scholarly journals The relative rate of kill of the MMV Malaria Box compounds provides links to the mode of antimalarial action and highlights scaffolds of medicinal chemistry interest

2019 ◽  
Author(s):  
Imran Ullah ◽  
Raman Sharma ◽  
Antonio Mete ◽  
Giancarlo A Biagini ◽  
Dawn M Wetzel ◽  
...  
Keyword(s):  
Medicinal Chemistry ◽  
Relative Rate ◽  
Parasite Burden ◽  
Radical Cure ◽  
Factors Affecting ◽  
Complex Core ◽  
Target Candidate Profile ◽  
Malaria Box ◽  
Antimalarial Action ◽  
Key Parameter

Abstract Objectives Rapid rate-of-kill (RoK) is a key parameter in the target candidate profile 1 (TCP1) for the next-generation antimalarial drugs for uncomplicated malaria, termed Single Encounter Radical Cure and Prophylaxis (SERCaP). TCP1 aims to rapidly eliminate the initial parasite burden, ideally as fast as artesunate, but minimally as fast as chloroquine. Here we explore whether the relative RoK of the Medicine for Malaria Venture (MMV) Malaria Box compounds is linked to their mode of action (MoA) and identify scaffolds of medicinal chemistry interest. Methods We used a bioluminescence relative RoK (BRRoK) assay over 6 and 48 h, with exposure to equipotent IC50 concentrations, to compare the cytocidal effects of Malaria Box compounds with those of benchmark antimalarials. Results BRRoK assay data demonstrate the following relative RoKs, from fast to slow: inhibitors of PfATP4 > parasite haemoglobin catabolism > dihydrofolate reductase-thymidylate synthase (DHFR-TS) > dihydroorotate dehydrogenase (DHODH) > bc1 complex. Core-scaffold clustering analyses revealed intrinsic rapid cytocidal action for diamino-glycerols and 2-(aminomethyl)phenol, but slow action for 2-phenylbenz-imidazoles, 8-hydroxyquinolines and triazolopyrimidines. Conclusions This study provides proof of principle that a compound’s RoK is related to its MoA and that the target’s intrinsic RoK is also modified by factors affecting a drug’s access to it. Our findings highlight that as we use medicinal chemistry to improve potency, we can also improve the RoK for some scaffolds. Our BRRoK assay provides the necessary throughput for drug discovery and a critical decision-making tool to support development campaigns. Finally, two scaffolds, diamino-glycerols and 2-phenylbenzimidazoles, exhibit fast cytocidal action, inviting medicinal chemistry improvements towards TCP1 candidates.

scholarly journals FACTORS AFFECTING THE VIABILITY AND GERMINATION BEHAVIOR OF CONIFEROUS SEED: PART I: CONE AND SEED MATURITY, TSUGA HETEROPHYLLA (RAFN.) SARG.

1958 ◽  
Vol 34 (3) ◽  
pp. 266-274 ◽  
Author(s):  
G. S. Allen
Keyword(s):  
Marked Effect ◽  
Relative Rate ◽  
Germination Rate ◽  
Tsuga Heterophylla ◽  
Germination Capacity ◽  
Factors Affecting ◽  
Seed Processing ◽  
Seed Maturity ◽  
Commercial Seed ◽  
Basic Studies

The following three papers show that both germination capacity and germination behavior are influenced markedly by maturity of cones and seed, and by various treatments, all of which can be controlled. Basic studies to discover the reasons for the radical changes in germination rate described herein are indicated.Commercial cone and seed processing often reduces germination capacity and increases the absolute or relative rate of germination. Dewinging, particularly if prolonged or if done in the presence of hard and sharp debris, has a marked effect upon both seed characteristics.High kiln temperatures (above 52 °C.), impact, and other "drastic" treatments reduce viability and increase germination rate. Seed that has been affected in these ways usually produces germinates whose radicles are discolored and subject to decay in the incubator. The seed itself tends to darken abnormally during stratification and/or incubation, and usually becomes contaminated quickly during incubation. Commercial seed that shows evidence of harmful treatment is usually dull and dusty and produces similar symptoms of weakness during incubation.

Peak Cycle Stress Analysis of the II Type Dent on Pipeline Based on FE Calculation

2011 ◽  
Vol 55-57 ◽  
pp. 1659-1664 ◽  
Author(s):  
Wu Ying ◽  
Peng Zhang
Keyword(s):  
Regression Analysis ◽  
Fatigue Life ◽  
Linear Regression Analysis ◽  
Finite Element Models ◽  
Factors Affecting ◽  
Longitudinal Length ◽  
Calculation Results ◽  
The Relationship ◽  
Dent Depth ◽  
Key Parameter

Dent is one of the important factors affecting pipeline fatigue life, and it will greatly reduce the fatigue life of the pipeline in service. And the peak cycle stress on the dented pipeline is the key parameter to calculate pipeline fatigue life. For typical II type dent in the pipeline, the finite element models are established under different circumstances. A large number of the calculation results are sorted, inducted, drew. On this basis, the results are analysed by univariate and multivariate. Non-linear regression analysis was utilized to fit the results by matlab, some specific expressions of the relationship between the dented pipeline peak cycle stresses and the dent depth, diameter and thickness of pipeline, and the dent longitudinal length are obtained after much calculation and analog.

scholarly journals The Candidate Antimalarial Drug MMV665909 Causes Oxygen-Dependent mRNA Mistranslation and Synergizes with Quinoline-Derived Antimalarials

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Cindy Vallières ◽  
Simon V. Avery
Keyword(s):  
Mrna Translation ◽  
Aminoglycoside Antibiotic ◽  
New Drugs ◽  
Drug Candidate ◽  
Content Type ◽  
Translation Fidelity ◽  
Amino Acid Availability ◽  
Novel Target ◽  
Malaria Box ◽  
Antimalarial Action

ABSTRACT To cope with growing resistance to current antimalarials, new drugs with novel modes of action are urgently needed. Molecules targeting protein synthesis appear to be promising candidates. We identified a compound (MMV665909) from the Medicines for Malaria Venture (MMV) Malaria Box of candidate antimalarials that could produce synergistic growth inhibition with the aminoglycoside antibiotic paromomycin, suggesting a possible action of the compound in mRNA mistranslation. This mechanism of action was substantiated with a Saccharomyces cerevisiae model using available reporters of mistranslation and other genetic tools. Mistranslation induced by MMV665909 was oxygen dependent, suggesting a role for reactive oxygen species (ROS). Overexpression of Rli1 (a ROS-sensitive, conserved FeS protein essential in mRNA translation) rescued inhibition by MMV665909, consistent with the drug's action on translation fidelity being mediated through Rli1. The MMV drug also synergized with major quinoline-derived antimalarials which can perturb amino acid availability or promote ROS stress: chloroquine, amodiaquine, and primaquine. The data collectively suggest translation fidelity as a novel target of antimalarial action and support MMV665909 as a promising drug candidate.

Progress In The Practical Application Of Automated Image Analysis To Tem Negatives

1977 ◽  
Vol 35 ◽  
pp. 214-217
Author(s):  
F. A. Heckman ◽  
E. Redman ◽  
J.E. Connolly
Keyword(s):  
Image Analysis ◽  
Image Quality ◽  
Exposure Time ◽  
Image Contrast ◽  
Automated Image Analysis ◽  
Practical Application ◽  
Factors Affecting ◽  
High Image Quality ◽  
Qualitative Evidence ◽  
Comprehensive Study

In our initial publication on this subject1) we reported results demonstrating that contrast is the most important factor in producing the high image quality required for reliable image analysis. We also listed the factors which enhance contrast in order of the experimentally determined magnitude of their effect. The two most powerful factors affecting image contrast attainable with sheet film are beam intensity and KV. At that time we had only qualitative evidence for the ranking of enhancing factors. Later we carried out the densitometric measurements which led to the results outlined below.Meaningful evaluations of the cause-effect relationships among the considerable number of variables in preparing EM negatives depend on doing things in a systematic way, varying only one parameter at a time. Unless otherwise noted, we adhered to the following procedure evolved during our comprehensive study:Philips EM-300; 30μ objective aperature; magnification 7000- 12000X, exposure time 1 second, anti-contamination device operating.

Factors affecting microstructural scale in liquid crystalline polymers

1990 ◽  
Vol 48 (4) ◽  
pp. 220-221
Author(s):  
Christine M. Dannels ◽  
Christopher Viney
Keyword(s):  
Liquid Crystalline ◽  
Liquid Crystalline Polymers ◽  
Factors Affecting ◽  
Crystalline Polymers ◽  
Thermal Expansion Coefficients ◽  
Low Thermal Expansion ◽  
Lower Viscosity ◽  
Fine Microstructure ◽  
Planar Orientation ◽  
Strength And Stiffness

Processing polymers from the liquid crystalline state offers several advantages compared to processing from conventional fluids. These include: better axial strength and stiffness in fibers, better planar orientation in films, lower viscosity during processing, low solidification shrinkage of injection moldings (thermotropic processing), and low thermal expansion coefficients. However, the compressive strength of the solid is disappointing. Previous efforts to improve this property have focussed on synthesizing stiffer molecules. The effect of microstructural scale has been overlooked, even though its relevance to the mechanical and physical properties of more traditional materials is well established. By analogy with the behavior of metals and ceramics, one would expect a fine microstructure (i..e. a high density of orientational defects) to be desirable.Also, because much microstructural detail in liquid crystalline polymers occurs on a scale close to the wavelength of light, light is scattered on passing through these materials.

Factors affecting dentist participation in a state Medicaid program

1990 ◽  
Vol 54 (11) ◽  
pp. 638-643 ◽  
Author(s):  
PC Damiano ◽  
ER Brown ◽  
JD Johnson ◽  
JP Scheetz
Keyword(s):  
Medicaid Program ◽  
Factors Affecting

Speech Therapy Services in a Large School System: A Six-Year Overview

1976 ◽  
Vol 7 (4) ◽  
pp. 207-219 ◽  
Author(s):  
Constance P. DesRoches
Keyword(s):  
School System ◽  
Speech Therapy ◽  
Factors Affecting ◽  
Case Load ◽  
Number Of Children ◽  
School Population ◽  
System A ◽  
Therapy Services ◽  
And Shifts ◽  
Selection Factors

A statistical review provides analysis of four years of speech therapy services of a suburban school system which can be used for comparison with other school system programs. Included are data on the percentages of the school population enrolled in therapy, the categories of disabilities and the number of children in each category, the sex and grade-level distribution of those in therapy, and shifts in case-load selection. Factors affecting changes in case-load profiles are identified and discussed.

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