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Method validation of multi-element panel in whole blood by inductively coupled plasma mass spectrometry (ICP-MS) 电感耦合等离子体质谱(ICP-MS)测定全血中多元素板的方法验证
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2023-01-01 DOI: 10.1016/j.jmsacl.2022.12.005
Amol O. Bajaj , Rebecca Parker , Candice Farnsworth , Christian Law , Kamisha L. Johnson-Davis

Background

Analytical methods to measure trace and toxic elements are essential to evaluate exposure and nutritional status. A ten-element panel was developed and validated for clinical testing in whole blood. Retrospective data analysis was conducted on patient samples performed at ARUP Laboratories.

Methods

A method was developed and validated to quantify ten elements in whole blood by ICP-MS. Fifty microliters of sample were extracted with 950 μL of diluent containing 1 % ammonium hydroxide, 0.1 % Triton X-100, 1.75 % EDTA along with spiked internal standards. Four calibrators were used for each element and prepared in goat blood to match the patient specimen matrix. Samples were analyzed with an Agilent 7700 ICP-MS with a Cetac MVX 7100 μL Workstation autosampler.

Results

The assay was linear for all elements with inter- and intra-assay imprecision less than or equal to 11% CV at the low end of the analytical measurement range (AMR) and less than or equal to 4% CV at the upper end of the AMR for all elements. Accuracy was checked with a minimum of 40 repeat patient samples, proficiency testing samples, and matrix-matched spikes. The linear slopes for the ten elements ranged from 0.94 to 1.03 with intercepts below the AMR and R2 ranging from 0.97 to 1.00.

Conclusions

The multi-element panel was developed to analyze ten elements in whole blood to unify the sample preparation and increase batch run efficiency. The improved analytical method utilized matrix-matched calibrators for accurate quantification to meet regulatory requirements. The assay was validated according to guidelines for CLIA-certified clinical laboratories and was suitable for clinical testing to assess nutritional status and toxic exposure.

背景测量微量元素和有毒元素的分析方法对于评估接触和营养状况至关重要。开发并验证了一个用于全血临床测试的十元素面板。对ARUP实验室的患者样本进行了回顾性数据分析。方法开发并验证了一种通过ICP-MS定量全血中十种元素的方法。用950μL含有1%氢氧化铵、0.1%Triton X-100、1.75%EDTA的稀释剂以及加标的内标物提取50微升样品。每个元素使用四个校准器,并在山羊血中制备,以匹配患者样本基质。使用Agilent 7700 ICP-MS和Cetac MVX 7100μL工作站自动进样器对样品进行分析。结果所有元素的测定都是线性的,在分析测量范围(AMR)的低端,测定间和测定内的不精确性小于或等于11%CV,在AMR的高端,所有元素的不精确度小于或等于4%CV。使用至少40个重复患者样本、能力测试样本和矩阵匹配的尖峰来检查准确性。10种元素的线性斜率在0.94至1.03之间,AMR和R2以下的截距在0.97至1.00之间。结论开发了多元素面板来分析全血中的10种元素,以统一样品制备并提高批量运行效率。改进的分析方法利用矩阵匹配的校准器进行精确定量,以满足监管要求。该测定根据CLIA认证的临床实验室指南进行了验证,适用于评估营养状况和毒性暴露的临床测试。
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引用次数: 4
The VALIDity of laboratory developed tests: Leave it to the experts? 实验室开发测试的有效性:把它交给专家?
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2023-01-01 DOI: 10.1016/j.jmsacl.2022.12.002
Mark A. Marzinke , William Clarke , Dennis J. Dietzen , Andrew N. Hoofnagle , Gwendolyn A. McMillin , Maria Alice V. Willrich
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引用次数: 1
Effects of sample matrix in the measurement of antithrombin by LC-MS: A role for immunocapture 样品基质对LC-MS测定抗凝血酶的影响:免疫捕获的作用
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2023-01-01 DOI: 10.1016/j.jmsacl.2023.01.002
M. Kruijt , N.P.M. Smit , J.J. van Ham , C.M. Cobbaert , L.R. Ruhaak

Introduction

The sample matrix composition, which is greatly affected by the type of blood collection tube used during phlebotomy, is of major importance in laboratory testing as it can influence test results. We developed an LC-MRM-MS test to molecularly characterize antithrombin in citrate plasma. The test principle differs greatly from traditional laboratory tests and the influence of varying plasma sample matrices is largely unknown.

Objectives

To identify whether variations in sample matrix affect the LC-MRM-MS test for antithrombin and assess whether sample pre-processing by immunocapture reduces matrix-specific effects.

Methods

Samples (n = 45) originating from four different blood collection tubes (sodium citrate, lithium heparin, K2-EDTA and K2-EDTA with protease inhibitors) were processed directly or after immunocapture. Antithrombin was digested into proteotypic peptides, which were monitored by LC-MRM-MS. Results from lithium heparin and the K2-EDTA matrices were compared to the standard sample matrix, sodium citrate, using Deming regression analysis and repeated measures one-way ANOVA.

Results

Deming regression analysis of directly processed samples revealed slopes deviating >5% from the line of identity for at least six out of 22 peptides in all matrices. Significant differences between all matrices were found upon analysis by ANOVA for at least 10 peptides. Pre-processing by immunocapture led to slopes within 5% of the line of identity for nearly all peptides of the matrices. Furthermore, significant differences between matrices after immunocapture were only observed for four peptides.

Conclusion

Variations in the sample matrix affect the measurement of antithrombin by LC-MRM-MS, but observed effects are greatly reduced upon pre-processing by immunocapture.

引言样本基质成分在很大程度上受静脉切开术中使用的采血管类型的影响,在实验室检测中具有重要意义,因为它会影响检测结果。我们开发了一种LC-MRM-MS测试方法来对柠檬酸盐血浆中的抗凝血酶进行分子表征。测试原理与传统的实验室测试有很大不同,不同血浆样品基质的影响在很大程度上是未知的。目的确定样品基质的变化是否会影响LC-MRM-MS抗凝血酶测试,并评估免疫捕获预处理样品是否会降低基质特异性效应。方法对来源于四种不同采血管(柠檬酸钠、肝素锂、K2-EDTA和K2-EDTA-蛋白酶抑制剂)的样品(n=45)进行直接或免疫捕获处理。抗凝血酶被消化成蛋白型肽,并通过LC-MRM-MS进行监测。使用德明回归分析和重复测量单因素方差分析将肝素锂和K2-EDTA基质的结果与标准样品基质柠檬酸钠进行比较;在所有基质中的22个肽中的至少6个肽的同一性线的5%。通过ANOVA对至少10个肽进行分析,发现所有基质之间存在显著差异。免疫捕获的预处理导致基质的几乎所有肽的斜率在同一性线的5%以内。此外,仅对四种肽观察到免疫捕获后基质之间的显著差异。结论样品基质的变化影响LC-MRM-MS测定抗凝血酶,但免疫捕获预处理后观察到的效果大大降低。
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引用次数: 2
Validation of a quantitative multiplex LC-MS/MS assay of carvedilol, enalaprilat, and perindoprilat in dried blood spots from heart failure patients and its cross validation with a plasma assay 心衰患者干血斑中卡维地洛、依那普利特和培哚普利特的定量多重LC-MS/MS检测方法的验证及其与血浆检测方法的交叉验证
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2023-01-01 DOI: 10.1016/j.jmsacl.2022.12.003
Andre Joubert , Anton Joubert , Marthinus van der Merwe , Jennifer Norman , Sandra Castel , Paolo Denti , Karen Sliwa , Gary Maartens , Phumla Sinxadi , Lubbe Wiesner

Introduction

Adherence to medication is an important determinant of outcomes in chronic diseases like heart failure. Drug assays provide objective adherence biomarkers. Dried blood spots (DBS) are appealing samples for drug assays due to less demanding transportation and storage requirements.

Objectives

To analytically validate a LC-MS/MS method for the simultaneous quantification of carvedilol, enalaprilat, and perindoprilat in DBS and evaluate the feasibility of using the method as an adherence determining assay. To validate the assay further clinically by establishing correlation and agreement between plasma and DBS samples from a pharmacokinetic pilot study.

Methods

The method was validated over a concentration range of 1.00–200 ng/mL according to FDA guidelines. Adherence tracking ability of the assay was evaluated using a pharmacokinetic pilot study. Correlation and agreement were evaluated through Deming regression and Bland-Altman analysis, respectively.

Results

Accuracy, precision, selectivity, and sensitivity were proven with complete and reproducible extraction recovery at all concentrations tested. Stability of the analytes in the matrix and throughout sample processing was proven. The full range of concentrations of the pharmacokinetic pilot study could be quantified for enalaprilat, but not for carvedilol and perindoprilat. The difference between the observed and calculated plasma concentrations was less than 20 % of their mean for >67 % of samples for all analytes.

Conclusions

The assay is suitable as a screening tool for carvedilol and perindoprilat, while suitable as an adherence determining assay for enalaprilat. Equivalence between observed and predicted plasma concentrations proves DBS and plasma concentrations can be used interchangeably.

引言坚持服药是心力衰竭等慢性疾病预后的重要决定因素。药物测定提供了客观的粘附性生物标志物。干血点(DBS)是药物分析的有吸引力的样品,因为运输和储存要求较低。目的分析验证LC-MS/MS法同时定量DBS中卡维地洛、依那普利和培哚普利的方法,并评估该方法作为粘附性测定方法的可行性。通过建立血浆和来自药代动力学试点研究的DBS样品之间的相关性和一致性,进一步在临床上验证该测定。方法根据美国食品药品监督管理局的指导方针,在1.00–200 ng/mL的浓度范围内对该方法进行验证。使用药代动力学初步研究评估了该测定的依从性跟踪能力。分别通过Deming回归和Bland-Altman分析评估相关性和一致性。结果在所有测试浓度下,准确度、精密度、选择性和灵敏度都得到了验证,提取回收率完全且可重复。分析物在基质和整个样品处理过程中的稳定性得到了证实。药代动力学初步研究的全部浓度范围可以量化依那普利,但不能量化卡维地洛和培哚普利。对于>;67%的样品用于所有分析物。结论该方法适用于卡维地洛和培哚普利的筛选,也适用于依那普利的粘附性测定。观察到的和预测的血浆浓度之间的等效性证明DBS和血浆浓度可以互换使用。
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引用次数: 0
Development of Tier 2 LC-MRM-MS protein quantification methods for liquid biopsies 用于液体活检的Tier 2 LC-MRM-MS蛋白质定量方法的开发
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2023-01-01 DOI: 10.1016/j.jmsacl.2022.12.007
Nina Diederiks , Cor J. Ravensbergen , Maxim Treep , Madelein van Wezel , Matt Kuruc , L. Renee Ruhaak , Rob A.E.M. Tollenaar , Christa M. Cobbaert , Yuri E.M. van der Burgt , Wilma E. Mesker

In the pursuit of personalized diagnostics and tailored treatments, quantitative protein tests contribute to a more precise definition of health and disease. The development of new quantitative protein tests should be driven by an unmet clinical need and performed in a collaborative effort that involves all stakeholders. With regard to the analytical part, mass spectrometry (MS)-based platforms are an excellent tool for quantification of specific proteins in body fluids, for example focused on cancer. The obtained readouts have great potential in determining tumor aggressiveness to facilitate treatment decisions, and can furthermore be used to monitor patient response. Internationally standardized TNM classifications of malignant tumors are beneficial for diagnosis, however treatment outcome and survival of cancer patients is poorly predicted. To this end, the importance of the tumor microenvironment has endorsed the introduction of the tumor-stroma ratio as a prognostic parameter in solid primary tumor types. Currently, the stromal content of tumor tissues is determined via routine diagnostic pathology slides. With the development of liquid chromatography (LC)-MS methods we aim at quantification of tumor-stroma specific proteins in body fluids. In this mini-review the analytical aspect of this developmental trajectory is further detailed.

在追求个性化诊断和量身定制的治疗过程中,定量蛋白质测试有助于更准确地定义健康和疾病。新的定量蛋白质测试的开发应该由未满足的临床需求驱动,并在所有利益相关者参与的合作中进行。就分析部分而言,基于质谱(MS)的平台是用于量化体液中特定蛋白质的优秀工具,例如专注于癌症。所获得的读数在确定肿瘤侵袭性以促进治疗决策方面具有巨大潜力,并且可以进一步用于监测患者反应。国际标准化的恶性肿瘤TNM分类有利于诊断,但癌症患者的治疗结果和生存率预测较差。为此,肿瘤微环境的重要性支持将肿瘤间质比率作为实体原发性肿瘤类型的预后参数。目前,肿瘤组织的基质含量是通过常规诊断病理切片来确定的。随着液相色谱(LC)-MS方法的发展,我们的目标是定量体液中的肿瘤基质特异性蛋白质。在这篇小型综述中,进一步详细介绍了这一发展轨迹的分析方面。
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引用次数: 1
A distributable LC-MS/MS method for the measurement of serum thyroglobulin 可分配LC-MS/MS法测定血清甲状腺球蛋白
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.jmsacl.2022.09.005
Junyan Shi , William S. Phipps , Benjamin Y. Owusu , Clark M. Henderson , Thomas J. Laha , Jessica O. Becker , Morteza Razavi , Michelle A. Emrick , Andrew N. Hoofnagle

Background

Despite its clear advantages over immunoassay-based testing, the measurement of serum thyroglobulin by mass spectrometry remains limited to a handful of institutions. Slow adoption by clinical laboratories could reflect limited accessibility to existing methods that have sensitivity comparable to modern immunoassays, as well as a lack of tools for calibration and assay harmonization.

Methods

We developed and validated a liquid chromatography-tandem mass spectrometry-based assay for the quantification of serum thyroglobulin. The protocol combined peptide immunoaffinity purification using a commercially available, well-characterized monoclonal antibody and mobile phase modification with dimethylsulfoxide (DMSO) for enhanced sensitivity. To facilitate harmonization with other laboratories, we developed a novel, serum-based 5-point distributable reference material (Husky Ref).

Results

The assay demonstrated a lower limit of quantification of 0.15 ng/mL (<20 %CV). Mobile phase DMSO increased signal intensity of the target peptide at least 3-fold, improving quantification at low concentrations. Calibration traceable to Husky Ref enabled harmonization between laboratories in an interlaboratory study.

Conclusions

Sensitive mass spectrometry-based thyroglobulin measurement can be achieved using a monoclonal antibody during peptide immunoaffinity purification and the addition of mobile phase DMSO. Laboratories interested in deploying this assay can utilize the provided standard operating procedure and freely-available Husky Ref reference material.

背景:尽管质谱法比基于免疫分析的检测有明显的优势,但它仍然局限于少数机构。临床实验室采用缓慢可能反映了现有方法的可及性有限,这些方法具有与现代免疫测定相当的敏感性,以及缺乏校准和测定统一的工具。方法建立并验证了一种基于液相色谱-串联质谱的血清甲状腺球蛋白定量分析方法。该方案结合了多肽免疫亲和纯化,使用市售的、特性良好的单克隆抗体和二甲基亚砜(DMSO)的流动相修饰,以提高灵敏度。为了促进与其他实验室的协调,我们开发了一种新的、基于血清的5点可分发参考物质(Husky Ref)。结果该方法的定量下限为0.15 ng/mL (20% CV)。流动相DMSO使目标肽的信号强度增加了至少3倍,在低浓度下提高了定量。校准可追溯到赫斯基Ref使实验室之间的协调实验室间的研究。结论在多肽免疫亲和纯化和加入流动相DMSO的过程中,采用单克隆抗体可实现基于质谱法的甲状腺球蛋白检测。有兴趣部署此分析的实验室可以利用提供的标准操作程序和免费提供的赫斯基参考材料。
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引用次数: 5
Corrigendum to “Instability of 7-aminoclonazepam in frozen storage conditions” [Clin. Mass Spectrom. 9 (2018) 23–24] “7-氨基氯硝西泮在冷冻储存条件下的不稳定性”的勘误表[临床]。质谱,9 (2018)23-24 [j]
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.jmsacl.2022.09.006
Jayme L. Dahlin , Athena K. Petrides
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引用次数: 0
Advances in MS instrumentation: The present and future of the clinical lab 质谱仪器的进展:临床实验室的现在和未来
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.jmsacl.2022.08.003
Christopher D. Chouinard
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引用次数: 0
Validation of atovaquone plasma levels by liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring in pediatric patients 液相色谱-串联质谱法检测阿托伐醌血浆水平用于儿科患者治疗药物监测的验证
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.jmsacl.2022.09.004
Thomas D. Horvath , Izmarie Poventud-Fuentes , Lily Olayinka , Asha James , Sigmund J. Haidacher , Kathleen M. Hoch , Alexandra M. Stevens , Anthony M. Haag , Sridevi Devaraj

Background

Atovaquone has traditionally been used as an antiparasitic and antifungal agent, but recent studies have shown its potential as an anticancer agent. The high variability in atovaquone bioavailability highlights the need for therapeutic drug monitoring, especially in pediatric patients. The goal of our study was to develop and validate the performance of an assay to quantify atovaquone plasma concentrations collected from pediatric cancer patients using LC-MS/MS.

Methods

Atovaquone was extracted from a 10 µL volume of K2-EDTA human plasma using a solution consisting of ACN: EtOH: DMF (8:1:1 v:v:v), separated using reverse-phase chromatography, and detected using a SCIEX 5500 QTrap MS system. LC-MS/MS assay performance was evaluated for precision, accuracy, carryover, sensitivity, specificity, linearity, and interferences.

Results

Atovaquone and its deuterated internal standard were analyzed using a gradient chromatographic method that had an overall cycle-time of 7.4 min per injection, and retention times of 4.3 min. Atovaquone was measured over a dynamic concentration range of 0.63 – 80 µM with a deviation within ≤ ± 5.1 % of the target value. Intra- and inter-assay precision were ≤ 2.7 % and ≤ 8.4 %, respectively. Dilutional, carryover, and interference studies were also within acceptable limits.

Conclusions

Our studies have shown that our LC-MS/MS-based method is both reliable and robust for the quantification of plasma atovaquone concentrations and can be used to determine the effective dose of atovaquone for pediatric patients treated for AML.

托伐醌传统上被用作抗寄生虫和抗真菌剂,但最近的研究显示其作为抗癌剂的潜力。阿托伐醌生物利用度的高度可变性突出了治疗药物监测的必要性,特别是在儿科患者中。本研究的目的是开发并验证一种利用LC-MS/MS定量儿科癌症患者阿托伐醌血浆浓度的检测方法的性能。方法采用ACN: EtOH: DMF (8:1:1 v:v:v)溶液从10µL体积的K2-EDTA人血浆中提取satovaquone,反相色谱分离,SCIEX 5500 QTrap质谱系统检测。对LC-MS/MS分析的精密度、准确度、携带性、灵敏度、特异性、线性度和干扰度进行评价。结果采用梯度色谱法对阿托伐醌及其氘化内标进行分析,每次注射总循环时间为7.4 min,保留时间为4.3 min。阿托伐醌的动态浓度范围为0.63 ~ 80µM,与靶值的偏差≤±5.1%。测定内精密度≤2.7%,测定间精密度≤8.4%。稀释、结转和干扰研究也在可接受范围内。结论研究表明,基于LC-MS/ ms的方法定量测定阿托伐酮血浆浓度可靠、稳健,可用于确定小儿急性髓性白血病患者阿托伐酮的有效剂量。
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引用次数: 1
Imaging mass spectrometry reveals complex lipid distributions across Staphylococcus aureus biofilm layers 成像质谱显示复杂的脂质分布跨越金黄色葡萄球菌生物膜层
IF 2.2 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2022-11-01 DOI: 10.1016/j.jmsacl.2022.09.003
Emilio S. Rivera , Andy Weiss , Lukasz G. Migas , Jeffrey A. Freiberg , Katerina V. Djambazova , Elizabeth K. Neumann , Raf Van de Plas , Jeffrey M. Spraggins , Eric P. Skaar , Richard M. Caprioli

Introduction

Although Staphylococcus aureus is the leading cause of biofilm-related infections, the lipidomic distributions within these biofilms is poorly understood. Here, lipidomic mapping of S. aureus biofilm cross-sections was performed to investigate heterogeneity between horizontal biofilm layers.

Methods

S. aureus biofilms were grown statically, embedded in a mixture of carboxymethylcellulose/gelatin, and prepared for downstream matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS). Trapped ion mobility spectrometry (TIMS) was also applied prior to mass analysis.

Results

Implementation of TIMS led to a ∼ threefold increase in the number of lipid species detected. Washing biofilm samples with ammonium formate (150 mM) increased signal intensity for some bacterial lipids by as much as tenfold, with minimal disruption of the biofilm structure. MALDI TIMS IMS revealed that most lipids localize primarily to a single biofilm layer, and species from the same lipid class such as cardiolipins CL(57:0) – CL(66:0) display starkly different localizations, exhibiting between 1.5 and 6.3-fold intensity differences between layers (n = 3, p < 0.03). No horizontal layers were observed within biofilms grown anaerobically, and lipids were distributed homogenously.

Conclusions

High spatial resolution analysis of S. aureus biofilm cross-sections by MALDI TIMS IMS revealed stark lipidomic heterogeneity between horizontal S. aureus biofilm layers demonstrating that each layer was molecularly distinct. Finally, this workflow uncovered an absence of layers in biofilms grown under anaerobic conditions, possibly indicating that oxygen contributes to the observed heterogeneity under aerobic conditions. Future applications of this workflow to study spatially localized molecular responses to antimicrobials could provide new therapeutic strategies.

虽然金黄色葡萄球菌是生物膜相关感染的主要原因,但这些生物膜内的脂质组学分布尚不清楚。本研究对金黄色葡萄球菌生物膜横截面进行脂质组学作图,以研究水平生物膜层之间的异质性。金黄色葡萄球菌生物膜静态生长,包埋在羧甲基纤维素/明胶混合物中,制备用于下游基质辅助激光解吸/电离成像质谱(MALDI IMS)。捕获离子迁移谱法(TIMS)也应用于质量分析之前。结果TIMS的实施导致检测到的脂质种类增加了约三倍。用甲酸铵(150毫米)洗涤生物膜样品可使某些细菌脂质的信号强度提高10倍,同时对生物膜结构的破坏最小。MALDI TIMS IMS显示,大多数脂质主要定位于单一的生物膜层,而来自同一脂类的物种,如心磷脂CL(57:0) - CL(66:0)显示出明显不同的定位,在层之间表现出1.5至6.3倍的强度差异(n = 3, p <0.03)。厌氧培养的生物膜内无水平层,脂质分布均匀。结论利用MALDI TIMS IMS对金黄色葡萄球菌生物膜进行高空间分辨率分析,发现水平金黄色葡萄球菌生物膜层之间存在明显的脂质组学异质性,表明各层在分子上是不同的。最后,该工作流程揭示了厌氧条件下生长的生物膜中缺乏层,这可能表明氧气有助于在好氧条件下观察到的异质性。未来应用这一工作流程来研究对抗菌素的空间定位分子反应可以提供新的治疗策略。
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引用次数: 2
期刊
Journal of Mass Spectrometry and Advances in the Clinical Lab
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