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This study aimed to determine the antifungal activity of various compounds and develop a novel antifungal formulation against fungal pathogens, including Alternaria alternata, Botrytis cinerea, Penicillium expansum, and Rhizopus stolonifer. A total of 32 plant-derived secondary metabolites and three extracts (dichloromethane, ethyl acetate, and methanol) from Lawsonia inermis, Juglans regia, and Drosera intermedia were screened at a concentration of 250 ppm. The chemical composition of the D. intermedia ethyl acetate extract was characterized using chromatographic techniques. Subsequently, an emulsifiable concentrate formulation from this extract was prepared, and its efficacy was evaluated at concentrations ranging from 250 to 2000 ppm. The D. intermedia ethyl acetate extract was found to contain three flavonoids (1.4%) and three naphthoquinones (2.8%). The formulation exhibited optimal effect at 1000 ppm. Overall, the high efficacy of the formulation containing the dried D. intermedia extract (10:1, ethyl acetate) positions it as a promising and viable alternative to synthetic fungicides.

Alzheimer’s disease is a neurodegenerative disease characterized by progressive memory loss and cognitive impairment due to a severe loss of cholinergic neurons in specific brain areas. It is the most common type of dementia in the aging population. Although many anti-acetylcholinesterase (AChE) drugs are already available on the market, their performance sometimes yields unexpected results. For this reason, research works are ongoing to find potential anti-AChE agents both from natural and synthetic sources. In this study, 90 extracts from 30 native and naturalized medicinal plants are tested by TLC and Ellman’s colorimetric assay at 250, 125 and 62.5 μg/mL in order to determine the inhibitory effect on AChE. In total, 21 out of 90 extracts show high anti-AChE activity (75–100% inhibition) in a dose-dependent manner. Among them, ethanolic extract from aerial parts of O. vulgare ssp. vulgare shows an IC50 value 7.7 times lower than galantamine. This research also establishes the chemical profile of oregano extract by TLC, HPLC-DAD and LC-MS, and twenty-three compounds are identified and quantified. Dihydroxycinnamic acids and flavonoids are the most abundant ones (56.90 and 25.94%, respectively). Finally, total phenolic compounds and antioxidant properties are quantified by colorimetric methods. The total phenolic content is 207.64 ± 0.69 µg/mg of extract. The antioxidant activity is measured against two radicals, DPPH and ABTS. In both assays, the oregano extract shows high activity. The Pearson correlation matrix shows the relationship between syringic acids, a type of dihydroxybenzoic acid, and anti-AChE (r2 = −0.9864) and antioxidant activity (r2 = 0.9409 and 0.9976). In conclusion, the results of this study demonstrate promising potential new uses of these medicinal herbs for the treatment of Alzheimer’s. Origanum vulgare ssp. vulgare and syringic acids, which have anti-AChE activity and beneficial antioxidant capacity, can be highlighted as potential candidates for the development of drugs for the treatment of Alzheimer’s disease and other diseases characterized by a cholinergic deficit.

Three-dimensional (3D) cell culture technologies, such as organoids, are physiologically relevant models for basic and clinical applications. Automated microfluidics offers advantages in high-throughput and precision analysis of cells but is not yet compatible with organoids. Here, we present an automated, high-throughput, microfluidic 3D organoid culture and analysis system to facilitate preclinical research and personalized therapies. Our system provides combinatorial and dynamic drug treatments to hundreds of cultures and enables real-time analysis of organoids. We validate our system by performing individual, combinatorial, and sequential drug screens on human-derived pancreatic tumor organoids. We observe significant differences in the response of individual patient-based organoids to drug treatments and find that temporally-modified drug treatments can be more effective than constant-dose monotherapy or combination therapy in vitro. This integrated platform advances organoids models to screen and mirror real patient treatment courses with potential to facilitate treatment decisions for personalized therapy. The use of organoids in personalized medicine is promising but high throughput platforms are needed. Here the authors develop an automated, high-throughput, microfluidic 3D organoid culture system that allows combinatorial and dynamic drug treatments and real-time analysis of organoids.

This paper contributes, with a dynamic approach, to the research on the creation of comparable composite indicators by presenting a proposal for an exploratory factor analysis protocol to enable a comparative trend analysis. The originality of the study lies in the three dimensions of information for analysis: observations, variables and units of time. The proposal involves various stages of analysis with the ultimate, albeit not exclusive, aim of obtaining what is known as a Global Dynamic Indicator. The analysis process begins by structuring the data into a three-dimensional global matrix, thereby conditioning, while also, and primarily, enriching the later stages. A combination of multiple factor analysis and a clustering technique is the selected approach for successfully meeting the challenges involved. The appropriateness and versatility of the proposal are validated through the analysis of the trends of the EU member states towards the targets set by the 2020 Strategy. The study period runs from 2009 to 2018. The empirical work enables the visualisation and quantification of trend differences and similarities across member states collectively and individually, and across all the variables and years selected for analysis. The relevant findings will be quantified by means of a synthetic indicator for each unit of time and a global indicator for the period as a whole. Some of the conclusions reached by this paper are consistent with those already published by various authors.

Cellular differentiation requires extensive alterations in chromatin structure and function, which is elicited by the coordinated action of chromatin and transcription factors. By contrast with transcription factors, the roles of chromatin factors in differentiation have not been systematically characterized. Here, we combine bulk ex vivo and single-cell in vivo CRISPR screens to characterize the role of chromatin factor families in hematopoiesis. We uncover marked lineage specificities for 142 chromatin factors, revealing functional diversity among related chromatin factors (i.e. barrier-to-autointegration factor subcomplexes) as well as shared roles for unrelated repressive complexes that restrain excessive myeloid differentiation. Using epigenetic profiling, we identify functional interactions between lineage-determining transcription factors and several chromatin factors that explain their lineage dependencies. Studying chromatin factor functions in leukemia, we show that leukemia cells engage homeostatic chromatin factor functions to block differentiation, generating specific chromatin factor–transcription factor interactions that might be therapeutically targeted. Together, our work elucidates the lineage-determining properties of chromatin factors across normal and malignant hematopoiesis. Bulk ex vivo and single-cell in vivo CRISPR knockout screens are used to characterize 680 chromatin factors during mouse hematopoiesis, highlighting lineage-specific and normal and leukemia-specific functions.

The characterization of compounds with antioxidant activity is of great interest due to their ability to reduce reactive oxygen species production and, therefore, prevent some age-related diseases. Its antioxidant capacity can be analyzed by different methods both in vitro and in vivo. Caenorhabditis elegans is an in vivo model widely used in ageing research. Until now, available tests analyze functional effects in the worms, so the antioxidant activity of the compound is indirectly monitored. We have developed a simple and a reliable method to quantify internal antioxidant activity in vivo. To validate this method, we analyzed an aqueous green tea extract and two other compounds with a well-known antioxidant activity and without this activity. The results obtained (EC50 green tea = 21.76 ± 1.28 µg/mL; EC50 positive control = 8.50 ± 0.33 µg/mL; negative control EC50 > 500 µg/mL) can help in the design of further in vivo experiments. Thus, our method can be used as a previous screening capable of reducing the gap between in vitro and in vivo assays.

Fibroblast activation includes differentiation to myofibroblasts and is a key feature of organ fibrosis. The Notch pathway has been involved in myofibroblast differentiation in several tissues, including the lung. Here, we identify a subset of collagen-expressing cells in the lung that exhibit Notch3 activity at homeostasis. After injury, this activation increases, being found in αSMA-expressing myofibroblasts in the mouse and human fibrotic lung. Although previous studies suggest a contribution of Notch3 in stromal activation, evidence of the role of Notch3 in lung fibrosis remains unknown. In this study, we examine the effects of Notch3 deletion in pulmonary fibrosis and demonstrate that Notch3-deficient lungs are protected from lung injury with significantly reduced collagen deposition after bleomycin administration. The induction of profibrotic genes is reduced in bleomycin-treated Notch3- lungs that consistently present fewer αSMA-positive myofibroblasts. As a result, the volume of healthy lung tissue is higher and lung function is improved in the absence of Notch3. Using cultures of lung primary fibroblasts, we confirmed that Notch3 participates in their survival and differentiation. Thus, Notch3 deficiency mitigates the development of lung fibrosis because of its role in mediating fibroblast activation. Our findings reveal a previously unidentified mechanism underlying lung fibrogenesis and provide a potential novel therapeutic approach to target pulmonary fibrosis.

This pilot study analyzes the level of development of personal and social competencies linked to Effective Personality in Early Childhood Education pre-service teachers, to provide evidence for the construction of an inclusive teaching profile. Using a quantitative, descriptive, and cross-sectional design, the Effective Personality Questionnaire in the University Context (PECED) questionnaire was administered to 107 teacher candidates at a university in southern Chile. The results show a positive profile in dimensions such as academic self-actualization and problem-solving self-efficacy, along with moderate levels of social self-actualization and aspects of self-esteem. Differences were identified according to age, but not according to cohort. Moreover, a significant correlation was found between self-esteem and problem-solving self-efficacy. The main contribution of this study lies in the application of the PECED instrument in a still largely unexplored educational context, revealing the need for intentional pedagogical interventions for pre-service teachers’ social–emotional development. The findings support the redesign of Early Childhood teacher education curriculum proposals with an inclusive approach and suggest extending the research to other academic programs and regions, validating the usefulness of the Effective Personality construct as a diagnostic and training tool in initial teacher education.

Background: Non-insulin-dependent diabetes mellitus, or type 2 diabetes, is one of the diseases of greatest concern worldwide, and research into natural compounds that are capable of regulating glycemia and insulin resistance is therefore gaining importance. In the preclinical stages, Caenorhabditis elegans is considered a promising in vivo model for research into this disease. Most studies have been carried out using daf-2 mutant strains and observing changes in their phenotype rather than directly measuring the effects within the worms. Methods: We evaluated the in vitro α-glucosidase inhibition of two oral formulations of Origanum vulgare before and after a simulated gastrointestinal digestion process. After confirming this activity, we developed a method to measure α-glucosidase inhibition in vivo in the C. elegans wild-type strain. Results: The crude extract showed a similar IC50 value to that of acarbose (positive control), before and after gastrointestinal digestion. Formulation 1 also showed no differences with the positive control after digestion (111.86 ± 1.26 vs. 110.10 ± 1.00 µL/mL; p = 0.282). However, formulation 2 showed a higher hypoglycemic activity (59.55 ± 0.85 µL/mL; p < 0.05). The IC50 values obtained in the in vivo assays showed results that correlated well with the in vitro results, so the proposed new method of direct quantification of the in vivo activity seems suitable for directly quantifying the effects of this inhibition without the need to measure changes in the phenotype. Conclusion: A novel, simple and reliable method has been developed to directly determine pharmacological activities in an in vivo model of wild-type C. elegans. This allows the hypoglycemic activity to be directly attributed to in vivo treatment without quantifying phenotypic changes in mutant strains that may arise from other effects, opening the door to a simple analysis of in vivo pharmacological activities.

Embryonic stem cells (ESCs) can be maintained in the naïve state through inhibition of Mek1/2 and Gsk3 (2i). A relevant effect of 2i is the inhibition of Cdk8/19, which are negative regulators of the Mediator complex, responsible for the activity of enhancers. Inhibition of Cdk8/19 (Cdk8/19i) stimulates enhancers and, similar to 2i, stabilizes ESCs in the naïve state. Here, we use mass spectrometry to describe the molecular events (phosphoproteome, proteome, and metabolome) triggered by 2i and Cdk8/19i on ESCs. Our data reveal widespread commonalities between these two treatments, suggesting overlapping processes. We find that post-transcriptional de-repression by both 2i and Cdk8/19i might support the mitochondrial capacity of naive cells. However, proteome reprogramming in each treatment is achieved by different mechanisms. Cdk8/19i acts directly on the transcriptional machinery, activating key identity genes to promote the naïve program. In contrast, 2i stabilizes the naïve circuitry through, in part, de-phosphorylation of downstream transcriptional effectors. Naïve pluripotency can be stabilized through different pharmacological approaches. Here, the authors profile temporal changes of protein phosphorylation, proteome and metabolome as mESCs transition to the naïve state in response to two pharmacological treatments, revealing general and treatment-specific processes.