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Enyne metathesis (EM) has widely been used to prepare various synthetic and natural products. Further, a sequential use of EM and Diels-Alder (DA) reactions generates highly functionalized and intricate polycarbocycles and heterocyclic frameworks. In this critical review we describe the application of a unique combination of EM and DA reactions to prepare various amino acid derivatives, natural products and heterocycles. Some of the heterocyclic targets include cyclic peroxides, siloxanes and various nitrogen (or oxygen) containing compounds. Use of ethylene and cyclooctadiene (COD) for improving the yield of EM products are also discussed (69 references).

17031 Background: In the US, tobacco, alcohol and the synergistic combination of tobacco and alcohol are the most common risk factors for HNCA. Increasingly, worldwide and in the US as well, human ...

The past decade has seen remarkable developments in our under-standing of transition to turbulence. Much of this progress has been due to a synergistic combination of novel theory with large-scale numerical computation. In this brief overview, I would like to present some of the remaining challenges to our understanding of transition and suggest some ideas for overcoming these hurdles.

2070 Background: Coramsine (C) is a 1:1 mixture of solasonine and solamargine, plant glycoalkaloids found in the species Solanum Linneanum, with single agent and synergistic combination in vitro and in vivo preclinical efficacy in various tumor models through interaction with rhamnose-containing cell membrane glycoproteins and subsequent internalization. Methods: C initially as a 2-hr IV infusion daily × 5 every 2 weeks to define the MTD, recommended Phase II dose, toxicity and pharmacokinetics. Based on preclinical toxicology the infusion duration was increased to 4 hours and 24 hours (120 hr continuous infusion). Doses studied range from 0.75 mg/kg/day to 3.0 mg/kg/day. Results: 27 pts were treated. DLT occurred in 2/2 pts at 1.5 mg/kg/day (2 hr) and 2/2 pts each at 3.0 mg/kg/day (4 hr and 24 hr). Preceding dose levels 1.0 mg/kg (2 hr) and 1.5 mg/kg (4 hr) produced DLT in 2/6 pts each with no grade IV. Over 24 hr, 2.25 mg/kg/day produced DLT in 4/6 patients. Limiting toxicity at all schedules was grade III/IV transaminitis with grade I-III increases of bilirubin and grade I-II creatinine. Hepatotoxicity was maximal at days 3–5, resolved over 10–21 days, was clinically asymptomatic apart from grade I-II fatigue, and was not cumulative. No myelosuppression or other serious drug-related toxicity was recorded. Partial responses were documented in 2 pts (renal, NSCLC) and minor response in 1 pt with unknown primary. Responses were seen using both 2 hr and 4 hr infusions. Pharmacokinetic parameters for solasonine and solamargine are linear across the narrow range of doses studied with elimination T1/2 of 5.57 ± 1.27 hr (solasonine), 8.40 ± 2.00 hr (solamargine) and Cl of 5.6 ± 1.6 L/hr (solasonine), 3.0 ± 0.7 L/hr (solamargine). Peak levels of both exceed active in vitro levels (>2,000 ng/ml). Conclusions: Coramsine produces dose-limiting hepatotoxicity at doses above 1.0 mg/kg/day over 2 hours or 1.5 mg/kg/day over 4 hours. 2.25 mg/kg/day over 24 hours exceeds the MTD. Activity has been seen against resistant solid tumors. Phase II studies in renal cancer and melanoma will be performed using 1.5 mg/kg/day over 4 hours. [Table: see text]

Ceramides are the main constituents of the epidermal permeability barrier, and it has been demonstrated that the application of ceramide enriched creams promotes epidermal barrier repair. However, nature-identical ceramides are extremely expensive and difficult to formulate. We therefore developed a new pseudoceramide, N-palmitoyl-4-hydroxy-l-proline palmityl ester (BIO391). Due to its low melting point of £60°C the pseudoceramide BIO391 can easily be incorporated into cosmetic formulations. In addition, it is very safe for use in cosmetics. The efficacy of the pseudoceramide BIO391 was investigated in vivo in a model for detergent-induced barrier disruption. Trans-epidermal water loss, redness, and skin hydration were recorded before and after barrier disruption as well as during the subsequent 9-day treatment with the test products. Barrier repair of skin treated with the pseudoceramide BIO391 was accomplished earlier than that of untreated and vehicle treated skin. Optimum barrier repair was achieved with 1.0% pseudoceramide BIO391 and optimum erythema reduction with 0.5% pseudoceramide BIO391. The optimum dosage could be reduced to 0.1% pseudo-ceramide by synergistic combination with 0.1% (-)-a-bisabolol. In addition, the pseudoceramide BIO391 proved to be as effective as nature-identical ceramides 2 and 3. In summary, N-palmitoyl-4-hydroxy-l-proline palmityl ester is a highly efficient barrier repair agent with efficacy equivalent to that of nature-identical ceramides, and it has excellent formulation properties.

4703 Background: Docetaxel plus prednisone is the current therapeutic choice in the management of metastatic AIPC. Capecitabine is an oral prodrug of 5-fluorouracil which is selectively converted i...

This paper traces the evolution of Total Quality Management (TQM) at Xerox Corporation. The authors examine the TQM experience at Xerox as a synergistic combination of three strategic thrusts: customer focus, total involvement, and process improvement. Over the course of more than a decade, TQM at Xerox has evolved from a special emphasis to a fundamental business principle. Xerox's success with TQM allowed the company to regain market share without government assistance and positioned the company well for the 21st century. Other companies experimenting with TQM can learn valuable lessons from Xerox's experience.

In a Ricardian factor endowment model with different technologies, trade is determined by the location of the factors with first- and second-best comparative advantages as well as world demand. When both technology factor endowment differences between countries explain trade, the usual empirical strategy of running regressions of trade against factor endowments is inadequate. Trade is explained by the synergistic combination of factor endowments, technology differences and world demand. Indeed, under various parametric situations the various elements play quite different roles.

• In recent years there has been increased discussion about goals of antihypertensive therapy other than blood pressure reduction. The development of angiotensin-converting enzyme inhibitors has provided a class of drugs with a very low sideeffect profile. However, single-drug therapy is effective in only about half of hypertensive patients. In the past, diuretics have traditionally been used as the initial or second antihypertensive. Increasingly, diuretic therapy is being avoided, and other antihypertensive combinations are being used. In controlled trials, combination converting enzyme inhibitor-diuretic therapy is effective in about 85% of patients. This synergistic combination allows the diuretic dose to be reduced so that the adverse effects and metabolic complications are minimized. At this time, the combination of converting enzyme inhibitor and diuretic provides an ideal choice in terms of efficacy, compliance, side effects, and cost. ( Arch Intern Med . 1990;150:1175-1183)

The distribution ratio of neodymium(III) in extraction with mono(2-ethylhexyl)-phosphoric acid was determined as a function of extractant and Nd(III) concentrations, and effect of co-existing DEHPA was studied. A characteristic extraction of a tracer quantity of Nd(III) was found at an extractant concentration of approximately 0.01 M. Di(2-ethylhexyl)phosphoric acid depresses the extraction of Nd(III) in MEHPA of a concentration of 0.01M, but enhances it at higher concentrations of MEHPA. Owing to the high Df values against lanthanides(III) and an excellent radiation stability, the synergistic combination of MEHPA-DEHPA, preferably at a DEHPA/MEHPA mole ratio of 3, was concluded to be applicable to the isolation of lanthanides (and actinides) from highly acidic solutions.

A synergistic combination of bis(diisopropyl)thiophosphoryl disulfide, dimorpholyl disulfide, and sulfur is used to produce an efficient vulcanizing system for a range of rubbers. This produces vulcanizates with the exceptional thermal and thermal-oxidative stability characteristic of sulfur donor vulcanizates and the rapid and extensive crosslinking reaction normally associated with a conventional sulfur–accelerator combination. A pronounced induction period is noted. The crosslinks initially produced in cis-1,4-polyisoprene rubbers are predominantly polysulfide but reduce to mono- and disulfides at optimum and extended cures. The crosslinks of the ethylene–propylene terpolymer and the styrene–butadiene vulcanizates are initially mainly disulfide but are rapidly reduced to monosulfides at the high curing temperatures (180°C) used. A comparison with vulcanization systems based on tetramethylthiuram disulfide and bis(diisopropyl)thiophosphoryl tri-and tetrasulfides as sulfur donors and with a conventional cyclohexylbenthazyl-2-sulfenamide–sulfur combination, respectively, shows it to have distinct advantages.

This paper examines the development of a solution procedure for many types of combinatorial problems. The technique known as the trainable heuristic procedure uses algorithmic procedures to gain experience on heuristic approaches to combinatorial problems. The synergistic combination of these approaches leads to a learning mechanism which has proven very effective in the solution of the assembly line balancing problem.

Highly purified resting B lymphocytes stimulated for 3 days to high-rate DNA synthesis by a synergistic combination of phorbol dibutyrate and ionomycin soon returned to quiescence once those signals had been removed. The maintenance of DNA synthesis in such cultures was found to provide a sensitive assay for revealing the factors that interact with cycling B cells. Whereas several activities - namely, interleukin 4, anti-Bp50 and a low molecular weight B cell growth factor - were, by themselves, capable of prolonging DNA synthesis over a further day or so, no single factor was capable of sustaining the replication cycle out to day 6 of culture. By contrast, certain combinations of activities displayed significant synergy in the restimulation assay. The most striking observed was that between interleukin 4 and anti-Bp50 where, by day 6, their combined effect on maintaining DNA synthesis in 3-day stimulated cells was the same as having kept phorbol dibutyrate and ionomycin in the culture system. The implications of these findings are discussed.

Interaction of heat and radiation treatments on the survival of conidia of Aspergillus flavus was studied, using five different temperatures, ranging from 35 °C to 55 °C, and five different doses, ranging from 25 to 125 Krad. In most combinations these treatments showed a synergistic rather than simply an additive lethal effect. The extent of synergism depended considerably on the sequence in which these treatments were applied. Heating at 45 °C, 50 °C or 55 °C followed immediately by irradiation was the most effective synergistic combination for the inactivation of conidia.

This paper provides an overview of the modular window concept and how Polyurethane-Reaction Injection Molding (PU-RIM) has played an integral part in pushing this concept beyond its previous economic and design limitations. The incentives and motives for the development and expansion of modular win dow technology will be reviewed.

Seven strains of Streptococcus faecalis, of which two possessed high-level resistance to streptomycin (MIC greater than or equal to 2000 mcg/ml), and two strains of Streptococcus faecium were evaluated with respect to killing-effect and duration of post-antibiotic effect (PAE) of ampicillin and vancomycin in combination with streptomycin, gentamicin, tobramycin and netilmicin. No synergistic combination effects were seen with the two strains highly-resistant to streptomycin or with the two Streptococcus faecium strains to netilmicin and tobramycin. When these strains were excluded, no significant difference in average killing could be detected between the four aminoglycosides. The mean prolongation in recovery period of susceptible strains was significantly longer with combinations of ampicillin and netilmicin or streptomycin as compared with either gentamicin or tobramycin. A similar relationship was seen for combinations of vancomycin with the four aminoglycosides.

Summary1. The results of microbiological assays on a large number of oligosaccharides obtained from human milk and on simple derivatives (disaccharides or simple synthetic compounds) of N-acetyl-D-glucosamine are reported. The high microbiological activity of 4-0-β-D-galactopyranosyl-N-acetyl-D-glucosamine and of ethyl- and n-propyl-N-acetyl-β-D-glucosamine has not been exceeded by any other compound tested. 2. The “true” specific bifidus factor has either still to be found or several related compounds may act as precursors or in synergistic combination.

The rapidly growing area of iminium and enamine catalysis in enantioselective photochemistry is reviewed, with an emphasis on catalytic modes and reaction types., Although enantioselective catalysis under thermal conditions has been well established over the last few decades, the enantioselective catalysis of photochemical reactions is still a challenging task resulting from the complex enantiotopic face differentiation in the photoexcited state. Recently, remarkable achievements have been reported by a synergistic combination of organocatalysis and photocatalysis, which have led to the expedient construction of a diverse range of enantioenriched molecules which are generally not easily accessible under thermal conditions. In this tutorial review, we summarize and highlight the most significant advances in iminium and enamine catalysis of enantioselective photochemical reactions, with an emphasis on catalytic modes and reaction types.

Improving energy efficiency is the most effective and least expensive way to reduce carbon dioxide (CO2) emissions in most industrialized nations— including the UK. A report from the UKAEA's own Energy Technology Support Unit concludes that energy efficiency can displace nearly four times more CO2 than nuclear power can - more quickly and more cost-effectively. Each pound invested in efficient lighting can displace four to five times as much CO2 as a pound invested in new nuclear power. Meanwhile, given recent dramatic progress in renewable energy technologies, the most promising long-term CO2-abatement strategy may be a synergistic combination of energy efficiency and renewable energy.

Menogarol is a new anthracycline undergoing phase I clinical trial. We report here the lethality after 2 hr exposure to 2 drug combinations of menogarol and several antitumor agents. A new statistical procedure was used to identify synergistic combinations. Most of these combinations were additive, except for menogarol plus melphalan, which was synergistic. Adriamycin plus melphalan was also synergistic. The menogarol-melphalan combination was studied in detail with regard to the effect of dose and drug-schedule, lethality for exponential and plateau phase cells and effect on cell cycle progression. Although the combination was synergistic for exponential cells it was additive for plateau phase cells. The combination exerted a synergistic effect in inhibiting progression of cells through the cell cycle. After 2 hr menogarol exposure cells were blocked in G2 for about 12 hr following which the block was reversed. This reversal was inhibited when menogarol was combined with melphalan. The uptake of menogarol or melphalan was not changed in the presence of the other drug.

Candida endophthalmitis, caused by transient candidemia, developed in a 14-year-old white girl receiving intravenous hyperalimentation. Antifungal synergism was established in vitro for the combination of amphotericin B and rifampin against the C. albicans isolate. A combined ten-day course of intravenous amphotericin B and oral rifampin was followed by the elimination of the infection and the preservation of good visual acuity.

The administration of a combination of penicillin and gentamicin to mice given an intraperitoneal challenge of a highly pathogenic strain of Listeria monocytogenes resulted in increased survival as compared with groups receiving penicillin alone or gentamicin alone or a control group that received no antibiotic. The median survival of animals that eventually died was no longer than in groups receiving single antibiotics and suggests that additional studies should be carried out to further investigate the possibility of synergism in animal models.

The preliminary results of a pilot trial of initial empirical antibiotic therapy for febrile episodes in neutropenic cancer patients are described. Infection was proven in 52% of the episodes. Responses were excellent for all three antitiotic combinations. Overall, 88% of infections improved, as did 63% of the infections with associated bacteraemia. So far we have inadequate data to judge the relative efficacy of the three combinations described with respect to specific bacteria. Therefore, we cannot comment on whether a cell wall active agent or an aminoglycoside, or their possibly synergistic combination, is superior. Superinfections, subsequent infections and toxicities were acceptably low for each regimen.

Chinese hamster ovary cells have been treated in vitro with the platinum coordination complexes cis-PAD or CHIP and with radiation, either alone or in combination with different doses and time intervals. The isobologram method has been used to make a graphic comparison of these combined-modality data in terms of additivity and enhancement. The data showed enhancement of the radiation effect by these platinum complexes in many combinations, and a truly synergistic effect in one case. This method of analysis points to the limited usefulness of the parameter dose-modifying effect (DMF) since the most synergistic combination did not have the highest DMF.

An oscilloscope presents a graphical display of amplitude vs. time. The amplitude is usually voltage. It allows the electrical designer to see what is occurring in a circuit. The CRT display was originally a qualitative one and provided the designer with an idea of what was occurring. Through improvements in vertical amplifier design, sweep linearity, and CRT performance, a calibrated graticule was added to the CRT face and quantitative measurements could be made. These improvements continued and resulted in measurement accuracies in the 2 percent to 3 percent category, with some timing measurements reaching the 1 percent area. These accuracies represent the state-of-the-art performance with traditional techniques. A new set of techniques was becoming an obvious need in order to make major improvements in the measurement capabilities of oscilloscopes.

The use of two or more antimicrobial agents is frequently necessary for the successful therapy of bacterial infections, but the combination may result in unanticipated effects on the host and his microbial flora. Thus it is necessary to review present considerations for the use of antimicrobials in combination, the liabilities of multiple drug use, and the clinical role of recently introduced agents. Of particular interest is the new synergistic combination trimethoprim-sulfamethoxazole, and use of penicillins in combination with aminoglycosides.

In spite of a large volume of data regarding the in vitro activity of single and combined antimicrobial activity, the clinical relevance of these studies is unclear. Few comparative trials of combined and single antibiotic therapy of human infection have been performed. Synergistic combination therapy has been shown to be beneficial in a few specific circumstances. Antagonistic combinations should be avoided in the treatment of meningitis, endocarditis, and infections of immunocompromised patients. The bactericidal titer of serum or spinal fluid should reflect adequacy of therapy of meningitis, endocarditis, and osteomyelitis, and adjustments can be made accordingly.

Many vitally important functions in living systems are carried out by metal ions held as complexes within organic ligands, the organic part of the molecule being a tetrapyrrolic macrocycle. Chlorophyll, haemoglobin, the cytochromes and vitamin B 12 all fall into this family of ‘pigments of life’, a list that emphasizes their central importance in living systems. Research on the biosynthesis of these pigments has involved the synergistic combination of synthesis, structure determination, carbon nuclear magnetic resonance and isotopic labelling with radioactive and stable isotopes in conjunction with enzymology and kinetics. The lecture describes the logical series of experiments based on these approaches which have led to a step-by-step knowledge of the biosynthesis of the parent macrocycle (uroporphyrinogen-III) from which the other pigments are derived. One main pathway from the parent macrocycle involves oxidative transformations and leads eventually to protohaem required inter alia for haemoglobin and myoglobin. The second important pathway makes use of C-methylation to convert the parent macrocycle through many stages finally into vitamin B 12 . The biosynthetic studies on vitamin B 12 are outlined with particular emphasis on the use of isotopic labelling with both radioactive and stable isotopes of carbon and hydrogen. Roughly two-thirds of the entire biosynthetic pathway to vitamin B 12 has now been elucidated. The scarcity of several of the known intermediates on the pathway severely hampers future researches and progress towards the total synthesis of these key materials is reviewed. Finally, the lecture brings out the evolutionary interest of what has been discovered about the biosynthesis of the pigments of life.

Publisher Summary This chapter discusses electrophoretic techniques that have played a significant role in detecting and studying subunit heterogeneity. Charge heterogeneity is not readily detectable by other techniques. It plays a major role in the subsequent purification and characterization of the constituent subunits of mollusk and arthropod hemocyanins. The synergistic combination of immunology and electrophoresis in immunoelectrophoresis is very useful in identifying homology in subunit mixtures and in determining the uniqueness of an electrophoretically identified bond. This technique continues to be important in current studies, focusing on the specific interactions and mechanisms of assembly of high-molecular–weight proteins. One of the most important characteristics that have made hemocyanins very useful tools in studying protein assembly is the ease of purifying the electrophoretically identified constituent subunits from a number of species.

There is still great interest in controlling bacterial endospores. The use of chemical disinfectants and, notably, oxidizing agents to sterilize medical devices is increasing. With this in mind, hydrogen peroxide (H 2 O 2 ) and peracetic acid (PAA) have been used in combination, but until now there has been no explanation for the observed increase in sporicidal activity. This study provides information on the mechanism of synergistic interaction of PAA and H 2 O 2 against bacterial spores. We performed investigations of the efficacies of different combinations, including pretreatments with the two oxidizers, against wild-type spores and a range of spore mutants deficient in the spore coat or small acid-soluble spore proteins. The concentrations of the two biocides were also measured in the reaction vessels, enabling the assessment of any shift from H 2 O 2 to PAA formation. This study confirmed the synergistic activity of the combination of H 2 O 2 and PAA. However, we observed that the sporicidal activity of the combination is largely due to PAA and not H 2 O 2 . Furthermore, we observed that the synergistic combination was based on H 2 O 2 compromising the spore coat, which was the main spore resistance factor, likely allowing better penetration of PAA and resulting in the increased sporicidal activity.

Serious games receive increasing interest in the area of e-learning. Their development, however, is often still a demanding, specialized and arduous process, especially when regarding reasonable non-player character behaviour. Reinforcement learning and, since recently, also deep reinforcement learning have proven to automatically generate successful AI behaviour to a certain degree. These methods are computationally expensive and hardly scalable to various complex serious game scenarios. For this reason, we introduce a new approach of augmenting the application of deep reinforcement learning methods by interactively making use of domain experts' knowledge to guide the learning process. Thereby, we aim to create a synergistic combination of experts and emergent cognitive systems. We call this approach interactive deep reinforcement learning and point out important aspects regarding realization within a framework.

Serious games belong to the most important future e-learning trends and are frequently used in recruitment and training. Their development, however, is still a demanding and tedious process, especially when regarding reasonable non-player character behaviour. Serious games can generally profit from diverse, adaptive behaviour to increase learning effectiveness. Deep reinforcement learning has already shown considerable results in automatically generating successful AI behaviour, but its past applications were mainly focused on optimization and short-horizon games. To expand the underlying ideas to serious games, we introduce a new approach of augmenting the application of deep reinforcement learning methods by interactively making use of domain experts’ knowledge to guide the learning process. Thereby, we aim to establish a synergistic combination of experts and emergent cognitive systems to create adaptive and more human behaviour. We call this approach interactive deep reinforcement learning and point out important aspects regarding realization within a novel framework.

The development of simple, cost-effective and sustainable methods to transform CO2 into feedstock chemicals is essential to reduce the dependence on fossil fuels of the chemical industry. Here, we report the selective and efficient catalytic hydrogenation of CO2 to formic acid (FA) using a synergistic combination of an ionic liquid (IL) with basic anions and relatively simple catalysts derived from the precursor Ru3(CO)12]. Very high values of TON (17000) and TOF have been observed and FA solutions with concentrations of up to 1.2 M have been produced. In this system, the imidazolium based IL associated with the acetate anion acts as precursor for the formation of the catalytically active Ru-H species, catalyst stabilizer and as an acid buffer, shifting the equilibrium towards free formic acid. Moreover, the IL acts as an entropic driver (via augmentation of the number of microstates), lowering the entropic contribution imposed by the IL surrounding the catalytically active sites. The favorable thermodynamic conditions enable the reaction to proceed efficiently at low pressure pressures, and furthermore the immobilization of the IL onto a solid support facilitates the separation of FA at the end of the reaction.

The studies of human and environment interactions usually consider the extremes of environment on individuals or how humans affect the environment. It is well known that physical activity improves both physiological and psychological well-being, but further evidence is required to ascertain how different environments influence and shape health. This review considers the declining levels of physical activity, particularly in the Western world, and how the environment may help motivate and facilitate physical activity. It also addresses the additional physiological and mental health benefits that appear to occur when exercise is performed in an outdoor environment. However, people's connectedness to nature appears to be changing and this has important implications as to how humans are now interacting with nature. Barriers exist, and it is important that these are considered when discussing how to make exercise in the outdoors accessible and beneficial for all. The synergistic combination of exercise and exposure to nature and thus the 'great outdoors' could be used as a powerful tool to help fight the growing incidence of both physical inactivity and non-communicable disease.