, also called stock characters, always look and act the same way and reveal the same traits of character.
150. Stream of consciousness: “Stream-of-Consciousness” or “interior monologue”, is one of the modern literary techniques. It is the style of writing that attempts to imitate the natural flow of a character’s thoughts, feelings, reflections, memories, and mental images as the character experiences them. It was first used in 1922 by the Irish novelist James Joyce. Those novels broke through the bounds of time and space, and depicted vividly and skillfully the unconscious activity of the mind fast changing and flowing incessantly, particularly the hesitant, misted, distracted and illusory psychology people had when they faced reality. The modern American writer William Faulkner successfully advanced this technique. In his stories, action and plots were less important than the reactions and inner musings of the narrators. Time sequences were often dislocated. The reader feels himself to be a participant in the stories, rather than an observer. A high degree of emotion can be achieved by this technique.
151. Style: An author’s characteristic way of writing, determined by the choice of words, the arrangement of words in sentences, and the relationship of the sentences to one another.
152. Suspense: The quality of a story, novel, or drama that makes the reader or audience uncertain or tense about the outcome of events.
153. Symbol: A symbol is a sign which suggests more than its literal meaning. In other words, a symbol is both literal and figurative. A symbol is a way of telling a story and a way of conveying meaning. The best symbols are those that are believable in the lives of the characters and also convincing as they convey a meaning beyond the literal level of the story. If the symbol is obscure or ambiguous, then the very obscurity and the ambiguity may also be part of the meaning of the story.
154. Symbolism: Symbolism is the writing technique of using symbols. It’s a literary movement that arose in France in the last half of the 19th century and that greatly influenced many English writers, particularly poets, of the 20th century. It enables poets to compress a very complex idea or set of ideas into one image or even one word. It’s one of the most powerful devices that poets employ in creation.
155. Synecdoche: A figure of speech that substitutes a part for a whole.
156. Terza rima: An Italian verse form consisting of a series of three-line stanzas in which the middle line of each stanza rhymes with the first and third lines of the following stanza.
157. Theme; The general idea or insight about life that a writer wishes to express in a literary work. All the elements of a literary work-plot, setting, characterization, and figurative language-contribute to the development of its theme.
158. Tone: The attitude a writer takes toward his or her subject, characters, or audience. The tone of a speech or a piece of writing can be formal or intimate; outspoken or reticent; abstruse or simple; solemn or playful; angry or loving; serious or ironic.
159. Tragedy: In general, a literary work in which the protagonist meets an unhappy or disastrous end. Unlike comedy, tragedy depicts the actions of a central character who is usually dignified or heroic.
160. Triplet: The three-line stanza. Tercet: aaa, bbb, ccc, and so on; terza rima: aba, bcb cdc, and so on.
161. Trochee扬抑格: the reverse of the iambic foot.
162. Villanelle维拉内拉诗: An intricate verse form of French origin, consisting of several three-line stanzas and a concluding four-line stanza.
163. Wit: A brilliance and quickness of perception combined with a cleverness of expression. In the 18th century, wit and nature were related-nature provided the rules of the universe; wit allowed these rules to be interpreted and expressed.
暗黑破坏神用符文组成最实用的装备是什么？要哪些符文？
1. Wang J, Liu J, Hu Y, Ying SH, Feng MG. Cytokinesis-required Cdc14 is a signaling hub of asexual development and multi-stress tolerance in Beauveria bassiana. Scientific Reports, submitted on 17 Jul 2013, revised on 28 Sep 2013.2. Wang CS, Feng MG. Advances in fundamental and applied studies in China of fungal biocontrol agents for use against arthropod pests.Biological Control, 2013, doi:10.1016/j.biocontrol.2013.06.017.
3. Ying SH, Feng MG, Keyhani NO. A carbon responsive G-protein coupled receptor modulates broad developmental and genetic networks in the entomopathogenic fungus, Beauveria bassiana. Environmental Microbiology, 2013, doi:10.1111/1462-2920.12169
4. Liu YJ, Liu J, Ying SH, Liu SS, Feng MG. A fungal insecticide engineered for fast per os kill of caterpillars has high field efficacy and safety in full-season control of cabbage insect pests. Applied and Environmental Microbiology, 2013, 79(20): 6452-6458.
5. Wang XX, Ji XP, Li JX, Keyhani NO, Feng MG, Ying SH. A putative α-glucoside transporter gene BbAGT1 contributed to carbohydrate utilization, growth, conidiation and virulence of filamentous entomopathogenic fungi Beauveria bassiana. Research in Microbioloty, 2013,164(5): 480-489.
6. Xia J, Zhang CR, Li FF, Zhang S, Feng MG, Wang XW, Liu SS. Analysis of whitefly transcriptional responses to Beauveria bassiana infection Reveals new insights into insect-fungus interactions. PLoS ONE, 2013. 8(7): e68185. doi:10.1371/journal.pone.0068185
7. Liu Q, Ying SH, Li JG, Tian CG, Feng MG. Insight into the transcriptional regulation of Msn2 required for conidiation, multi-stress responses and virulence of two entomopathogenic fungi. Fungal Genetics and Biology, 2013, 54(1): 42-51.
8. Ying SH, Feng MG, Keyhani NO. Use of uridine auxotrophy (ura3) for markerless transformation of the mycoinsecticideBeauveria bassiana. Applied Microbiology and Biotechnology, 2013, 97(7): 3017-3025.
9. Song TT, Zhao J, Ying SH, Feng MG. Differential contributions of five ABC transporters to mutidrug resistance, antioxidion and virulence of Beauveria bassiana, an entomopathogenic fungus. PLoS ONE, 2013, 8(4): e62179.
10. Zhang L, Wang J, Xie XQ, Keyhani NO, Feng MG, Ying SH. The autophagy gene BbATG5, involved in the formation of the autophagosome, contributes to cell differentiation and growth but is dispensable for pathogenesis in the entomopathogenic fungus Beauveria bassiana. Microbiology-SGM, 2013, 159: 243-252.
求一首英文歌曲的名字
最实用的确实是精神Spirit
精神
4 孔剑类（Sword）/格挡护具
7 + 10 + 9 + 11
Tal + Thul + Ort + Amn
[盾牌]
+2 级所有技能
+25-35% 快速施放法术 (可变)
+55% 快速恢复打击
+250 防御力对远程攻击
+22 活力
+89-112 Mana (可变)
攻击者受到反伤害 14
防冰 +35%
防毒 +35%
防电 +35%
+3-8 魔法吸收 (可变) 还有些比如Fortitude
刚毅
4 孔武器（Weapons）/盔甲类（Body Armor）
1 + 12 + 14 + 28
El + Sol + Dol + Lo
20% 概率当被击中时施放出 15 级 Chilling Armor( 寒冰装甲)
+25% 快速施放法术
+300% 伤害力
+200% 防御力
+（1-1.5）(每级) 生命 (在角色级别基础上) (可变)(注)
+15 防御力 (盔甲) | +50 命中率 (武器)
自动恢复生命速度 +7 (盔甲) | 命中时 25%概率吓跑怪物 (武器)
+5% 防电上限 (盔甲) | +20% 概率双倍打击 (武器)
抵消物理伤害 7 (盔甲) | +9 最小伤害力(武器)
四防 +25-30 (可变)
12% 伤害力转化为 mana
+1 光明度是小兵最好的衣服 Heart of the Oak
橡树之心
4 孔法杖类（Staff）/钉锤类（Mace）
18 + 26 + 21 + 10
Ko + Vex + Pul + Thul
+3 所有技能
+40% 快速施放法术
+75% 伤害力对恶魔系怪物
+100 点命中率对恶魔系怪物
+3-14 冰伤害，3 秒时间
每次命中偷取 7% Mana
+10 点敏捷
快速恢复生命 +20
提升最大 Mana 15%
四防 +30-40 (可变)
4 级 Oak Sage (25 次)
14 级 Raven (60 次)这个事施法角色最好的武器 比如锤子圣骑士 风德 电mm 骨系死灵等 用处很大Call To Arms
战争召唤
5 孔武器（Weapons）
11 + 8 + 23 + 24 + 27
Amn + Ral + Mal + Ist + Ohm
+1 所有技能
+40% 提升攻击速度
+250-290% 伤害力 (可变)
+5-30 火伤害
每次命中偷取 7% 生命
+2-6 级 Battle Command (可变)
+1-6 级 Battle Orders (可变)
+1-4 级 Battle Cry (可变)
防止怪物自疗
快速恢复生命 +12
30% 提升魔法装备出现概率这个也是超级实用的东西 几乎人手必备 除了波爸bb 还有些实用的神器Faith
信心
4 孔远程武器（Missile Weapon）
27 + 31 + 20 + 2
Ohm + Jah + Lem + Eld
当装备后拥有 12-15 级 Fanaticism Aura (可变) (狂热灵气)
+1-2 级所有技能 (可变)
+330% 伤害力
忽略目标防御
300% 提升命中率
+75% 伤害力对不死系怪物
+50 攻击命中率对不死系怪物
+120 火伤害
四防 +15
10% 概率将杀死的怪物转换为复活尸
从怪物身上得到 75% 额外金钱这个是弓箭亚马的神器 Infinity
无限
4 孔长柄类（Polearm）
30 + 23 + 30 + 24
Ber + Mal + Ber + Ist
50% 概率当你杀死敌人时施放出 20 级 Chain Lightning(连锁闪电)
当装备后拥有 12 级 Conviction Aura(审判灵气)
+35% 快速移动/奔跑
+255-325% 伤害力 (可变)
-55% 敌人电防
40% 概率决定性打击
防止怪物自疗
+0.5 (每级) 活力 (在角色级别基础上)
30% 提升魔法装备出现概率
21 级 Cyclone Armor (30 次) 这个事电法师的神器 Enigma
迷 团
3 孔盔甲类（Body Armor）
31 + 6 + 30
Jah + Ith + Ber
+2 所有技能
+45% 快速移动/奔跑
+1 级 Teleport
+750-775 防御力
+ (0.75 每级) +0-74 点强壮 (在角色级别基础上)
提升生命上限 5%
抵消物理伤害 8%
每杀一个敌人 +14 生命
15% 伤害转移到 Mana
+ (1 每级) +1-99% 魔法装备出现概率 (在角色级别基础上) 这个不用说了 俗称tp+ 用处最多的神器 没了他 很多角色pk就是废物 战网最常用的就这些个 当然还有其他 比如赌博弓 凤凰 流亡 押韵 荣耀之链 强制 悔恨 眼光 财富等等也很常用
什么是内质网相关降解（ERAD）？国自然开始了，研究一下！
已经尽力听了，听到如下内容：
i wanna ……stars……to the rainbow in the sky follow me and make my dream come true i wanna fly with you ……
已经尽力搜索了，仍然没找到。
希望对lz有所帮助。
ERAD简介
内质网相关降解（ERAD）△
内质网应激想必大家都是很熟悉这个概念了。 它由三个主要的通路构成 ：(i) 通过PERK-诱导的eIF2α磷酸化来减弱翻译从而调节ER蛋白的合成；(ii) 基因表达诱导ER腔分子伴侣(luminal?chaperones)，例如BiP/GRP78和GRP94，以及其他促进蛋白折叠的组分；(iii) 通过内质网相关降解（ ERAD ）从内质网中清除未折叠蛋白。
通常，细胞通过多种控制蛋白质质量的信号通路来维持蛋白质组的健康状态，这个过程叫 蛋白质内稳态 。细胞糖蛋白的分泌并维持稳定的糖蛋白稳态主要通过ERQC（内质网糖蛋白折叠质量控制）和ERAD来实现。ERAD作用的底物的范围是相当广泛的，从ER定位的错误组装蛋白到错折叠的膜和（管）腔蛋白。
错误折叠的ERAD-L和ERAD-C蛋白的递送，泛素化和降解的ERAD机制△
在ERAD过程中，待降解的底物（分三种：ERAD-L (lumen)、ERAD-M (membrane)和ERAD-C (cytosol)）通过E3连接酶标记上泛素，之后，通过特定的运输机制运回到细胞质中，然后，被细胞质 26S蛋白酶体 所降解。ERAD中最有意思的一个特征便是需要将底物从ER常驻位置移动到它们在细胞质中的最终目的地以实现蛋白酶体降解，即 受Cdc48/p97 AAA-ATP酶（也叫VCP）驱动的逆向转位 的过程。
ERAD过程示意图△
ERAD相关蛋白
1. 菱形假蛋白酶
Derlins是酵母和哺乳动物中最初被发现的介导ERQC的蛋白。基于序列和结构的同源性，derlins蛋白与菱形样蛋白超家族具有类似的结构特征。具体来说，它们是ER常驻性完整膜蛋白，拒预测可跨磷脂双分子层6次。
维持蛋白稳态，尤其是在内质网中，是极具挑战性的，因为内质网中蛋白合成的高需求不断的产生错误折叠应激。为了抵消伴随着缺陷蛋白累积产生的灾难性效应，错误折叠的ER蛋白会通过ERAD靶向降解。
Derlin-1是一种ER常驻的多次跨膜蛋白，与酵母Der1具有同源性，参与了ERAD。尽管许多研究证明了derlins协助了一些底物的ERAD，它们在逆向转位中的直接的功能仍然不清楚。
其他的一些蛋白及其生理和病理功能详见文献： The role of rhomboid superfamily members in protein homeostasis: Mechanistic insight and physiological implications.
2. 菱形蛋白酶
RHBDL4（RHBDD1）是一种参与ERAD的ER常驻菱形蛋白酶。与Derlins相比，Derlins主要参与从ER中逆转运全长缺陷蛋白，而 RHBDL4将特异性膜基质裂解为片段，随后逆向转运到细胞质中被蛋白酶体降解 。RHBDL4发挥其在ERAD中作用的两个重要特征是泛素化互作模体（motif，motif定义： 蛋白质的超二级结bai构，由2个或2个以上具有二级结构的的肽段，在空间上相互接近，形成一个特殊的空间构象，并发挥专一的功能 ）UIM和缬酪肽结合模体VBM，此模体可招募AAA-ATPase p97。有研究表明，特异性抑制p97会引起多聚泛素化蛋白的聚集、 ERAD底物的滞留和无法解决的蛋白毒性应激 ，导致未折叠蛋白响应的凋亡通路的激活，最终发挥治疗癌症的作用（ Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis ）。
Lember课题组最初报道了RHBDL4具有裂解膜蛋白，并靶向它们使其发生ERAD的作用。在这个极具创造力的研究中，他们发现 RHBDL4在逆向转运和降解之前，能裂解若干膜蛋白 ，而且裂解不仅发生在它们的膜内段，在跨膜段也可发生。该团队更近的研究也证实了RHBDL4具有介导错误折叠的 腔蛋白 （luminal protein）的周转（turnover）的作用。RHBDL4与ERAD组分 Erlin1和Erlin2形成一种底物适配器性质的复合物靶向腔蛋白。RHBDL4在具有腔聚集倾向性的蛋白的ERAD通路中发挥作用，这些蛋白会首先被裂解为片段，随后被蛋白酶体清除和降解，而不是以全长的形式逆向转运。
癌症中的ERAD
高生长速率、ATP生成受损、低氧、低血糖以及特定的突变会扰乱内质网蛋白稳态，可能会引起UPR（unfolded protein response, 未折叠蛋白反应），继而可导致细胞死亡。ERAD会在不经意间（unwittingly，这个词有点意思）赋予癌细胞耐受糖蛋白毒性应激的能力，从而帮助癌细胞。慢性内质网应激下的细胞生存是侵略性癌症的一个特征，肿瘤细胞会试图通过劫持ERAD来维持生存。（老编插一句：下划线的两句中，描述的ERAD作用是矛盾的：前者是ERAD促癌，后者是ERAD抑癌。这其实跟自噬比较相似，过头了，反而对细胞的生存是不利的。后一句作者 引用的文献 讲的是，急性的ER应激会引起细胞凋亡。）基于这些理由，有人提出 用终末端的ERAD组分的抑制剂来特异性靶向破坏癌细胞的生存 。阻断ERAD同样能激发细胞凋亡。
在ERAD通路中 早期 发挥作用的组分是内质网降解增强性甘露糖苷酶（endoplasmic reticulum degradation-enhancing mannosidases, EDEM），它会将错误折叠的糖基化蛋白呈递进入降解过程中。一旦EDEM引发的去甘露糖苷化（demannosylated）发生，内质网腔中和内质网膜上的错误折叠的糖蛋白会被OS-9（osteosarcoma 9）和XTP3B ERAD凝集素招募至内质网膜连接的复合物，该复合物是围绕着E3泛素连接酶组装起来的。OS-9和XTP3B定位于内质网腔中，可特异性识别N-连接聚糖的经处理的C臂上Man α(1,6)-Man?α(1,6)-Man残基。XTP3B也会抑制非糖基化蛋白的降解。然而，不同研究发现不同癌症中ERAD凝集素的作用可以是相反的。例如，OS-9在骨肉瘤中上调，XTP3B对于人肺癌细胞的转移特征至关重要，而lncRNA可通过增加OS-9的mRNA和蛋白水平来抑制胰腺癌的侵袭。
如前所述，p97 AAA-ATP酶是ERAD的关键分子。通过抑制p97很可能会导致不可逆的蛋白毒性应激，这些通路为我们提供了一个潜在可靶向的癌细胞的弱点。目前，有很多p97抑制剂在癌症治疗中的研究，如NMS-873和CB-5083，在实体瘤中，有的甚至比蛋白酶体抑制剂更加有效（ Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis ）。这种积极的结果可能预示着，靶向ERAD的治疗可能成为治疗癌症的一种新思路。
更多资料
Structural view of ERQC/ERAD△
与不同组成的聚糖结合的糖蛋白折叠阶段的ER轨迹是通过其与ER腔或与ER膜相关的ERQC/ERAD组分的相互作用来进行的。
剩下的就看图说话吧！
文献来源
1. Kandel, R. R., & Neal, S. E. (2020). The role of rhomboid superfamily members in protein homeostasis: Mechanistic insight and physiological implications. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 118793.
2. Anderson, D. J., Le Moigne, R., Djakovic, S., Kumar, B., Rice, J., Wong, S., ... & Madriaga, A. (2015). Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis. Cancer cell, 28(5), 653-665.
3.?Tax, G., Lia, A., Santino, A., & Roversi, P. (2019). Modulation of ERQC and ERAD: A Broad-Spectrum Spanner in the Works of Cancer Cells?. Journal of oncology, 2019.
好了，关于“insight cdc”的话题就讲到这里了。希望大家能够对“insight cdc”有更深入的了解，并且从我的回答中得到一些启示。
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