14 results on '"Stathis M"'
Search Results
2. EmptyDropsMultiome discriminates real cells from background in single-cell multiomics assays
- Author
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Stathis Megas, Valentina Lorenzi, and John C. Marioni
- Subjects
Multiomics ,Single-cell ,Method ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Multiomic droplet-based technologies allow different molecular modalities, such as chromatin accessibility and gene expression (scATAC-seq and scRNA-seq), to be probed in the same nucleus. We develop EmptyDropsMultiome, an approach that distinguishes true nuclei-containing droplets from background. Using simulations, we show that EmptyDropsMultiome has higher statistical power and accuracy than existing approaches, including CellRanger-arc and EmptyDrops. On real datasets, we observe that CellRanger-arc misses more than half of the nuclei identified by EmptyDropsMultiome and, moreover, is biased against certain cell types, some of which have a retrieval rate lower than 20%.
- Published
- 2024
- Full Text
- View/download PDF
3. Low-Rank Methods in Event Detection With Subsampled Point-to-Subspace Proximity Tests
- Author
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Jakub Marecek, Stathis Maroulis, Vana Kalogeraki, and Dimitrios Gunopulos
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Multidimensional signal processing ,monitoring ,matrix completion ,point-to-subspace proximity ,probably approximately correct learning ,Electrical engineering. Electronics. Nuclear engineering ,TK1-9971 - Abstract
Monitoring of streamed data to detect abnormal behaviour (variously known as event detection, anomaly detection, change detection, or outlier detection) underlies many applications, especially within the Internet of Things. There, one often collects data from a variety of sources, with asynchronous sampling, and missing data. In this setting, one can detect abnormal behavior using low-rank techniques. In particular, we assume that normal observations come from a low-rank subspace, prior to being corrupted by a uniformly distributed noise. Correspondingly, we aim to recover a representation of the subspace, and perform event detection by running point-to-subspace distance query for incoming data. We use a variant of low-rank factorisation, which considers interval uncertainty sets around “known entries”, on a suitable flattening of the input data to obtain a low-rank model. On-line, we compute the distance of incoming data to the low-rank normal subspace and update the subspace to keep it consistent with the seasonal changes present. For the distance computation, we consider subsampling. We bound the one-sided error as a function of the number of coordinates employed. In our computational experiments, we test the proposed algorithm on induction-loop data from Dublin, Ireland.
- Published
- 2022
- Full Text
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4. 2d TQFTs and baby universes
- Author
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John Gardiner and Stathis Megas
- Subjects
AdS-CFT Correspondence ,Models of Quantum Gravity ,Topological Field Theories ,Nuclear and particle physics. Atomic energy. Radioactivity ,QC770-798 - Abstract
Abstract In this work, we extend the 2d topological gravity model of [1] to have as its bulk action any open/closed TQFT obeying Atiyah’s axioms. The holographic duals of these topological gravity models are ensembles of 1d topological theories with random dimension. Specifically, we find that the TQFT Hilbert space splits into sectors, between which correlators of boundary observables factorize, and that the corresponding sectors of the boundary theory have dimensions independently chosen from different Poisson distributions. As a special case, we study in detail the gravity model built from the bulk action of 2d Dijkgraaf-Witten theory, with or without end-of-the-world branes, and for arbitrary finite group G. The dual of this Dijkgraaf-Witten gravity model can be interpreted as a 1d topological theory whose Hilbert space is a random representation of G and whose aforementioned sectors are labeled by the irreducible representations of G. These holographic interpretations of our gravity models require projecting out negative-norm states from the baby universe Hilbert space, which in [1] was achieved by the (only seemingly) ad hoc solution of adding a nonlocal boundary term to the bulk action. In order to place their solution in the completely local framework of a TQFT with defects, we couple the boundaries of the gravity model to an auxiliary 2d TQFT in a non-gravitational (i.e. fixed topology) region. In this framework, the difficulty of negative-norm states can be remedied in a local way by the introduction of a defect line between the gravitational and non-gravitational regions. The gravity model is then holographically dual to an ensemble of boundary conditions in an open/closed TQFT without gravity.
- Published
- 2021
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5. Anomalous dimensions from thermal AdS partition functions
- Author
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Per Kraus, Stathis Megas, and Allic Sivaramakrishnan
- Subjects
AdS-CFT Correspondence ,1/N Expansion ,Nuclear and particle physics. Atomic energy. Radioactivity ,QC770-798 - Abstract
Abstract We develop an efficient method for computing thermal partition functions of weakly coupled scalar fields in AdS. We consider quartic contact interactions and show how to evaluate the relevant two-loop vacuum diagrams without performing any explicit AdS integration, the key step being the use of Källén-Lehmann type identities. This leads to a simple method for extracting double-trace anomalous dimensions in any spacetime dimension, recovering known first-order results in a streamlined fashion.
- Published
- 2020
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6. A Learning-Automata-Based Congestion-Aware Scheme for Energy-Efficient Elastic Optical Networks
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Georgia A. Beletsioti, Georgios I. Papadimitriou, Petros Nicopolitidis, Emmanouel Varvarigos, and Stathis Mavridopoulos
- Subjects
Adaptivity ,elastic optical networks ,energy-efficiency ,learning automata ,metropolitan networks ,Electrical engineering. Electronics. Nuclear engineering ,TK1-9971 - Abstract
The flexible nature of elastic optical networks (EONs) effectively uses spectral resources for optical communication by allocating the minimum required bandwidth to network connections. Since the energy consumption of such networks scales with the magnitude of bandwidth demand, addressing the issue of energy wastage is important. This fact has a profound impact on the design of efficient schemes for energy aware optical networks, and adaptivity arises as one of the most important properties of these networks. Learning Automata are Artificial Intelligence tools that have been used in networking algorithms, when adaptivity to the characteristics of the network environment can result in significantly improved network performance. In this work, a new adaptive power-aware algorithm is introduced, which selectively switches off bandwidth-variable optical transponders (BVTs) under low utilization conditions, to achieve energy efficiency. A novel adaptive scheme, which makes use of Learning Automata to significantly reduce the total energy consumption, while at the same time avoiding the onset of congestion, is proposed. The proposed scheme monitors network congestion, in terms of Bandwidth Blocking Probability (BBP), and the learning mechanism finds the optimal amount of energy-saving so that congestion is avoided, while at the same time significant energy savings are achieved. The proposed Learning Energy-Saving Algorithm (LESA) is evaluated via extensive simulation results, which indicate that it achieves an energy saving of up to 50%, compared to other energy efficient solutions.
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- 2020
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7. Creating a comprehensive research strategy for cutaneous neurofibromas.
- Author
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Blakeley JO, Wolkenstein P, Widemann BC, Lee J, Le LQ, Jackson R, Stathis M, and Verma SK
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- Clinical Trials as Topic, Dermatology, Humans, Neurofibroma complications, Neurology, Research Design, Skin Neoplasms complications, Neurofibroma therapy, Neurofibromatosis 1 complications, Skin Neoplasms therapy
- Abstract
Objective: Outside of procedural-based methods, there are currently no established medical treatments for cutaneous neurofibroma (cNF), which afflict up to 99% of patients with NF1. Further, adult patients often report cNF are the greatest burden of living with NF1. The Neurofibromatosis Therapeutic Acceleration Program (NTAP) launched a think tank to address core questions to facilitate development of effective therapeutics for cNF in people with NF1., Methods: Experts (with and without explicit experience with NF1 or cNF) from multiple scientific and medical disciplines, representing the ranks of academia, industry, and government agencies, were invited to become a member of a team addressing a specific subset of questions pertinent to cNF. Teams met monthly to review published and unpublished materials, and created summaries about the material known and unknown that may influence therapeutic development for cNF. Teams prioritized questions and organized supporting data, which was presented to the entire body of experts by each team at a research summit., Results: Four themes were identified as being relevant to creating a comprehensive research strategy for cNF: (1) establishing definitions of cNF, (2) determining the biology of cNF with respect to tumor initiation, progression, and maintenance, (3) outlining the factors that guide therapies development, and (4) defining core considerations for clinical trials design and optimization for cNF., Conclusion: Considerations and key questions for each of the thematic areas were identified and provided basis for a request for applications launched by NTAP focused on cNF and are described in the accompanying articles of this supplement., (© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
- Published
- 2018
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8. Pharmacological and genomic profiling of neurofibromatosis type 1 plexiform neurofibroma-derived schwann cells.
- Author
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Ferrer M, Gosline SJC, Stathis M, Zhang X, Guo X, Guha R, Ryman DA, Wallace MR, Kasch-Semenza L, Hao H, Ingersoll R, Mohr D, Thomas C, Verma S, Guinney J, and Blakeley JO
- Subjects
- Antineoplastic Agents therapeutic use, Cell Line, Tumor, Humans, Neurofibroma, Plexiform genetics, Neurofibroma, Plexiform pathology, Neurofibroma, Plexiform therapy, Gene Expression Profiling, Neurofibromatosis 1 genetics, Neurofibromatosis 1 pathology, Neurofibromatosis 1 therapy, Schwann Cells
- Abstract
Neurofibromatosis type I (NF1) is an autosomal dominant genetic condition characterized by peripheral nervous system tumors (PNSTs), including plexiform neurofibromas (pNFs) that cause nerve dysfunction, deformity, pain damage to adjacent structures, and can undergo malignant transformation. There are no effective therapies to prevent or treat pNFs. Drug discovery efforts are slowed by the 'benign' nature of the Schwann cells that are the progenitor cells of pNF. In this work we characterize a set of pNF-derived cell lines at the genomic level (via SNP Arrays, RNAseq, and Whole Exome- Sequencing), and carry out dose response-based quantitative high-throughput screening (qHTS) with a collection of 1,912 oncology-focused compounds in a 1536-well microplate cell proliferation assays. Through the characterization and screening of NF1
-/- , NF1+/+ and NF1+/- Schwann cell lines, this resource introduces novel therapeutic avenues for the development for NF1 associated pNF as well as all solid tumors with NF1 somatic mutations. The integrated data sets are openly available for further analysis at http://www.synapse.org/pnfCellCulture.- Published
- 2018
- Full Text
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9. The Low-Affinity Binding of Second Generation Radiotracers Targeting TSPO is Associated with a Unique Allosteric Binding Site.
- Author
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Rojas C, Stathis M, Coughlin JM, Pomper M, and Slusher BS
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- Binding Sites, Genotype, Humans, Receptors, GABA analysis, Neuroimaging methods, Positron-Emission Tomography methods, Radiopharmaceuticals chemistry, Receptors, GABA chemistry, Receptors, GABA genetics
- Abstract
[
11 C]-PK11195 (PK11195) has been widely used with positron emission tomography (PET) to assess levels of the translocator protein 18 kDa (TSPO) as a marker of neuroinflammation. Recent ligands, such as [11 C]-PBR28 and [11 C]-DPA713, have improved signal-to-noise ratio and specificity for TSPO over PK11195. However, these second generation radiotracers exhibit binding differences due to a single polymorphism (rs6971) that leads to three genotypes: C/C, C/T and T/T associated with high, mixed and low binding affinities, respectively. Here we report that [3 H]-DPA-713 in the presence of cholesterol or PK11195 has an accelerated dissociation rate from TSPO in platelets isolated from individuals with the T/T genotype. This allosteric interaction was not observed in platelets isolated from individuals with the C/C or C/T genotype. The results provide a molecular rationale for low binding affinity of T/T TSPO and further support the exclusion of these subjects from PET imaging studies using second generation TSPO ligands.- Published
- 2018
- Full Text
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10. Development of a primary microglia screening assay and its use to characterize inhibition of system x c - by erastin and its analogs.
- Author
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Figuera-Losada M, Thomas AG, Stathis M, Stockwell BR, Rojas C, and Slusher BS
- 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 x
C - 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
- Full Text
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11. FOLH1 /GCPII is elevated in IBD patients, and its inhibition ameliorates murine IBD abnormalities.
- Author
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Rais R, Jiang W, Zhai H, Wozniak KM, Stathis M, Hollinger KR, Thomas AG, Rojas C, Vornov JJ, Marohn M, Li X, and Slusher BS
- Abstract
Recent gene-profiling analyses showed significant upregulation of the folate hydrolase ( FOLH1 ) gene in the affected intestinal mucosa of patients with inflammatory bowel disease (IBD). The FOLH1 gene encodes a type II transmembrane glycoprotein termed glutamate carboxypeptidase II (GCPII). To establish that the previously reported increased gene expression was functional, we quantified the glutamate carboxypeptidase enzymatic activity in 31 surgical specimens and report a robust 2.8- to 41-fold increase in enzymatic activity in the affected intestinal mucosa of IBD patients compared with an uninvolved area in the same patients or intestinal mucosa from healthy controls. Using a human-to-mouse approach, we next showed a similar enzymatic increase in two well-validated IBD murine models and evaluated the therapeutic effect of the potent FOLH1 / GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) (IC
50 = 300 pM). In the dextran sodium sulfate (DSS) colitis model, 2-PMPA inhibited the GCPII activity in the colonic mucosa by over 90% and substantially reduced the disease activity. The significance of the target was confirmed in FOLH1-/- mice who exhibited resistance to DSS treatment. In the murine IL-10-/- model of spontaneous colitis, daily 2-PMPA treatment also significantly reduced both macroscopic and microscopic disease severity. These results provide the first evidence of FOLH1 /GCPII enzymatic inhibition as a therapeutic option for IBD.- Published
- 2016
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12. Allosteric Glutaminase Inhibitors Based on a 1,4-Di(5-amino-1,3,4-thiadiazol-2-yl)butane Scaffold.
- Author
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Zimmermann SC, Wolf EF, Luu A, Thomas AG, Stathis M, Poore B, Nguyen C, Le A, Rojas C, Slusher BS, and Tsukamoto T
- Abstract
A series of allosteric kidney-type glutaminase (GLS) inhibitors were designed and synthesized using 1,4-di(5-amino-1,3,4-thiadiazol-2-yl)butane as a core scaffold. A variety of modified phenylacetyl groups were incorporated into the 5-amino group of the two thiadiazole rings in an attempt to facilitate additional binding interactions with the allosteric binding site of GLS. Among the newly synthesized compounds, 4-hydroxy-N-[5-[4-[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]butyl]-1,3,4-thiadiazol-2-yl]-benzeneacetamide, 2m, potently inhibited GLS with an IC50 value of 70 nM, although it did not exhibit time-dependency as seen with CB-839. Antiproliferative effects of 2m on human breast cancer lines will be also presented in comparison with those observed with CB-839.
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- 2016
- Full Text
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13. Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration.
- Author
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Rais R, Wozniak K, Wu Y, Niwa M, Stathis M, Alt J, Giroux M, Sawa A, Rojas C, and Slusher BS
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- Administration, Intranasal, Animals, Area Under Curve, Cerebellar Cortex metabolism, Chromatography, High Pressure Liquid, Glutamate Carboxypeptidase II metabolism, Glutarates administration & dosage, Glutarates analysis, Glutarates pharmacokinetics, Half-Life, Injections, Intraperitoneal, Macaca fascicularis, Male, Olfactory Bulb metabolism, Organophosphorus Compounds analysis, Organophosphorus Compounds pharmacokinetics, ROC Curve, Rats, Rats, Wistar, Sulfhydryl Compounds administration & dosage, Sulfhydryl Compounds analysis, Sulfhydryl Compounds pharmacokinetics, Tandem Mass Spectrometry, Central Nervous System metabolism, Glutamate Carboxypeptidase II antagonists & inhibitors, Organophosphorus Compounds administration & dosage
- Abstract
Glutamate carboxypeptidase II (GCP-II) is a brain metallopeptidase that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to NAA and glutamate. Small molecule GCP-II inhibitors increase brain NAAG, which activates mGluR3, decreases glutamate, and provide therapeutic utility in a variety of preclinical models of neurodegenerative diseases wherein excess glutamate is presumed pathogenic. Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration. Herein we report a non-invasive route for delivery of GCP-II inhibitors to the brain via intranasal (i.n.) administration. Three structurally distinct classes of GCP-II inhibitors were evaluated including DCMC (urea-based), 2-MPPA (thiol-based) and 2-PMPA (phosphonate-based). While all showed some brain penetration following i.n. administration, 2-PMPA exhibited the highest levels and was chosen for further evaluation. Compared to intraperitoneal (i.p.) administration, equivalent doses of i.n. administered 2-PMPA resulted in similar plasma exposures (AUC0-t, i.n./AUC0-t, i.p. = 1.0) but dramatically enhanced brain exposures in the olfactory bulb (AUC0-t, i.n./AUC0-t, i.p. = 67), cortex (AUC0-t, i.n./AUC0-t, i.p. = 46) and cerebellum (AUC0-t, i.n./AUC0-t, i.p. = 6.3). Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas. Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement. Lastly, because the rodent nasal system is not similar to humans, we evaluated i.n. 2-PMPA also in a non-human primate. We report that i.n. 2-PMPA provides selective brain delivery with micromolar concentrations. These studies support intranasal delivery of 2-PMPA to deliver therapeutic concentrations in the brain and may facilitate its clinical development.
- Published
- 2015
- Full Text
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14. Cambinol, a novel inhibitor of neutral sphingomyelinase 2 shows neuroprotective properties.
- Author
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Figuera-Losada M, Stathis M, Dorskind JM, Thomas AG, Bandaru VV, Yoo SW, Westwood NJ, Rogers GW, McArthur JC, Haughey NJ, Slusher BS, and Rojas C
- Subjects
- Animals, Cattle, Cell Death drug effects, Cell Survival drug effects, Ceramides biosynthesis, Cytokines pharmacology, Dendrites drug effects, Dendrites pathology, Drug Evaluation, Preclinical, Enzyme Assays, Enzyme Inhibitors pharmacology, Fluorescence, HEK293 Cells, Hippocampus pathology, Humans, Interleukin-1beta pharmacology, Naphthalenes chemistry, Neurons drug effects, Neurons metabolism, Neuroprotective Agents chemistry, Pyrimidinones chemistry, Radioactivity, Rats, Sprague-Dawley, Recombinant Proteins pharmacology, Sphingomyelin Phosphodiesterase metabolism, Structure-Activity Relationship, Tumor Necrosis Factor-alpha pharmacology, Naphthalenes pharmacology, Neuroprotective Agents pharmacology, Pyrimidinones pharmacology, Sphingomyelin Phosphodiesterase antagonists & inhibitors
- Abstract
Ceramide is a bioactive lipid that plays an important role in stress responses leading to apoptosis, cell growth arrest and differentiation. Ceramide production is due in part to sphingomyelin hydrolysis by sphingomyelinases. In brain, neutral sphingomyelinase 2 (nSMase2) is expressed in neurons and increases in its activity and expression have been associated with pro-inflammatory conditions observed in Alzheimer's disease, multiple sclerosis and human immunodeficiency virus (HIV-1) patients. Increased nSMase2 activity translates into higher ceramide levels and neuronal cell death, which can be prevented by chemical or genetic inhibition of nSMase2 activity or expression. However, to date, there are no soluble, specific and potent small molecule inhibitor tool compounds for in vivo studies or as a starting point for medicinal chemistry optimization. Moreover, the majority of the known inhibitors were identified using bacterial, bovine or rat nSMase2. In an attempt to identify new inhibitor scaffolds, two activity assays were optimized as screening platform using the recombinant human enzyme. First, active hits were identified using a fluorescence-based high throughput compatible assay. Then, hits were confirmed using a 14C sphingomyelin-based direct activity assay. Pharmacologically active compounds and approved drugs were screened using this strategy which led to the identification of cambinol as a novel uncompetitive nSMase2 inhibitor (Ki = 7 μM). The inhibitory activity of cambinol for nSMase2 was approximately 10-fold more potent than for its previously known target, silence information regulator 1 and 2 (SIRT1/2). Cambinol decreased tumor necrosis factor-α or interleukin-1 β-induced increases of ceramide and cell death in primary neurons. A preliminary study of cambinol structure and activity allowed the identification of the main structural features required for nSMase2 inhibition. Cambinol and its analogs may be useful as nSMase2 inhibitor tool compounds to prevent ceramide-dependent neurodegeneration.
- Published
- 2015
- Full Text
- View/download PDF
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