PeerJ Preprints: Drugs and Deviceshttps://peerj.com/preprints/index.atom?journal=peerj&subject=4100Drugs and Devices articles published in PeerJ PreprintsA guide to applying the Good Publication Practice 3 Guidelines in the Asia-Pacific regionhttps://peerj.com/preprints/278922019-08-192019-08-19Blair HespKatsuhisa AraiMagdalene ChuStefanie ChuahJose Miguel CuramengSandeep KamatZhigang MaAndrew SakkoHazel Fernandez
Numerous recommendations and guidelines aim to improve the quality, timeliness and transparency of medical publications. However, these guidelines use ambiguous language that can be challenging to interpret, particularly for speakers of English as a second language. Cultural expectations within the Asia-Pacific region raise additional challenges. Several studies have suggested that awareness and application of ethical publication practices in the Asia-Pacific region is relatively low compared with other regions. However, guidance on applying ethical publication practice guidelines in the Asia-Pacific region is lacking. This review aims to improve publication practices in the Asia-Pacific region by providing guidance on applying the 10 principles of the Good Publication Practice 3 (GPP3) guidelines and the International Committee of Medical Journal Editors (ICMJE) criteria for authorship. Recommendations are provided for encore presentations, applying the ICMJE authorship criteria in the context of regional cultural expectations, and the role of study sponsors and professional medical writers. Ongoing barriers to compliance with guidelines are also highlighted, and additional guidance is provided to support authors submitting manuscripts for publication. The roles of regional journals, regulatory authorities and professional bodies in improving practices are also discussed.
Numerous recommendations and guidelines aim to improve the quality, timeliness and transparency of medical publications. However, these guidelines use ambiguous language that can be challenging to interpret, particularly for speakers of English as a second language. Cultural expectations within the Asia-Pacific region raise additional challenges. Several studies have suggested that awareness and application of ethical publication practices in the Asia-Pacific region is relatively low compared with other regions. However, guidance on applying ethical publication practice guidelines in the Asia-Pacific region is lacking. This review aims to improve publication practices in the Asia-Pacific region by providing guidance on applying the 10 principles of the Good Publication Practice 3 (GPP3) guidelines and the International Committee of Medical Journal Editors (ICMJE) criteria for authorship. Recommendations are provided for encore presentations, applying the ICMJE authorship criteria in the context of regional cultural expectations, and the role of study sponsors and professional medical writers. Ongoing barriers to compliance with guidelines are also highlighted, and additional guidance is provided to support authors submitting manuscripts for publication. The roles of regional journals, regulatory authorities and professional bodies in improving practices are also discussed.L-methionine sulfoximine interacted with propofol and showed toxicity in PC12 cellshttps://peerj.com/preprints/278032019-06-162019-06-16Ruicong GuanJing ChenFei XiaoYubo Xie
Background: L-Methionine sulfoximine (MSO) inhibits glutamine synthesis in a rodent animal model, and its limited clinical use is implicitly associated with glutamate deprivation and neurotoxicity. The purpose of this experiment was to determine the effect of MSO on pheochromocytoma (PC12) cells and its interaction with propofol-induced neuro-apoptosis. Objective: To study the effects of MSO on cell viability following 100 μM propofol treatment and the impact of ribosomal S6 kinase 1 (RSK1) signaling on the PC12 cell line. Methods: PC12 cells were exposed to propofol-triggered neurotoxicity for 6 h and then subjected to MSO treatment. The gene and protein expression levels of members of the RSK1 signaling pathway were determined by real-time polymerase chain reaction, Western blot and histological analyses. The CCK8 test was used to assess cell viability, and cell proliferation and apoptosis were evaluated by flow cytometric analysis. Results: Propofol, a gamma-aminobutyric acid (GABA) agonist widely used in general anesthesia, significantly changed the expr ession level of cAMP response element-binding protein (CREB) and B cell lymphoma 2 (Bcl2) and solute carrier family 1 member 3 (Slc1a3), but not extracellular signal-regulated kinase 1/2 (ERK1/2). PC12 cells that were exposed to propofol for more than 6 h exhibited downregulation of RSK1. MSO aggravated the toxicity of propofol in PC12 cells via inhibition of the p90RSK1/CREB/Bcl2 signaling pathway.
Background: L-Methionine sulfoximine (MSO) inhibits glutamine synthesis in a rodent animal model, and its limited clinical use is implicitly associated with glutamate deprivation and neurotoxicity. The purpose of this experiment was to determine the effect of MSO on pheochromocytoma (PC12) cells and its interaction with propofol-induced neuro-apoptosis. Objective: To study the effects of MSO on cell viability following 100 μM propofol treatment and the impact of ribosomal S6 kinase 1 (RSK1) signaling on the PC12 cell line. Methods: PC12 cells were exposed to propofol-triggered neurotoxicity for 6 h and then subjected to MSO treatment. The gene and protein expression levels of members of the RSK1 signaling pathway were determined by real-time polymerase chain reaction, Western blot and histological analyses. The CCK8 test was used to assess cell viability, and cell proliferation and apoptosis were evaluated by flow cytometric analysis. Results: Propofol, a gamma-aminobutyric acid (GABA) agonist widely used in general anesthesia, significantly changed the expr ession level of cAMP response element-binding protein (CREB) and B cell lymphoma 2 (Bcl2) and solute carrier family 1 member 3 (Slc1a3), but not extracellular signal-regulated kinase 1/2 (ERK1/2). PC12 cells that were exposed to propofol for more than 6 h exhibited downregulation of RSK1. MSO aggravated the toxicity of propofol in PC12 cells via inhibition of the p90RSK1/CREB/Bcl2 signaling pathway.Synthesis, characterization, and biological evaluation of new spebrutinib analogues: potential candidates with enhanced activity and reduced toxicity profileshttps://peerj.com/preprints/277552019-05-242019-05-24Zaid M Jaber Al-ObaidiOmar F Abdul-RasheedMonther F MahdiAyad M R Raauf
Background: Cancer is regarded as an undoubtable major concern for both researchers and the general public because of its high mortality rates. While breast cancer has the highest incidence of malignancy globally, colon cancer also has high morbidity and mortality rates. Currently, researchers are working on designing, synthesizing, and biologically investigating the effects of some potential anticancer candidates.
Methods: The authors successfully synthesized and characterized two potential spebrutinib analogues. These analogues were evaluated with the employment of MCF-7, HCT116, and MDCK cell lines.
Results: With respect to the spebrutinib standard, one of these analogues had superior activity against the MCF-7 cell line (IC50; 10.744 µg/mL against 13.566 µg/mL for spebrutinib) and an enhanced toxicity profile on the MDCK cell line (IC50; 8.653 mg/mL against 4.011 mg/mL for spebrutinib).
Background: Cancer is regarded as an undoubtable major concern for both researchers and the general public because of its high mortality rates. While breast cancer has the highest incidence of malignancy globally, colon cancer also has high morbidity and mortality rates. Currently, researchers are working on designing, synthesizing, and biologically investigating the effects of some potential anticancer candidates.Methods: The authors successfully synthesized and characterized two potential spebrutinib analogues. These analogues were evaluated with the employment of MCF-7, HCT116, and MDCK cell lines.Results: With respect to the spebrutinib standard, one of these analogues had superior activity against the MCF-7 cell line (IC50; 10.744 µg/mL against 13.566 µg/mL for spebrutinib) and an enhanced toxicity profile on the MDCK cell line (IC50; 8.653 mg/mL against 4.011 mg/mL for spebrutinib).Simulation of cancer cell line pharmacogenomics data to optimise experimental design and analysis strategyhttps://peerj.com/preprints/273452018-11-132018-11-13Hitesh MistryPhil Chapman
Explaining the variability in drug sensitivity across a panel of cell lines using genomic information is a key aspect of cancer drug discovery. The results of such analyses may ultimately determine which patients are likely to benefit from a new treatment. There are numerous experimental factors that can influence the outcomes of cell line screening panels such as the number of replicates, number of doses explored etc. Simulation studies can aid in understanding how variability in these experimental factors can affect the statistical power of a given analysis method. In this study dose response data was simulated for a variety of experimental designs and the ability of different methods to retrieve the original simulation parameters was compared. The analysis methods under consideration were a combination of non-linear least squares and ANOVA, conventional approach, versus non-linear mixed effects. Across the simulation studies explored the mixed-effects approach gave similar and in some situations greater statistical power than the conventional approach. In particular the mixed-effects approach gave significantly greater power when there was less information per dose response curve, and when more cell lines screened.More generally the best way to improve statistical power was to screen more cell lines. This study demonstrates the value of simulating data to understand design and analysis choices in the context of cancer drug sensitivity screening. By illustrating the performance of different methods in different situations these results will help researchers in the field generate and analyse data on future preclinical compounds. Ultimately this will benefit patients by ensuring that biomarkers of drug sensitivity have an increased chance of being identified at the preclinical stage.
Explaining the variability in drug sensitivity across a panel of cell lines using genomic information is a key aspect of cancer drug discovery. The results of such analyses may ultimately determine which patients are likely to benefit from a new treatment. There are numerous experimental factors that can influence the outcomes of cell line screening panels such as the number of replicates, number of doses explored etc. Simulation studies can aid in understanding how variability in these experimental factors can affect the statistical power of a given analysis method. In this study dose response data was simulated for a variety of experimental designs and the ability of different methods to retrieve the original simulation parameters was compared. The analysis methods under consideration were a combination of non-linear least squares and ANOVA, conventional approach, versus non-linear mixed effects. Across the simulation studies explored the mixed-effects approach gave similar and in some situations greater statistical power than the conventional approach. In particular the mixed-effects approach gave significantly greater power when there was less information per dose response curve, and when more cell lines screened.More generally the best way to improve statistical power was to screen more cell lines. This study demonstrates the value of simulating data to understand design and analysis choices in the context of cancer drug sensitivity screening. By illustrating the performance of different methods in different situations these results will help researchers in the field generate and analyse data on future preclinical compounds. Ultimately this will benefit patients by ensuring that biomarkers of drug sensitivity have an increased chance of being identified at the preclinical stage.Modelling of the SDF-1/CXCR4 regulated in vivo homing of therapeutic mesenchymal stem/stromal cells in micehttps://peerj.com/preprints/271442018-08-272018-08-27Wang JinXiaowen LiangAnastasia BrooksKathryn FutregaXin LiuMichael R. DoranMatthew J. SimpsonMichael S. RobertsHaolu Wang
Background. Mesenchymal stem/stromal cells (MSCs) are a promising tool for cell-based therapies in the treatment of tissue injury. The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays a significant role in directing MSC homing to sites of injury. However in vivo MSC distribution following intravenous transplantation remains poorly understood, potentially hampering the precise prediction and evaluation of therapeutic efficacy.
Methods. A murine model of partial ischemia/reperfusion (I/R) is used to induce liver injury, increase the hepatic levels of SDF-1, and study in vivo MSC distribution. Hypoxia-preconditioning increases the expression of CXCR4 in human bone marrow-derived MSCs. Quantitative assays for human DNA allow us to examine the in vivo kinetics of intravenously infused human MSCs in mouse blood and liver. A mathematical model-based system is developed to characterize in vivo homing of human MSCs in mouse models with SDF-1 levels in liver and CXCR4 expression on the transfused MSCs. The model is calibrated to experimental data to provide novel estimates of relevant parameter values.
Results. Images of immunohistochemistry for SDF-1 in the mouse liver with I/R injury show a significantly higher SDF-1level in the I/R injured liver than that in the control. Correspondingly, the ELISA results illustrate a higher MSC dose in the I/R injured liver than the normal liver. CXCR4 is overexpressed in hypoxia-preconditioned MSCs. An increased number of hypoxia-preconditioned MSCs in the I/R injured liver is observed from the ELISA results. The model simulations align with the experimental data of control and hypoxia-preconditioned human MSC distribution in normal and injured mouse livers, and accurately predict the experimental outcomes with different MSC doses.
Discussion. The modelling results suggest that SDF-1 in organs is an effective in vivo attractant for MSCs through the SDF-1/CXCR4 axis and reveals the significance of the SDF-1/CXCR4 chemotaxis on in vivo homing of MSCs, especially under hypoxic preconditioning. The impact of the liver and MSC conditions on passive homing is small. This in vivo modelling approach allows qualitative characterization and prediction of the MSC homing to normal and injured organs on the basis of clinically accessible variables, such as the MSC dose and SDF-1 concentration in blood. This model could also be adapted to abnormal conditions and/or other types of circulating cells to predict in vivo homing patterns.
Background. Mesenchymal stem/stromal cells (MSCs) are a promising tool for cell-based therapies in the treatment of tissue injury. The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays a significant role in directing MSC homing to sites of injury. However in vivo MSC distribution following intravenous transplantation remains poorly understood, potentially hampering the precise prediction and evaluation of therapeutic efficacy.Methods. A murine model of partial ischemia/reperfusion (I/R) is used to induce liver injury, increase the hepatic levels of SDF-1, and study in vivo MSC distribution. Hypoxia-preconditioning increases the expression of CXCR4 in human bone marrow-derived MSCs. Quantitative assays for human DNA allow us to examine the in vivo kinetics of intravenously infused human MSCs in mouse blood and liver. A mathematical model-based system is developed to characterize in vivo homing of human MSCs in mouse models with SDF-1 levels in liver and CXCR4 expression on the transfused MSCs. The model is calibrated to experimental data to provide novel estimates of relevant parameter values.Results. Images of immunohistochemistry for SDF-1 in the mouse liver with I/R injury show a significantly higher SDF-1level in the I/R injured liver than that in the control. Correspondingly, the ELISA results illustrate a higher MSC dose in the I/R injured liver than the normal liver. CXCR4 is overexpressed in hypoxia-preconditioned MSCs. An increased number of hypoxia-preconditioned MSCs in the I/R injured liver is observed from the ELISA results. The model simulations align with the experimental data of control and hypoxia-preconditioned human MSC distribution in normal and injured mouse livers, and accurately predict the experimental outcomes with different MSC doses.Discussion. The modelling results suggest that SDF-1 in organs is an effective in vivo attractant for MSCs through the SDF-1/CXCR4 axis and reveals the significance of the SDF-1/CXCR4 chemotaxis on in vivo homing of MSCs, especially under hypoxic preconditioning. The impact of the liver and MSC conditions on passive homing is small. This in vivo modelling approach allows qualitative characterization and prediction of the MSC homing to normal and injured organs on the basis of clinically accessible variables, such as the MSC dose and SDF-1 concentration in blood. This model could also be adapted to abnormal conditions and/or other types of circulating cells to predict in vivo homing patterns.Comparing enzyme activity modifier equations through the development of global data fitting templates in Excelhttps://peerj.com/preprints/30942018-08-062018-08-06Ryan Walsh
The classical way of defining enzyme inhibition has obscured the distinction between inhibitory effect and the inhibitor binding constant. This article examines the relationship between the simple binding curve used to define biomolecular interactions and the standard inhibitory term (1+([I]/Ki)). By understanding how this term relates to binding curves which are ubiquitously used to describe biological processes, a modifier equation which distinguishes between inhibitor binding and the inhibitory effect, is examined. This modifier equation which can describe both activation and inhibition is compared to standard inhibitory equations with the development of global data fitting templates in Excel and via the global fitting of these equations to simulated and previously published datasets. In both cases, this modifier equation was able to match or outperform the other equations by providing superior fits to the datasets. The ability of this single equation to outperform the other equations suggests an over-complication of the field. This equation and the template developed in this article should prove to be useful tools in the study of enzyme inhibition and activation.
The classical way of defining enzyme inhibition has obscured the distinction between inhibitory effect and the inhibitor binding constant. This article examines the relationship between the simple binding curve used to define biomolecular interactions and the standard inhibitory term (1+([I]/Ki)). By understanding how this term relates to binding curves which are ubiquitously used to describe biological processes, a modifier equation which distinguishes between inhibitor binding and the inhibitory effect, is examined. This modifier equation which can describe both activation and inhibition is compared to standard inhibitory equations with the development of global data fitting templates in Excel and via the global fitting of these equations to simulated and previously published datasets. In both cases, this modifier equation was able to match or outperform the other equations by providing superior fits to the datasets. The ability of this single equation to outperform the other equations suggests an over-complication of the field. This equation and the template developed in this article should prove to be useful tools in the study of enzyme inhibition and activation.Automatic discovery of transferable patterns in protein-ligand interaction networkshttps://peerj.com/preprints/270022018-06-222018-06-22Aida MrzicDries Van RompaeyStefan NaulaertsHans De WinterWim Vanden BerghePieter MeysmanKris Laukens
In recent years, the pharmaceutical industry has been confronted with rising R&D costs paired with decreasing productivity. Attrition rates for new molecules are tremendous, with a substantial number of molecules failing in an advanced stage of development. Repositioning previously approved drugs for new indications can mitigate these issues by reducing both risk and cost of development. Computational methods have been developed to allow for the prediction of drug-target interactions, but it remains difficult to branch out into new areas of application where information is scarce.
Here, we present a proof-of-concept for discovering patterns in protein-ligand data using frequent itemset mining. Two key advantages of our method are the transferability of our patterns to different application domains and the facile interpretation of our recommendations. Starting from a set of known protein-ligand relationships, we identify patterns of molecular substructures and protein domains that lie at the basis of these interactions. We show that these same patterns also underpin metabolic pathways in humans. We further demonstrate how association rules mined from human protein-ligand interaction patterns can be used to predict antibiotics susceptible to bacterial resistance mechanisms.
In recent years, the pharmaceutical industry has been confronted with rising R&D costs paired with decreasing productivity. Attrition rates for new molecules are tremendous, with a substantial number of molecules failing in an advanced stage of development. Repositioning previously approved drugs for new indications can mitigate these issues by reducing both risk and cost of development. Computational methods have been developed to allow for the prediction of drug-target interactions, but it remains difficult to branch out into new areas of application where information is scarce.Here, we present a proof-of-concept for discovering patterns in protein-ligand data using frequent itemset mining. Two key advantages of our method are the transferability of our patterns to different application domains and the facile interpretation of our recommendations. Starting from a set of known protein-ligand relationships, we identify patterns of molecular substructures and protein domains that lie at the basis of these interactions. We show that these same patterns also underpin metabolic pathways in humans. We further demonstrate how association rules mined from human protein-ligand interaction patterns can be used to predict antibiotics susceptible to bacterial resistance mechanisms.Saving the horseshoe crab: A synthetic alternative to horseshoe crab blood for endotoxin detectionhttps://peerj.com/preprints/269222018-05-102018-05-10Tom MaloneyRyan PhelanNaira Simmons
Horseshoe crabs have been integral to the safe production of vaccines and injectable medications for the past forty years. The bleeding of live horseshoe crabs, a process that leaves thousands dead annually, is an ecologically unsustainable practice for all four species of horseshoe crab and the shorebirds that rely on their eggs as a primary food source during spring migration. Populations of both horseshoe crabs and shorebirds are in decline. This study confirms the efficacy of recombinant Factor C, a synthetic alternative that eliminates the need for animal products in endotoxin detection. Furthermore, our findings confirm that the biomedical industry can achieve a 90-percent reduction in the use of reagents derived from horseshoe crabs by using the synthetic alternative for the testing of water and other common materials used in during the manufacturing process. This represents an extraordinary opportunity for the biomedical and pharmaceutical industries to significantly contribute to the conservation of horseshoe crabs and the birds that depend on them.
Horseshoe crabs have been integral to the safe production of vaccines and injectable medications for the past forty years. The bleeding of live horseshoe crabs, a process that leaves thousands dead annually, is an ecologically unsustainable practice for all four species of horseshoe crab and the shorebirds that rely on their eggs as a primary food source during spring migration. Populations of both horseshoe crabs and shorebirds are in decline. This study confirms the efficacy of recombinant Factor C, a synthetic alternative that eliminates the need for animal products in endotoxin detection. Furthermore, our findings confirm that the biomedical industry can achieve a 90-percent reduction in the use of reagents derived from horseshoe crabs by using the synthetic alternative for the testing of water and other common materials used in during the manufacturing process. This represents an extraordinary opportunity for the biomedical and pharmaceutical industries to significantly contribute to the conservation of horseshoe crabs and the birds that depend on them.Sideritis scardica extracts inhibit aggregation and toxicity of amyloid-β in Caenorhabditis elegans used as a model for Alzheimer's diseasehttps://peerj.com/preprints/34832017-12-222017-12-22Felix HeinerBjörn FeistelMichael Wink
Background. Beyond its traditional uses in the Balkan area, Sideritis scardica (known as Greek mountain tea, Lamiaceae) is currently extensively investigated for its pharmacological activity in the central nervous system. Antidepressant, psychostimulating, cognition-enhancing and neuroprotective properties have been described. In this study, we tested hydroalcoholic extracts of S. scardica for their potential to counteract amyloid-β toxicity and aggregation, which plays a crucial role in the pathogenesis of Alzheimer's disease.
Methods. For this purpose, we have chosen the nematode Caenorhabditis elegans, which is used as a model organism for neurodegenerative diseases. The concentration of different polyphenols in extracts prepared from water, 20, 40, 50, and 70 % ethanol was analysed by HPLC. Additionally, polar and unpolar fractions were prepared from the 40 % ethanolic extract and phytochemically analysed.
Results. Essentially, the contents of all measured constituents increased with the lipophilicity of the extraction solvents. Treatment of transgenic C. elegans strains expressing amyloid-β with the extracts resulted in a reduced number of peptide aggregates in the head region of the worms and alleviated toxicity of amyloid-β, observable through the degree of paralysed animals. The mid-polar extracts (40 and 50 % ethanol) turned out be the most active, decreasing the plaque number by 21 % and delaying the amyloid-β-induced paralysis by up to 3.5 h. The more lipophilic extract fractions exhibited higher activity than the hydrophilic ones.
Discussion. Sideritis scardica extracts demonstrated pharmacological activity against characteristics of Alzheimer's disease also in C. elegans, supporting current efforts to assess its potential for the treatment of cognitive decline. The active principle as well as the mode of action needs to be investigated in more detail.
Background. Beyond its traditional uses in the Balkan area, Sideritis scardica (known as Greek mountain tea, Lamiaceae) is currently extensively investigated for its pharmacological activity in the central nervous system. Antidepressant, psychostimulating, cognition-enhancing and neuroprotective properties have been described. In this study, we tested hydroalcoholic extracts of S. scardica for their potential to counteract amyloid-β toxicity and aggregation, which plays a crucial role in the pathogenesis of Alzheimer's disease.Methods. For this purpose, we have chosen the nematode Caenorhabditis elegans, which is used as a model organism for neurodegenerative diseases. The concentration of different polyphenols in extracts prepared from water, 20, 40, 50, and 70 % ethanol was analysed by HPLC. Additionally, polar and unpolar fractions were prepared from the 40 % ethanolic extract and phytochemically analysed.Results. Essentially, the contents of all measured constituents increased with the lipophilicity of the extraction solvents. Treatment of transgenic C. elegans strains expressing amyloid-β with the extracts resulted in a reduced number of peptide aggregates in the head region of the worms and alleviated toxicity of amyloid-β, observable through the degree of paralysed animals. The mid-polar extracts (40 and 50 % ethanol) turned out be the most active, decreasing the plaque number by 21 % and delaying the amyloid-β-induced paralysis by up to 3.5 h. The more lipophilic extract fractions exhibited higher activity than the hydrophilic ones.Discussion.Sideritis scardica extracts demonstrated pharmacological activity against characteristics of Alzheimer's disease also in C. elegans, supporting current efforts to assess its potential for the treatment of cognitive decline. The active principle as well as the mode of action needs to be investigated in more detail.Four simple ways to increase power without increasing the sample sizehttps://peerj.com/preprints/33632017-10-232017-10-23Stanley E Lazic
Underpowered experiments have three problems: the probability of a false positive result is higher, true effects are harder to detect, and the true effects that are detected tend to have inflated effect sizes. Many biology experiments are underpowered and recent calls to change the traditional 0.05 significance threshold to a more stringent value of 0.005 will further reduce the power of the average experiment. Increasing power by increasing the sample size is often the only option considered, but more samples increases costs, makes the experiment harder to conduct, and is contrary to the 3Rs principles for animal research. We show how the design of an experiment and some analytical decisions can have a surprisingly large effect on power.
Underpowered experiments have three problems: the probability of a false positive result is higher, true effects are harder to detect, and the true effects that are detected tend to have inflated effect sizes. Many biology experiments are underpowered and recent calls to change the traditional 0.05 significance threshold to a more stringent value of 0.005 will further reduce the power of the average experiment. Increasing power by increasing the sample size is often the only option considered, but more samples increases costs, makes the experiment harder to conduct, and is contrary to the 3Rs principles for animal research. We show how the design of an experiment and some analytical decisions can have a surprisingly large effect on power.