The Cyrilka Cave-the longest crevice-type cave in Czechia: structural controls, genesis, and age

The Cyrilka Cave is the second longest pseudokarst cave and the longest crevice-type cave in Czechia. Developed within the headscarp area of a deep-seated landslide, the cave became a focus of scientific research in recent years when new passages were discovered. Structural analysis provided a general tectonic plan of the cave, as well as more detailed data on geometry and kinematics of the relaxed rock massif. The primary structure of NNE- to ENE-striking bedding is broken by a system of NNE-striking fissures interconnected by two continuous ENE-striking dextral fracture zones. Abundant signs of recent sinistral strike-slips within the rock massif represent a bold structural feature of the cave. Along with DEM imaging and a detailed survey of the cave, 2-D and 3-D ERT measurements completed an image of the main predispositions and revealed the internal structure of the slope deformation. These measures also detected unknown crevices above the existing headscarp, which indicate the retrograde evolution of the landslide. Methodologically, we used the 3-D electrical resistivity tomography in the incoherent sedimentary flysch rocks for the first time. Based on radiocarbon dating of the stalactite core, the minimum age of the cave is up to 19,900 +/- 280 cal BP, which is the oldest age detected in the area of the Outer Flysch Carpathians so far; we thoroughly discuss further indirect evidence indicating a probable Late Pleistocene age of the cave.Web of Science47339237

ATM-deficient neural precursors develop senescence phenotype with disturbances in autophagy.

ATM is a kinase involved in DNA damage response (DDR), regulation of response to oxidative stress, autophagy and mitophagy. Mutations in the ATM gene in humans result in ataxi A-Telangiectasia disease (A-T) characterized by a variety of symptoms with neurodegeneration and premature ageing among them. Since brain is one of the most affected organs in A-T, we have focused on senescence of neural progenitor cells (NPCs) derived from A-T reprogrammed fibroblasts. Accordingly, A-T NPCs obtained through neural differentiation of iPSCs in 5% oxygen possessed some features of senescence including increased activity of SA-β-gal and secretion of IL6 and IL8 in comparison to control NPCs. This phenotype of A-T NPC was accompanied by elevated oxidative stress. A-T NPCs exhibited symptoms of impaired autophagy and mitophagy with lack of response to chloroquine treatment. Additional sources of oxidative stress like increased oxygen concentration (20 %) and H2O2 respectively aggravated the phenotype of senescence and additionally disturbed the process of mitophagy. In both cases only A-T NPCs reacted to the treatment. We conclude that oxidative stress may be responsible for the phenotype of senescence and impairment of autophagy in A-T NPCs. Our results point to senescent A-T cells as a potential therapeutic target in this disease

Dlaczego farmaceuci proponują zamianę leków?

INTRODUCTION: The Article is bringing up the problem of the exchange of prescribed medicines for the recipe for their counterparts in the context of motivation and the reflectiveness of pharmacists participating in this process.MATERIAL AND METHODS: 50 questionnaire forms, get from pharmacists working in pharmacies in Lesser Poland province, in which they were asking for motivation for proposing patients the exchange of medicines for equivalents, perception of anxieties of patients in the discussed situation of the exchange of medicines and the awareness, that pharmacists apart from delivering the specific medicinal product additionally are going up the position of the third participant of the therapeutic relation.RESULTS: Collected data are indicating that, submitting to the proposal the exchange of medicines is a general practice in polled pharmacies. They are most often declared motivations for the exchange of medicines in the equal proportion declared „good of the patient” as well as convincing the pharmacist that the patient is bothered about the minimum price of the medicine. It only recognised the 10% of polled pharmacists that the good of the patient is guaranteed when he receives this medicine which the doctor prescribed exactly.CONCLUSIONS: Achieved results are pointing indirectly at the significant influence of the promotion of medicines for the forming of the motivation system of pharmacists and to their low awareness, that proposing the exchange of medicines actively are joining in the therapeutic relation.WSTĘP: W artykule porusza się problem zamiany leków przepisywanych na receptę na ich odpowiedniki w kontekście motywacji i refleksyjności uczestniczących w tym procesie farmaceutów.MATERIAŁ I METODY: Poddano analizie 50 ankiet, uzyskanych od farmaceutów pracujących w aptekach w Małopolsce, w których pytano o motywację do proponowania pacjentom zamiany leków na odpowiedniki, percepcję obaw pacjentów w omawianej sytuacji zamiany leków oraz świadomość, że farmaceuci poza dostarczaniem określonego „produktu leczniczego” jako sprzedawcy dodatkowo wchodzą na pozycję „trzeciego” uczestnika w proces relacji terapeutycznej.WYNIKI: Uzyskane dane wskazują, że składanie propozycji zamiany leków jest powszechną praktyką w ankietowanych aptekach. Najczęściej deklarowanymi motywacjami do zamiany leków są w równej proporcji deklarowane „dobro pacjenta” oraz przekonanie farmaceuty, że pacjentowi zależy na niższej „cenie leku”. Tylko 10% ankietowanych farmaceutów uznało, że dobro pacjenta zagwarantowane jest wtedy, kiedy otrzyma on dokładnie ten lek, który przepisał lekarz.WNIOSKI: Uzyskane wyniki wskazują pośrednio na istotny wpływ promocji leków na kształtowanie systemu motywacyjnego farmaceutów oraz na ich niską świadomość, że proponując zamianę leków aktywnie włączają się w relację terapeutyczną

Increased activity of the sterol branch of the mevalonate pathway elevates glycosylation of secretory proteins and improves antifungal properties of Trichoderma atroviride.

Some Trichoderma spp. have an ability to inhibit proliferation of fungal plant pathogens in the soil. Numerous compounds with a proven antifungal activity are synthesized via the terpene pathway. Here, we stimulated the activity of the mevalonate pathway in T. atroviride P1 by expressing the Saccharomyces cerevisiae ERG20 gene coding for farnesyl pyrophosphate (FPP) synthase, a key enzyme of this pathway. ERG20-expressing Trichoderma strains showed higher activities of FPP synthase and squalene synthase, the principal recipient of FPP in the mevalonate pathway. We also observed activation of dolichyl phosphate mannose (DPM) synthase, an enzyme in protein glycosylation, and significantly increased O- and N-glycosylation of secreted proteins. The hyper-glycosylation of secretory hydrolases could explain their increased activity observed in the ERG20 transformants. Analysis of the antifungal properties of the new strains revealed that the hydrolases secreted by the transformants inhibited growth of a plant pathogen, Pythium ultimum more efficiently compared to the control strain. Consequently, the biocontrol activity of the transgenic strains, determined as their ability to protect bean seeds and seedlings against harmful action of P. ultimum, was also improved substantially

Expression of Saccharomyces cerevisiae RER2 Gene Encoding Cis-Prenyltransferase in Trichoderma atroviride Increases the Activity of Secretory Hydrolases and Enhances Antimicrobial Features

Some Trichoderma spp. exhibit natural abilities to reduce fungal diseases of plants through their mycoparasitic and antagonistic properties. In this study, we created new Trichoderma atroviride strains with elevated antifungal activity. This effect was achieved by improving the activity of cis-prenyltransferase, the main enzyme in dolichol synthesis, by expressing the RER2 gene from Saccharomyces cerevisiae. Since dolichyl phosphate is the carrier of carbohydrate residues during pro�tein glycosylation, activation of its synthesis enhanced the activities of dolichyl-dependent enzymes,DPM synthase and N-acetylglucosamine transferase, as well as stimulated glycosylation of secretory proteins. Cellulases secreted by the transformants revealed significantly higher levels or activities compared to the control strain. Consequently, the resulting Trichoderma strains were more effective against the plant pathogens Pythium ultimum

Inhibition of Dephosphorylation of Dolichyl Diphosphate Alters the Synthesis of Dolichol and Hinders Protein N-Glycosylation and Morphological Transitions in Candida albicans

The essential role of dolichyl phosphate (DolP) as a carbohydrate carrier during protein N-glycosylation is well established. The cellular pool of DolP is derived from de novo synthesis in the dolichol branch of the mevalonate pathway and from recycling of DolPP after each cycle of N-glycosylation, when the oligosaccharide is transferred from the lipid carrier to the protein and DolPP is released and then dephosphorylated. In Saccharomyces cerevisiae, the dephosphorylation of DolPP is known to be catalyzed by the Cwh8p protein. To establish the role of the Cwh8p orthologue in another distantly related yeast species, Candida albicans, we studied its mutant devoid of the CaCWH8 gene. A double Cacwh8∆/Cacwh8∆ strain was constructed by the URA-blaster method. As in S. cerevisiae, the mutant was impaired in DolPP recycling. This defect, however, was accompanied by an elevation of cis-prenyltransferase activity and higher de novo production of dolichols. Despite these compensatory changes, protein glycosylation, cell wall integrity, filamentous growth, and biofilm formation were impaired in the mutant. These results suggest that the defects are not due to the lack of DolP for the protein N-glycosylation but rather that the activity of oligosacharyltransferase could be inhibited by the excess DolPP accumulating in the mutant

Pseudanabaena galeata CCNP1313 : biological activity and peptides production

Even cyanobacteria from ecosystems of low biodiversity, such as the Baltic Sea, can constitute a rich source of bioactive metabolites. Potent toxins, enzyme inhibitors, and anticancer and antifungal agents were detected in both bloom-forming species and less commonly occurring cyanobacteria. In previous work on the Baltic Pseudanabaena galeata CCNP1313, the induction of apoptosis in the breast cancer cell line MCF-7 was documented. Here, the activity of the strain was further explored using human dermal fibroblasts, African green monkey kidney, cancer cell lines (T47D, HCT-8, and A549(ACE2/TMPRSS2)) and viruses (SARS-CoV-2, HCoV-OC43, and WNV). In the tests, extracts, chromatographic fractions, and the main components of the P. galeata CCNP1313 fractions were used. The LC-MS/MS analyses of the tested samples led to the detection of forty-five peptides. For fourteen of the new peptides, putative structures were proposed based on MS/MS spectra. Although the complex samples (i.e., extracts and chromatographic fractions) showed potent cytotoxic and antiviral activities, the effects of the isolated compounds were minor. The study confirmed the significance of P. galeata CCNP1313 as a source of metabolites with potent activity. It also illustrated the difficulties in assigning the observed biological effects to specific metabolites, especially when they are produced in minute amounts

Monocyte subpopulations display disease-specific miRNA signatures depending on the subform of Spondyloarthropathy

Spondyloarthropathies (SpA) are a family of rheumatic disorders that could be divided into axial (axSpA) and peripheral (perSpA) sub-forms depending on the disease clinical presentation. The chronic inflammation is believed to be driven by innate immune cells such as monocytes, rather than self-reactive cells of adaptive immune system. The aim of the study was to investigate the micro-RNA (miRNA) profiles in monocyte subpopulations (classical, intermediate and non-classical subpopulations) acquired from SpA patients or healthy individuals in search for prospective disease specific and/or disease subtype differentiating miRNA markers. Several SpA-specific and axSpA/perSpA differentiating miRNAs have been identified that appear to be characteristic for specific monocyte subpopulation. For classical monocytes, upregulation of miR-567 and miR-943 was found to be SpA-specific, whereas downregulation of miR-1262 could serve as axSpA-differentiating, and the expression pattern of miR-23a, miR-34c, mi-591 and miR-630 as perSpA-differentiating markers. For intermediate monocytes, expression levels of miR-103, miR-125b, miR-140, miR-374, miR-376c and miR-1249 could be used to distinguish SpA patients from healthy donors, whereas the expression pattern of miR-155 was identified as characteristic for perSpA. For non-classical monocytes, differential expression of miR-195 was recognized as general SpA indicator, while upregulation of miR-454 and miR-487b could serve as axSpA-differentiating, and miR-1291 as perSpA-differentiating markers. Our data indicate for the first time that in different SpA subtypes, monocyte subpopulations bear disease-specific miRNA signatures that could be relevant for SpA diagnosis/differentiation process and may help to understand SpA etiopathology in the context of already known functions of monocyte subpopulations

Variants in CUL4B are Associated with Cerebral Malformations

Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B