hello腾它，大家好乒裆，隨著我們分析的深入璃俗，單細胞TCR和BCR的分析也要大量進入我們的視野了奴璃，之前也分享了一些有關TCR的文章，以后我們慢慢豐富這塊的內(nèi)容城豁。關于TCR（BCR）分析其實有兩個角度苟穆，一個是基因序列角度，一個是氨基酸序列角度唱星，個人傾向于氨基酸序列角度雳旅，每個氨基酸的理化性質(zhì)是固定的，更能從功能角度認識TCR與MHC的結合特性间聊，做單細胞的同學不妨試一試攒盈。

先來學習一下基礎知識

MHC（我們需要知道MHC的主要功能）

• 每個人的每個細胞表面都有一組特異的糖蛋白分子，簡稱MHC哎榴。它是由遺傳決定的型豁，不同人的MHC不同。各種哺乳動物都擁有主要組織相容性復合體（major histocompatibility complex, MHC)叹话，人的MHC統(tǒng)稱為HLA偷遗。

• 根據(jù)基因的位置和功能墩瞳，主要組織相容性復合體分為三類驼壶，分別為MHC class I,MHC class II,MHC class III。

• MHC class I（MHC I）：位于一般細胞表面上喉酌，可以提供一般細胞內(nèi)的一些狀況热凹，比如該細胞遭受病毒感染泵喘，則將病毒外膜碎片之氨基酸鏈（peptide）透過MHC提示在細胞外側(cè)，可以供殺手CD8+ T細胞等辨識般妙，以進行撲殺纪铺。

• MHC class Ⅱ（MHC Ⅱ）：大多位于抗原提呈細胞（APC)上，如巨噬細胞等碟渺。這類提供則是細胞外部的情況鲜锚，像是組織中有細菌侵入，則巨噬細胞進行吞食后苫拍，把細菌碎片利用MHC提示給輔助T細胞芜繁，啟動免疫反應。

• MHCIII類绒极，位于MHCI和MHCII類基因區(qū)之間的一組基因骏令。編碼產(chǎn)物為某些血清補體成分，如人C2垄提、Bf榔袋、C4A和C4B。其中我們主要關注的就是前兩類铡俐。

TCR（BCR）的結構

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如圖所示凰兑，BCR由兩條重鏈和兩條輕鏈連接而成，其中重鏈分為可變區(qū)(V區(qū))高蜂、恒定區(qū)(C區(qū))聪黎、跨膜區(qū)及胞質(zhì)區(qū)；輕鏈則只有V區(qū)和C區(qū)备恤。TCR每條肽鏈可分為V區(qū)稿饰、C區(qū)、跨膜區(qū)和胞質(zhì)區(qū)露泊。TCR分為兩類喉镰，多數(shù)T細胞的TCR由α和β鏈組成, 少數(shù)TCR由γ和δ肽鏈組成。BCR和TCR有三個高變區(qū)CDR1惭笑、CDR2侣姆、CDR3，其中以CDR3變異最大沉噩，直定了抗原結合特異性捺宗，對于B細胞和T細胞多樣性的研究也就集中在CDR3 區(qū)。

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如圖所示川蒙，BCR的CDR3區(qū)包括輕鏈V蚜厉、J基因片段和重鏈V、D畜眨、J基因片段昼牛，TCR的CDR3區(qū)包括α鏈V术瓮、J基因片段和和β鏈V、D贰健、J基因片段胞四。依據(jù)CDR3氨基酸序列的差異對BCR或TCR進行分析，可以揭示其clonotype分型伶椿、V-J基因豐度分析和相關免疫解析辜伟。

今天我們分享的文章是Repertoire analyses reveal TCR sequence features that influence T cell fate，里面有很多值得學習的地方脊另，我們需要精讀文獻游昼。

ABSTRACT

1、T cells acquire a regulatory phenotype when their T cell receptors (TCRs) experience an intermediate-high affinity interaction with a self-peptide presented on MHC.

2尝蠕、Using TCR sequences from FACS-sorted human cells, we identified TCR features that shape affinity to these self-peptide-MHC complexes（TCR塑造MHC復合物的親和力）.

3烘豌、CDR3β hydrophobicity（疏水性） and certain TRBV genes promote Treg fate（這一點還是很重要的，需要學習）看彼。

4廊佩、found that within the tumor microenvironment clones exhibiting Treg-Tconv plasticity had higher TiRP than expanded clones maintaining the Tconv phenotype（腫瘤組織T細胞具有更高的調(diào)控潛能，我們后面會詳細講解）靖榕。

INTRODUCTION（這個地方對于我來說标锄，知識量很大，免疫做的很少茁计，需要補充）

1料皇、During T cell development, regulatory T cells (Tregs) acquire their suppressive phenotype（抑制表型） when the affinity of their TCR to the peptide-MHC complex (pMHC) is intermediate high.

2、In most cases, randomly rearranged V, D, and J genes produce a TCR without enough affinity to pMHC, and so most developing T cells do not survive positive selection in the thymus（這一點我也是第一次知道星压，/(ㄒoㄒ)/~~）

3践剂、On the other hand, TCRs with too strong affinity to pMHC result in apoptosis and negative selection for the expressing T cell（感覺有點像負反饋調(diào)節(jié)的意思）。

4娜膘、For the T cells that survive both positive and negative selection, however, a divergence in phenotype emerges: those whose TCRs have lower affinity to pMHC tend to become conventional T cells (Tconvs) and those whose TCRs have higher affinity tend to gain the Treg phenotype（胸腺保留了這兩種T細胞類型逊脯，很智能的調(diào)控，Tconvs 和 Treg）竣贪。

5军洼、Following thymic selection, a crucial prerequisite（先決條件） for the peripheral induction（外周感應，專業(yè)詞匯真的多） of Tregs is suprathreshold affinity to pMHC, though other factors such as costimulatory signals exert additional influence.（這應該會介導我們的細胞免疫吧）演怎。

6匕争、The body of evidence that regulatory versus conventional T cell phenotypes are largely driven by TCR signal strength suggests that the developmental fate of CD4+ T cells may be influenced by sequence features of the TCR.（TCR信號強度驅(qū)動，這一點很關鍵爷耀，需要多多研究）甘桑。

7、Indeed, the degree of overlap in TCR sequence between Tregs and Tconvs is minimal compared to T cell samples of the same phenotype。（兩種表型的TCR重疊程度很猩茸　）。

8盗胀、The distinguishing features of Treg and Tconv TCRs could shed light on the determinants of TCR strength, but the majority of extant work has focused on exact sequence matching rather than generalizable TCR sequence features.（但現(xiàn)有的大部分工作都集中在精確序列匹配上艘蹋，而不是可概括的 TCR 序列特征，這一片的空間需要填補）票灰。

接下來看看作者是怎么做的

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圖注：(a) T cell receptor (TCR) β chain in complex with antigenic peptide（抗原肽） (red) and human MHC II molecules (brown). The TCR is colored by region: V-region (including CDR1β and CDR2β loops) in green, CDR3β middle region (CDR3βmr) in orange, and J-region in pink. We considered 798 candidate TCR sequence features and selected 612 nonredundant（非冗余） TCR features that best explained variance in T cell state. (b) To develop a TCR-intrinsic regulatory potential (TiRP) scoring system, we first split the discovery and replication cohorts into data for training,calibration, and testing. Each human figure represents an individuals’ TCR repertoire sample and is colored according to cohort. We fit logistic regression models for the discovery and replication cohorts separately, and combined the effect sizes for each TCR feature across the two cohorts via inverse variance-weighted meta-analysis (看來涉及到很深的算法知識女阀，后面我們詳細分解). We calibrated（校準） the P value threshold for including a TCR feature in TiRP based on held-out data from both cohorts. We then tested TiRP in held-out donors from both cohorts, as well as two independent cohorts of T cells sampled from the tumor microenvironment. (c) We then examined TiRP in mixed clones: groups of Tregs and Tconvs with the same TRB and TRA sequences observed in the same individual. These mixed clones likely represent lineages of T cells that have undergone peripheral conversions between the regulatory and conventional phenotypes, which include induced or iTregs (Tconv cells that have acquired a regulatory phenotype) and exTregs (Treg cells that have lost the regulatory phenotype). (d) We then investigated the drivers of TiRP by separately examining the two elements of the human Treg TCR ligand: the self-peptide and the human MHC II molecule.（原理看起來很難，我們需要慢慢來分解了）.

First, we derived a comprehensive collection of TCR features and tested them for differential abundance(差異豐度) between Tregs and Tconvs in two human cohorts of TCRβ chains from FACS-sorted T cells（對應上圖a）屑迂。

第二步浸策，F(xiàn)rom these results, we developed a Treg-propensity scoring system for the TCR (referred to as TCR-intrinsic regulatory potential or TiRP)（對應上圖b，需要深刻的算法知識）惹盼。

第三步庸汗，Upon confirming its accuracy in two independent cohorts of T cells sampled from the tumor microenvironment, we used TiRP to examine Treg-Tconv plasticity of tumor-infiltrating clones（對應上圖b，c,這個地方應該是我們的終極目標）手报。

第四步蚯舱，F(xiàn)inally, to shed light on the etiology（病因） of the observed TCR sequence biases, we separately examined the two elements of the Treg TCR ligand: 1) the self-peptide and 2) the human MHC II molecule by calculating TiRP in 1) murine Tregs and 2) human memory Tconvs（對應上圖d，感覺比較難）掩蛤。

最后來一句總結枉昏，Our work reveals that CDR3β hydrophobicity（疏水性） promotes reactivity to self-peptides, while TRBV gene usage shapes the TCR’s general propensity（一般傾向） for activation in the context of human MHC II restriction.

Result

Defining independent features of the T cell receptor sequence（看一看標準）

1、The TCR is a membrane-anchored heterodimeric protein（膜錨定異二聚體蛋白） consisting of an α and a β chain揍鸟。

2兄裂、Each of the two chains includes three highly variable peptide loops that protrude into the TCR-pMHC complex.（這個參考前面的TCR結構圖）。

3阳藻、The most variable of these loops is the CDR3β region in the β chain which mediates recognition of specific antigens.

4晰奖、Because TRBV, TRBD, and TRBJ genes each encode regions of CDR3β, we anticipated that the CDR3β sequence would feature blocks of strongly correlated residues.（以此為特征最合適不過 ，很多分析都是測到CDR3序列）.

5腥泥、TCR的測序結構

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圖注：(a) Probability of each amino acid in each CDR3β position depicted by a sequence logo, with a heatmap of normalized mutual information between each pair of CDR3β residues for the most frequent CDR3β length, 15 amino acids. Based on this mutual information structure, we partitioned the CDR3β sequence into a Vmotif within a V-region, a CDR3β middle region (CDR3βmr), and a Jmotif within a J-region. (b) Schematic showing TCRs of multiple lengths aligned to the TCR β chain structure. Three complementary-determining regions within the TCR β chain protrude as loops into the pMHC-TCR complex: CDR1β, CDR2β, and CDR3β. CDR1β and CDR2β are encoded by the TRBV gene, while CDR3β spans TRBV-encoded residues, random nucleotide insertion畅涂。

the V-region (IMGT position 1–107), CDR3β middle region、(CDR3βmr, p108–p112), and J-region (p113–p118)道川。雖然高度可變的 CDR3βmr 中的隨機核苷酸插入掩蓋了 TRBD 基因的身份午衰，但種系編碼的 V 和 J 區(qū)顯示出序列保守性和高殘基間互信息 。

6冒萄、Mutual information was concentrated at the flanking ends of CDR3β such that eight p104-p106 tripeptides (“Vmotifs”) and 42 p113-p118 pentapeptides (“Jmotifs”) accounted for >90% of observations.（這個區(qū)域最為關鍵,examine the V-, middle, and J- regions independently）.

結果2臊岸、Regulatory T cells use specific amino acids within the CDR3β middle region

1、We first examined the middle region of CDR3β (“CDR3βmr”) of Tregs (CD4+CD127-CD25+) and Tconvs (CD4+CD127+) in the discovery cohort.

2尊流、計算每個氨基酸占據(jù)的 CDR3βmr 殘基的平均百分比在供體之間產(chǎn)生了驚人一致的 Treg-Tconv 差異：苯丙氨酸 (F)帅戒、亮氨酸 (L)、色氨酸 (W) 和酪氨酸 (Y) 始終富含 Treg，而天冬氨酸(D) 和谷氨酸 (E) 始終富含 Tconv（研究很精細啊逻住，值得深入學習）钟哥。

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3、Categorization of amino acids by physicochemical features（理化性質(zhì)） showed that hydrophobic amino acids（疏水氨基酸） were enriched in Tregs, while negatively charged amino acids（帶負電荷的氨基酸） were enriched in Tconvs.

4瞎访、To statistically assess these differences, we used nested conditional mixed effect logistic regression models(嵌套條件混合效應邏輯回歸模型,后續(xù)方法我們會詳細解釋) which account for inter-individual differences such as those driven by HLA genotype and tissue source.

5腻贰、observed that 15 amino acids had an independent effect on Treg fate。To confirm that these effects were consistent across donors and clinical phenotypes, we estimated them in each of the 18 individuals and in T1D cases and controls separately 扒秸。 We found consistent effect sizes in all contexts（這個發(fā)現(xiàn)很有意思）.

6播演、然后運用該模型scores CDR3βmr 理化特征（之前是用于單個的氨基酸）,Physicochemical features did not capture as much information as amino acid percentages ，因此伴奥，繼續(xù)研究基于氨基酸的 CDR3βmr 模型写烤。

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7、We then ran a separate mixed effects model for each CDR3βmr position (IMGT p108 -112)（看來這個模型相當重要）拾徙，testing whether the amino acid at the given position explained variance in T cell fate beyond that accounted for by the CDR3βmr amino acid percentages洲炊。每個位置確實傳達了關于 Treg 命運可能性的額外信息，但這些位置特異性效應并不能解釋像 CDR3βmr 的一般氨基酸組成一樣多的變異

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注：Percent of explained variance by each TCR feature type,summing to 100% for each length of CDR3β. VGSR = V gene selection rate尼啡。CDR3βmr %AAs = percent composition of amino acids in the CDR3βmr选浑。

結果3.CDR3β V and J regions explain variance in T cell state

1、We then examined the V-region of the TCR.先前的研究已經(jīng)確定玄叠，MHC 基因座中的遺傳變異決定了 TR(A/B)V 基因在repertoire中的使用頻率 古徒。

2、Interestingly, MHC polymorphisms explained far more variance in TRAV gene usage compared to TRBV读恃，consistent with protein structure data demonstrating that TRAV contacts MHC at polymorphic sites while TRBV contacts MHC at conserved sites隧膘。（與蛋白質(zhì)結構數(shù)據(jù)一致，表明TRAV在多態(tài)位點接觸MHC寺惫，而TRBV在保守位點接觸MHC疹吃。）假設 TRBV 編碼殘基的變異可能會改變 TCR 對這些保守 MHC 位點的親和力，從而影響 T 細胞命運.

3西雀、To test this hypothesis, we extracted sequence features from the V-region and tested their association with Treg fate using mixed effects logistic regression萨驶。通過模型比較，發(fā)現(xiàn)包含 TRBV 基因identity和 p107 的聯(lián)合模型最能代表該區(qū)域艇肴，因為 58 個 TRBV 基因比 8 個 Vmotif 解釋了更多的variance腔呜。

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注：Incremental variance explained by the addition of labeled TCR features to the V-region mixed effect logistic regression models.（通過將標記的 TCR 特征添加到 V 區(qū)域混合效應邏輯回歸模型來解釋增量方差。 ）

4再悼、為了解釋 TRBV 基因選擇的個體間差異核畴，我們?yōu)槊總€ TRBV 基因推導出胸腺選擇參數(shù) (VGSR) 作為協(xié)變量 .盡管控制了 VGSR，TRBV 基因identity繼續(xù)解釋了 T 細胞命運的顯著差異冲九，與參考基因 TRBV05-01 相比谤草，三個 TRBV 基因?qū)?Treg 命運的幾率降低了 30% 以上 .(P = 1.3 x 10^-804,算法很深， 基礎需要的也很多，理解起來有點費勁).

5丑孩、看一看V基因的結論冀宴，The consistency in TRBV gene effects across individuals suggests that their influence on Treg fate indeed occurs through interactions with conserved MHC residues, and is largely independent of MHC variability between individuals（個體間 TRBV 基因效應的一致性表明它們對 Treg 命運的影響確實是通過與保守的 MHC 殘基相互作用而發(fā)生的，并且在很大程度上獨立于個體之間的 MHC 變異性温学，具有普遍性）略贮。

接下來是Jgene，We then examined the J-region.

1枫浙、然后我們檢查了 J 區(qū)卫枝。 與 V 區(qū)相反谍夭，其中強 p104-p106 序列保守性將多個 TRBV 基因限制為相同的 Vmotif，D/J 連接處的可變核苷酸編輯導致與每個 TRBJ 基因相關的多個 Jmotif叔锐。

2黄痪、The 42 Jmotifs explained slightly more variance than the 13 TRBJ genes 紧帕，and so we proceeded with a joint model containing the Jmotif and p113 residue

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3、the most important TCR features for T cell fate determination were the TRBV gene identity and the percent composition of amino acids in the CDR3βmr桅打。

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結果4是嗜、Treg TCRs are enriched for CDR1β apex positive charge and CDR3β middle region hydrophobicity（特征分析）.

1、We wanted to localize physicochemical effects underlying CDR3βmr residue enrichments to specific sequence positions.在CDR(1-3)β三個區(qū)域估計重要的理化性質(zhì)挺尾、等電點鹅搪、and volume in influencing Treg fate using a ridge regression model（又是一個模型，數(shù)學遭铺，難＠鍪痢！；旯摇）

2甫题、Tregs were enriched for positively charged amino acids at p37 of CDR1β

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注：Estimated odds ratio (per standard deviation) for each physicochemical feature at each CDRβ(1-3) loop position; features with an estimate > 1 are positively associated with Treg fate while features with an estimate < 1 are negatively associated. Odds ratios denote the change in Treg odds per standard deviation increase in the given physicochemical feature at the given TCR position. For each CDR3β length, all effects were estimated jointly in an L2-regularized logistic regression with 10-fold cross-validation (Methods). Shown are the odds ratio estimates for each position-feature averaged across the six CDR3β lengths. Vertical lines denote the boundaries of each CDRβ loop

3、seven TRBV genes assessed in our models harbor a negatively charged residue at p37涂召。all seven of these were significantly depleted for Tregs compared to the reference gene TRBV05-01, which has a positively charged Arginine (R) at p37

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4坠非、CDR3βmr 在每個位置都具有正的疏水系數(shù)，At each of these positions, every standard deviation increase in hydrophobicity led to a 2.5% (L17,p113) – 6.3% (L12, p113) increase in odds of Treg fate果正。

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5炎码、To directly visualize the amino acids associated with Treg fate, we generated sequence logo representation of the CDR3βmr based on differential amino acid usage at each position,hydrophobicity at p109 and p110 promotes the development of T cells that recognize self-antigens.

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6、this principle extends beyond p109-110 throughout the stretch of entropic CDR3β residues.

結果5秋泳、在獨立數(shù)據(jù)集中再現(xiàn) TCR 關聯(lián)（上述模型在未知數(shù)據(jù)中的運用）

1辅肾、Despite a different distribution of tissue sources in this data set, the CDR3βmr amino acid percentage effects were nearly identical（下圖a），Effects for individual TRBV genes, Jmotifs, and position-specific amino acid effects were also consistent with discovery（下圖b）.

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注：Correspondence between the discovery and replication cohort odds ratios for all 612 nonredundant TCR features. Odds ratios for CDR3βmr percent composition amino acids are shown on the left; OR corresponds to the change in Treg odds associated with one standard deviation increase in the given CDR3βmr amino acid percentage. All other TCR features are shown on the right; OR corresponds to the change in Treg odds associated with the presence of the given TCR sequence feature compared to the reference feature.

結果6轮锥、Developing TiRP: a Treg-propensity scoring scheme for the TCR

1矫钓、for a given TCR, TiRP is the sum of Treg association effect sizes of independent sequence features in all three TCR regions（這個對單細胞數(shù)據(jù)不友好啊）。

2新娜、tested TiRP score on the four discovery cohort donors and two replication赵辕，cohort donors whose repertoire data had been withheld from all former analyses。observed that a one standard deviation increase in TiRP in these held-out data resulted in a 23% increase in the odds of Treg status概龄。

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注：Validation of TCR-intrinsic regulatory potential (TiRP) in held out donors of the discovery and replication dataset (n = 3,277,036 TCRs). Each standard deviation increase in TiRP was associated with a 23% increase in the odds of Treg status (OR: 1.231, 95% CI:1.227 – 1.235, P = 2.4 x 10-3248, LRT). Percentile points are colored by Treg:Tconv ratio ranging from blue (lowest) to purple (highest)还惠。

結果7、運用TiRP helps to explain Treg-Tconv plasticity in the tumor microenvironment私杜。（單細胞數(shù)據(jù)）

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1蚕键、與前面的研究結果一致

2、We next asked whether TiRP could help to explain regulatory T cell plasticity.It is well recognized that na?ve Tconv thymic emigrants can be peripherally induced to adopt a regulatory phenotype. Conversely, some Tregs have been observed to lose FOXP3 expression and adopt a pro-inflammatory phenotype. Expanded T cell clones (possessing the same TCR) observed as both Tregs and Tconvs within the same donor (hereafter referred to as “mixed clones”) may represent lineages of T cells that have undergone such peripheral conversions. We hypothesized that the TiRP of these T cells may be intermediate, rendering them most susceptible to peripheral conversion.

3衰粹、單細胞數(shù)據(jù)的基礎分析

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On average, 19.2% of expanded clones from the same donor were observed in both the Treg and Tconv state, including a few large clones with a relatively even balance锣光。

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4、We next tested whether the TiRP score of mixed clones was in between that of purely Tconv and Treg clones (Methods). In the previously held-out bulk sequencing data, the TiRP scores of mixed clones were significantly greater than those of expanded Tconv clones and less than those of expanded Treg clones (上圖f, mixed-Tconv difference = 0.03, P = 2.0 x 10-40; mixed-Treg difference = -0.29, P = 9.1 x 10-16). These single cell data confirmed that Tregs of mixed clones indeed exhibited greater FOXP3 expression than Tconvs within the same clonal expansion铝耻。As in the previously held-out bulk sequencing data, mixed clones in single cell data had intermediate TiRP scores which were significantly greater than the scores of expanded, pure Tconv clones(上圖g).

5誊爹、來個結論To our knowledge, TiRP is the first metric to identify TCR-intrinsic, rather than TCR-extrinsic factors relevant to peripheral phenotypic conversion.

結果8、Separable components of TiRP: affinity to self-peptides and affinity to human MHC

1瓢捉、conducted a principal components analysis (PCA) of TCR feature frequencies in the sorted samples of the replication dataset, in which all T cell states of interest were available频丘。observed that the major axes of TCR sequence variation corresponded to T cell state, rather than donor HLA genotype or clinical phenotype。While our previous supervised modeling was designed to focus on Treg-Tconv differences, this approach recovered the importance of T cell state in an unsupervised manner.

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2泡态、PC軸的意義,antigen-experienced (Treg and memory Tconv) versus na?ve (PC1), and regulatory versus conventional (PC2).The axis dividing antigen-experienced from inexperienced samples (PC1) was most reliant on TRBV gene frequencies,while the axis dividing regulatory versus conventional samples (PC2) was most reliant on mean percent composition of amino acids in CDR3βmr and the CDR3βmr adjacent residue p113.

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3搂漠、Since TiRP is a weighted sum of TCR features from the V-, J- and middle regions, the score can be divided into three score components corresponding to these three regions. TiRP scoring by TCR region revealed that V-region-specific TiRP (vTiRP) and CDR3βmr-specific TiRP (mTiRP) indeed captured PC1 and PC2, respectively(Figure 7d-e, vTiRP – PC1 R = -0.86, P = 1.5 x 10-20, mTiRP – PC2 R = 0.85, P = 2.6 x 10-20).

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4、We next investigated possible biological drivers for vTiRP and mTiRP某弦。The biological structure of the pMHC-TCR complex suggests that different regions of the TCR may promote Treg fate via particular affinities: MHC II mostly contacts the V-region of the TCR, while the self peptide is in closest contact with CDR3βmr状答。Thus, we hypothesized that vTiRP was driven by affinity to human MHC II, while mTiRP was driven by affinity to self peptides. To test this idea, we examined TiRP in two complementary datasets: 1) murine Treg TCRs, which recognize self-peptide but not human MHC, and 2) human memory Tconv TCRs, which recognize human MHC but not self-peptide.

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5、Applying our scoring system to murine data revealed that human TiRP was significantly elevated in murine Tregs compared to Tconvs刀崖。Because the self-peptide is the only consistent element of the Treg ligand between these species, the best explanation for such cross-species Treg TCR similarity is affinity to thymic self-peptides.

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最后看看方法

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真的是相當難惊科，看來讀懂需要好幾遍啊

生活很好，有你更好