@misc{bedlack_barkhaus_barnes_bereman_bertorini_carter_crayle_kihuwa-mani_bowser_kittrell_et al._2022, title={ALSUntangled #60: light therapy}, volume={23}, ISSN={["2167-9223"]}, DOI={10.1080/21678421.2021.1883668}, abstractNote={ALSUntangled reviews alternative and off-label treatments for people with ALS. Here we review light therapy. We show that it has theoretically plausible mechanisms, three flawed pre-clinical data, studies, and one incompletely documented case report supporting its use. We explain why further studies are needed to determine whether any specific light therapy protocol can help people with ALS.}, number={3-4}, journal={AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION}, author={Bedlack, Richard and Barkhaus, Paul and Barnes, Ben and Bereman, Michael and Bertorini, Tulio and Carter, Gregory and Crayle, Jesse and Kihuwa-Mani, Sky and Bowser, Robert and Kittrell, Pamela and et al.}, year={2022}, month={Apr}, pages={315–319} }
 @article{amato_fricke_marella_mogus_bereman_mccoy_2022, title={An experimental evaluation of the efficacy of perinatal sulforaphane supplementation to decrease the incidence and severity of vinclozolin-induced hypospadias in the mouse model}, volume={451}, ISSN={["1096-0333"]}, DOI={10.1016/j.taap.2022.116177}, abstractNote={Determining the mechanisms of toxicity induced by pollutants has long been a research priority in lieu of considering the mechanisms of resilience that prevent deleterious impacts. Protective mechanisms in many taxa can be therapeutically targeted to enhance resilience to synthetic toxicants. For example, the environmental sensor, Nuclear factor (erythroid-derived 2)-like 2 (Nfe2l2 or Nrf2), a transcription factor, facilitates transcription of many protective genes. Hypospadias is a common malformation of the penis. The risk of being born with hypospadias increases with pollutant exposure. We use vinclozolin-induced hypospadias in the mouse as a model to test the hypothesis that pollutant-induced birth defects can be prevented and reduced in severity by augmenting natural mechanisms of resilience. Pregnant mice were exposed to the demasculinizing toxicant, vinclozolin, in combination with increasing doses of the NRF2 activator, sulforaphane. The sulforaphane dose that most effectively increased masculinization (anogenital distance) was identified and used to test the hypothesis that sulforaphane reduces the hypospadias-inducing potency of vinclozolin. Finally, a Nrf2 knockout study was conducted to test whether NRF2 was required for the sulforaphane-induced rescue effects. Sulforaphane supplementation to vinclozolin exposed embryos increased anogenital distance in a nonlinear fashion typical of Nrf2 activators. The most effective dose of sulforaphane (45 mg/kg) reduced the occurrence and severity of vinclozolin-induced hypospadias and corrected penis morphogenesis. The sulforaphane-induced rescue effect was dependent on the presence of Nrf2. Nrf2 plays a critical role in protecting the fetus from vinclozolin and reduces the incidence and severity of hypospadias, the most common birth defect in boys in many countries. This work lays a foundation for developing prenatal supplements that will protect the fetus from pollutant-induced hypospadias. Studying the protective mechanisms that drive resilience to toxicants will facilitate innovation of protective therapies.}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={Amato, Ciro M. and Fricke, Ariel and Marella, Sahiti and Mogus, Joshua P. and Bereman, Michael and McCoy, Krista A.}, year={2022}, month={Sep} }
 @article{martin_bereman_marsden_2022, title={The Cyanotoxin 2,4-DAB Reduces Viability and Causes Behavioral and Molecular Dysfunctions Associated with Neurodegeneration in Larval Zebrafish}, volume={40}, ISSN={["1476-3524"]}, url={https://doi.org/10.1007/s12640-021-00465-4}, DOI={10.1007/s12640-021-00465-4}, abstractNote={Exposure to cyanotoxins has been linked to neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease. While the cyanotoxin β-methylamino-L-alanine (BMAA) has received much attention, cyanobacteria produce many cyanotoxic compounds, several of which have been detected in nature alongside BMAA, including 2,4-diaminobutyric acid (2,4-DAB) and N-(2-aminoethyl)glycine (AEG). Thus, the question of whether 2,4-DAB and AEG also cause neurotoxic effects in vivo is of great interest, as is the question of whether they interact to enhance toxicity. Here, we evaluate the toxic and neurotoxic effects of these cyanotoxins alone or in combination by measuring zebrafish larval viability and behavior after exposure. 2,4-DAB was the most potent cyanotoxin as it decreased larval viability by approximately 50% at 6 days post fertilization, while BMAA and AEG decreased viability by just 16% and 8%, respectively. Although we only observed minor neurotoxic effects on spontaneous locomotion, BMAA and AEG enhanced acoustic startle sensitivity, and they interacted in an additive manner to exert their effects. 2,4-DAB; however, only modulated startle kinematics, an indication of motor dysfunction. To investigate the mechanisms of 2,4-DAB's effects, we analyzed the protein profile of larval zebrafish exposed to 500 µM 2,4-DAB at two time points and identified molecular signatures consistent with neurodegeneration, including disruption of metabolic pathways and downregulation of the ALS-associated genes SOD1 and UBQLN4. Together, our data demonstrate that BMAA and its isomers AEG and 2,4-DAB cause neurotoxic effects in vivo, with 2,4-DAB as the most potent of the three in the zebrafish model.}, number={2}, journal={NEUROTOXICITY RESEARCH}, publisher={Springer Science and Business Media LLC}, author={Martin, Rubia M. and Bereman, Michael S. and Marsden, Kurt C.}, year={2022}, month={Jan} }
 @article{bedlack_stephens_barkhaus_bereman_caress_crayle_pattee_heiman patterson_wicks_zach_et al._2021, title={ALSUntangled 59: Tamoxifen THE ALSUNTANGLED GROUP}, volume={22}, ISSN={["2167-9223"]}, DOI={10.1080/21678421.2021.1876731}, abstractNote={Here we use the ALSUntangled methodology to review Tamoxifen as an ALS treatment. We show that it has plausible mechanisms, a positive preclinical study, a case report and 2 small trials suggesting benefits. We show that it appears reasonably safe, though there is a small risk of developing cancer with long term use. While we cannot yet endorse this as an ALS treatment, there is enough evidence to warrant another larger ALS trial.}, number={7-8}, journal={AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION}, author={Bedlack, Richard and Stephens, James and Barkhaus, Paul E. and Bereman, Michael and Caress, James B. and Crayle, Jesse and Pattee, Gary L. and Heiman Patterson, Terry and Wicks, Paul and Zach, Neta and et al.}, year={2021}, month={Oct}, pages={595–598} }
 @article{martin_bereman_marsden_2021, title={BMAA and MCLR Interact to Modulate Behavior and Exacerbate Molecular Changes Related to Neurodegeneration in Larval Zebrafish}, volume={179}, ISSN={["1096-0929"]}, url={https://doi.org/10.1093/toxsci/kfaa178}, DOI={10.1093/toxsci/kfaa178}, abstractNote={Exposure to toxins produced by cyanobacteria (ie, cyanotoxins) is an emerging health concern due to their increasing prevalence and previous associations with neurodegenerative diseases including amyotrophic lateral sclerosis. The objective of this study was to evaluate the neurotoxic effects of a mixture of two co-occurring cyanotoxins, β-methylamino-l-alanine (BMAA) and microcystin leucine and arginine (MCLR), using the larval zebrafish model. We combined high-throughput behavior-based toxicity assays with discovery proteomic techniques to identify behavioral and molecular changes following 6 days of exposure. Although neither toxin caused mortality, morphological defects, nor altered general locomotor behavior in zebrafish larvae, both toxins increased acoustic startle sensitivity in a dose-dependent manner by at least 40% (p < .0001). Furthermore, startle sensitivity was enhanced by an additional 40% in larvae exposed to the BMAA/MCLR mixture relative to those exposed to the individual toxins. Supporting these behavioral results, our proteomic analysis revealed a 4-fold increase in the number of differentially expressed proteins in the mixture-exposed group. Additionally, prediction analysis reveals activation and/or inhibition of 8 enriched canonical pathways (enrichment p-value < .01; z-score≥|2|), including ILK, Rho Family GTPase, RhoGDI, and calcium signaling pathways, which have been implicated in neurodegeneration. We also found that expression of TDP-43, of which cytoplasmic aggregates are a hallmark of amyotrophic lateral sclerosis pathology, was significantly upregulated by 5.7-fold following BMAA/MCLR mixture exposure. Together, our results emphasize the importance of including mixtures of cyanotoxins when investigating the link between environmental cyanotoxins and neurodegeneration as we reveal that BMAA and MCLR interact in vivo to enhance neurotoxicity.}, number={2}, journal={TOXICOLOGICAL SCIENCES}, publisher={Oxford University Press (OUP)}, author={Martin, Rubia M. and Bereman, Michael S. and Marsden, Kurt C.}, year={2021}, month={Feb}, pages={251–261} }
 @article{rister_amato_nash_mccoy_bereman_mccoy_2021, title={Toxicant exposure during pregnancy increases protective proteins in the dam and a sexually dimorphic response in the fetus}, volume={413}, ISSN={["1096-0333"]}, DOI={10.1016/j.taap.2021.115407}, abstractNote={Endocrine disrupting compounds (EDCs) are ubiquitous environmental pollutants that alter endocrine system function, induce birth defects, and a myriad of other negative health outcomes. Although the mechanism of toxicity of many EDCs have been studied in detail, little work has focused on understanding the mechanisms through which pregnant dams and fetuses protect themselves from EDCs, or if those protective mechanisms are sexually dimorphic in fetuses. In this study, we examined proteomic alterations in the livers of mouse dams and their male and female fetuses induced by vinclozolin, a model antiandrogenic EDC. Dam livers upregulated nine phase I and phase II detoxification pathways and pathway analysis revealed that more pathways are significantly enriched in dam livers than in fetal livers. Phase I and II detoxification proteins are also involved in steroid and steroid hormone biosynthesis and vinclozolin likely alters steroid levels in both the dam and the fetus. The response of the fetal liver proteome to vinclozolin exposure is sexually dimorphic. Female fetal livers upregulated proteins in xenobiotic metabolism pathways, whereas male fetal livers upregulated proteins in oxidative phosphorylation pathways. These results suggest that female fetuses increase protective mechanisms, whereas male fetuses increase ATP production and several disease pathways that are indicative of oxidative damage. Females fetuses upregulate proteins and protective pathways that were similar to the dams whereas males did not. If this sexually dimorphic pattern is typical, then males might generally be more sensitive to EDCs.}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={Rister, Alana L. and Amato, Ciro M. and Nash, Tara and McCoy, Michael W. and Bereman, Michael and McCoy, Krista A.}, year={2021}, month={Feb} }
 @article{bereman_kirkwood_sabaretnam_furlong_rowe_guillemin_mellinger_muddiman_2020, title={Metabolite Profiling Reveals Predictive Biomarkers and the Absence of beta-Methyl Amino-L-alanine in Plasma from Individuals Diagnosed with Amyotrophic Lateral Sclerosis}, volume={19}, ISSN={["1535-3907"]}, DOI={10.1021/acs.jproteome.0c00216}, abstractNote={By employing chip-based capillary zone electrophoresis coupled to high-resolution mass spectrometry, we profiled the plasma metabolome of 134 patients diagnosed with sporadic amyotrophic lateral sclerosis (ALS) (81 males and 53 females) and 118 individuals deemed healthy (49 males and 69 females). The most significant markers (p < 0.01) were creatine, which was 49% elevated, and creatinine and methylhistidine, which were decreased by 20 and 24%, respectively, in ALS patients. The ratio of creatine versus creatinine increased 370 and 200% for male and female ALS patients, respectively. In addition, male ALS patients on an average had 5–13% lower amounts of seven essential amino acids, whereas females did not significantly differ from healthy controls. We developed two models using the metabolite abundances: (1) a classification model for the separation of ALS and healthy samples and (2) a classification model for the prediction of disease progression based on the ALS functional rating score. Utilizing a Monte Carlo cross-validation approach, a linear discriminant analysis model achieved a mean area under the receiver operating characteristic curve (AUC) of 0.85 (0.06) with a mean sensitivity of 80% (9%) and specificity of 78% (10%) for the separation of ALS and controls, respectively. A support vector machine classifier predicted progression categories with an AUC of 0.90 (0.06) with a mean sensitivity of 73% (10%) and a specificity of 86% (5%). Lastly, using a previously reported assay with a stable isotope-labeled (13C315N2) spike-in standard, we were unable to detect the exogenous neurotoxic metabolite, β-methylamino-l-alanine, in the free or protein-bound fraction of any of the 252 plasma samples.}, number={8}, journal={JOURNAL OF PROTEOME RESEARCH}, author={Bereman, Michael S. and Kirkwood, Kaylie I and Sabaretnam, Tharani and Furlong, Sarah and Rowe, Dominic B. and Guillemin, Gilles J. and Mellinger, Allyson L. and Muddiman, David C.}, year={2020}, month={Aug}, pages={3276–3285} }
 @article{mellinger_griffith_bereman_2020, title={Peptide variability and signatures associated with disease progression in CSF collected longitudinally from ALS patients}, volume={412}, ISSN={["1618-2650"]}, DOI={10.1007/s00216-020-02765-8}, number={22}, journal={ANALYTICAL AND BIOANALYTICAL CHEMISTRY}, author={Mellinger, Allyson L. and Griffith, Emily H. and Bereman, Michael S.}, year={2020}, month={Sep}, pages={5465–5475} }
 @article{hilton_barosova_petri-fink_rothen-rutishauser_bereman_2019, title={Leveraging proteomics to compare submerged versus air-liquid interface carbon nanotube exposure to a 3D lung cell model}, volume={54}, ISSN={["0887-2333"]}, DOI={10.1016/j.tiv.2018.09.010}, abstractNote={With the emerging concern over the potential toxicity associated with carbon nanotube inhalation exposure, several in vitro methods have been developed to evaluate cellular responses. Since the major concern for adverse effects by carbon nanotubes is inhalation, various lung cell culture models have been established for toxicity testing, thus creating a wide variation of methodology. Limited studies have conducted side-by-side comparisons of common methods used for carbon nanotube hazard testing. The aim of this work was to use proteomics to evaluate global cellular response, including pro-inflammatory and pro-fibrotic mediators, of a 3D lung model composed of macrophages, epithelial cells, and fibroblasts which mimics the human alveolar epithelial tissue barrier. The cells were exposed to Mitsui 7 (M-7) multi-walled carbon nanotubes (MWCNT) under submerged and air-liquid interface (ALI) conditions and discovery proteomics identified 3500 proteins. The M-7 ALI exposure compared to control was found to increase expression in proteins related to oxidative stress that were not found to be enriched in submerged exposure. Comparison of MWCNT exposure methods, M-7 ALI exposure versus M-7 submerged exposure, yielded protein enrichment in pathways known to be associated with carbon nanotube exposure stress response, such as acute phase response signaling and NRF2-mediated oxidative stress response. This study demonstrates a comparison of commonly deployed carbon nanotube exposure methods. These data should be considered by the nanotoxicology community when interpreting or cross comparing in vitro exposure results.}, journal={TOXICOLOGY IN VITRO}, author={Hilton, G. and Barosova, H. and Petri-Fink, A. and Rothen-Rutishauser, B. and Bereman, M.}, year={2019}, month={Feb}, pages={58–66} }
 @misc{ideraabdullah_belenchia_rosenfeld_kullman_knuth_mahapatra_bereman_levinlo_peterson_2019, title={Maternal vitamin D deficiency and developmental origins of health and disease (DOHaD)}, volume={241}, ISSN={["1479-6805"]}, DOI={10.1530/JOE-18-0541}, abstractNote={Vitamin D is an essential nutrient that is metabolized in the body to generate an active metabolite (1,25(OH) 2 D) with hormone-like activity and highly diverse roles in cellular function. Vitamin D deficiency (VDD) is a prevalent but easily preventable nutritional disturbance. Emerging evidence demonstrates the importance of sufficient vitamin D concentrations during fetal life with deficiencies leading to long-term effects into adulthood. Here, we provide a detailed review and perspective of evidence for the role of maternal VDD in offspring long-term health, particularly as it relates to developmental origins of health and disease (DOHaD). We focus on the roles in neurobehavioral and cardiometabolic disorders in humans and highlight recent findings from zebrafish and rodent models that probe potential mechanisms linking early life VDD to later life health outcomes. Moreover, we explore evidence implicating epigenetic mechanisms as a mediator of this link. Gaps in our current understanding of how maternal VDD might result in deleterious offspring outcomes later in life are also addressed.}, number={2}, journal={JOURNAL OF ENDOCRINOLOGY}, author={Ideraabdullah, Folami Y. and Belenchia, Anthony M. and Rosenfeld, Cheryl S. and Kullman, Seth W. and Knuth, Megan and Mahapatra, Debabrata and Bereman, Michael and Levinlo, Edward D. and Peterson, Catherine A.}, year={2019}, month={May}, pages={R65–R80} }
 @article{martin_stallrich_bereman_2019, title={Mixture designs to investigate adverse effects upon co-exposure to environmental cyanotoxins}, volume={421}, ISSN={0300-483X}, url={http://dx.doi.org/10.1016/J.TOX.2019.04.013}, DOI={10.1016/j.tox.2019.04.013}, abstractNote={The goal of this study was to implement powerful mixture design techniques, commonly used in process optimization, to investigate enhanced adverse effects upon co-exposure to environmental cyanotoxins. Exposure to cyanobacteria, which are found ubiquitously in environmental water reservoirs, have been linked to several neurodegenerative diseases. Despite the known co-occurrence of various cyanotoxins, the majority of studies investigating this link have focused on the investigation of a single cyanotoxin, a noncanonical amino acid called β-methylamino-L-alanine (BMAA), which poorly recapitulates an actual environmental exposure. Interactions amongst cyanotoxic compounds is an area of great concern and remains poorly understood. To this end, we describe the use of a simplex axial mixture design to screen for interactive adverse effects of cyanotoxic mixtures. Using a combination of basic toxicity assays coupled with contemporary proteomic techniques, our results show the existence of a significant (p ≤ 0.01) interaction between BMAA and its isomers aminoethyl glycine (AEG) and 2,4-diaminobutyric acid (2,4DAB). Cyanotoxic mixtures significantly decreased cell viability by an average of 19% and increased caspases 3/7 activities by an average of 110% when compared to individual cyanotoxins (p ≤ 0.05). Cyanotoxic mixtures perturbed various biological pathways associated with neurodegeneration, including inhibition of protective autophagy and activation of mitochondrial dysfunction (z-score >|2|). Additionally, exposure to mixtures perturbed important upstream regulators involved in cellular dysfunction, morbidity, and development. Taken together, our results highlight: (1) the need to study combinations of cyanotoxins when investigating the link between cyanobacteria and neurodegenerative pathologies and (2) the application of design of experiment (DoE) as an efficient methodology to study mixtures of relevant environmental toxins.}, journal={Toxicology}, publisher={Elsevier BV}, author={Martin, Rubia M. and Stallrich, Jonathan and Bereman, Michael S.}, year={2019}, month={Jun}, pages={74–83} }
 @article{beri_kirkwood_muddiman_bereman_2018, title={A novel integrated strategy for the detection and quantification of the neurotoxin beta-N-methylamino-l-alanine in environmental samples}, volume={410}, ISSN={["1618-2650"]}, DOI={10.1007/s00216-018-0930-0}, number={10}, journal={ANALYTICAL AND BIOANALYTICAL CHEMISTRY}, author={Beri, Joshua and Kirkwood, Kaylie I. and Muddiman, David C. and Bereman, Michael S.}, year={2018}, month={Apr}, pages={2597–2605} }
 @article{bereman_beri_enders_nash_2018, title={Machine Learning Reveals Protein Signatures in CSF and Plasma Fluids of Clinical Value for ALS}, volume={8}, ISSN={["2045-2322"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85056076502&partnerID=MN8TOARS}, DOI={10.1038/s41598-018-34642-x}, abstractNote={Abstract We use shotgun proteomics to identify biomarkers of diagnostic and prognostic value in individuals diagnosed with amyotrophic lateral sclerosis. Matched cerebrospinal and plasma fluids were subjected to abundant protein depletion and analyzed by nano-flow liquid chromatography high resolution tandem mass spectrometry. Label free quantitation was used to identify differential proteins between individuals with ALS (n = 33) and healthy controls (n = 30) in both fluids. In CSF, 118 (p-value < 0.05) and 27 proteins (q-value < 0.05) were identified as significantly altered between ALS and controls. In plasma, 20 (p-value < 0.05) and 0 (q-value < 0.05) proteins were identified as significantly altered between ALS and controls. Proteins involved in complement activation, acute phase response and retinoid signaling pathways were significantly enriched in the CSF from ALS patients. Subsequently various machine learning methods were evaluated for disease classification using a repeated Monte Carlo cross-validation approach. A linear discriminant analysis model achieved a median area under the receiver operating characteristic curve of 0.94 with an interquartile range of 0.88–1.0. Three proteins composed a prognostic model (p = 5e-4) that explained 49% of the variation in the ALS-FRS scores. Finally we investigated the specificity of two promising proteins from our discovery data set, chitinase-3 like 1 protein and alpha-1-antichymotrypsin, using targeted proteomics in a separate set of CSF samples derived from individuals diagnosed with ALS (n = 11) and other neurological diseases (n = 15). These results demonstrate the potential of a panel of targeted proteins for objective measurements of clinical value in ALS.}, number={1}, journal={SCIENTIFIC REPORTS}, author={Bereman, Michael S. and Beri, Joshua and Enders, Jeffrey R. and Nash, Tara}, year={2018}, month={Nov} }
 @article{wang_wander_yuan_bereman_cohen_2017, title={Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program}, volume={8}, ISSN={2041-1723}, url={http://dx.doi.org/10.1038/S41467-017-00088-4}, DOI={10.1038/S41467-017-00088-4}, abstractNote={Abstract TDP-43 pathology marks a spectrum of multisystem proteinopathies including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and sporadic inclusion body myositis. Surprisingly, it has been challenging to recapitulate this pathology, highlighting an incomplete understanding of TDP-43 regulatory mechanisms. Here we provide evidence supporting TDP-43 acetylation as a trigger for disease pathology. Using cultured cells and mouse skeletal muscle, we show that TDP-43 acetylation-mimics promote TDP-43 phosphorylation and ubiquitination, perturb mitochondria, and initiate degenerative inflammatory responses that resemble sporadic inclusion body myositis pathology. Analysis of functionally linked amyotrophic lateral sclerosis proteins revealed recruitment of p62, ubiquilin-2, and optineurin to TDP-43 aggregates. We demonstrate that TDP-43 acetylation-mimic pathology is potently suppressed by an HSF1-dependent mechanism that disaggregates TDP-43. Our study illustrates bidirectional TDP-43 processing in which TDP-43 aggregation is targeted by a coordinated chaperone response. Thus, activation or restoration of refolding mechanisms may alleviate TDP-43 aggregation in tissues that are uniquely susceptible to TDP-43 proteinopathies.}, number={1}, journal={Nature Communications}, publisher={Springer Science and Business Media LLC}, author={Wang, Ping and Wander, Connor M. and Yuan, Chao-Xing and Bereman, Michael S. and Cohen, Todd J.}, year={2017}, month={Jul} }
 @article{beck_camp_bereman_bollinger_egertson_maccoss_wolf-yadlin_2017, title={Development of selected reaction monitoring methods to systematically quantify kinase abundance and phosphorylation stoichiometry in human samples}, volume={1636}, journal={Kinase signaling networks}, author={Beck, K. and Camp, N. and Bereman, M. and Bollinger, J. and Egertson, J. and MacCoss, M. and Wolf-Yadlin, A.}, year={2017}, pages={353–369} }
 @article{beri_nash_martin_bereman_2017, title={Exposure to BMAA mirrors molecular processes linked to neurodegenerative disease}, volume={17}, ISSN={1615-9853}, url={http://dx.doi.org/10.1002/PMIC.201700161}, DOI={10.1002/PMIC.201700161}, abstractNote={The goal of this study is to investigate the molecular pathways perturbed by in vitro exposure of beta-methylamino-L-alanine (BMAA) to NSC-34 cells via contemporary proteomics. Our analysis of differentially regulated proteins reveals significant enrichment (p < 0.01) of pathways related to ER stress, protein ubiquitination, the unfolded protein response, and mitochondrial dysfunction. Upstream regulator analysis indicates that exposure to BMAA induces activation of transcription factors (X-box binding protein 1; nuclear factor 2 erythroid like 2; promyelocytic leukemia) involved in regulation of the UPR, oxidative stress, and cellular senescence. Furthermore, the authors examine the hypothesis that BMAA causes protein damage via misincorporation in place of L-Serine. The authors are unable to detect misincorporation of BMAA into protein via analysis of cellular protein, secreted protein, targeted detection of BMAA after protein hydrolysis, or through the use of in vitro protein translation kits.}, number={17-18}, journal={PROTEOMICS}, publisher={Wiley}, author={Beri, Joshua and Nash, Tara and Martin, Rubia M. and Bereman, Michael S.}, year={2017}, month={Aug}, pages={1700161} }
 @article{dogu_mohammad-taheri_abbatiello_bereman_maclean_schilling_vitek_2017, title={MSstatsQC: Longitudinal System Suitability Monitoring and Quality Control for Targeted Proteomic Experiments}, volume={16}, ISSN={["1535-9484"]}, DOI={10.1074/mcp.m116.064774}, abstractNote={Selected Reaction Monitoring (SRM) is a powerful tool for targeted detection and quantification of peptides in complex matrices. An important objective of SRM is to obtain peptide quantifications that are (1) suitable for the investigation, and (2) reproducible across laboratories and runs. The first objective is achieved by system suitability tests (SST), which verify that mass spectrometric instrumentation performs as specified. The second objective is achieved by quality control (QC), which provides in-process quality assurance of the sample profile. A common aspect of SST and QC is the longitudinal nature of the data. Although SST and QC have received a lot of attention in the proteomic community, the currently used statistical methods are limited. This manuscript improves upon the statistical methodology for SST and QC that is currently used in proteomics. It adapts the modern methods of longitudinal statistical process control, such as simultaneous and time weighted control charts and change point analysis, to SST and QC of SRM experiments, discusses their advantages, and provides practical guidelines. Evaluations on simulated data sets, and on data sets from the Clinical Proteomics Technology Assessment for Cancer (CPTAC) consortium, demonstrated that these methods substantially improve our ability of real time monitoring, early detection and prevention of chromatographic and instrumental problems. We implemented the methods in an open-source R-based software package MSstatsQC and its web-based graphical user interface. They are available for use stand-alone, or for integration with automated pipelines. Although the examples focus on targeted proteomics, the statistical methods in this manuscript apply more generally to quantitative proteomics.}, number={7}, journal={MOLECULAR & CELLULAR PROTEOMICS}, author={Dogu, Eralp and Mohammad-Taheri, Sara and Abbatiello, Susan E. and Bereman, Michael S. and MacLean, Brendan and Schilling, Birgit and Vitek, Olga}, year={2017}, month={Jul}, pages={1335–1347} }
 @article{hilton_taylor_hussain_dandley_griffith_garantziotis_parsons_bonner_bereman_2017, title={Mapping differential cellular protein response of mouse alveolar epithelial cells to multi-walled carbon nanotubes as a function of atomic layer deposition coating}, volume={11}, ISSN={["1743-5404"]}, DOI={10.1080/17435390.2017.1299888}, abstractNote={Carbon nanotubes (CNTs), a prototypical engineered nanomaterial, have been increasingly manufactured for a variety of novel applications over the past two decades. However, since CNTs possess fiber-like shape and cause pulmonary fibrosis in rodents, there is concern that mass production of CNTs will lead to occupational exposure and associated pulmonary diseases. The aim of this study was to use contemporary proteomics to investigate the mechanisms of cellular response in E10 mouse alveolar epithelial cells in vitro after exposure to multi-walled CNTs (MWCNTs) that were functionalized by atomic layer deposition (ALD). ALD is a method used to generate highly uniform and conformal nanoscale thin-film coatings of metals to enhance novel conductive properties of CNTs. We hypothesized that specific types of metal oxide coatings applied to the surface of MWCNTs by ALD would determine distinct proteomic profiles in mouse alveolar epithelial cells in vitro that could be used to predict oxidative stress and pulmonary inflammation. Uncoated (U)-MWCNTs were functionalized by ALD with zinc oxide (ZnO) to yield Z-MWCNTs or aluminum oxide (Al2O3) to yield A-MWCNTs. Significant differential protein expression was found in the following critical pathways: mTOR/eIF4/p70S6K signaling and Nrf-2 mediated oxidative stress response increased following exposure to Z-MWCNTs, interleukin-1 signaling increased following U-MWCNT exposure, and inhibition of angiogenesis by thrombospondin-1, oxidative phosphorylation, and mitochondrial dysfunction increased following A-MWCNT exposure. This study demonstrates that specific types of metal oxide thin film coatings applied by ALD produce distinct cellular and biochemical responses related to lung inflammation and fibrosis compared to uncoated MWCNT exposure in vitro.}, number={3}, journal={NANOTOXICOLOGY}, author={Hilton, Gina M. and Taylor, Alexia J. and Hussain, Salik and Dandley, Erinn C. and Griffith, Emily H. and Garantziotis, Stavros and Parsons, Gregory N. and Bonner, James C. and Bereman, Michael S.}, year={2017}, month={Apr}, pages={313–326} }
 @article{reaves_hoadley_fagan-solis_jima_bereman_thorpe_hicks_mcdonald_troester_perou_et al._2017, title={Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis}, volume={15}, ISSN={["1557-3125"]}, DOI={10.1158/1541-7786.mcr-16-0085-t}, abstractNote={Lipolysis-stimulated lipoprotein receptor (LSR) has been found in the plasma membrane and is believed to function in lipoprotein endocytosis and tight junctions. Given the impact of cellular metabolism and junction signaling pathways on tumor phenotypes and patient outcome, it is important to understand how LSR cellular localization mediates its functions. We conducted localization studies, evaluated DNA binding, and examined the effects of nuclear LSR in cells, xenografts, and clinical specimens. We found LSR within the membrane, cytoplasm, and the nucleus of breast cancer cells representing multiple intrinsic subtypes. Chromatin immunoprecipitation (ChIP) showed direct binding of LSR to DNA, and sequence analysis identified putative functional motifs and post-translational modifications of the LSR protein. While neither overexpression of transcript variants, nor pharmacologic manipulation of post-translational modification significantly altered localization, inhibition of nuclear export enhanced nuclear localization, suggesting a mechanism for nuclear retention. Coimmunoprecipitation and proximal ligation assays indicated LSR-pericentrin interactions, presenting potential mechanisms for nuclear-localized LSR. The clinical significance of LSR was evaluated using data from over 1,100 primary breast tumors, which showed high LSR levels in basal-like tumors and tumors from African-Americans. In tumors histosections, nuclear localization was significantly associated with poor outcomes. Finally, in vivo xenograft studies revealed that basal-like breast cancer cells that overexpress LSR exhibited both membrane and nuclear localization, and developed tumors with 100% penetrance, while control cells lacking LSR developed no tumors. These results show that nuclear LSR alters gene expression and may promote aggressive cancer phenotypes.LSR functions in the promotion of aggressive breast cancer phenotypes and poor patient outcome via differential subcellular localization to alter cell signaling, bioenergetics, and gene expression. Mol Cancer Res; 15(2); 165-78. ©2016 AACR.}, number={2}, journal={MOLECULAR CANCER RESEARCH}, author={Reaves, Denise K. and Hoadley, Katherine A. and Fagan-Solis, Katerina D. and Jima, Dereje D. and Bereman, Michael and Thorpe, Lynnelle and Hicks, Jyla and McDonald, David and Troester, Melissa A. and Perou, Charles M. and et al.}, year={2017}, month={Feb}, pages={165–178} }
 @article{bereman_beri_sharma_nathe_eckels_maclean_maccoss_2016, title={An Automated Pipeline to Monitor System Performance in Liquid Chromatography-Tandem Mass Spectrometry Proteomic Experiments}, volume={15}, ISSN={["1535-3907"]}, DOI={10.1021/acs.jproteome.6b00744}, abstractNote={We report the development of a completely automated pipeline to monitor system suitability in bottom-up proteomic experiments. LC-MS/MS runs are automatically imported into Skyline and multiple identification-free metrics are extracted from targeted peptides. These data are then uploaded to the Panorama Skyline document repository where metrics can be viewed in a web-based interface using powerful process control techniques, including Levey-Jennings and Pareto plots. The interface is versatile and takes user input, which allows the user significant control over the visualization of the data. The pipeline is vendor and instrument-type neutral, supports multiple acquisition techniques (e.g., MS 1 filtering, data-independent acquisition, parallel reaction monitoring, and selected reaction monitoring), can track performance of multiple instruments, and requires no manual intervention aside from initial setup. Data can be viewed from any computer with Internet access and a web browser, facilitating sharing of QC data between researchers. Herein, we describe the use of this pipeline, termed Panorama AutoQC, to evaluate LC-MS/MS performance in a range of scenarios including identification of suboptimal instrument performance, evaluation of ultrahigh pressure chromatography, and identification of the major sources of variation throughout years of peptide data collection.}, number={12}, journal={JOURNAL OF PROTEOME RESEARCH}, author={Bereman, Michael S. and Beri, Joshua and Sharma, Vagisha and Nathe, Cory and Eckels, Josh and MacLean, Brendan and MacCoss, Michael J.}, year={2016}, month={Dec}, pages={4763–4769} }
 @article{murray_walker_bereman_2016, title={Improving the analytical performance and versatility of paper spray mass spectrometry via paper microfluidics}, volume={141}, ISSN={["1364-5528"]}, DOI={10.1039/c6an00649c}, abstractNote={Paper-based microfluidic techniques were explored to increase paper spray mass spectrometry's performance and versatility.}, number={13}, journal={ANALYST}, author={Murray, Ian and Walker, Glenn and Bereman, Michael S.}, year={2016}, pages={4065–4073} }
 @article{porter_bereman_2015, title={Data-independent-acquisition mass spectrometry for identification of targeted-peptide site-specific modifications}, volume={407}, ISSN={["1618-2650"]}, DOI={10.1007/s00216-015-8819-7}, abstractNote={We present a novel strategy based on data-independent acquisition coupled to targeted data extraction for the detection and identification of site-specific modifications of targeted peptides in a completely unbiased manner. This method requires prior knowledge of the site of the modification along the peptide backbone from the protein of interest, but not the mass of the modification. The procedure, named multiplex adduct peptide profiling (MAPP), consists of three steps: 1) A fragment-ion tag is extracted from the data, consisting of the b-type and y-type ion series from the N and C-terminus, respectively, up to the amino-acid position that is believed to be modified; 2) MS1 features are matched to the fragment-ion tag in retention-time space, using the isolation window as a pre-filter to enable calculation of the mass of the modification; and 3) modified fragment ions are overlaid with the unmodified fragment ions to verify the mass calculated in step 2. We discuss the development, applications, and limitations of this new method for detection of unknown peptide modifications. We present an application of the method in profiling adducted peptides derived from abundant proteins in biological fluids with the ultimate objective of detecting biomarkers of exposure to reactive species.}, number={22}, journal={ANALYTICAL AND BIOANALYTICAL CHEMISTRY}, author={Porter, Caleb J. and Bereman, Michael S.}, year={2015}, month={Sep}, pages={6627–6635} }
 @article{beri_rosenblatt_strauss_urh_bereman_2015, title={Reagent for Evaluating Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Performance in Bottom-Up Proteomic Experiments}, volume={87}, ISSN={["1520-6882"]}, DOI={10.1021/acs.analchem.5b04121}, abstractNote={We present a novel proteomic standard for assessing liquid chromatography-tandem mass spectrometry (LC-MS/MS) instrument performance, in terms of chromatographic reproducibility and dynamic range within a single LC-MS/MS injection. The peptide mixture standard consists of six peptides that were specifically synthesized to cover a wide range of hydrophobicities (grand average hydropathy (GRAVY) scores of -0.6 to 1.9). A combination of stable isotope labeled amino acids ((13)C and (15)N) were inserted to create five isotopologues. By combining these isotopologues at different ratios, they span four orders of magnitude within each distinct peptide sequence. Each peptide, from lightest to heaviest, increases in abundance by a factor of 10. We evaluate several metrics on our quadrupole orbitrap instrument using the 6 × 5 LC-MS/MS reference mixture spiked into a complex lysate background as a function of dynamic range, including mass measurement accuracy (MMA) and the linear range of quantitation of MS1 and parallel reaction monitoring experiments. Detection and linearity of the instrument routinely spanned three orders of magnitude across the gradient (500 fmol to 0.5 fmol on column) and no systematic trend was observed for MMA of targeted peptides as a function of abundance by analysis of variance analysis (p = 0.17). Detection and linearity of the fifth isotopologue (i.e., 0.05 fmol on column) was dependent on the peptide and instrument scan type (MS1 vs PRM). We foresee that this standard will serve as a powerful method to conduct both intra-instrument performance monitoring/evaluation, technology development, and inter-instrument comparisons.}, number={23}, journal={ANALYTICAL CHEMISTRY}, author={Beri, Joshua and Rosenblatt, Michael M. and Strauss, Ethan and Urh, Marjeta and Bereman, Michael S.}, year={2015}, month={Dec}, pages={11635–11640} }
 @misc{bereman_2015, title={Tools for monitoring system suitability in LC MS/MS centric proteomic experiments}, volume={15}, ISSN={["1615-9861"]}, DOI={10.1002/pmic.201400373}, abstractNote={With advances in liquid chromatography coupled to tandem mass spectrometry technologies combined with the continued goals of biomarker discovery, clinical applications of established biomarkers, and integrating large multiomic datasets (i.e. "big data"), there remains an urgent need for robust tools to assess instrument performance (i.e. system suitability) in proteomic workflows. To this end, several freely available tools have been introduced that monitor a number of peptide identification (ID) and/or peptide ID free metrics. Peptide ID metrics include numbers of proteins, peptides, or peptide spectral matches identified from a complex mixture. Peptide ID free metrics include retention time reproducibility, full width half maximum, ion injection times, and integrated peptide intensities. The main driving force in the development of these tools is to monitor both intra- and interexperiment performance variability and to identify sources of variation. The purpose of this review is to summarize and evaluate these tools based on versatility, automation, vendor neutrality, metrics monitored, and visualization capabilities. In addition, the implementation of a robust system suitability workflow is discussed in terms of metrics, type of standard, and frequency of evaluation along with the obstacles to overcome prior to incorporating a more proactive approach to overall quality control in liquid chromatography coupled to tandem mass spectrometry based proteomic workflows.}, number={5-6}, journal={PROTEOMICS}, author={Bereman, Michael S.}, year={2015}, month={Mar}, pages={891–902} }
 @article{hilton_taylor_mcclure_parsons_bonner_bereman_2015, title={Toxicoproteomic analysis of pulmonary carbon nanotube exposure using LC-MS/MS}, volume={329}, ISSN={["0300-483X"]}, url={http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000350519500009&KeyUID=WOS:000350519500009}, DOI={10.1016/j.tox.2015.01.011}, abstractNote={Toxicoproteomics is a developing field that utilizes global proteomic methodologies to investigate the physiological response as a result of adverse toxicant exposure. The aim of this study was to compare the protein secretion profile in lung bronchoalveolar lavage fluid (BALF) from mice exposed to non-functionalized multi-walled carbon nanotubes (U-MWCNTs) or MWCNTs functionalized by nanoscale Al 2 O 3 coatings (A-MWCNT) formed using atomic layer deposition (ALD). Proteins were identified using liquid chromatography tandem mass spectrometry (LC-MS/MS), and quantified using a combination of two label-free proteomic methods: spectral counting and MS1 peak area analysis. On average 465 protein groups were identified per sample and proteins were first screened using spectral counting and the Fisher’s exact test to determine differentially regulated species. Significant proteins by Fisher’s exact test ( p < 0.05) were then verified by integrating the intensity under the extracted ion chromatogram from a single unique peptide for each protein across all runs. A two sample t -test based on integrated peak intensities discovered differences in 27 proteins for control versus U-MWCNT, 13 proteins for control versus A-MWCNT, and 2 proteins for U-MWCNT versus A-MWCNT. Finally, an in-vitro binding experiment was performed yielding 4 common proteins statistically different ( p < 0.05) for both the in-vitro and in-vivo study. Several of the proteins found to be significantly different between exposed and control groups are known to play a key role in inflammatory and immune response. A comparison between the in-vitro and in-vivo CNT exposure emphasized a true biological response to CNT exposure.}, journal={TOXICOLOGY}, author={Hilton, Gina M. and Taylor, Alexia J. and McClure, Christina D. and Parsons, Gregory N. and Bonner, James C. and Bereman, Michael S.}, year={2015}, month={Mar}, pages={80–87} }
 @article{hall_bereman_nepomuceno_thompson_muddiman_smart_2014, title={C/EBPα regulates CRL4Cdt2-mediated degradation of p21 in response to UVB-induced DNA damage to control the G1/S checkpoint}, volume={13}, ISSN={1538-4101 1551-4005}, url={http://dx.doi.org/10.4161/15384101.2014.962957}, DOI={10.4161/15384101.2014.962957}, abstractNote={The bZIP transcription factor, C/EBPα is highly inducible by UVB and other DNA damaging agents in keratinocytes. C/EBPα-deficient keratinocytes fail to undergo cell cycle arrest in G1 in response to UVB-induced DNA damage and mice lacking epidermal C/EBPα are highly susceptible to UVB-induced skin cancer. The mechanism through which C/EBPα regulates the cell cycle checkpoint in response to DNA damage is unknown. Here we report untreated C/EBPα-deficient keratinocytes have normal levels of the cyclin-dependent kinase inhibitor, p21, however, UVB-treated C/EBPα-deficient keratinocytes fail to up-regulate nuclear p21 protein levels despite normal up-regulation of Cdkn1a mRNA levels. UVB-treated C/EBPα-deficient keratinocytes displayed a 4-fold decrease in nuclear p21 protein half-life due to the increased proteasomal degradation of p21 via the E3 ubiquitin ligase CRL4Cdt2. Cdt2 is the substrate recognition subunit of CRL4Cdt2 and Cdt2 mRNA and protein levels were up-regulated in UVB-treated C/EBPα-deficient keratinocytes. Knockdown of Cdt2 restored p21 protein levels in UVB-treated C/EBPα-deficient keratinocytes. Lastly, the failure to accumulate p21 in response to UVB in C/EBPα-deficient keratinocytes resulted in decreased p21 interactions with critical cell cycle regulatory proteins, increased CDK2 activity, and inappropriate entry into S-phase. These findings reveal C/EBPα regulates G1/S cell cycle arrest in response to DNA damage via the control of CRL4Cdt2 mediated degradation of p21.}, number={22}, journal={Cell Cycle}, publisher={Informa UK Limited}, author={Hall, Jonathan R and Bereman, Michael S and Nepomuceno, Angelito I and Thompson, Elizabeth A and Muddiman, David C and Smart, Robert C}, year={2014}, month={Oct}, pages={3602–3610} }
 @article{pinheiro_bereman_burd_pals_armstrong_howe_thannhauser_maccoss_gray_cilia_2014, title={Evidence of the Biochemical Basis of Host Virulence in the Greenbug Aphid,Schizaphis graminum(Homoptera: Aphididae)}, volume={13}, ISSN={1535-3893 1535-3907}, url={http://dx.doi.org/10.1021/PR4012415}, DOI={10.1021/PR4012415}, abstractNote={Biotypes of aphids and many other insect pests are defined based on the phenotypic response of host plants to the insect pest without considering their intrinsic characteristics and genotypes. Plant breeders have spent considerable effort developing aphid-resistant, small-grain varieties to limit insecticide control of the greenbug, Schizaphis graminum. However, new S. graminum biotypes frequently emerge that break resistance. Mechanisms of virulence on the aphid side of the plant-insect interaction are not well understood. S. graminum biotype H is highly virulent on most small grain varieties. This characteristic makes biotype H ideal for comparative proteomics to investigate the basis of biotype virulence in aphids. In this study, we used comparative proteomics to identify protein expression differences associated with virulence. Aphid proteins involved in the tricarboxylic acid cycle, immune system, cell division, and antiapoptosis pathways were found to be up-regulated in biotype H relative to other biotypes. Proteins from the bacterial endosymbiont of aphids were also differentially expressed in biotype H. Guided by the proteome results, we tested whether biotype H had a fitness advantage compared with other S. graminum biotypes and found that biotype H had a higher reproductive fitness as compared with two other biotypes on a range of different wheat germplasms. Finally, we tested whether aphid genetics can be used to further dissect the genetic mechanisms of biotype virulence in aphids. The genetic data showed that sexual reproduction is a source of biotypic variation observed in S. graminum.}, number={4}, journal={Journal of Proteome Research}, publisher={American Chemical Society (ACS)}, author={Pinheiro, Patricia and Bereman, Michael S. and Burd, John and Pals, Melissa and Armstrong, Scott and Howe, Kevin J. and Thannhauser, Theodore W. and MacCoss, Michael J. and Gray, Stewart M. and Cilia, Michelle}, year={2014}, month={Mar}, pages={2094–2108} }
 @article{bereman_johnson_bollinger_boss_shulman_maclean_hoofnagle_maccoss_2014, title={Implementation of Statistical Process Control for Proteomic Experiments Via LC MS/MS}, volume={25}, ISSN={["1879-1123"]}, DOI={10.1007/s13361-013-0824-5}, abstractNote={Statistical process control (SPC) is a robust set of tools that aids in the visualization, detection, and identification of assignable causes of variation in any process that creates products, services, or information. A tool has been developed termed Statistical Process Control in Proteomics (SProCoP) which implements aspects of SPC (e.g., control charts and Pareto analysis) into the Skyline proteomics software. It monitors five quality control metrics in a shotgun or targeted proteomic workflow. None of these metrics require peptide identification. The source code, written in the R statistical language, runs directly from the Skyline interface, which supports the use of raw data files from several of the mass spectrometry vendors. It provides real time evaluation of the chromatographic performance (e.g., retention time reproducibility, peak asymmetry, and resolution), and mass spectrometric performance (targeted peptide ion intensity and mass measurement accuracy for high resolving power instruments) via control charts. Thresholds are experiment- and instrument-specific and are determined empirically from user-defined quality control standards that enable the separation of random noise and systematic error. Finally, Pareto analysis provides a summary of performance metrics and guides the user to metrics with high variance. The utility of these charts to evaluate proteomic experiments is illustrated in two case studies.}, number={4}, journal={JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY}, author={Bereman, Michael S. and Johnson, Richard and Bollinger, James and Boss, Yuval and Shulman, Nick and MacLean, Brendan and Hoofnagle, Andrew N. and MacCoss, Michael J.}, year={2014}, month={Apr}, pages={581–587} }
 @article{bereman_hsieh_corso_van pelt_maccoss_2013, title={Development and Characterization of a Novel Plug and Play Liquid Chromatography-Mass Spectrometry (LC-MS) Source That Automates Connections between the Capillary Trap, Column, and Emitter}, volume={12}, ISSN={1535-9476 1535-9484}, url={http://dx.doi.org/10.1074/MCP.O112.024893}, DOI={10.1074/MCP.O112.024893}, abstractNote={We report the development and characterization of a novel, vendor-neutral ultra-high pressure-compatible (~10,000 p.s.i.) LC-MS source. This device is the first to make automated connections with user-packed capillary traps, columns, and capillary emitters. The source uses plastic rectangular inserts (referred to here as cartridges) where individual components (i.e. trap, column, or emitter) can be exchanged independent of one another in a plug and play manner. Automated robotic connections are made between the three cartridges using linear translation powered by stepper motors to axially compress each cartridge by applying a well controlled constant compression force to each commercial LC fitting. The user has the versatility to tailor the separation (e.g. the length of the column, type of stationary phase, and mode of separation) to the experimental design of interest in a cost-effective manner. The source is described in detail, and several experiments are performed to evaluate the robustness of both the system and the exchange of the individual trap and emitter cartridges. The standard deviation in the retention time of four targeted peptides from a standard digest interlaced with a soluble Caenorhabditis elegans lysate ranged between 3.1 and 5.3 s over 3 days of analyses. Exchange of the emitter cartridge was found to have an insignificant effect on the abundance of various peptides. In addition, the trap cartridge can be replaced with minimal effects on retention time (<20 s).}, number={6}, journal={Molecular & Cellular Proteomics}, publisher={American Society for Biochemistry & Molecular Biology (ASBMB)}, author={Bereman, Michael S. and Hsieh, Edward J. and Corso, Thomas N. and Van Pelt, Colleen K. and MacCoss, Michael J.}, year={2013}, month={Feb}, pages={1701–1708} }
 @article{bereman_tomazela_heins_simonato_cogo_hamvas_patterson_cole_maccoss_2012, title={A method to determine the kinetics of multiple proteins in human infants with respiratory distress syndrome}, volume={403}, ISSN={1618-2642 1618-2650}, url={http://dx.doi.org/10.1007/S00216-012-5953-3}, DOI={10.1007/S00216-012-5953-3}, abstractNote={We report a method to measure in vivo turnover of four proteins from sequential tracheal aspirates obtained from human newborn infants with respiratory distress syndrome using targeted proteomics. We detected enrichment for all targeted proteins approximately 3 h from the start of infusion of [5,5,5-2H3] leucine, secretion times that varied from 1.2 to 2.5 h, and half lives that ranged between 10 and 21 h. Complement factor B, a component of the alternative pathway of complement activation, had an approximately twofold-longer half-life than the other three proteins. In addition, the kinetics of mature and carboxy-terminal tryptic peptides from the same protein (surfactant protein B) were not statistically different (p = 0.49).}, number={8}, journal={Analytical and Bioanalytical Chemistry}, publisher={Springer Science and Business Media LLC}, author={Bereman, Michael S. and Tomazela, Daniela M. and Heins, Hillary S. and Simonato, Manuela and Cogo, Paola E. and Hamvas, Aaron and Patterson, Bruce W. and Cole, F. Sessions and MacCoss, Michael J.}, year={2012}, month={Apr}, pages={2397–2402} }
 @article{egertson_eng_bereman_hsieh_merrihew_maccoss_2012, title={De Novo Correction of Mass Measurement Error in Low Resolution Tandem MS Spectra for Shotgun Proteomics}, volume={23}, ISSN={1044-0305 1879-1123}, url={http://dx.doi.org/10.1007/S13361-012-0482-Z}, DOI={10.1007/S13361-012-0482-Z}, abstractNote={We report an algorithm designed for the calibration of low resolution peptide mass spectra. Our algorithm is implemented in a program called FineTune, which corrects systematic mass measurement error in 1 min, with no input required besides the mass spectra themselves. The mass measurement accuracy for a set of spectra collected on an LTQ-Velos improved 20-fold from -0.1776 ± 0.0010 m/z to 0.0078 ± 0.0006 m/z after calibration (avg ± 95 % confidence interval). The precision in mass measurement was improved due to the correction of non-linear variation in mass measurement accuracy across the m/z range.}, number={12}, journal={Journal of The American Society for Mass Spectrometry}, publisher={American Chemical Society (ACS)}, author={Egertson, Jarrett D. and Eng, Jimmy K. and Bereman, Michael S. and Hsieh, Edward J. and Merrihew, Gennifer E. and MacCoss, Michael J.}, year={2012}, month={Sep}, pages={2075–2082} }
 @article{hsieh_bereman_durand_valaskovic_maccoss_2012, title={Effects of Column and Gradient Lengths on Peak Capacity and Peptide Identification in Nanoflow LC-MS/MS of Complex Proteomic Samples}, volume={24}, ISSN={1044-0305 1879-1123}, url={http://dx.doi.org/10.1007/S13361-012-0508-6}, DOI={10.1007/S13361-012-0508-6}, abstractNote={Reversed-phase liquid chromatography is the most commonly used separation method for shotgun proteomics. Nanoflow chromatography has emerged as the preferred chromatography method for its increased sensitivity and separation. Despite its common use, there are a wide range of parameters and conditions used across research groups. These parameters have an effect on the quality of the chromatographic separation, which is critical to maximizing the number of peptide identifications and minimizing ion suppression. Here we examined the relationship between column lengths, gradient lengths, peptide identifications, and peptide peak capacity. We found that while longer column and gradient lengths generally increase peptide identifications, the degree of improvement is dependent on both parameters and is diminished at longer column and gradients. Peak capacity, in comparison, showed a more linear increase with column and gradient lengths. We discuss the discrepancy between these two results and some of the considerations that should be taken into account when deciding on the chromatographic conditions for a proteomics experiment.}, number={1}, journal={Journal of The American Society for Mass Spectrometry}, publisher={American Chemical Society (ACS)}, author={Hsieh, Edward J. and Bereman, Michael S. and Durand, Stanley and Valaskovic, Gary A. and MacCoss, Michael J.}, year={2012}, month={Nov}, pages={148–153} }
 @article{bereman_canterbury_egertson_horner_remes_schwartz_zabrouskov_maccoss_2012, title={Evaluation of Front-End Higher Energy Collision-Induced Dissociation on a Benchtop Dual-Pressure Linear Ion Trap Mass Spectrometer for Shotgun Proteomics}, volume={84}, ISSN={0003-2700 1520-6882}, url={http://dx.doi.org/10.1021/ac203210a}, DOI={10.1021/ac203210a}, abstractNote={We report the implementation of front-end higher energy collision-induced dissociation (fHCD) on a benchtop dual-pressure linear ion trap. Software and hardware modifications were employed, described in detail vide-infra, to allow isolated ions to undergo collisions with ambient gas molecules in an intermediate multipole (q00) of the instrument. Results comparing the performance of fHCD and resonance excitation collision-induced dissociation (RE-CID) in terms of injection time, total number of scans, efficiency, mass measurement accuracy (MMA), unique peptide identifications, and spectral quality of labile modified peptides are presented. fHCD is approximately 23% as efficient as RE-CID, and depending on the search algorithm, it identifies 6.6% more or 15% less peptides (q < 0.01) from a soluble whole-cell lysate (Caenorhabditis elegans) than RE-CID using Mascot or Sequest search algorithms, respectively. fHCD offers a clear advantage for the analysis of phosphorylated and glycosylated (O-GlcNAc) peptides as the average cross-correlation score (XCorr) for spectra using fHCD was statistically greater (p < 0.05) than for spectra collected using RE-CID.}, number={3}, journal={Analytical Chemistry}, publisher={American Chemical Society (ACS)}, author={Bereman, Michael S. and Canterbury, Jesse D. and Egertson, Jarrett D. and Horner, Julie and Remes, Philip M. and Schwartz, Jae and Zabrouskov, Vlad and MacCoss, Michael J.}, year={2012}, month={Jan}, pages={1533–1539} }
 @article{cilia_bereman_fish_maccoss_gray_2012, title={Homopteran Vector Biomarkers for Efficient Circulative Plant Virus Transmission are Conserved in Multiple Aphid Species and the Whitefly Bemisia tabaci}, volume={11}, ISSN={2095-3119}, url={http://dx.doi.org/10.1016/S2095-3119(12)60009-4}, DOI={10.1016/S2095-3119(12)60009-4}, abstractNote={Plant viruses in the families Luteoviridae and Geminiviridae are phloem restricted and are transmitted in a persistent, circulative manner by homopteran insects. Using fluorescence 2-D difference gel electrophoresis to compare the proteomes of F2 genotypes of Schizaphis graminum segregating for virus transmission ability, we recently discovered a panel of protein biomarkers that predict vector competency. Here we used aphid and whitefly nucleotide and expressed sequence tag database mining to test whether these biomarkers are conserved in other homopteran insects. S. graminum gene homologs that shared a high degree of predicted amino acid identity were discovered in two other aphid species and in the whitefly Bemisia tabaci. Selected reaction monitoring mass spectrometry was used to validate the expression of these biomarkers proteins in multiple aphid vector species. The conservation of these proteins in multiple insect taxa that transmit plant viruses along the circulative transmission pathway creates the opportunity to use these biomarkers to rapidly identify insect populations that are the most efficient vectors and allow them to be targeted for control prior to the spread of virus within a crop.}, number={2}, journal={Journal of Integrative Agriculture}, publisher={Elsevier BV}, author={Cilia, Michelle and Bereman, Michael and Fish, Tara and MacCoss, Michael J and Gray, Stewart}, year={2012}, month={Feb}, pages={249–262} }
 @article{spivak_bereman_maccoss_noble_2012, title={Learning Score Function Parameters for Improved Spectrum Identification in Tandem Mass Spectrometry Experiments}, volume={11}, ISSN={1535-3893 1535-3907}, url={http://dx.doi.org/10.1021/pr300234m}, DOI={10.1021/pr300234m}, abstractNote={The identification of proteins from spectra derived from a tandem mass spectrometry experiment involves several challenges: matching each observed spectrum to a peptide sequence, ranking the resulting collection of peptide-spectrum matches, assigning statistical confidence estimates to the matches, and identifying the proteins. The present work addresses algorithms to rank peptide-spectrum matches. Many of these algorithms, such as PeptideProphet, IDPicker, or Q-ranker, follow a similar methodology that includes representing peptide-spectrum matches as feature vectors and using optimization techniques to rank them. We propose a richer and more flexible feature set representation that is based on the parametrization of the SEQUEST XCorr score and that can be used by all of these algorithms. This extended feature set allows a more effective ranking of the peptide-spectrum matches based on the target-decoy strategy, in comparison to a baseline feature set devoid of these XCorr-based features. Ranking using the extended feature set gives 10-40% improvement in the number of distinct peptide identifications relative to a range of q-value thresholds. While this work is inspired by the model of the theoretical spectrum and the similarity measure between spectra used specifically by SEQUEST, the method itself can be applied to the output of any database search. Further, our approach can be trivially extended beyond XCorr to any linear operator that can serve as similarity score between experimental spectra and peptide sequences.}, number={9}, journal={Journal of Proteome Research}, publisher={American Chemical Society (ACS)}, author={Spivak, Marina and Bereman, Michael S. and MacCoss, Michael J. and Noble, William Stafford}, year={2012}, month={Aug}, pages={4499–4508} }
 @article{schilling_rardin_maclean_zawadzka_frewen_cusack_sorensen_bereman_jing_wu_et al._2012, title={Platform-independent and Label-free Quantitation of Proteomic Data Using MS1 Extracted Ion Chromatograms in Skyline}, volume={11}, ISSN={1535-9476 1535-9484}, url={http://dx.doi.org/10.1074/mcp.M112.017707}, DOI={10.1074/mcp.M112.017707}, abstractNote={Despite advances in metabolic and postmetabolic labeling methods for quantitative proteomics, there remains a need for improved label-free approaches. This need is particularly pressing for workflows that incorporate affinity enrichment at the peptide level, where isobaric chemical labels such as isobaric tags for relative and absolute quantitation and tandem mass tags may prove problematic or where stable isotope labeling with amino acids in cell culture labeling cannot be readily applied. Skyline is a freely available, open source software tool for quantitative data processing and proteomic analysis. We expanded the capabilities of Skyline to process ion intensity chromatograms of peptide analytes from full scan mass spectral data (MS1) acquired during HPLC MS/MS proteomic experiments. Moreover, unlike existing programs, Skyline MS1 filtering can be used with mass spectrometers from four major vendors, which allows results to be compared directly across laboratories. The new quantitative and graphical tools now available in Skyline specifically support interrogation of multiple acquisitions for MS1 filtering, including visual inspection of peak picking and both automated and manual integration, key features often lacking in existing software. In addition, Skyline MS1 filtering displays retention time indicators from underlying MS/MS data contained within the spectral library to ensure proper peak selection. The modular structure of Skyline also provides well defined, customizable data reports and thus allows users to directly connect to existing statistical programs for post hoc data analysis. To demonstrate the utility of the MS1 filtering approach, we have carried out experiments on several MS platforms and have specifically examined the performance of this method to quantify two important post-translational modifications: acetylation and phosphorylation, in peptide-centric affinity workflows of increasing complexity using mouse and human models. Despite advances in metabolic and postmetabolic labeling methods for quantitative proteomics, there remains a need for improved label-free approaches. This need is particularly pressing for workflows that incorporate affinity enrichment at the peptide level, where isobaric chemical labels such as isobaric tags for relative and absolute quantitation and tandem mass tags may prove problematic or where stable isotope labeling with amino acids in cell culture labeling cannot be readily applied. Skyline is a freely available, open source software tool for quantitative data processing and proteomic analysis. We expanded the capabilities of Skyline to process ion intensity chromatograms of peptide analytes from full scan mass spectral data (MS1) acquired during HPLC MS/MS proteomic experiments. Moreover, unlike existing programs, Skyline MS1 filtering can be used with mass spectrometers from four major vendors, which allows results to be compared directly across laboratories. The new quantitative and graphical tools now available in Skyline specifically support interrogation of multiple acquisitions for MS1 filtering, including visual inspection of peak picking and both automated and manual integration, key features often lacking in existing software. In addition, Skyline MS1 filtering displays retention time indicators from underlying MS/MS data contained within the spectral library to ensure proper peak selection. The modular structure of Skyline also provides well defined, customizable data reports and thus allows users to directly connect to existing statistical programs for post hoc data analysis. To demonstrate the utility of the MS1 filtering approach, we have carried out experiments on several MS platforms and have specifically examined the performance of this method to quantify two important post-translational modifications: acetylation and phosphorylation, in peptide-centric affinity workflows of increasing complexity using mouse and human models. Mass spectrometry has rapidly evolved into a high throughput methodology for identifying differentially expressed proteins or post-translational modifications (for review, see Ref. 1Bantscheff M. Schirle M. Sweetman G. Rick J. Kuster B. Quantitative mass spectrometry in proteomics: a critical review.Anal. Bioanal. Chem. 2007; 389: 1017-1031Crossref PubMed Scopus (1256) Google Scholar). These data can be used to improve the understanding of regulatory pathways, to discover novel disease biomarkers, and to characterize molecular mechanisms of both normal and pathological processes. There are several methodologies available for carrying out differential proteomics using both stable isotope labeling or label-free workflows as reviewed in Ref. 2Mueller L.N. Brusniak M.Y. Mani D.R. Aebersold R. An assessment of software solutions for the analysis of mass spectrometry based quantitative proteomics data.J. Proteome Res. 2008; 7: 51-61Crossref PubMed Scopus (380) Google Scholar. For metabolic labeling, stable isotope labeling by amino acids in cell culture or SILAC 1The abbreviations used are:SILACstable isotope labeling with amino acids in cell cultureiTRAQisobaric tag for relative and absolute quantitationMS/MStandem mass spectrometryMS1full scan mass spectrumPTMpost-translationally modifiedMRMmultiple reaction monitoringDCAdichloroacetic acidLODlimit of detectionLOQlimit of quantitationCVCoefficient of variationCMconditioned mediaSIRT3sirtuin 3IDHPisocitrate dehydrogenaseDHSAsuccinate dehydrogenase subunit AWTwild typeKOknock-out. 1The abbreviations used are:SILACstable isotope labeling with amino acids in cell cultureiTRAQisobaric tag for relative and absolute quantitationMS/MStandem mass spectrometryMS1full scan mass spectrumPTMpost-translationally modifiedMRMmultiple reaction monitoringDCAdichloroacetic acidLODlimit of detectionLOQlimit of quantitationCVCoefficient of variationCMconditioned mediaSIRT3sirtuin 3IDHPisocitrate dehydrogenaseDHSAsuccinate dehydrogenase subunit AWTwild typeKOknock-out. is typically used in cell culture experiments (3Ong S.E. Blagoev B. Kratchmarova I. Kristensen D.B. Steen H. Pandey A. Mann M. Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics.Mol. Cell. Proteomics. 2002; 1: 376-386Abstract Full Text Full Text PDF PubMed Scopus (4569) Google Scholar), although this approach has been recently adapted for studies in animals (4Krüger M. Moser M. Ussar S. Thievessen I. Luber C.A. Forner F. Schmidt S. Zanivan S. Fässler R. Mann M. SILAC mouse for quantitative proteomics uncovers kindlin-3 as an essential factor for red blood cell function.Cell. 2008; 134: 353-364Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar, 5Zanivan S. Krueger M. Mann M. In vivo quantitative proteomics: The SILAC mouse.Methods Mol. Biol. 2012; 757: 435-450Crossref PubMed Scopus (71) Google Scholar). As an alternative, isobaric labeling strategies that chemically tag peptides are carried out in a postmetabolic context after protein synthesis, isolation, and proteolytic digestion. iTRAQ (6Ross P.L. Huang Y.N. Marchese J.N. Williamson B. Parker K. Hattan S. Khainovski N. Pillai S. Dey S. Daniels S. Purkayastha S. Juhasz P. Martin S. Bartlet-Jones M. He F. Jacobson A. Pappin D.J. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents.Mol. Cell. Proteomics. 2004; 3: 1154-1169Abstract Full Text Full Text PDF PubMed Scopus (3680) Google Scholar) and more recently tandem mass tags (7Dayon L. Turck N. Kienle S. Schulz-Knappe P. Hochstrasser D.F. Scherl A. Sanchez J.C. Isobaric tagging-based selection and quantitation of cerebrospinal fluid tryptic peptides with reporter calibration curves.Anal. Chem. 2010; 82: 848-858Crossref PubMed Scopus (43) Google Scholar, 8Pichler P. Köcher T. Holzmann J. Möhring T. Ammerer G. Mechtler K. Improved precision of iTRAQ and TMT quantification by an axial extraction field in an Orbitrap HCD cell.Anal. Chem. 2011; 83: 1469-1474Crossref PubMed Scopus (45) Google Scholar) are two widely used examples of this strategy capable of multiplexing up to six to eight separate samples, respectively. Other methods have also been described, such as 18O labeling during proteolysis, but have not been widely adopted because of technical challenges. stable isotope labeling with amino acids in cell culture isobaric tag for relative and absolute quantitation tandem mass spectrometry full scan mass spectrum post-translationally modified multiple reaction monitoring dichloroacetic acid limit of detection limit of quantitation Coefficient of variation conditioned media sirtuin 3 isocitrate dehydrogenase succinate dehydrogenase subunit A wild type knock-out. stable isotope labeling with amino acids in cell culture isobaric tag for relative and absolute quantitation tandem mass spectrometry full scan mass spectrum post-translationally modified multiple reaction monitoring dichloroacetic acid limit of detection limit of quantitation Coefficient of variation conditioned media sirtuin 3 isocitrate dehydrogenase succinate dehydrogenase subunit A wild type knock-out. Despite these advances, the use of isobaric tags or SILAC for quantitation is not feasible for all experimental workflows. SILAC labeling, for example, may be cost prohibitive or even unfeasible in proteomic studies involving tissues from mammalian models (e.g. mice) or humans (e.g. plasma or tumor biopsies). Postmetabolic labeling strategies, such as iTRAQ, can in principle be used in mammalian systems, although it may be impractical in some cases. For example, in peptide-centric workflows that target post-translationally modified (PTM) peptides, antibody or other enrichment steps may be incompatible with the chemical tags. Our own effort to combine an anti-acetyllysine antibody enrichment step with iTRAQ was largely unsuccessful, with the enrichment efficiency of peptides containing this modification significantly lower than without chemical labeling. 2M. J. Rardin, and B. W. Gibson, unpublished results. 2M. J. Rardin, and B. W. Gibson, unpublished results. Label-free quantitative methods are better suited for proteomic experiments where SILAC labeling is not possible or where postmetabolic isobaric labeling approaches may result in substantial inefficiencies. In recent years several label-free approaches have been described including MS/MS spectral counting (9Liu H. Sadygov R.G. Yates 3rd, J.R. A model for random sampling and estimation of relative protein abundance in shotgun proteomics.Anal. Chem. 2004; 76: 4193-4201Crossref PubMed Scopus (2066) Google Scholar, 10Zybailov B. Coleman M.K. Florens L. Washburn M.P. Correlation of relative abundance ratios derived from peptide ion chromatograms and spectrum counting for quantitative proteomic analysis using stable isotope labeling.Anal. Chem. 2005; 77: 6218-6224Crossref PubMed Scopus (300) Google Scholar) and MS ion intensity measurements (11Neilson K.A. Ali N.A. Muralidharan S. Mirzaei M. Mariani M. Assadourian G. Lee A. van Sluyter S.C. Haynes P.A. Less label, more free: Approaches in label-free quantitative mass spectrometry.Proteomics. 2011; 11: 535-553Crossref PubMed Scopus (537) Google Scholar). However, spectral counting approaches are typically used for relative protein quantitation over a small dynamic range and are not appropriate for affinity enrichment workflows that are by nature peptide-centric. In contrast, label-free quantitation approaches that extract ion abundances from MS1 scans are more compatible with quantifying PTM-modified peptides, because each peptide analyte is treated separately. Methods of this type include MSQuant (12Mortensen P. Gouw J.W. Olsen J.V. Ong S.E. Rigbolt K.T. Bunkenborg J. Cox J. Foster L.J. Heck A.J. Blagoev B. Andersen J.S. Mann M. MSQuant, an open source platform for mass spectrometry-based quantitative proteomics.J. Proteome Res. 2010; 9: 393-403Crossref PubMed Scopus (221) Google Scholar), MaxQuant (13Cox J. Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification.Nat. Biotechnol. 2008; 26: 1367-1372Crossref PubMed Scopus (9150) Google Scholar), Census (14Park S.K. Venable J.D. Xu T. Yates 3rd, J.R. A quantitative analysis software tool for mass spectrometry-based proteomics.Nat. Methods. 2008; 5: 319-322Crossref PubMed Scopus (319) Google Scholar), MASIC (15Monroe M.E. Shaw J.L. Daly D.S. Adkins J.N. Smith R.D. MASIC: A software program for fast quantitation and flexible visualization of chromatographic profiles from detected LC-MS(/MS) features.Comput. Biol. Chem. 2008; 32: 215-217Crossref PubMed Scopus (106) Google Scholar), SuperHirn (16Mueller L.N. Rinner O. Schmidt A. Letarte S. Bodenmiller B. Brusniak M.Y. Vitek O. Aebersold R. Müller M. SuperHirn: A novel tool for high resolution LC-MS-based peptide/protein profiling.Proteomics. 2007; 7: 3470-3480Crossref PubMed Scopus (274) Google Scholar), and Spectrum Mill (17Addona T.A. Shi X. Keshishian H. Mani D.R. Burgess M. Gillette M.A. Clauser K.R. Shen D. Lewis G.D. Farrell L.A. Fifer M.A. Sabatine M.S. Gerszten R.E. Carr S.A. A pipeline that integrates the discovery and verification of plasma protein biomarkers reveals candidate markers for cardiovascular disease.Nat. Biotechnol. 2011; 29: 635-643Crossref PubMed Scopus (202) Google Scholar), among others (for review see Ref. 11Neilson K.A. Ali N.A. Muralidharan S. Mirzaei M. Mariani M. Assadourian G. Lee A. van Sluyter S.C. Haynes P.A. Less label, more free: Approaches in label-free quantitative mass spectrometry.Proteomics. 2011; 11: 535-553Crossref PubMed Scopus (537) Google Scholar). However, existing MS1 extraction tools are often limited to a particular instrument platform or tailored to a specific laboratory's data pipeline. In addition, graphical outputs that allow ready evaluation of processed multireplicate data sets and run to run feature comparisons are often absent. Perhaps most importantly, the lack of a true platform-independent quantitation program that could be used across multiple laboratories is clearly lacking, thus limiting the ability for large scale proteomic experiments or direct comparison of data sets from different laboratories and instruments. To address these limitations, we have adapted Skyline, a freely available open source software application (http://proteome.gs.washington.edu/software/skyline), to provide a label-free quantitation tool called Skyline MS1 filtering that efficiently extracts and processes ion intensity chromatograms from MS1 scans of peptide precursors across multiple experiments. We have extended the quantitative and graphical tools originally developed in Skyline for multiple reaction monitoring (MRM)-MS experiments (18MacLean B. Tomazela D.M. Shulman N. Chambers M. Finney G.L. Frewen B. Kern R. Tabb D.L. Liebler D.C. MacCoss M.J. Skyline: An open source document editor for creating and analyzing targeted proteomics experiments.Bioinformatics. 2010; 26: 966-968Crossref PubMed Scopus (2963) Google Scholar) to support interrogation of multiple sample acquisitions for MS1 filtering. These tools in Skyline provide graphical displays for peak selection, replicate views for peak area and retention time, and after review Skyline allows for manual peak integration (when necessary), key features often lacking in existing software. In addition, Skyline MS1 filtering displays direct links of selected MS1 peak features to their underlying MS/MS data to ensure proper peak selection and integration, as well as facile raw data file import to a vendor independent format. Since its release, Skyline has proven to be a highly reliable and flexible program for targeted MRM-MS analysis (19Maclean B. Tomazela D.M. Abbatiello S.E. Zhang S. Whiteaker J.R. Paulovich A.G. Carr S.A. Maccoss M.J. Effect of collision energy optimization on the measurement of peptides by selected reaction monitoring (SRM) mass spectrometry.Anal. Chem. 2010; 82: 10116-10124Crossref PubMed Scopus (175) Google Scholar, 20Stergachis A.B. MacLean B. Lee K. Stamatoyannopoulos J.A. MacCoss M.J. Rapid empirical discovery of optimal peptides for targeted proteomics.Nat. Methods. 2011; 8: 1041-1043Crossref PubMed Scopus (90) Google Scholar, 21Zhang H. Liu Q. Zimmerman L.J. Ham A.J. Slebos R.J. Rahman J. Kikuchi T. Massion P.P. Carbone D.P. Billheimer D. Liebler D.C. Methods for peptide and protein quantitation by liquid chromatography-multiple reaction monitoring mass spectrometry.Mol. Cell. Proteomics. 2011; 1010.1074/mcp.M110.006593Abstract Full Text Full Text PDF Scopus (99) Google Scholar). It is currently being used in the National Cancer Institute Clinical Proteomic Technology Assessment for Cancer program to assess reproducibility and accuracy of large scale proteomic experiments across multiple sites and laboratories2 (http://proteomics.cancer.gov/programs/cptacnetwork). To test the utility of Skyline MS1 filtering for label-free quantitative proteomics, we have carried out comparative experiments to examine the ability to process data from several instrument types, including QqTOF and LTQ FT-ICR mass spectrometers, and obtained appropriate linear and quantitative response curves for multiple peptides. Once these performance metrics were established, we then carried out a set of experiments that targeted two important PTMs, phosphorylation and N-ε-acetylation, that would provide a more rigorous evaluation of the performance and robustness of Skyline MS1 filtering, especially in peptide-centric workflows where quantitation methods are lacking. These experiments were carried out with samples of increasing complexity and workflow design, consisting of peptide affinity enrichment steps that targeted PTMs changes in breast cancer cell lines and mitochondria isolated from transgenic mouse models. HPLC solvents including acetonitrile and water were obtained from Burdick and Jackson (Muskegon, MI). Reagents for protein chemistry including iodoacetamide, DTT, ammonium bicarbonate, formic acid, trifluoroacetic acid, acetic acid, dichloroacetic acid (DCA), dodecyl-maltoside, urea, as well as the protein standards bovine hemoglobin, BSA, rabbit phosphorylase B, and yeast enolase were purchased from Sigma-Aldrich. All protein standards were >95% purity. Tris(2-carboxyethyl)phosphine was purchased from Thermo (Rockford, IL), and HLB Oasis SPE cartridges were purchased from Waters (Milford, MA). Dialysis cassettes (MWCO 3 kDa) were obtained from Pierce, and proteomics grade trypsin was from Promega (Madison WI). Trypsin-predigested β-galactosidase (a quality control standard) was purchased from AB SCIEX (Foster City, CA). Amino acid analysis was performed by AAA Laboratory (Mercer Island, WA). Protein standards in 5% acetic acid (2 mg/ml, w/v) were subjected to hydrolysis in a mixture of 6 n HCl, 0.05% β-mercaptoethanol, 0.02% phenol for 24 h at 110 °C. Concentrations of amino acids except cysteine and tryptophan were then measured by UV-visible LC and using a 6-point standard curve. Anti-acetylated lysine antibodies were purchased from ImmuneChem (ICP0380-100) and Cell Signaling (9441) for enrichment of acetylated peptides. Titanium dioxide chromatography for enrichment of phosphorylated peptides was performed using the Titanosphere Phos-TiO kit (200-μl columns, GL Sciences). Anti-pyruvate dehydrogenase 1α antibodies for Western blots were purchased from Abcam (whole protein), EMD (for pSer-293), or provided as a generous gift from Dr. J. Murray of Abcam (for Ser(P)-300 and Ser(P)-232). Acetylated and phosphorylated synthetic peptides containing stable isotope-labeled lysine or arginine residues (13C615N2-Lys and 13C615N4-Arg, respectively) were obtained from Thermo Fisher Scientific. The data associated with this manuscript may be downloaded from the University of Washington, Seattle-hosted server at http://proteome.gs.washington.edu/supplementary_data/MS1_Filtering/. All of the details for peptide quantitation using MS1 filtering, including peptide peak areas for all MS replicates, are provided as Excel files in a subfolder titled “Quantitation Details” (and are also provided as supplemental Table S6, A–I). An interactive Skyline spectral library file that contains all of the MS/MS spectra of PTM-containing peptides identified and that were subsequently used for MS1 filtering and quantitation is supplied as supplemental Document S1. Skyline is an open source program and can be downloaded at http://proteome.gs.washington.edu/software/skyline. All of the MS/MS spectral details underlying this data are displayed in supplemental Table S1 (A–F) with search engine parameters summarized in supplemental Methods S1 and Table S1G. PTM site assignment was initially suggested by search engines Protein Pilot and Mascot (for details see below) and confirmed by manual inspection using previously defined criteria (22Danielson S.R. Held J.M. Schilling B. Oo M. Gibson B.W. Andersen J.K. Preferentially increased nitration of α-synuclein at tyrosine-39 in a cellular oxidative model of Parkinson's disease.Anal. Chem. 2009; 81: 7823-7828Crossref PubMed Scopus (90) Google Scholar). All of the PTM-containing peptides are provided for review as part of this Spectral Viewer Skyline file. Skyline is an open source software project and can be freely installed (http://proteome.gs.washington.edu/software/skyline). Spectral libraries were generated in Skyline using the BiblioSpec algorithm (23Frewen B. MacCoss M.J. Using BiblioSpec for creating and searching tandem MS peptide libraries.Curr. Protoc. Bioinformatics. 2007; : 13.7.1-13.7.12Google Scholar) from database searches of the raw data files prior to MS1 filtering. Additional details and tutorials for creating spectral libraries and MS1 filtering can be viewed on the Skyline website (http://proteome.gs.washington.edu/software/skyline). For workflows focusing on PTM peptides, specific refinement features in Skyline were set to filter out nonacetylated or nonphosphorylated peptides from the Skyline peptide tree. Briefly, a comprehensive spectral library was created from the raw data containing MS/MS spectra, including repetitive sampling of a single peptide within a run as well as sampling across multiple acquisitions (see Fig. 2). The use of a redundant library enabled MS/MS-directed MS1 peak picking/integration and peak identification following raw data file import and MS1 filtering (see Fig. 3C). For peak picking and ion intensity integration of peptide isotopes, Skyline dynamically selects a constant time interval to use for intensity values over the entire measured range. The time interval is chosen by first calculating the mode or modes of the intervals between the raw acquired points and then choosing the minimum mode value. After the interval is chosen, all of the intensity values are mapped by linear interpolation to consistently spaced times an interval width apart. Peak detection is performed on the interpolated points, and the peak areas are calculated using trapezoidal summation in seconds of intensity (s * i) units (24Wang G. Wu W.W. Zeng W. Chou C.L. Shen R.F. Label-free protein quantification using LC-coupled ion trap or FT mass spectrometry: Reproducibility, linearity, and application with complex proteomes.J. Proteome Res. 2006; 5: 1214-1223Crossref PubMed Scopus (229) Google Scholar). The background area is subtracted from all peak areas, where background is defined as the rectangular area bounded by the integration boundaries, the x axis, and a line perpendicular to the minimum intensity at which the chromatogram crosses the integration boundaries. Typically, the precursor isotopic import filter was set to a count of three, (M, M + 1, and M + 2) at a resolution of 10,000–50,000 depending on mass spectrometric instrument platform (supplemental Fig. S1A). The use of multiple precursor isotopes per peptide enabled features that rank the theoretical and observed isotopic distribution using different novel metrics. These included the isotopic rank in the Skyline peptide tree and the “expected” isotopic distribution in the graphical interface (supplemental Fig. S2). In addition, an isotopic dot product score is generated from comparing the expected distribution to the observed distribution (scored from 0 to 1, where 1 is the highest) (supplemental Fig. S3). Skyline provides graphical tools to easily visually assess multiple precursors during MS1 filtering, to utilize that information to confirm confident peak picking, to identify potential interferences, and to visually assess extracted ion chromatogram quality (intensity and noise level) of the selected peak with its multiple precursor isoforms. Raw files were directly imported into Skyline in their native file format, which Skyline achieves using the ProteoWizard data access library (25Kessner D. Chambers M. Burke R. Agus D. Mallick P. ProteoWizard: Open source software for rapid proteomics tools development.Bioinformatics. 2008; 24: 2534-2536Crossref PubMed Scopus (1217) Google Scholar).Fig. 3Skyline MS1 filtering graphical user interface. A, Skyline peptide tree for peptide YAPVAKacDLASR (Kac is acetyllysine, and R is 13C615N4-Arg) showing three extracted molecular ion isotope peaks M, M + 1, and M + 2. B, chromatograms and peak intensity traces for four acquisitions from two samples run in duplicates with heavy peptides spiked at 1 and 3 fmol (S1R1, S1R2, S2R1, and S2R2, respectively). The vertical lines with annotated retention times and identification (ID) mark underlying MS/MS sampling that initially directed MS1 peak picking. C, Skyline displays a library of MS/MS spectra for the selected peptide that provides underlying peptide identification information for a specific acquisition replicate. In this case, the underlying MS/MS spectra for two of the four replicates, S1R1 and S2R2 are shown, although all spectra can be displayed. D and E, established Skyline visual displays previously developed for targeted LC-MRM data processing, include peak area replicate views (D) and retention time replicates (E) (further details on Skyline graphical displays, settings, and parameters see supplemental Figs. S1–S3).View Large Image Figure ViewerDownload Hi-res image Download (PPT) After data import, graphical displays of chromatographic traces (extracted ion chromatograms) were manually inspected for proper peak picking of MS1 filtered peptides. In some cases, the peak integration was adjusted manually in the chromatographic window. With the new MS1 filtering capabilities, other Skyline features were also updated and synchronized, such as the Skyline Custom Reports that can export additional relevant fields and parameters important for MS1 filtering analysis and quantitation (see tutorial section). All of the quantitations performed as part of this manuscript were done on the peptide level, because of the peptide centric approach that we took for PTM-containing peptides. All of the details for peptide quantitation using MS1 filtering, including peptide peak areas for all MS replicates, are provided as Excel files as supplemental Tables S6 (A–I). The Skyline website contains a detailed tutorial on MS1 filtering. A new MS1 filtering “step by step” tutorial has been posted on the Skyline website. The tutorial guides users through the proper use of Skyline MS1 filtering settings, parameters and graphical tools (http://proteome.gs.washington.edu/software/Skyline/tutorials/ms1filtering.html). The tutorial provides a test data set that the user can download and then describes protocols for importing spectral libraries, choosing proper settings and filters, populating the Skyline peptide tree, importing mass spectrometric raw files for MS1 filtering and ion chromatogram extractions, and utilizing new graphical tools that aid in assessing and further processing data sets. New features added to Skyline Custom Reports (“PrecursorResult.IsotopeDotProduct,” “PrecursorResult.Identified,” “Transition.IsotopeDistIndex,” “Transition.IsotopeDistRank,” “Transition.IsotopeDistProportion,” etc.) are explained in another detailed web tutorial titled “Custom Reports & Results Grids” (http://proteome.gs.washington.edu/software/Skyline/tutorials.html). The periodic revisions and updates will occur as additional features are added to Skyline MS1 filtering. Three mass spectrometry platforms were used to acquire all data used for MS1 filtering experiments. The samples were analyzed by reverse phase HPLC-ESI-MS/MS using (i) an Eksigent Ultra Plus nano-LC two-dimensional HPLC system (Dublin, CA) connected to a quadrupole time-of-flight TripleTOF 5600 mass spectrometer (AB SCIEX), (ii) an Eksigent nano-LC two-dimensional HPLC system connected to a quadrupole time-of-flight QSTAR Elite mass spectrometer (AB SCIEX), and (iii) a LTQ FT-ICR mass spectrometer equipped with a 7-Tesla superconducting magnet (Thermo Fisher Scientific) connected to a Waters ultra high pressure nano-Aquity liquid chromatography system (Milford, MA). For all details describing mass spectrometric instrument parameters and settings and all chromatographic setups and gradient conditions, please refer to the supplemental Methods S1. In this study, mass spectral data sets were analyzed and searched with minor differences. For QSTAR Elite data sets, typically peak lists were generated using Analyst Mascot.dll v1.6b27 (AB SCIEX), and the data were searched using a Mascot (26Pappin D.J. Hojrup P. Bleasby A.J. Rapid identification of proteins by peptide-mass fingerprinting.Curr. Biol. 1993; 3: 327-332Abstract Full Text PDF PubMed Scopus (1418) Google Scholar) server version 2.3.02. In addition, mass spectrometric data from the TripleTOF 5600 and QSTAR Elite was also analyzed usi}, number={5}, journal={Molecular & Cellular Proteomics}, publisher={American Society for Biochemistry & Molecular Biology (ASBMB)}, author={Schilling, Birgit and Rardin, Matthew J. and MacLean, Brendan X. and Zawadzka, Anna M. and Frewen, Barbara E. and Cusack, Michael P. and Sorensen, Dylan J. and Bereman, Michael S. and Jing, Enxuan and Wu, Christine C. and et al.}, year={2012}, month={Mar}, pages={202–214} }
 @article{bereman_maclean_tomazela_liebler_maccoss_2012, title={The development of selected reaction monitoring methods for targeted proteomics via empirical refinement}, volume={12}, ISSN={1615-9853}, url={http://dx.doi.org/10.1002/pmic.201200042}, DOI={10.1002/pmic.201200042}, abstractNote={Software advancements in the last several years have had a significant impact on proteomics from method development to data analysis. Herein, we detail a method, which uses our in-house developed software tool termed Skyline, for empirical refinement of candidate peptides from targeted proteins. The method consists of four main steps from generation of a testable hypothesis, method development, peptide refinement, to peptide validation. The ultimate goal is to identify the best performing peptide in terms of ionization efficiency, reproducibility, specificity, and chromatographic characteristics to monitor as a proxy for protein abundance. It is important to emphasize that this method allows the user to perform this refinement procedure in the sample matrix and organism of interest with the instrumentation available. Finally, the method is demonstrated in a case study to determine the best peptide to monitor the abundance of surfactant protein B in lung aspirates.}, number={8}, journal={PROTEOMICS}, publisher={Wiley}, author={Bereman, Michael S. and MacLean, Brendan and Tomazela, Daniela M. and Liebler, Daniel C. and MacCoss, Michael J.}, year={2012}, month={Apr}, pages={1134–1141} }
 @article{bereman_egertson_maccoss_2011, title={Comparison between procedures using SDS for shotgun proteomic analyses of complex samples}, volume={11}, ISSN={1615-9853}, url={http://dx.doi.org/10.1002/pmic.201100045}, DOI={10.1002/pmic.201100045}, abstractNote={Filter-aided sample preparation (FASP) and a new sample preparation method using a modified commercial SDS removal spin column are quantitatively compared in terms of their performance for shotgun proteomic experiments in three complex proteomic samples: a Saccharomyces cerevisiae lysate (insoluble fraction), a Caenorhabditis elegans lysate (soluble fraction), and a human embryonic kidney cell line (HEK293T). The characteristics and total number of peptides and proteins identified are compared between the two procedures. The SDS spin column procedure affords a conservative fourfold improvement in throughput, is more reproducible, less expensive (i.e. requires less materials), and identifies between 30 and 107% more peptides at q≤0.01, than the FASP procedure. The peptides identified by SDS spin column are more hydrophobic than species identified by the FASP procedure as indicated by the distribution of GRAVY scores. Ultimately, these improvements correlate to as great as a 50% increase in protein identifications with two or more peptides.}, number={14}, journal={PROTEOMICS}, publisher={Wiley}, author={Bereman, Michael S. and Egertson, Jarrett D. and MacCoss, Michael J.}, year={2011}, month={Jun}, pages={2931–2935} }
 @article{pierce_spurrell_mandell_lee_zeligson_bereman_stray_fokstuen_maccoss_levy-lahad_et al._2011, title={Garrod's fourth inborn error of metabolism solved by the identification of mutations causing pentosuria}, volume={108}, ISSN={0027-8424 1091-6490}, url={http://dx.doi.org/10.1073/pnas.1115888108}, DOI={10.1073/pnas.1115888108}, abstractNote={Pentosuria is one of four conditions hypothesized by Archibald Garrod in 1908 to be inborn errors of metabolism. Mutations responsible for the other three conditions (albinism, alkaptonuria, and cystinuria) have been identified, but the mutations responsible for pentosuria remained unknown. Pentosuria, which affects almost exclusively individuals of Ashkenazi Jewish ancestry, is characterized by high levels of the pentose sugar l -xylulose in blood and urine and deficiency of the enzyme l -xylulose reductase. The condition is autosomal-recessive and completely clinically benign, but in the early and mid-20th century attracted attention because it was often confused with diabetes mellitus and inappropriately treated with insulin. Persons with pentosuria were identified from records of Margaret Lasker, who studied the condition in the 1930s to 1960s. In the DCXR gene encoding l -xylulose reductase, we identified two mutations, DCXR c.583ΔC and DCXR c.52(+1)G > A , each predicted to lead to loss of enzyme activity. Of nine unrelated living pentosuric subjects, six were homozygous for DCXR c.583ΔC , one was homozygous for DCXR c.52(+1)G > A , and two were compound heterozygous for the two mutant alleles. l -Xylulose reductase was not detectable in protein lysates from subjects’ cells and high levels of xylulose were detected in their sera, confirming the relationship between the DCXR genotypes and the pentosuric phenotype. The combined frequency of the two mutant DCXR alleles in 1,067 Ashkenazi Jewish controls was 0.0173, suggesting a pentosuria frequency of approximately one in 3,300 in this population. Haplotype analysis indicated that the DCXR c.52(+1)G > A mutation arose more recently than the DCXR c.583ΔC mutation.}, number={45}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Pierce, S. B. and Spurrell, C. H. and Mandell, J. B. and Lee, M. K. and Zeligson, S. and Bereman, M. S. and Stray, S. M. and Fokstuen, S. and MacCoss, M. J. and Levy-Lahad, E. and et al.}, year={2011}, month={Oct}, pages={18313–18317} }
 @article{dixon_bereman_petitte_hawkridge_muddiman_2011, title={One-year plasma N-linked glycome intra-individual and inter-individual variability in the chicken model of spontaneous ovarian adenocarcinoma}, volume={305}, ISSN={["1387-3806"]}, url={http://europepmc.org/abstract/med/21845070}, DOI={10.1016/j.ijms.2010.05.023}, abstractNote={Spontaneous epithelial ovarian cancer (EOC) in the chicken presents a similar pathogenesis compared with humans including CA-125 expression and genetic mutational frequencies (e.g., p53). The high prevalence of spontaneous EOC chickens also provides a unique experimental model for biomarker discovery at the genomic, proteomic, glycomic, and metabolomic level. In an effort to exploit this unique model for biomarker discovery, longitudinal plasma samples were collected from chickens at three-month intervals for one year. The study described herein involved cleaving the N-glycans from these longitudinal chicken plasma samples and analyzing them via nanoLC–FTMS/MS. Glycans identified in this study were previously found in human plasma and this work provides a promising methodology to enable longitudinal studies of the N-linked plasma glycome profile during EOC progression. The structure, abundance, and intra-variability and inter-variability for 35 N-linked glycans identified in this study are reported. The full potential of the chicken model for biomarker discovery has yet to be realized, but the initial interrogation of longitudinally-procured samples provides evidence that supports the value of this strategy in the search for glycomic biomarkers.}, number={2-3}, journal={INTERNATIONAL JOURNAL OF MASS SPECTROMETRY}, author={Dixon, R. Brent and Bereman, Michael S. and Petitte, James N. and Hawkridge, Adam M. and Muddiman, David C.}, year={2011}, month={Aug}, pages={79–86} }
 @article{bereman_comins_muddiman_2010, title={Increasing the hydrophobicity and electrospray response of glycans through derivatization with novel cationic hydrazides}, volume={46}, ISSN={["1364-548X"]}, DOI={10.1039/b915589a}, abstractNote={Novel tags are used to increase the hydrophobicity of glycans and impart a permanent charge yielding as great as a approximately 5-fold increase in electrospray response from both a standard and complex mixture.}, number={2}, journal={CHEMICAL COMMUNICATIONS}, author={Bereman, Michael S. and Comins, Daniel L. and Muddiman, David C.}, year={2010}, pages={237–239} }
 @article{bereman_muddiman_2010, title={The effects of abundant plasma protein depletion on global glycan profiling using NanoLC FT-ICR mass spectrometry}, volume={396}, ISSN={["1618-2650"]}, DOI={10.1007/s00216-009-3368-6}, abstractNote={We report the results of abundant plasma protein depletion on the analysis of underivatized N-linked glycans derived from plasma proteins by nanoLC Fourier-transform ion cyclotron resonance mass spectrometry. N-linked glycan profiles were compared between plasma samples where the six most abundant plasma proteins were depleted (n = 3) through a solid-phase immunoaffinity column and undepleted plasma samples (n = 3). Three exogenous glycan standards were spiked into all samples which allowed for normalization of the N-glycan abundances. The abundances of 20 glycans varying in type, structure, composition, and molecular weight (1,200–3,700 Da) were compared between the two sets of samples. Small fucosylated non-sialylated complex glycans were found to decrease in abundance in the depleted samples (greater than or equal to tenfold) relative to the undepleted samples. Protein depletion was found to marginally effect (less than threefold) the abundance of high mannose, hybrid, and large highly sialylated complex species. The significance of these findings in terms of future biomarker discovery experiments via global glycan profiling is discussed.}, number={4}, journal={ANALYTICAL AND BIOANALYTICAL CHEMISTRY}, author={Bereman, Michael S. and Muddiman, David C.}, year={2010}, month={Feb}, pages={1473–1479} }
 @article{bereman_young_deiters_muddiman_2009, title={Development of a Robust and High Throughput Method for Profiling N-Linked Glycans Derived from Plasma Glycoproteins by NanoLC-FTICR Mass Spectrometry}, volume={8}, ISSN={["1535-3907"]}, DOI={10.1021/pr9002323}, abstractNote={Recent investigations continue to emphasize the importance of glycosylation in various diseases including cancer. In this work, we present a step-by-step protocol describing a method for N-linked glycan profiling of plasma glycoproteins by nanoflow liquid chromatography Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). A large experimental space was initially explored and is described herein. Three internal standards were spiked into the sample and provided normalization of plasma glycan abundance across different experimental conditions. Incubation methods and times and the effect of NP40 detergent on glycan abundance were explored. It was found that an 18-h incubation with no detergent led to the greatest ion abundance; however, data could be obtained in less than one day from raw plasma samples utilizing microwave irradiation or shorter incubation periods. The intersample precision of three different glycans was less than 5.5% (RSD) when the internal standards were added prior to the initial processing step. The high mass measurement accuracy (<3 ppm) afforded by the FTICR mass spectrometer provided confident identifications of several glycan species.}, number={7}, journal={JOURNAL OF PROTEOME RESEARCH}, author={Bereman, Michael S. and Young, Douglas D. and Deiters, Alexander and Muddiman, David C.}, year={2009}, month={Jul}, pages={3764–3770} }
 @article{bereman_williams_muddiman_2009, title={Development of a nanoLC LTQ Orbitrap Mass Spectrometric Method for Profiling Glycans Derived from Plasma from Healthy, Benign Tumor Control, and Epithelial Ovarian Cancer Patients}, volume={81}, ISSN={["1520-6882"]}, url={http://europepmc.org/abstract/med/19113831}, DOI={10.1021/ac802262w}, abstractNote={We report the development of split-less nano-flow liquid chromatography mass spectrometric analysis of glycans chemically cleaved from glycoproteins in plasma. Porous graphitized carbon operating under reverse-phase conditions and an amide-based stationary phase operating under hydrophilic interaction conditions are quantitatively compared for glycan separation. Both stationary phases demonstrated similar column efficiencies and excellent retention time reproducibility without an internal standard to correct for retention time shift. The 95% confidence intervals of the mean retention times were ±4 s across 5 days of analysis for both stationary phases; however, the amide stationary phase was observed to be more robust. The high mass measurement accuracy of less than 2 ppm and fragmentation spectra provided highly confident identifications along with structural information. In addition, data are compared among samples derived from 10 healthy controls, 10 controls with a differential diagnosis of benign gynecologic tumors, and 10 diseased epithelial ovarian cancer patients (EOC). Two fucosylated glycans were found to be up-regulated in healthy controls and provided an accurate diagnostic value with an area under the receiver operator characteristic curve of 0.87. However, these same glycans provided a significantly less diagnostic value when used to differentiate EOC from benign tumor control samples with an area under the curve of 0.73.}, number={3}, journal={ANALYTICAL CHEMISTRY}, author={Bereman, Michael S. and Williams, Taufika Islam and Muddiman, David C.}, year={2009}, month={Feb}, pages={1130–1136} }
 @article{bereman_lyndon_dixon_muddiman_2008, title={Mass measurement accuracy comparisons between a double-focusing magnetic sector and a time-of-flight mass analyzer}, volume={22}, ISSN={["0951-4198"]}, DOI={10.1002/rcm.3544}, abstractNote={We report a direct comparison of the mass measurement accuracies (MMAs) obtained on different mass spectrometry instrument types; a magnetic sector as the ‘gold standard’ and an electrospray ionization time-of-flight (ESI-TOF) instrument. Sixty samples, obtained from the Department of Chemistry at North Carolina State University, were analyzed on each instrument. Data are presented and compared between the different instruments. The average absolute MMAs achieved for the magnetic sector and Agilent ESI-TOF mass spectrometers were 3.0 and 1.1 ppm, respectively. Copyright © 2008 John Wiley & Sons, Ltd.}, number={10}, journal={RAPID COMMUNICATIONS IN MASS SPECTROMETRY}, author={Bereman, Michael S. and Lyndon, Matthew M. and Dixon, R. Brent and Muddiman, David C.}, year={2008}, month={May}, pages={1563–1566} }
 @article{bereman_williams_muddiman_2007, title={Carbohydrate analysis by desorption electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry}, volume={79}, ISSN={["0003-2700"]}, url={http://europepmc.org/abstract/med/17918969}, DOI={10.1021/ac0713858}, abstractNote={We report the use of desorption electrospray ionization hybrid Fourier transform ion cyclotron resonance mass spectrometry (DESI-FT-ICR-MS) for the analysis of carbohydrates. Spectra of neat carbohydrates are presented along with their mass measurement accuracies and limits of detection. Furthermore, a comparison is made between the analyses of O-linked glycans from mucin by DESI-FT-ICR-MS and matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry. Finally, glycans from mucin are identified by using the high mass measurement accuracy and tandem MS capabilities afforded by the hybrid FT-ICR-MS platform.}, number={22}, journal={ANALYTICAL CHEMISTRY}, author={Bereman, Michael S. and Williams, Taufika Islam and Muddiman, David C.}, year={2007}, month={Nov}, pages={8812–8815} }
 @article{bereman_muddiman_2007, title={Detection of attomole amounts of analyte by desorption electrospray ionization mass spectrometry (DESI-MS) determined using fluorescence spectroscopy}, volume={18}, ISSN={["1044-0305"]}, DOI={10.1016/j.jasms.2007.03.006}, abstractNote={We report the use of fluorescence spectroscopy to investigate the amount of material removed from a PTFE surface and detected during desorption electrospray ionization (DESI) mass spectrometry measurements. The fluorescence intensity before and after DESI analysis of rhodamine 6G is used to determine the amount of material removed from the surface per mass spectrum. Calculations indicate low attomole amounts are removed per linear ion trap mass spectrum.}, number={6}, journal={JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY}, author={Bereman, Michael S. and Muddiman, David C.}, year={2007}, month={Jun}, pages={1093–1096} }
 @article{dixon_bereman_muddiman_hawkridge_2007, title={Remote mass spectrometric sampling of electrospray- and desorption electrospra-generated ions using an air ejector}, volume={18}, DOI={10.1016/i.jasms.2007.07.024}, number={10}, journal={Journal of the American Society for Mass Spectrometry}, author={Dixon, R. B. and Bereman, M. S. and Muddiman, David and Hawkridge, A. M.}, year={2007}, pages={1844–1847} }
 @article{dixon_bereman_muddiman_hawkridge_2007, title={Remote mass spectrometric sampling of electrospray- and desorption electrospray-generated ions using an air ejector}, volume={18}, ISSN={1044-0305 1879-1123}, url={http://dx.doi.org/10.1016/J.JASMS.2007.07.024}, DOI={10.1016/J.JASMS.2007.07.024}, abstractNote={A commercial air ejector was coupled to an electrospray ionization linear ion trap mass spectrometer (LTQ) to transport remotely generated ions from both electrospray (ESI) and desorption electrospray ionization (DESI) sources. We demonstrate the remote analysis of a series of analyte ions that range from small molecules and polymers to polypeptides using the AE-LTQ interface. The details of the ESI-AE-LTQ and DESI-AE-LTQ experimental configurations are described and preliminary mass spectrometric data are presented.}, number={10}, journal={Journal of the American Society for Mass Spectrometry}, publisher={American Chemical Society (ACS)}, author={Dixon, R. Brent and Bereman, Michael S. and Muddiman, David C. and Hawkridge, Adam M.}, year={2007}, month={Oct}, pages={1844–1847} }
 @article{bereman_nyadong_fernandez_muddiman_2006, title={Direct high-resolution peptide and protein analysis by desorption electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry}, volume={20}, ISSN={0951-4198 1097-0231}, url={http://dx.doi.org/10.1002/rcm.2759}, DOI={10.1002/rcm.2759}, abstractNote={We report the first coupling of a desorption electrospray ionization (DESI) ion source to Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR-MS) for high-resolution protein analysis. The DESI FT-ICR-MS source design is described in detail along with preliminary data obtained on peptides and proteins ranging from 1 to 5.7 kDa.}, number={22}, journal={Rapid Communications in Mass Spectrometry}, publisher={Wiley}, author={Bereman, Michael S. and Nyadong, Leonard and Fernandez, Facundo M. and Muddiman, David C.}, year={2006}, pages={3409–3411} }