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Nanocrystallization of KLaF4 in a 70 SiO2–7 Al2O3–16 K2O–7 LaF3 (mol%) glass co-doped with 0.2 mol% Tm2O3 and 0.5 mol% YbF3 was achieved by heat treatment above the glass transition temperature. KLaF4 nanocrystals of 6 nm precipitated and the crystal size was constant from 10 to 150 h of annealing time. The crystalline fraction achieved was very low, due to the drastic effect of the addition of dopants. The optical characterization of the obtained transparent glass and glass-ceramic showed a blue up-conversion emission due to an energy transfer mechanism involving two photons. However, there were no significant differences in the optical features between glass and glass-ceramic due to a low-crystallization degree. The role of dopant ions in the crystallization mechanism has been discussed. [ABSTRACT FROM AUTHOR]

Background: Although chronic subjective tinnitus is one of the most common symptoms, the background of its pathophysiological mechanism and etiology is not fully understood. No studies are exploring various affective temperaments in persons with chronic tinnitus. Methods: We included in this study 57 patients with tinnitus who filled out the Serbian 41-item version of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Auto questionnaire (TEMPS-A) and a short sociodemographic questionnaire. Patients were assessed using audiometry (measuring the hearing threshold for frequencies of 250, 500, 1,000, 2,000, 4,000, and 8,000 Hz) and tympanometry. Results: Our research showed that patients with chronic tinnitus predominantly had anxious affective temperament [anxious-cognitive (AnxC): 26.23 %, anxious-somatic (AnxS): 25.6 %). AnxS was dominant in people without hearing loss (46 %) and males (37.39 %). AnxC was dominant in people with a significant hearing loss and females (30.3 %). Both AnxS and AnxC temperaments correlated with hearing loss in the right ear more than in the left one. Conclusion: Our study revealed that anxious temperaments (AnxC and AnxS) were predominant in patients with chronic subjective tinnitus. Affective temperaments could play a significant role in explaining this disorder's currently unclear pathophysiology of, but further research is needed. HIPPOKRATIA 2020, 24(2): 77-83. [ABSTRACT FROM AUTHOR]

Clozapine remains the only pharmacological treatment option for treatment-resistant schizophrenia. Therapeutic drug monitoring (TDM) of clozapine is recommended, although evidence for the therapeutic range of 350-600 ng/ml is limited. In various countries including Serbia, TDM of clozapine is not routinely performed. This study evaluated the distribution of clozapine levels and their relationship with clinical outcomes in Serbian patients who had not undergone prior TDM. 140 Patients with treatment-resistant schizophrenia and schizo-affective disorder were enrolled. Clozapine levels were measured by dried blood spot (DBS) analysis. Side effects were evaluated by GASS-c, severity of symptoms and functional impairment with WHODAS, CGI-S and GAF. Of the patients, 51.2% had subtherapeutic levels, 24.8% were in the therapeutic window, and 24% had supratherapeutic levels. Clozapine levels showed no association with side effects and a weak positive association with symptom severity and functional impairment. No serious side effects were observed in patients with clozapine levels surpassing 1000 ng/ml (n = 8). Based on these findings, we propose that the upper limit of the therapeutic range should not be regarded as an absolute barrier, and guidelines should allow for a personalized approach when prescribing clozapine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In vertebrates, the BRCA2 protein is essential for meiotic and somatic homologous recombination due to its interaction with the RAD51 and DMC1 recombinases through FxxA and FxPP motifs (here named A- and P-motifs, respectively). The A-motifs present in the eight BRC repeats of BRCA2 compete with the A-motif of RAD51, which is responsible for its self-oligomerization. BRCs thus disrupt RAD51 nucleoprotein filaments in vitro. The role of the P-motifs is less studied. We recently found that deletion of Brca2 exons 12-14 encoding one of them (the prototypical 'PhePP' motif), disrupts DMC1 but not RAD51 function in mouse meiosis. Here we provide a mechanistic explanation for this phenotype by solving the crystal structure of the complex between a BRCA2 fragment containing the PhePP motif and DMC1. Our structure reveals that, despite sharing a conserved phenylalanine, the A- and P-motifs bind to distinct sites on the ATPase domain of the recombinases. The P-motif interacts with a site that is accessible in DMC1 octamers and nucleoprotein filaments. Moreover, we show that this interaction also involves the adjacent protomer and thus increases the stability of the DMC1 nucleoprotein filaments. We extend our analysis to other P-motifs from RAD51AP1 and FIGNL1., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Objective: Various factors may influence the attitudes of medical students towards euthanasia, including personal values, beliefs, and personality traits. The objective of this study was to examine the attitudes of 2 nd and 5 th year medical students about euthanasia and the relationship between these attitudes and students' personality traits., Methods: Medical students from the Universities of Kragujevac and Belgrade, Serbia, participated in this study. A questionnaire was administered assessing attitudes toward euthanasia and student personality traits (honesty-humility, emotionality, extraversion, agreeableness, conscientiousness, and openness using the HEXACO-60)., Results: More than 50% of students in the second year and 60% of students in the fifth year were supportive of euthanasia. Students in the 5 th year were 2.5 times more likely to express a concern that euthanasia needs to be clearly regulated by law compared to students in the second year. Adjusted analyses indicated that lower levels of honesty-humility and emotionality were positively correlated with students' belief that euthanasia should be legalized., Conclusion: Many medical students in Serbia have a positive attitude towards euthanasia. It is important to consider the possible influences of culture, religion, and the law on attitudes towards euthanasia. Undergraduate medical training should include more hours dedicated to palliative care and end-of-life topics to raise awareness of patients' preferences in this regard., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Eosinophilic esophagitis (EoE) is a chronic, inflammatory, antigen-driven disease of the esophagus. Tissue EoE pathology has previously been extensively characterized by novel transcriptomics and proteomic platforms, however the majority of surface marker determination and screening has been performed in blood due to mucosal tissue size limitations. While eosinophils, CD4 + T cells, mast cells and natural killer (NK) T cells were previously investigated in the context of EoE, an accurate picture of the composition of peripheral blood mononuclear cells (PBMC) and their activation is missing., Methods: In this study, we aimed to comprehensively analyze the composition of peripheral blood mononuclear cells and their activation using surface marker measurements with multicolor flow cytometry simultaneously in both blood and mucosal tissue of patients with active EoE, inactive EoE, patients with gastroesophageal reflux disease (GERD) and controls. Moreover, we set out to validate our data in co-cultures of PBMC with human primary esophageal epithelial cells and in a novel inducible mouse model of eosinophilic esophagitis, characterized by extensive IL-33 secretion in the esophagus., Results: Our results indicate that specific PBMC populations are enriched, and that they alter their surface expression of activation markers in mucosal tissue of active EoE. In particular, we observed upregulation of the immunomodulatory molecule CD38 on CD4 + T cells and on myeloid cells in biopsies of active EoE. Moreover, we observed significant upregulation of PD-1 on CD4 + and myeloid cells, which was even more prominent after corticosteroid treatment. With co-culture experiments we could demonstrate that direct cell contact is needed for PD-1 upregulation on CD4 + T cells. Finally, we validated our findings of PD-1 and CD38 upregulation in an inducible mouse model of EoE., Discussion: Herein we show significant alterations in the PBMC activation profile of patients with active EoE in comparison to inactive EoE, GERD and controls, which could have potential implications for treatment. To our knowledge, this study is the first of its kind expanding the multi-color flow cytometry approach in different patient groups using in vitro and in vivo translational models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gruden, Kienzl, Ristic, Kindler, Kaspret, Schmid, Kargl, Sturm, Doyle, Wright, Baumann-Durchschein, Konrad, Blesl, Schlager and Schicho.)

The tumor microenvironment (TME) is pivotal in cancer progression and the response to immunotherapy. A "hot" tumor typically contains immune cells that promote anti-tumor immunity, predicting positive prognosis. "Cold" tumors lack immune cells, suggesting a poor outlook across various cancers. Recent research has focused on converting "cold" tumors into "hot" tumors to enhance the success of immunotherapy. A prerequisite for the studies of the TME is an accurate knowledge of the cell populations of the TME. This study aimed to describe the immune TME of lung and colorectal cancer and melanoma, focusing on lymphoid and myeloid cell populations. We induced heterotopic immunocompetent tumors in C57BL/6 mice, using KP and LLC (Lewis lung carcinoma) cells for lung cancer, MC38 cells for colorectal cancer, and B16-F10 cells for melanoma. Immune cell infiltration was analyzed using multicolor flow cytometry in single-cell suspensions after tumor excision. KP cell tumors showed an abundance of neutrophils and eosinophils; however, they contained much less adaptive immune cells, while LLC cell tumors predominated in monocytes, neutrophils, and monocyte-derived dendritic cells. Monocytes and neutrophils, along with a significant T cell infiltration, were prevalent in MC38 tumors. Lastly, B16-F10 tumors were enriched in macrophages, while showing only moderate T cell presence. In conclusion, our data provide a detailed overview of the immune TME of various heterotopic tumors, highlighting the variabilities in the immune cell profiles of different tumor entities. Our data may be a helpful basis when investigating new immunotherapies, and thus, this report serves as a helpful tool for preclinical immunotherapy research design.

In meiotic homologous recombination (HR), BRCA2 facilitates loading of the recombinases RAD51 and DMC1 at the sites of double-strand breaks (DSBs). The HSF2BP-BRME1 complex interacts with BRCA2. Its absence causes a severe reduction in recombinase loading at meiotic DSB. We previously showed that, in somatic cancer cells ectopically producing HSF2BP, DNA damage can trigger HSF2BP-dependent degradation of BRCA2, which prevents HR. Here, we report that, upon binding to BRCA2, HSF2BP forms octameric rings that are able to interlock into a large ring-shaped 24-mer. Addition of BRME1 leads to dissociation of both of these ring structures and cancels the disruptive effect of HSF2BP on cancer cell resistance to DNA damage. It also prevents BRCA2 degradation during interstrand DNA crosslink repair in Xenopus egg extracts. We propose that, during meiosis, the control of HSF2BPBRCA2 oligomerization by BRME1 ensures timely assembly of the ring complex that concentrates BRCA2 and controls its turnover, thus promoting HR.