scholarly journals Radical Stabilization Energies for Enzyme Engineering – Tackling the Substrate Scope of the Radical Enzyme QueE

2019 ◽  
Author(s):  
Christian Suess ◽  
Floriane Martins ◽  
Anna Croft ◽  
Christof Jaeger
Keyword(s):  
Screening Method ◽  
Cost Effective ◽  
Md Simulations ◽  
Enzyme Engineering ◽  
Radical Intermediates ◽  
Stabilization Energies ◽  
Effective Assessment ◽  
Semi Empirical ◽  
The Impact ◽  
Radical Enzymes

Experimental assessment of the reaction mechanisms and profiles of radical enzymes can be severely challenging due to the reactive nature of the intermediates, and sensitivity of cofactors such as iron sulfur clusters. Here we present an enzyme-directed computational methodology for the assessment of thermodynamic reaction profiles and screening for radical stabilization energies (RSEs) for the assessment of catalytic turnovers in radical enzymes. We have applied this new screening method to the radical SAM enzyme CPH4 synthase (QueE), following a detailed molecular dynamics (MD) analysis that clarifies the role of both specific enzyme residues and bound Mg2+, Ca2+ or Na+. The MD simulations provided the basis for a statistical approach to sample different conformational outcomes. RSE calculation at the M06-2X/6-31+G* level of theory provided the most computationally cost-effective assessment of enzyme-based energies, facilitated by an initial triage using semi-empirical methods. The impact of intermolecular interactions on RSE was clearly established and application to the assessment of potential alternative substrates (focusing on radical clock type rearrangements) proposes a selection of carbon-substituted analogues that would react to afford cyclopropylcarbinyl radical intermediates, as candidates for catalytic turnover by QueE.

scholarly journals Radical Stabilization Energies for Enzyme Engineering – Tackling the Substrate Scope of the Radical Enzyme QueE

2018 ◽  
Author(s):  
Christian Suess ◽  
Floriane Martins ◽  
Anna Croft ◽  
Christof Jaeger
Keyword(s):  
Screening Method ◽  
Cost Effective ◽  
Md Simulations ◽  
Enzyme Engineering ◽  
Radical Intermediates ◽  
Stabilization Energies ◽  
Effective Assessment ◽  
Semi Empirical ◽  
The Impact ◽  
Radical Enzymes

Experimental assessment of the reaction mechanisms and profiles of radical enzymes can be severely challenging due to the reactive nature of the intermediates, and sensitivity of cofactors such as iron sulfur clusters. Here we present an enzyme-directed computational methodology for the assessment of thermodynamic reaction profiles and screening for radical stabilization energies (RSEs) for the assessment of catalytic turnovers in radical enzymes. We have applied this new screening method to the radical SAM enzyme CPH4 synthase (QueE), following a detailed molecular dynamics (MD) analysis that clarifies the role of both specific enzyme residues and bound Mg2+, Ca2+ or Na+. The MD simulations provided the basis for a statistical approach to sample different conformational outcomes. RSE calculation at the M06-2X/6-31+G* level of theory provided the most computationally cost-effective assessment of enzyme-based energies, facilitated by an initial triage using semi-empirical methods. The impact of intermolecular interactions on RSE was clearly established and application to the assessment of potential alternative substrates (focusing on radical clock type rearrangements) proposes a selection of carbon-substituted analogues that would react to afford cyclopropylcarbinyl radical intermediates, as candidates for catalytic turnover by QueE.

scholarly journals Radical Stabilization Energies for Enzyme Engineering – Tackling the Substrate Scope of the Radical Enzyme QueE

2019 ◽  
Author(s):  
Christian Suess ◽  
Floriane Martins ◽  
Anna Croft ◽  
Christof Jaeger
Keyword(s):  
Screening Method ◽  
Cost Effective ◽  
Md Simulations ◽  
Enzyme Engineering ◽  
Radical Intermediates ◽  
Stabilization Energies ◽  
Effective Assessment ◽  
Semi Empirical ◽  
The Impact ◽  
Radical Enzymes

Experimental assessment of the reaction mechanisms and profiles of radical enzymes can be severely challenging due to the reactive nature of the intermediates, and sensitivity of cofactors such as iron sulfur clusters. Here we present an enzyme-directed computational methodology for the assessment of thermodynamic reaction profiles and screening for radical stabilization energies (RSEs) for the assessment of catalytic turnovers in radical enzymes. We have applied this new screening method to the radical SAM enzyme CPH4 synthase (QueE), following a detailed molecular dynamics (MD) analysis that clarifies the role of both specific enzyme residues and bound Mg2+, Ca2+ or Na+. The MD simulations provided the basis for a statistical approach to sample different conformational outcomes. RSE calculation at the M06-2X/6-31+G* level of theory provided the most computationally cost-effective assessment of enzyme-based energies, facilitated by an initial triage using semi-empirical methods. The impact of intermolecular interactions on RSE was clearly established and application to the assessment of potential alternative substrates (focusing on radical clock type rearrangements) proposes a selection of carbon-substituted analogues that would react to afford cyclopropylcarbinyl radical intermediates, as candidates for catalytic turnover by QueE.

A rapid and simple method for routine determination of antibiotic sensitivity to biofilm populations of Pseudomonas aeruginosa

2020 ◽  
Author(s):  
Dhammika Leshan Wannigama ◽  
Cameron Hurst ◽  
Parichart Hongsing ◽  
Lachlan Pearson ◽  
Thammakorn Saethang ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Screening Method ◽  
Antibiotic Sensitivity ◽  
Cost Effective ◽  
Response Patterns ◽  
Simple Method ◽  
Planktonic Bacteria ◽  
Antibiotic Response ◽  
The Impact

Abstract Treatment of infections of Pseudomonas aeruginosa forming biofilms after antimicrobial testing on planktonic bacteria can result in substantial failure. Therefore, we offer a robust and simple experimental platform to test the impact of antimicrobials on biofilms. Antibiotic response patterns varied uniquely within biofilm formation capacity and minimal biofilm eradication concentrations (MBECs) has a significantly better discriminatory power than minimum inhibitory concentrations (MICs) to differentiate the overall efficiency of antibiotics to eradicate biofilm. Our resazurin-based 96-well-plate platform is able to emulate bacterial responses to antibiotics under biofilm conditions in a fast, simple, and cost-effective screening method adaptable to automation, and warrants trials in the clinic.

scholarly journals A rapid and simple method for routine determination of antibiotic sensitivity to biofilm populations of Pseudomonas aeruginosa

2020 ◽  
Author(s):  
Dhammika Leshan Wannigama ◽  
Cameron Hurst ◽  
Parichart Hongsing ◽  
Lachlan Pearson ◽  
Thammakorn Saethang ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Screening Method ◽  
Antibiotic Sensitivity ◽  
Cost Effective ◽  
Response Patterns ◽  
Simple Method ◽  
Planktonic Bacteria ◽  
Antibiotic Response ◽  
The Impact

Abstract Treatment of infections of Pseudomonas aeruginosa forming biofilms after antimicrobial testing on planktonic bacteria can result in substantial failure. Therefore, we offer a robust and simple experimental platform to test the impact of antimicrobials on biofilms. Antibiotic response patterns varied uniquely within biofilm formation capacity and minimal biofilm eradication concentrations (MBECs) has a significantly better discriminatory power than minimum inhibitory concentrations (MICs) to differentiate the overall efficiency of antibiotics to eradicate biofilm. Our resazurin-based 96-well-plate platform is able to emulate bacterial responses to antibiotics under biofilm conditions in a fast, simple, and cost-effective screening method adaptable to automation, and warrants trials in the clinic.

Addressing patient sexuality issues in cancer and palliative care

2021 ◽  
Vol 30 (10) ◽  
pp. S24-S28
Author(s):  
Mary Williams ◽  
Gulen Addis
Keyword(s):  
Palliative Care ◽  
Clinical Practice ◽  
Sexuality Education ◽  
Cost Effective ◽  
Assessment Tools ◽  
Confidence Levels ◽  
Open Discussion ◽  
Training Programmes ◽  
Effective Assessment ◽  
The Impact

The impact of cancer and subsequent treatments can have serious implications for patient sexuality, both physically and psychologically. Patients report inadequate communication and support from professionals in relation to sexual issues. The aim of this literature review was to ascertain the educational requirements of health professionals practising in oncology and palliative care, to enable effective assessment and support in this area of clinical practice. There appear to be numerous barriers preventing professionals from addressing patient sexuality—lack of knowledge and poor confidence levels being among the most common. Appropriate education is required to equip staff, and it appears that short training programmes can be effective. The use of sexuality assessment tools and information cards, and accessing information from cancer charity websites may improve clinical practice. Addressing sexuality concerns is the responsibility of each person in the multidisciplinary team. Patients require open discussion and professionals must skilfully address the topic of sexuality. Education in this area must be accessible, cost effective and sustainable.

Regulatory and sustainability initiatives lead to improved polyaminopolyamide epichlorohydrin (PAE) wet-strength resins and paper products

TAPPI Journal ◽  
2018 ◽  
Vol 17 (09) ◽  
pp. 519-532 ◽  
Author(s):  
Mark Crisp ◽  
Richard Riehle
Keyword(s):  
Health And Safety ◽  
Cost Effective ◽  
Worker Safety ◽  
Regulatory Requirements ◽  
Wet Strength ◽  
The Past ◽  
Consumer Safety ◽  
Federal Institute ◽  
Sustainability Initiatives ◽  
The Impact

Polyaminopolyamide-epichlorohydrin (PAE) resins are the predominant commercial products used to manufacture wet-strengthened paper products for grades requiring wet-strength permanence. Since their development in the late 1950s, the first generation (G1) resins have proven to be one of the most cost-effective technologies available to provide wet strength to paper. Throughout the past three decades, regulatory directives and sustainability initiatives from various organizations have driven the development of cleaner and safer PAE resins and paper products. Early efforts in this area focused on improving worker safety and reducing the impact of PAE resins on the environment. These efforts led to the development of resins containing significantly reduced levels of 1,3-dichloro-2-propanol (1,3-DCP) and 3-monochloropropane-1,2-diol (3-MCPD), potentially carcinogenic byproducts formed during the manufacturing process of PAE resins. As the levels of these byproducts decreased, the environmental, health, and safety (EH&S) profile of PAE resins and paper products improved. Recent initiatives from major retailers are focusing on product ingredient transparency and quality, thus encouraging the development of safer product formulations while maintaining performance. PAE resin research over the past 20 years has been directed toward regulatory requirements to improve consumer safety and minimize exposure to potentially carcinogenic materials found in various paper products. One of the best known regulatory requirements is the recommendations of the German Federal Institute for Risk Assessment (BfR), which defines the levels of 1,3-DCP and 3-MCPD that can be extracted by water from various food contact grades of paper. These criteria led to the development of third generation (G3) products that contain very low levels of 1,3-DCP (typically <10 parts per million in the as-received/delivered resin). This paper outlines the PAE resin chemical contributors to adsorbable organic halogens and 3-MCPD in paper and provides recommendations for the use of each PAE resin product generation (G1, G1.5, G2, G2.5, and G3).

Exploring the Benefits of Early Contractor Involvement (ECI) and the Mechanism for Automated 5D BIM Quantification Process in Offsite Modular Construction

2016 ◽  
Author(s):  
Tochukwu Moses ◽  
David Heesom ◽  
David Oloke ◽  
Martin Crouch
Keyword(s):  
Effective Means ◽  
Cost Effective ◽  
Modular Construction ◽  
Automated Quantification ◽  
Building Information ◽  
Project Risks ◽  
Value Add ◽  
The Uk ◽  
The Impact ◽  
Level 2

The UK Construction Industry through its Government Construction Strategy has recently been mandated to implement Level 2 Building Information Modelling (BIM) on public sector projects. This move, along with other initiatives is key to driving a requirement for 25% cost reduction (establishing the most cost-effective means) on. Other key deliverables within the strategy include reduction in overall project time, early contractor involvement, improved sustainability and enhanced product quality. Collaboration and integrated project delivery is central to the level 2 implementation strategy yet the key protocols or standards relative to cost within BIM processes is not well defined. As offsite construction becomes more prolific within the UK construction sector, this construction approach coupled with BIM, particularly 5D automated quantification process, and early contractor involvement provides significant opportunities for the sector to meet government targets. Early contractor involvement is supported by both the industry and the successive Governments as a credible means to avoid and manage project risks, encourage innovation and value add, making cost and project time predictable, and improving outcomes. The contractor is seen as an expert in construction and could be counter intuitive to exclude such valuable expertise from the pre-construction phase especially with the BIM intent of äóÖbuild it twiceäó», once virtually and once physically. In particular when offsite construction is used, the contractoräó»s construction expertise should be leveraged for the virtual build in BIM-designed projects to ensure a fully streamlined process. Building in a layer of automated costing through 5D BIM will bring about a more robust method of quantification and can help to deliver the 25% reduction in overall cost of a project. Using a literature review and a case study, this paper will look into the benefits of Early Contractor Involvement (ECI) and the impact of 5D BIM on the offsite construction process.

Recent Advances of In-Silico Modeling of Potent Antagonists for the Adenosine Receptors

2019 ◽  
Vol 25 (7) ◽  
pp. 750-773 ◽  
Author(s):  
Pabitra Narayan Samanta ◽  
Supratik Kar ◽  
Jerzy Leszczynski
Keyword(s):  
Drug Targets ◽  
Biological Activities ◽  
Scoring Function ◽  
Md Simulations ◽  
Energy Calculation ◽  
Binding Modes ◽  
Macromolecular Systems ◽  
In Silico Modeling ◽  
Mathematical Algorithms ◽  
The Impact

The rapid advancement of computer architectures and development of mathematical algorithms offer a unique opportunity to leverage the simulation of macromolecular systems at physiologically relevant timescales. Herein, we discuss the impact of diverse structure-based and ligand-based molecular modeling techniques in designing potent and selective antagonists against each adenosine receptor (AR) subtype that constitutes multitude of drug targets. The efficiency and robustness of high-throughput empirical scoring function-based approaches for hit discovery and lead optimization in the AR family are assessed with the help of illustrative examples that have led to nanomolar to sub-micromolar inhibition activities. Recent progress in computer-aided drug discovery through homology modeling, quantitative structure-activity relation, pharmacophore models, and molecular docking coupled with more accurate free energy calculation methods are reported and critically analyzed within the framework of structure-based virtual screening of AR antagonists. Later, the potency and applicability of integrated molecular dynamics (MD) methods are addressed in the context of diligent inspection of intricated AR-antagonist binding processes. MD simulations are exposed to be competent for studying the role of the membrane as well as the receptor flexibility toward the precise evaluation of the biological activities of antagonistbound AR complexes such as ligand binding modes, inhibition affinity, and associated thermodynamic and kinetic parameters.

Pound Wise and Penny Foolish? Weight Loss and The Dynamics of Health Care Spending

2011 ◽  
Vol 14 (2) ◽  
Author(s):  
Thomas G Koch
Keyword(s):  
Weight Loss ◽  
Cost Savings ◽  
Cost Effective ◽  
Economic Consequences ◽  
Health Care Spending ◽  
Order Of Magnitude ◽  
Dynamic Measures ◽  
The Cost ◽  
The Impact ◽  
The Relationship

Current estimates of obesity costs ignore the impact of future weight loss and gain, and may either over or underestimate economic consequences of weight loss. In light of this, I construct static and dynamic measures of medical costs associated with body mass index (BMI), to be balanced against the cost of one-time interventions. This study finds that ignoring the implications of weight loss and gain over time overstates the medical-cost savings of such interventions by an order of magnitude. When the relationship between spending and age is allowed to vary, weight-loss attempts appear to be cost-effective starting and ending with middle age. Some interventions recently proven to decrease weight may also be cost-effective.

Motivating Compliance: Firm Response to Mandatory Disclosure Policies

2018 ◽  
Vol 32 (2) ◽  
pp. 103-119
Author(s):  
Colleen M. Boland ◽  
Chris E. Hogan ◽  
Marilyn F. Johnson
Keyword(s):  
Conflict Of Interest ◽  
Low Cost ◽  
Cost Effective ◽  
Data Availability ◽  
Policy Adoption ◽  
Future Research ◽  
Regulated Firms ◽  
Firm Response ◽  
Disclosure Rules ◽  
The Impact

SYNOPSIS Mandatory existence disclosure rules require an organization to disclose a policy's existence, but not its content. We examine policy adoption frequencies in the year immediately after the IRS required mandatory existence disclosure by nonprofits of various governance policies. We also examine adoption frequencies in the year of the subsequent change from mandatory existence disclosure to a disclose-and-explain regime that required supplemental disclosures about the content and implementation of conflict of interest policies. Our results suggest that in areas where there is unclear regulatory authority, mandatory existence disclosure is an effective and low cost regulatory device for encouraging the adoption of policies desired by regulators, provided those policies are cost-effective for regulated firms to implement. In addition, we find that disclose-and-explain regulatory regimes provide stronger incentives for policy adoption than do mandatory existence disclosure regimes and also discourage “check the box” behavior. Future research should examine the impact of mandatory existence disclosure rules in the year that the regulation is implemented. Data Availability: Data are available from sources cited in the text.

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