Biflavonoids are dimeric forms of flavonoids that have recently gained importance as an effective new scaffold for drug discovery. In particular, 3′-8″-biflavones exhibit antiviral and antimicrobial activity and are promising molecules for the treatment of neurodegenerative and metabolic diseases as well as cancer therapies. In the present study, we directly compared 3′-8″-biflavones (amentoflavone, bilobetin, ginkgetin, isoginkgetin, and sciadopitysin) and their monomeric subunits (apigenin, genkwanin, and acacetin) and evaluated their radical scavenging activity (with DPPH), antifungal activity against mycotoxigenic fungi (Alternaria alternata, Aspergillus flavus, Aspergillus ochraceus, Fusarium graminearum, and Fusarium verticillioides), and inhibitory activity on enzymes (acetylcholinesterase, tyrosinase, α-amylase, and α-glucosidase). All the tested compounds showed weak radical scavenging activity, while antifungal activity strongly depended on the tested concentration and fungal species. Biflavonoids, especially ginkgetin and isoginkgetin, proved to be potent acetylcholinesterase inhibitors, whereas monomeric flavonoids showed higher tyrosinase inhibitory activity than the tested 3′-8″-biflavones. Amentoflavone proved to be a potent α-amylase and α-glucosidase inhibitor, and in general, 3′-8″-biflavones showed a stronger inhibitory potential on these enzymes than their monomeric subunits. Thus, we can conclude that 3′-8″-dimerization enhanced acetylcholinesterase, α-amylase, and α-glucosidase activities, but the activity also depends on the number of hydroxyl and methoxy groups in the structure of the compound.

Simple Summary Merkel cell carcinoma (MCC) is a rare and highly aggressive type of skin neuroendocrine cancer that frequently recurs and metastasizes within a relatively short period. Despite rapid growth and characteristic skin color, MCC often goes undiagnosed in its early stage. Therefore, therapy is often initiated at the advanced stage, and selecting appropriate therapeutic interventions is critical. The emergence of novel immunotherapeutic agents, such as immune checkpoint inhibitors (ICI), presents a promising treatment option for advanced MCC. Several biomarkers, such as PD-L1 expression, tumor mutational burden (TMB), and microsatellite instability (MSI), showed significant potential as predictive biomarkers for treatment with ICI. Despite their predictive value, each has demonstrated limited value in MCC over recent years. Abstract Merkel cell carcinoma (MCC) is primarily a disease of the elderly Caucasian, with most cases occurring in individuals over 50. Immune checkpoint inhibitors (ICI) treatment has shown promising results in MCC patients. Although ~34% of MCC patients are expected to exhibit at least one of the predictive biomarkers (PD-L1, high tumor mutational burden/TMB-H/, and microsatellite instability), their clinical significance in MCC is not fully understood. PD-L1 expression has been variably described in MCC, but its predictive value has not been established yet. Our literature survey indicates conflicting results regarding the predictive value of TMB in ICI therapy for MCC. Avelumab therapy has shown promising results in Merkel cell polyomavirus (MCPyV)-negative MCC patients with TMB-H, while pembrolizumab therapy has shown better response in patients with low TMB. A study evaluating neoadjuvant nivolumab therapy found no significant difference in treatment response between the tumor etiologies and TMB levels. In addition to ICI therapy, other treatments that induce apoptosis, such as milademetan, have demonstrated positive responses in MCPyV-positive MCC, with few somatic mutations and wild-type TP53. This review summarizes current knowledge and discusses emerging and potentially predictive biomarkers for MCC therapy with ICI.

Simple Summary Our study centers on refining the diagnosis of small-cell lung cancer (SCLC), a unique subtype with distinct therapeutic implications compared to other lung cancers. Our primary goal is the identification of specific differentially expressed proteins in SCLC as opposed to healthy lung tissue. Additionally, we aim to discern the protein expression of SCLC from large cell neuroendocrine carcinoma (LCNEC), a closely related entity. This research has the potential to enhance our understanding of these intricate lung cancers, potentially transforming the landscape of detection and tailored treatment strategies. Abstract The accurate diagnosis of small-cell lung cancer (SCLC) is crucial, as treatment strategies differ from those of other lung cancers. This systematic review aims to identify proteins differentially expressed in SCLC compared to normal lung tissue, evaluating their potential utility in diagnosing and prognosing the disease. Additionally, the study identifies proteins differentially expressed between SCLC and large cell neuroendocrine carcinoma (LCNEC), aiming to discover biomarkers distinguishing between these two subtypes of neuroendocrine lung cancers. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive search was conducted across PubMed/MEDLINE, Scopus, Embase, and Web of Science databases. Studies reporting proteomics information and confirming SCLC and/or LCNEC through histopathological and/or cytopathological examination were included, while review articles, non-original articles, and studies based on animal samples or cell lines were excluded. The initial search yielded 1705 articles, and after deduplication and screening, 16 articles were deemed eligible. These studies revealed 117 unique proteins significantly differentially expressed in SCLC compared to normal lung tissue, along with 37 unique proteins differentially expressed between SCLC and LCNEC. In conclusion, this review highlights the potential of proteomics technology in identifying novel biomarkers for diagnosing SCLC, predicting its prognosis, and distinguishing it from LCNEC.

Thanks to the climatic and geographical conditions, the area of the Northwestern part of Bosnia and Herzegovina has a long tradition of producing honey and other bee products. However, there is little or no literature data on the physico-chemical properties and biological activity of different types of honey and other bee products from Bosnia and Herzegovina. Five different types of honey were analyzed: monofloral honey (acacia, chestnut, linden), meadow honey and forest honey. Physico-chemical parameters, sensory analysis, color of honey, antioxidant activity, and content of total phenols were analyzed in five types off collected honey samples. The analyzes performed showed that chestnut honey contains the highest and acacia honey has the lowest content oftotal phenolic compounds. The forest honey showed the best antioxidant activity. The color of the honey was measured according to the CIELab system and the estimated L, a, bparameters show that all types of honey from this area can be characterized asdark types of honey (L50) with the presence of a yellow color. The obtained results show that the analyzed samples of five different types of honey are rich in polyphenolic components and represent a good source of antioxidants in the human diet.KEYWORDS:honey,physico-chemical parameters, color, antioxidant activity, total phenols

The review and analysis of a timeline work and stoppage/failure of transportational complex on separation in SC coal mine „Gračanica“ LLC Gornji Vakuf – Uskoplje has been given in this work. The work is based on collecting and analysing data. Collecting data lasted for one year and it is analysed and shown in this work. Rightfully determined the state of work and stoppage/failure, allows precautions and choice of strategy for the next period. Conclusions about which stoppage/failure affected the stoppage of transportational system and separation in full are derived from the research, and based on those conclusions, suggestions about activities which would minimize these stoppages on acceptable value are given. Key words: mine, coal, effective work, stoppage, failure, transportational complex, separation, belt conveyor, scraper.

. Screening for lymphedema and accurate quantitative assessment of dermal backflow patterns on ICG represents a major shift in current clinical practice paradigms, putting an emphasis on early detection of lymphedema rather than palliative treatments and symptomatic relief. These findings set the stage for the development of a practical, universal, ICG-based quantification system for the staging of lymphedema, a significant advancement in the field of plastic surgery.

Purpose Lean Management (LM) is a process improvement approach with growing interest from healthcare organizations. Obtaining a culture of continuous improvement is a primary objective of LM, and a culture of continuous improvement indicates a mature LM approach, and here leadership plays a central role. However, a comprehensive overview of leadership activities influencing LM maturity is lacking. This study aims to identify leadership activities associated with continuous improvement and, thus, LM, maturity. Methods Following the PRISMA guidelines, a scoping literature review of peer-reviewed articles was conducted in twenty healthcare management journals. The search provided 466 articles published up until 2023. During the selection process, 23 studies were included in the review. The leadership activities related to continuous improvement maturity were identified using the grounded theory approach and data coding. Results The analysis highlighted a total of 58 leadership activities distributed across nine themes of LM leadership. Next, analysing leadership activities concerning the different maturity levels revealed three maturity stages: beginner, intermediate, and expert. Based on the findings, we propose a framework that guides suitable leadership activities at the various stages of LM maturity. The framework provides leaders in healthcare with a practical overview of actions to facilitate the growth of the LM approach, and the related propositions offer academics a theoretical basis for future studies. Conclusion This review presents the first comprehensive overview of LM leadership activities in relation to continuous improvement and LM maturity. To enhance LM maturity, leaders are encouraged to consider their leadership style, (clinical) stakeholder involvement, alignment with the organizational strategy, and their role in promoting employee autonomy.

The material extrusion fused deposition modeling (FDM) technique has become a widely used technique that enables the production of complex parts for various applications. To overcome limitations of PLA material such as low impact toughness, commercially available materials such as UltiMaker Tough PLA were produced to improve the parent PLA material that can be widely applied in many engineering applications. In this study, 3D-printed parts (test specimens) considering six different printing parameters (i.e., layer height, wall thickness, infill density, build plate temperature, printing speed, and printing temperature) are experimentally investigated to understand their impact on the mechanical properties of Tough PLA material. Three different standardized tests of tensile, flexural, and compressive properties were conducted to determine the maximum force and Young’s modulus. These six properties were used as responses in a design of experiment, definitive screening design (DSD), to build six regression models. Analysis of variance (ANOVA) is performed to evaluate the effects of each of the six printing parameters on Tough PLA mechanical properties. It is shown that all regression models are statistically significant (p<0.05) with high values of adjusted and predicted R2. Conducted confirmation tests resulted in low relative errors between experimental and predicted data, indicating that the developed models are adequately accurate and reliable for the prediction of tensile, flexural, and compressive properties of Tough PLA material.

We provide observational evidence that suggests the presence of a molten silicate layer above the core of Mars, which is overlain by a partially molten layer, indicating that the core of Mars is smaller than previously thought. The detection of deep reflected S waves on Mars inferred a core size of 1,830 ± 40 km (ref. ^ 1 ), requiring light-element contents that are incompatible with experimental petrological constraints. This estimate assumes a compositionally homogeneous Martian mantle, at odds with recent measurements of anomalously slow propagating P waves diffracted along the core–mantle boundary^ 2 . An alternative hypothesis is that Mars’s mantle is heterogeneous as a consequence of an early magma ocean that solidified to form a basal layer enriched in iron and heat-producing elements. Such enrichment results in the formation of a molten silicate layer above the core, overlain by a partially molten layer^ 3 . Here we show that this structure is compatible with all geophysical data, notably (1) deep reflected and diffracted mantle seismic phases, (2) weak shear attenuation at seismic frequency and (3) Mars’s dissipative nature at Phobos tides. The core size in this scenario is 1,650 ± 20 km, implying a density of 6.5 g cm^−3, 5–8% larger than previous seismic estimates, and can be explained by fewer, and less abundant, alloying light elements than previously required, in amounts compatible with experimental and cosmochemical constraints. Finally, the layered mantle structure requires external sources to generate the magnetic signatures recorded in Mars’s crust.