Synergy

Antibiotics have been effective in treating infectious diseases, but resistance to these drugs has led to the emergence of new and the reemergence of old infectious diseases. One strategy employed to overcome these resistance mechanisms is the use of combination of drugs, such as β-...

With reports of pandrug-resistant bacteria causing untreatable infections, the need for new antibacterial therapies is more pressing than ever. Alkaloids are a large and structurally diverse group of compounds, which have served as scaffolds for important antibacterial drugs like metronidazole and the quinolones. In this review we highlight other alkaloids with development potential. Natural, semi-synthetic, and synthetic alkaloids of all classes are considered, looking first at those with direct antibacterial activity and those with antibiotic-enhancing activity. Potent examples include CJ-13,136, a novel actinomycetederived quinolone alkaloid with MICs of 0.1 ng/mL against Helicobacter pylori, and squalamine, a polyamine alkaloid from the dogfish shark which renders Gram-negative pathogens 16 to >32-fold more susceptible to ciprofloxacin. Where available, information on toxicity, structure-activity relationships, mechanisms of action, and in vivo activity is presented. The effects of alkaloids on virulence gene regulatory systems such as quorum sensing, and virulence factors like sortases, adhesins, and secretion systems are also described. The synthetic isoquinoline alkaloid virstatin, for example, inhibits the transcriptional regulator ToxT in Vibrio cholerae, preventing expression of cholera toxin and fimbriae, and conferring in vivo protection against intestinal colonization. The review concludes with implications and limitations of the described research, and directions for future research.

Several nanosized catalysts Co 3 O 4 -CeO 2 with varying compositions were synthesized by a surfactant-template method and further promoted by a small amount of Pd (0.5 wt%). These catalysts exhibit uniform mesoporous structure and high surface area (>100 m 2 g −1 ). The Co 3 O 4 crystallites in these catalysts are encapsulated by nanosized CeO 2 with only a small fraction of Co ions exposing on the surface and strongly interacting with CeO 2 . Such structure maximizes the interaction between Co 3 O 4 and CeO 2 in three dimensions, resulting in unique redox properties. The introduction of Pd prominently enhances both the reduction and oxidation performance of the catalysts, due to hydrogen or oxygen spillover. These catalysts prepared by surfactant-template method exhibit excellent oxidation performance, especially the ones promoted with Pd, which show markedly enhanced CO oxidation activity even at room temperature. Based upon the results of structural properties, redox behaviors and in situ DRIFTS study, two different reaction pathways over Co 3 O 4 -CeO 2 and Pd/Co 3 O 4 -CeO 2 are proposed. (M. Meng). to the cobalt oxide catalysts (Co 3 O 4 , Co 3 O 4 /Al 2 O 3 ) due to their unique activity for ambient CO oxidation . It is reported that the light-off temperature (T 50 ) for CO oxidation over Co-based catalysts is as low as −63 • C [4]. Cerium oxide, as oxygen storage material, is often added to TWCs, since it not only possesses high oxygen storage capacity (OSC), but also enhances and stabilizes the dispersion of transition metal oxides. Consequently, it is feasible to develop oxidation catalysts mainly consisting of cobalt and cerium oxides.

Transdermal drug delivery system (TDDS) utilizes the skin as executable route for drug administration but the foremost barrier against drug permeability is the stratum corneum and therefore, it limits therapeutic bioavailability of the bioactive. This review focuses on the recent advancements in the TDDS which include iontophoresis, sonophoresis, electroporation, microneedles, magnetophoresis, photomechanical waves and electron beam irradiation. These advancements are exhaustively discussed with techniques involved with their beneficial claims for different categories of bioactive. However, a lot of research has been carried out in TDDS, still the system has many pros and cons such as inconsistent drug release, prevention of burst release formulation and problems related to toxicity. In addition to that, to exploit the TDDS more efficiently scientists have worked on some combinational approaches for manufacturing TDDS viz., chemical-iontophoresis, chemicalelectroporation, chemical-ultrasound, iontophoresis-ultrasound, electroporation-iontophoresis electroporationultrasound and pressure waves-chemicals and reported the synergistic effect of the same for safe, effective and practical use of TDDS. The present article covers all the above-mentioned aspects in detail and hence the article will assuredly serve as an enlightening tool for the visionaries working in the concerned area.

The relative disinfection efficiencies of peracetic acid (PAA), hydrogen peroxide (H 2 O 2 ) and sodium hypochlorite (NaOCl) against Escherichia coli, Enterococcus faecalis, Salmonella enteritidis and coliphage MS2 virus were studied in laboratory-scale experiments. This study also evaluated the efficiency of combined PAA/ultraviolet irradiation (UV) and H 2 O 2 /UV treatments to determine if the microbial inactivation was synergistic. Microbial cultures were added into a synthetic wastewater-like test medium and treated by chemical disinfectants with a 10 min contact time, UV irradiation or the combination of chemical and UV treatments. A peracetic acid dose of 3 mg/l resulted in approximately 2-3 log enteric bacterial reductions, whereas 7-15 mg/l PAA was needed to achieve 1-1.5 log coliphage MS2 reductions. Doses of 3-150 mg/l hydrogen peroxide achieved below 0.2 log microbial reductions. Sodium hypochlorite treatments caused 0.3-1 log microbial reductions at an 18 mg/l chlorine dose, while 2.6 log reductions of E. faecalis were achieved at a 12 mg/l chlorine dose. The results indicate that PAA could represent a good alternative to chlorine compounds in disinfection procedures, especially in wastewaters containing easily oxidizable organic matter. Hydrogen peroxide is not an efficient disinfectant against enteric microorganisms in wastewaters. The combined PAA/ UV disinfection showed increased disinfection efficiency and synergistic benefits with all the enteric bacteria tested but lower synergies for the coliphage MS2. This suggests that this method could improve the efficiency and reliability of disinfection in wastewater treatment plants. The combined H 2 O 2 /UV disinfection only slightly influenced the microbial reductions compared to UV treatments and showed some antagonism and no synergies.

Of the various attempts to generalize information theory to multiple variables, the most widely utilized, interaction information, suffers from the problem that it is sometimes negative. Here we reconsider from first principles the general structure of the information that a set of sources provides about a given variable. We begin with a new definition of redundancy as the minimum information that any source provides about each possible outcome of the variable, averaged over all possible outcomes. We then show how this measure of redundancy induces a lattice over sets of sources that clarifies the general structure of multivariate information. Finally, we use this redundancy lattice to propose a definition of partial information atoms that exhaustively decompose the Shannon information in a multivariate system in terms of the redundancy between synergies of subsets of the sources. Unlike interaction information, the atoms of our partial information decomposition are never negative and always support a clear interpretation as informational quantities. Our analysis also demonstrates how the negativity of interaction information can be explained by its confounding of redundancy and synergy.

With the increase in antibiotic-resistant bacteria and the lack of new antibiotics being brought onto the market, alternative strategies need to be found to cope with infections resulting from drug-resistant bacteria. A possible solution may be to combine existing antibiotics with phytochemicals to enhance the efficacy of antibiotics. A group of phytochemicals that is said to have such effects, according to in vitro studies, is essential oils (EOs) and their components. Amongst others, EOs containing carvacrol, cinnamaldehyde, cinnamic acid, eugenol and thymol can have a synergistic effect in combination with antibiotics. Several modes of action have been put forward by which antibiotics and the essential oil components may act synergistically, such as by affecting multiple targets; by physicochemical interactions and inhibiting antibacterial-resistance mechanisms. Many reported assays show additivity or moderate synergism, indicating that EOs may offer possibilities for reducing antibiotic use.

Recently, drug nanosuspensions have shown a potential for ophthalmic delivery. In this study, a hydrocortisone (HC) nanosuspension (NS) was developed using microfluidic nanoprecipitation as a recent, simple and cost-effective bottom-up technique of drug nanonization. For comparison, a second HC NS was prepared by top-down wet milling procedures. The produced nanosuspensions were characterized for particle size, shape and zeta potential. HC nanosuspensions of approximately 300 nm particle size were produced by adjusting experimental conditions of the two processing techniques. Results of X-ray diffraction and differential scanning calorimetry revealed that HC maintained the crystalline structure upon milling, while predominant amorphous particles were generated after precipitation. Ocular bioavailability of HC nanosuspensions was assessed in albino rabbits using HC solution as a control. A sustained drug action was maintained up to 9 h for the nanosuspensions compared to 5 h for the drug solution. The precipitated and milled NS achieved comparable AUC0–9h values of 28.06 ± 4.08 and 30.95 ± 2.2, respectively, that were significantly (P < 0.05) higher than that of HC solution (15.86 ± 2.7). After 2 months storage at room temperature, the milled HC NS showed good stability with no discernable changes in particle size, whereas the particle size of the precipitated HC NS increased to 440 nm.Changes in intraocular pressure (IOP) of Albino rabbits after administration of Hc solution and nanosuspensions produced by milling and precipitation.

Anxiety and panic are the most common adverse effects of cannabis intoxication; reactions potentiated by stress. Data suggest that cannabinoid (CB 1 ) receptor modulation of amygdalar activity contributes to these phenomena. Using Fos as a marker, we tested the hypothesis that environmental stress and CB 1 cannabinoid receptor activity interact in the regulation of amygdalar activation in male mice. Both 30 min of restraint and CB 1 receptor agonist treatment (D 9 -tetrahydrocannabinol (2.5 mg/kg) or CP55940 (0.3 mg/kg); by i.p. injection) produced barely detectable increases in Fos expression within the central amygdala (CeA). However, the combination of restraint and CB 1 agonist administration produced robust Fos induction within the CeA, indicating a synergistic interaction between environmental stress and CB 1 receptor activation. An inhibitor of endocannabinoid transport, AM404 (10 mg/kg), produced an additive interaction with restraint within the CeA. In contrast, fatty acid amide hydrolase (FAAH) inhibitor-treated mice (URB597, 1 mg/kg) and FAAH À/À mice did not exhibit any differences in amygdalar activation in response to restraint compared to control mice. In the basolateral (BLA) and medial amygdala, restraint stress produced a low level of Fos induction, which was unaffected by cannabinoid treatment. Interestingly, the CB 1 receptor antagonist SR141716 dose-dependently increased Fos expression in the BLA and CeA. These data suggest the CeA is an important neural substrate subserving the interactions between cannabinoids and environmental stress, and could be relevant to understanding the context-dependent emotional and affective changes induced by marijuana intoxication and the role of endocannabinoid signaling in the modulation of amygdalar activity.

We describe a "centipede's dilemma" that faces the sciences of human interaction. Research on human interaction has been involved in extensive theoretical debate, although the vast majority of research tends to focus on a small set of human behaviors, cognitive processes, and interactive contexts. The problem is that naturalistic human interaction must integrate all of these factors simultaneously, and grander theoretical mitigation cannot come only from focused experimental or computational agendas. We look to dynamical systems theory as a framework for thinking about how these multiple behaviors, processes, and contexts can be integrated into a broader account of human interaction. By introducing and utilizing basic concepts of self-organization and synergy, we review empirical work that shows how human interaction is flexible and adaptive and structures itself incrementally during unfolding interactive tasks, such as conversation, or more focused goal-based contexts. We end on acknowledging that dynamical systems accounts are very short on concrete models, and we briefly describe ways that theoretical frameworks could be integrated, rather than endlessly disputed, to achieve some success on the centipede's dilemma of human interaction.

c Advocates of the market for corporate control argue that takeover bids should be accepted because unsuccessful targets tend to lose market value. Other researchers argue that takeover bi& should be rejected because the combined firms often pe#orm poorly. However, missing in this debate is the infzuence of the source of takeover gains on the decision to reject or accept takeover bids. This study posits that value from takeovers can be created by synergy or restructuring. The study suggests that only if the synergy component is dominant should the target firm agree to be taken over. The study then tests the dominance of the source of value in takeovers by examining takeovers that were unsuccessful. The study concludes that, first, restructuring, not synergy, motivated the sample studied and target firms can create the same value independently. Second the need for restructuring was industry-wide. However, even if restructuring is the motive behind a takeover, the target firm has to carry out the restructuring, failing which it does not create any value. The study also suggests reasons for the ambiguous findings in the strategic management merger literature. I Also, a simple transfer of control without the physical consolidation of the assets of the two firms is unlikely to bring about any synergistic gains. These gains typically arise out of a rationalizing of the different functions-marketing, manufacturing etc-of the consolidated entity. Thus Unisys, notwithstanding their current situation, initially managed to extract substantial operating efficiencies by the physical consolidation of Burroughs and Sperry. Same is true for Kraft and General Foods.

The aim of this study was to assess the in vitro activity of a number of non-traditional antibiotics (colistin, azithromycin, doxycycline and rifampicin) against multidrug-resistant (MDR) strains of Pseudomonas aeruginosa and Acinetobacter baumannii isolated from Intensive Care Units (ICUs). We also used the checkerboard method to determine whether combinations of colistin with another non-traditional antibiotic or meropenem act synergistically against these strains. Thirty-five P. aeruginosa and 25 A. baumannii strains that were found to be MDR were included the study. Isolates were collected from the specimens of patients in ICUs from 2001 to 2003. All isolates were identified by standard methods and stored at −20 °C until use. Antibiotic powders of azithromycin, doxycycline, rifampicin, meropenem and colistin were obtained from their manufacturers. Minimum inhibitory concentrations (MICs) were determined by the agar dilution method on Mueller–Hinton agar. Five strains of A. baumannii and five strains of P. aeruginosa, all of which had different MIC values for colistin, were selected for the synergy study using the checkerboard titration method. The susceptibility results for doxycycline and meropenem were interpreted according to National Committee for Clinical Laboratory Standards guidelines. The susceptibility breakpoints for colistin and rifampicin were established as 4 mg/L and 2 mg/L, respectively, based on previous studies. Pseudomonas aeruginosa ATCC 27853 and Escherichia coli ATCC 25922 were used as control strains. Testing against the P. aeruginosa strains revealed high MIC50 values for all the drugs except colistin. Doxycycline and colistin were both effective against the A. baumannii strains, with high susceptibility rates of 92% and 100%, respectively. Azithromycin had a high MIC50 value against these strains, whilst rifampicin had a moderate effect (susceptibility rate 64%). The combination of colistin and rifampicin was fully synergistic against four A. baumannii and two P. aeruginosa strains. Combinations of colistin with meropenem and of colistin with azithromycin each showed synergistic activity against three A. baumannii isolates, whilst the same combinations resulted in generally additive or indifferent effects against P. aeruginosa strains. The colistin and doxycycline combination was generally partially synergistic or additive against all the isolates. MDR strains of P. aeruginosa and A. baumannii, which cause nosocomial infections with an increasing ratio in recent years, have limited treatment options. According to our in vitro study results, non-traditional antibiotics such as doxycycline and colistin can be an alternative for the treatment of infections caused by these strains. Combinations of colistin with non-traditional antibiotics or meropenem could be promising alternatives for the treatment of infections due to MDR strains of A. baumannii and P. aeruginosa.

We propose a new hierarchical model of online and offline advertising. This model incorporates within-media synergies and cross-media synergies and allows higher-order interactions among various media. We derive the optimal spending on each medium and the optimal total budget. We also develop three hypotheses on the effects of within-and across-media synergies on both the total budget and its allocation. We estimate media effectiveness as well as the within-and cross-media synergies of offline (television, print, and radio) and online (banners and search) ads using market data for a car brand. We show that both types of synergies -within-media (i.e., intra-offline) and cross-media (onlineoffline)-exist. We show how within-and cross-media synergies boost the total media budget and online spending due to synergies of the online media with various offline media.

Non-Darwinian theories about the emergence and evolution of complexity date back at least to Lamarck, and include those of Herbert Spencer and the &quot;emergent evolution&quot; theorists of the later nineteenth and early twentieth centuries. In recent decades, this approach has mostly been espoused by various practitioners in biophysics and complexity theory. However, there is a Darwinian alternative - in essence, an economic theory of complexity - proposing that synergistic effects of various kinds have played an important causal role in the evolution of complexity, especially in the &quot;major transitions&quot;. This theory is called the &quot;synergism hypothesis&quot;. We posit that otherwise unattainable functional advantages arising from various cooperative phenomena have been favored over time in a dynamic that the late John Maynard Smith characterized and modeled as &quot;synergistic selection&quot;. The term highlights the fact that synergistic &quot;wholes&quot; may beco...

There is a wide variety of cancer types yet, all share some common cellular and molecular behaviors. Most of the chemotherapeutic agents used in cancer treatment are designed to target common deregulated mechanisms within cancer cells. Many healthy tissues are also affected by the cytotoxic effects of these chemical agents. Fucoidan, a natural component of brown seaweed, has anti-cancer activity against various cancer types by targeting key apoptotic molecules. It also has beneficial effects as it can protect against toxicity associated with chemotherapeutic agents and radiation. Thus the synergistic effect of fucoidan with current anti-cancer agents is of considerable interest. This review discusses the mechanisms by which fucoidan retards tumor development, eradicates tumor cells and synergizes with anti-cancer chemotherapeutic agents. Challenges to the development of fucoidan as an anti-cancer agent will also be discussed.

This article introduces a micro-phenomenological method for interpersonal synergy research, which operates on a sub-second timescale or slightly higher. This is illustrated by two short sequences of joint creativity from Contact Improvisation (CI), a dance where duets produce spontaneous interaction patterns in constant flow and with deep connection of their bodiestheir synergies stretch across body boundaries. My aim was to systematically take stock of components of these synergies, to describe sharing patterns, and to reconstruct how joint functionalities such as acrobatic lifts may spontaneously emerge. One focus concerns synergy dynamics, from micro-scale processes of interactive synergy build-up to transitions and larger "flows" in which one synergy evolves into another. A complementary focus concerns how a duet structurally organizes its "collective physics" (weight sharing, skeletal alignment, inter-body muscle chains, etc.) and adjusts them for regulation purposes. The proposed method strikes a balance between subjective meanings and biomechanic descriptiveness, thus providing applied benefits (e.g., for trainers), scholarly benefits (e.g., for modeling improvised synergies), and benefits for interdisciplinary discourse.

The present study analyses the effect of two plant phenolic compounds, namely chlorogenic acid and ferulic acid, and a plant alkaloid, berberine, alone and also in combination with two commercial oral hypoglycemic drugs (OHD), namely metformin and 2,4-thiazolodinedione (THZ), on the uptake of 2-deoxyglucose (2DG) by L6 myotubes. 2-DG uptake is determined using an enzymatic assay. All the three natural products enhance the uptake of 2DG in time- and dose-dependent manner. A combination of different concentrations of chlorogenic acid and metformin or THZ, has a synergistic effect in the uptake of 2DG with a maximum of 5.0- and 5.3-times respectively, with reference to the base value (without the drugs or the natural products). Ferulic acid in combination with metformin or THZ has also shown a synergistic effect and the 2DG uptake increases by 4.98- and 5.11-fold when compared to the control respectively. Whereas, berberine, in combination with either metformin or THZ, has shown an additive effect with maximum 2DG uptake of 4.1- and 4.7-times from the base value, respectively. The synergistic interaction has been explained with the use of combination index and isobologram. Expression of GLUT4 and PPAR-γ gene were elevated in chlorogenic acid and berberine treated cells, whereas expression of GLUT4 and PI3K transcripts were significantly enhanced in ferulic acid treated cells. The studies indicate that chlorogenic acid enhances glucose uptake by increasing GLUT4 expression via PI3K independent pathway whereas ferulic acid increases glucose uptake by PI3K dependent pathway. The current findings suggest that the phytochemicals can replace the commercial drugs in part, which could lead to a reduction in toxicity and side effects of the later.

Tetracycline resistance has been used as the key determinant to monitor resistance genes in natural environments such as rivers, lakes or seawater. The aim of this study was evaluate the frequency of tetA, tetB, tetC, tetD and tetE genes in 52 tetracycline-resistant Enterobacteriacea isolated from river water in the North East Black Sea Region of Turkey. In 52 tetracycline-resistant strains, resistance was mediated by tetA in eight (15.3%) strains, tetB in ten (19.2%) strains and both tetA and tetB in one (1.9%) strain. No tetC, tetD or tetE-mediated resistance was detected. In conclusion, the river water may be considered as a reservoir for the antibiotic resistance genes and the people living in this area may be under risk. To our knowledge, this is the first report for molecular characterization of tetracycline resistance in Enterobacteriaceae of river water origin in Turkey.

Competition with pathogens for adhesion and colonization of the mucosal surfaces are possible protective mechanisms of probiotics. In this study we evaluated the ability of commercial strains (Lactobacillus rhamnosus GG, L. rhamnosus LC705, B. breve 99 and Propionibacterium freudenreichii ssp. shermanii JS) each strain alone and in diVerent combinations to inhibit, displace and compete with selected pathogens in order to test the inXuence of the presence of the other probiotic in the adhesion pathogens to immobilized mucus. The ability to inhibit the adhesion or to displace adhered pathogens was variable depending on both the probiotic combination and the pathogen tested. Our results demonstrate that diVerent probiotic combinations were able to enhance the inhibition percentages to pathogen adhesion to intestinal mucus. All probiotic combinations tested in this study showed inhibition abilities against pathogen infection with values which were over 40% for some pathogens tested. Combinations had speciWc properties and inhibition abilities against some or all of the tested pathogens. These results suggest that combinations of probiotics strains could be useful and more eVective in inhibition of pathogen adhesion. The inhibition and displacement proWles were very diVerent suggesting that diVerent mechanisms are implied in both processes. Selection of new probiotic combinations should be conducted for speciWc target pathogens or pathogen associated microbiota aberrancies.

The possible role of spinal prostanoids in the tactile allodynia and thermal hyperalgesia associated with an experimental model of neuropathic pain was investigated. Neuropathic pain was induced by tight ligation of the L5 and L6 spinal nerves. Tactile allodynia was assessed 7 days after the surgery by measuring hindpaw withdrawal threshold to probing with von Frey filaments. Thermal hyperalgesia and nociception were determined by the 52°C warm-water tail-flick test and by applying radiant heat to the plantar aspect of the hindpaw ipsilateral to the ligation. Minimal antiallodynic effect was produced by intrathecal (i.th.) administration of ketorolac or morphine up to the highest testable dose (100 mg) or by the (R)-or (S)-enantiomers of ketorolac (up to 6 mg) when administered alone. However, i.th. administration of a fixed ratio (1:1) of morphine plus racemic ketorolac or of morphine plus the (S)-enantiomer of ketorolac (S-ketorolac) produced a dose-and time-related antiallodynic effect: ED 50 114 ± 35.9 mg (total dose) for morphine plus ketorolac and 70.5 ± 21.0 mg (total dose) for morphine plus S-ketorolac. The combination of i.th. morphine plus the (R)-enantiomer of ketorolac (R-ketorolac) (up to 200 mg total dose) was without effect. Similar antiallodynic activity was obtained for the co-administration of i.th. morphine and intravenous (i.v.) racemic ketorolac. In order to investigate the role of cyclooxygenase (COX) isozymes, relatively selective COX 1 (piroxicam) and COX 2 N- [2-cyclohexyloxy-4-nitrophenyl] metanesulfonamide (NS-398) inhibitors were administered i.th. (60 mg) alone or together with i.th. morphine. Piroxicam, NS-398, morphine and vehicle (90% DMSO) were without significant antiallodynic effect when administered alone, but moderate antiallodynic effects were produced by i.th. administration of fixed ratio (1:1) combinations of morphine with 60 mg each (highest soluble dose) of piroxicam (%MPE = 40.8 ± 10.2) or NS-398 (%MPE = 32.4 ± 9.5). Further, the combined i.th. administration of morphine, piroxicam and NS-398 in fixed 1:1:1 ratio (60 mg each) resulted in a supraadditive antiallodynic effect (%MPE = 70.4 ± 10.8). Finally, morphine, but not ketorolac, given i.th. produced dose-dependent anti nociception in either the tailflick or the paw-flick tests. However, there was no synergy between morphine and ketorolac against thermal nociception in either of the tests. These findings suggest that spinal prostanoids produced via both COX

Arsenic exposure is associated with an increased risk of urothelial carcinoma (UC). To explore the association between individual risk and urinary arsenic profile in subjects without evident exposure, 177 UC cases and 313 age-matched controls were recruited between September 2002 and May 2004 for a case-control study. Urinary arsenic species including the following three categories, inorganic arsenic (As III + As V ), monomethylarsonic acid (MMA V ) and dimethylarsinic acid (DMA V ), were determined with high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Arsenic methylation profile was assessed by percentages of various arsenic species in the sum of the three categories measured. The primary methylation index (PMI) was defined as the ratio between MMA V and inorganic arsenic. Secondary methylation index (SMI) was determined as the ratio between DMA V and MMA V . Smoking is associated with a significant risk of UC in a dose-dependent manner. After multivariate adjustment, UC cases had a significantly higher sum of all the urinary species measured, higher percent MMA V , lower percent DMA V , higher PMI and lower SMI values compared with controls. Smoking interacts with the urinary arsenic profile in modifying the UC risk. Differential carcinogenic effects of the urinary arsenic profile, however, were seen more prominently in nonsmokers than in smokers, suggesting that smoking is not the only major environmental source of arsenic contamination since the UC risk differs in non-smokers. Subjects who have an unfavorable urinary arsenic profile have an increased UC risk even at low exposure levels.

Biodiversity-ecosystem functioning theory would predict that increasing natural enemy richness should enhance prey consumption rate due to functional complementarity of enemy species. However, several studies show that ecological interactions among natural enemies may result in complex effects of enemy diversity on prey consumption. Therefore, the challenge in understanding natural enemy diversity effects is to predict consumption rates of multiple enemies taking into account effects arising from patterns of prey use together with species interactions. Here, we show how complementary and redundant prey use patterns result in additive and saturating effects, respectively, and how ecological interactions such as phenotypic niche shifts, synergy and intraguild predation enlarge the range of outcomes to include null, synergistic and antagonistic effects. This study provides a simple theoretical framework that can be applied to experimental studies to infer the biological mechanisms underlying natural enemy diversity effects on prey.

Unlike individuals with mild stroke, individuals with severe stroke are constrained to stereotypical movement patterns attributed to abnormal coupling of shoulder abductors with elbow flexors, and shoulder adductors with elbow extensors. Whether abnormal muscle coactivation and associated joint torque patterns can be changed in this population is important to determine given that it bears on the development of effective rehabilitation interventions. Eight subjects participated in a protocol that was designed to reduce abnormal elbow/shoulder joint torque coupling by training them to generate combinations of isometric elbow and shoulder joint torques away from the constraining patterns. After training, subjects demonstrated a significant reduction in abnormal torque coupling and a subsequent significant increase in ability to generate torque patterns away from the abnormal pattern. We suggest the rapid time-course of these changes reflects a residual capacity of the central nervous system to adapt to a novel behavioral training environment.

Abstract. A system of plant, soil, water and nutrient management for irrigated rice developed in Madagascar has been yielding 5, 10, even 15 t ha−1 on farmers&#x27; fields where previous yields averaged around 2 t ha−1. This is achieved using whatever variety of rice the farmer is ...

BHJ) structure. The BHJ requires delicate tailoring of n-and p-particles in order to avoid the electronic short-circuit problem and make fuel cell function properly. Hereby, we introduce the different Schottky junction type FC confi guration by means of combined nano and composite approach that is even simpler and more effective than EFFC.

The objective of this study was to examine the pharmacodynamic basis for the potent preclinical and clinical anti-leukemic activity of CPX-351, a nano-scale liposome formulation of cytarabine and daunorubicin co-encapsulated at a synergistic 5:1 molar ratio. A bone marrow-engrafting CCRF-CEM leukemia model in Rag2-M mice was utilized to correlate the therapeutic and myelosuppressive properties of CPX-351 with bone marrow delivery and drug uptake in leukemia cells relative to normal bone marrow cell populations. When administered to mice bearing CCRF-CEM human leukemia xenografts, CPX-351 ablated bone marrow (BM) leukemic cells to below detectable levels for multiple weeks, whereas the free-drug cocktail only transiently suppressed leukemia growth. In contrast to the activity against leukemia cells, CPX-351 and free-drug cocktail induced similar myelosuppression in non-tumor-bearing BM. In leukemia-laden BM, drug concentrations were markedly elevated for CPX-351 over free-drug cocktail and the first dose of CPX-351, but not free-drug cocktail, potentiated BM drug accumulation for subsequent doses. Confocal fluorescence microscopy revealed that CPX-351 liposomes are taken up by CCRF-CEM cells and subsequently release drugs intracellularly. The improved in vivo efficacy of CPX-351 appears related to increased and prolonged exposure of synergistic cytarabine:daunorubicin ratios in BM, and the selective killing of leukemia may arise from direct liposome-leukemia cell interactions. These features may also have broader applicability in the treatment of other haematological malignancies.

The aim of this paper was to determine if growth factors, known to be upregulated in proliferative diabetic retinopathy, exerted combined effects on retinal endothelial cells. The authors explored the individual and collective actions of insulin-like growth factor I (IGF-I), vascular endothelial growth factor (VEGF), platelet-derived growth factor-BB (PDGF-BB), ®broblast growth factor-2 (FGF-2) and placenta growth factor (PlGF) on several parameters that re¯ect the angiogenic potential of endothelial cells. The effect of growth factors on cell migration and survival/proliferation was examined using primary cultures of bovine retinal endothelial cells (BREC). The authors also determined the growth factor action on capillary-like tube formation on a reconstituted basement membrane matrix and on the newly described phenomenon of secondary sprouting, in which endothelial cell colonies spontaneously survive, proliferate, migrate and invade the matrix after the original capillary-like tubes have collapsed. Sprouting cells were positive for von Willebrand factor and could aggregate into larger tubes with lumens. Incubation with VEGFIGF-I or PlGFFGF-2 enhanced tube stability by 40±50 %, more than each growth factor alone or other combinations (5±20 %). The concurrent addition of four growth factors did not improve the response seen with growth factor pairs. Surprisingly, PDGF-BB induced tube collapse. IGF-I and FGF-2 mildly enhanced BREC proliferation/survival (5±15 %). However, VEGFIGF-I or PlGFFGF-2 increased BREC proliferation/survival by 25 % under low serum conditions, whereas combinations of all four growth factors exerted a clearly synergistic effect (250 % increase). PDGF-BB or FGF-2 stimulated secondary sprouting and were the only factors capable of exerting this effect alone. Even though VEGF, IGF-I or PlGF were not effective, if administered in pairs, they demonstrated increased responses. PDGF-BB was also able to enhance the effect of FGF-2IGF-IVEGF on BREC secondary sprouting, but not of any of them individually. No other growth factor tested was able to signi®cantly improve the action of combinations of three other growth factors. VEGF increased cell migration in a wounded monolayer assay two-fold and PDGF-BB, 2 . 5 times, but other individual growth factors were ineffective. PlGFFGF-2 enhanced cell migration more than each factor alone. VEGFIGF-IPlGFFGF-2, however, increased cell migration four-fold. In summary, this study indicates that growth factors, overexpressed in diabetic retinopathy eyes, enhance the angiogenic characteristics of cultured cells (tube formation, proliferation, secondary sprouting and migration). Their effects, however, can be greatly augmented by other growth factors that alone exert little or no action. Therefore, diabetic retinal neovascularization may result from the additive or synergistic action of several growth factors.

Discussions of relatedness in the strategy literature concentrate on linkages among business units in terms of key business functions such as marketing and production. While much is known about relatedness from the standpoint of corporate diversification, evidence about the relationship between relatedness and performance at the business unit level has been notably lacking, To further our understanding of the benefits and costs of relatedness, this study examined the perspectives of business unit managers to assess: (1) how the relationship between the two primary types of relatedness-production and marketing-are emphasized at the business unit level, and (2) how these types of relatedness affect business unit performance.

Photodegradation of methylene blue on a carbon-doped TiO 2 and on pure TiO 2 was studied. The materials were prepared by solvothermal synthesis and by calcinations. N 2 adsorption, XRD, SEM and TEM characterization was performed. Both nanomaterials exhibited mesoporous textures and the TiO 2 frameworks consist mainly of anatase phase. SEM images showed spherical microparticles while the TEM images showed hierarchically nanostructured morphologies on both samples. C-TiO 2 exhibited higher apparent first-order rate constants for the degradation of methylene blue than those obtained on pure TiO 2. It could be concluded that under visible light, the photoactivity of carbon-doped TiO 2 was clearly higher than that of a commercial TiO 2 photocatalyst suggesting that the carbon part photo assist the TiO 2 in the photodegradation of methylene blue.

Exfoliated clay nanocomposites of flame retarded/glass fibre reinforced polyamide 6 were prepared by twin-screw extrusion compounding. A flame retardant system based on phosphorus compounds and zinc borate was used at various levels in glass fibre reinforced PA6 and nanocomposites. Thermal stability and combustion behaviours were evaluated by TGA, LOI, UL94 and cone calorimetry. Substitution of a certain fraction of the flame retardant with nanoclays was found to significantly reduce the peak heat release rate and delay ignition in the cone calorimeter. Moreover, remarkable improvements were obtained in LOI along with maintained UL94 ratings. Residue characterization by FTIR, XRD and SEM ascribed the enhanced flame retardancy of nanocomposite formulations to the formation of a glassy boron/aluminium phosphate barrier reinforced by clay layers at the nanoscale. The physically strong and consolidated barriers formed from nanocomposites were much more effective in impeding heat and mass transfer compared to those from conventional formulations.

We evaluated the ability of commercial probiotic strains (Lactobacillus rhamnosus GG, L. rhamnosus LC705, Bifidobacterium breve 99, and Propionibacterium freudenreichii ssp. shermanii JS) to adhere alone or in different combinations to immobilized mucus. Probiotic combinations were clearly able to enhance the adhesion of L. rhamnosus GG, L. rhamnosus LC705, and P. freudenreichii ssp. shermanii JS. For L. rhamnosus GG and P. freudenreichii JS, all the combinations significantly improved adhesion to intestinal mucus, from 29.7 to 34.9% and from 1.9 to 2.3%, respectively. The adhesion of L. rhamnosus LC705 was improved from 0 to 46.4%. The adhesion of B. breve 99 was improved only in combination with L. rhamnosus GG and P. freudenreichii JS. Our results suggest that probiotic combinations could increase the beneficial health effects as compared with individual strains. Combinations of probiotic strains may therefore have synergistic adhesion effects, and such combinations also should be assessed in clinical studies.

A group of proteins including expansins, swollenins, and polysaccharide monooxygenases are non-hydrolytic cellulose active proteins (NHCAPs), which have been shown to enhance significantly cellulase-driven plant cell wall hydrolysis at reduced protein loadings. NHCAP-mediated enhancement of cellulase cocktails makes them important accessories in the molecular toolbox for producing fuels and chemicals from lignocellulose. This review presents an overview of the fundamental research advances involving these groups of proteins and considers their applicability to processes in the ongoing pursuit of an economically viable biorefinery.

Ethnopharmacological relevance: Astragali Radix (AR) and Rehmanniae Radix (RR) are two traditional Chinese medicines widely used in China for treating diabetes mellitus and its complications, such as diabetic foot ulcer. Aim of study: In our previous study, a herbal formula NF3 comprising AR and RR in the ratio of 2:1 was found effective in enhancing diabetic wound healing in rats through the actions of tissue regeneration, angiogenesis promotion and inflammation inhibition. The aims of the present study were to investigate the herb-herb interaction (or the possible synergistic effect) between AR and RR in NF3 to promote diabetic wound healing and to identify the principal herb in the formula by evaluating the potencies of individual AR and RR in different mechanistic studies. Materials and methods: A chemically induced diabetic foot ulcer rat model was used to examine the wound healing effect of NF3 and its individual herbs AR and RR. For mechanistic studies, murine macrophage cell (RAW 264.7) inflammation, human fibroblast (Hs27) proliferation and human endothelial cell (HMEC-1) migration assays were adopted to investigate the anti-inflammatory, granulation formation and angiogenesis-promoting activities of the herbal extracts, respectively. Results: In the foot ulcer animal model, neither AR nor RR at clinical relevant dose (0.98 g/kg) promoted diabetic wound healing. However, when they were used in combination as NF3, synergistic interaction was demonstrated, of which NF3 could significantly reduce the wound area of rats when compared to water group (p < 0.01). For anti-inflammation and granulation formation, AR was more effective than RR in inhibiting lipopolysaccharide (LPS)-induced nitric oxide production from RAW 264.7 cells and promoting Hs27 fibroblast proliferation. In the aspect of angiogenesis promotion, only NF3 promoted cell migration of HMEC-1 cells. Conclusions: AR plays a preeminent role in the anti-inflammatory and fibroblast-proliferating activities of NF3. The inclusion of RR, however, is crucial for NF3 to exert its overall wound-healing as well as the underlying angiogenesis-promoting effects. The results of present study justified the combined usage of AR and RR in the ratio of 2:1 as NF3 to treat diabetic foot ulcer and illustrated that AR is the principal herb in this herbal formula.

Excess synchrony in motor cortical neurons provides redundant direction information with that from coarse temporal measures. J Neurophysiol 86: 1700 -1716, 2001. Previous studies have shown that measures of fine temporal correlation, such as synchronous spikes, across responses of motor cortical neurons carries more directional information than that predicted from statistically independent neurons. It is also known, however, that the coarse temporal measures of responses, such as spike count, are not independent. We therefore examined whether the information carried by coincident firing was related to that of coarsely defined spike counts and their correlation. Synchronous spikes were counted in the responses from 94 pairs of simultaneously recorded neurons in primary motor cortex (MI) while monkeys performed arm movement tasks. Direct measurement of the movementrelated information indicated that the coincident spikes (1-to 5-ms precision) carry ϳ10% of the information carried by a code of the two spike counts. Inclusion of the numbers of synchronous spikes did not add information to that available from the spike counts and their coarse temporal correlation. To assess the significance of the numbers of coincident spikes, we extended the stochastic spike count matched (SCM) model to include correlations between spike counts of the individual neural responses and slow temporal dependencies within neural responses (ϳ30 Hz bandwidth). The extended SCM model underestimated the numbers of synchronous spikes. Therefore as with previous studies, we found that there were more synchronous spikes in the neural data than could be accounted for by this stochastic model. However, the SCM model accounts for most (R 2 ϭ 0.93 Ϯ 0.05, mean Ϯ SE) of the differences in the observed number of synchronous spikes to different directions of arm movement, indicating that synchronous spiking is directly related to spike counts and their broad correlation. Further, this model supports the information theoretic analysis that the synchronous spikes do not provide directional information beyond that available from the firing rates of the same pool of directionally tuned MI neurons. These results show that detection of precisely timed spike patterns above chance levels does not imply that those spike patterns carry information unavailable from coarser population codes but leaves open the possibility that excess synchrony carries other forms of information or serves other roles in cortical information processing not studied here.

The aim of this study was to screen certain plant essential oils and active compounds for antifungal activity and their in vitro interaction with fluconazole against drugresistant pathogenic fungi. The methods employed in this work included disc diffusion, broth macrodilution, time kill methods and checkerboard microtiter tests. Oil compositions were evaluated by gas chromatography-mass spectrometry (GC-MS) analysis. Transmission electron microscopy was used to assess the effect of essential oils on cellular structures of test fungi. Test fungal strains exhibited resistance to at least two drugs (fluconazole and itraconazole). Among the 21 essential oils or active compounds tested, ten showed promising antifungal activity. GC-MS analysis revealed the presence of major active compounds in the essential oils used. Cinnamaldehyde showed the most promising antifungal activity and killing potency against Aspergillus fumigatus MTCC2550 and Trichophyton rubrum IOA-9. Cinnamaldehyde showed strongest synergy with fluconazole against A. fumigatus and T. rubrum by reducing the minimum inhibitory concentration of fluconazole up to 8-fold. Zones of lysis of the cell wall and cell membrane appeared to be where cinnamaldehyde acted on fungi. This study highlights the broad spectrum antifungal activity of essential oils and active compounds and their synergy with fluconazole against drug-resistant fungi.

Neuronal responses to alcohol involve several hormone-and neurotransmitter-activated signal transduction pathways. Recent studies suggest that the adenosine A2 receptor (A2) mediates important actions of alcohol. Ethanol inhibits adenosine reuptake, increases extracellular adenosine, and promotes activation of A2. This leads to enhanced cAMP/protein kinase A (PKA) signaling ranging from increases in cAMP to stimulation of cAMP-dependent cAMP response element (CRE)-mediated gene expression. Medium spiny neurons in the striatum/nucleus accumbens (NAc) express A2 and dopamine D2 receptor (D2) on the same cells. Studies in model neuronal cell lines and primary neurons in culture expressing A2 and D2 provide evidence for synergy between ethanol/A2 and D2. Subthreshold concentrations of ethanol or a D2 agonist, without effect separately, synergistically activate cAMP/PKA signaling. Thus, neurons expressing A2 and D2 on the same cells, like in the NAc, are characterized by hypersensitivity to ethanol with a simultaneous activation of dopaminergic signaling. Synergy requires adenosine and appears to be mediated by the release of free hg dimers from G i/o via D2 activation. The release of free hg has pathophysiological significance in the drinking animal because specific blockade of hg signaling in the NAc strikingly reduces voluntary alcohol consumption. These findings suggest that signaling pathways, which regulate synergy between A2 and D2, might contain molecular targets for the prevention and treatment of alcoholism and alcohol abuse. D

Diabetes mellitus is a chronic disorder characterized by increased blood glucose level. The available commercial oral antidiabetic drugs have some serious side effects; hence there is a need for new hypoglycemic agents which will have therapeutic efficacy as well as less side effects. Ferulic acid, a phytochemical, might be a good supplement to manage diabetes. We investigated the antidiabetic and antilipidemic effect of ferulic acid alone and in combination with oral antidiabetic drugs (metformin and Thiazolidinedione (THZ)). Blood glucose, plasma lipid profiles levels, liver function and kidney function markers were measured in control and streptozotocin induced diabetic rats three weeks after administrating ferulic acid and OHDs (oral hypoglycemic drugs) alone and in combinations. The histopathological analysis of the pancreas was also carried out. Ferulic acid and OHDs significantly reduced the blood glucose, lipid profile, urea, creatinine, serum glutamic pyruvic transaminases (SGPT) and serum glutamic oxaloacetate transaminases (SGOT) in diabetic rats. Same level of reduction in blood glucose levels was achieved when ferulic acid was used in combination with even reduced amounts of OHDs. It decreased most of the side effects when used in combination with THZ. Histopathological analysis showed that combinations increased the number of islets. Ferulic acid interacts synergistically with both the drugs. It might be a good supplement with the OHDs to manage diabetic complications as well as reduces the use of the later.

We studied the coordination of muscle activity during voluntary body sway performed by human subjects at different frequencies. Subjects stood on the force platform and performed cyclic shifts of the center of pressure (COP) while being paced by the metronome. A major question was: does the makeup of muscle synergies and their ability to assure reproducible sway trajectory vary with the speed of the sway? Principal component analysis was used to identify three muscle groups (M-modes) within the space of integrated indices of muscle activity. M-mode vectors were similar across both subjects and sway frequencies. There were also similar relations between changes in the magnitudes of all three M-modes and COP shifts (the Jacobians) across the sway frequencies. Variance in the M-mode space across sway cycles was partitioned into two components, one that did not affect the average value of COP shift (“good variance”) and the other that did. An index (ΔV) was computed reflecting the relative amount of the “good variance”; this index has been interpreted as reflecting a multi-M-mode synergy stabilizing the COP trajectory. The average value of ΔV was similar across all sway frequencies; ΔV showed a within-a-cycle modulation at low but not at high sway frequencies. The modulation was mostly due to variations in the “good variance”. We conclude that muscle modes and their mapping on COP shifts are robust across a wide range of rates of COP shifts. Multi-M-mode synergies stabilize COP shifts (assure its reproducibility) within a wide range of its speeds, but only during cyclic COP changes. Taken together with earlier studies that showed weak or absent multi-M-mode synergies during fast discrete COP shifts, the results suggest a basic difference between the neural control assuring stability of steady-state processes (postural or oscillatory) and transient processes (such as discrete actions). Current results provide the most comprehensive support for the notion of multi-M-mode synergies stabilizing time profiles of important performance variables in motor tasks involving large muscle groups.

Pretreating a carbon nanotube (CNT) support by refluxing it in 35 vol % nitric acid and then heating it at temperatures of 600-900°C was found to result in the formation of defects on the CNTs. Increasing the temperature of the pretreatment of the CNTs from 600 to 900°C enhanced the fraction of cobalt oxide nanoparticles encapsulated in the channels of the CNTs from 31% to 70%. The performance of Co/CNTs in Fischer-Tropsch synthesis (FTS) was evaluated in a fixed-bed microreactor at a temperature of 240°C and a pressure of 2.0 MPa. The highest CO conversion obtained over Co/CNTs pretreated at 900°C was 59%, which dropped by~3% after 130 h of time on stream. In contrast, the maximum CO conversion obtained using Co/CNTs pretreated at 600°C catalysts was 28%, which decreased rapidly by about 54% after 130 h of time on stream. These findings show that the combined acid and thermal pretreatment of the CNT support at 900°C improved the stability and activity of the Co/CNTs catalyst in FTS.

This study investigates the value creation mechanism in cross-border acquisitions (CBAs) by employing a structural equation modeling technique and surveying 103 CBAs performed by Nordic fi rms. The results reveal that resource possession, resource picking, and resource utilization are three important strategic dimensions for realizing synergy and creating value in CBAs. Furthermore, mediation analysis shows that the two acquisition-based dynamic capabilities-value identifi cation and resource reconfi guration-act as important mediators in how the joining fi rms' resource base impacts acquisition outcomes. The results shed light on the mechanisms through which the constructs infl uence value creation in CBAs and highlight the procedural and dynamic character of these determinants. The results also indicate that an integrative and process perspective, such as the "input-process-output" model proposed in this study, is an important step forward in merger and acquisition (M&A) research. Moreover, numerous research fi ndings offer tactical implications for international acquirers.