成功大學博碩士論文系統

簡易檢索 / 詳目顯示

回結果列表

研究生：	陳芳旭 Chen, Fang-Hsu
論文名稱：	利用相位調制及輔助共振改善射頻離子阱質譜平台完整大蛋白分子偵測之解析能力 Using phase modulation & auxiliary resonance,to improve the resolution of RF ion trap mass spectrometer for intact protein analysis
指導教授：	葉明龍 Yeh, Ming-Long
共同指導教授:	鄭俊彥 Cheng, Chun-Yen
學位類別：	博士 Doctor
系所名稱：	工學院 - 生物醫學工程學系 Department of BioMedical Engineering
論文出版年：	2024
畢業學年度：	113
語文別：	英文
論文頁數：	107
中文關鍵詞：	完整蛋白、質譜儀、離子阱、逐步調頻掃描、共振拋出、高解析、等相位銜接、等質量差、相位調製
外文關鍵詞：	intact protein, mass spectrometer, ion trap, stepwise frequency-scan, constant phases conjunctions, high resolution, DMZ, phase modulation, resonance ejection
相關次數：	點閱：152 下載：25
分享至:	分享至facebook 分享至twitter

查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

隨著精準化醫療世代來臨，針對蛋白質的分析需求日漸增加，而質譜儀因具有快速偵測分子量的能力，在臨床診斷及藥物開發中扮演重要角色。惟因蛋白質分子量大且結構複雜，導致不易游離或容易破碎，故質譜偵測需藉由樣本前處理針對完整蛋白進行胺基酸水解或片段化，才能接續小分子質譜分析及資料庫鑑定。然而，這些方法存在著片段不完整、候選物過多導致錯誤關聯判讀的問題，嚴重影響蛋白質鑑定的準確性及可信性。此外，當直接鑑定數十至數百千道爾吞 (kilodalton, kDa) 的完整蛋白時，除了樣本製備的工序繁雜及游離不易，在飛行時間質量分析器的使用上，也會因蛋白質於電場中動能較小，訊號難以被後端偵測器成功偵測，使得蛋白質質譜分析受到技術限制。
本篇研究利用基質輔助雷射脫附游離法(MALDI)進行軟性游離，避免蛋白質在受到高能雷射照射後碎裂，而在質量分析器部分，則選擇電四極離子阱，透過調頻技術克服過去電壓掃描的質量偵測極限，並利用感應電荷偵測器來提升微小訊號偵測能力。
在理想的情況中，固定振幅和頻率的交流電驅動下，阱內帶電粒子的運動軌跡與交流電的相位相關，且會具有固定比例的長週期和短週期關係。然而，真實情況下離子阱質譜掃描尚需考量到許多外部誤差，包含緩衝氣流的阻滯、阱內離子間的相互作用、阱內電極的加工組裝不完美、或調幅及變頻手段等帶來的干擾，這些外在誤差都讓質譜偵測會受到一定的干擾，造成譜線增寛、訊號減弱情形。
為了減少這些誤差，本研究就離子運動相位，提出了四項改善流程，並利用細胞色素C（Cytochrome C, Cyto C）針對12.5 kDa區段來進行質譜確認。首先，規劃等質量差(difference of m/z, DMZ)的逐步調頻掃描方式，透過短暫的相位暫停來銜接各個掃描步驟，利用相位暫停來重製連續變頻電場的累積誤差，並於每個步驟中設定足夠長度的週期數，讓離子群能拋出完全。其次，利用等相位銜接(constant phase conjunctions, CPCs) 進行相位調製，在相位靜止時改變離子瞬時速度，作為調製讓離子運動相位漸趨一致。透過CPCs銜接設計，可讓阱內質荷比相同的離子其運動相位一致，且拋出更為集中。第三，將DMZ技術有技巧地施加CPC，可觀察到譜線更接近目標拋出質量位置，以及僅有正確調制時，離子運動會受簡併態影響而僅有局部作用，而不會造成調製過度譜線往低質量轉移。從不穩定拋出的質譜結果中，可以確認阱內質荷比相同的離子可以因調製而集中，進而產生高解析譜線。然而每次流程受到干擾不一，使得離子運動及譜線較寬，此時便須透過加入輔助波型達到共振抛出效果，此為第四項改善程序。其執行方式是在離子運動長週期的特定間距中，額外放置兩個成對輔助脈衝，使得阱內質荷比相同的離子中，會有一部分離子運動和相位嚴格相關，最後共振抛出的高解析譜線。
本篇研究指出，透過針對離子運動考量所設計的質譜流程，利用DMZ還有等相位銜接技術，完整蛋白Cyto C可在未片段化處理下，直接被質譜儀偵測得到游離佳且訊號強且清楚對比的圖譜，達到隨DMZ設定逐一拋出(DMZ-by-DMZ)的高解析特徵。再者，針對未進行疊加的單一質譜圖的譜線分析，其半高寬可達20 Da，在離子集中程度有明顯改善；分布的寬度可由加入輔助波型後因共振拋出而集中，且輔助脈衝的設計和長週期和離子運動週期比例相關，在β為2/3時，在距起始點相位各相差120度的 (0 , 1/3, 2/3 ,3/3)有共振效果。這套掃描方法也成功驗證於其他完整蛋白，其質量範圍從5 kDa 至大於100 kDa，透過合適的DMZ選用，較小的DMZ能獲得掃描更細的圖譜，而對於低頻運動緩慢的大分子，則需要仰賴更大的DMZ設定才能機會被成功辨別出。
本篇研究成功利用電四極離子阱搭配MALDI及感應電荷偵測器，可成功讓完整蛋白質在無需水解或片段化下直接偵測，也可透過各項調頻技術或相位相關的調製手段改善不穩定拋出前的誤差，或加入輔助脈衝達成共振拋出提升離子運動同步性，繼而取得高解析譜線，可望加速蛋白質體學研究發展。

Due to the need for clinical diagnosis and drug development, the demand for mass spectrometry (MS) in protein detection and identification is increasing; however, the protein's massive molecular size and complex structure lead to poor ionization and tend to break. The current method involves protein fragmentation through peptide hydrolysis, followed by MS analysis and database investigation. However, this method needs to improve on issues such as incomplete fragmentation, excessive candidate identification, and incorrect associations, leading to limitations in the accuracy and reliability of intact protein identification. Additionally, direct identification of intact large protein molecules ranging from tens to hundreds of kilodaltons (kDa) has always been a challenge in MS analysis, including sample preparation, ionization, mass analyzer, and detector, involving physic limitations in MS.

This research explores the use of a quadrupole ion trap (QIT) mass spectrometer featuring the matrix-assisted laser desorption/ionization (MALDI) soft ionization method, along with a charge sensing particle detector (CSPD) for analyzing mass-to-charge ratios (m/z). The step-wise frequency MS scan technique was applied to achieve protein MS analysis by comparing the conventional ion trap using an amplitude scan. The ion trap operates with a fixed amplitude and frequency, which governs the motion of single charged particles based on their specific secular to micro-period ratio. However, various disturbances—including damping from buffer gas flow, ion-ion interactions, and electrode defects—can disrupt the ion's motion, resulting in spectral line broadening and weak signals.
This study introduces a four-stage process aimed at minimizing ion motion deviations to enhance the quality of mass spectra. The protein target in this research is Cytochrome C (CytoC), which has a mass of approximately 12.5 kDa. First, the MS process is restructured into a series of steps, each maintained at constant frequency and connected by constant-phase conjunctions (CPCs) and frequency jumps corresponding to a specific mass difference (DMZ). This structure ensures that ions are fully ejected from the trap within a single step due to sufficient radio-frequency (RF) cycles.
Second, applying CPCs has two critical implications: it minimizes instantaneous changes in the displacement of trapped ions. It ensures that the instant change in their velocity is proportional to their phase in motion. By establishing periodic conjunctions, ions can be stabilized within the trap and brought into phase alignment.

Third, the procedure involves repeating each constant-frequency step twice with alternating modulation, allowing for the observation of dissipation accumulation during the MS process. This modulation shows efficacy just before the ejection of unstable ions.

Finally, auxiliary resonance methods are introduced to improve synchronization. By incorporating two auxiliary pulses separated by a specific secular period, the synchronized and resonant ions become phase-correlated within the MS process.

By utilizing an InTrap-ion motion-based MS design, appropriate DMZ values, and optimal conjunction modulation, we have improved the detection of intact Cyto C proteins compared to traditional fragmentation-based methods. Combining the constant mass-difference scan method (DMZ=20) with alternating CPCs has led to improvements in ion motion and reductions in the dissipative effects seen during unstable ejection. Furthermore, adding auxiliary pulses has enhanced synchronization through resonance ejection, thereby improving motion synchronization and overall analysis capability.

In this research, Cyto C, with m/z values around 12.5 kDa, has achieved a full-width half maximum (FWHM) of 20 Da in a single mass spectrum, providing a high-resolution detection for protein MS analysis. This intact protein MS analysis has also detected proteins ranging from 5 kDa to 66 kDa and those exceeding 110 kDa, with recommended corresponding DMZ values of 20, 500, and 1000.

Overall, the stepwise frequency-scan method, which utilizes phase modulation and auxiliary resonance, effectively detects intact proteins within the molecular weight range of 5 to 110 kDa. This approach is particularly efficient for proteins in the 10 to 20 kDa range, leading to high-resolution mass spectrometry patterns with DMZ-by-DMZ characteristics. Our research demonstrates significant advancements in intact protein mass spectrometry, which has the potential to improve mass spectrometry analysis and its applications in proteomics.

中文摘要			IV
Abstract			VII
致謝				X
Tables of Contents	        XV
List of Figures	                XVIII
List of Tables		        XX
Lists of Abbreviations	        XXI
Lists of Symbols	        XXIII
Chapter 1.Introduction	             1
Chapter 2.Materials and Methods 　   17
Chapter 3.Results and Discussion     38
Chapter 4.Conclusions	             57
Chapter 5.Future Works	             59
Chapter 6.Supplementary Information　60
References		             76
作者介紹		             82

Chapter 1. Introduction 1
1. Mass spectrometry 1
2. Biological mass spectrometry 1
2.1.Soft ionization for protein analysis 3
2.2.Limitations of current MS for intact protein analysis 6
3. Ion trap 7
3.1.Paul Trap (Quadrupole ion trap, QIT) 8
3.2.MS scan approach of the QIT 9
3.3.InTrap ion’s motion & two other Mathieu’s equations 11
3.4.Ion trap plus charge detector as an alternative platform 14
4. Aim of the research 16

Chapter 2.Materials and Methods 17
1. Sample preparation 17
1.1.Standard protein preparation 17
1.2.Two-layer MALDI loading method 18
2. Instrumental setup of the mass spectrometer 19
2.1.InTrap mass spectrometer 19
2.2.InTrap ionization 22
2.3.ATI mass platform – QIT explorer 22
2.4.Charge sensing particle detector (CSPD) 23
3. Waveform-programmable MS platform 25
3.1.[Process A - DMZ scan]: linear DMZ scan without conjunction 25
3.2.Constant-Phase Conjunction to Bridge Constant-Frequency Steps 27
3.3.[Process B – phase modulation]: linear DMZ scan with conjunction modulation 30
3.4.[Process C- Compound two-step modulation]: linear DMZ scan, alternating with & without modulation	31
3.5.[Process D- Auxiliary resonance]: linear DMZ scan, with modulation & auxiliary resonance 32
4. Signal post-processing and data statistics 35
4.1.Rectification 36
4.2.Correlation convolution 36
4.3.Filter convolution 36

Chapter 3. Results and Discussion 38
1. Process A: DMZ scan (simply conjunction-bridged constant-frequency steps, with DMZ fixed) 38
2. Process B: conjunction modulation (Process A plus phase modulation on every step) 40
3. Process C: linear DMZ scan, alternating with & without modulation (alternative steps in A & B) 45
4. Process D: linear DMZ scan, with modulation & auxiliary resonance 46
5. MS analysis of variant intact protein 50
6. MS analysis of the Standard protein mixture 52
7. Applying the concepts of the Fluctuation-dissipation theorem to the MS analysis 54
8. Other applications of modern ion traps 56

Chapter 4. Conclusions 57

Chapter 5. Future Works 59

Chapter 6. Supplementary Information 60
1. Gibbs phase rule in the MALDI sample preparation 61
2. Floquet's theorem describes the status of the ion motion 63
3. Using a linear differential equation to find the solution to Mathieu's equation 65
4. Conversion of ion mass and waveform frequency 68
5. Appendix for the AMS-200 69
5.1.Python script of the MS platform 69
5.2.Post-processing Script of the MATLAB platform 73
6. Degeneracy-states of the ion trap 75

References 76
                                    

1.Thomas S.N., Chapter 10 - Mass spectrometry, in Contemporary Practice in Clinical Chemistry (Fourth Edition), W. Clarke and M.A. Marzinke, Editors. 2019, Academic Press. p. 171-185.
2.Grandviewresearch. Mass Spectrometry Market Size, Share & Trends Analysis Report , 2023 - 2030. 2024 [cited 2024 Sep 23]; Available from: https://www.grandviewresearch.com/industry-analysis/mass-spectrometry-market.
3.Angel T.E., U.K. Aryal, S.M. Hengel, E.S. Baker, R.T. Kelly, et al., Mass spectrometry-based proteomics: existing capabilities and future directions. Chem Soc Rev, 2012. 41(10): p. 3912-28.
4.Hu Y., Z. Wang, L. Liu, J. Zhu, D. Zhang, et al., Mass spectrometry-based chemical mapping and profiling toward molecular understanding of diseases in precision medicine. Chemical Science, 2021. 12(23): p. 7993-8009.
5.Chait B.T., Mass Spectrometry: Bottom-Up or Top-Down? Science, 2006. 314(5796): p. 65-66.
6.Compton P.D., L. Zamdborg, P.M. Thomas and N.L. Kelleher, On the scalability and requirements of whole protein mass spectrometry. Anal Chem, 2011. 83(17): p. 6868-74.
7.Nesvizhskii A.I., A. Keller, E. Kolker and R. Aebersold, A Statistical Model for Identifying Proteins by Tandem Mass Spectrometry. Analytical Chemistry, 2003. 75(17): p. 4646-4658.
8. Hillenkamp F., M. Karas, R.C. Beavis and B.T. Chait, Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry of Biopolymers. Analytical Chemistry, 1991. 63(24): p. 1193A-1203A.
9.Strupat K., Molecular weight determination of peptides and proteins by ESI and MALDI. Methods Enzymol, 2005. 405: p. 1-36.
10.Chen K., D. Baluya, M. Tosun, F. Li, M. Maletic-Savatic, et al., metabolites Imaging Mass Spectrometry: A New Tool to Assess Molecular Underpinnings of Neurodegeneration. Vol. 9. 2019.
11.Clark A., E. Kaleta, A. Arora and D. Wolk, Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry: a Fundamental Shift in the Routine Practice of Clinical Microbiology. Clin. Microbiol. Rev., 2013. 26: p. 547-603.
12.Fukuyama Y., MALDI Matrix Research for Biopolymers. Mass Spectrom (Tokyo), 2015. 4(1): p. A0037.
13.Nadler W.M., D. Waidelich, A. Kerner, S. Hanke, R. Berg, et al., MALDI versus ESI: The Impact of the Ion Source on Peptide Identification. Journal of Proteome Research, 2017. 16(3): p. 1207-1215.
14.Lin Y., W.S. Dynan, J.R. Lee, Z.H. Zhu and R.R. Schade, The current state of proteomics in GI oncology. Dig Dis Sci, 2009. 54(3): p. 431-57.
15.Luca Signor E.B.E., Matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometric analysis of intact proteins larger than 100 kDa. J Vis Exp, 2013(79).
16.Donnelly D.P., C.M. Rawlins, C.J. Dehart, L. Fornelli, L.F. Schachner, et al., Best practices and benchmarks for intact protein analysis for top-down mass spectrometry. Nat. Methods, 2019. 16(7): p. 587-594.
17.Szabo Z. and T. Janaky, Challenges and developments in protein identification using mass spectrometry. TrAC Trends in Analytical Chemistry, 2015. 69: p. 76-87.
18.Bowman A.P., G.T. Blakney, C.L. Hendrickson, S.R. Ellis, R.M.A. Heeren, et al., Ultra-High Mass Resolving Power, Mass Accuracy, and Dynamic Range MALDI Mass Spectrometry Imaging by 21-T FT-ICR MS. Anal. Chem., 2020. 92(4): p. 3133-3142.
19.Li C., S. Chu, S. Tan, X. Yin, Y. Jiang, et al., Towards Higher Sensitivity of Mass Spectrometry: A Perspective From the Mass Analyzers. Front. Chem., 2021. 9: p. 813359.
20.Hsiao C.J., A. özdemir, J.L. Lin and C.H. Chen, Portable particle mass spectrometer. Analyst, 2022. 147(12): p. 2644-2654.
21.Lin J.L., M.L. Chu and C.H. Chen, A portable multiple ionization source biological mass spectrometer. Analyst, 2020. 145(10): p. 3495-3504.
22.Penning F.M., Die glimmentladung bei niedrigem druck zwischen koaxialen zylindern in einem axialen magnetfeld. Physica, 1936. 3(9): p. 873-894.
23.Paul W., Electromagnetic traps for charged and neutral particles. Rev. Mod. Phys., 1990. 62(3): p. 531-540.
24.Yu Q., M. Li, X. Lu and X. Wang, Geometric optimization of toroidal ion trap based on electric field analysis and SIMION simulation. International Journal of Mass Spectrometry, 2018. 434: p. 60-64.
25.Lammert S.A., A.A. Rockwood, M. Wang, M.L. Lee, E.D. Lee, et al., Miniature Toroidal Radio Frequency Ion Trap Mass Analyzer. Journal of the American Society for Mass Spectrometry, 2006. 17(7): p. 916-922.
26.Tian Y., J. Higgs, A. Li, B. Barney and D.E. Austin, How far can ion trap miniaturization go? Parameter scaling and space-charge limits for very small cylindrical ion traps. J Mass Spectrom, 2014. 49(3): p. 233-40.
27.Paul W., H.P. Reinhard and U. Von Zahn, Das elektrische Massenfilter als Massenspektrometer und Isotopentrenner. Zeitschrift für Physik, 1958. 152(2): p. 143-182.
28.Paul W. and H. Steinwedel, Notizen: Ein neues Massenspektrometer ohne Magnetfeld. Zeitschrift für Naturforschung A, 1953. 8(7): p. 448-450.
29.Zhou X., C. Xiong, S. Zhang, N. Zhang and Z. Nie, Study of Nonlinear Resonance Effect in Paul Trap. J. Am. Soc. Mass Spectrom., 2013. 24(5): p. 794-800.
30.Zhukas L.A., M.J. Millican, P. Svihra, A. Nomerotski and B.B. Blinov, Direct observation of ion micromotion in a linear Paul trap. Phys. Rev. A, 2021. 103(2): p. 023105.
31.March R.E., Quadrupole ion trap mass spectrometry: a view at the turn of the century. Int. J. Mass Spectrom., 2000. 200(1): p. 285-312.
32.March R.E., Quadrupole Ion Trap Mass Spectrometer. Encyclopedia of Analytical Chemistry, 2006.
33.March R.E., Quadrupole ion traps. Mass Spectrom. Rev., 2009. 28 6: p. 961-89.
34.Raffaelli A. and A. Saba, Ion scanning or ion trapping: Why not both? Mass Spectrometry Reviews, 2023. 42(4): p. 1152-1173.
35.Doroshenko V.M. and R.J. Cotter, A quadrupole ion trap/time-of-flight mass spectrometer with a parabolic reflectron. J. Mass Spectrom., 1998. 33(4): p. 305-18.
36.Ding L. and S. Kumashiro, Ion motion in the rectangular wave quadrupole field and digital operation mode of a quadrupole ion trap mass spectrometer. Rapid Commun. Mass Spectrom., 2006. 20(1): p. 3-8.
37.Ding L., M. Sudakov, F.L. Brancia, R. Giles and S. Kumashiro, A digital ion trap mass spectrometer coupled with atmospheric pressure ion sources. J. Mass Spectrom., 2004. 39(5): p. 471-84.
38.Ding L. and F.L. Brancia, Electron Capture Dissociation in a Digital Ion Trap Mass Spectrometer. Analytical Chemistry, 2006. 78(6): p. 1995-2000.
39.Chen F.-H., C.-Y. Cheng, S.-W. Chou, C.-H. Yang, I.C. Lu, et al., High-Resolution Intact Protein Analysis via Phase-Modulated, Stepwise Frequency Scan Ion Trap Mass Spectrometry. Analytical Chemistry, 2024.
40.Cheng C.-Y., Y.-H. Tseng, S.-W. Chou, Y.-K. Lee, S.-C. Yang, et al., QUADRUPOLE ION TRAP APPARATUS AND QUADRUPOLE MASS SPECTROMETER. WIPO patent, 2018. Patent Number WO2018208810(PCT/US2018/031642).
41.Leibfried D., R. Blatt, C. Monroe and D. Wineland, Quantum dynamics of single trapped ions. Reviews of Modern Physics, 2003. 75(1): p. 281-324.
42.Snyder D.T., W.-P. Peng and R.G. Cooks, Resonance methods in quadrupole ion traps. Chem. Phys. Lett., 2017. 668: p. 69-89.
43.Feng C., S. Liu, T. Jiang and W. Xu, Multiplexing Quadrupole and Ion Trap Operation Modes on a “Brick” Miniature Mass Spectrometer. Molecules, 2023. 28(22): p. 7640.
44.Zhang H., H. Jia, J. Hong, M. Zhang, T. Jiang, et al., Development of a High-Field “Brick” Mass Spectrometer with Extended Mass Range and Capable of Characterizing Native Proteins. Anal. Chem., 2023. 95(36): p. 13503-13508.
45.Peng W.P., S.W. Chou and A.A. Patil, Measuring masses of large biomolecules and bioparticles using mass spectrometric techniques. Analyst, 2014. 139(14): p. 3507-23.
46.Acar G. and B.F. Feeny, Floquet-Based Analysis of General Responses of the Mathieu Equation. Journal of Vibration and Acoustics, 2016. 138(4).
47.Floquet G., Sur les équations différentielles linéaires à coefficients périodiques. Annales Scientifiques de l’école Normale Supérieure, 1883. 12: p. 47-88.
48.Siverns J.D., L.R. Simkins, S. Weidt and W.K. Hensinger, On the application of radio frequency voltages to ion traps via helical resonators. Applied Physics B, 2012. 107(4): p. 921-934.
49.Cheng C.-Y., Y.-H. Tseng, S.-W. Chou, Y.-K. Lee, S.-C. Yang, et al., QUADRUPOLE ION TRAP APPARATUS AND QUADRUPOLE MASS SPECTROMETER. USA patents, 2018. Patent Number US20190228960A1.
50.Chou S.-W., Y.-K. Lee, Y.-T. Hsiao, L.-C. Fan, C.-Y. Cheng, et al., Charge-sensing particle detector (CSPD): a sensitivity-enhanced Faraday cup. 2019.
51.Sun C., S.-W. Chou, Y.-K. Lee, S.C. Yang, Y.-H. Tseng, et al., Detection of Intact Biomolecular Ions by inTrap MALDI & Charge-Sensing Particle Detector, in 2018 Annual Conference of MSSJ. 2018.
52.Chassela O.B., A. Grigoriev, A. Fedorov, N. André, E. Le Comte, et al., Thermal characterization of resistance and gain of microchannel plate (MCP) detectors for the JENI experiment. CEAS Space Journal, 2019. 11(4): p. 597-605.
53.Jenčič B., P. Vavpetič, M. Kelemen and P. Pelicon, Secondary Ion Yield and Fragmentation of Biological Molecules by Employing 35Cl Primary Ions within the MeV Energy Domain. Journal of the American Society for Mass Spectrometry, 2020. 31(1): p. 117-123.
54.Zheng J., N. Li, M. Ridyard, H. Dai, S.M. Robbins, et al., Simple and Robust Two-Layer Matrix/Sample Preparation Method for MALDI MS/MS Analysis of Peptides. Journal of Proteome Research, 2005. 4(5): p. 1709-1716.
55.Yuqin Dai R.M.W., Liang Li, Two-Layer Sample Preparation: A Method for MALDI-MS Analysis of Complex Peptide and Protein Mixtures. Analytical Chemistry, 1999. 71(5): p. 1087-1091.
56.Cheng C.-Y., Y.-H. Tseng, S.-W. Chou, L. Yi-Kun, S.-C. Yang, et al., Quadrupole ion trap apparatus and quadrupole mass spectrometer. USA patents, 2020(16336426): p. US20190228960.
57.Hsieh H.-L., C.-Y. Cheng, Y.-K. Lee, C.-H. Yang, L.-C. Fan, et al., DEVICE FOR DETECTING CHARGED PARTICLES AND AN APPARATUS FOR MASS SPECTROMETRY INCORPORATING THE SAME. USA patents, 2021. Patent Number US10984999B2.
58.Mathew A., G.B. Eijkel, I.G.M. Anthony, S.R. Ellis and R.M.A. Heeren, Characterization of microchannel plate detector response for the detection of native multiply charged high mass single ions in orthogonal-time-of-flight mass spectrometry using a Timepix detector. J. Mass Spectrom., 2022. 57(4): p. e4820.
59.Li N., S. Dou, L. Feng, Q. Zhu and N. Lu, Eliminating sweet spot in MALDI-MS with hydrophobic ordered structure as target for quantifying biomolecules. Talanta, 2020. 218: p. 121172.
60.鄭俊彥, 陳芳旭 and 盧怡綾, 簡介生物檢體細胞之完整蛋白分子質譜技術. 科儀新知, 2021(229): p. 19-35.
61.Gareth Brenton R.G., Accurate mass measurement: terminology and treatment of data. J Am Soc Mass Spectrom, 2010. 21(11): p. 1821-35.
62.Kubo R., The fluctuation-dissipation theorem. Reports on Progress in Physics, 1966. 29(1): p. 255.
63.Breuker K., R. Knochenmuss, J. Zhang, A. Stortelder and R. Zenobi, Thermodynamic Control of Final Ion Distributions in MALDI: In-Plume Proton Transfer Reactions. International Journal of Mass Spectrometry, 2003. 226: p. 211-222.
64.Nabika H., M. Itatani and I. Lagzi, Pattern Formation in Precipitation Reactions: The Liesegang Phenomenon. Langmuir, 2020. 36(2): p. 481-497.
65.Janakiraman D., The Gibbs Phase Rule: What Happens When Some Phases Lack Some Components? Journal of Chemical Education, 2018. 95(11): p. 2086-2088.
66.Křížek M., Relativistic perihelion shift of Mercury revisited. Astronomische Nachrichten, 2022. 343(5): p. e220016.
67.Dawson P.H., Quadrupole Mass Spectrometry and Its Applications. 1976: Elsevier Scientific Publishing Company.

校內：立即公開
校外：立即公開

簡易檢索 / 詳目顯示

相關論文