Synergy, emerges from synchronized reciprocal positive feedback loops between a network of diverse actors. For this process to proceed, compatible information from different sources synchronically coordinates the actions of the actors resulting in a nonlinear increase in the useful work or potential energy the system can manage. In contrast noise is produced when incompatible information is mixed. This synergy produced from the coordination of different agents achieves non-linear gains in free energy and in information (negentropy) that are greater than the sum of the parts. The final product of new synergies is an increase in individual autonomy of an organism that achieves increased emancipation from the environment with increases in productivity, efficiency, capacity for flexibility, self-regulation and self-control of behavior through a synchronized division of ever more specialized labor. Examples that provide quantitative data for this phenomenon are presented. Results show that increases in free energy density require decreases in entropy density. This is proposed as a law of thermodynamics.

Pseudomonas aeruginosa infections are the focus of new treatment alternatives due to their frequent development of resistance to antibiotics and formation of biofilms. Recently, emphasis has been placed on combinations of antibiotics with drugs used for different indications. In this study the combined effects of metformin with imipenem, ceftazidime, cefepime, ciprofloxacin and levofloxacin has been investigated. 50 P. aeruginosa isolates isolated from patients with cystic fibrosis come to Gaziantep University Microbiology Laboratory were included in the study. The susceptibilities of the isolates to antibiotics were investigated by the liquid microdilution method and the combined effect of metformin and antibiotics by the chequerboard synergy test. In our study, as a result of the chequerboard synergy test; synergy between ceftazidime and metformin 6%, partial synergistic 22% isolates; while no synergistic effect was detected between cefepime and metformin in any isolate, partially synergy 46%; synergy between imipenem and metformin 4%, partial synergy 10%; synergy between ciprofloxacin and metformin 6%, partial synergy 6%, antagonist effect 2%; synergy was detected between levofloxacin and metformin 2% and a partial synergy was detected 12%. This study shows that metformin could be a potential antibiotic in its current form or in different chemical forms to be produced synthetically.

Antibiotic resistance is now a first-order health problem, which makes the development of new families of antimicrobials an imperative. These compounds should ideally be inexpensive, readily available, highly active and non-toxic. Here we present the results on the antimicrobial activity of a series of natural and synthetic polyamines with different architectures (linear, tripodal and macrocyclic) and their derivatives containing the oxygen containing aromatic functional groups 1,3-benzodioxol, ortho/para phenol or 2,3-dihydrobenzofuran. The new compounds were prepared through a non-expensive process and their activity was tested against selected strains of yeast, gram-positive and gram-negative bacteria. In all cases, the conjugated derivatives showed antimicrobial activity higher than the unsubstituted polyamines. Several factors, such as the overall charge at physiological pH, the lipophilicity and the topology of the polyamine scaffold were relevant to their activity. The nature of the lipophilic moiety was also determinant on human cell toxicity. The lead compounds showed to be bactericidal and fungistatic, and they were synergic with the commercial antifungals fluconazole, cycloheximide and amphotericin B against the yeast strains tested.

Background: There are ongoing workforce challenges with the delivery of long-term care (LTC), such as staffing decisions based on arbitrary standards. The Synergy tool, a resident-centered approach to staffing, pro-vides objective, real-time acuity and dependency scores (Synergy scores) for residents. The purpose of this study was to implement and evaluate the impact of the Synergy tool on LTC delivery. Methods: A longitudinal mixed methods study took place within two publicly-funded LTC homes in British Columbia, Canada. Quantitative data included weekly Synergy scores for residents (24 weeks), monthly aggregated resident falls data (18 months) and a six-month economic evaluation. Qualitative data were gathered from family caregivers and thematically analyzed. Results: Quantitative findings from Synergy scores revealed considerable variability for resident acuity/dependency needs within and across units; and falls decreased during implementation. The six-month economic evaluation demonstrated some cost savings by comparing Synergy tool training and implementation costs with savings from resident fall rates reductions. Qualitative analyses yielded three positive impacts themes (improved care delivery, better communication, and improved resident-family-staff relationships), and two negative structural themes (language barrier and staff shortages). Conclusions: The Synergy tool provides useful data for enhancing a ‘fit’ between resident needs and available staff.

The prevalence of multidrug resistant bacterial diseases is a major global health risk. Multidrug resistant bacterial diseases are prevalent, and the need for novel methods of treatment is essential to the preservation of public health. Annually foodborne pathogens cause 1.35 million infections and 26,500 hospitalizations in the United States alone. Foodborne pathogens such as Salmonella spp. are a major threat to public health. Bacteriophages offer a unique method for the treatment of these multidrug resistant bacteria. We studied the infection dynamics of a potential mono-phage therapy of Salmonella typhimurium under various pathophysiological conditions. Furthermore, we determined the resistance dynamics of Salmonella typhimurium against P22 phage treatment. We also determined synergy with antibiotics such as ampicillin and kanamycin. This research helps to further define and show the versatility of bacteriophages as potential novel treatment methods.

: We report on a direct correlation between macroscale structural variations and the gas sorption capacities of an ion gel. Here, we chose 1-ethyl-3-methylimidazolium bis(trifluoromethyl sulfonyl)imide ([Emim][TF2N]) and poly(vinylidene fluoride)-co-hexafluoropropylene (PVDF-HFP) as the ionic liquid and host polymer, respectively. The CO2 sorption in the thin films of IL-polymer was measured by the gravimetric method. The results of our experiment show that the trend of CO2 uptake of these mixtures is non-linearly correlated with the content of IL. Here we highlight the variation in the molecular structure of the polymers is the main reason behind the observed trend. The presented data suggest the possibility of using the composition of mixtures containing IL and polymers to realize a synergistic gain for gas sorption in these mixtures.

High-throughput screening technologies continues to produce large amounts of multiomics data from different populations and cell types for various diseases, such as cancer. However, analysis of such data encounters difficulties due to cancer heterogeneity, further exacerbated by human biological complexity and genomic variability. There is a need to redefine the drug discovery development pipeline, bringing an Artificial Intelligence (AI)-powered informational view that integrates relevant biological information and explores new ways to develop effective anticancer approaches. Here, we show SynPred, an interdisciplinary approach that leverages specifically designed ensembles of AI-algorithms, links omics and biophysical traits to predict synergistic anticancer drug synergy. SynPred exhibits state-of-the-art performance metrics: accuracy – 0.85, precision – 0.77, recall – 0.75, AUROC – 0.82, and F1-score - 0.76 in an independent test set. Moreover, data interpretability was achieved by deploying the most current and robust feature importance approaches. A simple web-based application available online at http://www.moreiralab.com/resources/synpred/ was constructed to predict synergistic anticancer drug combinations requiring only the upload of the two drug SMILES to be tested, allowing easy access by non-expert researchers.

Different from national systems of innovation, a knowledge-based economy is grounded in the volatility of discursive knowledge enabling us to specify expectations. Expectations can be improved by testing against observations. Furthermore, expectations can differently be codified; for example, in terms of market perspectives and technological opportunities. The Triple Helix of university-industry-government relations provides first a (neo-)institutional model. However, three functions are recombined at the systems level in each instantiation: wealth generation (by industry), novelty production (academia), and legislation and regulation (government). The Triple-Helix synergy indicator enables us to use the institutional arrangements as instantiations of the knowledge-dynamics and thus to assess the generation of options and reduction of uncertainty in information-theoretical terms. The Fourth Industrial Revolution entails the transition to the reflexive entertaining of expectations in terms of models as increasingly the sources of innovations.

Fungal infections impact the lives of at least 12 million people every year, killing over 1.5 million. Wide-spread use of fungicides and prophylactic antifungal therapy have driven resistance in many serious fungal pathogens, and there is an urgent need to expand the current antifungal ar-senal. Recent research has focused on improving azoles, our most successful class of antifungals, by looking for synergistic interactions with secondary compounds. Synergists can co-operate with azoles by targeting steps in related pathways, or they may act on mechanisms related to re-sistance like active efflux or on totally disparate pathways or processes. A variety of sources of potential synergists have been explored, including pre-existing antimicrobials, pharmaceuticals approved for other uses, bioactive natural compounds and phytochemicals, and novel synthetic compounds. Synergy can successfully widen the antifungal spectrum, decrease inhibitory dosag-es, reduce toxicity, and prevent the development of resistance. This review highlights the diversity of mechanisms that have been exploited for the purposes of azole synergy and demonstrates that synergy remains a promising approach for meeting the urgent need for novel antifungal strate-gies.

Background: The commonly known assumption that combinations of several herbs in one formulation can have better efficacy due to additive or synergistic effects has not been systematically studied despite some evidence supporting the synergy concept. Study aim: The study aimed to reveal the molecular interactions in situ of host cells in response to the intervention of BHP and justify the benefits of implementing BHP in clinical practice. Results: This overview provides the results of recent clinical and network pharmacology studies of botanical herbal preparations (BHP) of Rhodiola with other plants, including Ashwagandha, Green Tea, Eleutherococcus, Schisandra, Eleutherococcus, Leuzea, Caffeine, Cordyceps, Gingko, Black Cohosh, saffron, and L-carnosine. Conclusions: The most important finding from network pharmacology studies of BHP was the evidence supporting the synergistic interaction of BHP ingredients, revealing unexpected new pharmacological activities unique and specific to the new BHP. Some studies show the superior efficacy of BHP compared with mono-drugs. At the same time, some a priori-designed combinations can fail, presumably due to antagonistic interactions and crosstalk between molecular targets within molecular networks involved in the cellular and overall response of organisms on the intervention. Network pharmacology studies help predict the results of studies to discover new indications and unpredicted adverse events.

Red fruits such as grapes and blueberries are known for their high content of bioactive compounds and antioxidants. In Mediterranean winemaking, traditional sun drying can be replaced by controlled airflow chamber drying which provides better quality, higher phenolic content, and increased antioxidants. This study aimed to increase the sugar content and phenolic compounds of the must by drying the fruits to 50% of their original moisture content. Two musts were prepared by combining fresh grapes and dried blueberries (M1), and the other using dried grapes and fresh blueberries (M2), followed by fermentation at 25 ºC with M05 Mead and X5 yeast strains. Must M2 showed the highest level of phenolic compounds, A520, total anthocyanins and antioxidant activity. During fermentation, the anthocyanin content increased mainly in the dried blueberry macerates, which raised between 4 to 5.5-fold. More bioactive compounds were extracted from wines produced by yeast inoculation despite shorter maceration times. Sensory analysis demonstrated consumer acceptance of the wines in terms of color, flavor and aroma. In conclusion, the use of red grapes in the production of blueberry red wine proved to be effective, providing sugars and higher must yields, while the dried fruits improved the fermentable sugar content and the levels of bioactive compounds, increasing the antioxidant capacity of the resulting red fruit wines.

Introduction: This study aims to investigate the activity of the remdesivir-nirmatrelvir combination against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and to report a case of Coronavirus Disease 2019 (COVID-19) cured with this combination. Methods: A Vero E6 cell-based infection assay was used to investigate the in vitro activity of the remdesivir-nirmatrelvir combination. The SARS-CoV-2 strains tested were 20A.EU1, BA.1 and BA.5. After incubation, a viability assay was performed. The supernatants were collected and used for viral titration. The Highest Single Agent (HSA) reference model was calculated. An HSA score >10 is considered synergic. Results: Remdesivir and nirmatrelvir showed synergistic activity at 48 and 72 h with an HSA score of 52.8 and 28.6, respectively (p<0.0001). This data has been confirmed performing supernatant titration and against the omicron variants: the combination reduced the viral titer better than the more active compound alone. An immunocompromised patient with prolonged and critical COVID-19 was successfully treated with remdesivir, nirmatrelvir/ritonavir, tixagevimab/cilgavimab, and dexamethasone, with an excellent clinical-radiological response. However, she required further off-label prolonged therapy with nirmatrelvir/ritonavir up to the negativization. Conclusion: Remdesivir-nirmatrelvir combination has synergic activity in vitro. This combination may have a role in immunosuppressed patients with severe COVID-19 and prolonged viral shedding.

Information theory provides robust measures of multivariable interdependence, but classically does little to characterize the multivariable relationships it detects. The Partial Information Decomposition (PID) characterizes the mutual information between variables by decomposing it into unique, redundant, and synergistic components. This has been usefully applied, particularly in neuroscience, but there is currently no generally accepted method for its computation. Independently, the Information Delta framework characterizes non-pairwise dependencies in genetic datasets. This framework has developed an intuitive geometric interpretation for how discrete functions encode information, but lacks some important generalizations. This paper shows that the PID and Delta frameworks are largely equivalent. We equate their key expressions, allowing for results in one framework to apply towards open questions in the other. For example, we find that the approach of Bertschinger et al. is useful for the open Information Delta question of how to deal with linkage disequilibrium. We also show how PID solutions can be mapped onto the space of delta measures. Using Bertschinger et al. as an example solution, we identify a specific plane in delta-space on which this approach’s optimization is constrained, and compute it for all possible three-variable discrete functions of a three-letter alphabet. This yields a clear geometric picture of how a given solution decomposes information

The global health emergency caused by multi-drug resistant bacteria has led to the search for and development of new antimicrobial agents. Phage therapy is an abandoned antimicrobial therapy that has been resumed in recent years. In this study, we mutated a lysogenic phage from Acinetobacter baumannii into a lytic phage (Ab105-2phiΔCI) showing antimicrobial activity against A.baumannii clinical strains (such as Ab177_GEIH-2000 which showed MICs to meropenem and imipenem of 32 µg/ml and 16 µg/ml, respectively as well as belonging to GEIH-REIPI Spanish Multicenter A. baumannii Study II 2000/2010, Umbrella Genbank Bioproject PRJNA422585). We then enhanced the time kill curves (in vitro) and in Galleria mellonella survival assays (in vivo) antimicrobial activity of the new lytic phage by combining it with carbapenem antibiotics (meropenem and imipenem). We observed in vitro, an antimicrobial synergistic effect (from 4 log to 7 log CFU/ml) with meropenem plus lytic phage in all combinations analysed (0.1, 1 and 10 MOI of Ab105-2phiΔCI mutant as well as 1/4 and 1/8 MIC of meropenem). Moreover, we had a decrease in bacterial growth of 8 log CFU/ml for the combination of imipenem at 1/4 MIC plus lytic phage (Ab105-2phiΔCI mutant) and of 4 log CFU/ml for the combination of imipenem at 1/8 MIC plus lytic phage (Ab105-2phiΔCI mutant) in both MOI 1 and 10. These results were confirmed in in vivo (G. mellonella) obtaining a higher effectiveness in the combination of imipenem and Ab105-2phiΔCI mutant (P<0.05 by Log Rank-Matel Cox test). This approach could help to reduce the emergence of phage resistant bacteria and restore sensitivity to the antibiotics when used to combat multiresistant strains of Acinetobacter baumannii.

For efficient electrode development in an electrolysis system, Fe₂O₃, MnO, and heterojunction Fe₂O₃-MnO materials were synthesized via a simple sol-gel method. These particles were coated on a Ni-foam electrode, and the resulting material was used as an electrode to be used during an oxygen evolution reaction (OER). A 1000-cycle OER test in a KOH alkaline electrolyte indicated that the heterojunction Fe₂O₃-MnO/NF electrode exhibited the most stable and highest OER activity: it exhibited a low overvoltage (n) of 370 mV and a small Tafel slope of 66 mV/dec. X-ray photoelectron spectroscopy indicated that the excellent redox performance contributed to the synergy of Mn and Fe, which enhanced the OER performance of the Fe₂O₃-MnO/NF electrode. Furthermore, the effective redox reaction of Mn and Fe indicated that the structure maintained stability even under 1000 repeated OER cycles.

Partial Information Decompositions (PIDs) aim to categorize how a set of source variables provide information about a target variable redundantly, uniquely, or synergetically. The original proposal for such an analysis used a lattice-based approach and gained significant attention. However, finding a suitable underlying decomposition measure is still an open research question, even at an arbitrary number of discrete random variables. This work proposes a solution to this case with a non-negative PID that satisfies an inclusion-exclusion relation for any f-information measure. The decomposition is constructed from a pointwise perspective of the target variable to take advantage of the equivalence between the Blackwell and zonogon order in this setting. We prove that the decomposition satisfies the axioms of the original decomposition framework and guarantees non-negative partial information results. We highlight that our decomposition behaves differently depending on the used information measure, which can be utilized for different applications. We additionally show how our proposal can be used to obtain a non-negative decomposition of Rényi-information at a transformed inclusion-exclusion relation, and for tracing partial information flows through Markov chains.

The partial information decomposition (PID) framework is concerned with decomposing the information that a set of (two or more) random variables (the sources) has about another variable (the target) into three types of information: unique, redundant, and synergistic. Classical information theory alone does not provide a unique way to decompose information in this manner and additional assumptions have to be made. One often overlooked way to do this decomposition is using a so-called measure of union information – which quantifies the information that is present in at least one of the sources – from which a synergy measure stems. In this paper, we introduce a new measure of union information based on adopting a communication channel perspective, compare it with existing measures, and study some of its properties. We also include a comprehensive critical review of characterizations of union information and synergy measures that have been proposed in the literature.

Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses. In preparation for such outbreaks, and for more facile and cost-effective management of EVD, we seek a cocktail containing orally available and room temperature stable drugs with strong activity against multiple filoviruses. We previously showed that (bepridil + sertraline) and (sertraline + toremifene) synergistically suppress EBOV in cell cultures. Here we describe steps towards testing these combinations in a mouse model of EVD. We identified a vehicle suitable for oral delivery of the component drugs and determined that, thus formulated the drugs are equally active against EBOV as preparations in DMSO, and they maintain activity upon storage in solution for up to seven days. Pharmacokinetic (PK) studies indicated that the drugs in the oral delivery vehicle are well tolerated in mice at the highest doses tested. Collectively the data support advancement of these combinations to tests for synergy in a mouse model of EVD. Moreover, mathematical modeling based on human oral PK projects that the combinations would be more active in humans than their component single drugs.

Under the big unified framework of quantum gravitational field and quantum repulsive field, the earlier in this series of work has comprehensively expanded the general relativity and loop quantum ring gravitation theory, set up the quantum repulsive field equation corresponding to the quantum gravitational field equation, and then established the quantum hedge-unified field equation describing the interaction of quantum gravitational field and quantum repulsive field; On this basis, the quantum repulsive universe equation corresponding to the quantum gravitational universe equation has be established, thus a set of new equations describing the expansive universe model under the condition of fully considering the hedge effect of quantum gravitational field and quantum repulsion field, which can be called the expansive universe equation of quantum hedge-unified field theory, has be established. Now, let's go deep into the arche-unified physics behind the creation of the universe. Although all kinds of inflationary universe models can solve cosmological problems to a certain extent, there is no natural and reasonable analysis and explanation for all cosmological and physical consequences. For example, it is impossible to predict a large tensor-scale ratio and a relatively large spectral index run at the same time. At present, string theory, membrane theory, loop quantum gravity theory, super-gravitational holography principle and M theory, which are the theoretical basis of cosmology, are basically established by simplification in the case of breaking away from the extreme background conditions of the universe. While cosmology, which is deficient in nature, cannot provide strong support for particle physics to further advance to a wider field and a deeper level. Due to the lack of new ideas, the construction of existing theoretical models is difficult. Therefore, the existing research can only be further promoted by new astronomical observation. Unlike existing studies, we concentrate on the emergence of the big rip-rebound clusters of quantum chaotic-reticulate distribution between the outwards-push of the universe as a whole (related to pseudo-vacuum energy, Higgs field, dark energy, etc.) and the inwards-pull of the universe in local scale (related to dark matter, quantum gravity and initial gravity separated from high-dimensional supergravity, and the initial strong force separated from the grand unified force subsequently). On the one hand, we find a great impetus to make the inflation of the universe into firstly-imposed suppression, then-imposed acceleration and finally-imposed deceleration, which really explains why the universe expands at a critical rate and has the same temperature in different regions, on the other hand, we find a fundamental unit of matter and its emerging clusters evolving in the big bang, inflation and expansion of the universe accompanied by the great rip-rebound clusters of quantum chaos-reticulate distribution, which can be reduced to an arche-pulsator of neither punctiform particle nor linear string. From these two aspects, it can been seen that the evolution of the early universe is much more complicated than people originally thought. The complexity of the super inflation of the universe is mainly reflected in the big rip-rebound cluster emerging behind the gravitational disturbance (the pressure and tensor disturbance related to dark matter), the repulsive disturbance (the pressure and scalar disturbance related to dark energy), the cosmological disturbance (related to the interaction between high-dimensional supergravity and high-dimensional superrepulsion). This is a system of nonlinear stochastic differential dynamics, or a quantum statistical physical process of nonlinear nonequilibrium state. In the new research paradigms established in this series, the arche-conjugation between the high-dimensional supergravity and the high-dimensional superrepulsion, as well as between the quantum gravity and the quantum repulsion, is higher than the supersymmetry, and then becomes the core concept of the new theory. In this series, cluster-inflating configuration, spin network space and cosmic paradigm vectors are proposed, so the model of the super-inflated universe with quantum chaos-reticulate distribution emerged under the great impetus. The new model reveals that the unified inflation of the universe as a whole and the local inflation of the universe emerge together in the great impetus of the big rip-rebound cluster of quantum chaos-reticulate distribution. As a spin network model variable, the spatiotemporal mode variable is a vector composed of a series of variables, which variables include: dimension, curvature, range, expansion speed, dynamics, quantization, chaotic-reticulate distribution (inhomogeneity, concentration, fluctuation), synergy, and so on. Between particle physics and cosmology, this series of papers proposes the cosmic quantum evolution mode, the physical-sphere distributing configuration and the interaction situation variables, organizes the concepts, variables and models of these three levels, and establishes a systematic super-synergy paradigm. In this paradigm, the general Langevan equation and the general Fokker-Planck equation are established. For the quantum cosmic-sphere, a series of trend parameters are introduced to establish the dynamics of quantum gravitational mode and its master equation, and then to establish the operator distribution function and its motion equation of the action mode. For the Tachyon of upheaval in the rip-rebound-inflating of the universe, the hypothesis on the bifurcate-chaos wave of quantum is given, the quantum theory of the early photons in upheaval is set up, and the analysis on the particles of the ultrahigh energy cosmic ray from the γ ray burst is made. Finally, using Wigner-Ville distribution as a nonlinear time-frequency distribution, we establish the ultra-synergistic field equation of quantum-classic unifying action-sphere.

Electrically conductive polymer composites are in high demand for modern technologies, however, the intrinsic brittleness of conducting conjugated polymers and the moderate electrical conductivity of engineering polymer/carbon composites have highly constrained their applications. In this work, super high electrical conductive polymer composites were produced by a novel hot embossing design. The polydimethylsiloxane (PDMS) composites containing short carbon fiber (SCF) exhibited an electrical percolation threshold at 0.45 wt%, and reached a saturated electrical conductivity of 49 S/m at 8 wt% of SCF. When reduced the sample thickness from 1.0 mm to 0.1 mm by the hot embossing process, a compression-induced percolation threshold occurred at 0.3 wt%, while the electrical conductivity was further enhanced to 378 S/m at 8 wt% SCF. Furthermore, the additional of a second nanofiller of 1 wt%, such as carbon nanotube or conducting carbon black further increased the electrical conductivity of the PDMS/SCF (8 wt%) composites to 909 S/m and 657 S/m, respectively. The synergy of the densified conducting filler network by the mechanical compression and the hierarchical micro-/nanoscale filler approach has realize super high electrical conductive yet mechanical flexible polymer composites for modern flexible electronics applications.

Introduction: The development of effective vaccines has partially mitigated the trend of the SARS-CoV-2 pandemic, however, the need for orally available antiviral drugs persists. This study aims to investigate the activity of molnupiravir in combination with nirmatrelvir or GC376 on SARS-CoV-2 to verify the synergistic effect. Methods: The SARS-CoV-2 strains 20A.EU, BA.1 and BA.2 were used to infect Vero E6 in presence of antiviral compounds alone or in combinations using 5 two-fold serial dilution of compound concentrations ≤EC90. After 48 and 72 h post-infection, viability was performed using MTT reduction assay. Supernatants were collected for plaque-assay titration. All experiments were conducted three times and in triplicate. The synergistic score was calculated using Synergy Finder version 2. Results: All compounds reached micromolar EC90. Molnupiravir and GC376 showed a synergistic activity at 48 h with an HSA score of 19.33 (p<0.0001) and an additive activity at 72 h with an HSA score of 8.61 (p<0.0001). Molnupiravir and nirmatrelvir showed a synergistic activity both at 48 h and 72 h with an HSA score of 14.2 (p=0.01) and 13.08 (p<0.0001), respectively. Conclusion: Molnupiravir associated with one of the two protease-inhibitors nirmatrelvir and GC376 showed good additive-synergic activity in vitro.

The nature of the sustainability crisis is characterized by high levels of complexity, thus it is not amenable to be approached from the linearity or reductionist paradigm. Emergence is a multilevel phenomenon that is characterized by qualitative novelty and is recognized as an important attribute of complex systems produced by self-organized processes, unveiled from a holistic stance. This conceptual-analytical article explores the emergence phenomenon and questions whether it can be a way of enhancing the solution process to meet the sustainability challenges. Emergent properties or behaviors emerge only when the system parts interact in a wider whole. Moreover, a systemic approach is proposed as an intermediary component in the process of emergence of creative and wise solutions to the wicked problems of unsustainability. This requires observation and entails analyzing open systems as a whole and recognizing the impact of traversing macro- and micro- scales on causal and creative emergence. The study also emphasizes synergies between emergence and creativity aimed at sustainability. Sustainable development requires leapfrogging past conventional practices, in an accelerated way, and the emergence phenomenon at play between systems levels, coupled with purposefully structured creative processes, holds the potential for catalyzing sustainable development efforts.

The insufficient flexibility of the hybrid renewable integrated energy system (HRIES) makes it difficult to accommodate renewable energy with a high proportion. It is thus necessary to excavate its potential flexibility to improve its operational performance and consume renewable energy. This paper unlocks the adjustment potential of flexible buildings and builds a flexible thermal load regulation model according to the dynamic thermal characteristics and thermal comfort elastic interval of the buildings and a regulation model of the flexible electrical load based on its transferability, resectability, and rigidity. An operation optimization model, which incorporates multiple flexible load regulations and the variable load of devices, is then developed. A case study is presented to analyze the regulation and synergy mechanism in different types of flexible loads. Its results show a saturation effect between the flexible thermal and electrical loads in increasing renewable energy consumption and a synergy effect in decreasing the total cost. This synergy can reduce the total cost by 0.73%. Besides, the total cost can be reduced by 15.13%, and the renewable energy curtailment rate can decrease by 12.08% if the flexible electric and thermal loads are integrated into the operation optimization of HRIES.

Ewing sarcoma (EWS) is an aggressive pediatric malignancy of the bone and soft tissues in need of novel therapeutic options. To identify potential therapeutic targets, we focused on essential biological pathways that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, including mitotic proteins such as Aurora Kinase A (AURKA), Kinesin Family Member 15 (KIF15) and its binding partner, targeting protein for Xklp2 (TPX2). KIF15/TPX2 cooperates with KIF11, a key mitotic kinesin essential for mitotic spindle orientation. Given the lack of clinical grade KIF15/TPX2 inhibitors, we chose to target KIF11 (using SB-743921) in combination with AURKA (using VIC-1911), given phosphorylation of KIF15S1169 by Aurora A is required for its targeting to the spindle. In vitro, the drug combination demonstrated strong synergy (Bliss score ≥10) at nanomolar doses. Colony formation assay revealed significant reduction in plating efficiency (1-3%) and increased percent accumulation of cells in G2/M phase with the combination treatment (45-52%) upon cell-cycle analysis indicating mitotic arrest. In vivo studies in EWS xenograft mouse models showed significant tumor reduction and overall effectiveness: drug combination vs vehicle control (p≤0.01), SB-743921 (p≤0.01) and VIC-1911 (p≤0.05). Kaplan-Meier curves demonstrated superior overall survival with the combination compared to vehicle or monotherapy arms (p≤0.0001).

Smart, reliable, and connected multi-modal mobility has been a long-standing goal of transit services. This paper focuses on the smart, seamless, and multi-modal mobility service in the context of “Mobility as a Service” (MaaS). Intelligent mobility is the smarter, greener, and more efficient movement of passengers around the world. Increasingly, mobility is approached as a service. This study first conducts an extensive literature review on mobility behavior and demand pattern of MaaS end-users. It then extends the mechanism of supply chain, MaaS, synergy (i.e., vertical cooperation synergy, horizontal competition synergy), and coopetition to develop the multi-tier closed-loop intelligent mobility service supply chain network. This paper explains the intelligent mobility service supply chain network from following perspectives: (i) mobility service taxonomy of MaaS; (ii) aims of intelligent mobility service supply chain network; (iii) urban rail transit (URT)-centered alternatives for integrated multimodal journey planning, i.e. access + URT + egress, and both access and egress can be served by Mobility-On-Demand (MOD) transport; (iv) node member imperatives. From a synthesis of insights from the ‘during’ journey, this study puts forward the synergetic design of intelligent mobility service supply chain network, including: (i) multi-tier closed-loop structure; (ii) key nodes identification for the physical multimodal transport network in the supply chain; (iii) hybrid synergy mechanisms among the partners, i.e., synergy principle, temporal splitting approach for coopetition synergy; (iv) index systems and evaluation methods for synergy measurement. This study also contributes to the integrated multimodal journey planning. In concluding, the paper highlights the important implications of the proposed intelligent mobility service supply chain network for MaaS bundle design and adverse effects reduction, resulting from 1 + 1 > 2 synergy effects.