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Identifying novel natural sources from the marine environment with unique immunomodulatory and antioxidant efficacies is of interest in intensive fish farming. In this sense, marine sponge extract derived from Smenospongia (SS-extract) was tested for its potential anti-inflammatory, antioxidant and antimicrobial activities during the concurrent infection with Trichodina sp. and Flavobacterium columnare in Nile tilapia. A total of 625 Nile tilapia fingerlings were distributed into five groups: the control group (with no additives) and four groups fed the control diet fortified with SS-extract at 50, 100, 150, and 200 mg/kg, respectively, for 60 days. The parasitic challenge with Trichodina sp was done at the endpoint of the feeding trial and at 7 days post-infection (dpi); the fish were coinfected with F. columnare. A significant improvement in growth-related parameters of Nile tilapia was detected in the groups that received SS-extract at the levels of 150 and 200 mg/kg. The scavenging ability for free radicals (2,2′-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH)) was maximized with higher SS-extract supplementation levels. Simultaneously, the antioxidant defense of the Nile tilapia fed 150 and 200 mg/kg was augmented with a decline in oxidation-associated indicators [reactive oxygen species (ROS), hydrogen peroxide (H2O2), and malondialdehyde (MDA)]. The higher concentrations of SS-extract in the feed potentiated the immune response of Nile tilapia before infection and even after coinfection and was paralleled by a subsiding in the exaggerated inflammatory response after concurrent infection. Concurrently, the mRNA expression of autophagy-encountered genes (Atg5 and 12, LC3-II and BCLN1) had its highest expression in the fish fed the 200 mg/kg diet with the lowest expression of the mTOR gene in the same fish. The lowest infection intensity and rate and mucus score were displayed in fish fed 200 mg/kg SS-extract at 20 dpi. Interestingly, higher levels of SS-extract triggered antimicrobial peptides (upregulation of Hepcidin and β-defensin-1). In contrast, excessive expression of endoplasmic reticulum genes (atf4 , JAK1 , PERK , and eif2α) in the control infected group was downregulated by 200 mg/kg of SS-extract. The quantification of F. columnare indicated that columnaris coinfection severity displayed its lowest rate in the group supplemented with 200 mg/kg of SS-extract. In conclusion, a strategic siting based on fortification of the diet of Nile tilapia with SS-extract was elucidated to reinforce its immune and antioxidant defenses during a concurrent infection. [ABSTRACT FROM AUTHOR]

Despite substantial breakthroughs in the treatment of hepatocellular carcinoma (HCC) in recent years, many patients are diagnosed in the middle or late stages, denying them the option for surgical excision. Therefore, it is of great importance to find effective therapeutic targets of HCC. In this study, it is found that Gap junction protein beta‐2 (GJB2) is highly enriched in malignant cells based on single‐cell RNA sequencing and higher expression of GJB2 indicates a worse prognosis. The localization of GJB2 in HCC cancer cells is changed compared with normal liver tissue. In cancer cells, GJB2 tends to be located in the cytoplasm and nucleus, while in normal tissues, GJB2 is mainly located on the cell membrane. GJB2 is related to glycolysis, promoting NF‐κB pathway via inducing the ubiquitination degradation of IκBa, and activating HIF‐1α/GLUT‐1/PD‐L1 pathway. In addition, GJB2 knockdown reshapes tumor immune microenvironment and Salvianolic acid B inhibits the activity of GJB2. In conclusion, GJB2 promotes HCC progression by activating glycolysis through cytoplasmic translocation and generating a suppressive tumor microenvironment. Salvianolic acid B inhibits the expression of GJB2 and enhances the sensitivity of anti‐PD1 therapy, which may provide insights into the development of novel combination therapeutic strategies for HCC. [ABSTRACT FROM AUTHOR]

Since the initial study on contextual interference (CI) in 1966, research has explored how practice schedules impact retention and transfer. Apart from support from scientists and practitioners, the CI effect has also faced skepticism. Therefore, we aimed to review the existing literature on the CI effect and determine how it affects transfer in laboratory and applied settings and in different age groups. We found 1,287 articles in the following databases: Scopus, EBSCO, Web of Science, ScienceDirect, supplemented by the Google Scholar search engine and manual search. Of 300 fully screened articles, 42 studies were included in the systematic review and 34 in the quantitative analysis (meta-analysis). The overall CI effect on transfer in motor learning was medium (SMD = 0.55), favoring random practice. Random practice was favored in the laboratory and applied settings. However, in laboratory studies, the medium effect size was statistically significant (SMD = 0.75), whereas, in applied studies, the effect size was small and statistically non-significant (SMD = 0.34). Age group analysis turned out to be significant only in adults and older adults. In both, the random practice was favored. In adults, the effect was medium (SMD = 0.54), whereas in older adults was large (SMD = 1.28). In young participants, the effect size was negligible (SMD = 0.12). [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cells often become resistant to treatment, making it harder to fight the disease effectively. This resistance can happen due to genetic changes, proteins that pump out drugs, or the environment around the tumor. Crizotinib is a drug that helps overcome this resistance in certain lung cancers and lymphomas by targeting specific proteins. It can also break down a harmful protein found in some cancers. Researchers have found that combining crizotinib with other drugs can improve its effectiveness, especially for cancers with specific genetic mutations. Chemoresistance is a major obstacle in cancer treatment, often leading to disease progression and poor outcomes. It arises through various mechanisms such as genetic mutations, drug efflux pumps, enhanced DNA repair, and changes in the tumor microenvironment. These processes allow cancer cells to survive despite chemotherapy, underscoring the need for new strategies to overcome resistance and improve treatment efficacy. Crizotinib, a first-generation multi-target kinase inhibitor, is approved by the FDA for the treatment of ALK-positive or ROS1-positive non-small cell lung cancer (NSCLC), refractory inflammatory (ALK)-positive myofibroblastic tumors (IMTs) and relapsed/refractory ALK-positive anaplastic large cell lymphoma (ALCL). Crizotinib exists in two enantiomeric forms: (R)-crizotinib and its mirror image, (S)-crizotinib. It is assumed that the R-isomer is responsible for the carrying out various processes reviewed here The S-isomer, on the other hand, shows a strong inhibition of MTH1, an enzyme important for DNA repair mechanisms. Studies have shown that crizotinib is an effective multi-kinase inhibitor targeting various kinases such as c-Met, native/T315I Bcr/Abl, and JAK2. Its mechanism of action involves the competitive inhibition of ATP binding and allosteric inhibition, particularly at Bcr/Abl. Crizotinib showed synergistic effects when combined with the poly ADP ribose polymerase inhibitor (PARP), especially in ovarian cancer harboring BRCA gene mutations. In addition, crizotinib targets a critical vulnerability in many p53-mutated cancers. Unlike its wild-type counterpart, the p53 mutant promotes cancer cell survival. Crizotinib can cause the degradation of the p53 mutant, sensitizing these cancer cells to DNA-damaging substances and triggering apoptosis. Interestingly, other reports demonstrated that crizotinib exhibits anti-bacterial activity, targeting Gram-positive bacteria. Also, it is active against drug-resistant strains. In summary, crizotinib exerts anti-tumor effects through several mechanisms, including the inhibition of kinases and the restoration of drug sensitivity. The potential of crizotinib in combination therapies is emphasized, particularly in cancers with a high prevalence of the p53 mutant, such as triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC). [ABSTRACT FROM AUTHOR]

While the human gut microbiota has a significant impact on gut health and disease, understanding of the roles of gut microbes, interactions, and collective impact of gut microbes on various aspects of human gut health is limited by the lack of suitable in vitro model system that can accurately replicate gut‐like environment and enable the close visualization on causal and mechanistic relationships between microbial constitutents and the gut. , In this study, we present a scalable Gut Microbiome‐on‐a‐Chip (GMoC) with great imaging capability and scalability, providing a physiologically relevant dynamic gut‐microbes interfaces. This chip features a reproducible 3D stratified gut epithelium derived from Caco‐2 cells (µGut), mimicking key intestinal architecture, functions, and cellular complexity, providing a physiolocially relevant gut environment for microbes residing in the gut. Incorporating tumorigenic bacteria, enterotoxigenic Bacteroides fragilis (ETBF), into the GMoC enable the observation of pathogenic behaviors of ETBF, leading to µGut disruption and pro‐tumorigenic signaling activations. Pre‐treating the µGut with a beneficial gut microbe Lactobacillus spp., effectively prevent ETBF‐mediated gut pathogenesis, preserving the healthy state of the µGut through competition‐mediated colonization resistance. The GMoC holds potential as a valuable tool for exploring unknown roles of gut microbes in microbe‐induced pathogenesis and microbe‐based therapeutic development. [ABSTRACT FROM AUTHOR]

Nitrosative stress promotes protein glycoxidation, and both processes can occur during an infection with the SARS-CoV-2 virus. Therefore, the aim of this study was to assess selected nitrosative stress parameters and protein glycoxidation products in COVID-19 patients and convalescents relative to healthy subjects, including in reference to the severity of COVID-19 symptoms. The diagnostic utility of nitrosative stress and protein glycoxidation biomarkers was also evaluated in COVID-19 patients. The study involved 218 patients with COVID-19, 69 convalescents, and 48 healthy subjects. Nitrosative stress parameters (NO, S-nitrosothiols, nitrotyrosine) and protein glycoxidation products (tryptophan, kynurenine, N-formylkynurenine, dityrosine, AGEs) were measured in the blood plasma or serum with the use of colorimetric/fluorometric methods. The levels of NO (p = 0.0480), S-nitrosothiols (p = 0.0004), nitrotyrosine (p = 0.0175), kynurenine (p < 0.0001), N-formylkynurenine (p < 0.0001), dityrosine (p < 0.0001), and AGEs (p < 0.0001) were significantly higher, whereas tryptophan fluorescence was significantly (p < 0.0001) lower in COVID-19 patients than in the control group. Significant differences in the analyzed parameters were observed in different stages of COVID-19. In turn, the concentrations of kynurenine (p < 0.0001), N-formylkynurenine (p < 0.0001), dityrosine (p < 0.0001), and AGEs (p < 0.0001) were significantly higher, whereas tryptophan levels were significantly (p < 0.0001) lower in convalescents than in healthy controls. The ROC analysis revealed that protein glycoxidation products can be useful for diagnosing infections with the SARS-CoV-2 virus because they differentiate COVID-19 patients (KN: sensitivity—91.20%, specificity—92.00%; NFK: sensitivity—92.37%, specificity—92.00%; AGEs: sensitivity—99,02%, specificity—100%) and convalescents (KN: sensitivity—82.22%, specificity—84.00%; NFK: sensitivity—82,86%, specificity—86,00%; DT: sensitivity—100%, specificity—100%; AGE: sensitivity—100%, specificity—100%) from healthy subjects with high sensitivity and specificity. Nitrosative stress and protein glycoxidation are intensified both during and after an infection with the SARS-CoV-2 virus. The levels of redox biomarkers fluctuate in different stages of the disease. Circulating biomarkers of nitrosative stress/protein glycoxidation have potential diagnostic utility in both COVID-19 patients and convalescents. [ABSTRACT FROM AUTHOR]

Tau, a microtubule-associated protein (MAP), is essential to maintaining neuronal stability and function in the healthy brain. However, aberrant modifications and pathological aggregations of Tau are implicated in various neurodegenerative disorders, collectively known as tauopathies. The most common Tauopathy is Alzheimer's Disease (AD) counting nowadays more than 60 million patients worldwide. This comprehensive review delves into the multifaceted realm of Tau protein, puzzling out its intricate involvement in both physiological and pathological roles. Emphasis is put on Tau Protein-Protein Interactions (PPIs), depicting its interaction with tubulin, microtubules and its cross-interaction with other proteins such as Aβ1-42, α-synuclein, and the chaperone machinery. In the realm of therapeutic strategies, an overview of diverse possibilities is presented with their relative clinical progresses. The focus is mostly addressed to Tau protein aggregation inhibitors including recent small molecules, short peptides and peptidomimetics with specific focus on compounds that showed a double anti aggregative activity on both Tau protein and Aβ amyloid peptide. This review amalgamates current knowledge on Tau protein and evolving therapeutic strategies, providing a comprehensive resource for researchers seeking to deepen their understanding of the Tau protein and for scientists involved in the development of new peptide-based anti-aggregative Tau compounds., (© 2024 The Author(s). ChemMedChem published by Wiley-VCH GmbH.)

Introduction: In the field of education, new technologies have enhanced the objectivity and scientificity of educational evaluation. However, concerns have been raised about the fairness of evaluators, such as artificial intelligence (AI) algorithms. This study aimed to assess college students’ perceptions of fairness in educational evaluation scenarios through three studies using experimental vignettes. Methods: Three studies were conducted involving 172 participants in Study 1, 149 in Study 2, and 145 in Study 3. Different evaluation contexts were used in each study to assess the influence of evaluators on students’ perception of fairness. Information transparency and explanations for evaluation outcomes were also examined as potential moderators. Results: Study 1 found that different evaluators could significantly influence the perception of fairness under three evaluation contexts. Students perceived AI algorithms as fairer evaluators than teachers. Study 2 revealed that information transparency was a mediator, indicating that students perceived higher fairness with AI algorithms due to increased transparency compared with teachers. Study 3 revealed that the explanation of evaluation outcomes moderated the effect of evaluator on students’ perception of fairness. Specifically, when provided with explanations for evaluation results, the effect of evaluator on students’ perception of fairness was lessened. Discussion: This study emphasizes the importance of information transparency and comprehensive explanations in the evaluation process, which is more crucial than solely focusing on the type of evaluators. It also draws attention to potential risks like algorithmic hegemony and advocates for ethical considerations, including privacy regulations, in integrating new technologies into educational evaluation systems. Overall, this study provides valuable theoretical insights and practical guidance for conducting fairer educational evaluations in the era of new technologies. [ABSTRACT FROM AUTHOR]

Tissue-engineered muscle grafts (TEMGs) are a promising treatment for volumetric muscle loss (VML). In this study, human myogenic progenitors (hMPs) cultured on electrospun fibrin microfiber bundles and evaluated the therapeutic potential of engineered hMP TEMGs in the treatment of murine tibialis anterior (TA) VML injuries is employed. In vitro, the hMP TEMGs express mature muscle markers by 21 days. Upon implantation into VML injuries, the hMP TEMGs enable remarkable regeneration. To further promote wound healing and myogenesis, human adipose-derived stem/stromal cells (hASCs) as fibroadipogenic progenitor (FAP)-like cells with the potential to secrete pro-regenerative cytokines are incorporated. The impact of dose and timing of seeding the hASCs on in vitro myogenesis and VML recovery using hMP-hASC TEMGs are investigated. The hASCs increase myogenesis of hMPs when co-cultured at 5% hASCs: 95% hMPs and with delayed seeding. Upon implantation into immunocompromised mice, hMP-hASC TEMGs increase cell survival, collagen IV deposition, and pro-regenerative macrophage recruitment, but result in excessive adipose tissue growth after 28 days. These data demonstrate the interactions of hASCs and hMPs enhance myogenesis in vitro but there remains a need to optimize treatments to minimize adipogenesis and promote full therapeutic recovery following VML treatment., (© 2024 Wiley‐VCH GmbH.)

A new series of heterocyclic derivatives with a 1,7,7-trimethylbicyclo[2.2.1]heptane fragment was designed, synthesised and biologically evaluated. Synthesis of the target compounds was performed using the Cu(I) catalysed cycloaddition reaction. The key starting substances in the click reaction were an alkyne containing a 1,7,7-trimethylbicyclo[2.2.1]heptane fragment and a series of azides with saturated nitrogen-containing heterocycles. Some of the derivatives were found to exhibit strong antiviral activity against Marburg and Ebola pseudotype viruses. Lysosomal trapping assays revealed the derivatives to possess lysosomotropic properties. The molecular modelling study demonstrated the binding affinity between the compounds investigated and the possible active site to be mainly due to hydrophobic interactions. Thus, combining a natural hydrophobic structural fragment and a lysosome-targetable heterocycle may be an effective strategy for designing antiviral agents., (© 2023 Deutsche Pharmazeutische Gesellschaft.)