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Inherited thrombocytopenias (ITs) encompass a group of rare disorders characterized by diminished platelet count. Recent advancements have unveiled various forms of IT, with inherited thrombocytopenia 2 (THC2) emerging as a prevalent subtype associated with germline variants in the critical 5’ untranslated region of the ANKRD26 gene. This region is crucial in regulating the gene expression of ANKRD26, particularly in megakaryocytes. THC2 is an autosomal dominant disorder presenting as mild-to-moderate thrombocytopenia with minimal symptoms, with an increased risk of myeloproliferative malignancies. In our study of a family with suspected IT, three affected individuals harbored the c.-118C>T ANKRD26 variant, while four healthy members carried the c.-140C>G ANKRD26 variant. We performed a functional analysis by studying platelet-specific ANKRD26 gene expression levels using quantitative real-time polymerase-chain reaction. Functional analysis of the c.-118C>T variant showed a significant increase in ANKRD26 expression in affected individuals, supporting its pathogenicity. On the contrary, carriers of the c.-140C>G variant exhibited normal platelet counts and no significant elevation in the ANKRD26 expression, indicating the likely benign nature of this variant. Our findings provide evidence confirming the pathogenicity of the c.-118C>T ANKRD26 variant in THC2 and suggest the likely benign nature of the c.-140C>G variant.

IntroductionWithin oncology research, there is a high effort for new approaches to prevent and treat cancer as a life-threatening disease. Specific plant species that adapt to harsh conditions may possess unique properties that may be utilized in the management of cancer.HypothesisChokeberry fruit is rich in secondary metabolites with anti-cancer activities potentially useful in cancer prevention and treatment.Aims of the study and MethodsBased on mentioned hypothesis, the main goal of our study was to evaluate the antitumor effects of dietary administered Aronia melanocarpa L. fruit peels (in two concentrations of 0.3 and 3% [w/w]) in the therapeutic syngeneic 4T1 mouse adenocarcinoma model, the chemopreventive model of chemically induced mammary carcinogenesis in rats, a cell antioxidant assay, and robust in vitro analyses using MCF-7 and MDA-MB-231 cancer cells.ResultsThe dominant metabolites in the A. melanocarpa fruit peel extract tested were phenolic derivatives classified as anthocyanins and procyanidins. In a therapeutic model, aronia significantly reduced the volume of 4T1 tumors at both higher and lower doses. In the same tumors, we noted a significant dose-dependent decrease in the mitotic activity index compared to the control. In the chemopreventive model, the expression of Bax was significantly increased by aronia at both doses. Additionally, aronia decreased Bcl-2 and VEGF levels, increasing the Bax/Bcl-2 ratio compared to the control group. The cytoplasmic expression of caspase-3 was significantly enhanced when aronia was administered at a higher dosage, in contrast to both the control group and the aronia group treated with a lower dosage. Furthermore, the higher dosage of aronia exhibited a significant reduction in the expression of the tumor stem cell marker CD133 compared to the control group. In addition, the examination of aronia`s epigenetic impact on tumor tissue through in vivo analyses revealed significant alterations in histone chemical modifications, specifically H3K4m3 and H3K9m3, miRNAs expression (miR155, miR210, and miR34a) and methylation status of tumor suppressor genes (PTEN and TIMP3). In vitro studies utilizing a methanolic extract of A.melanocarpa demonstrated significant anti-cancer properties in the MCF-7 and MDA-MB-231 cell lines. Various analyses, including Resazurin, cell cycle, annexin V/PI, caspase-3/7, Bcl-2, PARP, and mitochondrial membrane potential, were conducted in this regard. Additionally, the aronia extract enhanced the responsiveness to epirubicin in both cancer cell lines.ConclusionThis study is the first to analyze the antitumor effect of A. melanocarpa in selected models of experimental breast carcinoma in vivo and in vitro. The utilization of the antitumor effects of aronia in clinical practice is still minimal and requires precise and long-term clinical evaluations. Individualized cancer-type profiling and patient stratification are crucial for effectively implementing plant nutraceuticals within targeted anti-cancer strategies in clinical oncology.

Abstract Microfluidic devices play a crucial role in advanced cell biology applications, including cell separations, cultivations, migration and interaction studies, diagnostic devices, and organ‐on‐chips. One of the frequent purposes of such devices is the ability to selectively address the attachment of cells at defined locations on the surface. This study explores the application of middle‐energy carbon, oxygen, and nitrogen ions to locally modify the surface of cyclic olefin copolymer (COC) thermoplastic material, allowing selective cell growth on patterned polymer surfaces. The investigation considers ion element type, ion beam energy, and ion irradiation fluence, analyzing their influence on the modification effect. Characterization of the modified surfaces involves various surface‐analytical methods such as contact angle, energy dispersive spectroscopy (SEM‐EDX), atomic force microscopy (AFM), x‐ray photoelectron spectroscopy (XPS), rutherford backscattering spectrometry (RBS), and elastic recoil detection analysis (ERDA). The study extends to practical aspects, with a representative cancer cell line, MCF‐7, grown on the patterned surface to evaluate the degree of selective attachment. Additionally, the stability of the irradiated patterns is tested under elevated temperatures beyond the glass transition temperature (Tg), demonstrating the compatibility of the approach with hot embossing technology. The findings underscore the potential of ion beam treatment for COC in cell‐biology‐related applications, offering insights into surface modification techniques for enhanced functionality in microfluidic devices.

Background: Cancer management faces multiple obstacles, including resistance to current therapeutic approaches. In the face of challenging microenvironments, cancer cells adapt metabolically to maintain their supply of energy and precursor molecules for biosynthesis and thus sustain rapid proliferation and tumor growth. Among the various metabolic adaptations observed in cancer cells, the altered glucose metabolism is the most widely studied. The aberrant glycolytic modification in cancer cells has been associated with rapid cell division, tumor growth, cancer progression, and drug resistance. The higher rates of glycolysis in cancer cells, as a hallmark of cancer progression, is modulated by the transcription factor hypoxia inducible factor 1 alpha (HIF-1α), a downstream target of the PI3K/Akt signaling, the most deregulated pathway in cancer. Aim of Review: We provide a detailed overview of current, primarily experimental, evidence on the potential effectiveness of flavonoids to combat aberrant glycolysis-induced resistance of cancer cells to conventional and targeted therapies. The manuscript focuses primarily on flavonoids reducing cancer resistance via affecting PI3K/Akt, HIF-1α (as the transcription factor critical for glucose metabolism of cancer cells that is regulated by PI3K/Akt pathway), and key glycolytic mediators downstream of PI3K/Akt/HIF-1α signaling (glucose transporters and key glycolytic enzymes). Key Scientific Concepts of Review: The working hypothesis of the manuscript proposes HIF-1α – the transcription factor critical for glucose metabolism of cancer cells regulated by PI3K/Akt pathway as an attractive target for application of flavonoids to mitigate cancer resistance. Phytochemicals represent a source of promising substances for cancer management applicable to primary, secondary, and tertiary care. However, accurate patient stratification and individualized patient profiling represent crucial steps in the paradigm shift from reactive to predictive, preventive, and personalized medicine (PPPM / 3PM). The article is focused on targeting molecular patterns by natural substances and provides evidence-based recommendations for the 3PM relevant implementation.

Although public service media is a trusted island in the media landscape of many countries, trust in public service media is not absolute and universal. This study adopts a qualitative approach to explore what trust and distrust entail for the public, a perspective rarely applied in trust research. Also, it explores the extent to which the sources of trust and distrust are the same and whether the concepts of trust and distrust are identical (only inverse), or linked but separate. It focuses on the Czech Republic, where the level of trust in the news is among the lowest in the world, yet public service media is the most trusted news source (Newman et al., 2022). Based on four focus group discussions with the general public (N = 24), this study analyzes the reasons for the audience’s trust and distrust in Czech public service media. There are three main categories: trust in the message (i.e., people trust public service media if, in their view, it provides objective, truthful, reliable, relevant, and fast information without sensationalism and anti-system views); trust in the source (i.e., people trust public service media if they perceive the public service media journalists as professional); and trust in the public service media organizations (i.e., people trust public service media if they perceive the regulatory framework as effective in ensuring independence from politics and oversight boards as a guarantee for quality). As the reasons leading to trust were not identical (only inverse) to the reasons leading to distrust, our findings suggest that trust and distrust in public service media are not two sides of the same coin.

Despite the elevated heat flow known in the Western part of the South Slave Region (Northwest Territories, Canada), a continuous and equilibrium geothermal gradient was never measured in boreholes below the communities where geothermal energy could be developed. This paper aims to predict the geothermal gradient and assess the Earth’s natural heat flow below the communities of Fort Providence, Kakisa, Hay River, and Enterprise. Temperatures from drill-stem tests and bottom well logs were corrected for drilling disturbance and paleoclimate. The thermal conductivity and heat generation rate of the geological formations were determined from the literature and with new laboratory measurements. Original 1D models were developed to evaluate subsurface temperature through the sedimentary formations based on a thermostratigraphic assessment. The results indicate a geothermal gradient that varies from 44.1 ± 10.6 °C km−1 to 59.1 ± 14.9 °C km−1 and heat flow that varies from 105.5 mW m−2 to 160.2 mW m−2 below the communities. These estimates were in agreement with the equilibrium geothermal gradients measured in Cameron Hills, south of the four communities, and were used to verify our predictions. The highest geothermal gradient (59.1 ± 14.9 °C km−1) was estimated at Hay River, which, therefore, has the most favorable geological conditions for geothermal development.

Introduction: Based on extensive data from oncology research, the use of phytochemicals or plant-based nutraceuticals is considered an innovative tool for cancer management. This research aimed to analyze the oncostatic properties of Salvia officinalis L. [Lamiaceae; Salviae officinalis herba] using animal and in vitro models of breast carcinoma (BC).Methods: The effects of dietary administered S. officinalis in two concentrations (0.1%/SAL 0.1/and 1%/SAL 1/) were assessed in both syngeneic 4T1 mouse and chemically induced rat models of BC. The histopathological and molecular evaluations of rodent carcinoma specimens were performed after the autopsy. Besides, numerous in vitro analyses using two human cancer cell lines were performed.Results and Conclusion: The dominant metabolites found in S. officinalis propylene glycol extract (SPGE) were representatives of phenolics, specifically rosmarinic, protocatechuic, and salicylic acids. Furthermore, the occurrence of triterpenoids ursolic and oleanolic acid was proved in SPGE. In a mouse model, a non-significant tumor volume decrease after S. officinalis treatment was associated with a significant reduction in the mitotic activity index of 4T1 tumors by 37.5% (SAL 0.1) and 31.5% (SAL 1) vs. controls (set as a blank group with not applied salvia in the diet). In addition, salvia at higher doses significantly decreased necrosis/whole tumor area ratio by 46% when compared to control tumor samples. In a rat chemoprevention study, S. officinalis at a higher dose significantly lengthened the latency of tumors by 8.5 days and significantly improved the high/low-grade carcinomas ratio vs. controls in both doses. Analyses of the mechanisms of anticancer activities of S. officinalis included well-validated prognostic, predictive, and diagnostic biomarkers that are applied in both oncology practice and preclinical investigation. Our assessment in vivo revealed numerous significant changes after a comparison of treated vs. untreated cancer cells. In this regard, we found an overexpression in caspase-3, an increased Bax/Bcl-2 ratio, and a decrease in MDA, ALDH1, and EpCam expression. In addition, salvia reduced TGF-β serum levels in rats (decrease in IL-6 and TNF-α levels were with borderline significance). Evaluation of epigenetic modifications in rat cancer specimens in vivo revealed a decline in the lysine methylations of H3K4m3 and an increase in lysine acetylation in H4K16ac levels in treated groups. Salvia decreased the relative levels of oncogenic miR21 and tumor-suppressive miR145 (miR210, miR22, miR34a, and miR155 were not significantly altered). The methylation of ATM and PTEN promoters was decreased after S. officinalis treatment (PITX2, RASSF1, and TIMP3 promoters were not altered). Analyzing plasma metabolomics profile in tumor-bearing rats, we found reduced levels of ketoacids derived from BCAAs after salvia treatment. In vitro analyses revealed significant anti-cancer effects of SPGE extract in MCF‐7 and MDA-MB-231 cell lines (cytotoxicity, caspase‐3/-7, Bcl‐2, Annexin V/PI, cell cycle, BrdU, and mitochondrial membrane potential). Our study demonstrates the significant chemopreventive and treatment effects of salvia haulm using animal or in vitro BC models.

Observations of the anomalous Hall effect in RuO2 and MnTe have demonstrated unconventional time-reversal symmetry breaking in the electronic structure of a recently identified new class of compensated collinear magnets, dubbed altermagnets. While in MnTe, the unconventional anomalous Hall signal accompanied by a vanishing magnetization is observable at remanence, the anomalous Hall effect in RuO2 is excluded by symmetry for the Néel vector pointing along the zero-field [001] easy-axis. Guided by a symmetry analysis and ab initio calculations, a field-induced reorientation of the Néel vector from the easy-axis toward the [110] hard-axis was used to demonstrate the anomalous Hall signal in this altermagnet. We confirm the existence of an anomalous Hall effect in our RuO2 thin-film samples, whose set of magnetic and magneto-transport characteristics is consistent with the earlier report. By performing our measurements at extreme magnetic fields up to 68 T, we reach saturation of the anomalous Hall signal at a field Hc ≃ 55 T that was inaccessible in earlier studies but is consistent with the expected Néel-vector reorientation field.

Geothermal energy exploration, development, and research have been ongoing in Canada for several decades. The country’s cold climate and the push to develop renewable energy sources have driven interest in geothermal energy. Despite this drive, regulatory complexities and competition with other relatively inexpensive energy sources with existing infrastructure have hindered development. As such, interest has grown and waned with changes in the energy economy over several decades, leaving many projects at a standstill. As of January 2023, there are currently no operational geothermal power projects in Canada. Many hot spring pool and spa complexes remain active, and Canada is a leading country in the installation of ground source heat pumps (GSHPs; also called geo-exchange systems). However, in the last decade, the interest in deep geothermal systems has renewed, with many new projects starting up across several provinces and territories. Moreover, projects that had shown limited progress for many years—such as Mount Meager in British Columbia—have begun to renew their development efforts. Research is also expanding within prominent research groups and universities. The areas of focus include both building upon previous studies (such as thermal gradients and the heat flow in sedimentary basins) and researching new methods and resources (such as GSHPs, closed-loop systems, integrated geothermal operations, and hybrid systems, including heat storage). The development is supported by federal, provincial, and territorial governments through grants and the development of regulatory frameworks. Although challenges still remain for Canada to develop its geothermal energy resources, several power, thermal, and co-production projects, ongoing research, funding, and regulatory acts are all moving forward to support geothermal development. This paper aims to study Canada’s geothermal energy update in 2023 regarding the aspects mentioned above.

The hydrophilic–lipophilic balance (HLB) is a valuable parameter used to determine the relative hydrophobicity of a compound based on its chemical structure. This semi-empirical parameter has been instrumental in formulating oil-in-water and water-in-oil emulsions using well-characterized ingredients with known HLB values. However, recent trends toward the use of minimally processed “virgin” oils of therapeutic or nutritional value may render the reported “required HLB” values inaccurate. Minimally processed oils can contain numerous compounds at varying or unknown concentrations, rendering the HLB value incalculable. Factors such as regional source, growing season, and processing method contribute to the variability in oil composition. Furthermore, the solubilization of lipophilic bioactives in oils can significantly alter the HLB of the oil phase in a concentration-dependent manner. This complicates the formulation of emulsions, as the HLB values of both the oil phase and emulsifiers must be closely matched to achieve stable formulations. This study presents a simple and efficient experimental method to determine an HLB value of a complex ingredient without resorting to lengthy Design-of-Experiment (DoE) matrices and trial-and-error approaches. The optimal HLB of a formulation can be determined from a series of experiments in which two well-characterized surfactants of known HLB values are mixed at varying proportions with an unknown oil phase, where the HLB of the oil is considered to match the HLB value of the surfactants combined at the proportion at which nanoemulsions with the smallest, most stable oil droplets are formed. Similarly, when the HLB values of the oil phase and other contributing components are precisely known, the unknown HLB of a complex natural surfactant can be calculated. These calculations assist in formulating emulsions efficiently and effectively by ensuring optimal compatibility among all the components.

Hepatocellular carcinoma (HCC) cells critically depend on PARP1 and CHK1 activation for survival. Combining the PARP inhibitor (PARPi) olaparib with a CHK1 inhibitor (MK-8776, CHK1i) produced a synergistic effect, reducing cell viability and inducing marked oxidative stress and DNA damage, particularly in the HepG2 cells. This dual treatment significantly increased apoptosis markers, including γH2AX and caspase-3/7 activity. Both HCC cell lines exhibited heightened sensitivity to the combined treatment. The effect of drugs on the expression of proliferation markers in an olaparib-resistant patient-derived xenograft (PDX) model of ovarian cancer was also investigated. Ovarian tumors displayed reduced tissue growth, as reflected by a drop in proliferation marker Ki-67 levels in response to PARPi combined with CHK1i. No changes were observed in corresponding liver tissues using Ki-67 and pCHK staining, which indicates the absence of metastases and a hepatotoxic effect. Thus, our results indicate that the dual inhibition of PARP and CHK1 may prove to be a promising therapeutic approach in the treatment of primary HCC as well as OC tumors without the risk of liver metastases, especially in patients with olaparib-resistant tumor profiles. [ABSTRACT FROM AUTHOR]

The paper addresses the role of Czech public service television in a polarized society. The research on public service media (PSM) is salient concerning their specific role; however, it is increasingly questioned in a fragmented and polarized environment. The paper builds on data from 27 semi-structured interviews and a survey conducted in 2019–2020 (N = 3,251). While for some audiences, Czech television is a trustworthy medium protecting exemplary sets of values, for others, it is biased and hostile. The study reveals the deeper interplay between political attitudes and media practices, potentially endangering PSM's role and position in polarized settings. [ABSTRACT FROM AUTHOR]

Though strong-field induced carrier excitation allows for exploring ultrafast electronic properties of a material, characterizing post-excitation dynamics is a challenge. Here, the authors report linear petahertz photoconductive sampling in a solid and use it to real-time probe conduction band electron motion.

Humic substances (HS) are often used as feesd additives in livestock feeding. The long-term effects of different concentrations of HS additives in aquafeed on growth and production performance, antioxidant status, stress resistance, gut microbiome, overall health condition, final product yield, sensory properties of fresh and cooked meat, and composition of fatty acids of market size in African catfish (Clarias gariepinus) originating from aquaculture were compared in this study. C. gariepinus were exposed to dietary inclusions of HS (0, 1, and 3, and 6% w/w) in a long-term experiment (six months in total) until fish reached market size. The growth parameters, condition factor, and selected somatic indices did not differ (p > 0.05) between the tested groups (HS0–HS6). Biochemical parameters were not different between the tested HS groups by the end of experiment, and only glucose (GLC) levels significantly increased (p < 0.05) with increasing concentrations of HS fed as an additive. The levels of cortisol (COR) and GLC did not differ between the tested groups (p > 0.05) after the stress challenge, but the results of GLC levels before and after the stress challenge showed an increasing tendency with increasing levels of HS addition in the diet. The levels of COR were slightly lower in groups HS3 and HS6 than in HS1 and the control group. In the case of protein and fat contents, differences between groups (HS0–HS6) were statistically insignificant. Significant differences were found, however, in water and ash content. In some cases, statistically significant differences were found in fatty acid profiles and in nutritional indices assessing fatty acids between samples. Sensory characteristics of fresh fillets did not differ between the tested groups HS0–HS6. The total content of polyphenols increased depending on the addition of humates. The main gut microbiota of samples analyzed (HS0–HS3 group) comprised the following three genera: Ralstonia, Pseudomonas and Cetobacterium; other genera were present in all samples at a low relative abundance: Staphylococcus, Bradyrhizobium, Bacillus, and Anaerobacillus. The relative abundance of Pseudomonas decreased while the presence of Cetobacterium increased in samples fed with 3% of HS. The results of our study yielded a comprehensive set of experimental results about African catfish fed with HS as additives. Although a significant effect of HS on overall performance of C. gariepinus was not proven, a positive effect on antioxidant status was seen as well as a decrease in gut microorganisms that can be present as pathogenic contaminants in aquatic environments.

Background von Willebrand disease (VWD) is a genetic bleeding disorder caused by defects of von Willebrand factor (VWF), quantitative (type 1 and 3) or qualitative (type 2). The laboratory phenotyping is heterogenic making diagnosis difficult. Objectives Complete laboratory analysis of VWD as an expansion of the previously reported cross-sectional family-based VWD study in the Czech Republic (BRNO-VWD) and Slovakia (BRA-VWD) under the name “Heart of Europe,” in order to improve the understanding of laboratory phenotype/genotype correlation. Patients and Methods In total, 227 suspected VWD patients were identified from historical records. Complete laboratory analysis was established using all available assays, including VWF multimers and genetic analysis. Results A total of 191 patients (from 119 families) were confirmed as having VWD. The majority was characterized as a type 1 VWD, followed by type 2. Multimeric patterns concordant with laboratory phenotypes were found in approximately 83% of all cases. A phenotype/genotype correlation was present in 84% (77% type 1, 99% type 2, and 61% type 3) of all patients. Another 45 candidate mutations (23 novel variations), not found in the initial study, could be identified (missense 75% and truncating 24%). An exon 1–3 gene deletion was identified in 14 patients where no mutation was found by direct DNA sequencing, increasing the linkage up to 92%, overall. Conclusion This study provides a cross-sectional overview of the VWD population in a part of Central Europe. It is an addition to the previously published BRNO-VWD study, and provides important data to the International Society of Thrombosis and Haemostasis/European Association for Haemophilia and Allied Disorders VWD mutation database with identification of novel causal mutations.