scholarly journals Assessing target engagement using proteome-wide solvent shift assays

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Jonathan G Van Vranken ◽  
Jiaming Li ◽  
Dylan C Mitchell ◽  
José Navarrete-Perea ◽  
Steven P Gygi
Keyword(s):  
Quantitative Proteomics ◽  
Area Under The Curve ◽  
Absolute Number ◽  
Mechanisms Of Action ◽  
Curve Analysis ◽  
Alternative Methods ◽  
Target Engagement ◽  
High Quality ◽  
Proteome Profiling ◽  
Solvent Shift

Recent advances in mass spectrometry (MS) have enabled quantitative proteomics to become a powerful tool in the field of drug discovery, especially when applied toward proteome-wide target engagement studies. Similar to temperature gradients, increasing concentrations of organic solvents stimulate unfolding and precipitation of the cellular proteome. This property can be influenced by physical association with ligands and other molecules, making individual proteins more or less susceptible to solvent-induced denaturation. Herein, we report the development of proteome-wide solvent shift assays by combining the principles of solvent-induced precipitation (Zhang et al., 2020) with modern quantitative proteomics. Using this approach, we developed solvent proteome profiling (SPP), which is capable of establishing target engagement through analysis of SPP denaturation curves. We readily identified the specific targets of compounds with known mechanisms of action. As a further efficiency boost, we applied the concept of area under the curve analysis to develop solvent proteome integral solubility alteration (solvent-PISA) and demonstrate that this approach can serve as a reliable surrogate for SPP. We propose that by combining SPP with alternative methods, like thermal proteome profiling, it will be possible to increase the absolute number of high-quality melting curves that are attainable by either approach individually, thereby increasing the fraction of the proteome that can be screened for evidence of ligand binding.

scholarly journals Assessing target engagement using proteome-wide solvent shift assays

2021 ◽  
Author(s):  
Jonathan G Van Vranken ◽  
Jiaming Li ◽  
Jose Navarrete Perea ◽  
Steven P Gygi
Keyword(s):  
Quantitative Proteomics ◽  
Area Under The Curve ◽  
Absolute Number ◽  
Mechanisms Of Action ◽  
Curve Analysis ◽  
Alternative Methods ◽  
Target Engagement ◽  
High Quality ◽  
Proteome Profiling ◽  
Solvent Shift

Recent advances in mass spectrometry (MS) have enabled quantitative proteomics to become a powerful tool in the field of drug discovery, especially when applied toward proteome-wide target engagement studies. Similar to temperature gradients, increasing concentrations of organic solvents stimulate unfolding and precipitation of the cellular proteome. This property can be influenced by physical association with ligands and other molecules, making individual proteins more or less susceptible to solvent-induced denaturation. Herein, we report the development of proteome-wide solvent shift assays by combining the principles of solvent-induced precipitation (Zhang et al., 2020) with modern quantitative proteomics. Using this approach, we developed solvent proteome profiling (SPP), which is capable of establishing target engagement through analysis of SPP denaturation curves. We readily identified the specific targets of compounds with known mechanisms of action. As a further efficiency boost, we applied the concept of area-under the-curve analysis to develop solvent proteome integral solubility alteration (solvent-PISA) and demonstrate that this approach can serve as a reliable surrogate for SPP. We propose that by combining SPP with alternative methods, like thermal proteome profiling, it will be possible to increase the absolute number of high-quality melting curves that are attainable by either approach individually thereby increasng the fraction of the proteome that can be screened 1 for evidence of ligand binding.

scholarly journals Levels of Evidence in Rhinology and Skull Base Surgery Research

2021 ◽  
pp. 019459982098713
Author(s):  
Jennifer A. Silver ◽  
Marco Mascarella ◽  
George Tali ◽  
Rickul Varshney ◽  
Marc A. Tewfik ◽  
...  
Keyword(s):  
Skull Base ◽  
Skull Base Surgery ◽  
Absolute Number ◽  
High Quality ◽  
Level Of Evidence ◽  
Levels Of Evidence ◽  
The Past ◽  
Significant Difference ◽  
Surgery Research ◽  
Based Medicine

Objective The purpose of this study was to evaluate the quality of evidence of rhinology and rhinologic skull base surgery (RSBS) research and its evolution over the past decade. Study Design Review article. Setting We reviewed articles from 2007 to 2019 in 4 leading peer-reviewed otolaryngology journals and 3 rhinology-specific journals. Methods The articles were reviewed and levels of evidence were assigned using the Oxford Centre for Evidence-Based Medicine 2011 guidelines. High quality was defined as level of evidence 1 or 2. Results In total, 1835 articles were reviewed in this study spanning a 13-year period. Overall, the absolute number of RSBS publications increased significantly 22.6% per year, from 108 articles in 2007 to 481 in 2019 ( P < .001; 95% CI, 7.9-37.2). In 2007, only 13 articles, or 15%, were high quality, and this grew to 146 articles, or 39%, in 2019. A 14.0% per year exponential increase in the number of high-quality publications was found to be statistically significant ( P < .001; 95% CI, 7.2, 20.7). Overall, high-quality publications represented just 25.8% of RSBS articles overall. There was no significant difference in quality between rhinology-specific journals and general otolaryngology journals (χ2 = 3.1, P = .077). Conclusion The number of overall publications and of high-quality RSBS publications has significantly increased over the past decade. However, the proportion of high-quality studies continues to represent a minority of total RSBS research.

Quantitative proteomics analysis reveals novel insights into mechanisms of action of disulfiram (DSF)

2021 ◽  
pp. 2100031
Author(s):  
Peng Zheng ◽  
Chenglinzi Liu ◽  
Yaoqin Wu ◽  
Ruifeng Xu ◽  
Ying Chen ◽  
...  
Keyword(s):  
Quantitative Proteomics ◽  
Mechanisms Of Action ◽  
Proteomics Analysis

scholarly journals Quantifying relative virulence: when μ max fails and AUC alone just is not enough

2020 ◽  
Author(s):  
Ruben Michael Ceballos ◽  
Carson Len Stacy
Keyword(s):  
Specific Growth ◽  
Area Under The Curve ◽  
Maximum Specific Growth Rate ◽  
Curve Analysis ◽  
Growth Curve Analysis ◽  
Virus Infections ◽  
Susceptible Host ◽  
Host Interactions ◽  
Biological Phenomena ◽  
Single Host

A challenge in virology is quantifying relative virulence (V R) between two (or more) viruses that exhibit different replication dynamics in a given susceptible host. Host growth curve analysis is often used to mathematically characterize virus–host interactions and to quantify the magnitude of detriment to host due to viral infection. Quantifying V R using canonical parameters, like maximum specific growth rate (μ max), can fail to provide reliable information regarding virulence. Although area-under-the-curve (AUC) calculations are more robust, they are sensitive to limit selection. Using empirical data from Sulfolobus Spindle-shaped Virus (SSV) infections, we introduce a novel, simple metric that has proven to be more robust than existing methods for assessing V R. This metric (I SC) accurately aligns biological phenomena with quantified metrics to determine V R. It also addresses a gap in virology by permitting comparisons between different non-lytic virus infections or non-lytic versus lytic virus infections on a given host in single-virus/single-host infections.

POLICY STATEMENT ON DAY CARE

PEDIATRICS ◽  
1973 ◽  
Vol 51 (5) ◽  
pp. 947-947
Keyword(s):  
Child Care ◽  
Day Care ◽  
The United States ◽  
Early Years ◽  
Alternative Methods ◽  
Policy Statement ◽  
High Quality ◽  
Governmental Agencies ◽  
Care Services ◽  
Family Discord

The American Academy of Pediatrics supports the continued expansion of high quality day care programs for the nation's children. It is preparing a booklet, Recommendations for Day Care Centers for Infants and Children, to serve as a guideline for establishing quality day care. The Academy also has embarked on a program to help pediatricians understand their role in fostering high quality day care. All children should have the opportunity to optimally develop their physical, intellectual, and social potential. The care and guidance they are given in their early years are of critical importance for such development. For most children, this child care and guidance are best given in their own homes, by their own families, but may need to be supplemented by child care services provided by private or governmental agencies. Because they are working, an increasing proportion of mothers are not at home to fulfill the maternal role in care and guidance. In 1971, 43% of mothers in the United States were employed: one-third of the mothers of preschool children and one-half of the single mothers of young children. For some children the home may not be the best place because of social or financial poverty or family discord which inhibit child development. Alternative methods of caring for children to help them achieve their fullest potential are needed more now than at any time in our history. Day care services should be a supplement to, not a substitute for, the family as the primary agent for the child's care and development.

Using MTurk to Distribute a Survey or Experiment: Methodological Considerations

2018 ◽  
Vol 33 (1) ◽  
pp. 43-65 ◽  
Author(s):  
Nicholas C. Hunt ◽  
Andrea M. Scheetz
Keyword(s):  
Mechanical Turk ◽  
Amazon Mechanical Turk ◽  
Alternative Methods ◽  
Technical Knowledge ◽  
Data Validation ◽  
High Quality ◽  
Manipulation Check ◽  
Screening Questions ◽  
Methodological Considerations ◽  
Firsthand Experience

ABSTRACT Amazon Mechanical Turk (MTurk) is a powerful tool that is more commonly being used to recruit behavioral research participants for accounting research. This manuscript provides practical and technical knowledge learned from firsthand experience to help researchers collect high-quality, defendable data for research purposes. We highlight two issues of particular importance when using MTurk: (1) accessing qualified participants, and (2) validating collected data. To address these issues, we discuss alternative methods of carrying out screens and different data validation techniques researchers may want to consider. We also demonstrate how some of the techniques discussed were implemented for a recent data collection. Finally, we contrast the use of unpaid screens with merely putting participation requirements in the MTurk instructions to examine the effectiveness of using screens. We find that screening questions significantly reduce the number of manipulation check failures as well as significantly increase the usable responses per paid participant.

Neurogranin as a Novel Biomarker in Alzheimer’s Disease

2020 ◽  
Author(s):  
Luisa Agnello ◽  
Caterina Maria Gambino ◽  
Bruna Lo Sasso ◽  
Giulia Bivona ◽  
Salvatore Milano ◽  
...  
Keyword(s):  
Operating Characteristic ◽  
Neurological Diseases ◽  
Area Under The Curve ◽  
Curve Analysis ◽  
Phosphorylated Tau ◽  
Roc Curve Analysis ◽  
Total Tau ◽  
Novel Biomarkers ◽  
Good Diagnostic Accuracy

Abstract Background In this study, we investigated the possible role of 2 novel biomarkers of synaptic damage, namely, neurogranin and α-synuclein, in Alzheimer disease (AD). Methods The study was performed in a cohort consisting of patients with AD and those without AD, including individuals with other neurological diseases. Cerebrospinal fluid (CSF) neurogranin and α-synuclein levels were measured by sensitive enzyme-linked immunosorbent assays (ELISAs). Results We found significantly increased levels of CSF neurogranin and α-synuclein in patients with AD than those without AD. Neurogranin was correlated with total tau (tTau) and phosphorylated tau (pTau), as well as with cognitive decline, in patients with AD. Receiver operating characteristic (ROC) curve analysis showed good diagnostic accuracy of neurogranin for AD at a cutoff point of 306 pg per mL with an area under the curve (AUC) of 0.872 and sensitivity and specificity of 84.2% and 78%, respectively. Conclusions Our findings support the use of CSF neurogranin as a biomarker of synapsis damage in patients with AD.

Plasma proteome profiling of high-altitude polycythemia using TMT-based quantitative proteomics approach

2019 ◽  
Vol 194 ◽  
pp. 60-69 ◽  
Author(s):  
Zongkui Wang ◽  
Fengjuan Liu ◽  
Shengliang Ye ◽  
Peng Jiang ◽  
Xiaochuan Yu ◽  
...  
Keyword(s):  
High Altitude ◽  
Quantitative Proteomics ◽  
Plasma Proteome ◽  
Proteome Profiling ◽  
Proteomics Approach

scholarly journals A Review of Neurostimulation for Epilepsy in Pediatrics

2019 ◽  
Vol 9 (10) ◽  
pp. 283 ◽  
Author(s):  
Keith Starnes ◽  
Kai Miller ◽  
Lily Wong-Kisiel ◽  
Brian Nils Lundstrom
Keyword(s):  
Central Nervous System ◽  
Vagus Nerve Stimulation ◽  
Magnetic Stimulation ◽  
Mechanisms Of Action ◽  
Pediatric Epilepsy ◽  
High Quality ◽  
High Quality Evidence ◽  
The Central Nervous System ◽  
Quality Evidence ◽  
Deep Brain

Neurostimulation for epilepsy refers to the application of electricity to affect the central nervous system, with the goal of reducing seizure frequency and severity. We review the available evidence for the use of neurostimulation to treat pediatric epilepsy, including vagus nerve stimulation (VNS), responsive neurostimulation (RNS), deep brain stimulation (DBS), chronic subthreshold cortical stimulation (CSCS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). We consider possible mechanisms of action and safety concerns, and we propose a methodology for selecting between available options. In general, we find neurostimulation is safe and effective, although any high quality evidence applying neurostimulation to pediatrics is lacking. Further research is needed to understand neuromodulatory systems, and to identify biomarkers of response in order to establish optimal stimulation paradigms.

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