bluuebunny/crossref_metadata_2025 huggingface dataset:
Fines Migration During CO2 Injection: A Review of the Phenomenon and New Breakthrough
Authors: Md Yusof Muhammad Aslam , Ibrahim Mohamad Arif , M. Saaid Ismail , Idris Ahmad Kamal , Idress Mazlin , Mohamed Muhammad Azfar
Published: March 2022

Large volume of CO2 injection into the saline aquifer is considered to be the high potential CO2 storage method. Until now, the field of CO2 injectivity has been completely dominated by salt precipitation – and by far the most studied mechanism for the loss of injectivity. In this paper, our aim is to focus on recent findings on CO2 injectivity impairment by fines migration that should not be overlooked. This paper summarizes the state-of-the-art knowledge obtained from theoretical, field studies, and experimental observations on CO2 injectivity impairment by fines migration in saline aquifers in the sense of CO2 storage. By gathering various data from books, DOE papers, field reports and SPE publications, a detailed and high quality data set for fines migration during CO2 injection into saline aquifer is created. Key reservoir/fluid/rock information, operational parameters and petrophysical evaluations are assessments are provided, providing the basis for comprehensive data analysis. The results are presented in terms of boxplot and histogram, where histogram displays the distribution of each parameter and identifies the best suitable ranges for best practices; boxplots are used to detect the special cases and summarize the ranges of each parameter. Previous coreflooding experiments concluded that salt precipitation, mineral precipitation, dissolution and mobilization are the main mechanisms that caused CO2 injectivity impairments. Dissolution of carbonate minerals is dominant and it increases the poro spaces and connectivity of sandstone core samples. Conversely, detachment, precipitation of salt and clay minerals and deposition of fines particles decreases the flow are and even clog the flow paths despite net dissolution. However, the results are case dependent and lack generality in terms of quantifying the petrophysical damage. It has been highlighted that injection scheme (flow rate, time frame), mineral composition (clay content, sensitive minerals), particulate process in porous media (pore geometry, particle and carrier fluid properties), and thermodynamic conditions (pressure, temperature, salinity, CO2 and brine composition) give substantial effect on the fines migration during CO2 injection. Additionally, the current experimental work is limited to rendering time and difficult to identify the dynamic process of fines migration during CO2 injection. A list of potential additional work has therefore been presented in this paper including the establishment of microscopic visualization of CO2-brine-rock interactions with representative pore-network under reservoir pressure and temperature. This is the first paper to summarize the contribution of fines migration on CO2 injectivity impairment in saline aquifer.
Legal bases for prosecution of medical staff for illegal acts during the soviet and post-soviet periods
Authors: Kobets P. N.
Published: March 2022

Objective: to study the historical retrospective of the Soviet (1917-1991) and post-Soviet (1991 – present) periods of healthcare, the evolution of their legal support; to conduct a comprehensive criminological study and analysis of the criminal liability of medical staff who committed illegal acts in the historical periods under consideration.

Methods: the methodological basis of the study was the methods of analysis, synthesis, comparison, formal and logical approach. In addition, the author used specific scientific methods, including the historical one.

Results: in general, the analysis of the legal foundations of criminal prosecution of medical staff who committed illegal acts during the Soviet and post-Soviet period suggests that the institute of legal liability of medical staff, the medical science and practice developed in parallel under the influence of social, economic and political factors. Since the beginning of the Soviet period, the issues of liability of medical staff have caused numerous disputes among both researchers and practitioners, and today these disputes continue and do not subside. At the same time, it is important to emphasize that the Russian legislative system in the field of healthcare has always been formed solely with the special attitude of the state and society to medical staff, who were perceived as guardians of the health of the citizens and enjoyed their confidence, which in turn gave rise to special caution and responsibility among medical personnel.

Scientific novelty: the study is distinguished by the author’s unique approach, which allowed stating the social conditionality of legal prohibitions for the illegal acts under consideration, as well as the causal relationship between the regulatory legal framework formed and the social consequences generated by it in the Soviet and post-Soviet periods.

Practical significance: the conclusions obtained by studying the genesis of the problems related to the liability of medical personnel for committing illegal acts will contribute to the development of a scientific understanding of the essence of the phenomenon under consideration, as well as the identification of a modern causal complex contributing to the occurrence of these illegal acts.
Role of cinematography in anticorruption enlightenment: global experience
Authors: Melnikova A. L. , Mitsul A. S.
Published: March 2022

Objective: to conduct a comprehensive interdisciplinary legal study of the role of cinematography in anti-corruption enlightenment of citizens.

Methods: a structural and functional approach to the interpretation of society as a connection of subsystems, in which cinematography is a part of the cultural subsystem, while anti-corruption policy refers simultaneously to the public subsystem (enlightenment) and the state subsystem (politics). The chosen approach determines a set of specific research methods, such as a critical analysis of theoretical literature on corruption behavior and on the relationship between a viewer and a cinematography product in conjunction with an empirical study of various cases in the form of films and film projects devoted to anti-corruption topics.

Results: the analysis of the mechanisms of building the relationships between a viewer and cinematography allowed identifying the possibilities of cinematography to have a long-term impact on a viewer, due not only to the technical capabilities of cinematography, but also to the psychobiological mechanisms of man. By the example of specific projects, the expediency of using cinema as an anti-corruption enlightenment tool was proved and justified. In particular, if the relevant messages are laid in the plot of a feature film, then, thanks to mirror neurons and human thinking mechanisms, they can serve educational purposes and demonstrate the consequences of corrupt behavior. It is important not to intimidate the audience with the horrors of living with corruption, but to show a positive way out and scenarios of living without it. This can lead to an increase in civic engagement, to an increase in interest in the issue under discussion, as well as to an increase in ratings of trust in the state.

Scientific novelty: the article proves the inexpediency of evaluating cinema solely as a form of entertainment, and for the first time examines examples of the practical application of cinema for anti-corruption policy and enlightenment by comparing approaches used in different countries.

Practical significance: the main conclusions of the article can be used in scientific, pedagogical and practical activities when developing long-term strategies and programs of anti-corruption enlightenment, as well as in the framework of cinematographic activities to assess the long-term consequences of the demonstrated film narrative.
Extending democracy to corporate governance and beyond: a theory of popular economic sovereignty
Authors: Rubin E. L.
Published: March 2022

Objective:to carry out a comprehensive analysis of the impact of democratic governance principles in a state on corporate governance.

Methods:dialectical approach to cognition of social phenomena, allowing to analyze them in historical development and functioning in the context of the totality of objective and subjective factors, which predetermined the following research methods: formal-logical and sociological.

Results:the article proposes a different rationale for corporate democracy based on an equivalence, not an analogy. The equivalence is that subordination feels essentially the same to an individual whether a public or a private entity carries it out. In the political system, democracy counteracts subordination by giving everyone political autonomy, an independent voice in controlling the power structure. By the same reasoning, those who work for a living should arguably control the institutions for which they work. Thus, the norms of democracy, when translated into the economic realm, yield the principle that people should not work for their livelihood on terms another person establishes. This can be called the principle of popular economic sovereignty.

Scientific novelty:for the first time, the work makes a conclusion that the modern understanding of both the state and the corporation developed from medieval corporativist thinking. This same mode of thought generated the idea of representation that enabled individuals who were not leaders of a structured hierarchy to participate in state decisions, certainly one of the great insights of Western political thought. Representation became the mechanism by which democratic government was instituted. As democracy developed, the scope of representation expanded to include all competent adults. This same expanded concept of representation can be extended to employment relations and would serve the same purposes as it serves in the political arena – individual autonomy and opposition to oppression. Corporations would be controlled by boards elected by the workers; small employers and individuals would be required to hire employees from labor exchanges run by the workers who are being provided. This proposal, although it sounds radical and impractical, could rather easily be implemented for both major corporations and all other employment relationships as well, and might well be more economically efficient than current modes of economic organization, as well as being more fair to the workers.

Practical significance:the main provisions and conclusions of the article can be used in scientific, pedagogical and law enforcement activities when considering the issues related to the theory of popular economic sovereignty.
Model risks in the financial sphere under the conditions of the use of artificial intelligence and machine learning
Authors: Kirilyuk I. L.
Published: March 2022

Objective: within the framework of RegTech and SupTech technologies, to assess the transformation of model risks and ways to minimize them under the increasing use of artificial intelligence methods.

Methods: a systematic approach to the analysis of the quality of economic models. Historical, logical, and statistical methods of research.

Results: the Russian and foreign experience of accounting for model risks in the financial industry is considered. Theoretical and practical works on the regulation and management of model risks in the activities of financial sector organizations are studied. The role of machine learning and artificial intelligence technologies in solving the modern problems in the functioning and regulation of financial organizations is determined. The key model risks are considered, as well as the directions of changing their specifics as a result of the artificial intelligence technologies development, primarily machine learning, and increasing the capabilities for storage and transmission of a large amount of data. The main methods of data processing and model construction are considered, as well as their advantages in terms of reducing model risks. It is determined that the reduction of model risks using RegTech and SupTech technologies is possible due to the development of artificial intelligence technologies, which will require, among other things, the elaboration of the appropriate legal field.

Scientific novelty: the unique feature of the article is a comprehensive consideration of the problem of model risks in the finance industry and of the impact of artificial intelligence technologies on them in mathematical, legal, economic aspects, as well as the description of the situation in this area both abroad and in Russia.

Practical significance: the information presented in the article can be used by regulatory authorities and commercial banks in the tasks related to minimizing specific model risks in their activities.
Central bank digital currencies: experience of introducing a digital yuan and development of a digital ruble conception
Authors: Kochergin D. A.
Published: March 2022

Objective:to determine the essential foundations of digital currencies of central banks and, based on the experience of the digital Yuan introduction in China, to substantiate the directions for improving the concept of the digital ruble introduction in Russia and the feasibility of issuing a digital currency in Belarus.

Methods:the article uses empirical, logical, comparative and statistical methods within a systematic approach to determine the areas for improving the concept of development of a central banks digital currency.

Results:the key characteristics of central banks digital currencies are determined; the features of models of retail digital currency systems are revealed; the main characteristics of the digital Yuan design and the features of its emission-settlement system organization are investigated; the main elements of the digital ruble concept of the Bank of Russia, the structure of its emission-settlement system and digital platform are examined; the issue of the feasibility of introducing the digital Belarusian ruble in the Republic of Belarus is investigated. We propose to develop additional mechanisms to protect the integrity and confidentiality of the payment information stored in the register of the Bank of Russia on the digital ruble platform, to differentiate the tools of digital wallets, and to set limits on individual payment transactions with the digital ruble.

Scientific novelty:the study reveals the features of the model of a two-level system of retail digital currencies of central banks in China and Russia; the directions of improving the concept of the digital ruble introduction are determined and the expediency of issuing digital currency in the Republic of Belarus is justified.

Practical significance:the main provisions and conclusions of the article can be used by economists, central banks and credit institutions in the development and improvement of the national digital currency design, its emission and settlement model and the development of the concept of its implementation, taking the world experience into account.
Legal bases for prosecution of medical staff for illegal acts during the soviet and post-soviet periods
Authors: Lazarev V. V.
Published: March 2022

Objective: to study the methodology of constructivism in the constitutional arrangement of the state and society.

Methods: dialectical approach to the cognition of social phenomena, which determined the choice of the following research methods: formal-logical, comparative-legal, sociological.

Results: construction is a structure, mutual arrangement of the parts of something. Law is a systemic product, therefore constructivism is inherently and organically present in law in any of its known forms. The possibilities of constructivism manifest themselves especially vividly in legislation and make themselves felt the more abstractly, the more generally the will of the state is expressed. It is this feature that is characteristic for constitutional texts. The Constitution, as a written document, has all the signs and properties of a social structure. First, it is the product of rational activity of people pursuing well-defined goals. Second, it has a certain structure characterized by “constructionality”. Third, being a reflection and consolidation of the actual material, cultural and legal level, it enables to see not only the possibilities of cognition and interpretation of the will of power enshrined in it, but also the prospects for the effective use of relevant norms and institutions. Fourth, technically building the normative material and the system of mutual relations of the subjects of constitutional and legal communication, the Constitution is the optimal construction at the time of creation of their balanced rights, duties, and responsibilities. Moreover, while at the time of the birth of constitutions limiting state power was considered the primary task, the modern realities show the need for such restrictions in relation to citizens and civil associations.

Scientific novelty: the paper substantiates the conclusion that a constructive approach organizes the cognition of the ongoing constitutional reforms in the direction of identifying the functional capabilities inherent in the Constitution of the Russian Federation, and in practical terms enables to most optimally – clearly, economically, systematically – implement the will of the state (sovereign people’s will) in all areas of social development.

Practical significance: the conclusions and provisions of the article can be used in scientific, legislative and law enforcement activities, the educational process of educational institutions of higher education.
Key energy indicators for sustainable development goals in Ukraine
Authors: Naumenkova Svitlana , Mishchenko Volodymyr , Mishchenko Svitlana
Published: March 2022

Transforming the energy sector to provide universal access to reliable and modern energy services is an essential task for Ukraine, one of the Eastern Partnership countries with heavy energy dependence. It will help accelerate the achievement of the Sustainable Development Goals. The paper is devoted to studying Ukraine’s readiness to generate sustainable energy compared to the EU and other Eastern Partnership countries and the development of an information base for monitoring the achievement of SDG7.The data from the World Energy Council (WEC), the International Energy Agency (IEA), and the State Statistics Service of Ukraine are analyzed. Thus, the study proposed to expand the list of national monitoring indicators that more fully reflect the social, economic, and environmental results of SDG7 “Affordable and clean energy” in Ukraine. The development of an information monitoring base expands the opportunities to assess the availability, sustainability, and balance of national energy policy in green economic transformation. Furthermore, the indicators of energy intensity, carbon intensity, as well as access to sustainable energy for the population and business are emphasized. The findings are aimed to raise the level of awareness of government agencies and make balanced decisions to accelerate the achievement of SDG7 in Ukraine.
Development of Baper Bolu as a Chemistry Learning Media Based On Adiwiyata
Authors: Khasanah Uswatun
Published: March 2022

Higher Order Thinking Skills is one of the skills necessary in the 21st Century. So, learning media are required to improve students' higher-order thinking skills. Chemistry textbooks used as learning media should contain questions that will enhance students' thinking processes, especially higher-order thinking skills (HOTS). However, there are no criteria for assessing the questions in the textbook, especially for higher-order thinking questions. This study aims to determine the HOTS aspect using the Brookhart category on questions in the XII grade chemistry textbook. The research method used is the descriptive method of document analysis. The results showed that the average percentage of HOTS questions in the three class XII chemistry textbooks was 25.95%, covering aspects of analyzing 8.85%, creating 3.51%, reasoning and logic 8.35%, problem-solving 3.71%, and creative thinking 1.53%. Meanwhile, the aspects of evaluating and making decisions are not present in each analyzed chemistry textbook. Based on the research results, it can be seen that questions of low-level thinking skills still dominate the chemistry textbook for class XII.
Implementation of Flipped Classroom Model on Distance Learning on Volta Cell Application Topics
Authors: Latip Abdul , Sutantri Nursida
Published: March 2022

This study aims to analyze the implementation of the flipped classroom model in distance learning chemistry in the voltaic cell applications concept. This study used a descriptive method involving 1 teacher and 36 twelfth-grade students. The instrument used was an observation sheet to observe the flipped classroom model's learning process. The results showed that The implementation of the flipped classroom model in chemistry distance learning consists of 3 stages, namely before-class, during-class, and after-class, by combining synchronous and asynchronous activities. Students learn independently through videos with pre-learning questions as guidance in the before-class stage. In the during-class stage, synchronous learning is carried out through zoom meetings to discuss the concept of voltaic cell applications in specific contexts. At the after-class stage, learning is carried out asynchronously by providing a project to design an electrical energy generator that applies to the concept of a voltaic cell. The results showed that the flipped classroom model could be an alternative model for distance learning during the Covid 19 pandemic.
Development of Interactive Multimedia Assisted of The HPLC Simulator to Enhance Student's Analytical Thinking Skills
Authors: Yulina Indah Karina , Permanasari Anna , Hernani Hernani , Setiawan Wawan
Published: March 2022

This research aims to develop interactive multimedia by utilizing HPLC simulators to train students' analytical thinking skills, which will support dry lab practicum activities to be more meaningful. The research method is development research with a 4-D model design, defining, designing, developing, and disseminating. However, this research stage is limited to the development stage. The instruments used in this study include test and non-test instruments in student satisfaction questionnaires and observation of learning outcomes. The results showed that MMI assisted by an HPLC simulator helped students increase students' motivation and interest in studying HPLC material. In line with that, learning with the HPLC simulator can develop analytical thinking skills in the matching and classifying aspects, but has not trained in 3 other aspects, namely error analysis, generalizing, and specifying. It is recommended to use a learning approach such as STEM, which accommodates learning needs with the stages of inquiry, Engineering Design Process, and Product development to overcome the lack of development of analytical thinking skills in the aspects of analysis error, specifying, and generalizing.
The Profile of Students’ Self-Efficacy in Using Chemdroid Media in Thermochemistry Topics
Authors: Solikhin Febrian , Wijanarko Andang
Published: March 2022

Self-efficacy is one of the factors that affect learning achievement. This study has the aim of analyzing the self-efficacy profile of students in learning using Chemdroid (Chemistry on Android) media. This media is an android-based media for Thermochemical material. This research is descriptive research with a quantitative approach. The classes used in this study were 2 classes with 60 students. Both are randomly selected. The first class is the control class (C-Class) which carries out hybrid learning, as usual, namely face-to-face in class and online learning using WhatsApp groups. The second class is the experimental class (E-Class) with face-to-face in class and using Chemdroid media. The learning time and the teacher in this study were the same. The instrument used is a self-efficacy measuring instrument consisting of 3 main aspects with 22 statements adapted from previous research. The results of the study were then analyzed and categorized into 5 categories. The results obtained indicate that the profile of students’ self-efficacy of E-Class students is higher than other class.
Kuantum Fikrinin Yönetim Bilimine Katkısının İncelenmesi
Authors: Şengöz Murat
Published: March 2022

Günümüzde yönetim ile alakalı durum ve olaylar, rölatif bir biçimde, tüm bilgilerin bütüncül bir şekilde dikkate alınarak değerlendirilmesini zorunlu kılmaktadır. Bunun için bugünün iş ve yönetim dünyasında olayları çok yönlü ve rölâtivist bir bakış açısı ile ele almak gerekmektedir. Bu dinamik iş görme biçimi liderlerin yönetsel etki ve ilgi alanlarında daha fazla değişkeni dikkate almalarını zorunlu kılmaktadır. Günümüzün yönetsel alanı hareket tarzlarının belirlenmesi, seçilen hareket tarzlarının birbiriyle karşılaştırılması, çevrenin ve rakiplerin olası davranışlarının etkisi, beklentilerin karşılanması bağlamında çok çeşitli dinamikler ve yöntemler içeren karmaşık faaliyetlerin gerçekleştiği bir ortamı tarif etmektedir. Bu bağlamda kuantum düşüncesi sunduğu entelektüel verilerle yöneticilerin muğlak gerçekliğe ulaşmalarına fayda sağlayan yöntemlere rehberlik edebilme potansiyeline sahiptir. Bu çalışmada, esasen fizik bilim dalından türetilen kuantum teorisinin dolanıklık ve süperpozisyon ilkelerinin çıktılarının yönetim bilimi ile ilişkisi ortaya koyulmaya çalışılmıştır.
Octanol-Water Partition: Searching for Predictive Models
Authors: Buchwald Peter , Bodor Nicholas
Published: March 2022

The log n-octanol/water partition coefficient (log Po/w) still represents one of the most informative physicochemical parameters available to medicinal chemists. In the present work, principles, methodologies, and parameters are briefly reviewed for a variety of models developed to predict this parameter based on molecular structure. To include the developments of recent years, a total of more than 40 different approaches are mentioned with relevant bibliography within four major categories: group contribution methods, atomic contribution methods, molecular methods, and other physicochemical methods. To underscore once more the utility of this partition coefficient, a comprehensive and reevaluated correlation between log Polw and in vivo permeability data of rat brain capillaries is included. Most deviants that fell below the trendline are those that have been recently found to be substrates for P-glycoprotein, a multidrug transporter that actively removes them from the brain. Accurate predictions of log P0;w may necessitate many parameters, but there is mounting evidence that molecular size and hydrogen bonding ability can account for a major part of the variance. Our recently developed, molecular size-based approach is reviewed, and it is argued that introduction of three­ dimensionality allows the elimination of many empirically derived fragment constants without a significant deterioration of the predictive accuracy. A comparison of predictive power for six different methods on 145 molecules of interest for medicinal chemists is also included.
Review of Cardiovascular Effects of Fluoxetine, A Selective Serotonine Reuptake Inhibitor, Compared to Tricyclic Antidepressants
Authors: Pacher Pal , Ungvari Zoltan , Kecskemeti Valeria , Furst Susanna
Published: March 2022

Fluoxetine is an antidepressant drug, a potent and specific inhibitor of serotonin reuptake (SSRI). Evidence suggests that being compared with tricyclic antidepressants, fluoxetine may cause significantly fewer anticholinergic, antihistaminergic and cardiotoxic side effects in the treatment of major depressive disorders. Chronic treatment with fluoxetine was not reported to affect the electrocardiogram (ECG). There is no clinical evidence of conduction delay and very little evidence of orthostatic hypotension. In the overdosed patients fewer cardiac symptoms were reported than with tricyclic antidepressants. However, dysrhythmia (atrial fibrillation and bradycardia) and syncope associated with fluoxetine treatment and overdose were reported. Although such reports have not been common, they do raise concerns. Thus we investigated the direct cardiovascular effects of the fluoxetine in isolated heart preparations and vessels of rats and rabbits. From 10-6M to 10-4M concentrations fluoxetine showed cardiodepressant and vasodilatory effects. These effects were similar to those of previously reported on tricyclic compounds. This review is a brief summary of possible cardiovascular effects of fluoxetine and other new SSRis antidepressants from the literature based on experience of clinical studies and our experiments with fluoxetine on isolated rat and rabbit cardiac preparations and vessels. Possible explanations of the lower incidence of cardiovascular complications with fluoxetine in humans and cardiodepressant effects in vitro are discussed.
Biosynthetic Anthracyclines
Authors: Arcamone Federico , Cassinelli Giuseppe
Published: March 2022

This review summarizes the structure, the occurrence and the available data concerning the bioactivity of biosynthetic anthracyclines. The anthracyclines represent an important family of natural products produced by microorganisms of Streptomyces and related genera and include clinically useful agents for the medical treatment of human cancer. Chemically, the anthracyclines are glycosides characterized by a quinone tetracyclic aglycone and one or more deoxysugar units, mostly belonging to the L-hexopyranoside series, comprising generally an aminosugar. The different compounds belonging to this family are structurally related as they share a common biosynthetic pathway. Although some statements concerning structure activity relationships and molecular requirements for activity can be made, published data are not adequate for the comparative evaluation of potential antitumor efficacy of biosynthetic anthracyclines. This family of natural products is therefore still open for pharmacological investigation.
β-Lactamase Inhibitors: Agents to Overcome Bacterial Resistance
Authors: Maiti Samarendra N. , Phillips Oludotun  A. , Micetich Ronald  G. , Livermore David M.
Published: March 2022

The extensive use of β-lactam antibiotics in hospitals and community has created major resistance problems leading to increased morbidity, mortality and health-care costs. Resistance is most often mediated
by β-lactamases, which have emerged in both Gram-positive and Gram-negative bacteria. A novel approach to countering bacterial β-lactamases is the delivery of a β-lactam antibiotic in combination with a β-lactamase inhibitor. Several such combinations are currently available, containing inhibitors clavulanic acid, sulbactam and tazobactam. These inhibitors are not, however, active against all β-lactamases and the AmpC chromosomal enzymes that are hyperproduced by some enterobacteria and pseudomonas are a particular 'gap'. Moreover, genes for these AmpC enzymes have begun to escape to plasmids. Consequently, there is a growing need for new broad-spectrum β-lactamase inhibitors. This review offers an overview of synthetic β-lactamase inhibitors, emphasizing information on their structures, and highlighting their activity against various β-lactamases, particularly AmpC enzymes. Effective inhibition of AmpC enzymes are to be found among the penems and monobactams, but none of these has yet proved suitable for pharmaceutical development.
Progress Towards the Discovery of Orally Active Thrombin Inhibitors
Authors: Menear Keith
Published: March 2022

The serine protease thrombin is a key enzyme in the control of blood coagulation and displays numerous other effects on platelet, endothelial and smooth muscle cell function. The pre-eminence of thrombin in the coagulation cascade has made the enzyme a popular drug target in the search for more clinically acceptable and safe anti-coagulants. This concept has been particularly strengthened by the demonstration that direct inhibitors of thrombin such as Revasc™ are clinically effective. A number of low molecular weight thrombin inhibitors have now been described in the literature although to date because of their inherent low bioavailability compounds have been limited to the parentral route of administration. The introduction of appropriate pharmacokinetic properties into these first generation thrombin inhibitors has been problematic despite intensive research in this area. However, the first pre clinical examples of direct thrombin inhibitors possessing good oral bioavailability is now emerging. This review updates current developments in the progress towards the discovery of orally available thrombin inhibitors and suggests that the first clinical validation of drugs from this field is imminent.
Pyrroloquinoline and Pyridoacridine Alkaloids from Marine Sources
Authors: Ding Qizhu , Chichak Kelly , Lown J. William
Published: March 2022

Marine organisms are a rich source for natural products. Pyrrolo[4,3,2-de]quinolines and pyrido[4,3,2-mn]acridines are of major interest as metabolites in sponges and ascidians. Many of these compounds have generated interest both as challenging problems for structure elucidation and synthesis as well as for their cytotoxicities. The isolation,
structure proof, biological activities, chemical properties and synthesis have attracted the attention of chemists, biologists and pharmacists. The principal structural feature of these alkaloids is the core of a planar iminoquinone moiety which can intercalate into DNA and cleave the DNA double helix or inhibit the action of topoisomerase II. Of the makaluvamines, rhakaluvamine F and A are the most cytotoxic to the HCT 116 cell line. The enhanced toxicity of the makaluvamines towards xrs-6 cells shows that all of the makaluvamines, except makaluvamine B, act like m-AMSA and etoposide in inhibiting topoisomerases via cleavable complex formation, or via the direct induction of DNA double-strand breaks. They are also amongst the most potent inhibitors of topoisomerase II. Both makaluvamine A and C can decrease tumor size in a solid human tumor model. Discorhabdin A and C in contrast are of high cytotoxicity, but they exhibit no inhibition of topoisomerase II. As representatives of the derivatives of pyrido[4,3,2-mn]acridine, cystodytins, kuanoniamines and diplamine are the most potent to inhibit HCT replication. Eilatin, as a 1,10-phenanthroline derivative, can form complexes with metal ions. It has been shown that these metal complexes can bind to DNA by intercalation. The new members of the pyrrolo[4,3,2-de]quinolines and pyrido[4,3,2- mn]acridines, such as veiutamine, discorhabdin G, tsitsikammamines, epinartins, arnoamines as well as sagitol are reviewed. Some successful syntheses of pyrrolo[4,3,2- de]quinoline ring system and pyrido[4,3,2-mn]acridine ring system are also reviewed in this article.
Synthesis and Applications for Unnatural Sugar Nucleotides
Authors: Elhalabi Jordan M. , Rice Kevin G.
Published: March 2022

The synthesis and biological evaluation of carbohydrate mimetics has begun to more clearly define the diverse roles of carbohydrates in nature. Often the strategy invoves the design and synthesis of glycosyltransferase and glycosidase inhibitors both as tools to elucidate the mechanism of action of these enzymes and as potential therapeutic - agents.
An array of unnatural sugar nucleotides have found utility in chemo-enzymatic synthesis. The
regio- and stereoselective transfer of sugars by glycosyltransferases such as 1 ,4- galactosyltransferase, o:1,3-fucosyltransferase, o:2,3- and o:2,6-sialyltransferases and N­ acethylglucosaminyltransferase V has demonstrated the broad application of this approach.
This review summarizes the specificity of these well-studied glycosyltransferases for both unnatural sugar donors and acceptors. This information combined with the knowledge of the mechanism of action of those enzymes is valuable in the design of potent selective glycosyltransferase inhibitors and the chemo-enzymatic synthesis of novel carbohydrate mimetics.
Human Milk Glycoconjugates That Inhibit Pathogens
Authors: Newburg David S.
Published: March 2022

Breast-fed infants have lower incidence of diarrhea, respiratory disease, and otitis media. The protection by human milk has long been attributed to the presence of secretory lgA. However, human milk contains large numbers and amounts of complex carbohydrates, including glycopro­
teins, glycolipids, glycosaminoglycans, mucins, and especially oligosaccharides. The
oligosaccharides comprise the third most abundant solid constituent of human milk, and contain a myriad of structures. Complex carbohydrate moieties of glycoconjugates and oligosaccharides are synthesized by the many glycosyltransferases in the mammary gland; those with homology to cell surface glycoconjugate pathogen receptors may inhibit pathogen binding, thereby protecting the nursing infant. Several examples are reviewed: A fucosyloligosaccharide inhibits the diarrheagenic effect of stable toxin of Escherichia coli. A different fucosyloligosaccharide inhibits infection by Campylobacter jejuni. Binding of Streptococcus pneumoniae arid of enteropathogenic E. coli to their respective receptors is inhibited by human milk oligosaccharides. The 46-kD glycoprotein, lactadherin, inhibits rotavirus binding and infectivity. Low levels of lactadherin in human milk are associated with a higher incidence of symptomatic rotavirus in breast-fed infants. A mannosylated glycopeptide inhibits binding by enterohemorrhagic E. coli. A glycosaminoglycan inhibits binding of gp120 to CD4, the first step in HIV infection. Human milk mucin inhibits binding by $-fimbriated E. coli. The ganglioside, GM 1,
reduces diarrhea production by cholera toxin and labile toxin of E. coli. The neutral
glycosphingolipid, Gb3, binds to Shigatoxin. Thus, many complex carbohydrates of human milk may be novel antipathogenic agents, and the milk glycoconjugates and oligosaccharides may be a major source of protection for breastfeeding infants.
Thio Sugars: Biological Relevance as Potential New Therapeutics
Authors: Witczak Zbigniew J.
Published: March 2022

The biological relevance of sulfur containing carbohydrates is gaining substantial attention. Thus the new developments, especially in the synthetic and medicinal chemistry of thio-sugars are critically important for carbohydrate drug design. New studies of biological processes including bio­
synthetic reactions and enzyme control mechanisms, discovered during the last few years clearly contributed to an understanding of their biological roles. These roles of carbohydrates and thio­ sugars in particular through biological processes and diseases are becoming better understood now.
These new trends will provide tremendous opportunities for the development of carbohydrates as new potential drugs. The main objective of this article is to address these new promising advances and stimulate continuous development of carbohydrate pharmaceuticals.
Past and Present Scenario of Hepatoprotectants#
Authors: Ram Vishnu Ji , Goel Atul
Published: March 2022

The liver plays a significant role not only in metabolism and disposition of the chemicals to which it is exposed directly or indirectly but also plays a pivotal role in the metabolism of fats, carbohydrates, proteins and immunomodulations. The impairment of the liver generally results from viral or portozoal infections, excessive use of alcohol, drugs and xenobiotics. This review provides an overall view about the past and present status of the hepatoprotectants resulted from synthetic and plant origins.
Multi-Component Methodologies in Solid-Phase Organic Synthesis
Authors: Dax Scott L. , McNally James J. , Youngman Mark A.
Published: March 2022

Solid-phase organic synthesis, particularly when used in conjunction with combinatorial techniques, is emerging as a revolutionary technology in chemistry. Multi­ component reaction systems are particularly valued because several elements of diversity can be introduced in a single transformation thereby expanding the diversity of compound libraries. A variety of multi-component reactions have been successfully adapted for solid-phase technology as described in this review.
Analysis of Deprenyl Metabolites in the Rat Brain Using HPLC-ES­ MS
Authors: Kalasz H. , Bartok T. , Komoroczy R. , Szoko E. , Haberle D. , Kiss J.P. , Hennings E.C.P. , Magyar K. , Furst S.
Published: March 2022

Methylamphetamine and amphetamine, the two major metabolites of deprenyl in the rat brain were analyzed using HPLC method combined with electrospray-mass spectrometer. (-)-Deprenyl and (+)­ deprenyl were orally administered to rats either in a single dose of 10 mg/kg,
or three times a week for three weeks. The metabolites were determined in four different parts of the rat brain, such as in the frontal cortex, corpus striatum, hippocampus, and hypophysis. The ratio of methylamphetamine to amphetamine was also compared after (-)-deprenyl and(+)­ deprenyl treatments.
Glutathione S-Transferases - A Review
Authors: Salinas Anna E. , Wong Margaret G.
Published: March 2022

The Glutathione S-transferases (GSTs) form a group of multi-gene isoenzymes involved in the cellular detoxification of both xenobiotic and endobiotic compounds. GSTs have been divided into a number of subclasses, alpha (α), mu {μ), pi (π), and theta (θ). The classification was made on the basis of sequence similarity and immunological cross-reactivity. GSTs show a high level of specificity toward GSH but the electrophilic second substrate can vary significantly both between and within the classes in spite of their sequence similarity.
X-ray crystallography and site-directed mutagenesis studies have together elucidated the structure and mechanism of GSTs. Catalysis occurs by conjugation with glutathione (GSH) and the less toxic and more hydrophilic products can then be partially metabolised and excreted. This invaluable service is however disadvantageous during chemotherapy where GSTs have been associated with multi-drug resistance of tumour cells. Levels of expression of different isoforms of GSTs are tissue specific. The variations in expression between normal and tumour cells are of interest and in most cases the levels of GSTs are increased, especially n-GST. Understanding the complex role that GSTs play in drug resistance begins with determining the pattern of isoform expression and the substrate specificities of each isoform. The use of isozyme-specific, GSH analogues as inhibitors to modulate GST activity during chemotherapy is a promising strategy in the battle against cancer.
This review attempts to provide a detailed overview of the literature concerning the different classes of GSTs, their function and mechanism and the use of GSTs as therapeutic targets for disease as current at the time of submission.
The Unique Properties of Dipeptidyl-peptidase IV (DPP IV I CD26) and the Therapeutic Potential of DPP IV Inhibitors
Authors: Augustyns K. , Bala G. , Thonusa G. , Belyaeva A. , Zhanga X.M. , Bollaerta W. , Lambeirb A.M. , Durinxb C. , Goossensb F. , Haemersa A.
Published: March 2022

This review deals with the properties and functions of dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5). This membrane anchored ecto-protease has been identified as the leukocyte antigen CD26. The following aspects of DPP IV/CD26 will be discussed: the structure of DPP IV and the new family of serine proteases to which it belongs, the substrate specificity, the distribu­tion in the human body, specific DPP IV inhibitors and the role of CD26 in the intestinal and renal handling of proline containing peptides, in cell adhesion, in peptide metabolism, in the immune system and in HIV infection. Especially the latest developments in the search for new inhibitors will be reported as well as the discovery of new natural substrates for DPP IV such as the glucagon-like peptides and the chemokines. Finally the therapeutical perspectives for DPP IV inhibitors will be discussed.
Modulating Apoptosis: Current Applications and Prospects for Future Drug Development
Authors: Deigner H. P. , Kinscherf R.
Published: March 2022

Agents modulating apoptosis are of extraordinary promise for the treatment of several states of disease including cancer, AIDS, neurodegenerative and ischemic diseases. In this review a brief summary of cellular pathways relevant to programmed cell death first is given and potential therapeutic targets therein are emphasized. Current efforts in drug development are discussed from a mechanistic, biochemical point of view and pro- and anti-apoptotic strategies are related to the respective diseases. Therapeutic approaches addressed in this paper include the design and activity of novel low molecular weight agents (e.g. caspase inhibitors) as well as gene therapy (e.g. p53, adenovirus as vector in cancer treatment). In final sections, the latest findings in the field of apoptosis are highlighted and future applications are outlined.
Manoalide
Authors: Soriente A. , De  Rosa M. , Scettri A. , Sodano G. , Terencio M.C. , Paya M. , Alcaraz M.J.
Published: March 2022

Manoalide is a potent analgesic and antiinflammatory sesterterpene isolated in 1980 from a marine sponge. The antiinflammatory activity of manoalide is due to inhibition of PLA2  , through irreversible binding to several lysine residues. The binding is realized by means of the
two masked aldehyde functions present in the polar part of manoalide of the two aldehyde groups, only that present in they-hydroxybutenolide ring seems to be essential, since cacospongionolides, naturally occurring analogues lacking the second masked aldehyde group, were also shown to be irreversible PLA2  inhibitors.

It appears that the minimum structural requirement for exhibiting manoalide-like PLA2  inhibition would be the presence in the inhibitor of functional groups able to seize the amino groups of PLA2  lysine residues with formation of stable covalent bonds.

Many manoalide analogues have been isolated from marine sponges, most of them sharing PLA2  inhibitory properties. Other interesting bioactivities have also been reported for some of these compounds.