A shoebox-sized, 10-kg, handheld mass spectrometer, Mini 10, based on a rectilinear ion trap mass analyzer has been designed, built, and characterized. This instrument has evolved from a decade-long experimental and simulation program in mass spectrometer miniaturization. The rectilinear ion trap has a simplified geometry and high trapping capacity, and when used with a miniature and ruggedized pumping system, it allows chemical analysis while the instrument is being carried. Compact electronics, including an air core RF drive coil, were developed to control the instrument and to record mass spectra. The instrument runs on battery power, consuming less than 70 W, similar to a laptop computer. Wired and wireless networking capabilities are implemented. The instrument gives unit resolution and a mass range of over m/z 500. Tandem mass spectrometry capabilities are implemented using collision-induced dissociation, and they are used to provide confirmation of chemical structure during in situ analysis. Continuous monitoring of air and solution samples is demonstrated, and a limit of detection of 50 ppb was obtained for toluene vapor in air and for an aqueous naphthalene solution using membrane sample introduction.
The performance of mass spectrometers with limited pumping capacity is shown to be improved through use of a discontinuous atmospheric pressure interface (DAPI). A proof-of-concept DAPI interface was designed and characterized using a miniature rectilinear ion trap mass spectrometer. The interface consists of a simple capillary directly connecting the atmospheric pressure ion source to the vacuum mass analyzer region; it has no ion optical elements and no differential pumping stages. Gases carrying ionized analytes were pulsed into the mass analyzer for short periods at high flow rates rather than being continuously introduced at lower flow rates; this procedure maximized ion transfer. The use of DAPI provides a simple solution to the problem of coupling an atmospheric pressure ionization source to a miniature instrument with limited pumping capacity. Data were recorded using various atmospheric pressure ionization sources, including electrospray ionization (ESI), nano-ESI, atmospheric pressure chemical ionization (APCI), and desorption electrospray ionization (DESI) sources. The interface was opened briefly for ion introduction during each scan. With the use of the 18 W pumping system of the Mini 10, limits of detection in the low part-per-billion levels were achieved and unit resolution mass spectra were recorded.
A wireless-controlled miniature rectilinear ion trap mass spectrometer system, total weight with batteries 5.0 kg, consuming less than 35 W of power, and having dimensions of 22 cm in length by 12 cm in width by 18 cm in height, is characterized. The design and construction of the mass spectrometer including mass analyzer, vacuum system, electronics system, and data acquisition and processing systems, is detailed. The mass spectrometer is compatible with various types of ionization sources including a glow discharge electron impact ionization source used in the internal ionization mode, and various atmospheric pressure ionization sources, including electrospray ionization, atmospheric pressure chemical ionization, and desorption electrospray ionization, which are employed for external, atmospheric pressure ionization. These external sources are coupled to the miniature mass spectrometer via a capillary interface that is operated in a discontinuous fashion (discontinuous atmospheric pressure interface) to maximize ion transport. The performance of the mass spectrometer for large and small molecules is characterized. Limits of detection in the parts-per-billion range were obtained for selected compounds examined using both the internal ionization and external ionization modes. Tandem mass spectrometry and fast in situ analysis capabilities are also demonstrated using a variety of compounds and ionization sources. Protein molecules are analyzed as the multiply protonated molecules with mass/charge ratios up to 1500 Da/charge.Miniature mass spectrometers are useful because they combine the usual advantages of mass spectrometrysbroad applicability, high sensitivity, high specificityswith the convenience of fast in situ analysis. These features are important to many applications in the area of public safety, environmental protection, and industrial process monitoring, among others.1 After a decade of increased attention, progress in the development of hand-portable mass spectrometers is becoming increasingly rapid. Ion traps of a variety of types have been the mass analyzer of choice in most recent miniature mass spectrometers, a choice made mainly because of their inherent tandem MS capability, relaxed requirement for high vacuum, and flexible modes of operation.2-8 Batterypowered ion trap miniature mass spectrometers with weights below 10 kg have been developed and a few have began to appear as commercial products. [9][10][11][12]
Enterococcus faecalis is a Gram-positive, opportunistic, pathogenic bacterium that causes a significant number of antibiotic-resistant infections in hospitalized patients. The development of antibiotic resistance in hospital-associated pathogens is a formidable public health threat. In E. faecalis and other Gram-positive pathogens, correlations exist between lipid composition and antibiotic resistance. Resistance to the last-resort antibiotic daptomycin is accompanied by a decrease in phosphatidylglycerol (PG) levels, whereas multiple peptide resistance factor (MprF) converts anionic PG into cationic lysyl-PG via a trans-esterification reaction, providing resistance to cationic antimicrobial peptides. Unlike previous studies that relied on thin layer chromatography and spectrophotometry, we have performed liquid chromatography-tandem mass spectrometry (LC-MS/MS) directly on lipids extracted from E. faecalis, and quantified the phospholipids through multiple reaction monitoring (MRM). In the daptomycin-sensitive E. faecalis strain OG1RF, we have identified 17 PGs, 8 lysyl-PGs (LPGs), 23 cardiolipins (CL), 3 glycerophospho-diglucosyl-diacylglycerols (GPDGDAG), 5 diglucosyl-diacylglycerols (DGDAG), 3 diacylglycerols (DAGs), and 4 triacylglycerols (TAGs). We have quantified PG and shown that PG levels vary during growth of E. faecalis in vitro. We also show that two daptomycin-resistant (DapR) strains of E. faecalis have substantially lower levels of PG and LPG levels. Since LPG levels in these strains are lower, daptomycin resistance is likely due to the reduction in PG. This lipidome map is the first comprehensive analysis of membrane phospholipids and glycolipids in the important human pathogen E. faecalis, for which antimicrobial resistance and altered lipid homeostasis have been intimately linked.
The capabilities of a portable mass spectrometer for real-time monitoring of trace levels of benzene, toluene, and ethylbenzene in air are illustrated. An atmospheric pressure interface was built to implement atmospheric pressure chemical ionization for direct analysis of gas-phase samples on a previously described miniature mass spectrometer (Gao et al. Anal. Chem. 2006, 78, 5994 -6002). Linear dynamic ranges, limits of detection and other analytical figures of merit were evaluated: for benzene, a limit of detection of 0.2 parts-per-billion was achieved for air samples without any sample preconcentration. The corresponding limits of detection for toluene and ethylbenzene were 0.5 parts-per-billion and 0.7 parts-per-billion, respectively. These detection limits are well below the compounds' permissible exposure levels, even in the presence of added complex mixtures of organics at levels exceeding the parts-per-million level. The linear dynamic ranges of benzene, toluene, and ethylbenzene are limited to approximately two orders of magnitude by saturation of the detection electronics. (J Am Soc Mass Spectrom 2010, 21, 132-135)
The first coupling of atmospheric pressure ionization methods, electrospray ionization (ESI) and desorption electrospray ionization (DESI), to a miniature hand-held mass spectrometer is reported. The instrument employs a rectilinear ion trap (RIT) mass analyzer and is battery-operated, hand-portable, and rugged (total system: 10 kg, 0.014 m(3), 75 W power consumption). The mass spectrometer was fitted with an atmospheric inlet, consisting of a 10 cm x 127 microm inner diameter stainless steel capillary tube which was used to introduce gas into the vacuum chamber at 13 mL/min. The operating pressure was 15 mTorr. Ions, generated by the atmospheric pressure ion source, were directed by the inlet along the axis of the ion trap, entering through an aperture in the dc-biased end plate, which was also operated as an ion gate. ESI and DESI sources were used to generate ions; ESI-MS analysis of an aqueous mixture of drugs yielded detection limits in the low parts-per-billion range. Signal response was linear over more than 3 orders of magnitude. Tandem mass spectrometry experiments were used to identify components of this mixture. ESI was also applied to the analysis of peptides and in this case multiply charged species were observed for compounds of molecular weight up to 1200 Da. Cocaine samples deposited or already present on different surfaces, including currency, were rapidly analyzed in situ by DESI. A geometry-independent version of the DESI ion source was also coupled to the miniature mass spectrometer. These results demonstrate that atmospheric pressure ionization can be implemented on simple portable mass spectrometry systems.
Enzymes at the phosphoenolpyruvate (PEP)–pyruvate–oxaloacetate or anaplerotic (ANA) node control the metabolic flux to glycolysis, gluconeogenesis, and anaplerosis. Here we used genetic, biochemical, and 13C isotopomer analysis to characterize the role of the enzymes at the ANA node in intracellular survival of the world's most successful bacterial pathogen, Mycobacterium tuberculosis (Mtb). We show that each of the four ANA enzymes, pyruvate carboxylase (PCA), PEP carboxykinase (PCK), malic enzyme (MEZ), and pyruvate phosphate dikinase (PPDK), performs a unique and essential metabolic function during the intracellular survival of Mtb. We show that in addition to PCK, intracellular Mtb requires PPDK as an alternative gateway into gluconeogenesis. Propionate and cholesterol detoxification was also identified as an essential function of PPDK revealing an unexpected role for the ANA node in the metabolism of these physiologically important intracellular substrates and highlighting this enzyme as a tuberculosis (TB)-specific drug target. We show that anaplerotic fixation of CO2 through the ANA node is essential for intracellular survival of Mtb and that Mtb possesses three enzymes (PCA, PCK, and MEZ) capable of fulfilling this function. In addition to providing a back-up role in anaplerosis we show that MEZ also has a role in lipid biosynthesis. MEZ knockout strains have an altered cell wall and were deficient in the initial entry into macrophages. This work reveals that the ANA node is a focal point for controlling the intracellular replication of Mtb, which goes beyond canonical gluconeogenesis and represents a promising target for designing novel anti-TB drugs.
The identification of serum biomarkers to improve the diagnosis and prognosis of hepatocellular carcinoma has been elusive to date. In this study, we took a mass spectroscopic approach to characterize metabolic features of the liver in hepatocellular carcinoma patients to discover more sensitive and specific biomarkers for diagnosis and progression. Global metabolic profiling of 50 pairs of matched liver tissue samples from hepatocellular carcinoma patients was performed. A series of 62 metabolites were found to be altered significantly in liver tumors; however, levels of acetylcarnitine correlated most strongly with tumor grade and could discriminate between hepatocellular carcinoma tumors and matched normal tissues. Post hoc analysis to evaluate serum diagnosis and progression potential further confirmed the diagnostic capability of serum acetylcarnitine. Finally, an external validation in an independent batch of 58 serum samples (18 hepatocellular carcinoma patients, 20 liver cirrhosis patients, and 20 healthy individuals) verified that serum acetylcarnitine was a meaningful biomarker reflecting hepatocellular carcinoma diagnosis and progression. These findings present a strong new candidate biomarker for hepatocellular carcinoma with potentially significant diagnostic and prognostic capabilities.
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