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Value in mergers and acquisitions (M&A) derives from the synergistic combination of an acquirer and a target. We advance the existing conceptualization of synergies in three ways. First, we develop...

Solving the problem of antibiotic resistance requires the development of new antimicrobial drugs and/or new therapeutic strategies. A promising strategy to combat resistant pathogens is to combine antimicrobials with different mechanisms of action, since it is more difficult for bacteria to develop resistance against several mechanisms at the same time. Of particular interest are antimicrobial peptides, resistance to which develops much more slowly than to conventional antibiotics. Most of the superbugs that pose a serious threat to human health today are gram-negative. Their outer membrane plays the role of a barrier for antimicrobial agents whose targets are located in the inner membrane or in the cytoplasm of bacteria. Review of research reports over the past seven years suggests that combining polymyxins with nisin results in a synergistic or additive antimicrobial effect. Polymyxin- nisin combinations have been shown to be effective against clinically significant gram-negative pathogens such as Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli. The probable mechanism of synergy consists in providing polymyxin due to the violation of the integrity of the outer membrane of nisin access to the target on the inner membrane (lipid II) with the subsequent realization of its antimicrobial potential. The synergistic interaction of an antibiotic with a lantibiotic allows to reduce the concentration of the antibiotic, thereby reducing the likelihood of developing toxic effects. The additive effect also has an important positive value, as it is accompanied by a decrease of antibiotic`s minimal inhibition concentration and indicates the possibility of restoring the sensitivity of bacteria to it. Therefore, synergistic polymyxin-nisin combinations deserve further study and application in clinical practice., {"references":["1. \tBreijyeh, Z.; Jubeh, B.; Karaman, R. Resistance of Gram-Negative Bacteria to Current Antibacterial Agents and Approaches to Resolve It. Molecules 2020, 25 (6), 1340. https://doi.org/10.3390/molecules25061340.","2. \tChurch, N. A.; McKillip, J. L. Antibiotic Resistance Crisis: Challenges and Imperatives. Biologia (Bratisl.) 2021, 76 (5), 1535–1550. https://doi.org/10.1007/s11756-021-00697-x.","3. \tTacconelli, E.; Carrara, E.; Savoldi, A.; et al. Discovery, Research, and Development of New Antibiotics: The WHO Priority List of Antibiotic-Resistant Bacteria and Tuberculosis. Lancet Infect. Dis. 2018, 18 (3), 318–327. https://doi.org/10.1016/S1473-3099(17)30753-3.","4. \tWHO. Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development of New Antibiotics (WHO, 2017).","5. \tChahine, E. B.; Dougherty, J. A.; Thornby, K.-A.; et al. Antibiotic Approvals in the Last Decade: Are We Keeping Up With Resistance? Ann. Pharmacother. 2022, 56 (4), 441–462. https://doi.org/10.1177/10600280211031390.","6. \tLewies, A.; Plessis, L. H. D.; Wentzel, J. F. The Cytotoxic, Antimicrobial and Anticancer Properties of the Antimicrobial Peptide Nisin Z Alone and in Combination with Conventional Treatments. In Cytotoxicity; Çelik, T. A., Ed.; InTech, 2018. https://doi.org/10.5772/intechopen.71927.","7. \tSoltani, S.; Hammami, R.; Cotter, P. D.; et al. Bacteriocins as a New Generation of Antimicrobials: Toxicity Aspects and Regulations. FEMS Microbiol. Rev. 2021, 45 (1), fuaa039. https://doi.org/10.1093/femsre/fuaa039.","8. \tJahangiri, A.; Neshani, A.; Mirhosseini, S. A.; et al. Synergistic Effect of Two Antimicrobial Peptides, Nisin and P10 with Conventional Antibiotics against Extensively Drug-Resistant Acinetobacter Baumannii and Colistin-Resistant Pseudomonas Aeruginosa Isolates. Microb. 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Colistin Resistance in Enterobacterales Strains – A Current View. Pol. J. Microbiol. 2019, 68 (4), 417–427. https://doi.org/10.33073/pjm-2019-055.","21. \tNation, R.; Rigatto, M.; Falci, D.; et al. Polymyxin Acute Kidney Injury: Dosing and Other Strategies to Reduce Toxicity. Antibiotics 2019, 8 (1), 24. https://doi.org/10.3390/antibiotics8010024.","22. \tNang, S. C.; Li, J.; Velkov, T. The Rise and Spread of Mcr Plasmid-Mediated Polymyxin Resistance. Crit. Rev. Microbiol. 2019, 45 (2), 131–161. https://doi.org/10.1080/1040841X.2018.1492902.","23. \tBertani, B.; Ruiz, N. Function and Biogenesis of Lipopolysaccharides. EcoSal Plus 2018, 8 (1), ecosalplus.ESP-0001-2018. https://doi.org/10.1128/ecosalplus.ESP-0001-2018.","24. \tSun, J.; Rutherford, S. T.; Silhavy, T. J.; et al. Physical Properties of the Bacterial Outer Membrane. Nat. Rev. Microbiol. 2022, 20 (4), 236–248. https://doi.org/10.1038/s41579-021-00638-0.","25. \tLi, Z.; Velkov, T. Polymyxins: Mode of Action. In Polymyxin Antibiotics: From Laboratory Bench to Bedside; Li, J., Nation, R. L., Kaye, K. S., Eds.; Springer International Publishing: Cham, 2019; Vol. 1145, pp 37–54. https://doi.org/10.1007/978-3-030-16373-0_4.","26. \tKhadka, N. K.; Aryal, C. M.; Pan, J. Lipopolysaccharide-Dependent Membrane Permeation and Lipid Clustering Caused by Cyclic Lipopeptide Colistin. ACS Omega 2018, 3 (12), 17828–17834. https://doi.org/10.1021/acsomega.8b02260.","27. \tSi, W.; Wang, L.; Usongo, V.; et al. Colistin Induces S. Aureus Susceptibility to Bacitracin. Front. Microbiol. 2018, 9, 2805. https://doi.org/10.3389/fmicb.2018.02805.","28. \tLima, M. R.; Ferreira, G. F.; Nunes Neto, W. R.; et al. Evaluation of the Interaction between Polymyxin B and Pseudomonas Aeruginosa Biofilm and Planktonic Cells: Reactive Oxygen Species Induction and Zeta Potential. BMC Microbiol. 2019, 19 (1), 115. https://doi.org/10.1186/s12866-019-1485-8.","29. \tYu, Z.; Zhu, Y.; Fu, J.; et al. Enhanced NADH Metabolism Involves Colistin-Induced Killing of Bacillus Subtilis and Paenibacillus Polymyxa. Molecules 2019, 24 (3), 387. https://doi.org/10.3390/molecules24030387.","30. \tKoen, N.; van Breda, S. V.; Loots, D. T. Elucidating the Antimicrobial Mechanisms of Colistin Sulfate on Mycobacterium Tuberculosis Using Metabolomics. Tuberculosis 2018, 111, 14–19. https://doi.org/10.1016/j.tube.2018.05.001.","31. \tThe European Committee on Antimicrobial Susceptibility Testing.","32. \tClinical Laboratory and Standards Instiute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing, 30th e.","33. \tGai, Z.; Samodelov, S.; Kullak-Ublick, G.; et al. Molecular Mechanisms of Colistin-Induced Nephrotoxicity. Molecules 2019, 24 (3), 653. https://doi.org/10.3390/molecules24030653.","34. \tVaara, M. New Polymyxin Derivatives That Display Improved Efficacy in Animal Infection Models as Compared to Polymyxin B and Colistin. Med. Res. Rev. 2018, 38 (5), 1661–1673. https://doi.org/10.1002/med.21494.","35. \tGallardo-Godoy, A.; Hansford, K.; Muldoon, C.; et al. Structure-Function Studies of Polymyxin B Lipononapeptides. Molecules 2019, 24 (3), 553. https://doi.org/10.3390/molecules24030553.","36. \tBrennan-Krohn, T.; Pironti, A.; Kirby, J. E. Synergistic Activity of Colistin-Containing Combinations against Colistin-Resistant Enterobacteriaceae. Antimicrob. Agents Chemother. 2018, 62 (10), e00873-18. https://doi.org/10.1128/AAC.00873-18.","37. \tMacNair, C. R.; Stokes, J. M.; Carfrae, L. A.; et al. Overcoming Mcr-1 Mediated Colistin Resistance with Colistin in Combination with Other Antibiotics. Nat. Commun. 2018, 9 (1), 458. https://doi.org/10.1038/s41467-018-02875-z.","38. \tLoose, M.; Naber, K. G.; Hu, Y.; et al. Urinary Bactericidal Activity of Colistin and Azidothymidine Combinations against Mcr-1-Positive Colistin-Resistant Escherichia Coli. Int. J. Antimicrob. Agents 2019, 54 (1), 55–61. https://doi.org/10.1016/j.ijantimicag.2019.04.011.","39. \tTyrrell, J. M.; Aboklaish, A. F.; Walsh, T. R.; et al. The Polymyxin Derivative NAB739 Is Synergistic with Several Antibiotics against Polymyxin-Resistant Strains of Escherichia Coli, Klebsiella Pneumoniae and Acinetobacter Baumannii. Peptides 2019, 112, 149–153. https://doi.org/10.1016/j.peptides.2018.12.006.","40. \tThomas, V. M.; Brown, R. M.; Ashcraft, D. S.; et al. Synergistic Effect between Nisin and Polymyxin B against Pandrug-Resistant and Extensively Drug-Resistant Acinetobacter Baumannii. Int. J. Antimicrob. Agents 2019, 53 (5), 663–668. https://doi.org/10.1016/j.ijantimicag.2019.03.009.","41. \tLewies, A.; Wentzel, J. F.; Jordaan, A.; et al. Interactions of the Antimicrobial Peptide Nisin Z with Conventional Antibiotics and the Use of Nanostructured Lipid Carriers to Enhance Antimicrobial Activity. Int. J. Pharm. 2017, 526 (1–2), 244–253. https://doi.org/10.1016/j.ijpharm.2017.04.071.","42. \tO'Sullivan, J. N.; O'Connor, P. M.; Rea, M. C.; et al. Nisin J, a Novel Natural Nisin Variant, Is Produced by Staphylococcus Capitis Sourced from the Human Skin Microbiota. J. Bacteriol. 2020, 202 (3). https://doi.org/10.1128/JB.00639-19.","43. \tHatziioanou, D.; Gherghisan-Filip, C.; Saalbach, G.; et al. Discovery of a Novel Lantibiotic Nisin O from Blautia Obeum A2-162, Isolated from the Human Gastrointestinal Tract. Microbiology 2017, 163 (9), 1292–1305. https://doi.org/10.1099/mic.0.000515.","44. \tLawrence, G. W.; Garcia-Gutierrez, E.; Walsh, C. J.; et al. Nisin G Is a Novel Nisin Variant Produced by a Gut-Derived Streptococcus Salivarius; preprint; Microbiology, 2022. https://doi.org/10.1101/2022.02.15.480493.","45. \tMeade; Slattery; Garvey. Bacteriocins, Potent Antimicrobial Peptides and the Fight against Multi Drug Resistant Species: Resistance Is Futile? Antibiotics 2020, 9 (1), 32. https://doi.org/10.3390/antibiotics9010032.","46. \tEFSA Panel on Food Additives and Nutrient Sources added to Food (ANS); Younes, M.; Aggett, P.; et al. Safety of Nisin (E 234) as a Food Additive in the Light of New Toxicological Data and the Proposed Extension of Use. EFSA J. 2017, 15 (12). https://doi.org/10.2903/j.efsa.2017.5063.","47. \tBarbosa, A. A. T.; de Melo, M. R.; da Silva, C. M. R.; et al. Nisin Resistance in Gram-Positive Bacteria and Approaches to Circumvent Resistance for Successful Therapeutic Use. Crit. Rev. Microbiol. 2021, 47 (3), 376–385. https://doi.org/10.1080/1040841X.2021.1893264.","48. \tLi, Q.; Montalban-Lopez, M.; Kuipers, O. P. Increasing the Antimicrobial Activity of Nisin-Based Lantibiotics against Gram-Negative Pathogens. Appl. Environ. Microbiol. 2018, 84 (12), e00052-18. https://doi.org/10.1128/AEM.00052-18.","49. \tPrince, A.; Sandhu, P.; Ror, P.; et al. Lipid-II Independent Antimicrobial Mechanism of Nisin Depends On Its Crowding And Degree Of Oligomerization. Sci. Rep. 2016, 6 (1), 37908. https://doi.org/10.1038/srep37908.","50. \tGalván Márquez, I. J.; McKay, B.; Wong, A.; et al. Mode of Action of Nisin on Escherichia Coli. Can. J. Microbiol. 2020, 66 (2), 161–168. https://doi.org/10.1139/cjm-2019-0315.","51. \tJensen, C.; Li, H.; Vestergaard, M.; et al. Nisin Damages the Septal Membrane and Triggers DNA Condensation in Methicillin-Resistant Staphylococcus Aureus. Front. Microbiol. 2020, 11, 1007. https://doi.org/10.3389/fmicb.2020.01007.","52. \tÖzdemir, F. N.; Buzrul, S.; Özdemir, C.; et al. Determination of an Effective Agent Combination Using Nisin against Salmonella Biofilm. Arch. Microbiol. 2022, 204 (3), 167. https://doi.org/10.1007/s00203-022-02766-4.","53. \tChi, H.; Holo, H. Synergistic Antimicrobial Activity Between the Broad Spectrum Bacteriocin Garvicin KS and Nisin, Farnesol and Polymyxin B Against Gram-Positive and Gram-Negative Bacteria. Curr. Microbiol. 2018, 75 (3), 272–277. https://doi.org/10.1007/s00284-017-1375-y.","54. \tField, D.; Seisling, N.; Cotter, P. D.; et al. Synergistic Nisin-Polymyxin Combinations for the Control of Pseudomonas Biofilm Formation. Front. Microbiol. 2016, 7. https://doi.org/10.3389/fmicb.2016.01713.","55. \tMathur, H.; Field, D.; Rea, M. C.; et al. Fighting Biofilms with Lantibiotics and Other Groups of Bacteriocins. Npj Biofilms Microbiomes 2018, 4 (1), 9. https://doi.org/10.1038/s41522-018-0053-6"]}

The natural product family of the fusicoccanes (FCs) has been shown to display anti-cancer activity, especially when combined with established therapeutic agents. FCs stabilize 14-3-3 protein-protein interactions (PPIs). Here, we tested combinations of a small library of FCs with interferon α (IFNα) on different cancer cell lines and report a proteomics approach to identify the specific 14-3-3 PPIs that are induced by IFNα and stabilized by FCs in OVCAR-3 cells. Among the identified 14-3-3 target proteins are THEMIS2, receptor interacting protein kinase 2 (RIPK2), EIF2AK2, and several members of the LDB1 complex. Biophysical and structural biology studies confirm these 14-3-3 PPIs as physical targets of FC stabilization, and transcriptome as well as pathway analyses suggest possible explanations for the observed synergistic effect of IFNα/FC treatment on cancer cells. This study elucidates the polypharmacological effects of FCs in cancer cells and identifies potential targets from the vast interactome of 14-3-3s for therapeutic intervention in oncology.

The advancement and growth of nanotechnology lead to realizing new and novel multi-metallic nanostructures with well-defined sizes and morphology, resulting in an improvement in their performance in various catalytic applications. The trimetallic nanostructured materials are synthesized and designed in different architectures for energy conversion electrocatalysis. The as-synthesized trimetallic nanostructures have found unique physiochemical properties due to the synergistic combination of the three different metals in their structures. A vast array of approaches such as hydrothermal, solvothermal, seed-growth, galvanic replacement reaction, biological, and other methods are employed to synthesize the trimetallic nanostructures. Noteworthy, the trimetallic nanostructures showed better performance and durability in the electrocatalytic fuel cells. In the present review, we provide a comprehensive overview of the recent strategies employed for synthesizing trimetallic nanostructures and their energy-related applications. With a particular focus on hydrogen evolution, alcohol oxidations, oxygen evolution, and others, we highlight the latest achievements in the field.

Most studies of animal coloration focus on spectral colours, which are colours evoked by single peaks within the wavelengths of visible light. It is poorly understood how non-spectral colours (those produced by a combination of reflectance peaks) are produced, despite their potential significance to both animal communication and biomimicry. Moreover, although both pigmentary and structural colour production mechanisms have been well characterized in feathers independently, their interactions have received considerably less attention, despite their potential to broaden the available colour spectrum. Here, we investigate the colour production mechanisms of the purple feathers of the purple-breasted cotinga (Cotinga cotinga). The purple feather colour results from both the coherent scattering of light by a sphere-type nanomatrix of β-keratin and air (spongy layer) in the barbs, which produces a blue–green colour, and the selective absorption of light in the centre of the bird-visible spectrum by the methoxy-carotenoid, cotingin. This unusual combination of carotenoid and nanostructure with a central air vacuole, in the absence of melanin, is a blueprint of a synergistic way to produce a non-spectral colour that would be difficult to achieve with only a single colour production mechanism.

Gliomas and glioblastoma comprise the majority of brain malignancies and are difficult to treat despite standard of care and advances in immunotherapy. The challenges of controlling glioma growth and recurrence involve the uniquely immunosuppressive tumor microenvironment and systemic blunting of immune responses. In addition to highlighting key features of glioma and glioblastoma composition and immunogenicity, this review presents several future directions for immunotherapy, such as vaccines and synergistic combination treatment regimens, to better combat these tumors.

The chiral (salen)Cr(III)/BF3·OEt2 catalytic combination was found to be an effective catalyst for intramolecular Friedel–Crafts cyclization of electron-deficient Morita–Baylis–Hillman adducts. In presence of mild reaction conditions the chiral (salen)Cr(III)/BF3·OEt2 complex affords 2-substituted-1H-indenes from unique substrates of Morita–Baylis–Hillman adducts via an easy operating practical procedure.

In the past three years, the use of combinational chemodynamic therapy (CDT) and photodynamic therapy (PDT) for antitumor treatments has exploded. Combinational antitumor CDT/PDT (C/PDT) brings promises of enhanced efficacy by using synergistic mechanisms.

Introduction: TNF-α/NF-kB signaling pathway plays an important role in promoting the inflammatory process and growth of breast cancer. Accordingly, the aim of the present study was to investigate the synergistic combination effect of endurance exercise with curcumin on breast cancer progression through TNF-α/NF-kB signaling axes in female BALB/c mice with breast cancer. Methods: The design of the present study was experimental. After transplanting 4T1 breast cancer into the right flank of 40 BALB/c mice, all mice were randomly divided into four groups, including endurance training (E), endurance training-curcumin (EC), curcumin (CC), and control (C). Then, E and EC groups (5 days per week) were performed for 5 weeks. Curcumin (6 times per week) was given by gavage to EC and CC groups for five weeks. The intratumoral expression of TNF-α and NF-kβ were measured using the qRT-PCR method. One-way analysis of variance and LSD post hoc test with SPSS version 16 were used for statistical analysis. P< 0.05 was considered statistically significant. Results: A significant decline in cancer growth and the gene expression of NF-kβ and TNF-α was observed in E, CC, and EC compared to the C group (P =0.001). Furthermore, a significant decline in expression of both genes was observed in EC compared with E. Conclusion: Endurance training combined with curcumin supplementation has a more effective role in reducing TNF-α and NF-κβ, and slowing the growth of breast cancer cells when compared with either of other interventions alone.

The insertion of nanoparticles into smart hydrogels can diversify their functionalities by a synergistic combination of the components properties within the hydrogels. While these hybrid systems are attractive to the biomaterials field, careful design and control of their properties are required since the new interactions between the polymer and the nanoparticles can result in changes or the loss of hydrogels stimuli response. In order to understand the physicochemical aspects of the thermoresponsive systems, nanocomposites of poly(N-vinylcaprolactam) (PNVCL) and silica nanoparticles with different sizes and concentrations were synthesized. The UV-vis and DLS techniques showed that the PNVCL has a sharp phase transition at 34 °C, while the nanocomposites have a diffuse transition. The nanocomposites showed an initial coil-globule transition before the phase transition takes place. This was identified by the evolution of the hydrodynamic diameter of the nanocomposite globules before the cloud point temperature (Tcp), which remained constant for PNVCL. This new transition profile can be described by two stages in which microscopic volume transitions occur first, followed by the macroscopic transition that forms the hydrogel. These results show that the proposed nanocomposites can be designed to have tunable stimuli response to smaller temperature variations with the formation of intermediate globule states.

The anti-inflammatory properties of the combination of meloxicam and atypical NSAID N-acetyl-L-proline (Groceprol®) after intragastric administration in a model of carrageenan paw edema in mice were studied. The average effective dose of N-acetyl-L-proline calculated by the regression analysis method in this model was 414 mg/kg, and the average effective dose of meloxicam was 2.85 mg/kg. In the combination in a ratio of 40:1, the activity of the compounds increases significantly, the ED50 of meloxicam decreases to 1 mg/kg, a similar value of N-acetyl-L-proline becomes 43 mg/kg. The same trend was also observed with another mass ratio of components of 20:1. The analysis of the pharmacodynamics of the combination of drugs according to the T. Chou method showed an additive type of interaction, typical for compounds with different mechanisms of primary action. It was established that a combination of N-acetyl-L-proline and meloxicam in the weight ratios of 40:1 and 20:1 demonstrate synergism, allowing to reduce the dose of the components in 2.7–9.6 times as compared with the effect of the drugs individually.The results of the study are the experimental justification for the use of anti-inflammatory synergistic combination of N-acetyl-L-proline and meloxicam.

Combination drug therapies have become an integral part of precision oncology, and while evidence of clinical effectiveness continues to grow, the underlying mechanisms supporting synergy are poorly understood. Immortalized human lymphoblastoid cell lines (LCLs) have been proven as a particularly useful, scalable and low-cost model in pharmacogenetics research, and are suitable for elucidating the molecular mechanisms of synergistic combination therapies. In this review, we cover the advantages of LCLs in synergy pharmacogenomics and consider recent studies providing initial evidence of the utility of LCLs in synergy research. We also discuss several opportunities for LCL-based systems to address gaps in the research through the expansion of testing regimens, assessment of new drug classes and higher-order combinations, and utilization of integrated omics technologies.

The activation of molecular oxygen is a fundamental step in almost all catalytic oxidation reactions. We have studied this topic and the role of surface vacancies for Co3O4(100) films with a synergistic combination of experimental and theoretical methods. We show that the as‐prepared surface is B‐layer terminated and that mild reduction produces oxygen single and double vacancies in this layer. Oxygen adsorption experiments clearly reveal different superoxide species below room temperature. The superoxide desorbs below ca. 120 K from a vacancy‐free surface and is not active for CO oxidation while superoxide on a surface with oxygen vacancies is stable up to ca. 270 K and can oxidize CO already at the low temperature of 120 K. The vacancies are not refilled by oxygen from the superoxide, which makes them suitable for long‐term operation. Our joint experimental/theoretical effort highlights the relevance of surface vacancies in catalytic oxidation reactions., Activated molecular oxygen (superoxide, O2 −) can oxidize CO already at 120 K on B‐layer terminated Co3O4(100) with oxygen vacancies. This rendered scheme illustrates how a vibrational spectrum of the adsorbed superoxide is recorded with surface action spectroscopy.

Optoacoustic (OA, photoacoustic) imaging capitalizes on the synergistic combination of light excitation and ultrasound detection to empower biological and clinical investigations with rich optical contrast while effectively bridging the gap between micro and macroscopic imaging realms. State-of-the-art OA embodiments consistently provide images at micron-scale resolution through superficial tissue layers by means of focused illumination that can be smoothly exchanged for acoustic-resolution images at diffuse light depths of several millimetres to centimetres via ultrasound beamforming or tomographic reconstruction. Taken together, this unique multi-scale imaging capacity opens unprecedented capabilities for high-resolution in vivo interrogations of the skin at scalable depths. Moreover, diverse anatomical and functional information is retrieved via dynamic mapping of endogenous chromophores such as haemoglobin, melanin, lipids, collagen, water and others. This, along with the use of non-ionizing radiation, facilitates a clinical translation of the OA modalities. We review recent progress in OA imaging of the skin in preclinical and clinical studies exploiting the rich contrast provided by endogenous substances in tissues. The imaging capabilities of existing approaches are discussed in the context of initial translational studies on skin cancer, inflammatory skin diseases, wounds and other conditions.

Supramolecular drug self-delivery systems (SDSDSs) involving active drugs as building blocks linked by supramolecular interactions have been well defined as an advanced chemotherapy strategy. However, the lack of detecting release of drugs from SDSDSs at specific tumor sites inevitably leads to unsatisfactory therapeutic effects, owing to the lack of information regarding the administration of these drugs. In this work, predesigned platinum-containing supramolecular drug self-delivery nanomicelles (SDSDNMs) were employed to synchronously realize drug monitoring by computed tomography imaging, immediately reflecting the evolution of drug release and real-time treatment at the tumor site. The appropriate administration dosage (1.2 mg mL-1,100 μL) and the injection interval (once every 3 days) needed to guide the antitumor activity of SDSDNMs were then defined, thereby attaining the aim of efficient synergistic combination chemotherapy. In vivo tumor inhibition and histological analyses showed that SDSDNMs exhibited a strong tumor inhibition effect and good safety with respect to normal organs. Such a supramolecular drug self-delivery strategy with monitored functions may offer new potential opportunities for application in the field of synergistic combination chemotherapy.

The promotional effects of sodium on Fe5C2 catalysts for CO2 hydrogenation were systematically investigated by a synergistic combination of density functional theory (DFT) calculations and experime...

Background The bio-preservation of food products using various natural ingredients and metabolites from various types of beneficial microorganisms released during targeted fermentation is a method that simultaneously has a preservative effect on the food product and provides a model of its composition in order to ensure its functional and health properties. This double effect can be achieved by incorporating ingredients with proven preservative and functional effects into the food product, such as essential oils from various plant species and probiotic bacteria. The aim of the present research was to study the synergistic effect of selected probiotic lactic acid bacteria (LAB) and essential oils with high antimicrobial activity against pathogenic and spoilage microorganisms for the bio-preservation of chocolate mousse food emulsion. Methods The susceptibility of the selected probiotic strain Lactobacillus plantarum D2 to different concentrations of the selected lemon or grapefruit essential oil was examined using the disc-diffusion method. Nine chocolate mousse variants were prepared with the inclusion of free or immobilized cells of the probiotic strain L. plantarum D2 and/or lemon or grapefruit zest essential oils. The chocolate mousse variants were stored for 20 days in refrigerated conditions, and changes in the concentration of viable lactobacilli cells, the pH and the microbiological purity were monitored in accordance with standard requirements by taking samples on the 0th, 5th, 10th, 15th, and 20th days of storage. An organoleptic evaluation of the chocolate variants was performed on the 0th day. Results Concentrations of up to 1% lemon or grapefruit essential oil did not affect the growth of the probiotic strain L. plantarum D2, which revealed opportunities for their joint application for the bio-preservation of food emulsions. The obtained chocolate mousse variants were characterized by preserved organoleptic characteristics and microbiological safety. Free or immobilized probiotic L. plantarum D2 cells applied alone or in combination with lemon or grapefruit essential oils provided bio-preservation of the food emulsions, maintaining a high concentration of viable cells (106-107 cfu/g) during storage under refrigerated conditions for 20 days. Conclusions The combined application of free or immobilized probiotic LAB and lemon or grapefruit essential oils resulted in better bio-preservation results than in the use of probiotic LAB or essential oils alone, thus suggesting a synergistic effect between the two bio-preservative agents. Moreover, the obtained chocolate mousse emulsions can be classified as functional foods and the chocolate mousse food matrix can successfully be used as a vehicle for delivery of probiotic LAB to a wide range of food consumers. The obtained results and the developed successful bio-preservation strategy for the production of chocolate mousse food emulsions would provide grounds for the future selection of other probiotic lactobacilli strains, essential oils and synergistic combinations of them for the development of successful bio-preservation strategies for other types of food and beverage products.

Fueled by CRISPR-Cas technology, a synergistic combination of advances in genomics, synthetic biology and bioinformatics have ushered in an era of genome-guided natural product discovery and engineering. As a versatile, programmable DNA targeting tool, CRISPR-Cas is increasingly employed to accelerate host and pathway engineering of actinomycetes, which are prolific producers of bioactive natural products. Here, we discuss the current state of the art, challenges and opportunities of CRISPR-Cas strategies to discover, diversify and improve the production of natural products from actinomycetes. Special emphasis is placed on the rapidly expanding CRISPR-Cas toolboxes for genome editing of non-Streptomyces actinomycetes.

Microbially influenced corrosion (MIC) is responsible for significant damage to major marine infrastructure worldwide. While the microbes responsible for MIC typically exist in the environment in a synergistic combination of different species, the vast majority of laboratory-based MIC experiments are performed with single microbial pure cultures. In this work, marine grade steel was exposed to a single sulfate reducing bacterium (SRB, Desulfovibrio desulfuricans) and various combinations of bacteria (both pure cultures and mixed communities), and the steel corrosion studied. Differences in the microbial biofilm composition and succession, steel weight loss and pitting attack were observed for the various test configurations studied. The sulfate reduction phenotype was successfully shown in half-strength marine broth for both single and mixed communities. The highest corrosion according to steel weight loss and pitting, was recorded in the tests with D. desulfuricans alone when incubated in a nominally aerobic environment. The multispecies microbial consortia yielded lower general corrosion rates compared to D. desulfuricans or for the uninoculated control.

The understanding of drug-carrier interactions is essential for the design and applications of metal-organic framework (MOF)-based drug delivery systems. While such drug-carrier interactions can be fundamentally different for MOFs with or without defects. In this work, we revealed that the defects in MOFs play a key role in the loading of many pharmaceuticals with phosphate or phosphonate groups. The host-guest interaction is dominated by the Coulombic attraction between phosphate/phosphonate groups and defect sites and it strongly enhances the loading capacity. For similar molecules without a phosphate/phosphonate group or for MOF without defects, the loading capacity is greatly reduced. We employed solid-state nuclear magnetic resonance (NMR) and molecular simulations to elucidate the drug-carrier interaction mechanisms. Through a synergistic combination of experimental and theoretical analyses, the docking conformations of pharmaceuticals at the defects have been revealed.

Background Laser hair reduction is one of the most common laser procedures in dermatology. Laser systems available are Ruby at 694 nm, Alexandrite (755 nm), Diode (810nm), and Nd:YAG (1064 nm). Recently, devices presenting a combination of wavelengths have shown to produce high effective hair reduction with no related risks. This study was conducted with the Soprano Ice Platinum (Alma Lasers, GMBH, Germany) that emits a combination of three wavelengths at 755, 810, and 1064 nm in a single pulse. Aims To establish the efficacy and safety of novel triple wavelength laser hair reduction technology in skin types IV to V. Patients and methods This was an investigator initiated, single-center, prospective clinical study conducted between December 2017 and June 2019 with a total of 25 patients (23 female and two male) above 18 years with skin types IV and V, areas included are face, beard, neck, chest, and others. Results Hair reduction was assessed using the physician GAIS (global esthetic improvement scale) score: no results 0% reduction, poor 0%-25% reduction, average 25%-50%, good 50%-75%, and excellent 75%-100%. All 25 patients (mean age 28 years, range 18-52 y/o) completed all six sessions of the study. Conclusion Objective clinical assessment of hair reduction using the physician GAIS score in 90 anatomical sites scores an excellent reduction in 95.5% areas and good reduction in 80% areas. This current study shows that a synergistic combination of three diode laser wavelengths used for hair removal (755, 810, 1064 nm) is effective and safe to use in subjects skin types IV and V for facial and body hair.

Constructing the highly efficient and stable quasi-solid-state even solid-state devices is one of the most significant tendency in the field of quantum dots sensitized solar cells (QDSCs). Herein, highly efficient and stable quasi-solid-state (QS)-QDSCs devices were fabricated via synergistically combining the TiO2-sol interconnecting-modified photoanodes with alginate hydrogel (AH)-assisted electrolyte films. TiO2-sol binding agent could incorporate into the surface and voids of TiO2 particles, which increased the surface area and roughness for QDs loading and induced better connection between the neighboring particles. Meanwhile, the AH-assisted QS-electrolyte films possessed the crosslinking hydrogel network structure and exhibited the perfect interfacial contact with the modified TiO2 surface, thus enhancing the ion transport and redox reaction of polysulfide couple. Benefited from the synergistic effect of TiO2-sol modified photoanodes and alginate hydrogel (AH)-assisted electrolytes, a champion power conversion efficiency (PCE) of 8.87% for model ZnCuInSe (ZCISe) based QS-QDSCs was achieved with an enhancement of near 10% related to that of the devices based the pristine devices (8.01%), and very close to that of liquid-junction QDSCs (9.06%). Moreover, the constructed QS-QDSCs devices exhibit the excellent stability. This work thus provides a facile and effective strategy to achieve the QS-QDSCs devices with both of high efficiency and good stability.

Translation of traditional medicine is moving away from the reductionist approach towards harnessing the synergy of poly-pharmacological phyto-combinations that modulate the activity of target networks of underlying disease phenotypes. Metabolomics enabled the profiling of herbal extracts and formulations in high resolution through LC-MS/MS, GC-MS and NMR providing the possibility of multi-component drug discovery. Phytopharmaceuticals are multi-molecular combinations which follow a combinatory treatment module which minimizes off-target toxicity by synergistic potency and improve outcomes by synergistic efficacy. Combination synergy is a multi-dimensional concept where synergy can be observed from a network pharmacology perspective. Network pharmacology uses systems-level drug–response phenotypes originating from various ‘omics’ platforms. This network pharmacology with metabolomics has been proven to be effective in elucidating the mechanisms of action of medicinal plants and complex traditional formulations. LC-MS/MS of medicinal plants along with network pharmacology unveil synergistic molecular combinations which interact with neighbouring targets in a combination synergy network. Case studies on some traditional herbs mentioned in Ayurveda, has been reported based on the combination of network-based methods and metabolomics for establishing the mechanism for their therapeutic potentials. The synergistic combination of molecules interacts with target-disease networks which provide novel, mechanistic insights towards understanding their therapeutic potentials. This review along with case-studies illustrates various strategies to explore the mechanism of action for different synergistic natural products combinations through neighbourhood-based network pharmacology approach.

It is well known that high-temperature curing of natural rubber (NR) with a conventional accelerated-sulfur (CV) system is limited because of reversion. This paper describes the curing behavior and the reversion resistance characteristics of unfilled NR with a CV system in the presence of two different bismaleimides: Perkalink 900 (PL) and Maleide F (MF). Rheometer studies reveal that MF can directly interact with the NR during accelerated-sulfur curing and forms some thermally stable bismaleimide type crosslinks in the beginning via Alder-ene reaction. However, even with the use of 4 phr of MF, a considerable reversion was noticed during the curing of NR with CV at 180 °C for 1 hr. A high dosage (5 phr) of MF was therefore required for a complete reversion free plateau type cure pattern. On the other hand, PL has no direct interaction with the NR at the beginning of the curing reaction. Moreover, even 1 phr PL exhibits a marching modulus curing behavior via Diels-Alder reaction. Therefore, to solve the individual issues of these chemicals, a synergistic combination of MF and PL has been identified and applied to facilitate the high-temperature curing of NR/CV devoid of reversion with a plateau type cure pattern.

New strategies to fabricate nanomedicines with high translational capacity are urgently desired. Herein, a new class of self-assembled drug cocktails that addresses the multiple challenges of manufacturing clinically useful cancer nanomedicines was reported. Methods: With the aid of a molecular targeted agent, dasatinib (DAS), cytotoxic cabazitaxel (CTX) forms nanoassemblies (CD NAs) through one-pot process, with nearly quantitative entrapment efficiency and ultrahigh drug loading of up to 100%. Results: Surprisingly, self-assembled CD NAs show aggregation-induced emission, enabling particle trafficking and drug release in living cells. In preclinical models of human cancer, including a patient-derived melanoma xenograft, CD NAs demonstrated striking therapeutic synergy to produce a durable recession in tumor growth. Impressively, CD NAs alleviated the toxicity of the parent CTX agent and showed negligible immunotoxicity in animals. Conclusions: Overall, this approach does not require any carrier matrices, offering a scalable and cost-effective methodology to create a new generation of nanomedicines for the safe and efficient delivery of drug combinations.

Protein-based therapeutics are part of the next-generation arsenal of drugs being developed against proto-oncoprotein Myc. We designed protein MEF to mimic the basic region/helix-loop-helix/leucine zipper (bHLHZ) domain of Max and Myc, which bind to the E-box motif (enhancer box, CACGTG). To make MEF, we started with our rationally designed ME47, a hybrid of the Max basic region and E47 HLH, that effectively inhibited tumor growth in a mouse model of breast cancer. We used phage-assisted continuous evolution (PACE), which uncovered mutations at Arg12 that contact the DNA phosphodiester backbone. The Arg12 mutations improved ME47's stability. We replaced Cys29 with Ala to eliminate potential undesired disulfide formation and fused the designed FosW leucine zipper to mutated ME47 to increase the dimerization interface and E-box targeting activity. This "franken-protein" MEF comprises the Max basic region, E47 HLH, and FosW leucine zipper. Compared with ME47, MEF gives 2-fold stronger binding to E-box and 4-fold increased specificity for E-box over nonspecific DNA. The synergistic combination of rational design and PACE allowed us to make MEF and demonstrates the power and utility of our two-pronged approach toward development of promising protein drugs with robust structure and DNA-binding function.

Though promising, identifying synergistic combinations from a large pool of candidate drugs remains challenging for cancer treatment. Due to unclear mechanism and limited confirmed cases, only a few computational algorithms are able to predict drug synergy. Yet they normally require the drug-cell treatment results as an essential input, thus exclude the possibility to pre-screen those unexplored drugs without cell treatment profiling. Based on the largest dataset of 33,574 combinational scenarios, we proposed a handy webserver, H-RACS, to overcome the above problems. Being loaded with chemical structures and target information, H-RACS can recommend potential synergistic pairs between candidate drugs on 928 cell lines of 24 prevalent cancer types. A high model performance was achieved with AUC of 0.89 on independent combinational scenarios. On the second independent validation of DREAM dataset, H-RACS obtained precision of 67% among its top 5% ranking list. When being tested on new combinations and new cell lines, H-RACS showed strong extendibility with AUC of 0.84 and 0.81 respectively. As the first online server freely accessible at http://www.badd-cao.net/h-racs, H-RACS may promote the pre-screening of synergistic combinations for new chemical drugs on unexplored cancers.

Inhibition effect of the synergistic combination of thymus mastichina and illicium verum oil extracts (TMAV) on the corrosion inhibition of low carbon steel in 0.5 M H2SO4 and HCl solution was studied by weight loss analysis, potentiodynamic polarization, open circuit potential measurement, ATF-FTIR spectroscopy, and optical microscopy and macroscopic characterization. Results from weight loss shows TMAV performed more effectively in H2SO4 solution compared to HCl with optimal inhibition efficiency of 81.24% and 68.33%. Effective inhibition performance was observed at all TMAV concentration in H2SO4 compared to HCl where TMAV performed poorly until 5% concentration. The optimal inhibition performances from potentiodynamic polarization are 80.85% and 70.43%. The corresponding corrosion current density and polarization resistance are 7.16 × 105 A/cm2 and 8.01 × 105 A/cm2, and 331.73 and 284 Ω. TMAV exhibited mixed type inhibition effect in both acid solutions, strongly influencing the anodic-cathodic plot configurations with respect to concentration. Open circuit potential plots without TMAV were significantly electronegative compared to the plots at 1% and 5% TMAV concentration which were relative electropositive due to decreased thermodynamic tendency of the carbon steel to corrode. The corresponding plots at 1% and 5% TMAV concentration from HCl solution were thermodynamically unstable with significant active-passive corrosion behaviour. TMAV inhibited through chemisorption adsorption according to Langmuir and Freudlich adsorption isotherms in H2SO4 solution, and Frumkin and Freundlich adsorption isotherms in HCl solution with correlation coefficient values between 0.7 and 0.9. FTIR spectroscopic analysis exposed the functional groups and atomic bonds responsible for corrosion inhibition.

Additive manufacturing enables the printing of metallic parts, such as customized implants for patients, durable single-crystal parts for use in harsh environments, and the printing of parts with site-specific chemical compositions and properties from 3D designs. However, the selection of alloys, printing processes and process variables results in an exceptional diversity of microstructures, properties and defects that affect the serviceability of the printed parts. Control of these attributes using the rich knowledge base of metallurgy remains a challenge because of the complexity of the printing process. Transforming 3D designs created in the virtual world into high-quality products in the physical world needs a new methodology not commonly used in traditional manufacturing. Rapidly developing powerful digital tools such as mechanistic models and machine learning, when combined with the knowledge base of metallurgy, have the potential to shape the future of metal printing. Starting from product design to process planning and process monitoring and control, these tools can help improve microstructure and properties, mitigate defects, automate part inspection and accelerate part qualification. Here, we examine advances in metal printing focusing on metallurgy, as well as the use of mechanistic models and machine learning and the role they play in the expansion of the additive manufacturing of metals. Several key industries routinely use metal printing to make complex parts that are difficult to produce by conventional manufacturing. Here, we show that a synergistic combination of metallurgy, mechanistic models and machine learning is driving the continued growth of metal printing.

Summary Porous ladder polymer networks (ladder PPNs) represent an emerging class of porous organic materials constituted by crosslinked, fully fused ladder-type backbones. Their unique structural characteristic allows for the integration of the properties of porous organic polymers and ladder polymers in a synergistic manner, affording materials featuring high porosity, structural diversity, backbone rigidity, extended π-conjugation, extraordinary stability, etc. These materials with various topologies can be bottom-up synthesized by either direct ring-fusing crosslinking or stepwise crosslinking followed by ladderization. These ladder PPNs exhibit the anticipated ultrahigh stability, electrical conductivity, functional rigid pores, or entropically favorable gas adsorption. The synergistic combination of these functions promises the great potential of ladder PPNs in a wide range of future applications, including energy storage, catalysis, and sensing. To achieve these goals, it is critical to address the fundamental and practical challenges associated with the narrow scope of topologies, structural defects, synthetic scalability, and processability of ladder PPNs.

Antimicrobial peptides (AMPs) are at the focus of attention due to their therapeutic importance and developing computational tools for the identification of efficient antibiotics from the primary structure. Here, we utilized the 13CNMR spectral of amino acids and clustered them into various groups. These clusters were used to build feature vectors for the AMP sequences based on the composition, transition, and distribution of cluster members. These features, along with the physicochemical properties of AMPs were exploited to learn computational models to predict active AMPs solely from their sequences. Naive Bayes (NB), k-nearest neighbors (KNN), support-vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost) were employed to build the classification system using the collected AMP datasets from the CAMP, LAMP, ADAM, and AntiBP databases. Our results were validated and compared with the CAMP and ADAM prediction systems and indicated that the synergistic combination of the 13CNMR features with the physicochemical descriptors enables the proposed ensemble mechanism to improve the prediction performance of active AMP sequences. Our web-based AMP prediction platform, IAMPE, is available at http://cbb1.ut.ac.ir/.

Stretchable conductors are important ingredients in the new emerging wearable systems. Here, intrinsically stretchable con­ductors (ISCs) based on carbon nanomaterials with a good balance of proper...

Conventional chemotherapeutics have been developed into clinically useful agents based on their ability to preferentially kill malignant cells, generally owing to their elevated proliferation rate. Nonetheless, the clinical activity of various chemotherapies is now known to involve the stimulation of anticancer immunity either by initiating the release of immunostimulatory molecules from dying cancer cells or by mediating off-target effects on immune cell populations. Understanding the precise immunological mechanisms that underlie the efficacy of chemotherapy has the potential not only to enable the identification of superior biomarkers of response but also to accelerate the development of synergistic combination regimens that enhance the clinical effectiveness of immune checkpoint inhibitors (ICIs) relative to their effectiveness as monotherapies. Indeed, accumulating evidence supports the clinical value of combining appropriately dosed chemotherapies with ICIs. In this Review, we discuss preclinical and clinical data on the immunostimulatory effects of conventional chemotherapeutics in the context of ICI-based immunotherapy.

The combination of synergistic stabilizers is a basic strategy for prolonging the lifetime of polymeric materials, but exploration of combinations has been minimally accomplished due to certain pro...

Purpose The purpose of this study is to enhance data quality and overall accuracy and improve certainty by reducing the negative impacts of the FCM algorithm while clustering real-world data and also decreasing the inherent noise in data sets. Design/methodology/approach The present study proposed a new effective model based on fuzzy C-means (FCM), ensemble filtering (ENS) and machine learning algorithms, called an FCM-ENS model. This model is mainly composed of three parts: noise detection, noise filtering and noise classification. Findings The performance of the proposed model was tested by conducting experiments on six data sets from the UCI repository. As shown by the obtained results, the proposed noise detection model very effectively detected the class noise and enhanced performance in case the identified class noisy instances were removed. Originality/value To the best of the authors’ knowledge, no effort has been made to improve the FCM algorithm in relation to class noise detection issues. Thus, the novelty of existing research is combining the FCM algorithm as a noise detection technique with ENS to reduce the negative effect of inherent noise and increase data quality and accuracy.

In this paper, we constructed a synergistic combination of the solar multifield, including the primary photo-field, sub-thermo-field, and sub-electro-field, and then utilized the device for the oxi...

Advances in high-throughput screening (HTS) metrologies could accelerate discovery of superior polymeric membranes for separation of liquid mixtures. However, HTS remains underexploited in membrane materials research. This review examines relevant advances in membrane materials and HTS techniques made since 2000, including both predictive and direct screening approaches that are applicable to membranes for liquid mixture separation. Advances in dense polymeric and mixed-matrix materials for hydrophilic and organophilic membranes are discussed. Recent studies demonstrating predictive and direct HTS approaches on membranes for separation of liquid mixtures are summarized. The synergistic combination of HTS with molecular simulations and machine learning is suggested as a potentially powerful approach to accelerating discovery of polymeric and mixed-matrix membranes that exhibit exceptional performance.

Non-surgical camouflage orthodontic treatment can be effective for the management of carefully selected patients with mild to moderate Class III malocclusion. This case report demonstrates how a synergistic combination of camouflage orthodontic treatment and appropriate adjunctive restorative procedures can provide a pleasing treatment outcome for a patient with a significant skeletal Class III malocclusion and diminutive maxillary lateral incisors.

In this study, an attempt has been made to investigate the wear characteristics of aluminium (Al) 6063 alloy reinforced with Al2O3/SiC/Al2O3 + SiC particles of double particle size (DPS) and triple particle size (TPS). The hybrid Al-metal matrix composites (MMC’s) were prepared by using a synergistic combination of fused deposition modeling and V-process assisted stir casting and wear performance was examined on pin-on disc tester. The outcome of this study reveals that DPS-based Al-MMC’s with hybrid reinforcement of Al2O3 and SiC exhibit better wear characteristic. In this case study, overall 6% improvement in wear resistance was observed at proposed parametric settings. The results have been supported by photomicrographs, which confirmed the presence of Al2O3 and SiC contributing towards the improved wear property of the hybrid Al-MMC’s.

High/Medium entropy alloys (H/MEAs) represent a new strategy for the design of materials with properties superior to those of conventional alloys. Here, we show a new field of application where the uniform mixtures of multiple principal elements in H/MEAs is utilized to create new type nanoporous alloys by dealloying. By using equiatomic CrCoNi MEAs as a proto-type system, we developed three-dimensional bi-continuous open nanoporous CoCr alloys composed of single-phase solid-solution with equiatomic ratios by liquid-metal dealloying methods. The morphology and size of ligaments and pores could be tailored by controlling dealloying time. Structural evolution of the nanoporous CoCr alloy during dealloying can be well described by surface smoothening and ligament pinch-off mediated coarsening process. This study opens up a new promising pathway for development of new type nanoporous alloys-nanoporous high entropy alloys, which are expected to have unprecedented structural and functional properties due to a unique synergistic combination of nanoporous structure and high-entropy effect.

Histone deacetylase (HDAC) inhibitors represent an encouraging class of antitumor drugs. HDAC inhibitors induce a series of molecular and biological responses and minimal toxicity to normal cells. Citarinostat (Acy-241) is a second generation, orally administered, HDAC6-selective inhibitor. Momelotinib (CYT387) is an orally administered inhibitor of Janus kinase/signal transducer of transcription-3 (JAK/STAT3) signaling. Momelotinib showed efficacy in patients with myelofibrosis. We hypothesized that both HDAC and JAK/STAT pathways were important in lymphoproliferative disorders, and that inhibiting JAK/STAT3 and HDAC simultaneously might enhance the efficacy of momelotinib and citarinostat without increasing toxicity. Accordingly, we tested the citarinostat + momelotinib combination in lymphoid cell lines. Citarinostat + momelotinib showed strong cytotoxicity; it significantly reduced mitochondrial membrane potential, down-regulated Bcl-2 and Bcl-xL, and activated caspases 9 and 3. Caspase-8 was upregulated in only two lymphoid cell lines, which indicated activation of the extrinsic apoptotic pathway. We identified a lymphoid cell line that was only slightly sensitive to the combination treatment. We knocked down thioredoxin expression by transfecting with small interfering RNA that targeted thioredoxin. This knockdown increased cell sensitivity to the combination-induced cell death. The combination treatment reduced Bcl-2 expression, activated caspase 3, and significantly inhibited cell viability and clonogenic survival. Electronic supplementary material The online version of this article (10.1007/s10495-020-01607-3) contains supplementary material, which is available to authorized users.

gem-Difluoroalkene bearing a carbonyl group is a challenging target to synthesize by conventional methods. Herein we report a mild and concise route to access the target compounds through the visible-light-mediated direct β-C-H gem-difluoroallylation of aliphatic aldehydes and cyclic ketones. Upon a synergistic combination of photoredox catalysis and organocatalysis, various α-CF3 alkenes were employed as the gem-difluoroallylation reagents via the C-F bond cleavage.

This study aimed to evaluate the effect of duloxetine hydrochloride (DH) on Cryptococcus neoformans. DH minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) were 18.5 µg/mL, and the combination with fluconazole (FLZ) reduced the MIC value by 16-and 4-fold for DH and FLZ, respectively. The capsule size decreased by 67% ​​and 16% when treated with DH and DH with FLZ, respectively. Therefore, this study showed that DH is active against C. neoformans alone and in combination with FLZ, leading to the reduction of the capsule size of this yeast.

In this paper, a synergistic combination of deep reinforcement learning and hierarchical game theory is proposed as a modeling framework for behavioral predictions of drivers in highway driving scenarios. The need for a modeling framework that can address multiple human-human and human-automation interactions, where all the agents can be modeled as decision makers simultaneously, is the main motivation behind this work. Such a modeling framework may be utilized for the validation and verification of autonomous vehicles: It is estimated that for an autonomous vehicle to reach the same safety level of cars with drivers, millions of miles of driving tests are required. The modeling framework presented in this paper may be used in a high-fidelity traffic simulator consisting of multiple human decision makers to reduce the time and effort spent for testing by allowing safe and quick assessment of self-driving algorithms. To demonstrate the fidelity of the proposed modeling framework, game theoretical driver models are compared with real human driver behavior patterns extracted from traffic data., Comment: 22 pages, 19 figures

Various types of lasers have been demonstrated to be effective in the treatment of vitiligo. The mode of action of these lasers is just as varied as the purpose of intervention. Many clinicians are not aware of the unique opportunity these lasers offer to improve the outcomes of vitiligo treatment. To date, no clear overview exists of the use of lasers in vitiligo treatment. Thus, the aim of this review is to discuss the various types of lasers and provide an overview of the evidence for their efficacy. We found good evidence from a systematic review that the excimer laser is effective, induces repigmentation rates comparable to NB-UVB and has improved outcomes when combined with calcineurin inhibitors. Ablative lasers are commonly used for tissue graft or melanocyte-keratinocyte cell graft transplantation. They provide safe, fast and uniform denudation of the epidermis with propitious repigmentation outcomes. We found conflicting evidence from two systematic reviews regarding the efficacy of fractional ablative lasers for improving outcomes of NB-UVB therapy, a systematic review including only fractional ablative lasers provided evidence for efficacy. Q-switched nanosecond lasers have shown to be safe and effective for inducing depigmentation, although recurrence is common, and most studies were small and retrospective. Despite proven efficacy and safety, laser treatments are relatively expensive and suited for limited body surface areas and selected cases. Each type of laser has benefits and risks associated and should, therefore, be individually chosen based on location, extent, activity and type of vitiligo.

As a major cause of deaths in developed countries, cardiovascular disease (CVD) has been a big burden for human health systems. Its early and rapid detection is crucial to efficiently apply appropriate on time therapy and to ultimately reduce the associated mortality rate. Aptamers, known as single-stranded DNA/RNA or oligonucleotides containing receptors and/or catalytic properties, have been widely employed in biodetection platforms due to their beneficial properties. Like antibodies, aptamers have served as artificial target receptors in affinity biosensors. Currently, advanced biosensors with improved sensitivity and specificity are fabricated by the synergistic combination of aptamers and diverse nanomaterials. Herein, we review the current development and applications of nanomaterial-based aptasensors for the recognition of CVD biomarkers with special emphasis on electrochemical and optical technologies. The performance of aptasensors has been assessed further in terms of key quality assurance metrics along with discussions on recent technologies developed for the amplification of signals with enhanced portability.

Owing to the over usage of carbapenems, carbapenem resistance has become a vital threat worldwide, and, thus, the World Health Organization announced the carbapenem-resistant Enterobacteriaceae (CRE) as the critical priority for antibiotic development in 2017. In the current situation, combination therapy would be one solution against CRE. Azidothymidine (AZT), a thymidine analog, has demonstrated its synergistically antibacterial activities with other antibiotics. The unexpected antimicrobial activity of the immunomodulator ammonium trichloro(dioxoethylene-o,o’)tellurate (AS101) has been reported against carbapenem-resistant Klebsiella pneumoniae (CRKP). Here, we sought to investigate the synergistic activity between AS101 and AZT against 12 CRKP clinical isolates. According to the gene detection results, the blaOXA-1 (7/12, 58.3%), blaDHA (7/12, 58.3%), and blaKPC (7/12, 58.3%) genes were the most prevalent ESBL, AmpC, and carbapenemase genes, respectively. The checkerboard analysis demonstrated the remarkable synergism between AS101 and AZT, with the observable decrease in the MIC value for two agents and the fractional inhibitory concentration (FIC) index ≤0.5 in all strains. Hence, the combination of AS101 and azidothymidine could be a potential treatment option against CRKP for drug development.

Herein, we show the synergistic combination of aggregation-caused quenching (ACQ) and aggregation-induced emission (AIE) units into two hexagonal metallacycles. The resultant metallacycles displayed emergent photophysical properties including tunable fluorescence using the polarity and solubility of the solvents as well as enhanced emissive efficacy. Our work demonstrates the synergistic enhancement of these two orthogonal effects via coordination-driven self-assembly.

Background A large-diameter femoral head is effective in preventing dislocation after total hip arthroplasty. However, although rare, catastrophic stem tribocorrosion may occur at the head-stem junction. Case presentation A 70-year-old woman underwent revision surgery 7.5 years after total hip arthroplasty because of catastrophic stem corrosion with dissociation of the metal head (cobalt/chromium) and stem (TiMo12Zr6Fe2). Abnormal levels of cobalt were found in the intra-articular fluid, capsule, hip muscle, and blood. Revision surgery was performed via the direct anterior approach. The well-fixed femoral stem was explanted, and a cemented stainless stem with stainless head was implanted. Three months after the revision surgery, the cobalt concentration in the blood had decreased to normal. Conclusions Stem dissociation in the present case might have been caused by synergistic combination of a 36-mm-diameter femoral head and long neck length offset with high frictional torque, a cobalt-chromium head with a high risk of galvanic corrosion, and a TMZF (TiMo12Zr6Fe2) alloy stem with a low Young’s modulus of elasticity. The combination of these factors must be avoided.