Apparent Synergy Research Articles

Screening the NCI diversity set V for anti-MRSA activity: cefoxitin synergy and LC-MS/MS confirmation of folate/thymidine biosynthesis inhibition.

New antibacterial agents and agent combinations are urgently needed to combat antimicrobial resistance. A multidimensional chemical library screening strategy was used to identify compounds in the National Cancer Institute (NCI) diversity set V library (1,593 compounds) with anti-methicillin-resistant Staphylococcus aureus (MRSA) activity. In this effort, library compounds were screened for anti-MRSA activity in both their original [un-metabolized (UM)] and human liver microsome-metabolized [post-metabolized (PM)] forms and in the absence and presence of sub-minimum inhibitory concentration (MIC) levels of cefoxitin. This strategy allows for the identification of intrinsically active agents, agents with active metabolites, and agents that can act synergistically with cefoxitin. Sixteen UM compounds with MICs ≤ 12.5 µM were identified. No agents with substantially enhanced activity after microsomal metabolism were found. Several agents showed significant apparent synergy with cefoxitin, and checkerboard assays were used to confirm synergy for four of these (celastrol, porfiromycin, 4-quinazolinediamine, and teniposide). A follow-up comparative screen in the absence and presence of 4-µM thymidine was used to identify three agents as likely folate/thymidine biosynthesis inhibitors. A liquid chromatography-mass spectrometry (LC-MS/MS) assay for deoxythymidine triphosphate (dTTP) was used to confirm these three as suppressing dTTP biosynthesis in MRSA. Bactericidal vs bacteriostatic activity was also evaluated. This study further demonstrates the utility of comparative library screening to identify novel bioactive agents with interesting synergies and biological activities. The identification of several folate/thymidine biosynthesis inhibitors from this small screen indicates that this pathway is a viable target for new drug discovery efforts. IMPORTANCE New antibacterial agents are urgently needed to counter increasingly resistant bacteria. One approach to this problem is library screening for new antibacterial agents. Library screening efforts can be improved by increasing the information content of the screening effort. In this study, we screened the National Cancer Institute diversity set V against methicillin-resistant Staphylococcus aureus (MRSA) with several enhancements. One of these is to screen the library before and after microsomal metabolism as means to identify potential active metabolites. A second enhancement is to screen the library in the absence and presence of sub-minimum inhibitory concentration levels of another antibiotic, such as cefoxitin in this study. This identified four agents with synergistic activity with cefoxitin out of 16 agents with good MRSA activity alone. Finally, active agents from this effort were counter-screened in the presence of thymidine, which quickly identified three folate/thymidine biosynthesis inhibitors, and also screened for bactericidal vs bacteriostatic activity.

Examining the relationships between supply, demand, and environmental policies for science and technology innovation using a system simulation model

The development of science and technology has been increasingly linked with the implementation of science and technology innovation (STI) policies with important strategic significance for promoting national and regional innovation. In actual implementation, many types of STI policies are often combined for a joint effect; however, existing studies tend to focus on the effect of a single policy. The system simulation method can break through the limitations of traditional methods in model assumptions and establish a model that is as close to reality as possible. Notably, it is unusual to use the system simulation method to investigate STI policies. Using a system simulation model, this study conducts a detailed analysis to examine the complex causal relationships of STI systems and study the impact and mechanism of STI policy from a systematic perspective. This study quantifies various STI policies, establishing a simulation model to reflect the dynamic behavior of the regional STI policy system. The empirical results demonstrate that when a single type of policy is examined, the STI supply policy has the most significant impact on promoting STI and economic development. When various STI policies are combined, the combination of supply and demand policies has the greatest promotional effect on STI and economic development, whereas the combination of demand and environmental policies has the least promotional effect on STI and economic development. The results also show that the combined effect of various STI policies is not based on the simple addition of the effects of various policies, as there is an apparent synergy phenomenon in the combined STI effects. This study contributes to the existing literature and provides practical insights for policymakers and policy enthusiasts to understand the relationships between STI supply, demand, and environmental policies to advance policy effectiveness and promote sustainable development.

Potentiation of Apoptotic Effect of Combination of Etoposide and Quercetin on HepG2 Liver Cancer Cells

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. The current remedies for cancer, including chemotherapy and radiation therapy, might damage patients’ organs, sometimes causing death. Etoposide (ETO), as a widely used chemo-drug, possesses the same problems. For years, combinational therapy has been considered a potential adjustor for common treatments, alleviating their side effects. Quercetin (Que), a phytochemical drug, has been used due to its potential against cancer. Objectives: This study explored whether synergy occurs between Que and ETO on the apoptosis of HepG2 HCC cells or not. Methods: The impacts of the drugs on cell growth were assessed through the MTT assay. The apoptotic death rates of treated cells were examined through Annexin/PI double staining and caspase-9 and caspase-3 activities. The relative expression of B-cell lymphoma 2 (Bcl-2) associated X-protein (Bax), and Bcl-2 genes and proteins were analyzed using quantitative reverse transcription polymerase chain reaction and western blot analysis. Additionally, the levels of p53 protein were determined. Results: Both Que and ETO reduced the cell viability and increased apoptotic rates, caspases activities, Bax gene and protein expression, and the p53 protein levels of HepG2 cells. The combination of Que and ETO showed apparent synergy in terms of cell growth and cell apoptosis. Que significantly enhanced the effects of ETO on caspase activities, Bax and Bcl-2 genes’ expression, and p53 protein levels. Conclusions: The obtained results demonstrated that Que showed synergy when co-treated with ETO on HepG2 cells. Therefore, it is concluded that further studies on the aforementioned combination could lead to a potential anticancer compound against HCC.

Incorporation of a Metal Catalyst for the Ammonia Synthesis in a Ferroelectric Packed-Bed Plasma Reactor: Does It Really Matter?

Plasma-catalysis has been proposed as a potential alternative for the synthesis of ammonia. Studies in this area focus on the reaction mechanisms and the apparent synergy existing between processes occurring in the plasma phase and on the surface of the catalytic material. In the present study, we approach this problem using a parallel-plate packed-bed reactor with the gap between the electrodes filled with pellets of lead zirconate titanate (PZT), with this ferroelectric material modified with a coating layer of alumina (i.e., Al2O3/PZT) and the same alumina layer incorporating ruthenium nanoparticles (i.e., Ru-Al2O3/PZT). At ambient temperature, the electrical behavior of the ferroelectric packed-bed reactor differed for these three types of barriers, with the plasma current reaching a maximum when using Ru-Al2O3/PZT pellets. A systematic analysis of the reaction yield and energy efficiency for the ammonia synthesis reaction, at ambient temperature and at 190 °C and various electrical operating conditions, has demonstrated that the yield and the energy efficiency for the ammonia synthesis do not significantly improve when including ruthenium particles, even at temperatures at which an incipient catalytic activity could be inferred. Besides disregarding a net plasma-catalysis effect, reaction results highlight the positive role of the ferroelectric PZT as moderator of the discharge, that of Ru particles as plasma hot points, and that of the Al2O3 coating as a plasma cooling dielectric layer.

Interactions and rheology of guar gum–mucin mixtures

This work studies the molecular interactions of guar gum, one of the major hydrocolloids, with mucin as to understand guar gum's behavior and functionality upon consumption. Guar gum, mucin, and their binary mixtures were studied at different pH values. The phase stability and particle size distributions were recorded over a pH range of 1–7, and at a range of guar gum to mucin ratios. Aggregations leading to phase separations are more pronounced at low pH, especially when mucin is involved. The effect of electrostatic repulsions on phase stability as function of pH is discussed. The shear viscosity of these systems is dominated by the presence of guar gum, with few, if any, apparent synergies with mucin. The image changes in extensional viscosity, where strong negative synergies are encountered when mucin co-exists with guar gum. Taking into account the intrinsic viscosity and existing thermodynamic data, these synergies are attributed to transient steric interactions. The different effect of mucin on the shear and extensional rheologies of guar gum are discussed on the basis of molecular interactions. The discussion highlights the potentially important implications in the behavior of these systems during oral and other processes. • The interactions between guar gum and mucin are studied. • Phase separations and particle sizes are mapped for a range of pH values. • Shear rheology is dominated by the presence of guar gum. • The presence of mucin strongly affects the extensional rheology of guar gum. • Synergies and antagonisms in rheology are attributed to intermolecular interactions.

Layered and integrated medical countermeasures against Burkholderia pseudomallei infections in C57BL/6 mice.

Burkholderia pseudomallei, the gram-negative bacterium that causes melioidosis, is notoriously difficult to treat with antibiotics. A significant effort has focused on identifying protective vaccine strategies to prevent melioidosis. However, when used as individual medical countermeasures both antibiotic treatments (therapeutics or post-exposure prophylaxes) and experimental vaccine strategies remain partially protective. Here we demonstrate that when used in combination, current vaccine strategies (recombinant protein subunits AhpC and/or Hcp1 plus capsular polysaccharide conjugated to CRM197 or the live attenuated vaccine strain B. pseudomallei 668 ΔilvI) and co-trimoxazole regimens can result in near uniform protection in a mouse model of melioidosis due to apparent synergy associated with distinct medical countermeasures. Our results demonstrated significant improvement when examining several suboptimal antibiotic regimens (e.g., 7-day antibiotic course started early after infection or 21-day antibiotic course with delayed initiation). Importantly, this combinatorial strategy worked similarly when either protein subunit or live attenuated vaccines were evaluated. Layered and integrated medical countermeasures will provide novel treatment options for melioidosis as well as diseases caused by other pathogens that are refractory to individual strategies, particularly in the case of engineered, emerging, or re-emerging bacterial biothreat agents.

Coupling a weather model directly to GNSS orbit determination – case studies with OpenIFS

Abstract. Neutral gas atmosphere bends and delays propagation of microwave signals in satellite-based navigation. Weather prediction models can be used to estimate these effects by providing three-dimensional refraction fields to ray-trace the signal delays. In this study, a global numerical weather prediction model (Open Integrated Forecasting System (OpenIFS) licensed for Academic use by the European Centre for Medium-Range Weather Forecast) is used to generate the refraction fields. The ray-traced slant delays are supplied as such – in contrast to mapping – for an orbit solver (GROOPS (Gravity Recovery Object Oriented Programming System) software toolkit of Graz University of Technology) which applies the raw observation method. Here we show that such a close coupling is possible without need for major additional modifications in the solver codes. The main finding here is that the adopted approach provides a very good a priori model for the atmospheric effects on navigation signals. We suspect that removal of the intermediate mapping step allows us to take advantage of the local refraction field asymmetries in the GNSS signal processing. Moreover, the direct coupling helps in identifying deficiencies in the slant delay computation because the modeling errors are not convoluted in the mapping procedures. These conclusions appear robust, despite the relatively small data set of raw code and phase observations covering the core network of 66 ground-based stations of the International GNSS Service over 1-month periods in December 2016 and June 2017. More generally, the new configuration enhances our control of geodetic and meteorological aspects of the orbit problem. This is pleasant because we can, for instance, regulate at will the weather model output frequency and increase coverage of spatiotemporal aspects of weather variations. The direct coupling of a weather model in precise GNSS orbit determination presented in this paper provides a unique framework for benefiting even more widely than previously the apparent synergies in space geodesy and meteorology.

Feedback between climate change and eutrophication: revisiting the allied attack concept and how to strike back

ABSTRACT Despite its well-established negative impacts on society and biodiversity, eutrophication continues to be one of the most pervasive anthropogenic influences along the freshwater to marine continuum. The interaction between eutrophication and climate change, particularly climate warming, was explicitly focused upon a decade ago by Brian Moss and others in “Allied attack: climate change and eutrophication,” which called for an integrated response to both problems, given their apparent synergy. In this review, we summarise advances in the theoretical framework and empirical research on this issue and analyse the current understanding of the major drivers and mechanisms by which climate change can enhance eutrophication, and vice versa, with a particular focus on shallow lakes. Climate change can affect nutrient loading through changes at the catchment and landscape levels by affecting hydrological patterns and fire frequency and through temperature effects on nutrient cycling. Biotic communities and their interactions can also be directly and indirectly affected by climate change, leading to an overall weakening of resilience to eutrophication impacts. Increasing empirical evidence now indicates several mechanisms by which eutrophying aquatic systems can increasingly act as important sources of greenhouse gases to the atmosphere, particularly methane. We also highlight potential feedback among eutrophication, cyanobacterial blooms, and climate change. Facing both challenges simultaneously is more pressing than ever. Meaningful and strong measures at the landscape and waterbody levels are therefore required if we are to ensure ecosystem resilience and safe water supply, conserve biodiversity, and decrease the carbon footprint of freshwaters.

The City Mindful: Commentary on “Mindful engagement, psychological restoration, and connection with nature in constrained nature experiences”

This commentary complements Macaulay et al.'s thoughtful and valuable perspective by attending to some additional matters of theoretical, ethical, and practical importance. First, I argue for how consideration of multiple levels of complementarity between processes in mindfulness and nature experience allow more powerful integrations than building on apparent synergies. Second, I outline how an understanding of mindfulness as a practice and training can illuminate relationships between states, traits and values of equal relevance for human health and sustainable transitions. Third, I discuss some caveats and considerations in planning for mindfulness, pointing to insights that researchers and professionals committed to sustainable cities can gain from “McMindfulness” debates and other controversies around meditation before outlining some tentative ideas for how urban environmental design could support mindful living and mindful action.

Mathematical Modelling of the Molecular Mechanisms of Interaction of Tenofovir with Emtricitabine against HIV

The combination of the two nucleoside reverse transcriptase inhibitors (NRTI) tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is used in most highly active antiretroviral therapies for treatment of HIV-1 infection, as well as in pre-exposure prophylaxis against HIV acquisition. Administered as prodrugs, these drugs are taken up by HIV-infected target cells, undergo intracellular phosphorylation and compete with natural deoxynucleoside triphosphates (dNTP) for incorporation into nascent viral DNA during reverse transcription. Once incorporated, they halt reverse transcription. In vitro studies have proposed that TDF and FTC act synergistically within an HIV-infected cell. However, it is unclear whether, and which, direct drug–drug interactions mediate the apparent synergy. The goal of this work was to refine a mechanistic model for the molecular mechanism of action (MMOA) of nucleoside analogues in order to analyse whether putative direct interactions may account for the in vitro observed synergistic effects. Our analysis suggests that depletion of dNTP pools can explain apparent synergy between TDF and FTC in HIV-infected cells at clinically relevant concentrations. Dead-end complex (DEC) formation does not seem to significantly contribute to the synergistic effect. However, in the presence of non-nucleoside reverse transcriptase inhibitors (NNRTIs), its role might be more relevant, as previously reported in experimental in vitro studies.

Process Design Guided by Life Cycle Assessment to Reduce Greenhouse Gas-Related Environmental Impacts of Food Processing

Food processing can generate large amounts of carbohydrate-rich waste that inevitably has environmental and social impacts. Meanwhile, certain heterotrophic marine microorganisms, including algae and thraustochytrids, have the potential to convert carbohydrate-rich substrates into oil-rich biomass over relatively short time frames. To assess the merits of this apparent synergy, an initial conceptual process was developed based on the use of raw potato processing waste as feed in an algal bioreactor to produce bio-oil for further use within the food industry. A practical flowsheet was established with a conventional 200 kL bioreactor whereby the unit processes were identified, the mass balance developed, and estimates made of the various material and energy demands. These inputs were used to develop a baseline life cycle assessment (LCA) model and to identify opportunities for reducing environmental impacts. With the functional unit (FU) being 1 tonne cooking oil, the baseline configuration had a greenhouse gas (GHG) footprint of 2.4 t CO2-e/FU, which is comparable to conventional process routes. More detailed LCA revealed that electricity for stirring the bioreactor contributed approximately 78% of the total GHG footprint. By adjusting the operating conditions, the most promising scenario produced 0.85 t CO2-e/FU—approximately four times less than the conventional process—and shows the potential advantages of applying LCA as a tool to develop and design a new production process.

Plasma-Enhanced High Temperature Solid-Oxide Electrolysis Cells: The Search for Synergy

High temperature solid-oxide electrolysis cells (SOECs) are a promising conversion technology to produce energy-rich molecules such as CO from CO2 [Song2019]. The high energy efficiency and separation of product streams intrinsic to oxygen ion-conducting electrolyte materials are desirable for renewable synthetic fuel and value-added chemical production at industrial scale.While most improvement in SOEC performance in recent years has been achieved by advancements in electrode materials and cell design, the use of plasmas to enhance SOEC performance also shows potential [Mori2017, Patel2019]. It is reported that the oxygen exchange rate for yttria-stabilized zirconia (YSZ) is 100 times higher simply by exposure to plasma [Rohnke2004]. Despite the apparent synergy in such plasma-SOEC approaches, the underlying mechanisms of plasma and surface processes are presently not well understood. A common explanation is that plasma-activated species (e.g., by vibrational excitation, plasma-dissociation and ionization) support the reduction kinetics on the surface. The effects of plasma-induced surface charging and local fields on, for instance, the vacancy concentration and exchange kinetics may also play a significant role. Dedicated experiments aimed to distinguish between these underlying mechanisms are essential to reveal the true nature of the synergy.In this contribution, we will present our novel hybrid plasma-SOEC reactor aimed at investigating fundamental aspects of SOEC-plasma synergy. The plasma is generated in a brushed electrode discharge in the quiescent region [Ratynskaia2015], which provides a highly stable, homogeneous and field-free plasma environment well suited for a controlled exposure of the SOEC. Langmuir probe measurements will help to obtain insights into the plasma properties, complemented with 1D plasma-kinetic modelling of the plasma bulk and wall region. With this combined experimental-modeling approach, we intend not only to quantify the plasma-effect on SOEC performance, but also to develop insights into the rate-limiting kinetics. We will share our first experimental results on plasma-enhanced oxygen pumping in an O2/He plasma environment.Song, Y., Zhang, X., Xie, K., Wang, G., & Bao, X. (2019). High-Temperature CO2 Electrolysis in Solid Oxide Electrolysis Cells: Developments, Challenges, and Prospects. Advanced MaterialsMori, S., & Tun, L. L. (2017). Synergistic CO2 conversion by hybridization of dielectric barrier discharge and solid oxide electrolyser cell. Plasma Processes and Polymers, 14(6), 1600153.Patel, H., Sharma, R. K., Kyriakou, V., Pandiyan, A., Welzel, S., Van De Sanden, M. C. M., & Tsampas, M. N. (2019). Plasma-Activated Electrolysis for Cogeneration of Nitric Oxide and Hydrogen from Water and Nitrogen. ACS Energy Letters, 4(9), 2091–2095.Rohnke, M., Janek, J., Kilner, J. A., & Chater, R. J. (2004). Surface oxygen exchange between yttria-stabilised zirconia and a low-temperature oxygen rf-plasma. Solid State Ionics, 166(1–2), 89–102.Ratynskaia, S., Dilecce, G., & Tolias, P. (2015). BABE – a brush cathode discharge for thermal fluctuation measurements. J. Plasma Physics, 81(2), 345810202.

Enhanced thermal conductivity and isotropy of polymer composites by fabricating 3D network structure from carbon‐based materials

AbstractGraphene‐based composite is promising as thermal interface material (TIM) due to its outstanding thermal properties. However, there are some bottlenecks to excellent performance, such as agglomeration of particles and undesirable voids between nanoplatelets. In this work, a composite with three‐dimensional (3D) thermally conductive network has been assembled, which combines three kinds of nanofillers varying geometric dimensions. Thermal conductivity (TC) of composite with graphene nanoplatelets (GNPs) and carbon‐nanotubes (CNTs) at a weight ratio of 3:1 is around 9% higher than that of GNP‐based composite. By the introduction of carbon spheres (CSs), the TC is further increased by 28%. The enhanced thermal property further demonstrated by FLIR infrared camera is attributed to the formation of 3D heat conduction paths by GNPs, CNTs, and CSs, where the GNPs play the role of thermally conductive backbones. The other two components are introduced to attenuate the aggregation and strong thermal anisotropy. Moreover, the TC is confirmed nearly isotropic, which is different from most graphene‐based TIMs because of the in‐plane alignment. Our results indicate that the apparent synergy endows this 3D nanofiller great potential for heat dissipation applications requiring heat removal in two directions.

The immunomodulatory capacity of aggregated MSCs is enhanced through synergy with glucocorticoid steroids

Background & Aim Upon local delivery, MSCs aggregate into spheroids leading to alterations in phenotype. While MSCs immunomodulatory potential in 2D cultures has been extensively studied, the effect of aggregation on this potential is less understood. Using a series of in vitro potency assays, we sought to evaluate changes to human MSCs ability to suppress activated human T cells and explore the interactions of these cells with locally delivered steroids. Methods, Results & Conclusion We used a T-cell suppression assay to compare the ability of MSCs, either in 2D or aggregated into spheroids, to suppress T-cell proliferation. 6 human MSC donors, 3 from bone marrow and 3 from umbilical cord, were co-cultured with PBMCs from 3 independent donors creating 18 distinct MSC:PBMC donor pairings. After 6 days of co-culture, PBMCs were analyzed by flow cytometry and the percent PBMC proliferation was calculated for each donor pairing. For adherent MSCs, all 18 pairings resulted in strong suppression of PBMC proliferation, while none of the spheroid MSCs showed any suppression (A). The addition of budesonide, a glucocorticoid steroid, to the co-culture resulted in a significant improvement in spheroid MSC suppression (A). This observation led us to examine the interaction between budesonide and spheroid MSCs mechanistically. While neither budesonide nor aggregated MSCs alone were capable of affecting PBMC proliferation, when combined they displayed an apparent synergy and suppressed a significant degree of PBMC proliferation. Profiling activity of COX-2 and IDO revealed distinct changes in PGE2 (B) and kynurenine (C) production by MSC spheroids with PGE2 over a 100-fold higher in MSC spheroid cultures compared to adherent MSC controls. To determine if the interaction between budesonide and MSC spheroids was mediated by elevated PGE2 levels, a series of inhibition and add-back experiments were performed using PBMC co-culture assays as a read-out. Blockade of EP2/EP4 receptors with small molecule inhibitors completely blocked the synergy between spheroid MSCs and budesonide (D) while replacing spheroid MSCs with synthetic PGE2 replicated the observed synergy (E). Conclusion We report a novel mechanism by which PGE2 from spheroid MSCs works in synergy with the glucocorticoid steroid, budesonide, to inhibit T cells. These findings shed light both on a distinct immunomodulatory phenotype of aggregated MSCs as well as their unique interactions with immunosuppressive drugs they may encounter in clinical settings.

Mycobacterium tuberculosis Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics.

The synergy between Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV-1) interferes with therapy and facilitates the pathogenesis of both human pathogens. Fundamental mechanisms by which M. tuberculosis exacerbates HIV-1 infection are not clear. Here, we show that exosomes secreted by macrophages infected with M. tuberculosis, including drug-resistant clinical strains, reactivated HIV-1 by inducing oxidative stress. Mechanistically, M. tuberculosis-specific exosomes realigned mitochondrial and nonmitochondrial oxygen consumption rates (OCR) and modulated the expression of host genes mediating oxidative stress response, inflammation, and HIV-1 transactivation. Proteomics analyses revealed the enrichment of several host factors (e.g., HIF-1α, galectins, and Hsp90) known to promote HIV-1 reactivation in M. tuberculosis-specific exosomes. Treatment with a known antioxidant-N-acetyl cysteine (NAC)-or with inhibitors of host factors-galectins and Hsp90-attenuated HIV-1 reactivation by M. tuberculosis-specific exosomes. Our findings uncover new paradigms for understanding the redox and bioenergetics bases of HIV-M. tuberculosis coinfection, which will enable the design of effective therapeutic strategies.IMPORTANCE Globally, individuals coinfected with the AIDS virus (HIV-1) and with M. tuberculosis (causative agent of tuberculosis [TB]) pose major obstacles in the clinical management of both diseases. At the heart of this issue is the apparent synergy between the two human pathogens. On the one hand, mechanisms induced by HIV-1 for reactivation of TB in AIDS patients are well characterized. On the other hand, while clinical findings clearly identified TB as a risk factor for HIV-1 reactivation and associated mortality, basic mechanisms by which M. tuberculosis exacerbates HIV-1 replication and infection remain poorly characterized. The significance of our research is in identifying the role of fundamental mechanisms such as redox and energy metabolism in catalyzing HIV-M. tuberculosis synergy. The quantification of redox and respiratory parameters affected by M. tuberculosis in stimulating HIV-1 will greatly enhance our understanding of HIV-M. tuberculosis coinfection, leading to a wider impact on the biomedical research community and creating new translational opportunities.

Exploring synergies and trade-offs among the sustainable development goals: collective action and adaptive capacity in marginal mountainous areas of India

Global environmental change (GEC) threatens to undermine the sustainable development goals (SDGs). Smallholders in marginal mountainous areas (MMA) are particularly vulnerable due to precarious livelihoods in challenging environments. Acting collectively can enable and constrain the ability of smallholders to adapt to GEC. The objectives of this paper are: (i) identify collective actions in four MMA of the central Indian Himalaya Region, each with differing institutional contexts; (ii) assess the adaptive capacity of each village by measuring livelihood capital assets, diversity, and sustainable land management practices. Engaging with adaptive capacity and collective action literatures, we identify three broad approaches to adaptive capacity relating to the SDGs: natural hazard mitigation (SDG 13), social vulnerability (SDG 1, 2 and 5), and social–ecological resilience (SDG 15). We then develop a conceptual framework to understand the institutional context and identify SDG synergies and trade-offs. Adopting a mixed method approach, we analyse the relationships between collective action and the adaptive capacity of each village, the sites where apparent trade-offs and synergies among SDGs occur. Results illustrate each village has unique socio-environmental characteristics, implying distinct development challenges, vulnerabilities and adaptive capacities exist. Subsequently, specific SDG synergies and trade-offs occur even within MMA, and it is therefore crucial that institutions facilitate locally appropriate collective actions in order to achieve the SDGs. We suggest that co-production in the identification, prioritisation and potential solutions to the distinct challenges facing MMA can increase understandings of the specific dynamics and feedbacks necessary to achieve the SDGs in the context of GEC.

PD-1 and LAG-3 synergize to drive tumour-infiltration of T cytotoxic cells in NSCLC tumours

Abstract Background Non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all lung cancer cases, and is characterized by a poor response to chemotherapy and a low survival rate. Treatment targeting the immune checkpoint inhibitor pathway PD-1/PD-L1 has been found to be effective against NSCLC with manageable side effects, but with only 20-25% of patients showing a positive response there is an urgent need for additional immunotherapy options for this group of patients. LAG-3 and PD-1 are often co-expressed and upregulated on T cells leading to immune exhaustion and tumor growth, and co-blockade of the LAG-3 and PD-1 pathways has been shown to synergize to improve T cytotoxic cell responses. Methods In order to perform a comprehensive immunoprofiling of NSCLC tumors we used MultiOmyx™, an immunofluorescence (IF) multiplexing assay that utilize a pair of directly conjugated Cyanine dye-labeled (Cy3, Cy5) antibodies per round of staining. Using a 16-marker panel we have analyzed the proportion of B cells, T cell subtypes, M1/M2-type tumor-associated macrophages, as well as the expression of PD-1, PD-L1, LAG-3, and TIM-3 in 20 samples from patients with NSCLC. Results LAG-3 was found to be expressed mainly on T cytotoxic cells in both subtypes, but the overall density of LAG-3 was 59% higher in squamous cell carcinoma (SCC) tumors compared to adenocarcinoma tumors. In both SCC and adenocarcinoma subtypes TIM-3 was found primarily on tumor-associated macrophages (TAMs), followed by an equal distribution on helper and cytotoxic T cells. When analyzing the proportion of T cytotoxic cells infiltrating into the tumor area, we observed an apparent synergy between LAG-3 and PD-1, suggesting a therapeutic benefit of dual checkpoint blockade of LAG-3 and PD-1 in NSCLC. Conclusion It is our hope that these data will help provide new insights into the biology of NSCLC that can ultimately be used to explore novel immunotherapeutic interventions for lung cancer treatment. Legal entity responsible for the study NeoGenomics. Funding NeoGenomics. Disclosure A. Juncker-Jensen: Full / Part-time employment: NeoGenomics. M. Nagy: Full / Part-time employment: NeoGenomics. J. Kuo: Full / Part-time employment: NeoGenomics. E. Leones: Full / Part-time employment: NeoGenomics. F. Sahafi: Full / Part-time employment: NeoGenomics. K. Pham: Full / Part-time employment: NeoGenomics. E. Parnell: Full / Part-time employment: NeoGenomics.

Chimeric Murine Polyomavirus Virus-Like Particles Induce Plasmodium Antigen-Specific CD8+ T Cell and Antibody Responses.

An effective vaccine against the Plasmodium parasite is likely to require the induction of robust antibody and T cell responses. Chimeric virus-like particles are an effective vaccine platform for induction of antibody responses, but their capacity to induce robust cellular responses and cell-mediated protection against pathogen challenge has not been established. To evaluate this, we produced chimeric constructs using the murine polyomavirus structural protein with surface-exposed CD8+ or CD4+ T cell or B cell repeat epitopes derived from the Plasmodium yoelii circumsporozoite protein, and assessed immunogenicity and protective capacity in a murine model. Robust CD8+ T cell responses were induced by immunization with the chimeric CD8+ T cell epitope virus-like particles, however CD4+ T cell responses were very low. The B cell chimeric construct induced robust antibody responses but there was no apparent synergy when T cell and B cell constructs were administered as a pool. A heterologous prime/boost regimen using plasmid DNA priming followed by a VLP boost was more effective than homologous VLP immunization for cellular immunity and protection. These data show that chimeric murine polyomavirus virus-like particles are a good platform for induction of CD8+ T cell responses as well as antibody responses.

Inhibitory Effect of Dietary Curcumin on 1, 2-Dimethylhydrazine-Induced Colon Preneoplasia in Irradiated Rats

Introduction: Prevention of cancer remains a primary need and new chemopreventive agents must be developed for this purpose. It is well known that the radiotherapy is associated with severe side effects and offers no firm expectation for a cure. Thus, there is a constant need for the investigation of other potentially useful options. One of the widely sought approaches is cancer chemoprevention that uses natural agents. Curcumin, a natural plant product, has been shown to have anti-inflammatory and antioxidant properties and which, thus, may be a potential anticancer drug. Material and Methods: The inhibitory effects of dietary curcumin (0.6 % in diet) on colonic precancerous lesions in rats treated with 1,2-dimethylhydrazine, (DMH, 20 mg/kg, s.c. once weekly for 6 weeks) or exposed to γ-radiation (6.5 Gy) alone or in combination were evaluated histologically and histochemically. Results: The results showed clear features of colonic dysplasia with DMH treatment. The dysplastic crypts exhibited marked hyperchromatism, loss of polarity besides nuclear and cellular stratification. Whereas, γ-irradiation revealed marked crypt dilatation accompanied by disorganized crypt structure and alteration of surface epithelium. The results also demonstrate an apparent synergy between the radiation and the chemical carcinogen in the induction of augmentation of mucosal abnormalities accompanied with increased total DNA content and cell proliferation. Consistent with these observations, changes in the type of mucous secretion with predominance of sialomucins were observed in the areas of mild to moderate dysplasia whilst the surrounding normal epithelium produced sulphated material. Mucus depletion was a common feature in areas of severe dysplasia. Addition of curcumin to the diet remarkably reduced the amount and severity of dysplastic lesions with DMH-induced colon preneoplasia without appreciable toxicity. Moreover, curcumin could prevent or improve the disruption of colonic architecture caused by γ- irradiation. Such improvement was also investigated but to a lesser extent with the combined radiation and DMH. Conclusion: These results indicated that curcumin is potent in inhibiting the preneoplastic lesions and other cellular events relevant to colon and was, therefore, of value as a safe chemotherapeutic agent.

Decoupling the role of stress and corrosion in the intergranular cracking of noble-metal alloys.

Intergranular stress-corrosion cracking (IGSCC) is a form of environmentally induced crack propagation causing premature failure of elemental metals and alloys. It is believed to require the simultaneous presence of tensile stress and corrosion; however, the exact nature of this synergy has eluded experimental identification. For noble metal alloys such as Ag-Au, IGSCC is a consequence of dealloying corrosion, forming a nanoporous gold layer that is believed to have the ability to transmit cracks into grain boundaries in un-dealloyed parent phase via a pure mechanical process. Here using atomic-scale techniques and statistical characterizations for this alloy system, we show that the separate roles of stress and anodic dissolution can be decoupled and that the apparent synergy exists owing to rapid time-dependent morphology changes at the dealloyed layer/parent phase interface. We discuss the applicability of our findings to the IGSCC of important engineering Fe- and Ni-based alloys in critical applications.