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AimAstrocytes respond to stressors by acquiring a reactive state characterized by changes in their morphology and function. Molecules underlying reactive astrogliosis, however, remain largely unknown. Given that several studies observed increase in the Amyloid Precursor Protein (APP) in reactive astrocytes, we here test whether APP plays a role in reactive astrogliosis.MethodsWe investigated whether APP instigates reactive astroglios by examining in vitro and in vivo the morphology and function of naive and APP-deficient astrocytes in response to APP and well-established stressors.ResultsOverexpression of APP in cultured astrocytes led to remodeling of the intermediate filament network, enhancement of cytokine production, and activation of cellular programs centered around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion abrogated remodeling of the intermediate filament network and blunted expression of IFN-stimulated gene products in response to lipopolysaccharide. Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein observed canonically in astrocytes in response to TBI.ConclusionsThe APP thus represents a candidate molecular inducer and regulator of reactive astrogliosis. This finding has implications for understanding pathophysiology of neurodegenerative and other diseases of the nervous system characterized by reactive astrogliosis and opens potential new therapeutic avenues targeting APP and its pathways to modulate reactive astrogliosis.

Abstract Background Delivering serious news is usually challenging for healthcare professionals and the pandemic of COVID-19 and related restrictions brought additional challenges in this process. Aims To explore the experience of bereaved relatives with receiving serious news from healthcare professionals during the pandemic COVID-19. Design A qualitative study using thematic analysis and a codebook approach of data collected in semi-structured interviews with bereaved relatives. Setting/participants Data were collected from July to August 2022 in person/via phone with bereaved relatives who lost their relatives during the pandemic (from March 2020 to March 2022). Participants were recruited using a convenience sample and snowball method through social media and through one university hospital palliative care unit that invited bereaved relatives of deceased patients treated at the unit to participate in this study. Results A total of 22 participants, consisting of 4 men and 18 women, were interviewed for this study. Most of the participants were sons or daughters of individuals who had died (5 grandchildren, 14 sons/daughters, 2 spouses, 1 great-niece). Six themes were identified: Burden caused by visit ban, Fear of COVID-19, Inappropriate behaviour and communication of healthcare professionals, High need for emotional support, Need for detailed and honest communication, Tendency to make excuses for mistakes and lapses by healthcare professionals. Conclusions Delivering serious news during a pandemic was negatively influenced by a lack of contact with patients and a lack of support and empathetic communication with staff. Overcoming these circumstances can be achieved by frequent communication using various communication tools (such as videoconferences or phone calls), and maintaining empathy and honesty in the communication process.

Thanks to the continuous development of artificial intelligence (AI), more and more tools are available to help students to practice their language skills. Nowadays, there are various ways of using AI-driven technology in the process of language learning, one example is the use of chatbots. This pilot study aims to investigate the impact of the conversational chatbot on learning a foreign language and to understand learners' perceptions of using a chatbot as a complementary language tool. Altogether 58 university students learning English as an applied foreign language with B2 and C1 levels of English proficiency participated in the experiment during the period of one month. The qualitative results show a significant improvement in the student's language skills thanks to the use of smart AI. Furthermore, the questionnaire survey reveals positive perceptions of this additional learning tool. Therefore, the findings indicate that working with this AI-driven technology can contribute to improving language skills and its perceived usefulness in the process of second language acquisition at the university level.

This study investigates the effectiveness of ChatGPT feedback in enhancing the writing skills of Gen Z students, who constitute a significant portion of today's global population. Utilizing a mixed-methods approach, the research explores both quantitative and qualitative aspects of students' interactions with ChatGPT in the context of foreign language education. A quasi-experimental design was employed, involving 110 university students learning English as a Foreign Language (EFL). Through pre-tests, post-tests, questionnaires, and focus group interviews, the impact of ChatGPT feedback on students' writing proficiency was evaluated. Quantitative analysis revealed significant improvements in various aspects of writing, including conciseness, grammar, inclusion of key information, and the use of passive voice, following ChatGPT feedback. Qualitative insights from focus group interviews corroborated these findings, with students expressing positive perceptions of ChatGPT's role in enhancing their writing skills. Overall, the study demonstrates the potential of ChatGPT as an innovative educational tool for fostering writing proficiency among Gen Z students. The findings underscore the importance of integrating AI-driven technologies into language learning processes to meet the evolving needs of contemporary learners.

Background Chronic lymphocytic leukemia (CLL) is a common adult leukemia characterized by the accumulation of neoplastic mature B cells in blood, bone marrow, lymph nodes, and spleen. The disease biology remains unresolved in many aspects, including the processes underlying the disease progression and relapses. However, studying CLL in vitro poses a considerable challenge due to its complexity and dependency on the microenvironment. Several approaches are utilized to overcome this issue, such as co-culture of CLL cells with other cell types, supplementing culture media with growth factors, or setting up a three-dimensional (3D) culture. Previous studies have shown that 3D cultures, compared to conventional ones, can lead to enhanced cell survival and altered gene expression. 3D cultures can also give valuable information while testing treatment response in vitro since they mimic the cell spatial organization more accurately than conventional culture. Methods In our study, we investigated the behavior of CLL cells in two types of material: (i) solid porous collagen scaffolds and (ii) gel composed of carboxymethyl cellulose and polyethylene glycol (CMC-PEG). We studied CLL cells’ distribution, morphology, and viability in these materials by a transmitted-light and confocal microscopy. We also measured the metabolic activity of cultured cells. Additionally, the expression levels of MYC, VCAM1, MCL1, CXCR4, and CCL4 genes in CLL cells were studied by qPCR to observe whether our novel culture approaches lead to increased adhesion, lower apoptotic rates, or activation of cell signaling in relation to the enhanced contact with co-cultured cells. Results Both materials were biocompatible, translucent, and permeable, as assessed by metabolic assays, cell staining, and microscopy. While collagen scaffolds featured easy manipulation, washability, transferability, and biodegradability, CMC-PEG was advantageous for its easy preparation process and low variability in the number of accommodated cells. Both materials promoted cell-to-cell and cell-to-matrix interactions due to the scaffold structure and generation of cell aggregates. The metabolic activity of CLL cells cultured in CMC-PEG gel was similar to or higher than in conventional culture. Compared to the conventional culture, there was (i) a lower expression of VCAM1 in both materials, (ii) a higher expression of CCL4 in collagen scaffolds, and (iii) a lower expression of CXCR4 and MCL1 (transcript variant 2) in collagen scaffolds, while it was higher in a CMC-PEG gel. Hence, culture in the material can suppress the expression of a pro-apoptotic gene (MCL1 in collagen scaffolds) or replicate certain gene expression patterns attributed to CLL cells in lymphoid organs (low CXCR4, high CCL4 in collagen scaffolds) or blood (high CXCR4 in CMC-PEG).

Objective: A prominent, safe and efficient therapy for patients with chronic myeloid leukemia (CML) is inhibiting oncogenic protein BCR::ABL1 in a targeted manner with imatinib, a tyrosine kinase inhibitor. A substantial part of patients treated with imatinib report skeletomuscular adverse events affecting their quality of life. OCTN2 membrane transporter is involved in imatinib transportation into the cells. At the same time, the crucial physiological role of OCTN2 is cellular uptake of carnitine which is an essential co-factor for the mitochondrial β-oxidation pathway. This work investigates the impact of imatinib treatment on carnitine intake and energy metabolism of muscle cells. Methods: HTB-153 (human rhabdomyosarcoma) cell line and KCL-22 (CML cell line) were used to study the impact of imatinib treatment on intracellular levels of carnitine and vice versa. The energy metabolism changes in cells treated by imatinib were quantified and compared to changes in cells exposed to highly specific OCTN2 inhibitor vinorelbine. Mouse models were used to test whether in vitro observations are also achieved in vivo in thigh muscle tissue. The analytes of interest were quantified using a Prominence HPLC system coupled with a tandem mass spectrometer. Results: This work showed that through the carnitine-specific transporter OCTN2, imatinib and carnitine intake competed unequally and intracellular carnitine concentrations were significantly reduced. In contrast, carnitine preincubation did not influence imatinib cell intake or interfere with leukemia cell targeting. Blocking the intracellular supply of carnitine with imatinib significantly reduced the production of most Krebs cycle metabolites and ATP. However, subsequent carnitine supplementation rescued mitochondrial energy production. Due to specific inhibition of OCTN2 activity, the influx of carnitine was blocked and mitochondrial energy metabolism was impaired in muscle cells in vitro and in thigh muscle tissue in a mouse model. Conclusions: This preclinical experimental study revealed detrimental effect of imatinib on carnitine-mediated energy metabolism of muscle cells providing a possible molecular background of the frequently occurred side effects during imatinib therapy such as fatigue, muscle pain and cramps.

Abstract Background To evaluate the outcomes of first‐line imatinib versus nilotinib treatment for chronic myeloid leukemia in the chronic phase (CML‐CP) in real‐world clinical practice. Methods A propensity score analysis was performed to eliminate imbalances between the treatment groups. In the analysis, 163 patients in the nilotinib group and 163 patients in the matched imatinib group were retrospectively evaluated. Results Nilotinib‐treated patients achieved complete cytogenetic response (CCyR) and major molecular response more rapidly than imatinib‐treated patients. However, there was no significant difference in 5‐year overall survival (OS) or progression‐free survival (PFS) between the two groups (OS: 94.3% vs. 90.5%, p = 0.602; PFS: 92.9% vs. 88.0%, p = 0.614). Nilotinib‐treated patients had a higher failure‐free survival (FFS) and event‐free survival (EFS) than imatinib‐treated patients (FFS: 71.7% vs. 54.3%, p = 0.040; EFS: 71.7% vs. 53.5%, p = 0.025). Conclusions This retrospective analysis from clinical practice did not confirm any benefit of frontline nilotinib treatment for OS and PFS; however, it did demonstrate higher FFS and EFS in the nilotinib cohort.

Purpose: This study aimed to evaluate whether long-term averaged spectrum (LTAS) descriptors for reading and monologue are suitable to detect worsening of dysarthria in patients with Parkinson's disease (PD) treated with subthalamic nucleus deep brain stimulation (STN-DBS) with potential effect of ON and OFF stimulation conditions and types of connected speech. Method: Four spectral moments based on LTAS were computed for monologue and reading passage collected from 23 individuals with PD treated with bilateral STN-DBS and 23 age- and gender-matched healthy controls. Speech performance of patients with PD was compared in ON and OFF STN-DBS conditions. Results: All LTAS spectral moments including mean, standard deviation, skewness, and kurtosis across both monologue and reading passage were able to significantly distinguish between patients with PD in both stimulation conditions and control speakers. The spectral mean was the only LTAS measure sensitive to capture better speech performance in STN-DBS ON, as compared to the STN-DBS OFF stimulation condition (p < 0.05). Standardized reading passage was more sensitive compared to monologue in detecting dysarthria severity via LTAS descriptors with an area under the curve of up to 0.92 obtained between PD and control groups. Conclusions: Our findings confirmed that LTAS is a suitable approach to objectively describe changes in speech impairment severity due to STN-DBS therapy in patients with PD. We envisage these results as an important step toward a continuum development of technological solutions for the automated assessment of stimulation-induced dysarthria.

Mobile devices have penetrated all spheres of human activities, including education. Previous research has shown that smartphones are becoming widely used in learning as they can improve knowledge retention and increase student engagement. The purpose of this study was to discuss students' perception of the use of a mobile application aimed at learning new English vocabulary and phrases and describe its strengths and weaknesses as perceived by the students. In total, 28 university students answered a pen and paper questionnaire survey after experiencing the app during one semester. Overall, the students' agreement to the positive aspects displayed in the questionnaire prevailed over their disagreement or neutral opinions. The mobile app helped students prepare for the final achievement test, learning was accessible from anywhere and at any time, students appreciated the corrective feedback and would opt for the implementation of the mobile app in other courses taught at the faculty. On the other hand, as the findings indicate, the students reported that the app was not very supportive regarding communication performance; they did not find the teachers' notifications encouraging and they did not use the pronunciation support much, which was caused by various factors, such as offering students words and phrases without context or not testing all the items in the final credit test. The findings of this study contribute to the existing knowledge of students' perceptions of the use of mobile apps for learning purposes.

Abstract Background Effective cooperation between a pediatric palliative care team (PPCT), primary treating specialists, patients and families is crucial for high quality care of children with complex life-limiting conditions. Several barriers among patients, families and treating specialists have been identified in the context of initializing pediatric palliative care. The aim of the study was to assess the experience with initial pediatric palliative care consultations from perspectives of family caregivers and treating physicians with a special focus on two innovative approaches: attendance of the treating specialist and the opportunity for parents to give feedback on the written report from the consultation. Methods This was a qualitative study using semi-structured interviews with family caregivers of children with malignant and non-malignant disease and their treating specialists. Framework analysis was used to guide the data collection and data analysis. Results In total, 12 family caregivers and 17 treating specialists were interviewed. Four main thematic categories were identified: (1) expectations, (2) content and evaluation, (3) respect and support from the team and (4) consultation outcomes. Parents viewed the consultation as a unique opportunity to discuss difficult topics. They perceived the attendance of the treating specialist at the initial consultation as very important for facilitating communication. Treating specialists valued the possibility to learn more about psychosocial issues of the child and the family while attending the initial palliative care consultation. All participants perceived the written report from the consultation as useful for further medical decisions. Family members appreciated the chance to give feedback on the consultation report. Conclusions Our study identified several clinically relevant issues that can help initialize pediatric palliative care and establish effective collaboration between families and PPCT and treating specialists. Supporting treating specialists in their ability to explain the role of palliative care is important in order to reduce the risk of misunderstanding or unrealistic expectations. Developing more specific expectations seems to be one of the ways to further increase the effectiveness of initial consultations. The results of the study can be especially helpful for the initial phase of implementing pediatric palliative care and initializing the process of setting up a collaborative relationship with palliative care teams in the hospital.

Background The genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and the relationship between genotype status and clinical outcome is incompletely resolved. Methods and Results We assessed a large international HCM cohort to define in contemporary terms natural history and clinical consequences of genotype. Consecutive patients (n=1468) with established HCM diagnosis underwent genetic testing. Patients with pathogenic (or likely pathogenic) variants were considered genotype positive (G+; n=312; 21%); those without definite disease‐causing mutations (n=651; 44%) or variants of uncertain significance (n=505; 35%) were considered genotype negative (G−). Patients were followed up for a median of 7.8 years (interquartile range, 3.5–13.4 years); HCM end points were examined by cumulative event incidence. Over follow‐up, 135 (9%) patients died, 33 from a variety of HCM‐related causes. After adjusting for age, all‐cause and HCM‐related mortality did not differ between G− versus G+ patients (hazard ratio [HR], 0.78 [95% CI, 0.46–1.31]; P=0.37; HR, 0.93 [95% CI, 0.38–2.30]; P=0.87, respectively). Adverse event rates, including heart failure progression to class III/IV, heart transplant, or heart failure death, did not differ (G− versus G+) when adjusted for age (HR, 1.20 [95% CI, 0.63–2.26]; P=0.58), nor was genotype independently associated with sudden death event risk (HR, 1.39 [95% CI, 0.88–2.21]; P=0.16). In multivariable analysis, age was the only independent predictor of all‐cause and HCM‐related mortality, heart failure progression, and sudden death events. Conclusions In this large consecutive cohort of patients with HCM, genotype (G+ or G−) was not a predictor of clinical course, including all‐cause and HCM‐related mortality and risk for heart failure progression or sudden death. G+ status should not be used to dictate clinical management or predict outcome in HCM.

In Russia's long-standing vision of organizing international relations, only the great powers enjoy full sovereignty. They are entitled to their security, which they ensure by maintaining a zone of influence around themselves, where they retain a degree of control over neighboring states. The great powers then respect each other's spheres of influence. This is, of course, completely incompatible with Western notions of world order and international law. The reliance of the EU and, indirectly, the UK on Russian gas supplies has intensified over the last decade. Over that period, natural gas consumption in the EU and the UK has not increased, but production has fallen by a third. Imports have met the shortfall. In 2021, Russian gas accounted for 32% of European demand, up from 25% in 2009. Meanwhile, the construction of additional transit corridors, such as Nord Stream piping Russian gas to the EU and the UK, has reduced Ukraine's importance as a transit country. As one of the authors of this article pointed out for the first time in 2017 (Polak, 2017), Russia can finance its current wars overseas mainly with profits from the extraction and sale of oil, coal, and natural gas., Author(s): Petr Polak [sup.1] , Barbora Polakova [sup.2] [sup.3] Author Affiliations: (1) grid.7112.5, 0000000122191520, Mendel University in Brno, , Brno, Czech Republic (2) grid.10267.32, 0000 0001 2194 0956, Masaryk University, [...]