搜索结果：Synergy

Abstract Background This study aimed to examine the effect of pool walking on renal function in pregnant women. Methods Fifteen pregnant women (mean gestational age, 37.8 weeks) walked in a pool (depth 1.3 m) for 1 h. A few days later, they walked on a street for 1 h. Within each activity, the starting and ending levels of plasma renin activity (PRA) and serum aldosterone (SA) were compared using paired t-test. Total urine volume, creatinine clearance, and change in PRA levels between each activity were compared by t-test. Regression coefficients for total urine volume and creatinine clearance during pool walking were estimated by linear regression and additionally controlled for the change in PRA levels. Land walking served as the reference group. Results Within each activity, the renin-angiotensin-aldosterone levels were suppressed during pool walking: the mean starting and ending values of PRA and SA were 6.8 vs. 5.5 ng/mL/h (p=0.002) and 654 vs. 473 pg/mL (p=0.02), respectively. Compared to land walking, the decrease in PRA level was more evident in pool walking (−1.27 vs. 0.81 ng/mL/h, p=0.004), resulting in higher total urine volume and creatinine clearance in pool walking (both p Conclusions Pool walking may temporarily improve renal function in pregnant women, partly through the suppressed renin-angiotensin-aldosterone system. Clinical Trial Registration URL: https://upload.umin.ac.jp/cgi-bin/ctr/ctr_view_reg.cgi?recptno=10618 Unique Identifier: UMI09051

Motivation: While drug combination therapies are a well-established concept in cancer treatment, identifying novel synergistic combinations is challenging due to the size of combinatorial space. However, computational approaches have emerged as a time- and cost-efficient way to prioritize combinations to test, based on recently available large-scale combination screening data. Recently, Deep Learning has had an impact in many research areas by achieving new state-of-the-art model performance. However, Deep Learning has not yet been applied to drug synergy prediction, which is the approach we present here, termed DeepSynergy. DeepSynergy uses chemical and genomic information as input information, a normalization strategy to account for input data heterogeneity, and conical layers to model drug synergies. Results: DeepSynergy was compared to other machine learning methods such as Gradient Boosting Machines, Random Forests, Support Vector Machines and Elastic Nets on the largest publicly available synergy dataset with respect to mean squared error. DeepSynergy significantly outperformed the other methods with an improvement of 7.2% over the second best method at the prediction of novel drug combinations within the space of explored drugs and cell lines. At this task, the mean Pearson correlation coefficient between the measured and the predicted values of DeepSynergy was 0.73. Applying DeepSynergy for classification of these novel drug combinations resulted in a high predictive performance of an AUC of 0.90. Furthermore, we found that all compared methods exhibit low predictive performance when extrapolating to unexplored drugs or cell lines, which we suggest is due to limitations in the size and diversity of the dataset. We envision that DeepSynergy could be a valuable tool for selecting novel synergistic drug combinations. Availability and implementation: DeepSynergy is available via www.bioinf.jku.at/software/DeepSynergy. Contact: klambauer@bioinf.jku.at. Supplementary information: Supplementary data are available at Bioinformatics online.

Cocktail effects and synergistic interactions of chemicals in mixtures are an area of great concern to both the public and regulatory authorities. The main concern is whether some chemicals can enhance the effect of other chemicals, so that they jointly exert a larger effect than predicted. This phenomenon is called synergy. Here we present a review of the scientific literature on three main groups of environmentally relevant chemical toxicants: pesticides, metal ions and antifouling compounds. The aim of the review is to determine 1) the frequency of synergy, 2) the extent of synergy, 3) whether any particular groups or classes of chemicals tend to induce synergy, and 4) which physiological mechanisms might be responsible for this synergy. Synergy is here defined as mixtures with minimum two-fold difference between observed and predicted effect concentrations using Concentration Addition (CA) as a reference model and including both lethal and sub-lethal endpoints. The results showed that synergy occurred in 7%, 3% and 26% of the 194, 21 and 136 binary pesticide, metal and antifoulants mixtures included in the data compilation on frequency. The difference between observed and predicted effect concentrations was rarely more than 10-fold. For pesticides, synergistic mixtures included cholinesterase inhibitors or azole fungicides in 95% of 69 described cases. Both groups of pesticides are known to interfere with metabolic degradation of other xenobiotics. For the four synergistic metal and 47 synergistic antifoulant mixtures the pattern in terms of chemical groups inducing synergy was less clear. Hypotheses in terms of mechanisms governing these interactions are discussed. It was concluded that true synergistic interactions between chemicals are rare and often occur at high concentrations. Addressing the cumulative rather than synergistic effect of co-occurring chemicals, using standard models as CA, is therefore regarded as the most important step in the risk assessment of chemical cocktails.

Many advertisers adopt the integrated marketing communications perspective that emphasizes the importance of synergy in planning multimedia activities. However, the role of synergy in multimedia communications is not well understood. Thus, the authors investigate the theoretical and empirical effects of synergy by extending a commonly used dynamic advertising model to multimedia environments. They illustrate how advertisers can estimate and infer the effectiveness of and synergy among multimedia communications by applying Kalman filtering methodology. Using market data on Dockers brand advertising, the authors first calibrate the extended model to establish the presence of synergy between television and print advertisements in consumer markets. Second, they derive theoretical propositions to understand the impact of synergy on media budget, media mix, and advertising carryover. One of the propositions reveals that as synergy increases, advertisers should not only increase the media budget but also allocate more funds to the less effective activity. The authors also discuss the implications for advertising overspending. Finally, the authors generalize the model to include multiple media, differential carryover, and asymmetrical synergy, and they identify topics for further research.

SynergyFinder (https://synergyfinder.fimm.fi) is a stand-alone web-application for interactive analysis and visualization of drug combination screening data. Since its first release in 2017, SynergyFinder has become a widely used web-tool both for the discovery of novel synergistic drug combinations in pre-clinical model systems (e.g. cell lines or primary patient-derived cells), and for better understanding of mechanisms of combination treatment efficacy or resistance. Here, we describe the latest version of SynergyFinder (release 2.0), which has extensively been upgraded through the addition of novel features supporting especially higher-order combination data analytics and exploratory visualization of multi-drug synergy patterns, along with automated outlier detection procedure, extended curve-fitting functionality and statistical analysis of replicate measurements. A number of additional improvements were also implemented based on the user requests, including new visualization and export options, updated user interface, as well as enhanced stability and performance of the web-tool. With these improvements, SynergyFinder 2.0 is expected to greatly extend its potential applications in various areas of multi-drug combinatorial screening and precision medicine.

Abstract Acquisitions, in general, have been demonstrated to create economic value. The intuitive reason underlying this value creation stems either from an ability to reduce costs of the combined entity, an ability to charge higher prices, or both. Current research in the area attributes these abilities to an opportunity to utilize a specialized resource. Our focus in this study is to compare three broad classes of resources that contribute to the creation of value. Following the conventional wisdom, these resources are classified as cost of capital related (resulting in financial synergy), cost of production related (resulting in operational synergy), and price related (resulting in collusive synergy). Given the limitations of our sample and research design, we find that collusive synergy is, on average, associated with the highest value. Further, the resources behind financial synergy tend to create more value than the resources behind operational synergy.

Mergers and acquisitions are complex events in organizational life for which we have incomplete understanding, in part because researchers have tended to consider only partial explanations of them. The authors addressed that problem by developing a conceptual framework that integrates theoretical perspectives from economics, finance, and especially strategy, organization theory, and human resource management to offer a broader process-oriented integrative model. The integrative model explicitly describes how synergy realization is a function of the similarity and complementarity of the two merging businesses (combination potential), the extent of interaction and coordination during the organizational integration process, and the lack of employee resistance to the combined entity. The approach differs from traditional methods of studying mergers and acquisitions in three ways: (1) the success of a merger or acquisition is gauged by the degree of synergy realization rather than more removed and potentially ambiguous criteria such as accounting or market returns; (2) the key attribute of combination potential is conceptualized not only in terms of the similarities present across businesses, as in most studies of mergers and acquisitions, but also in terms of the production and marketing complementarities between the two businesses; and (3) the data are derived from a case survey method that combines the richness of in-depth case studies with the breadth and generalizability of large-sample empirical investigations. The framework was tested empirically across a sample of 61 mergers and acquisitions. The extent to which a merger or acquisition resulted in synergistic benefits was related to the strategic potential of the combination, the degree of organizational integration after the deal was completed, and the lack of employee resistance to the integration of the joining firms. Furthermore, the analysis revealed that (1) independent of any similarities across joining firms, the presence of complementary operations increased the probability of acquisition success by boosting synergy realization, (2) organizational integration was the single most important factor in explaining synergy realization, even to the extent that M&As with high combination potential were significantly more successful when coupled with high organizational integration than when integration efforts were less forceful, and (3) mergers and acquisitions that were dependent on gains from combining similar production and marketing operations tended to elicit more resistance from employees than M&As focused on realizing complementary benefits. Overall, the findings provide strong support for an integrative theory of mergers and acquisitions.

Tumoricidal photodynamic (PDT) and photothermal (PTT) therapies harness light to eliminate cancer cells with spatiotemporal precision by either generating reactive oxygen species or increasing temperature. Great strides have been made in understanding biological effects of PDT and PTT at the cellular, vascular and tumor microenvironmental levels, as well as translating both modalities in the clinic. Emerging evidence suggests that PDT and PTT may synergize due to their different mechanisms of action, and their nonoverlapping toxicity profiles make such combination potentially efficacious. Moreover, PDT/PTT combinations have gained momentum in recent years due to the development of multimodal nanoplatforms that simultaneously incorporate photodynamically- and photothermally active agents. In this review, we discuss how combining PDT and PTT can address the limitations of each modality alone and enhance treatment safety and efficacy. We provide an overview of recent literature featuring dual PDT/PTT nanoparticles and analyze the strengths and limitations of various nanoparticle design strategies. We also detail how treatment sequence and dose may affect cellular states, tumor pathophysiology and drug delivery, ultimately shaping the treatment response. Lastly, we analyze common experimental design pitfalls that complicate preclinical assessment of PDT/PTT combinations and propose rational guidelines to elucidate the mechanisms underlying PDT/PTT interactions.

The standard checkerboard titration for detecting synergy between antibiotics is practicable for combinations of two antibiotics, laborious for combinations of three, and not feasible for combinations of four or more. Nevertheless, methods for testing of combinations of several antibiotics are urgently needed because some combinations might be superior to those in use and enable the successful treatment of infections resistant to current therapy. A simple method for measurement of synergy (or antagonism) with combinations of any number of agents has been developed which requires less effort than the standard checkerboard titration of two agents. With this method, the concentrations of each of n agents producing some specified effect (such as minimal inhibitory concentration or minimal bactericidal concentration) are determined. A reference combination made up of 1/n of each of these concentrations is titrated to find a dilution that produces the specified effect. The degree of dilution required is equal to the sum of the fractional inhibitory concentrations (concentration of each agent in combination/concentration of each agent alone) as conventionally determined by checkerboard titrations; sums of less than 1, 1, and greater than 1 indicate synergy, additivity, and antagonism, respectively.

Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL(-1) . They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant. http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Recent advancements in the periodontal research field are consistent with a new model of pathogenesis according to which periodontitis is initiated by a synergistic and dysbiotic microbial community rather than by select 'periopathogens', such as the 'red complex'. In this polymicrobial synergy, different members or specific gene combinations within the community fulfill distinct roles that converge to shape and stabilize a disease-provoking microbiota. One of the core requirements for a potentially pathogenic community to arise involves the capacity of certain species, termed 'keystone pathogens', to modulate the host response in ways that impair immune surveillance and tip the balance from homeostasis to dysbiosis. Keystone pathogens also elevate the virulence of the entire microbial community through interactive communication with accessory pathogens. Other important core functions for pathogenicity require the expression of diverse molecules (e.g. appropriate adhesins, cognate receptors, proteolytic enzymes and proinflammatory surface structures/ligands), which in combination act as community virulence factors to nutritionally sustain a heterotypic, compatible and proinflammatory microbial community that elicits a non-resolving and tissue-destructive host response. On the basis of the fundamental concepts underlying this model of periodontal pathogenesis, that is, polymicrobial synergy and dysbiosis, we term it the PSD model.

The substantial interest and investment in health partnerships in the United States is based on the assumption that collaboration is more effective in achieving health and health system goals than efforts carried out by single agents. A clear conceptualization of the mechanism that accounts for the collaborative advantage, and a way to measure it are needed to test this assumption and to strengthen the capacity of partnerships to realize the full potential of collaboration. The mechanism that gives collaboration its unique advantage is synergy. A framework for operationalizing and assessing partnership synergy, and for identifying its likely determinants, can be used to address critical policy, evaluation, and management issues related to collaboration.

Abstract Adhering hydrogels to various materials is fundamental to a large array of established and emerging applications. The last few years have seen transformative advances in achieving strong hydrogel adhesion, which is a supramolecular phenomenon. Two adherends connect through covalent bonds, noncovalent complexes, polymer chains, polymer networks, or nanoparticles. Separating the adherends dissipates energy through cascading events across length scales, including bond cleavage, chain retraction, and bulk hysteresis. A unifying principle has emerged: strong hydrogel adhesion requires the synergy of chemistry of bonds, topology of connection, and mechanics of dissipation. This synergy characterizes hydrogel adhesion to various materials (another hydrogel, tissue, elastomer, plastic, metal, glass, and ceramic) in various operations (cast, coat, print, attach, pierce, and glue). Strong adhesion can be made permanent, reversible, degradable, or on‐demand detachable. The development of hydrogel adhesion and its applications adheres disciplines, discovers interlinks, and forges cohesion. Discussed throughout the review are immediate opportunities for fundamental studies and practical applications.

How the CNS selects the appropriate muscle patterns to achieve a behavioral goal is an open question. To gain insight into this process, we characterized the spatiotemporal organization of the muscle patterns for fast-reaching movements. We recorded electromyographic activity from up to 19 shoulder and arm muscles during point-to-point movements between a central location and 8 peripheral targets in each of 2 vertical planes. We used an optimization algorithm to identify a set of time-varying muscle synergies, i.e., the coordinated activations of groups of muscles with specific time-varying profiles. For each one of nine subjects, we extracted four or five synergies whose combinations, after scaling in amplitude and shifting in time each synergy independently for each movement condition, explained 73-82% of the data variation. We then tested whether these synergies could reconstruct the muscle patterns for point-to-point movements with different loads or forearm postures and for reversal and via-point movements. We found that reconstruction accuracy remained high, indicating generalization across these conditions. Finally, the synergy amplitude coefficients were directionally tuned according to a cosine function with a preferred direction that showed a smaller variability with changes of load, posture, and endpoint than the preferred direction of individual muscles. Thus the complex spatiotemporal characteristics of the muscles patterns for reaching were captured by the combinations of a small number of components, suggesting that the mechanisms involved in the generation of the muscle patterns exploit this low dimensionality to simplify control.

Our “stakeholder synergy” perspective identifies new value creation opportunities that are especially effective strategically because a single strategic action (1) increases different types of value for two or more essential stakeholder groups simultaneously, and (2) does not reduce the value already received by any other essential stakeholder group. This result is obtainable because multiple potential sources of value creation exist for each essential stakeholder group. Actions that meet these criteria increase the size of the value “pie” available for essential stakeholder groups, and thereby serve to attract exceptional stakeholders and obtain their increasing effort and commitment. The stakeholder synergy perspective extends stakeholder theory further into the strategy realm, and offers insights for realizing broader value creation that is more likely to produce sustainable competitive advantage . Copyright © 2014 John Wiley & Sons, Ltd.

This brief perspective article focuses on the most common errors and pitfalls, as well as the do's and don'ts in drug combination studies, in terms of experimental design, data acquisition, data interpretation, and computerized simulation. The Chou-Talalay method for drug combination is based on the median-effect equation, derived from the mass-action law principle, which is the unified theory that provides the common link between single entity and multiple entities, and first order and higher order dynamics. This general equation encompasses the Michaelis-Menten, Hill, Henderson-Hasselbalch, and Scatchard equations in biochemistry and biophysics. The resulting combination index (CI) theorem of Chou-Talalay offers quantitative definition for additive effect (CI = 1), synergism (CI < 1), and antagonism (CI > 1) in drug combinations. This theory also provides algorithms for automated computer simulation for synergism and/or antagonism at any effect and dose level, as shown in the CI plot and isobologram, respectively.

Metals can be processed to reach ultra-high strength, but usually at a drastic loss of ductility. Here, we review recent advances in overcoming this tradeoff, by purposely deploying heterogeneous nanostructures in an otherwise single-phase metal. Several structural designs are being explored, including bimodal, harmonic, lamellar, gradient, domain-dispersed, and hierarchical nanostructures. These seemingly distinct tactics share a unifying design principle in that the intentional structural heterogeneities induce non-homogeneous plastic deformation, and the nanometer-scale features dictate steep strain gradients, thereby enhancing strain hardening and consequently uniform tensile ductility at high flow stresses. Moreover, these heterogeneous nanostructures in metals play a role similar to multiple phases in complex alloys, functionally graded materials and composites, sharing common material design and mechanics principles. Our review advocates this broad vision to help guide future innovations towards a synergy between high strength and high ductility, through highlighting several recent designs as well as identifying outstanding challenges and opportunities.

This article delineates parallel frameworks that grew out of the research on risk and resilience over the past four decades, a framework for research and a framework for practice, and then discusses the promise of an emerging synthesis. The research framework defined the meaning, models, and methods that successfully guided four waves of research to date on the nature and processes involved in human resilience. The applied framework emerged in response to urgent needs of children and families faced by adversity and those charged with helping them, resulting in guidelines for translating the unfolding but incomplete research evidence into action. The application of a resilience approach transformed practice in many fields concerned with promoting resilience in people at risk for problems, revolutionizing the mission, models, measures, and methods of practice to align with the emphasis on positive adaptation and strengths defining a resilience-based approach. Yet these interventions rarely translated back to inform and refine resilience theory in ways that would accelerate progress to promote resilience more effectively. The concluding section on translational synergy discusses the potential for a synthesis of basic and applied resilience frameworks as the next steps toward realizing the original objective and promise of resilience science.

Understanding the role of other sexually transmitted diseases (STDs) in the transmission of human immunodeficiency virus (HIV), the role of STDs in progression of HIV disease, and the role of HIV infection in alterations of natural history, diagnosis, or response to therapy of STDs is critical to the development of optimal strategies for HIV control. One hundred sixty-three studies on the interrelationships between HIV infection and other STDs were examined. Of 75 studies on the role of STDs in HIV transmission, the 15 analyses of examination or laboratory evidence of STDs adjusted for sexual behavior showed that both ulcerative and nonulcerative STDs increase the risk of HIV transmission approximately 3- to 5-fold. Due to limited data, the role of STDs in progression of disease remains unclear. Preliminary data from 83 reports on the impact of HIV infection on STDs suggest that, at a community level, HIV infection may increase the prevalence of some STDs (e.g., genital ulcers). If coinfection with HIV prolongs or augments the infectiousness of individuals with STDs, and if the same STDs facilitate transmission of HIV, these infections may greatly amplify one another. This “epidemiological synergy” may be responsible for the explosive growth of the HIV pandemic in some populations. Effective STD control programs will be essential to HIV prevention in these communities.