The Mu2e experiment at Fermilab will search for the neutrinoless μ−→e− conversion in the field of an aluminum nucleus. The Mu2e data-taking plan assumes two running periods, Run I and Run II, separated by an approximately two-year-long shutdown. This paper presents an estimate of the expected Mu2e Run I search sensitivity and includes a detailed discussion of the background sources, uncertainties of their prediction, analysis procedures, and the optimization of the experimental sensitivity. The expected Run I 5σ discovery sensitivity is Rμe=1.2×10−15, with a total expected background of 0.11±0.03 events. In the absence of a signal, the expected upper limit is Rμe<6.2×10−16 at 90% CL. This represents a three order of magnitude improvement over the current experimental limit of Rμe<7×10−13 at 90% CL set by the SINDRUM II experiment.

We describe a mass spectrometry (MS) analytical platform resulting from the novel integration of acoustic droplet ejection (ADE) technology, an open-port interface (OPI), and electrospray ionization (ESI)-MS that creates a transformative system enabling high-speed sampling and label-free analysis. The ADE technology delivers nanoliter droplets in a touchless manner with high speed, precision, and accuracy. Subsequent sample dilution within the OPI, in concert with the capabilities of modern ESI-MS, eliminates the laborious sample preparation and method development required in current approaches. This platform is applied to a variety of experiments, including high-throughput (HT) pharmacology screening, label-free in situ enzyme kinetics, in vitro absorption, distribution, metabolism, elimination, pharmacokinetic and biomarker analysis, and HT parallel medicinal chemistry.

The muon-to-electron conversion (Mu2e) experiment at Fermilab will be used to search for the charged lepton flavor-violating conversion of muons to electrons in the field of an atomic nucleus. The Mu2e experiment is currently in the design and construction stage and is expected to begin operations in 2022. The Mu2e experiment uses four large superconducting solenoid magnets including a Production Solenoid (PS), an Upstream and Downstream Transport Solenoid (TSu and TSd) and a Detector Solenoid (DS). This paper will focus on the cryogenic distribution system for these four solenoid magnets. Liquid helium will be supplied from two re-purposed Tevatron satellite refrigerators. A large cryogenic distribution box (DB) is located in the Mu2e building to distribute the required cryogens to each of the four solenoid magnets. Each solenoid magnet will have a dedicated transfer line and cryogenic feed box (FB). The solenoid magnets each require two liquid helium circuits and two liquid nitrogen circuits. The most unique feature about this cryogenic system is that the assemblies for the start of the superconducting portion of the power leads are mounted in feed boxes that are in the range of 23 m to 31 m away from the solenoid magnets. The cryogenic feed boxes are located remotely to provide protection from radiation damage and high magnetic fields. The power leads are NbTi superconducting cable stabilized with high conductivity aluminum. The 6061-T6 aluminum grade was selected for the transfer line piping so that the piping would thermally contract at the same rate as the power lead. A major concern for this transfer line is that a small helium leak could create an electric discharge arc due to the Paschen effect. This paper includes a description of the design features and testing done to ensure that the power leads are protected from the Paschen effect while still being adequately cooled to liquid helium temperatures.

A microfluidic system has been designed that integrates both imaged capillary isoelectric focusing (iCIEF) separations and downstream MS detection into a single assay. Along with the construction of novel instrumentation and an innovative microfluidic chip, conversion to MS‐compatible separation reagents has also been established. Incorporation of 280 nm absorbance iCIEF‐MS analysis not only permits photometric quantitation of separated charge isoforms but also facilitates the direct monitoring of analyte focusing and mobilization in real‐time. The outcome of this effort is a device with the unique ability to allow for both the characterization and identification of protein charge and mass isoforms in under 15 min. Acquisition, quantitation, and identification of highly resolved intact mAb charge isoforms along with their critical N‐linked glycan pairs clearly demonstrate analytical utility of our innovative system. In total, 33 separate molecular features were characterized by the iCIEF‐MS system representing a dramatic increase in the ability to monitor multiple intact mAb critical quality attributes in a single comprehensive assay. Unlike previously reported CIEF‐MS results, relatively high ampholyte concentrations, of up to 4% v/v, were employed without impacting MS sensitivity, observed to be on the order of 1% composition.

In recent years, the direct coupling of solid phase microextraction (SPME) and mass spectrometry (MS) has shown its great potential to improve limits of quantitation, accelerate analysis throughput, and diminish potential matrix effects when compared to direct injection to MS. In this study, we introduce the open port probe (OPP) as a robust interface to couple biocompatible SPME (Bio-SPME) fibers to MS systems for direct electrospray ionization. The presented design consisted of minimal alterations to the front-end of the instrument and provided better sensitivity, simplicity, speed, wider compound coverage, and high-throughput in comparison to the LC-MS based approach. Quantitative determination of clenbuterol, fentanyl, and buprenorphine was successfully achieved in human urine. Despite the use of short extraction/desorption times (5 min/5 s), limits of quantitation below the minimum required performance levels (MRPL) set by the world antidoping agency (WADA) were obtained with good accuracy (≥90%) and linearity (R2 > 0.99) over the range evaluated for all analytes using sample volumes of 300 μL. In-line technologies such as multiple reaction monitoring with multistage fragmentation (MRM3) and differential mobility spectrometry (DMS) were used to enhance the selectivity of the method without compromising analysis speed. On the basis of calculations, once coupled to high throughput, this method can potentially yield preparation times as low as 15 s per sample based on the 96-well plate format. Our results demonstrated that Bio-SPME-OPP-MS efficiently integrates sampling/sample cleanup and atmospheric pressure ionization, making it an advantageous configuration for several bioanalytical applications, including doping in sports, in vivo tissue sampling, and therapeutic drug monitoring.

Thesolenoid test facility at Fermilab was built using a large vacuum vessel for testing of conduction-cooled superconducting solenoid magnets, and was first used to determine the performance of the MICE coupling coil. The facilitywas modified recently to enable the testing of solenoid magnets for the muon-to-electron (Mu2e) experiment, which operates at much higher current than the coupling coil. One pair of low-current conduction-cooled copper and NbTi leads was replaced with two pairs of 10-kA high-temperature superconducting leads cooled by heat exchange with liquid nitrogen and liquid helium. The new design, with additional control and monitoring capability, also provides helium cooling of the superconducting magnet leads by conduction. A high current power supply with energy extraction was added, and several improvements to the quench protection and characterization system were made. Here, we present details of these changes and report on performance results from a test of the Mu2e prototype transport solenoid (TS) module. Progress on additional improvements in preparation for production TS module testing will be presented.

Mass spectrometry (MS) based quantitative approaches typically require a thorough sample clean-up and a decent chromatographic step in order to achieve needed figures of merit. However, in most cases, such processes are not optimal for urgent assessments and high-throughput determinations. The direct coupling of solid phase microextraction (SPME) to MS has shown great potential to shorten the total sample analysis time of complex matrices, as well as to diminish potential matrix effects and instrument contamination. In this study, we demonstrate the use of the open-port probe (OPP) as a direct and robust sampling interface to couple biocompatible-SPME (Bio-SPME) fibres to MS for the rapid quantitation of opioid isomers (i.e. codeine and hydrocodone) in human plasma. In place of chromatography, a differential mobility spectrometry (DMS) device was implemented to provide the essential selectivity required to quantify these constitutional isomers. Taking advantage of the simplified sample preparation process based on Bio-SPME and the fast separation with DMS-MS coupling via OPP, a high-throughput assay (10-15 s per sample) with limits of detection in the sub-ng/mL range was developed. Succinctly, we demonstrated that by tuning adequate ion mobility separation conditions, SPME-OPP-MS can be employed to quantify non-resolved compounds or those otherwise hindered by co-extracted isobaric interferences without further need of coupling to other separation platforms.

BioanalysisVol. 5, No. 11 EditorialMicro-LC–MS/MS: the future of bioanalysisDon W Arnold & Shane R NeedhamDon W Arnold* Author for correspondenceEksigent, part of AB Sciex, 1201 Radio Road, Redwood Shores, CA 94065, USA. Search for more papers by this authorEmail the corresponding author at dwarnold@eksigent.com & Shane R NeedhamAlturas Analytics, Inc. 1324 Alturas Dr. Moscow, ID 83843, USASearch for more papers by this authorPublished Online:6 Jun 2013https://doi.org/10.4155/bio.13.31AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail View articleKeywords: delay volumemicro-LCmicro-LC–MS/MSUHPLCReferences1 Knox JH. Theoretical aspects of LC with packed and open small-bore columns. J. Chromatogr. Sci.18(9),453–461 (1980).Crossref, CAS, Google Scholar2 Reese CE, Scott RPW. Microbore columns – design, construction, and operation. J. Chromatogr. Sci.18(9),479–486 (1980).Crossref, CAS, Google Scholar3 Visser JPC, Claessens HA, Cramers CA. Microcolumn liquid chromatography: instrumentation, detection and applications. J. Chromatogr. A77,1–28 (1997).Crossref, Google Scholar4 Villiers A, Lauer H, Szucs R, Goodall S, Sandra P. Influence of frictional heating on temperature gradients in ultra-high-pressure liquid chromatography on 2.1 mm I.D. columns. J. Chrom. A1113(1–2),84–91 (2006).Crossref, Medline, Google Scholar5 Gritti F, Martin M, Guiochon G. Influence of viscous friction heating on the efficiency of columns operated under very high pressures. Anal. Chem.81,3365–3384 (2009).Crossref, Medline, CAS, Google Scholar6 Colón LA, Cintrón JM, Anspach JA, Fermier AM, Swinney KA. Very high pressure HPLC with 1 mm ID columns. Analyst129,503–504 (2004).Crossref, Medline, CAS, Google Scholar7 Covey TR, Devanand P. Nanospray Electrospray Ionization Development: LC/MS, CE/MS Application. Practical Spectroscopy Series, Volume 32: Applied Electrospray Mass Spectrometry. Pramanik BN, Ganguly AK, Gross ML (Eds). Marcel Dekker, NY, USA (2002).Google Scholar8 Christianson CC, Johnson CJL, Needham SR. The advantages of microflow LC–MS/MS compared with conventional HPLC–MS/MS for the analysis of methotrexate from human plasma. Bioanalysis5(11),1387–1396 (2013).Link, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByComparison of pharmacokinetic study profiles of insulin in rat plasma through conventional sampling and microsampling by micro-LC–MS/MSGaudry Bruno Troché, Tue Søeborg, Thóra Brynja Bödvarsdottir, Mads Bjelke & Nikoline Juul Nielsen14 April 2023 | Bioanalysis, Vol. 15, No. 5Bioanalytical LC–MS/MS method for simultaneous estimation of atorvastatin, its major active metabolites and ezetimibeEhab F Elkady, Bushra M Jaadan, Elsayed Ramadan & Ayman Abo Elmaaty9 January 2023 | Bioanalysis, Vol. 14, No. 21Research Progress on Quantification Methods of Drug Concentration of Monoclonal AntibodiesCurrent Pharmaceutical Analysis, Vol. 18, No. 7On the potential of micro-flow LC-MS/MS in proteomics18 October 2022 | Expert Review of Proteomics, Vol. 19, No. 3Omics in medicinal plantsPharmacokinetic and metabolic analysis of an Alzheimer's disease therapeutic in rat serum via microfluidic CZE–MS4 October 2021 | Biomedical Chromatography, Vol. 36, No. 1Evaluation of OptiFlow™-MS/MS for bioanalysis of pharmaceutical drugs and metabolitesJason Barricklow, Joseph Tweed, Christopher L Holliman & Ragu Ramanathan18 December 2019 | Bioanalysis, Vol. 12, No. 1Metaproteomics of the human gut microbiota: Challenges and contributions to other OMICSClinical Mass Spectrometry, Vol. 14Microflow UPLC and high-resolution MS as a sensitive and robust platform for quantitation of intact peptide hormonesZhuo Chen, Yun W Alelyunas, Mark D Wrona, Jonathan R Kehler, Matthew E Szapacs & Christopher A Evans12 July 2019 | Bioanalysis, Vol. 11, No. 13Instrumental and technical evolution over the past decade in bioanalysisRobert MacNeill4 April 2019 | Bioanalysis, Vol. 11, No. 7Qualitative and quantitative characterization of protein biotherapeutics with liquid chromatography mass spectrometry20 April 2016 | Mass Spectrometry Reviews, Vol. 36, No. 6Peptide and Protein Bioanalysis Using Integrated Column‐to‐Source Technology for High‐Flow Nanospray2 June 2017SWATH-MS as a tool for biomarker discovery: From basic research to clinical applications16 February 2017 | PROTEOMICS, Vol. 17, No. 3-4Micro-liquid chromatography mass spectrometry for the analysis of antineoplastic drugs from wipe samples21 September 2016 | Analytical and Bioanalytical Chemistry, Vol. 408, No. 28Advances in LC: bioanalytical method transferPatricia Wright & Adrian Wright5 August 2016 | Bioanalysis, Vol. 8, No. 17Key Mass Spectrometry Techniques Used in Clinical Biomarker Research23 August 2016Method development strategies in bioanalysis28 October 2015Sense and nonsense of miniaturized LC–MS/MS for bioanalysisMartijn Hilhorst, Chad Briscoe & Nico van de Merbel23 December 2014 | Bioanalysis, Vol. 6, No. 24Quantitative bioanalysis by microflow LC–MS to support discovery-based pharmacokinetic studies24 October 2014Applications of low-flow LC–SRM for the analysis of large molecules in pharmaceutical R&DMichael E Lassman & Carmen Fernandez-Metzler26 August 2014 | Bioanalysis, Vol. 6, No. 13Quantitation of human peptides and proteins via MS: review of analytically validated assaysDerek L Chappell, Michael E Lassman, Thomas McAvoy, Mingxiang Lin, Daniel S Spellman, Omar F Laterza26 August 2014 | Bioanalysis, Vol. 6, No. 13 Vol. 5, No. 11 STAY CONNECTED Metrics Downloaded 546 times History Published online 6 June 2013 Published in print June 2013 Information© Future Science LtdKeywordsdelay volumemicro-LCmicro-LC–MS/MSUHPLCFinancial & competing interests disclosureDW Arnold is a Vice President and Principal Scientist at Eksigent, part of AB SCIEX, a manufacturer of micro-LC–MS/MS systems. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download

The Eksigent ExpressLC Ultra micro high pressure LC system was evaluated and found to provide separation efficiency and system reproducibility comparable with conventional HPLC instruments, albeit with somewhat higher UV detector noise. The dwell volume of the system was measured and found to be extremely small compared with conventional HPLC and UHPLC system which makes the Eksigent micro UHPLC an excellent choice for super fast gradient separation.

The Eksigent ExpressLC Ultra micro high pressure LC system was evaluated and found to provide separation efficiency and system reproducibility comparable with conventional HPLC instruments, albeit with somewhat higher UV detector noise. The dwell volume of the system was measured and found to be extremely small compared with conventional HPLC and UHPLC system which makes the Eksigent micro UHPLC an excellent choice for super fast gradient separation.

A superconducting, 3.9 GHz, third harmonic accelerating cavity, developed at Fermilab, required a completely new main power coupler design to meet performance requirements, cost, and manufacturability. The RF design and optimization, multipactor problem analysis, and solid modeling were completed for non-adjustable version of the coupler. We have also begun a new power coupler design for the 325 MHz single, double and triple spoke cavities. The analysis of the couplers included magnetic and electrical coupling versions. In this paper, we discuss the status of the coupler development for 3.9 GHz and 325 MHz cavities . INTRODUCTION Fermilab is working on a few SC projects. One of them is 3rd harmonic 3.9 GHz accelerating cavity, developing for TTF/FEL facility to increase beam peak current [1-3]. Another project is Proton Driver (PD), designing to generate powerful 1GeV proton beam for neutrino physics [2]. The medium energy part of the PD linac will explore 325 MHz single, double and triple spoke SC cavities. Needed power level to feed SC cavities in both projects is from tens to hundreds of kW peak power. Since the chosen cavity frequencies are quite different from what is used in other SC projects (SNS, TESLA, etc.) none of existing power coupler can be easily adopted for projects.. COUPLER DESIGN FOR THIRD HARMONIC CAVITY Fig. 1. Coupler layout in cryostat The module with the four 3rd harmonic cavities is planning to install at DESY TTF/FEL facility. Since the available space is limited, the cryostat with cavities will be build as an extension of existing TTF cryostat. So, geometrical and assembly constrains for the coupler, as well as requirements are similar to the 1.3 GHz TTF coupler [5]. The required power level ~50 kW is defined by accelerating gradient 14 MV/m and beam loading. Layout of the final coupler in cryostat is shown on Fig.1. Coaxial part has 50Ω with a 30mm outer diameter to prevent excitation of the asymmetrical modes. All components of the coupler: cold and warm windows, bellow section, coax-to-waveguide transition, vacuum and diagnostic ports, were optimized by HFSS for low reflection (S11<0.05) at the operating frequency.

We report the development of a hand-held instrument capable of performing two simultaneous microchip separations (gel and zone electrophoresis), and demonstrate this instrument for the detection of protein biotoxins. Two orthogonal analysis methods are chosen over a single method in order to improve the probability of positive identification of the biotoxin in an unknown mixture. Separations are performed on a single fused-silica wafer containing two separation channels. The chip is housed in a microfluidic manifold that utilizes o-ring sealed fittings to enable facile and reproducible fluidic connection to the chip. Sample is introduced by syringe injection into a septumsealed port on the device exterior that connects to a sample loop etched onto the chip. Detection of low nanomolar concentrations of fluorescamine-labeled proteins is achieved using a miniaturized laser-induced fluorescence detection module employing two diode lasers, one per separation channel. Independently controlled miniature highvoltage power supplies enable fully programmable electrokinetic sample injection and analysis. As a demonstration of the portability of this instrument, we evaluated its performance in a laboratory field test at the Defence Science and Technology Laboratory with a series of biotoxin variants. The two separation methods cleanly distinguish between members of a biotoxin test set. Analysis of naturally occurring variants of ricin and two closely related staphylococcal enterotoxins indicates the two methods can be used to readily identify ricin in its different forms and can discriminate between two enterotoxin isoforms.