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Article: Is the threat of digital disruption overhyped?

Posner, Bruce

MIT sloan management review Vol. 59, No. 2 , p. 96

2018 Volume 59, Issue 2, Page(s) 96

Author's details	by Bruce Posner
Language	English
Publisher	MIT
Publishing place	Cambridge, Mass
Document type	Article
ZDB-ID	2039388-X ; 2070928-6
ISSN	1532-8937 ; 1532-9194
ISSN (online)	1532-8937
ISSN	1532-9194
Database	ECONomics Information System

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Article: Helping employees improve performance

Posner, Bruce

MIT sloan management review Vol. 59, No. 1 , p. 96

2017 Volume 59, Issue 1, Page(s) 96

Author's details	reported by Bruce Posner
Language	English
Publisher	MIT
Publishing place	Cambridge, Mass
Document type	Article
ZDB-ID	2039388-X ; 2070928-6
ISSN	1532-8937 ; 1532-9194
ISSN (online)	1532-8937
ISSN	1532-9194
Database	ECONomics Information System

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Article ; Online: LIMS-Kinase provides sensitive and generalizable label-free

Meyer, Cynthia / McCoy, Melissa / Li, Lianbo / Posner, Bruce / Westover, Kenneth D

Cell reports. Physical science

2023 Volume 4, Issue 10

Abstract: Measurements of kinase activity are important for kinase-directed drug development, analysis of inhibitor structure and function, and understanding mechanisms of drug resistance. Sensitive, accurate, and miniaturized assay methods are crucial for these ... ...

Abstract	Measurements of kinase activity are important for kinase-directed drug development, analysis of inhibitor structure and function, and understanding mechanisms of drug resistance. Sensitive, accurate, and miniaturized assay methods are crucial for these investigations. Here, we describe a label-free, high-throughput mass spectrometry-based assay for studying individual kinase enzymology and drug discovery in a purified system, with a focus on validated drug targets as benchmarks. We demonstrate that this approach can be adapted to many known kinase substrates and highlight the benefits of using mass spectrometry to measure kinase activity
Language	English
Publishing date	2023-09-26
Publishing country	United States
Document type	Journal Article
ISSN	2666-3864
ISSN (online)	2666-3864
DOI	10.1016/j.xcrp.2023.101599
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Article ; Online: Identification of a Class of WNK Isoform-Specific Inhibitors Through High-Throughput Screening.

Chlebowicz, Julita / Akella, Radha / Humphreys, John M / He, Haixia / Kannangara, Ashari R / Wei, Shuguang / Posner, Bruce / Goldsmith, Elizabeth J

Drug design, development and therapy

2023 Volume 17, Page(s) 93–105

Abstract: Introduction: WNK [with no lysine (K)] kinases are serine/threonine kinases associated with familial hyperkalemic hypertension (FHHt). WNKs are therapeutic targets for blood pressure regulation, stroke and several cancers including triple negative ... ...

Abstract	Introduction: WNK [with no lysine (K)] kinases are serine/threonine kinases associated with familial hyperkalemic hypertension (FHHt). WNKs are therapeutic targets for blood pressure regulation, stroke and several cancers including triple negative breast cancer and glioblastoma. Here, we searched for and characterized novel WNK kinase inhibitors. Methods: We used a ~210,000-compound library in a high-throughput screen, re-acquisition and assay, commercial specificity screens and crystallography to identify WNK-isoform-selective inhibitors. Results: We identified five classes of compounds that inhibit the kinase activity of WNK1: quinoline compounds, halo-sulfones, cyclopropane-containing thiazoles, piperazine-containing compounds, and nitrophenol-derived compounds. The compounds are strongly pan-WNK selective, inhibiting all four WNK isoforms. A class of quinoline compounds was identified that further shows selectivity among the WNK isoforms, being more potent toward WNK3 than WNK1. The crystal structure of the quinoline-derived SW120619 bound to the kinase domain of WNK3 reveals active site binding, and comparison to the WNK1 structure reveals the potential origin of isoform specificity. Discussion: The newly discovered classes of compounds may be starting points for generating pharmacological tools and potential drugs treating hypertension and cancer.
MeSH term(s)	Humans ; High-Throughput Screening Assays ; Hypertension ; Protein Isoforms ; Protein Serine-Threonine Kinases/metabolism ; WNK Lysine-Deficient Protein Kinase 1/antagonists & inhibitors
Chemical Substances	Protein Isoforms ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; WNK Lysine-Deficient Protein Kinase 1 (EC 2.7.11.1)
Language	English
Publishing date	2023-01-20
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2451346-5
ISSN	1177-8881 ; 1177-8881
ISSN (online)	1177-8881
ISSN	1177-8881
DOI	10.2147/DDDT.S389461
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Article ; Online: A cholesterol-binding bacterial toxin provides a strategy for identifying a specific Scap inhibitor that blocks lipid synthesis in animal cells.

Xu, Shimeng / Smothers, Jared C / Rye, Daphne / Endapally, Shreya / Chen, Hong / Li, Shili / Liang, Guosheng / Kinnebrew, Maia / Rohatgi, Rajat / Posner, Bruce A / Radhakrishnan, Arun

Proceedings of the National Academy of Sciences of the United States of America

2024 Volume 121, Issue 7, Page(s) e2318024121

Abstract: Lipid synthesis is regulated by the actions of Scap, a polytopic membrane protein that binds cholesterol in membranes of the endoplasmic reticulum (ER). When ER cholesterol levels are low, Scap activates SREBPs, transcription factors that upregulate ... ...

Abstract	Lipid synthesis is regulated by the actions of Scap, a polytopic membrane protein that binds cholesterol in membranes of the endoplasmic reticulum (ER). When ER cholesterol levels are low, Scap activates SREBPs, transcription factors that upregulate genes for synthesis of cholesterol, fatty acids, and triglycerides. When ER cholesterol levels rise, the sterol binds to Scap, triggering conformational changes that prevent activation of SREBPs and halting synthesis of lipids. To achieve a molecular understanding of how cholesterol regulates the Scap/SREBP machine and to identify therapeutics for dysregulated lipid metabolism, cholesterol-mimetic compounds that specifically bind and inhibit Scap are needed. To accomplish this goal, we focused on Anthrolysin O (ALO), a pore-forming bacterial toxin that binds cholesterol with a specificity and sensitivity that is uncannily similar to Scap. We reasoned that a small molecule that would bind and inhibit ALO might also inhibit Scap. High-throughput screening of a ~300,000-compound library for ALO-binding unearthed one molecule, termed UT-59, which binds to Scap's cholesterol-binding site. Upon binding, UT-59 triggers the same conformation changes in Scap as those induced by cholesterol and blocks activation of SREBPs and lipogenesis in cultured cells. UT-59 also inhibits SREBP activation in the mouse liver. Unlike five previously reported inhibitors of SREBP activation, UT-59 is the only one that acts specifically by binding to Scap's cholesterol-binding site. Our approach to identify specific Scap inhibitors such as UT-59 holds great promise in developing therapeutic leads for human diseases stemming from elevated SREBP activation, such as fatty liver and certain cancers.
MeSH term(s)	Animals ; Mice ; Humans ; Sterol Regulatory Element Binding Protein 1/metabolism ; Lipogenesis ; Intracellular Signaling Peptides and Proteins/metabolism ; Cholesterol/metabolism ; Bacterial Toxins/metabolism
Chemical Substances	Sterol Regulatory Element Binding Protein 1 ; Intracellular Signaling Peptides and Proteins ; Cholesterol (97C5T2UQ7J) ; Bacterial Toxins
Language	English
Publishing date	2024-02-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2318024121
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Article: 12 essential innovation insights

Posner, Bruce / Mangelsdorf, Martha E

MIT sloan management review Vol. 59, No. 1 , p. 28-36

2017 Volume 59, Issue 1, Page(s) 28–36

Title variant	twelve
Author's details	by Bruce Posner and Martha E. Mangelsdorf
Language	English
Publisher	MIT
Publishing place	Cambridge, Mass
Document type	Article
ZDB-ID	2039388-X ; 2070928-6
ISSN	1532-8937 ; 1532-9194
ISSN (online)	1532-8937
ISSN	1532-9194
Database	ECONomics Information System

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Article ; Online: Structural Insights into Novel 15-Prostaglandin Dehydrogenase Inhibitors.

Mallipeddi, Prema L / Zhang, Yongyou / Li, Hongyun / Markowitz, Sanford D / Posner, Bruce

Molecules (Basel, Switzerland)

2021 Volume 26, Issue 19

Abstract: We discovered SW033291 in a high throughput chemical screen aimed at identifying 15-prostaglandin dehydrogenase (15-PGDH) modulators. The compound exhibited inhibitory activity in in vitro biochemical and cell-based assays of 15-PGDH activity. We ... ...

Abstract	We discovered SW033291 in a high throughput chemical screen aimed at identifying 15-prostaglandin dehydrogenase (15-PGDH) modulators. The compound exhibited inhibitory activity in in vitro biochemical and cell-based assays of 15-PGDH activity. We subsequently demonstrated that this compound, and several analogs thereof, are effective in in vivo mouse models of bone marrow transplant, colitis, and liver regeneration, where increased levels of PGE2 positively potentiate tissue regeneration. To better understand the binding of SW033291, we carried out docking studies for both the substrate, PGE2, and an inhibitor, SW033291, to 15-PGDH. Our models suggest similarities in the ways that PGE2 and SW033291 interact with key residues in the 15-PGDH-NAD+ complex. We carried out molecular dynamics simulations (MD) of SW033291 bound to this complex, in order to understand the dynamics of the binding interactions for this compound. The butyl side chain (including the sulfoxide) of SW033291 participates in crucial binding interactions that are similar to those observed for the C15-OH and the C16-C20 alkyl chain of PGE2. In addition, interactions with residues Ser138, Tyr151, and Gln148 play key roles in orienting and stabilizing SW033291 in the binding site and lead to enantioselectivity for the
MeSH term(s)	Binding Sites ; Humans ; Hydroxyprostaglandin Dehydrogenases/antagonists & inhibitors ; Molecular Dynamics Simulation ; Pyridines/chemistry ; Pyridines/pharmacology ; Thiophenes/chemistry ; Thiophenes/pharmacology
Chemical Substances	Pyridines ; SW033291 ; Thiophenes ; Hydroxyprostaglandin Dehydrogenases (EC 1.1.1.-) ; 15-hydroxyprostaglandin dehydrogenase (EC 1.1.1.141)
Language	English
Publishing date	2021-09-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules26195903
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Article: GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology.

DiCesare, Sophia M / Ortega, Antonio J / Collier, Gracen E / Daniel, Steffi / Thompson, Krista N / McCoy, Melissa K / Posner, Bruce A / Hulleman, John D

bioRxiv : the preprint server for biology

2023

Abstract: Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy (ML/DHRD) is an age-related macular degeneration (AMD)-like retinal dystrophy caused by an autosomal dominant R345W mutation in the secreted glycoprotein, fibulin-3 (F3). To identify new small ... ...

Abstract	Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy (ML/DHRD) is an age-related macular degeneration (AMD)-like retinal dystrophy caused by an autosomal dominant R345W mutation in the secreted glycoprotein, fibulin-3 (F3). To identify new small molecules that reduce F3 production from retinal pigmented epithelium (RPE) cells, we knocked-in a luminescent peptide tag (HiBiT) into the endogenous F3 locus which enabled simple, sensitive, and high throughput detection of the protein. The GSK3 inhibitor, CHIR99021 (CHIR), significantly reduced F3 burden (expression, secretion, and intracellular levels) in immortalized RPE and non-RPE cells. Low-level, long-term CHIR treatment promoted remodeling of the RPE extracellular matrix (ECM), reducing sub-RPE deposit-associated proteins (e.g., amelotin, complement component 3, collagen IV, and fibronectin), while increasing RPE differentiation factors (e.g., tyrosinase, and pigment epithelium derived factor). In vivo, treatment of 8 mo R345W
Language	English
Publishing date	2023-12-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.14.571757
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Article: Small molecule glucagon release inhibitors with activity in human islets.

Kalwat, Michael A / Rodrigues-Dos-Santos, Karina / Binns, Derk D / Wei, Shuguang / Zhou, Anwu / Evans, Matthew R / Posner, Bruce A / Roth, Michael G / Cobb, Melanie H

Frontiers in endocrinology

2023 Volume 14, Page(s) 1114799

Abstract: Purpose: Type 1 diabetes (T1D) accounts for an estimated 5% of all diabetes in the United States, afflicting over 1.25 million individuals. Maintaining long-term blood glucose control is the major goal for individuals with T1D. In T1D, insulin-secreting ...

Abstract	Purpose: Type 1 diabetes (T1D) accounts for an estimated 5% of all diabetes in the United States, afflicting over 1.25 million individuals. Maintaining long-term blood glucose control is the major goal for individuals with T1D. In T1D, insulin-secreting pancreatic islet β-cells are destroyed by the immune system, but glucagon-secreting islet α-cells survive. These remaining α-cells no longer respond properly to fluctuating blood glucose concentrations. Dysregulated α-cell function contributes to hyper- and hypoglycemia which can lead to macrovascular and microvascular complications. To this end, we sought to discover small molecules that suppress α-cell function for their potential as preclinical candidate compounds. Prior high-throughput screening identified a set of glucagon-suppressing compounds using a rodent α-cell line model, but these compounds were not validated in human systems. Results: Here, we dissociated and replated primary human islet cells and exposed them to 24 h treatment with this set of candidate glucagon-suppressing compounds. Glucagon accumulation in the medium was measured and we determined that compounds SW049164 and SW088799 exhibited significant activity. Candidate compounds were also counter-screened in our InsGLuc-MIN6 β-cell insulin secretion reporter assay. SW049164 and SW088799 had minimal impact on insulin release after a 24 h exposure. To further validate these hits, we treated intact human islets with a selection of the top candidates for 24 h. SW049164 and SW088799 significantly inhibited glucagon release into the medium without significantly altering whole islet glucagon or insulin content. In concentration-response curves SW088799 exhibited significant inhibition of glucagon release with an IC50 of 1.26 µM. Conclusion: Given the set of tested candidates were all top hits from the primary screen in rodent α-cells, this suggests some conservation of mechanism of action between human and rodents, at least for SW088799. Future structure-activity relationship studies of SW088799 may aid in elucidating its protein target(s) or enable its use as a tool compound to suppress α-cell activity
MeSH term(s)	Humans ; Animals ; Glucagon/metabolism ; Diabetes Mellitus, Type 1/drug therapy ; Diabetes Mellitus, Type 1/metabolism ; Insulin/metabolism ; Islets of Langerhans/metabolism ; Glucagon-Secreting Cells/metabolism
Chemical Substances	Glucagon (9007-92-5) ; Insulin
Language	English
Publishing date	2023-04-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2023.1114799
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Article ; Online: Identification of Glucose Transport Modulators In Vitro and Method for Their Deep Learning Neural Network Behavioral Evaluation in Glucose Transporter 1-Deficient Mice.

Kathote, Gauri / Ma, Qian / Angulo, Gustavo / Chen, Hong / Jakkamsetti, Vikram / Dobariya, Aksharkumar / Good, Levi B / Posner, Bruce / Park, Jason Y / Pascual, Juan M

The Journal of pharmacology and experimental therapeutics

2023 Volume 384, Issue 3, Page(s) 393–405

Abstract: Metabolic flux augmentation via glucose transport activation may be desirable in glucose transporter 1 (Glut1) deficiency syndrome (G1D) and dementia, whereas suppression might prove useful in cancer. Using lung adenocarcinoma cells that predominantly ... ...

Abstract	Metabolic flux augmentation via glucose transport activation may be desirable in glucose transporter 1 (Glut1) deficiency syndrome (G1D) and dementia, whereas suppression might prove useful in cancer. Using lung adenocarcinoma cells that predominantly express Glut1 relative to other glucose transporters, we screened 9,646 compounds for effects on the accumulation of an extracellularly applied fluorescent glucose analog. Five drugs currently prescribed for unrelated indications or preclinically characterized robustly enhanced intracellular fluorescence. Additionally identified were 37 novel activating and nine inhibitory compounds lacking previous biologic characterization. Because few glucose-related mechanistic or pharmacological studies were available for these compounds, we developed a method to quantify G1D mouse behavior to infer potential therapeutic value. To this end, we designed a five-track apparatus to record and evaluate spontaneous locomotion videos. We applied this to a G1D mouse model that replicates the ataxia and other manifestations cardinal to the human disorder. Because the first two drugs that we examined in this manner (baclofen and acetazolamide) exerted various impacts on several gait aspects, we used deep learning neural networks to more comprehensively assess drug effects. Using this method, 49 locomotor parameters differentiated G1D from control mice. Thus, we used parameter modifiability to quantify efficacy on gait. We tested this by measuring the effects of saline as control and glucose as G1D therapy. The results indicate that this in vivo approach can estimate preclinical suitability from the perspective of G1D locomotion. This justifies the use of this method to evaluate our drugs or other interventions and sort candidates for further investigation. SIGNIFICANCE STATEMENT: There are few or no activators and few clinical inhibitors of glucose transport. Using Glut1-rich cells exposed to a glucose analog, we identified, in highthroughput fashion, a series of novel modulators. Some were drugs used to modify unrelated processes and some represented large but little studied chemical compound families. To facilitate their preclinical efficacy characterization regardless of potential mechanism of action, we developed a gait testing platform for deep learning neural network analysis of drug impact on Glut1-deficient mouse locomotion.
MeSH term(s)	Animals ; Humans ; Mice ; Carbohydrate Metabolism, Inborn Errors/metabolism ; Deep Learning ; Glucose/metabolism ; Glucose Transporter Type 1
Chemical Substances	Glucose (IY9XDZ35W2) ; Glucose Transporter Type 1 ; Slc2a1 protein, mouse
Language	English
Publishing date	2023-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.122.001428
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