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Asymmetric T-segment binding and gate dynamics govern the final stages of the type IIA topoisomerase catalytic cycle
Get PDFType IIA DNA topoisomerases are molecular nanomachines that alter DNA topology during essential cellular processes. The final steps of their catalytic cycle, after translocation of the transported (T-) segment into the C- gate, are still not fully understood. Here, we performed all-atom molecular dynamics simulations of several conformational states of Saccharomyces cerevisiae topoisomerase IIA, each with a T-segment inserted into the C- gate. Bound ATP and ADP nucleotides allosterically modulated the N-gate dynamics, likely stabilizing the dimer and preventing premature dissociation. The T-segment was asymmetrically bound and stabilized within the C- gate by positively charged residues, and this gate remained structurally rigid, highlighting its role as a retention site. The positioning of the T-segment in the C-gate allosterically influenced the G-segment to a straighter geometry that favors religation and release. Our simulations support coordinated release of DNA segments and point to a potentially important role for dynamic communication between the gates in the mechanism. These results provide new insights into the late stages of the catalytic cycle and highlight the intertwined roles of nucleotide binding, DNA topology and coupled protein domain dynamics in regulating this important enzyme
Melanoma antigens in pediatric medulloblastoma contribute to tumor heterogeneity and species-specificity of group 3 tumors
Get PDFMedulloblastoma (MB) is the most malignant childhood brain cancer. Group 3 MB (G3 MB) subtype accounts for about 25% of MB and is associated with the worst outcomes. Herein, we report that more than half of G3 MB tumors express melanoma antigens (MAGEs), which are potential prognostic and therapeutic markers. MAGEs are cancer‑testis antigens, aberrantly expressed in several adult cancers, and associated with poorer prognosis and therapy resistancehowever, their role in pediatric cancers is mostly unknown. This study aimed to determine whether MAGEs are activated and important in pediatric MB. We obtained formalin‑fixed paraffin‑embedded tumor samples of 34 patients, collected between 2008 and 2015 at the Children’s Medical Center in Dallas and applied our validated reverse transcription quantitative PCR (RT‑qPCR) assay to measure the expression of 23 MAGE genes. To validate our data, we analyzed published datasets from pediatric MB tumors and patient‑derived orthotopic xenografts, totaling 949 patients. Our RT‑qPCR analysis suggested that MAGEs were expressed in G3/4MB. Further mining of bulk and single‑cell RNA‑sequencing datasets confirmed that 50–75% of G3 tumors activate several MAGEs. Intriguingly, single‑cell data analysis showed that MAGEs are expressed in distinct subsets of cells in MAGE‑positive tumors and are not activated in mouse genetic models, suggesting they contribute to the tumor heterogeneity and species‑specificity of G3 MB. We then examined how MAGE expression affects the growth and oncogenic potential by CRISPR‑Cas9‑ and siRNA‑mediated gene depletion. Depletion of MAGEAs, ‑B2, and ‑Cs altered cell survival, viability, and clonogenic growth due to decreased proliferation and increased apoptosis of MAGE‑positive MB cells. These findings suggested that targeting MAGEs could represent a viable therapeutic strategy for G3 MB. A deeper understanding of MAGE regulation and function is warranted and could aid in improving prognostic and therapeutic approaches for this poorly characterized subgroup of pediatric brain tumors
Implications for karst system evolution
Get PDFVelika Pasica Cave, situated on a karst plateau at an altitude of 665 meters above sea level, offers a unique record of paleontological, speleological, and tectonic processes. The cave, predominantly filled with allogenic sediments and speleothems, contains fossilized remains of the aquatic cave invertebrate Marifugia cavatica and terrestrial small mammals, characteristic of the early Pliocene (MN15–16). Paleontological dating estimates the cave sediments to be approximately 4 Ma old, while U/Th dating of the overlying flowstone indicates deposition at 410 ± 21 ka. These findings suggest that stagnant phreatic conditions prevailed prior to tectonic uplift and basin subsidence, which reshaped the karst landscape. This study highlights the dynamic interplay between neotectonics, karst system evolution, and biodiversity changes. By integrating speleobiology, geomorphology, and biostratigraphy, it provides valuable in-sights into the environmental history of the northern Dinarides and the impact of geological processes on karst ecosystems.Jama Velika Pasica, ki leži na kraški planoti na nadmorski višini 665 metrov, nudi edinstven zapis paleontoloških, speleoloških in tektonskih dogajanj. Jama, pretežno zapolnjena z alogenimi sedimenti in sigami, vsebuje fosilne ostanke vodnega jamskega nevretenčarja Marifugia cavatica ter kopenskih malih sesalcev, značilnih za zgodnji pliocen (biocona MN15–16). Paleontološke analize kažejo, da so sedimenti stari približno 4 milijone let, medtem ko U/Th datacije na njih odložene sige kažejo na odlaganje pred približno 410 ± 21 tisoč leti (ka). Ti rezultati nakazujejo, da so v jami pred tektonskim dvigom in pogrezanjem bazena prevladovali mirni freatični pogoji, kar dokazuje prisotnost M. cavatica. Študija izpostavlja dinamično prepletanje neotektonskih procesov, razvoja kraškega sistema in sprememb v biotski raznovrstnosti. Z združevanjem spoznanj iz speleobiologije, geomorfologije in biostratigrafije prispeva dragocena spoznanja o okoljski zgodovini severnih Dinaridov ter o vplivu geoloških procesov na kraške ekosisteme
Senzorialni jezik
Get PDFZa senzorialni jezik je značilen svojstven pristop do občinstva – senzibilen, čuječ in buden. Interakcija z njim je vzpodbujena organsko, spontano, obiskovalca ne izpostavlja pred drugimi. Oblikoval se je vse od prvih raziskovalnih Vargasovih skupin v Kolumbiji, se nadgrajeval na vsakem gostovanju v Evropi ali na drugih celinah in se nenehno izboljševal. Preizkušali so ga v različnih kulturnih, geografskih okoljih in v sodelovanju s številnimi sodelavci po vsem svetu. Metoda, ki se že četrto desetletje razvija neinstitucionalno, vključuje celosten pristop do gledalcev, prav tako koncept varnosti občinstva in izvajalcev. Drugi načini uprizoritev (odrske, ulične, ambientalne) si prizadevajo vzpostaviti stik z gledalci oziroma obiskovalci in se vedno znova srečujejo z vprašanjem »kako«, senzorialni jezik pa to že desetletja počne na svoj način, tiho in umirjeno, z vsako uprizoritvijo vse bolje. Načelo komunikacije in organizacije občinstva je uporabno za gledališke, muzejske in galerijske koncepte, saj gre večinoma (ne pa izključno) za individualen obisk ali majhne skupine ljudi, ki se jim posveča na različnih prizoriščih znotraj scenske postavitve. Zato bi lahko bil/je primeren tudi za veččutna vodenja po muzejih in galerijah
Pedagoški leksikon
Get PDFElektronska publikacija vsebuje poskusni izbor gesel s področja pedagogike, ki predstavljajo podlago in konceptualni okvir za dolgoročni projekt, v katerem se povezujeta leksikografska veda ter raziskovalno področje vzgoje in izobraževanja. Glavni namen tovrstnega povezovanja je zasnova dinamične, kontinuirano izhajajoče elektronske publikacije – tematskega leksikona, ki temelji na akademskih standardih pisanja in z avtorskimi geselskimi članki o temeljnih pojmih s področja vzgoje in izobraževanja predstavlja referenčno delo na omenjenem področju v slovenskem jeziku
An innovative approach to implementing advanced energy projects in urban areas: from comprehensive simulation to actual implementation
Get PDFThe recent energy crisis has once again confirmed that energy and resource efficiency, combined with the use of renewable-energy sources, must be the backbone of future sustainable development across all sectors. It is also clear that achieving climate neutrality by 2050, or sooner, will require new approaches. At the implementation level, the social, technical and financial realities of local energy projects demand solutions that appeal to a variety of stakeholders, including utilities, energy service companies, banks, and end users, who must collaborate to bring projects from the idea to a practical implementation. Presented here is a methodical approach to establishing advanced energy communities in complex urban environments and implementing advanced projects with a common energy infrastructure. The outcomes of the first use case clearly indicate that investing in an energy community is beneficial from multiple perspectives. Detailed simulations enabled an accurate assessment of additional renewable-energy potential, revealing that the company in question has the capacity to install another 11,000 kWp of PV in Ljubljana and other locations across Slovenia. This would increase the share of renewable energy in its total electricity consumption to 31 %, which is in line with the national target for 2030. In the second use case, a significant potential for utilizing excess heat from a data room was identified. An economic analysis showed that the excess-heat utilization project has a payback period of 2.5 years, a net present value of over EUR 47,000 and an internal rate of return of 40 %
Relationship between job characteristics and music performance anxiety in collaborative pianists working in Slovenian music schools
Get PDFIntroduction: Music performance anxiety (MPA) is a significant challenge for amateur and professional musicians, as well as music students. Systematic literature reviews highlight a lack of research on the role of contextual variables in MPA. This study contributes to existing knowledge by examining how job characteristics, particularly job demands and job resources, influence MPA among collaborative pianists. Method: A cross-sectional quantitative study was conducted on 94 collaborative pianists (24% of the population) working at all three levels of the Slovenian music education system. Data were collected through an online survey, including demographic characteristics, objective workload measures, and perceived job characteristics scales (cognitive job demands, emotional demands, job influence, role clarity, role conflict, and organizational justice), along with an adapted MPA scale. Confirmatory factor analysis and internal consistency analysis were conducted for each scale, followed by correlation analysis and a multiple linear regression model to predict MPA. Results: The study tested six hypotheses, with mixed support for the proposed relationships. The regression model explained 50% (F = 5.11df1 = 10, df2 = 51, p < 0.001) of the variance in MPA, with perceived emotional demands (β = 0. 50t = 3.57p < 0.001) and role conflict (β = 0.38t = 2.65p = 0.011) playing significant roles in predicting MPA. Discussion and conclusions: The findings enhance the understanding of MPA in the job context and have practical implications for music school management. Future research should explore the interaction between job characteristics and individual psychological resources across diverse professional and cultural contexts with representative samples
Deregulations of DNA damage-responsive genes, genes involved in the endocrine system, in an advanced in vitro 3D zebrafish hepatic cell model after exposure to Bisphenol A (BPA) and its emerging alternatives BPAF, BPAP and BPPH
Get PDFBisphenol AF (BPAF), Bisphenol AP (BPAP), and Bisphenol PH (BPPH) are being introduced into consumer products to replace BPA and are subsequently detected in ecosystems. This study investigates the genotoxic and endocrine-disruptive potential of these emerging bisphenols using a 3D in vitro liver spheroid model derived from Danio rerio (ZFL cell line), on the transcriptional level. The selected genes targeted DNA damage response pathways (TP53, NER, BER) and endocrine-related signalling (Table 1). ZFL spheroids were prepared by a force floating method as described by Štampar et al. (2019)1. Four-day-old ZFL spheroids were exposed to BPA (50 and 200 µM), BPAF (25 and 100 µM), BPAP (25 and 100 µM), and BPPH (10 and 50 µM) for 24 (Table 2) and 96 (Table 3) hours. Following exposure, total RNA was extracted using the RNeasy® Mini Kit (Qiagen, Germany). RNA quality and quantity were assessed prior to reverse transcription (Applied Biosystems, USA), followed by gene-specific preamplification (TATAA PreAmp GrandMasterMix, Tataa Biocenter, Sweden). Gene expression analysis was performed using TaqMan Gene Expression Assays (Applied Biosystems, USA) on the Fluidigm One 48.48 Dynamic Array IFC microfluidic system as described by Štern et al. (2024)2. The generated data was analysed using the Fluidigm Gene Expression Analysis Software and with a free-accessible web program, quantGenious3. The difference in gene expression greater than 1.5-fold was considered a biologically important up/downregulation (relative expression >1.5 or <0.66, respectively). Statistically significant differences were analysed using ANOVA and Dunnett’s multiple comparison test in GraphPad Prism v9 (GraphPad Software, San Diego, CA, USA)
