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1. Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms

Author

Chovanec, Jack, Tunc, Ilker, Hughes, Jason, Halstead, Joseph, Mateja, Allyson, Liu, Yihui, O’Connell, Michael P., Kim, Jiwon, Park, Young Hwan, Wang, Qinlu, Le, Quang, Pirooznia, Mehdi, Trivedi, Neil N., Bai, Yun, Yin, Yuzhi, Hsu, Amy P., McElwee, Joshua, Lassiter, Sheryce, Nelson, Celeste, Bandoh, Judy, DiMaggio, Thomas, Šelb, Julij, Rijavec, Matija, Carter, Melody C., Komarow, Hirsh D., Sabato, Vito, Steinberg, Joshua, Hafer, Kurt M., Feuille, Elizabeth, Hourigan, Christopher S., Lack, Justin, Khoury, Paneez, Maric, Irina, Zanotti, Roberta, Bonadonna, Patrizia, Schwartz, Lawrence B., Milner, Joshua D., Glover, Sarah C., Ebo, Didier G., Korošec, Peter, Caughey, George H., Brittain, Erica H., Busby, Ben, Metcalfe, Dean D., and Lyons, Jonathan J.

Published
2023
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2. An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma

Author

Maun, Henry R, Jackman, Janet K, Choy, David F, Loyet, Kelly M, Staton, Tracy L, Jia, Guiquan, Dressen, Amy, Hackney, Jason A, Bremer, Meire, Walters, Benjamin T, Vij, Rajesh, Chen, Xiaocheng, Trivedi, Neil N, Morando, Ashley, Lipari, Michael T, Franke, Yvonne, Wu, Xiumin, Zhang, Juan, Liu, John, Wu, Ping, Chang, Diana, Orozco, Luz D, Christensen, Erin, Wong, Manda, Corpuz, Racquel, Hang, Julie Q, Lutman, Jeff, Sukumaran, Siddharth, Wu, Yan, Ubhayakar, Savita, Liang, Xiaorong, Schwartz, Lawrence B, Babina, Magda, Woodruff, Prescott G, Fahy, John V, Ahuja, Rahul, Caughey, George H, Kusi, Aija, Dennis, Mark S, Eigenbrot, Charles, Kirchhofer, Daniel, Austin, Cary D, Wu, Lawren C, Koerber, James T, Lee, Wyne P, Yaspan, Brian L, Alatsis, Kathila R, Arron, Joseph R, Lazarus, Robert A, and Yi, Tangsheng

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Clinical Research, Asthma, Lung, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Respiratory, Adolescent, Allosteric Regulation, Animals, Antibodies, Monoclonal, Humanized, Cell Line, Female, Humans, Macaca fascicularis, Male, Mast Cells, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Mice, SCID, Rabbits, Tryptases, allosteric protease inhibitor, anti-IgE, anti-tryptase, antibody engineering, asthma, mast cell, non-type 2 asthma, serine protease, tryptase, tryptase genetics, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Severe asthma patients with low type 2 inflammation derive less clinical benefit from therapies targeting type 2 cytokines and represent an unmet need. We show that mast cell tryptase is elevated in severe asthma patients independent of type 2 biomarker status. Active β-tryptase allele count correlates with blood tryptase levels, and asthma patients carrying more active alleles benefit less from anti-IgE treatment. We generated a noncompetitive inhibitory antibody against human β-tryptase, which dissociates active tetramers into inactive monomers. A 2.15 Å crystal structure of a β-tryptase/antibody complex coupled with biochemical studies reveal the molecular basis for allosteric destabilization of small and large interfaces required for tetramerization. This anti-tryptase antibody potently blocks tryptase enzymatic activity in a humanized mouse model, reducing IgE-mediated systemic anaphylaxis, and inhibits airway tryptase in Ascaris-sensitized cynomolgus monkeys with favorable pharmacokinetics. These data provide a foundation for developing anti-tryptase as a clinical therapy for severe asthma.

Published
2019

3. Gene signatures common to allograft rejection are associated with lymphocytic bronchitis

Author

Greenland, John R, Wang, Ping, Brotman, Joshua J, Ahuja, Rahul, Chong, Tiffany A, Kleinhenz, Mary Ellen, Leard, Lorriana E, Golden, Jeffrey A, Hays, Steven R, Kukreja, Jasleen, Singer, Jonathan P, Rajalingam, Raja, Jones, Kirk, Laszik, Zoltan G, Trivedi, Neil N, Greenland, Nancy Y, and Blanc, Paul D

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Organ Transplantation, Transplantation, Clinical Research, Lung, Adult, Allografts, Biomarkers, Bronchitis, Female, Follow-Up Studies, Gene Expression Profiling, Graft Rejection, Graft Survival, Humans, Lung Transplantation, Lymphocytes, Male, Middle Aged, Prognosis, Prospective Studies, molecular biology, monitoring, immune, rejection, acute, monitoring: immune, rejection: acute, Surgery, Clinical sciences
Abstract

Lymphocytic bronchitis (LB) precedes chronic lung allograft dysfunction. The relationships of LB (classified here as Endobronchial or E-grade rejection) to small airway (A- and B-grade) pathologies are unclear. We hypothesized that gene signatures common to allograft rejection would be present in LB. We studied LB in two partially overlapping lung transplant recipient cohorts: Cohort 1 included large airway brushes (6 LB cases and 18 post-transplant referents). Differential expression using DESeq2 was used for pathway analysis and to define an LB-associated metagene. In Cohort 2, eight biopsies for each pathology subtype were matched with pathology-free biopsies from the same subject (totaling 48 samples from 24 subjects). These biopsies were analyzed by multiplexed digital counting of immune transcripts. Metagene score differences were compared by paired t tests. Compared to referents in Cohort 1, LB demonstrated upregulation of allograft rejection pathways, and upregulated genes in these cases characterized an LB-associated metagene. We observed statistically increased expression in Cohort 2 for this LB-associated metagene and four other established allograft rejection metagenes in rejection vs paired non-rejection biopsies for both E-grade and A-grade subtypes, but not B-grade pathology. Gene expression-based categorization of allograft rejection may prove useful in monitoring lung allograft health.

Published
2019

4. Risk assessment for indeterminate pulmonary nodules using a novel, plasma-protein based biomarker assay.

Author

Trivedi, Neil N, Arjomandi, Mehrdad, Brown, James K, Rubenstein, Tess, Rostykus, Abigail D, Esposito, Stephanie, Axler, Eden, Beggs, Mike, Yu, Heng, Carbonell, Luis, Juang, Alice, Kamer, Sandy, Patel, Bhavin, Wang, Shan, Fish, Amanda L, Haddad, Zaid, and Wu, Alan Hb

Subjects
biomarkers, diagnosis, lung cancer, pulmonary nodules, risk models
Abstract

BackgroundThe increase in lung cancer screening is intensifying the need for a noninvasive test to characterize the many indeterminate pulmonary nodules (IPN) discovered. Correctly identifying non-cancerous nodules is needed to reduce overdiagnosis and overtreatment. Alternatively, early identification of malignant nodules may represent a potentially curable form of lung cancer.ObjectiveTo develop and validate a plasma-based multiplexed protein assay for classifying IPN by discriminating between those with a lung cancer diagnosis established pathologically and those found to be clinically and radiographically stable for at least one year.MethodsUsing a novel technology, we developed assays for plasma proteins associated with lung cancer into a panel for characterizing the risk that an IPN found on chest imaging is malignant. The assay panel was evaluated with a cohort of 277 samples, all from current smokers with an IPN 4-30 mm. Subjects were divided into training and test sets to identify a Support Vector Machine (SVM) model for risk classification containing those proteins and clinical factors that added discriminatory information to the Veteran's Affairs (VA) Clinical Factors Model. The algorithm was then evaluated in an independent validation cohort.ResultsAmong the 97 validation study subjects, 68 were grouped as having intermediate risk by the VA model of which the SVM model correctly identified 44 (65%) of these intermediate-risk samples as low (n=16) or high risk (n=28). The SVM model negative predictive value (NPV) was 94% and its sensitivity was 94%.ConclusionThe performance of the novel plasma protein biomarker assay supports its use as a noninvasive risk assessment aid for characterizing IPN. The high NPV of the SVM model suggests its application as a rule-out test to increase the confidence of providers to avoid aggressive interventions for their patients for whom the VA model result is an inconclusive, intermediate risk.

Published
2018

5. Analytical validation of a novel multi-analyte plasma test for lung nodule characterization.

Author

Trivedi, Neil N, Brown, James K, Rubenstein, Tess, Rostykus, Abigail D, Fish, Amanda L, Yu, Heng, Carbonell, Luis, Juang, Alice, Kamer, Sandy, Patel, Bhavin, Sidhu, Manpreet, Vuong, Doris, Wang, Shan, Beggs, Mike, Wu, Alan Hb, and Arjomandi, Mehrdad

Subjects
biomarkers, diagnosis, lung cancer, pulmonary nodules, risk models
Abstract

BackgroundIn the National Lung Screening Trial, 96.4% of nodules had benign etiology. To avoid unnecessary actions and exposure to harm, individuals with benign disease must be identified. We describe herein the analytical validation of a multi-analyte immunoassay for characterizing the risk that a lung nodule found on CT is malignant. Those at lower risk may be considered for serial surveillance to avoid unnecessary and potentially harmful procedures. While those nodules characterized at higher risk may be appropriate for more aggressive actions.ObjectiveTo validate the analytical performance of multiplexed plasma protein assays used in a novel test for lung nodule characterization.MethodsA multiplexed immunoassay panel for the measurement of plasma proteins in current smokers who present with a lung nodule on CT scan was evaluated in a clinical testing laboratory. Assay analytical sensitivity, reproducibility, precision, and recovery of Epidermal Growth Factor Receptor (EGFR), Prosurfactant protein B (ProSB), and Tissue Inhibitor of Metalloproteinases 1 (TIMP1) from human EDTA plasma samples were evaluated across multiple runs, lots, and technicians. Interfering substances and sample pre-analytical storage conditions were evaluated for their effect on analyte recovery. The lung nodule risk score reproducibility was assessed across multiple lots.ResultsThe assay sensitivities were 0.10 ng/mL EGFR, 0.02 ng/mL ProSB, and 0.29 ng/mL TIMP1 with over three orders of magnitude in the assay dynamic ranges. The assays and analytes are robust to pre-analytical sample handling and the plasma can be stored for up to 4 days at 4°C either when freshy collected or thawed after long-term storage at -80°C. Total imprecision after 20 days of testing remained under 9% for all three assays. Risk score variability remained within a ± 10% risk score range.ConclusionsThe three protein assays comprising the multi-analyte plasma test for lung nodule characterization performed quite acceptably in a clinical laboratory.

Published
2018

6. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number

Author

Lyons, Jonathan J, Yu, Xiaomin, Hughes, Jason D, Le, Quang T, Jamil, Ali, Bai, Yun, Ho, Nancy, Zhao, Ming, Liu, Yihui, O'Connell, Michael P, Trivedi, Neil N, Nelson, Celeste, DiMaggio, Thomas, Jones, Nina, Matthews, Helen, Lewis, Katie L, Oler, Andrew J, Carlson, Ryan J, Arkwright, Peter D, Hong, Celine, Agama, Sherene, Wilson, Todd M, Tucker, Sofie, Zhang, Yu, McElwee, Joshua J, Pao, Maryland, Glover, Sarah C, Rothenberg, Marc E, Hohman, Robert J, Stone, Kelly D, Caughey, George H, Heller, Theo, Metcalfe, Dean D, Biesecker, Leslie G, Schwartz, Lawrence B, and Milner, Joshua D

Subjects
Biological Sciences, Ecology, Digestive Diseases, Adolescent, Adult, Aged, Child, Chronic Pain, Connective Tissue Diseases, DNA Copy Number Variations, Dysautonomia, Familial, Female, Gastrointestinal Diseases, Humans, Male, Middle Aged, Pruritus, Skin Diseases, Tryptases, Young Adult, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology, Genetics
Abstract

Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase-encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.

Published
2016

7. Mutational Tail Loss Is an Evolutionary Mechanism for Liberating Marapsins and Other Type I Serine Proteases from Transmembrane Anchors*

Author

Raman, Kavita, Trivedi, Neil N, Raymond, Wilfred W, Ganesan, Rajkumar, Kirchhofer, Daniel, Verghese, George M, Craik, Charles S, Schneider, Eric L, Nimishakavi, Shilpa, and Caughey, George H

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Genetics, Biological Sciences, 2.1 Biological and endogenous factors, Aetiology, Animals, CHO Cells, Cattle, Cricetinae, Cricetulus, Evolution, Molecular, Guinea Pigs, Humans, Membrane Proteins, Mice, Mice, Mutant Strains, Mole Rats, Mutation, Pan paniscus, Pan troglodytes, Protease Inhibitors, Rats, Serine Endopeptidases, Solubility, Species Specificity, Chemical Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

Human and mouse marapsins (Prss27) are serine proteases preferentially expressed by stratified squamous epithelia. However, mouse marapsin contains a transmembrane anchor absent from the human enzyme. To gain insights into physical forms, activities, inhibition, and roles in epithelial differentiation, we traced tail loss in human marapsin to a nonsense mutation in an ancestral ape, compared substrate preferences of mouse and human marapsins with those of the epithelial peptidase prostasin, designed a selective substrate and inhibitor, and generated Prss27-null mice. Phylogenetic analysis predicts that most marapsins are transmembrane proteins. However, nonsense mutations caused membrane anchor loss in three clades: human/bonobo/chimpanzee, guinea pig/degu/tuco-tuco/mole rat, and cattle/yak. Most marapsin-related proteases, including prostasins, are type I transmembrane proteins, but the closest relatives (prosemins) are not. Soluble mouse and human marapsins are tryptic with subsite preferences distinct from those of prostasin, lack general proteinase activity, and unlike prostasins resist antiproteases, including leupeptin, aprotinin, serpins, and α2-macroglobulin, suggesting the presence of non-canonical active sites. Prss27-null mice develop normally in barrier conditions and are fertile without overt epithelial defects, indicating that marapsin does not play critical, non-redundant roles in development, reproduction, or epithelial differentiation. In conclusion, marapsins are conserved, inhibitor-resistant, tryptic peptidases. Although marapsins are type I transmembrane proteins in their typical form, they mutated independently into anchorless forms in several mammalian clades, including one involving humans. Similar pathways appear to have been traversed by prosemins and tryptases, suggesting that mutational tail loss is an important means of evolving new functions of tryptic serine proteases from transmembrane ancestors.

Published
2013

8. Association of Large-Airway Lymphocytic Bronchitis with Bronchiolitis Obliterans Syndrome

Author

Greenland, John R, Jones, Kirk D, Hays, Steve R, Golden, Jeffrey A, Urisman, Anatoly, Jewell, Nicholas P, Caughey, George H, and Trivedi, Neil N

Subjects
Transplantation, Organ Transplantation, Lung, Clinical Research, Rare Diseases, Infectious Diseases, Respiratory, Biopsy, Bronchi, Bronchiolitis Obliterans, Bronchitis, Bronchoscopy, Female, Graft Rejection, Humans, Inflammation, Lung Transplantation, Lymphocytes, Male, Middle Aged, Predictive Value of Tests, Risk Factors, Severity of Illness Index, Syndrome, bronchiolitis obliterans, graft rejection, bronchoscopy, lung transplantation, Medical and Health Sciences, Respiratory System
Abstract

RationaleLung transplantation offers great promise for otherwise terminal lung diseases, but the development of bronchiolitis obliterans syndrome (BOS) continues to limit survival. Although acute rejection and lymphocytic bronchiolitis have been identified as risk factors for the development of BOS, it is unclear whether large-airway lymphocytic inflammation conveys the same risk.ObjectivesWe evaluated lymphocytic bronchitis on endobronchial biopsies as a risk factor for BOS and mortality.MethodsEndobronchial biopsies were collected and graded during surveillance after lung transplantation. We assessed samples with negative cultures collected in the first 90 days from 298 subjects and compared large-airway lymphocytic bronchitis assessed by a 0-2 "E-score" and with standard A and BR pathology scores for acute rejection and small-airway lymphocytic bronchiolitis, respectively.Measurements and main resultsWe found surprisingly little association between large- and small-airway lymphocytic inflammation scores from a given bronchoscopy. Endobronchial lymphocytic bronchitis was more prevalent in subjects in BOS stage 0p and BOS stages 1-3 at the time of biopsy. Within 90 days after transplantation, increasing maximum E-score was associated with greater risk of BOS (adjusted hazard ratio, 1.76; 95% confidence interval, 1.11-2.78; P = 0.02) and in this analysis 90-day maximum E-scores were the only score type predictive of BOS (P < 0.01).ConclusionsThese results support a multicenter study to evaluate endoscopic biopsies for the identification of patients at increased risk for BOS. The association of endobronchial lymphocytic inflammation and BOS may have mechanistic implications.

Published
2013

9. Genetically determining individualized clinical reference ranges for the biomarker tryptase can limit unnecessary procedures and unmask myeloid neoplasms

Author

Chovanec, Jack, primary, Tunc, Ilker, additional, Hughes, Jason, additional, Halstead, Joseph, additional, Mateja, Allyson, additional, Liu, Yihui, additional, O’Connell, Michael P., additional, Kim, Jiwon, additional, Park, Young Hwan, additional, Wang, Qinlu, additional, Le, Quang, additional, Pirooznia, Mehdi, additional, Trivedi, Neil N., additional, Bai, Yun, additional, Yin, Yuzhi, additional, Hsu, Amy P., additional, McElwee, Josh, additional, Lassiter, Sheryce, additional, Nelson, Celeste, additional, Bandoh, Judy, additional, DiMaggio, Thomas, additional, Šelb, Julij, additional, Rijavec, Matija, additional, Carter, Melody C., additional, Komarow, Hirsh D., additional, Sabato, Vito, additional, Steinberg, Joshua, additional, Hafer, Kurt M., additional, Feuille, Elizabeth, additional, Hourigan, Christopher S., additional, Lack, Justin, additional, Khoury, Paneez, additional, Maric, Irina, additional, Zanotti, Roberta, additional, Bonadonna, Patrizia, additional, Schwartz, Lawrence B., additional, Milner, Joshua D., additional, Glover, Sarah C., additional, Ebo, Didier G., additional, Korošec, Peter, additional, Caughey, George H., additional, Brittain., Erica H., additional, Busby, Ben, additional, Metcalfe, Dean D., additional, and Lyons, Jonathan J., additional

Published
2022
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12. Contributors

Author

Abbott, Catherine Anne, primary, Abraham, Carmela R., additional, Adachi, Hideki, additional, Adachi, Osao, additional, Adam, Zach, additional, Adams, Michael W.W., additional, Adang, Michael J., additional, Adham, Ibrahim M., additional, Aducci, Patrizia, additional, Agard, David A., additional, Agranovsky, Alexey A., additional, Akamatsu, Tetsuya, additional, Akiyama, Yoshinori, additional, Albrechtsen, Reidar, additional, Alejo, Alí, additional, Amberg, Sean M., additional, Amerik, Alexander Y., additional, Amparyup, Piti, additional, Andrade, Felipe, additional, Andrés, Germán, additional, Andrews, Daniel M., additional, Andrews, Robert K., additional, Antalis, Toni M., additional, Anthony, Colin S., additional, Aoki, Naoya, additional, Apte, Suneel S., additional, Arima, Kazunari, additional, Arlaud, Gérard, additional, Arni, Raghuvir Krishnaswamy, additional, Arnoux, Pascal, additional, Aronson, Nathan N., additional, Arthur, Michel, additional, Asano, Yasuhisa, additional, Ascenzi, Paolo, additional, Assakura, Marina T., additional, Auld, David S., additional, Ávila, Veridiana de Melo Rodrigues, additional, Avilés, Francesc X., additional, Awad, William M., additional, Bachhawat, Anand K., additional, Bai, Shan, additional, Baird, Teaster T., additional, Bajaj, S. Paul, additional, Baker, Susan C., additional, Banbula, Agnieszka, additional, Barrett, Alan J., additional, Barrowman, Jemima, additional, Bartlett, John D., additional, Bartsch, Jörg W., additional, Baschuk, Nikola, additional, Baskova, Isolda P., additional, Batra, Jyotsna, additional, Bauer, Karl, additional, Baumann, Ulrich, additional, Baumeister, Wolfgang, additional, Bauvois, Cédric, additional, Bayés, Alex, additional, Beauvais, Anne, additional, Becker-Pauly, Christoph, additional, Begley, Tadhg P., additional, Békés, Miklós, additional, Belas, Robert, additional, Beleford, Daniah, additional, Beppu, Teruhiko, additional, Bergmann, Ernst M., additional, Bernard, Bruno A., additional, Bernard, Dominique, additional, Berndt, Michael C., additional, Berruti, Giovanna, additional, Berry, Colin, additional, Bertenshaw, Greg P., additional, Betzel, Christian, additional, Bhaskarla, Chetana, additional, Bhosale, Manoj, additional, Bierbaum, Gabriele, additional, Bjarnason Jón, B., additional, Blaber, Michael, additional, Blackman, Michael J., additional, Blinkovsky, Alexander, additional, Boeke, Jef D., additional, Bogyo, Matthew, additional, Bohn, Stefan, additional, Boileau, Guy, additional, Boland, Mike, additional, Bolken, Tové C., additional, Bond, Judith S., additional, Bondeson, Jan, additional, Bordallo, Javier, additional, Borelli, Claudia, additional, Botelho, Tiago O., additional, Bott, Richard R., additional, Bourne, David G., additional, Bovenschen, Niels, additional, Bradshaw, Ralph A., additional, Breddam, Klaus, additional, Brew, Keith, additional, Brindley, Paul J., additional, Brinkman, Diane L., additional, Britton, Collette, additional, Broadbent, Jeff R., additional, Broadhurst, Anne, additional, Brómme, Dieter, additional, Broom, Murray, additional, Brown, Jeremy S., additional, Brown, Mark A., additional, Bruchhaus, Iris, additional, Burleigh, Barbara A., additional, Burns, Kristin E., additional, Burrows, James F., additional, Butler, Michael J., additional, Buttle, David J., additional, Byrd, Chelsea M., additional, Byun, Tony, additional, Cadel, Sandrine, additional, Caffrey, Conor R., additional, Cal, Santiago, additional, Caldentey, Javier, additional, Candela, Thomas, additional, Capasso, Clemente, additional, Capriogilio, Daniel R., additional, Carginale, Vincenzo, additional, Carmona, Adriana Karaoglanovic, additional, Carruthers, Vern B., additional, Castellino, Francis J., additional, Catanese, Joseph J., additional, Caterson, Bruce, additional, Caughey, George H., additional, Cawley, Naimh X., additional, Cawston, Tim E., additional, Cazzulo, Juan José, additional, Chai, Jijie, additional, Chai, Karl X., additional, Chaim, Olga Meiri, additional, Chang, L.S., additional, Chao, Julie, additional, Chapot-Chartier, Marie-Pierre, additional, Charli, Jean-Louis, additional, Charlier, Paulette, additional, Chave, Karen J., additional, Chen, Jian-Min, additional, Chen, Jinq-May, additional, Chen, Li-Mei, additional, Chen, Ya-Wen, additional, Chen, Yu-Yen, additional, Chevrier, Bernard, additional, Chich, Jean-François, additional, Chien, Jeremy, additional, Chimalapati, Suneeta, additional, Cho, Ki Joon, additional, Choi, Kwan Yong, additional, Chuang, Woei-Jer, additional, Chung, Chin Ha, additional, Chung, Ivy Yeuk Wah, additional, Clamagirand, Christine, additional, Clark, Ian M., additional, Clarke, Adrian K., additional, Clarke, Nicola E., additional, Clarke, Steven Gerard, additional, Clauziat, Philippe, additional, Clements, Judith A., additional, Coffinier, Catherine, additional, Cohen, Paul, additional, Colige, Alain, additional, Collignon, Anne, additional, Colloms, Sean D., additional, Conzelmann, Andreas, additional, Coombs, Graham H., additional, Cooney, Jakki C., additional, Cooper, Jonathan B., additional, Cooper, Max D., additional, Copeland, Nikki A., additional, Cottrell, Graeme S., additional, Coyle, Joseph T., additional, Craik, Charles S., additional, Creemers, John W.M., additional, Cretu, Daniela, additional, Croce, Jenifer, additional, Cross, Keith J., additional, Cueva, Rosario, additional, Cui, Sheng, additional, Cunha, Luis, additional, Cutting, Simon, additional, d’Enfert, Christophe, additional, D’Orchymont, Hugues, additional, Dahlbäck, Björn, additional, Dai, Shujia, additional, Dalbey, Ross E., additional, Dalton, John P., additional, Dando, Pam M., additional, Daniel, R.M., additional, Danilov, Sergei M., additional, Davies, Donna E., additional, De Araujo, Heloisa S., additional, De los Santos, Teresa, additional, de Luca, Viviana, additional, De Meester, Ingrid, additional, de Oliveira, Ana Karina, additional, de Oliveira, Eduardo Brandt, additional, De Oliveira, Pedro Lagerblad, additional, de Vos, Sarah, additional, Declercq, Jeroen, additional, Declercq, Wim, additional, Deghmane, Ala-Eddine, additional, Dekker, Niek, additional, Del Prete, Sonia, additional, Del Rosal, Marina, additional, Delmas, Bernard, additional, DeLotto, Robert, additional, Demidyuk, Ilya V., additional, Denison, Mark R., additional, Deussing, Jan M., additional, Devi, Lakshmi A., additional, Diamandis, Eleftherios P., additional, Diaz, Isabel, additional, Díaz-Perales, Araceli, additional, Dijkstra, Bauke W., additional, Ding, Yan, additional, Dixon, Jack E., additional, Dodt, Johannes, additional, Dokland, Terje, additional, Dolenc, Iztok, additional, Dong, Ningzheng, additional, Dong, Tran Cat, additional, Dong, Ying, additional, Dongre, Mitesh, additional, Donovan, Mark, additional, Dore, Timothy M., additional, Dorstyn, Loretta, additional, Dou, Hong, additional, Dou, Zhicheng, additional, Dougall, Annette M., additional, Drag, Marcin, additional, Dudley, Edward G., additional, Dunn, Ben M., additional, Dupuy, Bruno, additional, Duque-Magalhāes, Maria Conceicāo, additional, Durá, M. Asunción, additional, Eeckhout, Yves, additional, Eijsink, Vincent, additional, Eisen, Arthur Z., additional, Eissa, Azza, additional, Eklund, Sandra, additional, Eletr, Ziad M., additional, Ellis, Vincent, additional, Engel, Wolfgang, additional, Erdös, Ervin G., additional, Escalante, Teresa, additional, Estell, David A., additional, Etscheid, Michael, additional, Evans, Herbert J., additional, Everett, Roger D., additional, Faesen, Alex C., additional, Fahrenholz, Falk, additional, Fanjul-Fernández, Miriam, additional, Farady, Christopher J., additional, Feller, Georges, additional, Feng, Hong, additional, Fenster, Kurt M., additional, Férec, Claude, additional, Ferrari, Silvia, additional, Fingleton, Barbara, additional, Fisher, Jed F., additional, Fives-Taylor, Paula M., additional, Fong, Loren G., additional, Forneris, F., additional, Forster, Brian M., additional, Forster, Friedrich, additional, Foster, Simon J., additional, Foulon, Thierry, additional, Foundling, Stephen I., additional, Fox, Jay William, additional, Franzetti, Bruno, additional, Frasch, Alejandra P., additional, Freeze, Hudson H., additional, Frère, Jean-Marie, additional, Frey, Teryl K., additional, Fricke, Beate, additional, Fricker, Lloyd D., additional, Fridman, Rafael, additional, Froelich, Christopher J., additional, Fröhlich, Camilla, additional, Fu, Hsueh-Liang, additional, Fuhrmann, Cynthia N., additional, Fujimura, Satoshi, additional, Fujiwara, Hiroshi, additional, Fukushima, Jun, additional, Fukuyama, Keiichi, additional, Fuller, Robert S., additional, Fusek, Martin, additional, Gaboriaud, Christine, additional, Gache, Christian, additional, Gakh, Oleksandr, additional, Gal, Peter, additional, Gao, Junjun, additional, García-Sastre, Adolfo, additional, Gardiner, Donald L., additional, Gatehouse, John A., additional, Gaucher, G.M., additional, Gauthier, Francis, additional, Ghuysen, Jean-Marie, additional, Gibson, Wade, additional, Gillies, Jennifer, additional, Glaser, Elzbieta, additional, Glaser, Fabian, additional, Glickman, Michael H., additional, Goettig, Peter, additional, Goffin, Colette, additional, Gohda, Eiichi, additional, Goldberg, Alfred L., additional, Goldberg, Daniel E., additional, Goldberg, Gregory I., additional, Goldfarb, Nathan E., additional, Gomis-Rüth, F. Xavier, additional, Gopal, B., additional, Gorbalenya, Alexander E., additional, Gordon, Stuart G., additional, Gorrell, Mark D., additional, Götz, Friedrich, additional, Goulas, Theodoros, additional, Gouzy-Darmon, Cécile, additional, Govind, K., additional, Gráf, Lászlo, additional, Granados, Robert R., additional, Gräwert, Melissa Ann, additional, Gray, Douglas A., additional, Graycar, Thomas P., additional, Green, Jonathan A., additional, Gremski, Luiza Helena, additional, Groll, Michael, additional, Gromova, Tania Yu, additional, Gros, P., additional, Grubman, Marvin J., additional, Grunden, Amy M., additional, Gudmundsdóttir, Ágústa, additional, Guinand, Micheline, additional, Gully, Djamel, additional, Gustchina, Alla, additional, Gutiérrez, José María, additional, Ha, Byung Hak, additional, Haeggström, Jesper Z., additional, Hageman, James H., additional, Haiko, Johanna, additional, Hailfinger, Stephan, additional, Haitchi, Hans Michael, additional, Han, Ji Seon, additional, Hanquez, Chantal, additional, Harada, Minoru, additional, Hara-Nishimura, Ikuko, additional, Harboe, Marianne, additional, Härd, Torleif, additional, Harris, David A., additional, Hassiepen, Ulrich, additional, Hata, Shoji, additional, Hattori, Akira, additional, He, Rong-Qiao, additional, Heck, Albert J.R., additional, Hendricks, Dirk F., additional, Henrich, Bernhard, additional, Henriet, Patrick, additional, Hernández-Arana, Andrés, additional, Herrera-Camacho, Irma, additional, Heussipp, Gerhard, additional, Hibino, Toshihiko, additional, Hicks, P.M., additional, Hillman, Bradley I., additional, Hiraoka, B. Yukihiro, additional, Hiratake, Jun, additional, Hizukuri, Yohei, additional, Ho, Heng-Chien, additional, Hoa, Ngo Thi, additional, Hochstrasser, Mark, additional, Hodge, Kathryn M., additional, Hofmann, Theo, additional, Hohn, Thomas, additional, Hoidal, John R., additional, Höltje, Joachim-Volker, additional, Homma, Koichi J., additional, Honek, John F., additional, Hook, Vivian Y.H., additional, Hooper, John D., additional, Hooper, Nigel M., additional, Hosoi, Kazuo, additional, Howe, Christopher J., additional, Hruby, Dennis E., additional, Hseih, James J.-D., additional, Hsu, Chun-Chieh, additional, Huang, Tony T., additional, Huang, Tur-Fu, additional, Huet, Yoann, additional, Hughes, Clare, additional, Hugonnet, Jean-Emmanuel, additional, Huston, Adrienne L., additional, Ibrahim-Granet, Oumaïma, additional, Ichishima, Eiji, additional, Ikehara, Yukio, additional, Inagami, Tadashi, additional, Ingram, Jessica, additional, Isaac, R.E., additional, Isaya, Grazia, additional, Isaza, Clara E., additional, Ishii, Shin-ichi, additional, Isnard, Amandine, additional, Ito, Kiyoshi, additional, Ito, Koreaki, additional, Itoh, Yoshifumi, additional, Iturrioz, Xavier, additional, Iwanaga, Sadaaki, additional, Jack, Ralph W., additional, Jackson, Mel C., additional, James, Michael N.G., additional, Janata, Jiří, additional, Janoir, Claire, additional, Janska, Hanna, additional, Jarrell, Ken F., additional, Jaskolski, Mariusz, additional, Jaswal, Sheila S., additional, Jean, Ying Y., additional, Jenne, Dieter E., additional, Jeon, Young Joo, additional, Jiang, Ping, additional, Johnson, John E., additional, Johnson, Michael D., additional, Johnston, James A., additional, Jones, Amanda, additional, Jones, Elizabeth W., additional, Joudiou, Carine, additional, Juliano, Luiz, additional, Jung, Hea-Jin, additional, Jupp, Ray, additional, Kagawa, Todd F., additional, Kalbacher, Hubert, additional, Kamata, Yayoi, additional, Kaminogawa, Shuichi, additional, Kamio, Yoshiyuki, additional, Kaneda, Makoto, additional, Kang, Sung Gyun, additional, Kang, Sung Hwan, additional, Kania, Mary, additional, Kantyka, Tomasz, additional, Kanzawa, Nobuyuki, additional, Karim, Abdulkarim Y., additional, Kasumi, Takafumi, additional, Kataoka, Hiroaki, additional, Kaur, Hardeep, additional, Kawabata, Shun-Ichiro, additional, Kawaguchi, Mari, additional, Kay, John, additional, Kaynar, Murat, additional, Keiler, Kenneth C., additional, Kelly, R.M., additional, Kenton, Nathaniel T., additional, Kerr, Michael A., additional, Kersse, Kristof, additional, Kervinen, Jukka, additional, Kessler, Benedikt M., additional, Kessler, Efrat, additional, Khoronen, Timo K., additional, Kidd, Simon, additional, Kikkert, Marjolein, additional, Kilian, Mogens, additional, Kim, Do-Hyung, additional, Kim, Doyoun, additional, Kim, Eunice EunKyeong, additional, Kim, In Seop, additional, Kim, Jung-Gun, additional, Kim, Kyeong Kyu, additional, Kim, Kyung Hyun, additional, Kimber, Matthew S., additional, Kimura, Yukio, additional, Kirschke, Heidrun, additional, Kiso, Yoshiaki, additional, Kleanthous, Colin, additional, Klein, Jürgen R., additional, Klemba, Michael, additional, Kmiec, Beata, additional, Kobayashi, Hideyuki, additional, Kodama, Hiroyuki, additional, Koelsch, Gerald, additional, Kok, Jan, additional, Kolattukody, P.E., additional, Kolb, Fabrice A., additional, Kolmar, Harald, additional, Komori, Yumiko, additional, Konvalinka, Jan, additional, Korkmaz, Brice, additional, Kostrov, Sergey V., additional, Kräusslich, Hans-Georg, additional, Krczal, Gabi, additional, Kress, Lawrence F., additional, Kristjánsson, Magnüs Már, additional, Kučera, Tomáš, additional, Kukday, Sayali S., additional, Kumagai, Hidehiko, additional, Kumar, Sharad, additional, Kumarasiri, Malika, additional, Kumazaki, Takashi, additional, Kümmerer, Beate M., additional, Kuno, Kouji, additional, Kurkinen, Markku, additional, Kutejová, Eva, additional, Kveiborg, Marie, additional, Kwarciak, Agnieszka, additional, Laakkonen, Liisa, additional, Labrou, Nikolaos E., additional, Laing, Gavin D., additional, Lamppa, Gayle, additional, Langer, Thomas, additional, Laursen, Richard A., additional, Lawrenson, Richard A., additional, Layne, Matthew D., additional, Le Bonniec, Bernard F., additional, Leal, María C., additional, Lechan, Ronald M., additional, Lee, David H., additional, Lee, Irene, additional, Lee, Jae, additional, Lee, Kye Joon, additional, Lee, Soohee, additional, Lei, Xiaobo, additional, Leis, Jonathan, additional, LeMosy, Ellen K., additional, Lepage, Thierry, additional, Leppla, Stephen H., additional, Lesner, Adam, additional, Lessard, Ivan A.D., additional, Lhomond, Guy, additional, Li, Huilin, additional, Li, Shu-Ming, additional, Li, Weiguo, additional, Liao, Ta-Hsiu, additional, Liddington, Robert C., additional, Lieber, Toby, additional, Lijnen, H.R., additional, Lima, Christopher D., additional, Lin, Chen-Yong, additional, Lin, Gang, additional, Lin, Ming T., additional, Lin, Xinli, additional, Lin, Yee-Shin, additional, Lindsay, L.L., additional, Lipscomb, William N., additional, Little, John W., additional, Liu, Ching-Chuan, additional, Liu, Chuan-ju, additional, Lively, Mark O., additional, Livnat-Levanon, Nurit, additional, Ljungdahl, Per O., additional, Llorens-Cortes, Catherine, additional, Lobel, Peter, additional, Loh, Y. Peng, additional, Lohi, Jouko, additional, Lomonossoff, G.P., additional, Looze, Yvan, additional, López-Otin, Carlos, additional, Lopez-Quezada, Landys, additional, Loukas, Alex, additional, Lu, Long-Sheng, additional, Lundwall, Áke, additional, Luo, Liu-Ying, additional, Lupas, Andrei, additional, Luthe, Dawn S., additional, Lynch, Nicholas J., additional, Lyons, Peter J., additional, MacKay, Vivian L., additional, Macleod, Jesica M. Levingston, additional, Magdolen, Viktor, additional, Mainardi, Jean-Luc, additional, Mäkinen, Kauko K., additional, Mallari, Jeremy P., additional, Manandhar, Surya P., additional, Mandelbaum, Fajga R., additional, Manicone, Anne M., additional, Mansfeld, Johanna, additional, Marcotrigiano, Joseph, additional, Mares, Michael, additional, Marfany, Gemma, additional, Markland, Francis S., additional, Marokházi, Judith, additional, Marquis, Hélène, additional, Marr, Robert A., additional, Martegani, Enzo, additional, Martin, Erik W., additional, Martinez, Manuel, additional, Martins, L. Miguel, additional, Maruyama, Masato, additional, Maruyama, Masugi, additional, Maruyama, Sususmu, additional, Masaki, Takeharu, additional, Massoumi, Ramin, additional, Mathew, Rency T., additional, Matrisian, Lynn M., additional, Matsuda, Yoshihiro, additional, Matsushita, Osamu, additional, Matuschek, Marco, additional, Matušková, Anna, additional, Matúz, Krisztina, additional, Mauch, Cornelia, additional, Maurizi, Michael R., additional, Mayr, Lorenz M., additional, McCafferty, Dewey G., additional, McDonald, J. Ken, additional, McKerrow, James H., additional, McMillan, David, additional, Mecham, Robert P., additional, Mehta, Darshini P., additional, Meisinger, Chris, additional, Mellors, Alan, additional, Melton, Roger G., additional, Melvin, Jeffrey A., additional, Ménard, Robert, additional, Menéndez-Arias, Luis, additional, Menezes, Milene C., additional, Mesecar, Andrew, additional, Mesnage, Stéphane, additional, Meyer, Diane H., additional, Meyers, Gregor, additional, Michaelis, Susan, additional, Michalska, Karolina, additional, Mielicki, Wojciech P., additional, Mierau, Igor, additional, Mikoulinskaia, Galina V., additional, Miller, Charles G., additional, Miller, Lydia K., additional, Mills, John, additional, Mills, Kenneth V., additional, Min, Jinrong, additional, Mistou, Michel-Yves, additional, Misumi, Yoshio, additional, Miyoshi, Shin-ichi, additional, Mizutani, Shigehiko, additional, Mobashery, Shahriar, additional, Mochizuki, Satsuki, additional, Mock, William L., additional, Möhrlen, Frank, additional, Moiré, Nathalie, additional, Monahan, Paul E., additional, Moncada-Pazos, Angela, additional, Monnet, Véronique, additional, Monod, Michel, additional, Montecucco, Cesare, additional, Morelli, Laura, additional, Mori, Sumiko, additional, Morita, Takashi, additional, Morrissey, James H., additional, Morse, Richard J., additional, Mort, John S., additional, Mortensen, Uffe H., additional, Morty, Rory E., additional, Moss, Joel, additional, Motoshima, Hidemasa, additional, Mottram, Jeremy C., additional, Moura-da-Silva, Ana M., additional, Mudgett, Mary Beth, additional, Mundt, Egbert, additional, Murakami, Kazuo, additional, Murakami, Mario Tyago, additional, MurakamiMurofoshi, Kimiko, additional, Murao, Sawao, additional, Murphy, Gillian, additional, Murthy, M.R.N., additional, Muta, Tatsushi, additional, Myburgh, Elmarie, additional, Mzhavia, Nino, additional, Nabi, A.H.M. Nurun, additional, Nagase, Hideaki, additional, Nagle, Michael W., additional, Nägler, Dorit K., additional, Naik, Rajesh R., additional, Nair, Divya B., additional, Nakai, Toshiki, additional, Nakajima, Yoshitaka, additional, Nakamura, Yukio, additional, Nakatogawa, Hitoshi, additional, Nakayama, Toru, additional, Nalivaeva, Natalia N., additional, Nandi, Dipankar, additional, Nascimento-Silva, Maria Clara Leal, additional, Nasmyth, Kim, additional, Nathan, Carl F., additional, Navarro-García, Fernando, additional, Naves, Dayane Lorena, additional, Nedialkova, Danny D., additional, Neuman, Keir C., additional, Nguyen, Jeffrey-Tri, additional, Nguyen, Ky-Anh, additional, Niemirowicz, Gabriela T., additional, Nikai, Toshiaki, additional, Nishi, Eiichiro, additional, Nishii, Wataru, additional, Nishiyama, Makoto, additional, Nishiyama, Yasuhiro, additional, Noda, Masatoshi, additional, Nomura, Seiji, additional, Norioka, Shigemi, additional, Nsangou, Desire M.M., additional, O’Brien, Amornrat, additional, O’Connor, Michael B., additional, Oda, Kohei, additional, Odinokova, Irina V., additional, Oetjen, Joyce, additional, Ogura, Teru, additional, Ohman, Dennis E, additional, Ohsumi, Yoshinori, additional, Ojha, Mukti, additional, Okabe, Akinobu, additional, Okada, Yasunori, additional, Okamoto, Keinosuke, additional, Okuda, Kenji, additional, Okumura, Nobuaki, additional, Okuno, Takashi, additional, Oleson, Kjeld, additional, Oliveira de Giuseppe, Priscila, additional, Olivier, Martin, additional, Ono, Yasuko, additional, Oroszlan, Stephen, additional, Ota, Nobuyuki, additional, Ovadia, Michael, additional, O-Wang, Jiyang, additional, Oxvig, Claus, additional, Packer, Jeremy C.L., additional, Padilla-López, Sergio, additional, Paetzel, Mark, additional, Page, Michael J., additional, Page-McCaw, Andrea, additional, Paine, Mark J.I., additional, Park, Byoung Chul, additional, Park, Eunyong, additional, Park, John E., additional, Park, Pyong Woo, additional, Park, Sung Goo, additional, Parkin, Kirk L., additional, Parks, William C, additional, Paschoalin, Thaysa, additional, Pastore, Annalisa, additional, Patananan, Alexander Nikolich, additional, Paul, Sudhir, additional, Paulson, Henry L., additional, Pawel-Rammingen, Ulrich von, additional, Pearce, David A., additional, Pearson, Mark S., additional, Pei, Duanqing, additional, Pejler, Gunnar, additional, Pemberton, Alan D., additional, Peng, Jianhao, additional, Pernier, Julien, additional, Peters, Jan-Michael, additional, Pfirrmann, Thorsten, additional, Pham, Viet-Laï, additional, Pichová, Iva, additional, Pickering, Darren, additional, Piesse, Christophe, additional, Pignol, David, additional, Pike, Robert N., additional, Pinck, Lothaire, additional, Pirkle, Hubert, additional, Pitot, Henry C., additional, Plaut, Andrew G., additional, Ploegh, Hidde, additional, Polgár, László, additional, Porter, Corrine, additional, Postina, Rolf, additional, Potempa, Jan, additional, Poulsen, Knud, additional, Power, Scott D., additional, Pratt, Rex. F., additional, Prehna, Gerd, additional, Prévost, Gilles, additional, Pshezhetsky, Alexey V., additional, Qasim, Mohammad A., additional, Qian, Feng, additional, Qiu, Jiazhou, additional, Quesada, Víctor, additional, Radisky, Evette S., additional, Rader, Stephen D., additional, Raman, Kavita, additional, Ramsay, Andrew J., additional, Rancourt, Derrick E., additional, Ranjit, Najju, additional, Rao, Narayanam V., additional, Ratia, Kiira, additional, Rawlings, Neil D., additional, Rawson, Robert B., additional, Reddy, Vijay, additional, Redman, Colvin M., additional, Regonesi, Maria Elena, additional, Reichert, Andreas S., additional, Reichl, Antonia P., additional, Remaut, Han, additional, Remington, S. James, additional, Renatus, Martin, additional, Reverter, David, additional, Reynolds, Eric C., additional, Rholam, Mohamed, additional, Rice, Charles M., additional, Ridky, Todd W., additional, Riezman, Howard, additional, Rijken, D.C., additional, Rio, Marie-Christine, additional, Ritchie, Alison, additional, Robert-Baudouy, Janine, additional, Robinson, Mark W., additional, Robinson, Michael, additional, Rodriguez-Romero, Adela, additional, Rodriques, Renata Santos, additional, Rogers, John C., additional, Rojas, Camilo, additional, Romesberg, Floyd E., additional, Roper, David J., additional, Rosas-Murrieta, Nora, additional, Rose, A.M., additional, Rosenthal, Philip J., additional, Rosing, J., additional, Rossetto, Ornella, additional, Rossi, Véronique, additional, Roth, Richard A., additional, Rottensteiner, Hanspeter, additional, Rowan, Andrew D., additional, Rozanov, Mikhail, additional, Rucavado, Alexandra, additional, Ruecker, Andrea, additional, Rul, Françoise, additional, Rümenapf, Till, additional, Russo, Ilaria, additional, Ryan, Martin D., additional, Sacco, Elena, additional, Sadler, J. Evan, additional, Saenger, W., additional, Sahl, Hans-Georg, additional, Sajid, Mohammed, additional, Sakaguchi, Masayoshi, additional, Sakiyama, Fumio, additional, Salas, Maria L., additional, Salgado, Maria Cristina O., additional, Salvesen, Guy S., additional, Sánchez, Edith, additional, Sanchez, Eladio F., additional, Sang, Qing-Xiang Amy, additional, Sankaran, Krishnan, additional, Sarkar, Susanta K., additional, Sarras, Michael P., additional, Sasagawa, Yoshikiyo, additional, Satohiko, Araki, additional, Sauvage, Eric, additional, Saveanu, Loredana, additional, Savithri, H.S., additional, Sawada, Hitoshi, additional, Sawers, R. Gary, additional, Scarisbrick, Isobel A., additional, Schaller, Andreas, additional, Scheer, Justin M., additional, Scheiflinger, Friedrich, additional, Schiene-Fischer, Cordelia, additional, Schlomann, Uwe, additional, Schlösser, Manfred, additional, Schmaier, Alvin H., additional, Schmidt, Walter K., additional, Schneemann, Anette, additional, Schnellmann, Rick G., additional, Scholze, Henning, additional, Schomburg, Lutz, additional, Schwaeble, Wilhelm J., additional, Scott, Christopher J., additional, Scudiero, Rosaria, additional, Sehara-Fujisawa, Atsuko, additional, Seidah, Nabil G., additional, Seiki, Motoharu, additional, Sekiguchi, Junichi, additional, Senff-Ribeiro, Andrea, additional, Seong, Ihn Sik, additional, Serpe, Mihaela, additional, Serrano, Solange M.T., additional, Setlow, Peter, additional, Shahian, Tina, additional, Shanks, M., additional, Shao, Feng, additional, Shapiro, Steven D., additional, Sharma, Navneet, additional, Shaw, Lindsey N., additional, Shen, Aimee, additional, Shen, Lei, additional, Sherwood, Roger F., additional, Shi, Yun-Bo, additional, Shimoi, Hitoshi, additional, Shimura, Yoichiro, additional, Shirras, A.D., additional, Shridhar, Viji, additional, Shukla, Jinal K., additional, Siigur, Ene, additional, Siigur, Jüri, additional, Silmon de Monerri, Natalie C., additional, Sim, Robert B., additional, Simmer, James P., additional, Simmons, William H., additional, Singh, Jaspreet, additional, Singleton, Alison, additional, Sirakova, Tatiana D., additional, Sixma, Titia K., additional, Skern, Tim, additional, Skidgel, Randal A., additional, Slack, Jeffrey, additional, Sleat, David E., additional, Slusher, Barbara S., additional, Smith, Janet L., additional, Smith, Matthew A., additional, Smyth, Mark J., additional, Snijder, Erik J., additional, Sobhanifar, Solmaz, additional, Söderhaäll, Kenneth, additional, Sohar, Istvan, additional, Sonderegger, Peter, additional, Sorgine, Marcos Henrique Ferreira, additional, Sorimachi, Hiroyuki, additional, Soukhodolets, Karen E., additional, Souza, Tatiana de Arruda Campos Brasil de, additional, Sperka, Tamás, additional, Sriskandan, Shiranee, additional, St. Geme, Joseph W., additional, St. Leger, Raymond J., additional, Staib, Peter, additional, Steele, James L., additional, Stefansson, Bjarki, additional, Steinkühler, Christian, additional, Stenberg, Leisa M., additional, Stenflo, Johan, additional, Stennicke, Henning R., additional, Stepanov, Valentin M., additional, Stepnaya, Olga A., additional, Steven, Frank, additional, Stevens, Richard L., additional, Stevenson, Kenneth J., additional, St-Louis, Mathieu, additional, Stobart, Christopher C., additional, Stöcker, Walter, additional, Storer, Andrew C., additional, Sträter, Norbert, additional, Strauss, Ellen G., additional, Strauss, James H., additional, Stříšovský, Kvido, additional, Strynadka, Natalie C.J., additional, Sturrock, Edward D., additional, Su, Dan, additional, Su, Xiao-Dong, additional, Suárez-Rendueles, Paz, additional, Sulea, Traian, additional, Sundararajan, Venkatesh, additional, Suno, Ryoji, additional, Suzuki, Carolyn K., additional, Suzuki, Fumiaki, additional, Suzuki, Hideyuki, additional, Suzuki, Nobuhiro, additional, Swenson, Stephen, additional, Szabady, Rose L., additional, Szecsi, Pal Bela, additional, Szilágyi, Lászlo, additional, Taha, Muhamed-Kheir, additional, Takahashi, Eizo, additional, Takahashi, Kenji, additional, Takai, Toshiro, additional, Takeda, Atsushi, additional, Takeda, Soichi, additional, Tame, Jeremy J.R.H., additional, Tamura, Tomohiro, additional, Tan, Fulong, additional, Tanaka, Keiji, additional, Tanase, Carmen, additional, Tang, Jordan, additional, Tanizaki, Martha M., additional, Tannich, Egbert, additional, Tans, Guido, additional, Tarentino, Anthony L., additional, Tassanakajon, Anchalee, additional, Tatsumi, Hiroki, additional, Tautz, Norbert, additional, Taylor, Erin Bassford, additional, Teixeira, Pedro Filipe, additional, Telugu, Bhanu Prakash V.L., additional, Templin, Markus F., additional, Terada, Shigeyuki, additional, Tetsuya, Uchikoba, additional, Thacker, C., additional, Thaker, Maulik, additional, Thiel, Heinz-Jürgen, additional, Thielens, Nicole, additional, Thierry, Gonzales, additional, Thivierge, Karine, additional, Thomas, Mark D., additional, Thome, Margot, additional, Thorsness, Mary K., additional, Thorsness, Peter E., additional, Tigue, Natalie J., additional, Todi, Sokol V., additional, Tomkinson, Birgitta, additional, Tonello, Fiorella, additional, Tong, Liang, additional, Toogood, H.S., additional, Tortora, Paolo, additional, Tözsèr, József, additional, Travassos, Luiz Rodolpho, additional, Travis, James, additional, Trevisan-Silva, Dilza, additional, Trinchella, Francesca, additional, Trivedi, Neil N., additional, Troy, Carol M., additional, Tschesche, Harald, additional, Tseng, Yu-Lun, additional, Tsujimoto, Masafumi, additional, Tu, Anthony T., additional, Tumelty, Kathleen E., additional, Turk, Boris, additional, Turk, Dusan, additional, Turk, Vito, additional, Turner, Anthony J., additional, Uchikoba, Tetsuya, additional, Ueno, Takayuki, additional, Ugalde, Alejandro P., additional, Uitto, Veli-Jukka, additional, Urban, Sinisa, additional, Valdenaire, Olivier, additional, Valli, Adrian, additional, Van Beeumen, Jozef, additional, Van den Burg, Bertus, additional, Van der Hoorn, Renier A.L., additional, van Dijl, Jan Maarten, additional, Van Endert, Peter, additional, Van Raam, Bram J., additional, Van Wart, Harold E., additional, Vanden Berghe, Tom, additional, Vandenabeele, Peter, additional, Vanoni, Margo, additional, Veiga, Silvio Sanches, additional, Velander, William H., additional, Velasco, Gloria, additional, Vendrell, Josep, additional, Venekei, I. István, additional, Vetvicka, Vaclav, additional, Vögtle, F.-Nora, additional, Vollmer, Waldemar, additional, Wada, Kei, additional, Wagner, Fred W., additional, Wai, Sun Nyunt, additional, Wai, Timothy, additional, Wainwright, Shane, additional, Walker, Kenneth W., additional, Walker, Stephen J., additional, Wallach, Jean, additional, Walling, Linda L., additional, Walsh, Peter N., additional, Wang, Hai-Yan, additional, Wang, Hengbin, additional, Wang, Jianwei, additional, Wang, Peng, additional, Wang, Ping, additional, Wassenegger, Michael, additional, Watanabe, Kunihiko, additional, Webb, Helen, additional, Weber, Joseph M., additional, Weber, Niklas, additional, Webster, Daniel R., additional, Wei, Shuo, additional, Welch, Rodney A., additional, Wells, James A., additional, Wenzel, Herbert, additional, Wertz, Ingrid E., additional, Wewer, Ulla W., additional, Whyteside, Alison R., additional, Wilk, Sherwin, additional, Wilkin, Jean-Marc, additional, Wilmes, Claudia, additional, Winther, Jakob R., additional, Wishart, David S., additional, Wlodawer, Alexander, additional, Woessner, J. Fred, additional, Wolfe, Michael S., additional, Wong, Wilson, additional, Woodgate, Roger, additional, Wright, Gerry, additional, Wu, Jiunn-Jong, additional, Wu, Qingyu, additional, Wysocka, Magdalena, additional, Xu, Chao, additional, Xu, Zhenghong, additional, Yahori, Kinnosuke, additional, Yamada, Shoji, additional, Yamaguchi, Nozomi, additional, Yamaguchi, Shinji, additional, Yamakawa, Yoshio, additional, Yamamoto, Hiroki, additional, Yana, Ikao, additional, Yang, Maozhou, additional, Yang, Na, additional, Yao, Chenjuan, additional, Yao, Tingting, additional, Yasuda, Noriko, additional, Yasuhara, Toshimasa, additional, Yasumasu, Shigeki, additional, Yeh, Edward T.H., additional, Yiallouros, Irene, additional, Yin, Jiang, additional, Yonezawa, Hiroo, additional, Yoo, Soon Ji, additional, Yoshimoto, Tadashi, additional, Young, Michael W., additional, Young, Stephen G., additional, Zaidi, Nousheen, additional, Zavalova, Ludmila L., additional, Zavodszky, Peter, additional, Zhang, Aidong, additional, Zhang, Xianming, additional, Zhang, Yi-Zheng, additional, Zheng, Dominick, additional, Zhong, Guangming, additional, Zhong, Rong, additional, Zhou, Yuan, additional, Zhou, Zhaohui Sunny, additional, Zick, Michael, additional, Zigrino, Paola, additional, and Zimin, Andrei A., additional

Published
2013
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14. A gut feeling

Author

Haberer, Jessica, Trivedi, Neil N., Kohlwes, Jeffrey, and Tierney, Lawrence, Jr.

Subjects
Atherosclerosis -- Case studies, Weight loss -- Causes of, Cachexia -- Causes of
Abstract

A 79-year-old man who had lost 30% of his body weight over a six-month period was found to have severe atherosclerosis affecting the blood vessels in his stomach. This is such an unusual condition that his doctors spent much of their time trying to find cancer, which is a much more common cause of severe weigh loss. He received a bypass much like the kind used to treat coronary artery disease and he regained the weight he had lost.

Published
2003

17. An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma

Author

Maun, Henry R., primary, Jackman, Janet K., additional, Choy, David F., additional, Loyet, Kelly M., additional, Staton, Tracy L., additional, Jia, Guiquan, additional, Dressen, Amy, additional, Hackney, Jason A., additional, Bremer, Meire, additional, Walters, Benjamin T., additional, Vij, Rajesh, additional, Chen, Xiaocheng, additional, Trivedi, Neil N., additional, Morando, Ashley, additional, Lipari, Michael T., additional, Franke, Yvonne, additional, Wu, Xiumin, additional, Zhang, Juan, additional, Liu, John, additional, Wu, Ping, additional, Chang, Diana, additional, Orozco, Luz D., additional, Christensen, Erin, additional, Wong, Manda, additional, Corpuz, Racquel, additional, Hang, Julie Q., additional, Lutman, Jeff, additional, Sukumaran, Siddharth, additional, Wu, Yan, additional, Ubhayakar, Savita, additional, Liang, Xiaorong, additional, Schwartz, Lawrence B., additional, Babina, Magda, additional, Woodruff, Prescott G., additional, Fahy, John V., additional, Ahuja, Rahul, additional, Caughey, George H., additional, Kusi, Aija, additional, Dennis, Mark S., additional, Eigenbrot, Charles, additional, Kirchhofer, Daniel, additional, Austin, Cary D., additional, Wu, Lawren C., additional, Koerber, James T., additional, Lee, Wyne P., additional, Yaspan, Brian L., additional, Alatsis, Kathila R., additional, Arron, Joseph R., additional, Lazarus, Robert A., additional, and Yi, Tangsheng, additional

Published
2020
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21. An Allosteric Anti-Tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma

Author

Maun, Henry R., primary, Jackman, Janet, additional, Choy, David F., additional, Loyet, Kelly M., additional, Jia, Guiquan, additional, Dressen, Amy, additional, Hackney, Jason A., additional, Bremer, Meire, additional, Walters, Benjamin T., additional, Vij, Rajesh, additional, Chen, Xiaocheng, additional, Trivedi, Neil N., additional, Morando, Ashley, additional, Lipari, Michael T., additional, Franke, Yvonne, additional, Wu, Xiumin, additional, Liu, John, additional, Wu, Ping, additional, Chang, Diana, additional, Guerra, Luz Orozco, additional, Lee, Wyne P., additional, Christensen, Erin, additional, Wong, Manda, additional, Corpuz, Racquel, additional, Hang, Julie Q., additional, Lutman, Jeff, additional, Sukumaran, Siddharth, additional, Wu, Yan, additional, Schwartz, Lawrence B., additional, Babina, Magda, additional, Woodruff, Prescott G., additional, Fahy, John V., additional, Ahuja, Rahul, additional, Caughey, George H., additional, Kusi, Aija, additional, Alatsis, Kathila R., additional, Dennis, Mark S., additional, Eigenbrot, Charles, additional, Kirchhofer, Daniel, additional, Wu, Lawren C., additional, Koerber, James T., additional, Staton, Tracy L., additional, Yaspan, Brian L., additional, Arron, Joseph R., additional, Lazarus, Robert A., additional, and Yi, Tangsheng, additional

Published
2019
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22. Guinea Pig Chymase Is Leucine-specific: A NOVEL EXAMPLE OF FUNCTIONAL PLASTICITY IN THE CHYMASE/GRANZYME FAMILY OF SERINE PEPTIDASES*

Author

Caughey, George H., Beauchamp, Jeremy, Schlatter, Daniel, Raymond, Wilfred W., Trivedi, Neil N., Banner, David, Mauser, Harald, and Fingerle, Jürgen

Subjects
Enzyme Catalysis and Regulation, Sequence Homology, Amino Acid, Guinea Pigs, Molecular Sequence Data, Granzymes, Rats, Mice, Chymases, Species Specificity, Leucine, Mutation, Serine, Animals, Humans, Amino Acid Sequence, Enzyme Inhibitors, Peptide Hydrolases
Abstract

To explore guinea pigs as models of chymase biology, we cloned and expressed the guinea pig ortholog of human chymase. In contrast to rats and mice, guinea pigs appear to express just one chymase, which belongs to the alpha clade, like primate chymases and mouse mast cell protease-5. The guinea pig enzyme autolyzes at Leu residues in the loop where human chymase autolyzes at Phe. In addition, guinea pig alpha-chymase selects P1 Leu in a combinatorial peptide library and cleaves Ala-Ala-Pro-Leu-4-nitroanilide but has negligible activity toward substrates with P1 Phe and does not cleave angiotensin I. This contrasts with human chymase, which cleaves after Phe or Tyr, prefers P1 Phe in peptidyl 4-nitroanilides, and avidly hydrolyzes angiotensin I at Phe8 to generate bioactive angiotensin II. The guinea pig enzyme also is inactivated more effectively by alpha1-antichymotrypsin, which features P1 Leu in the reactive loop. Unlike mouse, rat, and hamster alpha-chymases, guinea pig chymase lacks elastase-like preference for P1 Val or Ala. Partially humanized A216G guinea pig chymase acquires human-like P1 Phe- and angiotensin-cleaving capacity. Molecular models suggest that the wild type active site is crowded by the Ala216 side chain, which potentially blocks access by bulky P1 aromatic residues. On the other hand, the guinea pig pocket is deeper than in Val-selective chymases, explaining the preference for the longer aliphatic side chain of Leu. These findings are evidence that chymase-like peptidase specificity is sensitive to small changes in structure and provide the first example of a vertebrate Leu-selective peptidase.

Published
2008

25. Guinea Pig Chymase Is Leucine-specific

Author

Caughey, George H., primary, Beauchamp, Jeremy, additional, Schlatter, Daniel, additional, Raymond, Wilfred W., additional, Trivedi, Neil N., additional, Banner, David, additional, Mauser, Harald, additional, and Fingerle, Jürgen, additional

Published
2008
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27. Modulation of amplitude and direction ofin vivo immune responses by co-administration of cytokine gene expression cassettes with DNA immunogens

Author

Kim, Jong J., primary, Trivedi, Neil N., additional, Nottingham, Liesl K., additional, Morrison, Lake, additional, Tsai, Anthony, additional, Hu, Yin, additional, Mahalingam, Sundarasamy, additional, Dang, Kesen, additional, Ahn, Lois, additional, Doyle, Nicole K., additional, Wilson, Darren M., additional, Chattergoon, Michael A., additional, Chalian, Ara A., additional, Boyer, Jean D., additional, Agadjanyan, Michael G., additional, and Weiner, David B., additional

Published
1998
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30. Chimerism, point mutation, and truncation dramatically transformed mast cell delta-tryptases during primate evolution.

Author

Trivedi NN, Raymond WW, and Caughey GH

Subjects
Amino Acid Sequence, Animals, Base Sequence, Gorilla gorilla, Humans, Lemur, Macaca, Models, Molecular, Molecular Sequence Data, Pan troglodytes, Pongo pygmaeus, Protein Structure, Quaternary, Tryptases chemistry, Chimerism, Mast Cells enzymology, Phylogeny, Point Mutation, Primates genetics, Tryptases genetics
Abstract

Background: Tryptases are serine peptidases stored in mast cell granules. Rodents express 2 soluble tryptases, mast cell proteases (MCPs) 6 and 7. Human alpha- and beta-tryptases are orthologs of MCP-6. However, much of the ancestral MCP-7 ortholog was replaced by parts of other tryptases, creating chimeric delta-tryptase. Human delta-tryptase's limited activity is hypothesized to be due to truncation and processing mutations., Objective: We sought to probe the origins and consequences of mutations in primate delta-tryptases., Methods: Prosimian (lemur), monkey (macaque), great ape (orangutan, gorilla, and chimpanzee), and human delta-tryptase genes were identified by means of data mining and genomic sequencing. Resulting genes were analyzed phylogenetically and structurally., Results: The seminal conversion event generating the delta-tryptase chimera occurred early because all primates studied contain delta-tryptase genes. Truncation, resulting from a nonsense mutation of Trp206, occurred much later, after orangutans and other great apes last shared an ancestor. The Arg-3Gln propeptide mutation occurred most recently, being present in humans and chimpanzees but not in other primates. Surprisingly, the major active tryptase in monkeys is full-length delta-tryptase, not beta-tryptase, which is the main active tryptase in human subjects. Models of macaque delta-tryptase reveal that the segment truncated in human subjects contains antiparallel beta-strands coursing through the substrate-binding cleft, accounting for truncation's drastic effect on activity., Conclusions: Transformations in the ancestral MCP-7-like gene during primate evolution caused dramatic variations in function. Although delta-tryptases are nearly inactive in humans, they are active and dominant in monkeys.

Published
2008
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31. Mast cell alpha and beta tryptases changed rapidly during primate speciation and evolved from gamma-like transmembrane peptidases in ancestral vertebrates.

Author

Trivedi NN, Tong Q, Raman K, Bhagwandin VJ, and Caughey GH

Subjects
Animals, Base Sequence, Exons genetics, Genome genetics, Humans, Introns genetics, Molecular Sequence Data, Phylogeny, Sequence Alignment, Sequence Homology, Amino Acid, Solubility, Time Factors, Tryptases genetics, Vertebrates, Cell Membrane enzymology, Evolution, Molecular, Mast Cells enzymology, Tryptases metabolism
Abstract

Human mast cell tryptases vary strikingly in secretion, catalytic competence, and inheritance. To explore the basis of variation, we compared genes from a range of primates, including humans, great apes (chimpanzee, gorilla, orangutan), Old- and New-World monkeys (macaque and marmoset), and a prosimian (galago), tracking key changes. Our analysis reveals that extant soluble tryptase-like proteins, including alpha- and beta-like tryptases, mastins, and implantation serine proteases, likely evolved from membrane-anchored ancestors because their more deeply rooted relatives (gamma tryptases, pancreasins, prostasins) are type I transmembrane peptidases. Function-altering mutations appeared at widely separated times during primate speciation, with tryptases evolving by duplication, gene conversion, and point mutation. The alpha-tryptase Gly(216)Asp catalytic domain mutation, which diminishes activity, is present in macaque tryptases, and thus arose before great apes and Old World monkeys shared an ancestor, and before the alphabeta split. However, the Arg(-3)Gln processing mutation appeared recently, affecting only human alpha. By comparison, the transmembrane gamma-tryptase gene, which anchors the telomeric end of the multigene tryptase locus, changed little during primate evolution. Related transmembrane peptidase genes were found in reptiles, amphibians, and fish. We identified soluble tryptase-like genes in the full spectrum of mammals, including marsupial (opossum) and monotreme (platypus), but not in nonmammalian vertebrates. Overall, our analysis suggests that soluble tryptases evolved rapidly from membrane-anchored, two-chain peptidases in ancestral vertebrates into soluble, single-chain, self-compartmentalizing, inhibitor-resistant oligomers expressed primarily by mast cells, and that much of present numerical, behavioral, and genetic diversity of alpha- and beta-like tryptases was acquired during primate evolution.

Published
2007
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32. Clinical problem-solving. A gut feeling.

Author

Haberer J, Trivedi NN, Kohlwes J, and Tierney L Jr

Subjects
Abdominal Pain etiology, Aged, Anorexia etiology, Celiac Artery diagnostic imaging, Celiac Artery surgery, Diagnosis, Differential, Gastritis diagnosis, Humans, Ischemia complications, Ischemia surgery, Leukocytosis complications, Male, Mesenteric Arteries diagnostic imaging, Mesenteric Arteries surgery, Pulmonary Emphysema complications, Pulmonary Emphysema diagnostic imaging, Radiography, Smoking, Solitary Pulmonary Nodule complications, Solitary Pulmonary Nodule diagnostic imaging, Stomach pathology, Stomach Ulcer complications, Urinary Tract Infections complications, Ischemia diagnosis, Stomach blood supply, Weight Loss
Published
2003
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