scholarly journals Application of the direct peptide reactivity assay (DPRA) to inorganic compounds: a case study of platinum species

2019 ◽  
Vol 8 (6) ◽  
pp. 802-814
Author(s):  
Jocelyn D. C. Hemming ◽  
Mark Hosford ◽  
Martin M. Shafer
Keyword(s):  
High Throughput Screening ◽  
Inorganic Compounds ◽  
High Reactivity ◽  
Limited Attention ◽  
Adverse Outcome Pathway ◽  
Platinum Compounds ◽  
Metal Compounds ◽  
Work Supports ◽  
Platinum Species

Abstract The in chemico Direct Peptide Reactivity Assay (DPRA) was developed as a non-animal, relatively high throughput, screening tool for skin sensitization potential. Although the Adverse Outcome Pathway (AOP) for respiratory sensitization remains to be fully elucidated, it is recognized that the molecular initiation event for both skin and respiratory sensitization to low molecular weight chemicals involves haptenation with proteins. The DPRA examines the reactivity of a test compound to two model peptides (containing either cysteine or lysine) and consequently is able to screen for both skin and respiratory sensitization potential. The DPRA was primarily developed for and validated with organic compounds and assessment of the applicability of the assay to metal compounds has received only limited attention. This paper reports the successful application of the DPRA to a series of platinum compounds, including hexachloroplatinate and tetrachloroplatinate salts, which are some of the most potent chemical respiratory sensitizers known. Eleven platinum compounds were evaluated using the DPRA protocol as detailed by Lalko et al., with only minor modification. Two palladium compounds with structures similar to that of the platinum species studied and cobalt chloride were additionally tested for comparison. The hexachloroplatinate and tetrachloroplatinate salts showed exceptionally high reactivity with the cysteine peptide (EC15 values of 1.4 and 14 μM, respectively). However, for platinum compounds (e.g. hydrogen hexahydroxyplatinate and tetraammineplatinum) where clinical and epidemiological evidence indicates limited sensitization potential, the cysteine DPRA showed only minor or no reactivity (EC15 values of 24 600 and >30 000 μM, respectively). The outcomes of the lysine peptide assays were less robust and where EC15 was measurable, values were substantially higher than the corresponding results from the cysteine assay. This work supports the value of in chemico peptide reactivity as a metric for assessment of platinum sensitization potential and therefore in screening of new platinum compounds for low or absent sensitization potential. Additional studies are required to determine whether the DPRA may be successfully applied to other metals. We provide details on method modifications and precautions important to the success of the DPRA in the assessment of metal reactivity.

scholarly journals Toward a Working Model of Leadership in Nonprofit Sport Governance

2019 ◽  
Vol 33 (3) ◽  
pp. 189-202 ◽  
Author(s):  
Ian O’Boyle ◽  
David Shilbury ◽  
Lesley Ferkins
Keyword(s):  
Chief Executive Officers ◽  
Leadership Skills ◽  
Chief Executive ◽  
Future Research ◽  
Limited Attention ◽  
Study Approach ◽  
Working Model ◽  
Executive Officers ◽  
Scholarly Discourse

The aim of this study is to explore leadership within nonprofit sport governance. As an outcome, the authors present a preliminary working model of leadership in nonprofit sport governance based on existing literature and our new empirical evidence. Leadership in nonprofit sport governance has received limited attention to date in scholarly discourse. The authors adopt a case study approach involving three organizations and 16 participant interviews from board members and Chief Executive Officers within the golf network in Australia to uncover key leadership issues in this domain. Interviews were analyzed using an interpretive process, and a thematic structure relating to leadership in the nonprofit sport governance context was developed. Leadership ambiguity, distribution of leadership, leadership skills and development, and leadership and volunteerism emerged as the key themes in the research. These themes, combined with existing literature, are integrated into a preliminary working model of leadership in nonprofit sport governance that helps to shape the issues and challenges embedded within this emerging area of inquiry. The authors offer a number of suggestions for future research to refine, test, critique, and elaborate on our proposed working model.

scholarly journals Action plan for hit identification (APHID): KAT6A as a case study

2020 ◽  
Vol 12 (5) ◽  
pp. 423-437 ◽  
Author(s):  
Xiangyan Yi ◽  
Lian Xue ◽  
Tim Thomas ◽  
Jonathan B Baell
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Action Plan ◽  
Hit Identification

Here, we describe our action plan for hit identification (APHID) that guides the process of hit triage, with elimination of less tractable hits and retention of more tractable hits. We exemplify the process with reference to our high-throughput screening (HTS) campaign against the enzyme, KAT6A, that resulted in successful identification of a tractable hit. We hope that APHID could serve as a useful, concise and digestible guide for those involved in HTS and hit triage, especially those that are relatively new to this exciting and continually evolving technology.

The Case for Combining Pump Maintenance and Systematic Upgrading

2008 ◽  
Author(s):  
Heinz P. Bloch ◽  
Robert Bluse ◽  
James Steiger
Keyword(s):  
System Performance ◽  
Current System ◽  
Highly Qualified ◽  
Centrifugal Pumps ◽  
Term Operation ◽  
Performance Requirements ◽  
Periodic Maintenance ◽  
Work Supports

Virtually, all industrial machinery requires periodic maintenance for dependable long-term operation. In fact, the very term “maintenance” is defined as keeping machines in the as-designed or as-purchased and manufactured condition. At issue is whether the equipment owner’s profitability objectives are best served by “maintaining only”, or by judiciously combining maintenance and upgrading tasks. Assuming the answer favors combining maintenance and upgrading, the question arises whether an intelligent and well thought-out combination of maintenance and upgrading should be entrusted only to the original equipment manufacturer (OEM), or if qualified non-OEMs should be considered also. The co-authors would like to offer their answer to the question. Experience shows that a highly qualified independent rebuild shop with demonstrated capabilities and experienced personnel can offer high-quality upgrades that improve both uptime and efficiency. Such a shop can do so consistent with current system performance requirements. With the considerable consolidations in the pump industry, the distinct possibility exists that the OEM is not able to offer the same engineering competence he previously had and that independent shops should be considered. This presentation deals with a case study and details where such upgrading was being planned, implemented, and verified to have had the desired results. It further explains the role played by competent pump rebuild shops (we chose to call them “CPRS”) in these important endeavors. Our work supports the premise that rebuilding a vintage process pump to original OEM specifications makes no sense, given current pump rebuilding technology and changes to the system performance that occur over time. We find compelling reasons to systematically upgrade the efficiency and potential run length of large centrifugal pumps. Of course, this upgrading must be pre-planned and then carried out during a future maintenance outage.

scholarly journals Anatomical, morphological and phytochemical properties of Aegopodium alpestre Ledeb.: a case study of Kazakhstan

2020 ◽  
Vol 48 (3) ◽  
pp. 1473-1482
Author(s):  
Elzira A. KYRBASSOVA ◽  
Akmaral A. SARTAYEVA ◽  
Elmira M. IMANOVA ◽  
Nurdana N. SALYBEKOVA ◽  
Gulraikhan E. ZHANTEYEVA ◽  
...  
Keyword(s):  
Large Scale ◽  
Inorganic Compounds ◽  
Biologically Active Substances ◽  
Biologically Active ◽  
High Concentration ◽  
Vegetative Organs ◽  
Study Results ◽  
Cultivation Practice ◽  
Active Substances

This article deals with the phytochemical, morphological and anatomical investigation of ethanol-based extracts derived from the leaves and stems of the Aegopodium alpestre. The vegetative organs of A. alpestre were conserved according to Strasburger-Fleµming method using a 1:1:1 mixture of alcohol-glycerin-water. A total of 1200 ethanol-based extracts (2 from leaves and 2 from stem tissues per plant) were prepared using the Soxhlet extractor. All extracts were used to identify organic and inorganic compounds in the leaves and stems of the studied plant. Contents of biologically active substances, microelements, vitamins and amino acids were determined. This article is the first paper to display very high concentration and diversity of vitamins (6 types), micronutrients (5 types), and aminoacids (13 types) in the leaves and steams of A. alpestre. Findings conclude that identification of biologically active substances in the above the ground vegetative organs of A. alpestre may be a common practice in the future. Considering the study results, A. alpestre may be used as a medicinal plant on a large scale. For this, the cultivation practice needs to be scaled up.

Dynamic Optimization for Airline Maintenance Operations

2020 ◽  
Vol 54 (4) ◽  
pp. 998-1015 ◽  
Author(s):  
Carlos Lagos ◽  
Felipe Delgado ◽  
Mathias A. Klapp
Keyword(s):  
Dynamic Optimization ◽  
Function Approximation ◽  
Economies Of Scale ◽  
Maintenance Scheduling ◽  
Limited Attention ◽  
Aircraft Maintenance ◽  
Value Function Approximation ◽  
Markov Decision ◽  
Airline Maintenance

The occurrence of unexpected aircraft maintenance tasks can produce expensive changes in an airline’s operation. When it comes to critical tasks, it might even cancel programmed flights. Despite this, the challenge of scheduling aircraft maintenance operations under uncertainty has received limited attention in the scientific literature. We study a dynamic airline maintenance scheduling problem, which daily decides the set of aircraft to maintain and the set of pending tasks to execute in each aircraft. The objective is to minimize the expected costs of expired maintenance tasks over the operating horizon. To increase flexibility and reduce costs, we integrate maintenance scheduling with tail assignment decisions. We formulate our problem as a Markov decision process and design dynamic policies based on approximate dynamic programming, including value function approximation, rolling horizon techniques, and a hybrid policy between the latter two that delivers the best results. In a case study based on LATAM airline, we show the value of dynamic optimization by testing our best policies against a simple airline decision rule and a deterministic relaxation with perfect future information. We suggest to schedule tasks requiring less resources first to increase utilization of residual maintenance capacity. Finally, we observe strong economies of scale when sharing maintenance resources between multiple airlines.

scholarly journals Example of Adverse Outcome Pathway Concept Enabling Genome-to-Phenome Discovery in Toxicology

2020 ◽  
Vol 60 (2) ◽  
pp. 375-384 ◽  
Author(s):  
Kurt A Gust ◽  
Qing Ji ◽  
Xiao Luo
Keyword(s):  
Biological Sciences ◽  
Weight Loss ◽  
Body Weight ◽  
Amino Acid ◽  
Adverse Outcome ◽  
Body Weight Loss ◽  
Energy Budgets ◽  
Adverse Outcome Pathway ◽  
Biological Organization

Synopsis The following article represents a mini-review of an intensive 10-year progression of genome-to-phenome (G2P) discovery guided by the adverse outcome pathway (AOP) concept. This example is presented as a means to stimulate crossover of this toxicological concept to enhance G2P discovery within the broader biological sciences community. The case study demonstrates the benefits of the AOP approach for establishing causal linkages across multiple levels of biological organization ultimately linking molecular initiation (often at the genomic scale) to organism-level phenotypes of interest. The case study summarizes a US military effort to identify the mechanism(s) underlying toxicological phenotypes of lethargy and weight loss in response to nitroaromatic munitions exposures, such as 2,4,6-trinitrotoluene. Initial key discoveries are described including the toxicogenomic results that nitrotoluene exposures inhibited expression within the peroxisome proliferator activated receptor α (PPARα) pathway. We channeled the AOP concept to test the hypothesis that inhibition of PPARα signaling in nitrotoluene exposures impacted lipid metabolic processes, thus affecting systemic energy budgets, ultimately resulting in body weight loss. Results from a series of transcriptomic, proteomic, lipidomic, in vitro PPARα nuclear signaling, and PPARα knock-out investigations ultimately supported various facets of this hypothesis. Given these results, we next proceeded to develop a formalized AOP description of PPARα antagonism leading to body weight loss. This AOP was refined through intensive literature review and polished through multiple rounds of peer-review leading to final international acceptance as an Organisation for Economic Cooperation and Development-approved AOP. Briefly, that AOP identifies PPARα antagonist binding as the molecular initiating event (MIE) leading to a series of key events including inhibition of nuclear transactivation for genes controlling lipid metabolism and ketogenesis, inhibition of fatty acid beta-oxidation and ketogenesis dynamics, negative energy budget, and ultimately the adverse outcome (AO) of body-weight loss. Given that the PPARα antagonism MIE represented a reliable indicator of AO progression within the pathway, a phylogenetic analysis was conducted which indicated that PPARα amino acid relatedness generally tracked species relatedness. Additionally, PPARα amino acid relatedness analysis using the Sequence Alignment to Predict Across Species Susceptibility predicted susceptibility to the MIE across vertebrates providing context for AOP extrapolation across species. Overall, we hope this illustrative example of how the AOP concept has benefited toxicology sows a seed within the broader biological sciences community to repurpose the concept to facilitate enhanced G2P discovery in biology.

Reflexive Intervention Development: Using Qualitative Research to Inform the Development of an Intervention for Women With Metastatic Breast Cancer

2019 ◽  
Vol 30 (5) ◽  
pp. 666-678 ◽  
Author(s):  
Britta Wigginton ◽  
Zoe O. Thomson ◽  
Carolina X. Sandler ◽  
Marina M. Reeves
Keyword(s):  
Breast Cancer ◽  
Qualitative Research ◽  
Metastatic Breast Cancer ◽  
Intervention Development ◽  
Metastatic Breast ◽  
Interview Study ◽  
Limited Attention ◽  
Depth Interviews

There is growing consensus around the limited attention given to documenting the process of intervention development, specifically the role of qualitative research. In this article, we seek to describe a missing piece of this process: how qualitative research, and related methodologies and theories, informs intervention development. We use our research as a case study of “reflexive intervention development.” We begin by describing our interview study, consisting of 23 in-depth interviews with women diagnosed with metastatic breast cancer, and go on to detail our methodological framework and research team. We then explain how this interview study directly informed our development of the intervention materials, allowing us to attend carefully to language and its potential implications for women. We conclude by inviting researchers to reflect on the knowledge production process that is inherent in intervention development to consider not only their role in this process but also the role of qualitative research.

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