The Role of Macrophages in the Sequestration of Drug and Formation of Insoluble Drug Aggregates

Drugs with poor aqueous solubility generally possess unfavorable pharmacokinetic properties. Upon oral administration, such drugs can form supersaturated solutions within the gastrointestinal tract, causing the formation of insoluble aggregates which may be prone to precipitate out in the body. Clofazimine, an oral leprostatic drug in clinical use since the 1960s, is known to massively bioaccumulate in the form of insoluble, crystal-like drug inclusions (CLDIs). These CLDIs are primarily found within tissue macrophages of the liver, spleen, and lungs. Here, we hypothesized that CLDIs are stabilized by an active, macrophage-dependent concentrative proton and chloride transport process. To test this, we developed a multi-parameter imaging and analysis system which combines polarization and fluorescence microscopy to track the accumulation and stabilization of CLDIs in different macrophage populations throughout treatment, revealing tissue-specific differences in the ability to stabilize intracellular drug aggregates, and an active remodeling of the internal arrangement of the macrophage’s membranes to maximize drug loading. Additionally, following chemical depletion of macrophages in the liver and spleen, CLDI accumulation was significantly inhibited, resulting in a reduction in the total drug accumulation within the organs. Most importantly, depletion of hepatic macrophages alongside drug treatment caused liver damage and systemic toxicity, leading us to postulate that drug sequestration and subsequent granuloma formation by macrophages functions as a protective mechanism. When macrophage-depleted mice were injected with isolated CLDIs, there was a significant increase in the rate of decay of the crystals, indicating that phagocytosis by the macrophage stabilizes the crystal and prevents dissolution. Finally, we determined that CLDI-containing macrophages showed significantly higher levels TFEB activation, lysosomal content and autophagic flux, pointing to an active adaptation of the macrophages’ endolysosomal system to accommodate and stabilize CLDIs. To conclude, macrophages are actively involved in sequestering drug and help to limit drug toxicity.PHDPharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/144122/1/pmrzec_1.pd

Własność i władza. Ujęcie własności ziemi w myśli Stanisława Zaborowskiego

Main purpose of the article is to present relationships between property of land and political power in Stanisław Zaborowski’s thought. The starting point of his reflexions was a question of transition of the legal title to royal lands. With respect to this problem Zaborowski assumed that no kind of alienation of possible, since everything, what is public, should be at the service of common good. Due to this assumption political power becomes merely an administrator of public good entrusted to it, and the whole political community is its superior

A framework for analysis of the supplier selection in green supply chain

The main purpose of the article is to build the framework of the supplier assessment model in the green supply chain. To achieve this purpose, specific objectives were taken to consideration: 1) an indication of the basis for the analysis of supplier selection in green supply chain; 2) identify of the gaps that exist in this respect, in the literature; 3) the identification of the criteria catalogue for the supplier selection with the particular emphasis on the needs of green supply chain; 4) develop a model to assess the green supply chain, taking into account the sustainable aspects; 5) using AHP method to the investigation and analysis of the meaning of the selected criteria, on the example of companies operating in the Polish economy; 6) indication which of them are the most important and which of them did not play an important role in the selection process of the suppliers

Vulnerability of sustainable supply chains : demand-side approach

Purpose: Changing economic conditions, including increasingly complex relationships between actors in the supply chain, are making the supply chain more sensitive and are lacking in transparency. The main research problem was whether or not demand uncertainties affect the vulnerability of sustainable supply chains (SSC). Design/Methodology/Approach: The following research methods were selected: literature analysis, and empirical research - questionnaire. The analysis and interpretation of the data obtained from the qualitative research were developed using quantitative methods - descriptive, as well as statistical, where the analysis of variance-ANOVA was used. Findings: Several factors influencing the sensitivity of SSC has been identified. One of the most frequent factors was the uncertainty of demand. Global trends in the implementation of sustainable development principles in various economic spheres, as well as customer requirements to offer organic products, are forcing adjustment decisions in the supply chain. Demand side and consumer research allows to design supply side research. The results should give a chance to confront and explore the relationships between customer expectations and what in terms of vulnerability is done by the links in the supply chain. This approach can identify common elements and differences in understanding not only sustainable chain strategies but will also allow the creation of a catalogue or model to create defensive mechanisms and immunization of sustainable supply chains. Practical Implications: Implications for business practice may relate to the identification of directions, areas and processes for the implementation of sustainable development principles in the supply chain strategy, in order to increase their efficiency, competitive position and the level of innovation as well as to identify customer expectations regarding the purchase of organic products and to identify elements that may affect the vulnerability of such a chain. Originality/value: The novelty and originality of the considerations is to examine the demand side in the context of the sensitivity of sustainable supply chains. A novelty is shown how dedicated groups of buyers indicate assessment of the importance of the different aspects: social, ecological, financial, and economic aspects of SSC. This can be the basis for original supply side research.peer-reviewe

Factors of shaping logistic strategies in supply chains

Kompleksowa i dopasowana do warunków rynkowych strategia logistyczna to podstawa sprawnego i skutecznie działającego łańcucha dostaw. Dlatego tak ważnym elementem jest odpowiednia identyfikacja czynników wpływających na budowę strategii logistycznych. W artykule przedstawiono rozważania literaturowe na temat kształtowania strategii logistycznych na poziomie przedsiębiorstw, odnosząc się do ich wpływu na cały łańcuch dostaw. W końcowej części przedstawiono częściowe wyniki badań ankietowych dotyczących czynników kształtowania tychże strategii w warunkach polskich. W wynikach wskazano na spadające znaczenie czynników kosztowo-cenowych, które przez szereg lat w badaniach oraz literaturze przedmiotu zajmowały miejsca czołowe, a wzrost znaczenia czynników jakościowych (jakość produktu oraz obsługi).A comprehensive logistics strategy suited to market conditions is the basis for a smooth and efficient supply chain. That is why an important element is the proper identification of factors affecting the construction of logistics strategies. The article presents literature considerations on shaping logistics strategies at the level of enterprises, referring to their impact on the entire supply chain. The final part presents partial results of surveys concerning the factors shaping these strategies in Polish conditions. The results pointed to the decreasing importance of cost and price factors, which for several years in the research and literature on the subject occupied the front places, and the increase in the importance of quality factors (product quality and service)

Game theory in creating supply chain logistics strategy - the possibility of applying a holistic approach

The game theory, due to its potent ial in creat ing behavioral models, can become a tool used in the area of formulat ing or redesigning logist ic st rategies of supply chains (networks). The exist ing research in this field focuses on the analysis of individual decisions in one specific area. The art icle discusses the holist ic approach to this problem by ident ifying exist ing limitat ions and present ing a framework concept for the applicat ion of game theory in the design of supply chain logist ics st rategies. The conclusions were drawn on the basis o f theoret ical literature studies, supply chain surveys (on different level chain part icipants) and laboratory experiment . In results found that the idea of a common interpretat ion of the st rategy and the holist ic applicat ion of game theory in the search fo r opt imal solut ions to decision-making problems requires changing the approach to designing / redesigning the supply chain logist ics st rategy

Cooperative Games in Integration of Supply Chain on the Example of Purchasing Groups

Purchasing group can improve the chance of a higher return for individual entities in the supply chain. The greater sales occurs between companies, the higher the probability of deepening integration between them. Functioning of the purchasing group is, however, dependent on the justice of imputation the profits generated by it (discounts, cost reduction) for its entities. Article presents the use of cooperative game, in order to explain the possibility of optimizing and sharing the profits (payoffs), and in a longer perspective, build an integrated supply chain

Internet portal as a media company. Good and bad portal management practices

Przedmiotem pracy są ogólnie pojęte przedsiębiorstwa medialne, o charakterze portali internetowych, z naciskiem na wykorzystanie przy ich tworzeniu oprogramowania Joomla!. Celem pracy jest analiza portali internetowych w kontekście cyberbezpieczeństwa, kampanii reklamowych oraz portalu internetowego jako przedsiębiorstwa medialnego. Stanowi go też próba ewaluacji, oceny jakości portalu i analiza portalu jako pracy w zespole. Najważniejsze elementy pracy, które stanowią o innowacyjności badań, odnoszą się do analizy dokumentacji bezpieczeństwa użytkowania oprogramowania Joomla! i eksploracyjnych badań eksperymentalnych dotyczących jakości, jaką otrzymać może użytkownik portalu internetowego. Głównymi tezami stawianymi przez autora były potwierdzenie istnienia mitu absolutnych zabezpieczeń portali internetowych, istotność działania zespołowego oraz racjonalnego projektowania wizualnego w procesie zarządzania takimi przedsiębiorstwami medialnymi. Napisana przeze mnie praca ma charakter interdyscyplinarny. Łączy ona wiedzę z zakresu zarządzania, mediów, reklamy oraz informatyki. W pracy korzystałem zarówno ze źródeł tradycyjnych - takich jak książki - jak i stron internetowych. Materiał do badań czerpałem ze współtworzonego przeze mnie projektu portalu internetowego.The subject of the work are generally understood media enterprises, with the nature of internet portals, with an emphasis on using Joomla! software for their creation. The aim of the work is to analyze web portals in the context of cybersecurity, advertising campaigns and the Internet portal as a media enterprise. It is also an attempt to evaluate the quality of the portal and analyze the portal as a team work. The most important elements of the work, which constitute the innovation of research, refer to the analysis of the documentation of the security of use of the Joomla! and exploratory experimental research on the quality that an Internet portal user can receive. The main thesis put forward by the author were confirmation of the myth of security of internet portals, the importance of team working and rational visual design in the process of managing such media companies. The work I write is interdisciplinary. It combines knowledge in management, media, advertising and IT. At work, I used both traditional sources - such as books - as well as websites. I drew the material for the research from the web portal project I have created