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14 results on '"Barbara S. Slusher"'

1. Aged fibroblast-derived extracellular vesicles promote angiogenesis in melanoma

Author

Laura Hüser, Yash Chhabra, Olesia Gololobova, Vania Wang, Guanshu Liu, Agrani Dixit, Murilo Ramos Rocha, Elizabeth I. Harper, Mitchell E. Fane, Gloria E. Marino-Bravante, Daniel J. Zabransky, Kathy Q. Cai, Jochen Utikal, Barbara S. Slusher, Jeremy Walston, Evan J. Lipson, Kenneth W. Witwer, and Ashani T. Weeraratna

Subjects
CP: Cancer, Biology (General), QH301-705.5
Abstract

Summary: Advancing age is a negative prognostic factor for cutaneous melanoma. However, the role of extracellular vesicles (EVs) within the melanoma tumor microenvironment (TME) has remained unexplored in the context of aging. While the size and morphology of the EVs isolated from young vs. aged fibroblasts remained unaltered, the contents of the protein cargo were changed. Aging reduced the expression of the tetraspanin CD9 in both the dermal fibroblasts and released EVs. CD9 is a crucial regulator of EV cargo sorting. Modulating the CD9 expression in fibroblasts was sufficient to alter its levels in EVs. Mass spectrometry analysis of EVs released by CD9 knockdown (KD) vs. control cells revealed a significant increase in angiopoietin-like protein 2 (ANGPTL2), an angiogenesis promoter. Analysis of primary endothelial cells confirmed increased sprouting under CD9 KD conditions. Together, our data indicate that aged EVs play an important role in promoting a tumor-permissive microenvironment.

Published
2024
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2. Neuronal deletion of nSMase2 reduces the production of Aβ and directly protects neurons

Author

Sehmus Tohumeken, Pragney Deme, Seung Wan Yoo, Sujasha Gupta, Rana Rais, Barbara S. Slusher, and Norman J. Haughey

Subjects
Sphingomyelinase, nSMase2, Long term potentiation, LTP, Ceramide, Extracellular vesicles (EVs), Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Extracellular vesicles (EVs) have been proposed to regulate the deposition of Aβ. Multiple publications have shown that APP, amyloid processing enzymes and Aβ peptides are associated with EVs. However, very little Aβ is associated with EVs compared with the total amount Aβ present in human plasma, CSF, or supernatants from cultured neurons. The involvement of EVs has largely been inferred by pharmacological inhibition or whole body deletion of the sphingomyelin hydrolase neutral sphingomyelinase-2 (nSMase2) that is a key regulator for the biogenesis of at-least one population of EVs. Here we used a Cre-Lox system to selectively delete nSMase2 from pyramidal neurons in APP/PS1 mice (APP/PS1-SMPD3-Nex1) and found a ∼ 70% reduction in Aβ deposition at 6 months of age and ∼ 35% reduction at 12 months of age in both cortex and hippocampus. Brain ceramides were increased in APP/PS1 compared with Wt mice, but were similar to Wt in APP/PS1-SMPD3-Nex1 mice suggesting that elevated brain ceramides in this model involves neuronally expressed nSMase2. Reduced levels of PSD95 and deficits of long-term potentiation in APP/PS1 mice were normalized in APP/PS1-SMPD3-Nex1 mice. In contrast, elevated levels of IL-1β, IL-8 and TNFα in APP/PS1 mice were not normalized in APP/PS1-SMPD3-Nex1 mice compared with APP/PS1 mice. Mechanistic studies showed that the size of liquid ordered membrane microdomains was increased in APP/PS1 mice, as were the amounts of APP and BACE1 localized to these microdomains. Pharmacological inhibition of nSMase2 activity with PDDC reduced the size of the liquid ordered membrane microdomains, reduced the localization of APP with BACE1 and reduced the production of Aβ1–40 and Aβ1–42. Although inhibition of nSMase2 reduced the release and increased the size of EVs, very little Aβ was associated with EVs in all conditions tested. We also found that nSMase2 directly protected neurons from the toxic effects of oligomerized Aβ and preserved neural network connectivity despite considerable Aβ deposition. These data demonstrate that nSMase2 plays a role in the production of Aβ by stabilizing the interaction of APP with BACE1 in liquid ordered membrane microdomains, and directly protects neurons from the toxic effects of Aβ. The effects of inhibiting nSMase2 on EV biogenesis may be independent from effects on Aβ production and neuronal protection.

Published
2023
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3. Glutamine antagonist JHU083 improves psychosocial behavior and sleep deficits in EcoHIV-infected mice

Author

Benjamin J. Bell, Kristen R. Hollinger, Pragney Deme, Shinji Sakamoto, Yuto Hasegawa, David Volsky, Atsushi Kamiya, Norman Haughey, Xiaolei Zhu, and Barbara S. Slusher

Subjects
EcoHIV-infected mice, Psychosocial deficits, Sleep deficits, Microglial immune genes, Glutamine antagonist, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Combined antiretroviral therapy ushered an era of survivable HIV infection in which people living with HIV (PLH) conduct normal life activities and enjoy measurably extended lifespans. However, despite viral control, PLH often experience a variety of cognitive, emotional, and physical phenotypes that diminish their quality of life, including cognitive impairment, depression, and sleep disruption. Recently, accumulating evidence has linked persistent CNS immune activation to the overproduction of glutamate and upregulation of glutaminase (GLS) activity, particularly in microglial cells, driving glutamatergic imbalance with neurological consequences. Our lab has developed a brain-penetrant prodrug of the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON), JHU083, that potently inhibits brain GLS activity in mice following oral administration. To assess the therapeutic potential of JHU083, we infected mice with EcoHIV and characterized their neurobehavioral phenotypes. EcoHIV-infected mice exhibited decreased social interaction, suppressed sucrose preference, disrupted sleep during the early rest period, and increased sleep fragmentation, similar to what has been reported in PLH but not yet observed in murine models. At doses shown to inhibit microglial GLS, JHU083 treatment ameliorated all of the abnormal neurobehavioral phenotypes. To explore potential mechanisms underlying this effect, hippocampal microglia were isolated for RNA sequencing. The dysregulated genes and pathways in EcoHIV-infected hippocampal microglia pointed to disruptions in immune functions of these cells, which were partially restored by JHU083 treatment. These findings suggest that upregulation of microglial GLS may affect immune functions of these cells. Thus, brain-penetrable GLS inhibitors like JHU083 could act as a potential therapeutic modality for both glutamate excitotoxicity and aberrant immune activation in microglia in chronic HIV infection.

Published
2022
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4. Neutral sphingomyelinase 2 inhibition attenuates extracellular vesicle release and improves neurobehavioral deficits in murine HIV

Author

Xiaolei Zhu, Kristen R. Hollinger, Yiyao Huang, Alejandra Borjabad, Boe-Hyun Kim, Tanina Arab, Ajit G. Thomas, Mohammed Moniruzzaman, Lyndah Lovell, Andrey Turchinovich, Kenneth W. Witwer, David J. Volsky, Norman J. Haughey, and Barbara S. Slusher

Subjects
Neutral sphingomyelinase 2, Depression, Sleep, HIV, Extracellular vesicle, EcoHIV, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

People living with HIV (PLH) have significantly higher rates of cognitive impairment (CI) and major depressive disorder (MDD) versus the general population. The enzyme neutral sphingomyelinase 2 (nSMase2) is involved in the biogenesis of ceramide and extracellular vesicles (EVs), both of which are dysregulated in PLH, CI, and MDD. Here we evaluated EcoHIV-infected mice for behavioral abnormalities relevant to depression and cognition deficits, and assessed the behavioral and biochemical effects of nSMase2 inhibition. Mice were infected with EcoHIV and daily treatment with either vehicle or the nSMase2 inhibitor (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-carbamate (PDDC) began 3 weeks post-infection. After 2 weeks of treatment, mice were subjected to behavior tests. EcoHIV-infected mice exhibited behavioral abnormalities relevant to MDD and CI that were reversed by PDDC treatment. EcoHIV infection significantly increased cortical brain nSMase2 activity, resulting in trend changes in sphingomyelin and ceramide levels that were normalized by PDDC treatment. EcoHIV-infected mice also exhibited increased levels of brain-derived EVs and altered microRNA cargo, including miR-183-5p, miR-200c-3p, miR-200b-3p, and miR-429-3p, known to be associated with MDD and CI; all were normalized by PDDC. In conclusion, inhibition of nSMase2 represents a possible new therapeutic strategy for the treatment of HIV-associated CI and MDD.

Published
2022
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5. Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma

Author

Allison R. Hanaford, Jesse Alt, Rana Rais, Sabrina Z. Wang, Harpreet Kaur, Daniel L.J. Thorek, Charles G. Eberhart, Barbara S. Slusher, Allison M. Martin, and Eric H. Raabe

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

A subset of poor-prognosis medulloblastoma has genomic amplification of MYC. MYC regulates glutamine metabolism in multiple cellular contexts. We modified the glutamine analog 6-diazo-5-oxo-l-norleucine (DON) to mask its carboxylate and amine functionalities, creating a prodrug termed JHU-083 with increased oral bioavailability. We hypothesized that this prodrug would kill MYC-expressing medulloblastoma. JHU-083 treatment caused decreased growth and increased apoptosis in human MYC-expressing medulloblastoma cell lines. We generated a mouse MYC-driven medulloblastoma model by transforming C57BL/6 mouse cerebellar stem and progenitor cells. When implanted into the brains of C57BL/6 mice, these cells formed large cell/anaplastic tumors that resembled aggressive medulloblastoma. A cell line derived from this model was sensitive to JHU-083 in vitro. Oral administration of JHU-038 led to the accumulation of micromolar concentrations of DON in the mouse brain. JHU-083 treatment significantly increased the survival of immune-competent animals bearing orthotopic tumors formed by the mouse cerebellar stem cell model as well as immune-deficient animals bearing orthotopic tumors formed by a human MYC-amplified medulloblastoma cell line. These data provide pre-clinical justification for the ongoing development and testing of orally bioavailable DON prodrugs for use in medulloblastoma patients.

Published
2019
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6. Development of a primary microglia screening assay and its use to characterize inhibition of system xc- by erastin and its analogs

Author

Mariana Figuera-Losada, Ajit G. Thomas, Marigo Stathis, Brent R. Stockwell, Camilo Rojas, and Barbara S. Slusher

Subjects
Primary microglia, CCF-STTG-1 cells, System xc-, Erastin, Sulfasalazine, (S)-4-CPG, Biology (General), QH301-705.5, Biochemistry, QD415-436
Abstract

The inflammatory response in the central nervous system involves activated microglia. Under normal conditions they remove damaged neurons by phagocytosis. On the other hand, neurodegenerative diseases are thought to involve chronic microglia activation resulting in release of excess glutamate, proinflammatory cytokines and reactive oxygen species, leading to neuronal death. System xC- cystine/glutamate antiporter (SXC), a sodium independent heterodimeric transporter found in microglia and astrocytes in the CNS, imports cystine into the cell and exports glutamate. SXC has been shown to be upregulated in neurodegenerative diseases including multiple sclerosis, ALS, neuroAIDS Parkinson's disease and Alzheimer's disease. Consequently, SXC inhibitors could be of use in the treatment of diseases characterized by neuroinflammation and glutamate excitotoxicity. We report on the optimization of a primary microglia-based assay to screen for SXC inhibitors. Rat primary microglia were activated using lipopolysaccharides (LPS) and glutamate release and cystine uptake were monitored by fluorescence and radioactivity respectively. LPS-induced glutamate release increased with increasing cell density, time of incubation and LPS concentration. Conditions to screen for SXC inhibitors were optimized in 96-well format and subsequently used to evaluate SXC inhibitors. Known SXC inhibitors sulfasalazine, S-4CPG and erastin blocked glutamate release and cystine uptake while R-4CPG, the inactive enantiomer of S-4CPG, failed to inhibit glutamate release or cystine transport. In addition, several erastin analogs were evaluated using primary microglia and found to have EC50 values in agreement with previous studies using established cell lines.

Published
2017
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7. Maternal inflammation leads to impaired glutamate homeostasis and up-regulation of glutamate carboxypeptidase II in activated microglia in the fetal/newborn rabbit brain

Author

Zhi Zhang, Bassam Bassam, Ajit G. Thomas, Monica Williams, Jinhuan Liu, Elizabeth Nance, Camilo Rojas, Barbara S. Slusher, and Sujatha Kannan

Subjects
Cerebral palsy, Periventricular leukomalacia, Glutamate, Glutamate carboxypeptidase II (GCPII), Microglia, Astrocytes, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Astrocyte dysfunction and excessive activation of glutamatergic systems have been implicated in a number of neurologic disorders, including periventricular leukomalacia (PVL) and cerebral palsy (CP). However, the role of chorioamnionitis on glutamate homeostasis in the fetal and neonatal brains is not clearly understood. We have previously shown that intrauterine endotoxin administration results in intense microglial ‘activation’ and increased pro-inflammatory cytokines in the periventricular region (PVR) of the neonatal rabbit brain. In this study, we assessed the effect of maternal inflammation on key components of the glutamate pathway and its relationship to astrocyte and microglial activation in the fetal and neonatal New Zealand white rabbit brain. We found that intrauterine endotoxin exposure at gestational day 28 (G28) induced acute and prolonged glutamate elevation in the PVR of fetal (G29, 1 day post-injury) and postnatal day 1 (PND1, 3 days post-injury) brains along with prominent morphological changes in the astrocytes (soma hypertrophy and retracted processes) in the white matter tracts. There was a significant increase in glutaminase and N-Methyl-d-Aspartate receptor (NMDAR) NR2 subunit expression along with decreased glial L-glutamate transporter 1 (GLT-1) in the PVR at G29, that would promote acute dysregulation of glutamate homeostasis. This was accompanied with significantly decreased TGF-β1 at PND1 in CP kits indicating ongoing neuroinflammation. We also show for the first time that glutamate carboxypeptidase II (GCPII) was significantly increased in the activated microglia at the periventricular white matter area in both G29 and PND1 CP kits. This was confirmed by in vitro studies demonstrating that LPS activated primary microglia markedly upregulate GCPII enzymatic activity. These results suggest that maternal intrauterine endotoxin exposure results in early onset and long-lasting dysregulation of glutamate homeostasis, which may be mediated by impaired astrocyte function and GCPII upregulation in activated microglia.

Published
2016
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8. Preventing Allograft Rejection by Targeting Immune Metabolism

Author

Chen-Fang Lee, Ying-Chun Lo, Chih-Hsien Cheng, Georg J. Furtmüller, Byoungchol Oh, Vinicius Andrade-Oliveira, Ajit G. Thomas, Caitlyn E. Bowman, Barbara S. Slusher, Michael J. Wolfgang, Gerald Brandacher, and Jonathan D. Powell

Subjects
Biology (General), QH301-705.5
Abstract

Upon antigen recognition and co-stimulation, T lymphocytes upregulate the metabolic machinery necessary to proliferate and sustain effector function. This metabolic reprogramming in T cells regulates T cell activation and differentiation but is not just a consequence of antigen recognition. Although such metabolic reprogramming promotes the differentiation and function of T effector cells, the differentiation of regulatory T cells employs different metabolic reprogramming. Therefore, we hypothesized that inhibition of glycolysis and glutamine metabolism might prevent graft rejection by inhibiting effector generation and function and promoting regulatory T cell generation. We devised an anti-rejection regimen involving the glycolytic inhibitor 2-deoxyglucose (2-DG), the anti-type II diabetes drug metformin, and the inhibitor of glutamine metabolism 6-diazo-5-oxo-L-norleucine (DON). Using this triple-drug regimen, we were able to prevent or delay graft rejection in fully mismatched skin and heart allograft transplantation models.

Published
2015
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9. Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma

Author

Rana Rais, Daniel L.J. Thorek, Sabrina Wang, Harpreet Kaur, Charles G. Eberhart, Allison Martin, Jesse Alt, Allison Hanaford, Eric H. Raabe, and Barbara S. Slusher

Subjects
0301 basic medicine, Medulloblastoma, Cancer Research, Chemistry, Prodrug, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, In vitro, 3. Good health, Glutamine, 03 medical and health sciences, stomatognathic diseases, 030104 developmental biology, 0302 clinical medicine, Oncology, Cell culture, Apoptosis, 030220 oncology & carcinogenesis, medicine, Cancer research, Progenitor cell, Stem cell
Abstract

A subset of poor-prognosis medulloblastoma has genomic amplification of MYC. MYC regulates glutamine metabolism in multiple cellular contexts. We modified the glutamine analog 6-diazo-5-oxo-l-norleucine (DON) to mask its carboxylate and amine functionalities, creating a prodrug termed JHU-083 with increased oral bioavailability. We hypothesized that this prodrug would kill MYC-expressing medulloblastoma. JHU-083 treatment caused decreased growth and increased apoptosis in human MYC-expressing medulloblastoma cell lines. We generated a mouse MYC-driven medulloblastoma model by transforming C57BL/6 mouse cerebellar stem and progenitor cells. When implanted into the brains of C57BL/6 mice, these cells formed large cell/anaplastic tumors that resembled aggressive medulloblastoma. A cell line derived from this model was sensitive to JHU-083 in vitro. Oral administration of JHU-038 led to the accumulation of micromolar concentrations of DON in the mouse brain. JHU-083 treatment significantly increased the survival of immune-competent animals bearing orthotopic tumors formed by the mouse cerebellar stem cell model as well as immune-deficient animals bearing orthotopic tumors formed by a human MYC-amplified medulloblastoma cell line. These data provide pre-clinical justification for the ongoing development and testing of orally bioavailable DON prodrugs for use in medulloblastoma patients.

Published
2019

10. Neuroprotective effects of a dendrimer-based glutamate carboxypeptidase inhibitor on superoxide dismutase transgenic mice after neonatal hypoxic-ischemic brain injury

Author

Sujatha Kannan, O. Arteaga Cabeza, E. Smith Khoury, Barbara S. Slusher, Zhi Zhang, R A Sheldon, Donna M. Ferriero, Rangaramanujam M. Kannan, Fan Zhang, and Anjali Sharma

Subjects
0301 basic medicine, Glutamate Carboxypeptidase II, Transgenic, Mice, 0302 clinical medicine, Superoxide Dismutase-1, Nanoparticle, Enzyme Inhibitors, Pediatric, Dendrimer, Microglia, biology, Chemistry, Glutamate receptor, Brain, Neuroprotection, Stroke, medicine.anatomical_structure, Neuroprotective Agents, Neurology, Enzyme inhibitor, Hypoxia-Ischemia, Brain, medicine.symptom, Genetically modified mouse, medicine.medical_specialty, Dendrimers, Physical Injury - Accidents and Adverse Effects, Clinical Sciences, Mice, Transgenic, Brain damage, N-acetyl-aspartyl-glutamate, Article, lcsh:RC321-571, Superoxide dismutase, Glutarates, 03 medical and health sciences, Glutamate carboxypeptidase, Internal medicine, Hypoxia-Ischemia, medicine, Animals, Sulfhydryl Compounds, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Neurology & Neurosurgery, Neurosciences, N-acetyl-aspartyl-glutamate (NAAG), Perinatal Period - Conditions Originating in Perinatal Period, Newborn, Neonatal brain injury, Brain Disorders, 030104 developmental biology, Endocrinology, Animals, Newborn, biology.protein, 030217 neurology & neurosurgery
Abstract

The result of a deprivation of oxygen and glucose to the brain, hypoxic-ischemic encephalopathy (HIE), remains the most common cause of death and disability in human neonates globally and is mediated by glutamate toxicity and inflammation. We have previously shown that the enzyme glutamate carboxypeptidase (GCPII) is overexpressed in activated microglia in the presence of inflammation in fetal/newborn rabbit brain. We assessed the therapeutic utility of a GCPII enzyme inhibitor called 2-(3-Mercaptopropyl) pentanedioic acid (2MPPA) attached to a dendrimer (D-2MPPA), in order to target activated microglia in an experimental neonatal hypoxia-ischemia (HI) model using superoxide dismutase transgenic (SOD) mice that are often more injured after hypoxia-ischemia than wildtype animals. SOD overexpressing and wild type (WT) mice underwent permanent ligation of the left common carotid artery followed by 50min of asphyxiation (10% O2) to induce HI injury on postnatal day 9 (P9). Cy5-labeled dendrimers were administered to the mice at 6h, 24h or 72h after HI and brains were evaluated by immunofluorescence analysis 24h after the injection to visualize microglial localization and uptake over time. Expression of GCPII enzyme was analyzed in microglia 24h after the HI injury. The expression of pro- and anti-inflammatory cytokines were analyzed 24h and 72h post-HI. Brain damage was analyzed histologically 7days post-HI in the three randomly assigned groups: control (C); hypoxic-ischemic (HI); and HI mice who received a single dose of D-2MPPA 6h post-HI (HI+D-2MPPA). First, we found that GCPII was overexpressed in activated microglia 24h after HI in the SOD overexpressing mice. Also, there was an increase in microglial activation 24h after HI in the ipsilateral hippocampus which was most visible in the SOD+HI group. Dendrimers were mostly taken up by microglia by 24h post-HI; uptake was more prominent in the SOD+HI mice than in the WT+HI. The inflammatory profile showed significant increase in expression of KC/GRO following injury in SOD mice compared to WT at 24 and 72h. A greater and significant decrease in KC/GRO was seen in the SOD mice following treatment with D-2MPPA. Seven days after HI, D-2MPPA treatment decreased brain injury in the SOD+HI group, but not in WT+HI. This reduced damage was mainly seen in hippocampus and cortex. Our data indicate that the best time point to administer D-2MPPA is 6h post-HI in order to suppress the expression of GCPII by 24h after the damage since dendrimer localization in microglia is seen as early as 6h with the peak of GCPII upregulation in activated microglia seen at 24h post-HI. Ultimately, treatment with D-2MPPA at 6h post-HI leads to a decrease in inflammatory profiles by 24h and reduction in brain injury in the SOD overexpressing mice.

Published
2021

11. Development of a primary microglia screening assay and its use to characterize inhibition of system xc- by erastin and its analogs

Author

Marigo Stathis, Ajit G. Thomas, Brent R. Stockwell, Barbara S. Slusher, Mariana Figuera-Losada, and Camilo Rojas

Subjects
0301 basic medicine, CCF-STTG-1 cells, Biophysics, Cystine, Excitotoxicity, Pharmacology, (S)-4-CPG, medicine.disease_cause, Biochemistry, Proinflammatory cytokine, lcsh:Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Primary microglia, medicine, lcsh:QD415-436, System xc, lcsh:QH301-705.5, Neuroinflammation, chemistry.chemical_classification, Reactive oxygen species, Microglia, Chemistry, Erastin, Glutamate receptor, 3. Good health, Sulfasalazine, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), System X, Research Article
Abstract

The inflammatory response in the central nervous system involves activated microglia. Under normal conditions they remove damaged neurons by phagocytosis. On the other hand, neurodegenerative diseases are thought to involve chronic microglia activation resulting in release of excess glutamate, proinflammatory cytokines and reactive oxygen species, leading to neuronal death. System xC- cystine/glutamate antiporter (SXC), a sodium independent heterodimeric transporter found in microglia and astrocytes in the CNS, imports cystine into the cell and exports glutamate. SXC has been shown to be upregulated in neurodegenerative diseases including multiple sclerosis, ALS, neuroAIDS Parkinson's disease and Alzheimer's disease. Consequently, SXC inhibitors could be of use in the treatment of diseases characterized by neuroinflammation and glutamate excitotoxicity. We report on the optimization of a primary microglia-based assay to screen for SXC inhibitors. Rat primary microglia were activated using lipopolysaccharides (LPS) and glutamate release and cystine uptake were monitored by fluorescence and radioactivity respectively. LPS-induced glutamate release increased with increasing cell density, time of incubation and LPS concentration. Conditions to screen for SXC inhibitors were optimized in 96-well format and subsequently used to evaluate SXC inhibitors. Known SXC inhibitors sulfasalazine, S-4CPG and erastin blocked glutamate release and cystine uptake while R-4CPG, the inactive enantiomer of S-4CPG, failed to inhibit glutamate release or cystine transport. In addition, several erastin analogs were evaluated using primary microglia and found to have EC50 values in agreement with previous studies using established cell lines., Highlights • Conditions to screen for SXC inhibitors were optimized in 96-well format. • Assay enables higher throughput screens for SXC inhibitors with primary microglia. • Screening assay was used to evaluate prototype SXC inhibitors and erastin analogs.

Published
2017

12. Still NAAG’ing After All These Years

Author

Barbara S. Slusher, Kristen R. Hollinger, P F Jackson, Rana Rais, Krystyna M. Wozniak, Mohamed H. Farah, Pavel Majer, and James J. Vornov

Subjects
0301 basic medicine, Agonist, medicine.drug_class, Glutamate receptor, Pharmacology, Biology, 03 medical and health sciences, chemistry.chemical_compound, Glutamatergic, 030104 developmental biology, 0302 clinical medicine, chemistry, medicine, Glutamate carboxypeptidase II, Cholinergic, NMDA receptor, Neurotransmitter, Receptor, Neuroscience, 030217 neurology & neurosurgery
Abstract

Nearly two decades ago, Joe Coyle published a single-authored review with the provocative title, The Nagging Question of the Function of N-Acetylaspartylglutamate (Coyle, 1997). In this review, Coyle documented NAAG's localization to subpopulations of glutamatergic, cholinergic, GABAergic, and noradrenergic neurons, Ca(2+)-dependent release, mGlu3 receptor agonist and NMDA receptor antagonist activity, and cleavage by the glial enzyme glutamate carboxypeptidase II (GCPII). However, at the time of his review, NAAG's physiological function as a neurotransmitter remained elusive. Ironically his review was published months following the discovery of the first potent and selective GCPII inhibitor, 2-(phosphonomethyl)pentanedioc acid (2-PMPA) (Jackson et al., 1996). Over the ensuing decades, over a dozen independent laboratories used 2-PMPA and other GCPII inhibitors to elucidate two distinct neurotransmitter functions for NAAG. Under basal conditions, when GCPII activity is relatively low, intact NAAG dampens synaptic activity via presynaptic mGlu3 receptor activation and NMDA receptor blockade. However, under stimulated conditions, NAAG release and GCPII activity are enhanced resulting in excess glutamate generation, activating NMDA and other glutamate receptors, often pathologically. Diverse classes of GCPII inhibitors have been synthesized and shown to increase NAAG, decrease glutamate, and provide robust efficacy in many disease models wherein abnormal glutamatergic transmission is presumed pathogenic. In addition, over the past 20 years, basic questions regarding NAAG's synthesis, packaging into vesicles, and receptor selectivity profile have been eloquently elucidated. The purpose of this chapter is to summarize these advances and the promise of regulating NAAG metabolism through GCPII inhibition as a therapeutic strategy.

Published
2016

13. Glutamate Carboxypeptidase II

Author

Joseph T. Coyle, Barbara S. Slusher, and Camilo Rojas

Subjects
Dipeptidase, chemistry.chemical_classification, biology, Ligand (biochemistry), Molecular biology, Epithelium, Enzyme, Blood serum, medicine.anatomical_structure, chemistry, Biochemistry, Glutamate carboxypeptidase II, biology.protein, medicine, Immunohistochemistry, Cell fractionation
Abstract

Publisher Summary This chapter examines the structural chemistry and the biological aspects of glutamate carboxypeptidase II. This enzyme was first characterized in the rat nervous system by its hydrolysis of the neuropeptide N-acetylaspartylglutamate and was termed N-acetylated-alpha-linked acidic dipeptidase. The prostate cancer marker known as the prostate-specific membrane antigen also possesses NAALADase activity. Subcellular fractionation of brain reveals enrichment of the enzyme in neurosynaptosomal complexes. Electron microscopy localizes glutamate carboxypeptidase II immunoreactivity to the outer surface of the plasma membrane. The results indicate that the rat enzyme is expressed exclusively in astrocytic glial cells. Prostate-Specific Membrane (PSM) was characterized originally as the ligand of the monoclonal antibody 7E11.C5, which exhibited immunohistochemical staining restricted among human tissues to the prostate epithelium. The analyses have reported 7E11.C5 immunoreactivity and/or positive RNAase protection assays with PSM-derived probes in human salivary gland, brain, small intestine, seminal plasma and blood serum. Two gene loci closely related to PSM have been identified on human chromosome 11. The PSM form of glutamate carboxypeptidase II is expressed in normal and neoplastic prostate epithelial cells, and PSM has been examined for utility in the diagnosis, assessment and treatment of prostatic carcinoma.

Published
2013

14. Contributors

Author

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

Published
2013

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