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Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model1. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers2-6. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually7,8 and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids9.

Trapa natans (water chestnut) is an aquatic, thermophilic plant whose decline has been observed in many localities in central Europe during the last decades. In this paper, we present a description of two new T. natans subfossil sites located outside its present northern distribution in Poland. High-resolution analysis of plant macrofossils supported by geochemical analysis were undertaken to reconstruct the palaeoecological habitat and examine the cause of the late Holocene decline of T. natans that took place ca. 4000 calibrated years before AD 1950 (cal. yr BP) in a paleolake, presently the Bagno Kusowo bog. Its disappearance was a consequence of terrestrialisation and the development of peatland. In paleolake sediments covered by the peat layer in the Mechacz Wielki bog, T. natans macrofossils were found from before ca. 3300 cal. yr BP. The decline of T. natans could have resulted from the changes and development of other plant communities where the dominant role was played by Stratiotes aloides and Nymphaea sp. In our study sites, T. natans occurred together with Potamogeton crispus, Potamogeton obtusifolius, Nymphaea alba, and Nuphar sp. in eutrophic water dominated by Ca2+, Fe3+, and Al3+ ions. Our palaeobotanical and geochemical results align with the contemporary conditions of T. natans habitat.

This study investigated the history of the development of six, paleo-lakes, which are at present filled with sediments, in a dune area in Central Poland, based on multiproxy paleoecological analyses and accelerator mass spectrometry radiocarbon dating. The aims of the paleoecological studies were: i) to determine the initial age of lakes development, ii) to reconstruct the local and regional plant succession, as well as iii) to reconstruct the environmental conditions during the initial stage of the development of lakes and peatlands. The obtained results indicated that: the former lakes in dune depressions were developed during the Bølling and Allerød when sparse vegetation allowed strong aeolian activity. Climate warming in Bølling led to the development of a denser plant cover, inhibition of sand transportation and the formation of mid-dune reservoirs with the accumulation of organic sediments. As indicated by 14C dating, mid-dunes basins were formed between 14 686 ± 60 cal. yr BP and 13 421 ± 60 cal. yr BP. The results of the paleobotanical analysis suggested that the reservoirs were shallow, oligo-mesotrophic, inhabited by pioneer calcicole vascular plant species such as: Chara sp., Hippuris vulgaris, Potamogeton natans, Potamogeton fresii, Potamogeton alpinus and Potamogeton filiformis, and mosses such as: Pseudocalliergon trifarium, Calliergon sp. and Calliergonella cordifolium. The area next to the reservoirs was covered with sparse pine forests combined with birch, which is typical of the Late Glacial period. The open areas were dominated by psammophilic and steppe vegetation, including Poaceae, Artemisia and Hippophae rhamnoides. Geochemical analysis revealed that Ca2+ and Fe3+ were in high concentrations, which could have influenced the presence of taxa preferring soil with high Ca2+ content. The accumulation of calcium in sediments confirms that the reservoirs were fed by groundwater originating from the progressive degradation of permafrost associated with thermal changes. [ABSTRACT FROM AUTHOR]

The paper presents the results of physicochemical analyses of spring waters in the Postomia River valley (Northwest Poland). Multivariate statistical methods, i.e., cluster analysis (CA) and principal component analysis (PCA) were used to assess the spatial distribution of similarities and differences in the concentrations of individual elements. Concentrations of macro elements (MEs), trace elements (TEs) and rare-earth elements (REEs) were analysed concerning the spring's typology, land use structure and the distance from roads. The results showed that the springs waters are of the Ca2+-HCO3− and Ca2+-HCO3−-SO42− types, medium hardness and low mineralisation. The study revealed differences between valley springs and scarp-foot springs in terms of electrical conductivity and concentrations of F−, SO42−, NO3−, Mg2+, Ba, Zn, and U. Greater variability was observed between the physical and chemical conditions of the spring waters due to their location in terms of land use. Springs located in agricultural areas had lower pH values than those in other areas, and higher NO3− concentrations. The pH values and concentrations of Fe, Mo, Rb, and Th in urban areas were higher than in agricultural areas. Moreover, the concentrations of F−, Cl−, K+, Na+, Mo, Sb, Se, and Sr were higher in urban areas than in forested areas. The study shows that only HCO3− values and SO42− concentrations were related to the distance from the road network. The concentrations of Cl−, SO42−, and K+ were higher in the waters of springs located more than 50 m from the road network. The Ca and PCA analysis did not permit the identification of a single dominant origin of pollutants, suggesting an interaction of different types of pollution sources. [ABSTRACT FROM AUTHOR]

TMZ has an advantage over other traditional alkylating agents (carmustine, lomustine, procarbazine), which are highly toxic and have poor patient survival. TMZ circumvents these problems because cytochrome P450 enzymes and the kidneys are not involved in its metabolism, it has predictable side effects (nausea, vomiting, thrombocytopenia, neutropenia), which are usually reversible and only mild to moderate, have been widely described. About half of the patients treated with TMZ have high drug resistance induced by the activity of O6-methylguanine methyltransferase. Cancer stem cells (CSCs), which are found among the neoplastic cell population, have also been shown to be responsible for resistance to TMZ. Additionally, acquired immunity, induced by TMZ's epigenetic and genetic alterations, may develop. Currently, there are new therapeutic strategies for glioblastoma multiforme (GBM) based on nanotechnology, which are aimed at improving TMZ treatment (e.g. the use of apolipoprotein), or other techniques (siRNA, which increases the oxygen level in the tumor). Thus, although TMZ was discovered more than three decades ago, this drug will be used to treat not only GBM but also a large number of neoplastic pathologies. Further research focused on understanding the mechanisms of action and resistance to TMZ is required to improve its clinical application today and in the future. [ABSTRACT FROM AUTHOR]

Giant hiatal hernias with massive displacement of abdominal organs into the thoracic cage are known as non-typical hiatal hernias. They can occur with few clinical symptoms across many years, which often makes the diagnosis difficult. The method of choice for diagnosis is computer tomography. We present 4 cases of a giant hiatal hernia. Three out of 4 patients have been operated on because of an obstruction in the upper digestive system, whereas 1 had elective surgery. In all cases, we performed a fundoplication with good results and no mortality. [ABSTRACT FROM AUTHOR]

Aim. The subject of this article is the role of the Finnish Church institution and its influence on shaping the local community. The article presents the possibilities of using and shaping the interiors of temples, depending on the period in which they were created and the function they were to perform. Methods. The authors of the article present the role of Church institution in Finland from the Middle Ages to the present day. The historical educational role of the church and its contemporary community-building function will be outlined. The authors will also present how these assumptions translate into shaping its architecture. Results and conclusion. Despite the considerable secularization of society, the Protestant church in Finland still plays a central role in the local community. The church, with its dominant and educational role in the past, became a companion of the inhabitants, providing them with spaces adapted to their needs, regardless of their age or religion. Once limited, single-space forms of temples, today with an extensive program function as local cultural centers and meeting places adapted to the needs of their users. [ABSTRACT FROM AUTHOR]

We present results from a palaeoecological analysis conducted on deposits accumulated in an oxbow lake of the Prosna River (Poland), next to the Grodzisko fortified settlement. Palaeobotanical and geochemical analyses—supported by radiocarbon dating—were performed to (i) reconstruct palaeoenvironmental conditions of the oxbow lake and its surrounding area; (ii) determine the beginning of the human activity in the fortified settlement vicinity; and (iii) assess the impact of human pressure on the environment. The Grodzisko fortified settlement was originally located on a river island, encircled by a wetland, improving its defensive value. Increases in the water level (1800–1300 BC and 700–200 BC) created a small lake/moat around the fortified settlement. Indicators for human activity from pollen records suggest the presence of human populations from the late Neolithic, ca. 2800 BC, with a clear intensification ca. 1700 BC. From ca. 1600 BC, a decrease in some decidous trees suggests forest clearance. Low levels of human activity indicator pollen ca. 2000 BC suggest a reduction of human pressure (possible depopulation). The regular presence of macrocharcoal pieces and an increase in human activity indicator pollen from ca. 1300 to 200 BC provide evidence for renewed human habitation around the sampling site. [ABSTRACT FROM AUTHOR]

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