Academic literature on the topic 'Total Synthesis, Methodology'

Heterogeneity of meroterpenoids arising from their dual biosynthetic origins is constantly provoking synthetic chemists to utilize their ingenuity and revise their retrosynthetic logic. By studying recent publications on meroterpenoid synthesis,tremendous advances in the field of synthetic organic chemistry can be witnessed. This feature article covers some of the most intriguing total syntheses and synthetic studies towards the meroterpenoid class of natural products from the last five years.

In 1982, routine screening of the Pseudopterogorgia elizabethae stirred the scientific community by showing the presence of cytotoxic metabolites with antimicrobial activity. Since this discovery a vast amount of research has been conducted in synthesising metabolites of the soft coral. Herein we report the developments towards the synthesis of two metabolites (+)-Erogorgiaene and (+)-Elisabethadione utilising three key reactions in setting up the molecules three chiral centres. The use of asymmetric allylation, oxy-Cope rearrangement and cationic cyclisation was utilised to set up the desired stereocentres from a starting cinnamyl aldehyde. Natural elisabethadione was synthesised in a racemic form as a 2:1 mixture of diastereoisomers at the C-13 stereocentre.

Total synthesis of the pyrrolizidine alkaloid NP25302: (+)-NP25302 is an unusual vinylogous urea containing pyrrolizidine alkaloid shown to exhibit cell adhesion inhibition. It was envisaged that this natural product could be accessed by a novel 5-endo-dig cyclisation to construct the pyrrolizidine core, and a Curtius rearrangement to install the vinylogous urea motif. This methodology was first tested on a model system, furnishing nor-NP25302 from L-proline in 12 steps and 9% overall yield. The total synthesis of (±)-NP25302 was completed in 9 steps and 26% overall yield from ethyl 2-nitropropionate using similar methodology. Studies into the stereospecificity of the Au(I)-catalysed cyclisation of monoallylic diols: During the synthesis of (+)-isoaltholactone in the Robertson group, the key Au(I)-catalysed cyclisation was observed to occur with some stereospecificity. Further investigations were therefore conducted into the stereochemical outcome of this reaction using stereodefined allylic alcohols, and from the combined results a mnemonic was proposed to predict the stereochemistry of the products of this reaction. Studies into the total synthesis of ascospiroketals A and B: Investigations were conducted into the total synthesis of the recently isolated natural products ascospiroketals A and B. A second generation synthesis was used to construct advanced intermediates 1 and 2.

The base-catalysed reaction of 4H-pyran-4-one with a range of nucleophiles, namely diethyl malonate, ethyl acetoacetate, nitromethane, acetylacetone and ethyl cyanoacetate, was developed as a reliable, high yielding method for the preparation of para-substituted phenols. The methodology was extended to include the use of the substituted pyranones, maltol, 2,6-dimethyl-4H-pyran-4-one and diethyl chelidonate. Reactions were studied using conventional heating methods and microwave irradiation. Microwave irradiation had definite beneficial effects, with improved yields, reduced reaction times and cleaner reaction profiles. The potential of this methodology was examined for the regioselective placement of ¹³C-atoms into benzene rings using ¹³C-labelled nucleophiles or ¹³C-labelled 4H-pyran-4-ones. [3,5-13C₂]4H-Pyran-4-one and [2,6-13C₂]4H-pyran-4-one were prepared from various ¹³C-labelled versions of triethyl orthoformate and acetone. This methodology was applied to the synthesis of [1,3,5-¹³C₃]gallic acid, via the base-catalysed reaction of [3,5-¹³C₂]4H-pyran-4-one with diethyl [2-¹³C]malonate, followed by subsequent transformations to yield [1,3,5-¹³C₃]gallic acid. The preparation of [2-¹³C]phloroglucinol was carried out via [2-¹³C]resorcinol, with regioselective placement of a single ¹³C-atom into the aromatic ring. This was accomplished from non-aromatic precursors, with the source of the ¹³C-atom being [¹³C]methyl iodide. The key step in this synthesis was the introduction of the third hydroxyl group, which was achieved using a modified iridium-catalysed C-H activation/borylation/oxidation procedure. The scope of an existing C-H activation/borylation reaction was modified and expanded to include a range of protected resorcinol derivatives. A catalyst system was developed which allowed high conversion to the intermediate arylboronic acids, followed by oxidation using aqueous Oxone® to yield the corresponding phenols. Finally, to demonstrate the potential of these new methods for application in the synthesis of isotopically labelled natural products and polyphenols, the syntheses of ¹³C-labelled anthocyanins were studied. A route was developed that could be applied to the synthesis of either cyanidin-3-glucoside or delphinidin-3-glucoside. Only the final coupling/cyclisation step to yield the desired anthocyanin targets remains to be carried out.

La (-)-spongidepsine est un cyclodepsipeptide isolé de l'éponge marine Spongia sp. Ce composé présente des activités cytotoxiques et antiprolifératives contre plusieurs lignées cellulaires cancéreuses. Jusqu'à présent, cinq synthèses totales et deux formelles ont déjà été rapportées, toutes comprenant une déconnexion de la (-)-spongidepsine en trois fragments : un acide carboxylique (C1-C5), un alcool bis-homoallylique (C6-C13) et la N-méthyl-phénylalanine. Notre objectif était de développer une synthèse flexible, efficace de la (-)-spongidepsine qui pourrait être utilisée afin d’avoir suffisamment de matière et effectuer des études biologiques et pour la préparation d'analogues. La synthèse du fragment acide a été réalisée selon une des procédures décrites. Pour accéder au fragment C6-C13, une homoallylation énantiosélective, sans précédent, d'aldéhydes par des diènes catalysée par un sel de nickel a été développée. La réaction a été réalisée en utilisant une combinaison de NiCl2avec des phosphoramidites énantio-enrichis, dérivés de BINOL, en présence d'un donneur d'hydrogène, le Et2Zn, et d'un diène 1,3. Une variété d'aldéhydes aromatiques, aliphatiques et α,β-insaturés a été transformée en alcools bis-homoallyliques correspondants avec des rendements et une énantiosélectivité modérés à bons. La méthode a été appliquée avec succès à la synthèse du fragment C6-C13 de la (-)-spongidepsine
-)-Spongidepsin is a cyclodepsipeptide isolated from the marine sponge Spongia sp. This compound exhibitscytotoxic and antiproliferative activities against several cancer cell lines. Until now, five total syntheses and two formal ones have already been reported, all of them including a disconnection of (-)-spongidepsin into three fragments: a carboxylic acid (C1-C5), a bis-homoallylic alcohol (C6-C13) and N-methyl-phenylalanine. Our objective was to develop a flexible, short and scalable synthesis of (-)-spongidepsin that could be used for further biological studies and for the preparation of analogs. The synthesis of the acid fragment was achieved according to reported procedure. To access the C6-C13 fragment, an unprecedented enantioselective nickel-catalyzed homoallylation of aldehydes with dienes was developed. The reaction was performed using a combination of NiCl2 with enantio enriched phosphoramidites derived from BINOL in the presence of a hydrogen donor, Et2Zn and a 1,3-diene. A range of aromatic, aliphatic and α,β-unsaturated aldehydes were transformed into the corresponding bis-homoallylic alcohols with moderate to good yields and enantioselectivity. The method was successfully applied to the synthesis of C6-C13 fragment of (-)-spongidepsin

p>O primeira parte do trabalho descreve a preparação de um novo reagente de olefinação de HWE para o preparo de diazocetonas α, β-insaturadas com geometria Z e aplicação na síntese de núcleos piperidínicos funcionalizados. Através da otimização da reação de HWE empregando o benzaldeído como aldeído padrão foi possível maximizar a obtenção do isômero Z desejado (92%, Z:E 9:1). As reações-chave para a formação dos núcleos piperidínicos foram a de olefinação de HWE utilizando amino-aldeídos, obtendo-se bons rendimentos e boa seletividade, seguida de uma reação de inserção N-H catalisada por metais. A versatilidade da metodologia foi demostrada com a aplicação na síntese total de um produto natural: (±)-3,4,5-triidroxipiperidina e em estudos visando a síntese de outro produto natural, a (-)-1-deoxi-altronojirimicina. A química das diazocetonas α,β-insaturadas como intermediários avançados foi também empregada na síntese de um outro produto natural, a (±)-preussina. A rota empregada apresentou alta estereosseletividade na reação-chave (Rearranjo de Stevens) e posteriormente na redução da cetona formada com um redutor volumoso (L-selectride), obtendo um rendimento global de 40% em três etapas. Tentou-se também estender a metodologia para o preparo de diazocetonas α,β-insaturadas trissubstituídas, aplicando os reagentes de olefinação em reações com cetonas. No entanto, diversas tentativas foram feitas e não foi obtido as olefinas de interesse.
The first part of this work describes the preparation of a new HWE olefination reagent to prepare diazoketones α, β-unsaturated with Z geometry and its application in the synthesis of functionalized piperidine cores. After the optimization of the HWE reaction using benzaldehyde as a standard it was possible to prepare the desired Z isomer in 92% (Z:E 9:1). The key reaction for formation of the piperidine cores, N-H metal-catalyzed insertion performed to give a yield of up to 70%. The versatility of the methodology was demonstrated by an application to the synthesis of the natural product (±)-3,4,5-triidroxypiperidine and studies in the synthesis of (-)-1-deoxy-altronojirimicine. The chemistry of α, β-unsaturated diazoketones was also employed in the synthesis of another natural product, the alkaloid (±)-preussine. The employed route showed high stereoselectivity in the key-reaction (Stevens Rearrangement) as well as in the subsequent reduction of the formed ketone with a reducing agent (L-Selectride) giving an overall yield of 40%. We also tried to extend the methodology to prepare trisubstituted α, β-unsaturated diazoketones from the reaction with the olefination reagent and ketones. However, after several attempts no fruitful results were abtained.

Cyclobutanes represent an underutilised structural feature in medicinal chemistry, partially due to difficulties in forming them in an easy and controlled manner. Herein is described their application to a drug discovery project and development of the enamine [2+2] cyclisation; a straightforward synthesis of functionalised cyclobutanes. A library of 30 cyclobutane based integrin antagonists have been designed and synthesised to explore the SAR around the hit dual β3 integrin antagonist ICT9055. Several of which were shown to be highly potent antagonists inhibiting cancer cell adhesion, migration and invasion while remaining non-toxic. ICT9072 had comparable β3 activity to hit compound ICT9055 but also had activity against αvβ5 and therefore showed greater inhibition of migration of DLD-1 cells. This showed the ability to modify this scaffold for multi integrin antagonism and potential benefit of this. Synthetic studies towards the marine natural product providencin has led to the development of a previously unknown intramolecular enamine [2+2] cyclisation which has been shown to proceed in a diastereoselective manner. This reaction has been applied to the synthesis of a highly functionalised enatiopure cyclobutene suitable for inclusion into the total synthesis. A model furyl cyclobutane has also been synthesised to exemplify the route from the enantiopure cyclobutene through to the furyl cyclobutane fragment of providencin.

Bones are multifunctional passive organs of movement that supports soft tissue and directly attached muscles. They also protect internal organs and are a reserve of calcium, phosphorus and magnesium. Each bone is covered with periosteum, and the adjacent bone surfaces are covered by articular cartilage. Histologically, the bone is an organ composed of many different tissues. The main component is bone tissue (cortical and spongy) composed of a set of bone cells and intercellular substance (mineral and organic), it also contains fat, hematopoietic (bone marrow) and cartilaginous tissue. Bones are a tissue that even in adult life retains the ability to change shape and structure depending on changes in their mechanical and hormonal environment, as well as self-renewal and repair capabilities. This process is called bone turnover. The basic processes of bone turnover are: • bone modeling (incessantly changes in bone shape during individual growth) following resorption and tissue formation at various locations (e.g. bone marrow formation) to increase mass and skeletal morphology. This process occurs in the bones of growing individuals and stops after reaching puberty • bone remodeling (processes involve in maintaining bone tissue by resorbing and replacing old bone tissue with new tissue in the same place, e.g. repairing micro fractures). It is a process involving the removal and internal remodeling of existing bone and is responsible for maintaining tissue mass and architecture of mature bones. Bone turnover is regulated by two types of transformation: • osteoclastogenesis, i.e. formation of cells responsible for bone resorption • osteoblastogenesis, i.e. formation of cells responsible for bone formation (bone matrix synthesis and mineralization) Bone maturity can be defined as the completion of basic structural development and mineralization leading to maximum mass and optimal mechanical strength. The highest rate of increase in pig bone mass is observed in the first twelve weeks after birth. This period of growth is considered crucial for optimizing the growth of the skeleton of pigs, because the degree of bone mineralization in later life stages (adulthood) depends largely on the amount of bone minerals accumulated in the early stages of their growth. The development of the technique allows to determine the condition of the skeletal system (or individual bones) in living animals by methods used in human medicine, or after their slaughter. For in vivo determination of bone properties, Abstract 10 double energy X-ray absorptiometry or computed tomography scanning techniques are used. Both methods allow the quantification of mineral content and bone mineral density. The most important property from a practical point of view is the bone’s bending strength, which is directly determined by the maximum bending force. The most important factors affecting bone strength are: • age (growth period), • gender and the associated hormonal balance, • genotype and modification of genes responsible for bone growth • chemical composition of the body (protein and fat content, and the proportion between these components), • physical activity and related bone load, • nutritional factors: – protein intake influencing synthesis of organic matrix of bone, – content of minerals in the feed (CA, P, Zn, Ca/P, Mg, Mn, Na, Cl, K, Cu ratio) influencing synthesis of the inorganic matrix of bone, – mineral/protein ratio in the diet (Ca/protein, P/protein, Zn/protein) – feed energy concentration, – energy source (content of saturated fatty acids - SFA, content of polyun saturated fatty acids - PUFA, in particular ALA, EPA, DPA, DHA), – feed additives, in particular: enzymes (e.g. phytase releasing of minerals bounded in phytin complexes), probiotics and prebiotics (e.g. inulin improving the function of the digestive tract by increasing absorption of nutrients), – vitamin content that regulate metabolism and biochemical changes occurring in bone tissue (e.g. vitamin D3, B6, C and K). This study was based on the results of research experiments from available literature, and studies on growing pigs carried out at the Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences. The tests were performed in total on 300 pigs of Duroc, Pietrain, Puławska breeds, line 990 and hybrids (Great White × Duroc, Great White × Landrace), PIC pigs, slaughtered at different body weight during the growth period from 15 to 130 kg. Bones for biomechanical tests were collected after slaughter from each pig. Their length, mass and volume were determined. Based on these measurements, the specific weight (density, g/cm3) was calculated. Then each bone was cut in the middle of the shaft and the outer and inner diameters were measured both horizontally and vertically. Based on these measurements, the following indicators were calculated: • cortical thickness, • cortical surface, • cortical index. Abstract 11 Bone strength was tested by a three-point bending test. The obtained data enabled the determination of: • bending force (the magnitude of the maximum force at which disintegration and disruption of bone structure occurs), • strength (the amount of maximum force needed to break/crack of bone), • stiffness (quotient of the force acting on the bone and the amount of displacement occurring under the influence of this force). Investigation of changes in physical and biomechanical features of bones during growth was performed on pigs of the synthetic 990 line growing from 15 to 130 kg body weight. The animals were slaughtered successively at a body weight of 15, 30, 40, 50, 70, 90, 110 and 130 kg. After slaughter, the following bones were separated from the right half-carcass: humerus, 3rd and 4th metatarsal bone, femur, tibia and fibula as well as 3rd and 4th metatarsal bone. The features of bones were determined using methods described in the methodology. Describing bone growth with the Gompertz equation, it was found that the earliest slowdown of bone growth curve was observed for metacarpal and metatarsal bones. This means that these bones matured the most quickly. The established data also indicate that the rib is the slowest maturing bone. The femur, humerus, tibia and fibula were between the values of these features for the metatarsal, metacarpal and rib bones. The rate of increase in bone mass and length differed significantly between the examined bones, but in all cases it was lower (coefficient b <1) than the growth rate of the whole body of the animal. The fastest growth rate was estimated for the rib mass (coefficient b = 0.93). Among the long bones, the humerus (coefficient b = 0.81) was characterized by the fastest rate of weight gain, however femur the smallest (coefficient b = 0.71). The lowest rate of bone mass increase was observed in the foot bones, with the metacarpal bones having a slightly higher value of coefficient b than the metatarsal bones (0.67 vs 0.62). The third bone had a lower growth rate than the fourth bone, regardless of whether they were metatarsal or metacarpal. The value of the bending force increased as the animals grew. Regardless of the growth point tested, the highest values were observed for the humerus, tibia and femur, smaller for the metatarsal and metacarpal bone, and the lowest for the fibula and rib. The rate of change in the value of this indicator increased at a similar rate as the body weight changes of the animals in the case of the fibula and the fourth metacarpal bone (b value = 0.98), and more slowly in the case of the metatarsal bone, the third metacarpal bone, and the tibia bone (values of the b ratio 0.81–0.85), and the slowest femur, humerus and rib (value of b = 0.60–0.66). Bone stiffness increased as animals grew. Regardless of the growth point tested, the highest values were observed for the humerus, tibia and femur, smaller for the metatarsal and metacarpal bone, and the lowest for the fibula and rib. Abstract 12 The rate of change in the value of this indicator changed at a faster rate than the increase in weight of pigs in the case of metacarpal and metatarsal bones (coefficient b = 1.01–1.22), slightly slower in the case of fibula (coefficient b = 0.92), definitely slower in the case of the tibia (b = 0.73), ribs (b = 0.66), femur (b = 0.59) and humerus (b = 0.50). Bone strength increased as animals grew. Regardless of the growth point tested, bone strength was as follows femur > tibia > humerus > 4 metacarpal> 3 metacarpal> 3 metatarsal > 4 metatarsal > rib> fibula. The rate of increase in strength of all examined bones was greater than the rate of weight gain of pigs (value of the coefficient b = 2.04–3.26). As the animals grew, the bone density increased. However, the growth rate of this indicator for the majority of bones was slower than the rate of weight gain (the value of the coefficient b ranged from 0.37 – humerus to 0.84 – fibula). The exception was the rib, whose density increased at a similar pace increasing the body weight of animals (value of the coefficient b = 0.97). The study on the influence of the breed and the feeding intensity on bone characteristics (physical and biomechanical) was performed on pigs of the breeds Duroc, Pietrain, and synthetic 990 during a growth period of 15 to 70 kg body weight. Animals were fed ad libitum or dosed system. After slaughter at a body weight of 70 kg, three bones were taken from the right half-carcass: femur, three metatarsal, and three metacarpal and subjected to the determinations described in the methodology. The weight of bones of animals fed aa libitum was significantly lower than in pigs fed restrictively All bones of Duroc breed were significantly heavier and longer than Pietrain and 990 pig bones. The average values of bending force for the examined bones took the following order: III metatarsal bone (63.5 kg) <III metacarpal bone (77.9 kg) <femur (271.5 kg). The feeding system and breed of pigs had no significant effect on the value of this indicator. The average values of the bones strength took the following order: III metatarsal bone (92.6 kg) <III metacarpal (107.2 kg) <femur (353.1 kg). Feeding intensity and breed of animals had no significant effect on the value of this feature of the bones tested. The average bone density took the following order: femur (1.23 g/cm3) <III metatarsal bone (1.26 g/cm3) <III metacarpal bone (1.34 g / cm3). The density of bones of animals fed aa libitum was higher (P<0.01) than in animals fed with a dosing system. The density of examined bones within the breeds took the following order: Pietrain race> line 990> Duroc race. The differences between the “extreme” breeds were: 7.2% (III metatarsal bone), 8.3% (III metacarpal bone), 8.4% (femur). Abstract 13 The average bone stiffness took the following order: III metatarsal bone (35.1 kg/mm) <III metacarpus (41.5 kg/mm) <femur (60.5 kg/mm). This indicator did not differ between the groups of pigs fed at different intensity, except for the metacarpal bone, which was more stiffer in pigs fed aa libitum (P<0.05). The femur of animals fed ad libitum showed a tendency (P<0.09) to be more stiffer and a force of 4.5 kg required for its displacement by 1 mm. Breed differences in stiffness were found for the femur (P <0.05) and III metacarpal bone (P <0.05). For femur, the highest value of this indicator was found in Pietrain pigs (64.5 kg/mm), lower in pigs of 990 line (61.6 kg/mm) and the lowest in Duroc pigs (55.3 kg/mm). In turn, the 3rd metacarpal bone of Duroc and Pietrain pigs had similar stiffness (39.0 and 40.0 kg/mm respectively) and was smaller than that of line 990 pigs (45.4 kg/mm). The thickness of the cortical bone layer took the following order: III metatarsal bone (2.25 mm) <III metacarpal bone (2.41 mm) <femur (5.12 mm). The feeding system did not affect this indicator. Breed differences (P <0.05) for this trait were found only for the femur bone: Duroc (5.42 mm)> line 990 (5.13 mm)> Pietrain (4.81 mm). The cross sectional area of the examined bones was arranged in the following order: III metatarsal bone (84 mm2) <III metacarpal bone (90 mm2) <femur (286 mm2). The feeding system had no effect on the value of this bone trait, with the exception of the femur, which in animals fed the dosing system was 4.7% higher (P<0.05) than in pigs fed ad libitum. Breed differences (P<0.01) in the coross sectional area were found only in femur and III metatarsal bone. The value of this indicator was the highest in Duroc pigs, lower in 990 animals and the lowest in Pietrain pigs. The cortical index of individual bones was in the following order: III metatarsal bone (31.86) <III metacarpal bone (33.86) <femur (44.75). However, its value did not significantly depend on the intensity of feeding or the breed of pigs.

Due to the depletion of the raw material base and a technogenic materials addition into a raw mix for the Portland cement clinker synthesis, sulfur and its oxides amount in a raw mix increases. According to literature the Portland cement clinker synthesis in the presence of a sulfur oxides significant amount is difficult. As the content of SO3 in the raw mix increases the amount of C2S increases while C3S and C3A amount decrease. With an equal total content of C2S and C3S in the clinker their ratio C3S/C2S decreases with an increased content of SO3. These factors lead to a deterioration in the Portland cement clinker quality. The clinker formation reactions thermodynamic analysis and some experimental studies allow determining reasons for the Portland cement clinker quality deterioration. It was found that the presence significant amount of a SO3 in the raw mix the synthesis in solid phase of low-basic C4A3S¯ (ye’elimite) is the thermodynamically preferred rather than high-basic C3A and C4AF. As a result, excess and crystallized free lime inhibits the C3S synthesis through the liquid phase. The experimental studies result helped to develop a methodology for calculating the composition of a raw mix from materials with significant amount of SO3. It allows to reduce the SO3 negative effect on the Portland cement clinker synthesis and to obtain high-quality Portland cement.

The functioning of agricultural enterprises in modern economic conditions necessitates the improvement of both the production process itself and the mechanism for managing it. The role of the main driving force in the information support of enterprise management and production and economic activities of the modern agricultural enterprise as a whole is performed by the management accounting system. New forms of management and growing information needs of enterprise managers increase the role of management accounting tools to ensure the process of making management decisions. The effectiveness of the introduction of management accounting at Ukrainian enterprises significantly depends on the industry and technological features of production activities. To ensure the quality of beekeeping products on the market and increase its competitiveness, it is important to determine the priority areas for improving management accounting in the system of methodological and information support for industry management. The aim of the work is to study the scope of application of management accounting tools for the needs of the management of the beekeeping industry. The problem of creating management accounting in the modern period is of particular relevance for both scientists and practitioners. Under the current conditions, more and more managers are aware of the need to create management accounting and reporting systems at their enterprises. With increased competition and increasing instability of the external business environment, enterprise management is increasingly paying close attention to internal reserves for improving efficiency. An important place in the list of such reserves is occupied by management accounting. Therefore, it is relevant to study the principles, functions and tools of the method of management accounting to identify reserves for improving the efficiency of management and sustainable development of enterprises in the field of production of beekeeping products. The methodological basis of the research is the main theoretical provisions of ukrainian and foreign economic science in the field of operational management and dialectical approach to the functioning of the accounting system. In the process of research, various methods of information processing were used, in particular: system-structural, logical generalization, synthesis, comparison, induction and deduction – to determine the essence of the concepts of "management accounting"; for the formation of the structure of the mechanism of management accounting in beekeeping; system analysis – to determine the place of management accounting in the agricultural production management system; scientific abstraction – to identify objects and elements of management accounting, justification of the composition of cost items; observation – to study the state of management accounting and calculation of the cost of beekeeping products; economic and statistical – to process data on the use of accounting information in line with management decisions. The resultsof the study showed that Ukraine is positioning itself in the international community as a powerful producer and exporter of honey. Production is carried out by business entities of various organizational and legal forms. The biological properties of bees determine the technology of production of various products and a significant number of accounting objects. The main products are produced in a short period of time and are suitable for consumption or for further processing. The work identifies the distinctive features of management accounting and the tasks that he solves in beekeeping. Established factors influencing the organization of management accounting. The author's vision of areas for improving management accounting to meet management needs at different levels has been formed. The necessity of expanding the objects of management accounting and changing approaches to cost accounting and calculating the cost of beekeeping products has been proved. Practical implications.The necessity of accounting for expenses for the main processes is substantiated and accounts for their accounting are determined. An expanded list of production items of expenditure in beekeeping at the stage of primary production is proposed. The composition of the costs of ensuring the quality of beekeeping products is determined. Value/originality. Improving the organization of management accounting in beekeeping is proposed to be carried out in the direction of clarifying and supplementing the objects of accounting, cost items, analytical accounts, primary documents and internal reporting forms reflecting the quality characteristics of the products received. The organization of separate accounting of the costs of production of primary beekeeping products and production costs for its processing, processing and the cost of pollination of crops, in contrast to the current methodology of general accounting of costs for the enterprise, will allow to attribute to the crop industry a share of costs associated only with the maintenance of bee colonies, excluding from the total amount the cost of pollination and subsequent processing of beekeeping products.

Interferon-gamma belongs to a large family of cytokines – multifunctional secreted proteins involved in animal non-specific immune response. Previously inbred lines of Nicotiana tabacum L. plants harboring a heterologous gene of bovine interferon-gamma Bt-sIFNG under the control of a constitutive 35S CaMV promoter have been created by Agrobacterium-mediated genetic transformation. The antiviral and immunomodulatory activities of plant-produced interferon-gamma in bovine cell culture and laboratory animals (mice) were observed. A state-of-the-art GS-MS technique has been used to identify the possible effect of the transformation on the plant’s metabolome. Total profiles included 350 metabolites from leaves, among which 150 substances were identified up to their class and 80 up to the exact metabolite. Metabolite profiling revealed that plants able to synthesize interferon-gamma are characterized by a higher level of amino acids and other substances involved in nitrogen metabolism. In transgenic plants intensification of the secondary metabolism was also detected. Some alterations were distinguished in plant metabolome depending on cultivation conditions.

The Travel & Tourism Competitiveness Index (TTCI), developed by the World Economic Forum (WEF), is a composite indicator that integrates a total of 90 simple variables organized into 14 pillars or key dimensions of the tourism destination competitiveness. The main problem presented by this index comes from the aggregation of variables expressed in different measures, the duplicity of information, and their non-weighting in the synthetic index. This chapter proposes a new methodology for the construction of the TTCI that solves the previous problems and allows, in addition, identifying which are the pillars or dimensions that determine the differences in tourism competitiveness between the countries. The results have allowed authors to more precisely classify 136 countries according to their level of tourism competitiveness in 2017. To improve the tourism competitiveness of the countries, it is necessary to carry out policies that act on these pillars and others identified in this chapter.

An important feature of the contemporary human situation is the ever-increasing speed of sociocultural, economic and political transformations. Today, any stable elements are only temporary zones of stability, moments of «order» in a stream of «chaos». This situation leads to the actualization of the proportion of order and chaos in the existence of modern human beings and society. The deployment of the creative forces of the individual in the post-industrial economy leads to a total deconstruction of all the fundamental foundations of social being, and the creative activity of individuals begins to be interpreted as one of the manifestations of chaos, as «productive destruction». As a result, uncertainty, chaos, disorder, and risk are the result of the creative activity of «Prometheus Unbound» (H. Jonas). Purpose of the paper. It is important to investigate what forms human creative activity takes in modern conditions, what threats and prospects it can create as an irrational, chaotic force. Methodology. The study was conducted using the methods of theoretical generalization, comparative analysis, analysis and synthesis, which allowed to identify the educational content of nihilism as a revaluation of values. Scientific novelty. It is proved that chaos, irrational activity, as well as order, reasonable purposefulness, can erase the individual, dissolve it in the totality of the common. Each of these can form the basis of a special, totalitarian principle, indifferent to development. Chaos is the totality of the irrational. Order is the totality of the rational. Their interaction, then, is expressed as a flickering embodiment of a repressive totality in which all difference dissolves. Chaos appears as the controlled result of a hidden order, and the desire to organize the social world results in the spread of disorder and irrational consequences. On the contrary, creativity opens up a world beyond the extremes of order (law) and chaos (randomness). But this becomes possible in the space of vital, universal forms of human interaction and address to others and to oneself. People cease to be torn between the determinism of order and the arbitrariness of chaos when they enter the realm of caring interpersonal relationships created by humans. It is in them that the image of wholeness opens up, which is then realized in the interaction of community members with each other and society with nature. Creativity is always addressed to another person, it has an addressee, and therefore is dialogic. The search for completeness from which any creative act springs requires the other as co-creator, as one who is able to reflect the intent of the creator and through this to continue the creative process, to sustain life in the work. Hence the significance of the past for present creativity is revealed. In turn, the increasing efficiency of the rationalization of the social system is accompanied by a loss of meaning in the world around modern people. The connection of individual things into the unity of the world, of disconnected actions into the justification of personal destiny, of diverse thoughts, impressions, ideas, and desires into subjective identity is broken.

The synthesis of heat exchanger networks (HENs) is one of the most studied problems in process synthesis, because a high level of integration of the internal heat transfer is necessary to reduce both primary energy consumption and total costs. This work develops a methodology for the multi-objective optimization of HEN synthesis. A two-level hybrid algorithm operating on a population of candidate HEN topologies is proposed to search for the best tradeoffs between the maximization of energy recovery and the minimization of total HEN costs. The advantages deriving from graph representations of a HEN are fully exploited in order to handle topologies with arbitrary complexity and to simplify the optimization procedure required to evaluate the objective functions for a given topology. The Aromatics Plant problem, a well-known test case in the literature about HEN synthesis, is used as a test case to show the potentialities of the proposed methodology.

A decomposition methodology based on the concept of “thermoeconomic isolation” applied to the synthesis/design and operational optimization of a stationary cogeneration proton exchange membrane fuel cell (PEMFC) based total energy system (TES) for residential/commercial applications is the focus of this paper. A number of different configurations for the FC based TES were considered. The most promising set based on an energy integration analysis of candidate configurations was developed and detailed thermodynamic, kinetic, geometric, and economic models at both design and off-design were formulated and implemented. An original decomposition strategy called Iterative Local-Global Optimization (ILGO) developed in earlier work by two of the authors was then applied to the synthesis/design and operational optimization of the FC based TES. This decomposition strategy is the first to successfully closely approach the theoretical condition of “thermoeconomic isolation” when applied to highly complex, nonlinear systems. This contrasts with past attempts to approach this condition, all of which were applied to very simple systems under very special and restricted conditions such as those requiring linearity in the models and strictly local decision variables. This is a major advance in decomposition and has now been successfully applied to a number of highly complex, highly non-linear, and dynamic transportation and stationary systems. This paper presents the detailed results from one such application.

This study offers insight into the processes of expert designers at the Jet Propulsion Laboratory (JPL) and how they make use of heuristics in the design process. A methodology for the extraction, classification, and characterization of heuristics is presented. Ten expert participants were interviewed to identify design heuristics used during early stage space mission design at JPL. In total, 101 heuristics were obtained, classified, and characterized. Through the use of postinterview surveys, participants characterized heuristics based on attributes including source/origin, applicability based on concept maturity, frequency of use, reliability, and tendency to evolve. These findings are presented, and statistically analyzed to show correlations between the participant perceptions of frequency of use, reliability, and evolution of a heuristic. Survey results and analysis aim to identify valid attributes for assessing the applicability and value of multiple heuristics for design practice in early space mission formulation.

Abstract Many-objective optimization problem (MaOP) is defined as optimization with more than 3 objective functions. This high number of objectives makes the comparing solutions more challenging. This holds true for design problems which are MaOPs by nature due to the inherent complexity and multifaceted nature of real-life applications. In the last decades, many strategies have attempted to overcome MaOPs such as removing objectives based on their impact on the optimization. However, from a design perspective, removing objectives could lead to an under optimal, unfeasible or unreliable design. Consequently, objective aggregation seems to be a better approach since objectives can be grouped based on design features controlled by the designers. The proposed methodology uses Axiomatic Design to decompose a system into subsystems or components, and Product-Related Dependencies Management to identify the dependencies between components and formulate the objectives. Then, these objectives are aggregated based on the subsystems found with the Axiomatic Design. The methodology, applied to the layout synthesis of an autonomous greenhouse, can trim down the number of objectives from 15 to 5. Then, using a modified non-dominated sorting genetic algorithm-II (NSGA-II) combined with the objective aggregation, we were able to increase the number of “good” concepts found from 9 to 33 out of a total of 50 obtained designs.

The application of a decomposition methodology to the synthesis/design optimization of a stationary cogeneration fuel cell sub-system for residential/commercial applications is the focus of this paper. To accomplish this, a number of different configurations for the fuel cell sub-system were considered. The most promising candidate configuration, which combines features of different configurations found in the literature, is chosen for detailed thermodynamic, geometric, and economic modeling both at design and off-design. The case is then made for the usefulness and need of decomposition in large-scale optimization. The types of decomposition strategies considered are conceptual/time and physical decomposition. Specific solution approaches to the latter, namely Local-Global Optimization (LGO) are outlined in the paper. Conceptual/time decomposition and physical decomposition using the LGO approach are applied to the fuel cell sub-system. These techniques prove to be useful tools for simplifying the overall synthesis/design optimization problem of the fuel cell sub-system. Finally, the results of the decomposed synthesis/design optimization of the fuel cell sub-system indicate that this sub-system is more economical for a relatively large cluster of residences (i.e. 50). To achieve a unit cost of power production of less than 10 cents/kWh on an exergy basis requires the manufacture of more than 1500 fuel cell sub-system units per year. In addition, based on the off-design optimization results, the fuel cell sub-system is unable by itself to satisfy the winter heat demands. Thus, the case is made for integrating the fuel cell sub-system with another sub-system, namely, a heat pump, to form what is called a total energy system.

Abstract Project-Based Learning (PBL) is an active student-centered learning methodology. Several schools (of varying degrees of education) have implemented, in different ways, PBL, having as common strands that the student learns in teams, and being challenged in the context of a case-scenario. In Portugal, a PBL methodology has been implemented, in the first year of an Industrial Engineering and Management (IEM) program, for more than 15 years. This represents a total number above 700 students of IEM enrolled in PBL during the reported timeframe. A continuous improvement process of the PBL activities was relentlessly pursued during such period. Grounded on end-of-term on-line PBL process satisfaction questionnaires, as well as on results of each PBL edition final workshops, this paper studies and reports on a number of such achievements and shortcomings. Thus, this paper presents the analysis of the results of ten academic years of PBL evaluation process, grounded on the compiled results obtained from 2009/10 to 2019/20. Also, a synthesis of the effective findings (either positive or negative), systematically pointed out by the students, will be presented. Altogether, the PBL implementation in the IEM program has been very positive for students and teachers and worth for others to follow.

The aim of this work is to develop an optimization methodology for the design of the arm of a small-sized working machine. The workspace and a reference maneuver are firstly defined together with a pre-defined redundant kinematic topology. The kinematic synthesis is framed as a constrained multi-objective problem with respect to link length variables. The constraints consider the capability of the machine to follow the assigned trajectory and to fulfill the joint limits. The cost function incorporates the solution of the inverse kinematics and uses several indices, e.g., total link lengths, manipulability, energy consumption. The multi-objective optimization problem is solved employing the weighting method, converting the initial problem into a single-objective one. The final scalar cost function is minimized by the Nelder-Mead method. On the basis of the outcomes of numerical simulations, the effectiveness and versatility of the developed procedure for the design of novel working machine arms is verified.

A decomposition methodology based on the concept of “thermoeconomic isolation” applied to the synthesis/design and operational optimization of an advanced tactical fighter aircraft is the focus of this research. Conceptual, time, and physical decomposition were used to solve the system-level as well as unit-level optimization problems. The total system was decomposed into five sub-systems as follows: propulsion sub-system (PS), environmental control sub-system (ECS), fuel loop sub-system (FLS), vapor compression and PAO loops sub-system (VC/PAOS), and airframe sub-system (AFS) of which the AFS is a non-energy based sub-system. A number of different configurations for each sub-system were considered. The most promising set of candidate configurations, based on both an energy integration analysis and aerodynamic performance, were developed and detailed thermodynamic, geometric, physical, and aerodynamic models at both design and off-design were formulated and implemented. A decomposition strategy called Iterative Local-Global Optimization (ILGO) developed by Mun˜oz and von Spakovsky (2000b,c) was then applied to the synthesis/design and operational optimization of the advanced tactical fighter aircraft. This decomposition strategy is the first to successfully closely approach the theoretical condition of “thermoeconomic isolation” when applied to highly complex, highly dynamic non-liner systems. This contrasts with past attempts to approach this condition, all of which were applied to very simple systems under very special and restricted conditions such as those requiring linearity in the models and strictly local decision variables. This is a significant advance in decomposition and has now been successfully applied to a number of highly complex and dynamic transportation and stationary systems. This paper presents the detailed results from one such application, which additionally considers a non-energy based sub-system (AFS).

Fiscal collections administered by the Customs Service have the largest share in the total of taxes and fees levied in the National Public Budget. These receipts are represented by import-export rights that are collected by the customs authority when goods are introduced or removed from the customs territory of the Republic of Moldova and which, according to the provisions of the Customs Code, include: customs tax, tax for customs procedures, value added tax, excise duties and any other sums due to the state for the import of goods, collected by the customs institution. The purpose of the paper is determined by the analysis of customs statistics from the perspective of taxes and duties collected for import-export operations by the Customs Service of the Republic of Moldova, respectively the examination of their evolution and the contribution to the formation of NPB revenues. The researched subject is the collection of import and export duties for goods brought into or out of the territory of our country. In order to achieve the proposed goal, the research methodology was focused on the method of analysis and synthesis, and the results obtained were interpreted and the relevant conclusions were formulated respectively. The conclusions express the significant contribution of taxes collected on import-export operations as revenues administered by the Customs Service. Thus, analyzing all the taxes and charges levied on import and export and respectively collected as revenues in the national public budget, we found the significant weight held by excises and VAT for the goods produced and imported services compared to those provided on the territory of the Republic of Moldova and which cumulatively with the taxes on foreign trade and foreign operations constitute 37 percent of the total revenues of the NPB or 58 percent of the total taxes and fees.

The paper offers a renewed interest for Erwin Panofsky�s iconology, which consists of the applying of this concept and analytical method to musical art per se. Although Panofsky himself did not intend to introduce his methodology into the sphere of music, he establishes correlations between some musical compositions and painting. Thus, Panofsky felt the presence of certain general laws of the formation of structure of the artistic whole in painting and music. In terms of iconology, music, like painting, presupposes the original hermeneutic algorithm, which consists of three steps. Firstly, the �purely formal perception� generates the factual meaning and consists of primary ordering of expressive means and unconscious establishing of their relations; and the �emphatic� perception produces the expressional meaning that is induced by the modality of an artwork and properties of expressive means. Secondly, the intelligible signification depends on conventional meanings assigned to expressive means. Thirdly, the aesthetic synthesis depends on an author�s intention, causes the content and consists of considering each of constructive and expressive means (strokes, color areas, lines, sounds, chords, modes) as a sense-generating unit. In the same epoch and in the same style these units have the equal intentional characteristics within the boundaries of a concrete art because of transmitting the same symbolic values (Ernst Cassirer) relating to space, time, mentality and world perception. This paper presents the applying of this three-step algorithm to musical artworks in total.

Citrus fruit quality standards have been determined empirically, depending on species and on the particular growing regions. In general, the TSS (total soluble solids) to total acidity (TA) ratio determines whether citrus fruit can be marketed. Soluble sugars account for most of the TSS during harvest while TA is determined almost solely by the citric acid content, which reaches levels of 1-5% by weight in many cultivated varieties. Acid and sugar homeostasis in the fruit is critical for the management of existing cultivars, the development of new cultivars, the improvement of pre- and post-harvest strategies and the control of fruit quality and disorders. The current proposal (a continuation of a previous proposal) aimed at: (1) completing the citrus fruit proteome and metabolome, and establish a citrus fruit functional database, (2) further characterization of the control of fruit acidity by studying the regulation of key steps affecting citrate metabolism, and determine the fate of citrate during acid decline stage, and (3) Studying acid and sugar homeostasis in citrus fruits by characterizing transport mechanisms across membranes. These aims were completed as the following: (1) Our initial efforts were aimed at the characterization and identification of citric acid transporters in citrus juice cells. The identification of citrate transporters at the vacuole of the citrus juice cell indicated that the steady-state citrate cytosolic concentration and the action of the cytosolic aconitase were key elements in establishing the pH homeostat in the cell that regulates the metabolic shift towards carbon usage in the fruit during the later stages of fruit development. We focused on the action of aconitase, the enzyme mediating the metabolic use of citric acid in the cells, and identified processes that control carbon fluxes in developing citrus fruits that control the fruit acid load; (2) The regulation of aconitase, catalyzing a key step in citrate metabolism, was further characterized by using two inhibitors, citramalte and oxalomalte. These compounds significantly increased citrate content and reduced the enzyme’s activity. Metabolite profiling and changes of amino-acid metabolizing enzymes in oxalomalate- treated cells suggested that the increase in citrate, caused by aconitase inhibition, induces amino acid synthesis and the GABA shunt, in accordance with the suggested fate of citrate during the acid decline stage in citrus fruit. (3) We have placed a considerable amount of time on the development of a citrus fruit proteome that will serve to identify all of the proteins in the juice cells and will also serve as an aid to the genomics efforts of the citrus research community (validating the annotation of the fruit genes and the different ESTs). Initially, we identified more than 2,500 specific fruit proteins and were able to assign a function to more than 2,100 proteins (Katz et al., 2007). We have now developed a novel Differential Quantitative LC-MS/MS Proteomics Methodology for the identification and quantitation of key biochemical pathways in fruits (Katz et al., 2010) and applied this methodology to identify determinants of key traits for fruit quality (Katz et al., 2011). We built “biosynthesis maps” that will aid in defining key pathways associated with the development of key fruit quality traits. In addition, we constructed iCitrus (http://wiki.bioinformatics.ucdavis.edu/index.php/ICitrus), a “functional database” that is essentially a web interface to a look-up table that allows users to use functional annotations in the web to identify poorly annotated citrus proteins. This resource will serve as a tool for growers and field extension specialists.

The quantification of storm surge is vital for flood hazard assessment in communities affected by coastal storms. The astronomical tide is an integral component of the total still water level needed for accurate storm surge estimates. Coastal hazard analysis methods, such as the Coastal Hazards System and the StormSim Coastal Hazards Rapid Prediction System, require thousands of hydrodynamic and wave simulations that are computationally expensive. In some regions, the inclusion of astronomical tides is neglected in the hydrodynamics and tides are instead incorporated within the probabilistic framework. There is a need for a rapid, reliable, and accurate tide prediction methodology to provide spatially dense reconstructed or predicted tidal time series for historical, synthetic, and forecasted hurricane scenarios. A methodology is proposed to combine the tidal harmonic information from the spatially dense Advanced Circulation hydrodynamic model tidal database with a rapid tidal reconstruction and prediction program. In this study, the Unified Tidal Analysis program was paired with results from the tidal database. This methodology will produce reconstructed (i.e., historical) and predicted tidal heights for coastal locations along the United States eastern seaboard and beyond and will contribute to the determination of accurate still water levels in coastal hazard analysis methods.

The article analyzes the media discourse around the figure of Oriana Fallachi and her journalistic work during 2017-2020. The actual media image of the figure of Fallachi is highlighted, examples of positive and negative statements are given. It is substantiated why her journalism should be researched in various ways, taking into account other aspects of her work that are not related to Islamophobia. The subject of the study is critical texts in modern foreign media dedicated to the author’s work. The objective of the study is to outline the media discourse around the figure of Oriana Fallaci and her journalism during 2017-2020. The methodology. The following methods have been used in the process of scientific research: historical, comparative, systems analysis, content synthesis, and others. The main results. In total, we have analyzed eight materials in foreign publications, published over the past 3 years, as well as the two most famous biographies of Oriana Fallaci. Some of the most recent reviewed texts have been published in the last few months, reflecting the interest in the author’s journalism, her writing, and reporting. Therefore, we see the need for further tracking and analysis of this body of texts. Conclusions. Critics of Fallaci express polar views that are not all negative. Authors re­commend quite cautiously her texts for reading, emphasizing their positive aspects. Both Fallaci’s biographies are also not entirely complementary: some aspects of her work are glorified, others are condemned. We managed to find general tendencies in the criticism of Oriana Fallaci’s journalism. These include accusations of xenophobia and Islamophobia, uncompromisingness, lack of political correctness, and moral value. The authors emphasize, at the same time, the openness and directness that bribe the reader, patriotism and honesty, strength of spirit and firmness of position. Significance of the research. The analysis of the latest criticism reveals what kind of media image Fallachi’s figure has today, and gives the possibility to research it for demonization and one-sided coverage. This is important not only for thorough research of the author’s work but also for understanding how the modern world perceives journalism, which is contrary to the generally accepted principles of political correctness, journalistic ethics, and humanity.