Search Results (8)

Background/Objectives: Chronic lymphocytic leukemia (CLL) remains an incurable B-cell malignancy. B-CLL cells exhibit an extended lifespan in part due to the activation of survival pathways such as NF-kB. A crosstalk between NF-kB and GSK-3β pathways has been reported. NF-kB has also been identified as a primary target of the NEDD8-activating enzyme inhibitor MLN4924. Our objective was to investigate potential synergies of MLN4924 with other NF-kB-targeting agents for the treatment of CLL and elucidate the mechanisms of action underlying this pathway regulation. Methods: To assess the cytotoxic efficacy of the combined ex vivo treatment with CHIR-99021 and MLN4924, we employed 7-AAD staining and XTT viability assays on primary samples from CLL patients. Subsequently, we conducted various analyses to identify the molecular mechanisms underlying the cytotoxic effects of this combination. Results: We discovered a discrepancy between the mRNA and protein levels of IkBɑ and provided evidence of translational control over its expression. This observation may explain why, unlike other cell types, B-CLL cells did not activate NF-kB signaling following inhibition of GSK-3ß. Furthermore, we describe a synergistic effect between a specific GSK-3ß inhibitor, CHIR-99021/Laduviglusib, and the NEDD8-activating enzyme inhibitor MLN4924/Pevonedistat, at doses that only slightly affect healthy B cell viability ex vivo. We investigated the molecular basis of this co-induction of cell death by analyzing the alterations in apoptosis-related gene expression. We found that the combinational treatment enhances a reduction in BCL2 mRNA expression levels, providing an alternative approach for BCL-2 inhibition in CLL that could have therapeutic implications for the treatment of refractory CLL cases. Conclusions: our findings revealed a unique interaction between GSK-3ß and NF-kB pathways in CLL and their regulation of BCL2 expression. Full article

Soybean protein isolate (SPI), as a full-valued protein, is rich in nutrients, such as amino acids. However, the isolated structure of soybeans makes it difficult to react and thus prepare good gels. In order to further improve the properties of SPIs and to prepare plant-based gels with good performance, this experiment was conducted to prepare maltodextrin glycosylated soybean isolate (MGSI) by the glycosylation of SPI and maltodextrin (MD), and the gels were prepared by thermal induction, transglutaminase (TGase) induction, and TG-MgCl₂ co-induction of this glycosylated protein to investigate the effects of different induction methods on the structure and properties of the gels produced by MGSIs. Moreover, the effects of different induction methods on the structure and properties of the gels produced by MGSI were investigated. SDS-PAGE protein electrophoresis, FTIR spectroscopy, and endogenous fluorescence spectroscopy revealed that all three inductions result in the covalent bond cross-linking of MGSI during the gel formation process. Compared with thermal induction, the TGase-induced MGSI secondary structure had a higher content of β-folded structures, increased fluorescence intensity of tertiary structures, and produced a red shift. The gel induced by TGase in collaboration with MgCl₂ contains a more β-folded structure and irregular curl and increases the β-turned angle and α-helix content further, the endogenous fluorescence λmax is significantly red-shifted, and the fluorescence intensity increases, demonstrating that the tertiary structure of MGSI unfolds the most, forming multilayered gels with the tightest structures. The three gels were analyzed by rheology and SEM, showing that the TGase-MgCl₂ synergistically induced gel had the highest energy-storage modulus G’, viscoelasticity, and water-holding capacity, as well as the densest gel structure. In conclusion, the combined treatment of enzyme and MgCl₂ might be an effective way of improving the structure and gel properties of SPI. This study helps to promote the high-value utilization of SPI and the development of plant protein gels. Full article

Coevaluation, the coinductive interpretation of standard big-step evaluation rules, is a concise form of semantics, with the same number of rules as in evaluation, which intends to simultaneously describe finite and infinite computations. However, it is known that it is only able to express an infinite computations subset, and, to date, it remains unknown exactly what this subset is. More precisely, coevaluation behavior has several unusual features: there are terms for which evaluation is infinite but that do not coevaluate, it is not deterministic in the sense that there are terms which coevaluate to any value v, and there are terms for which evaluation is infinite but that coevaluate to only one value. In this work, we describe the infinite computations subset which is able to be expressed by coevaluation. More importantly, we introduce a coevaluation extension that is well-behaved in the sense that the finite computations coevaluate exactly as in evaluation and the infinite computations coevaluate exactly as in divergence. Consequently, no unusual features are presented; in particular, this extension captures all infinite computations (not only a subset of them). In addition, as a consequence of thiswell-behavior, we present the expected equivalence between (extended) coevaluation and evaluation union divergence. Full article

We obtained a new hybrid soybean (Hybrid) by hybridizing ?-carotene-enhanced soybean (BCE; Glycine max L.) containing the phytoene synthase-2A-carotene desaturase gene and wild-type soybean (Wild; Glycine soja). To investigate metabolic changes between variants, we performed metabolic profiling of leaves (three growth stages) and seeds. Multivariate analyses revealed significant metabolic differences between genotypes in seeds and leaves, with seeds showing accumulation of phytosterols, tocopherols, and carotenoids (BCE only), indicating co-induction of the methylerythritol 4-phosphate and mevalonic acid pathways. Additionally, Hybrid produced intermediate levels of carotenoids and high levels of amino acids. Principal component analysis revealed metabolic discrimination between growth stages of soybean leaves and identified differences in leaf groups according to different genotypes at 8, 12, and 16 weeks, with Wild showing higher levels of environmental stress-related compounds relative to BCE and Hybrid leaves. The metabolic profiling approach could be a useful tool to identify metabolic links in various soybean cultivars. Full article

Several methods for the stimulation of skin wound repair have been proposed over the last few decades. The most promising among them are gene and stem cell therapy. Our present experiments combined several approaches via the application of human umbilical cord blood mononuclear cells (hUCB-MC) that were transfected with pBud-VEGF165-FGF2 plasmid (gene-cell therapy) and direct gene therapy using pBud-VEGF165-FGF2 plasmid to enhance healing of full thickness skin wounds in rats. The dual expression cassette plasmid pBud-VEGF165-FGF2 encodes both VEGF and FGF2 therapeutic genes, expressing pro-angiogenic growth factors. Our results showed that, with two weeks post-transplantation, some transplanted cells still retained expression of the stem cell and hematopoietic markers C-kit and CD34. Other transplanted cells were found among keratinocytes, hair follicle cells, endothelial cells, and in the derma. PCNA expression studies revealed that transplantation of transfected cells terminated proliferative processes in regenerating wounds earlier than transplantation of untransfected cells. In the direct gene therapy group, four days post-operatively, the processes of flap revascularization, while using Easy LDI Microcirculation Camera, was higher than in control wounded skin. We concluded that hUCB-MC can be used for the treatment of skin wounds and transfection these cells with VEGF and FGF2 genes enhances their regenerative abilities. We also concluded that the application of pBud-VEGF165-FGF2 plasmids is efficient for the direct gene therapy of skin wounds by stimulation of wound revascularization. Full article

Background and Objectives: Elderly patients constitute a large segment of healthcare receivers. Considering the functional deterioration of multiple organ systems with aging, achieving a safe perioperative approach is challenging. Our aim is to study the safety and effectiveness of a genuinely regimented co-induction technique in order to minimize anesthesia-related complications. Materials and Methods: One hundred and five patients were assigned to three groups according to the induction technique: propofol, sevoflurane and co-induction group. Inclusion criteria: patients with age ≥65 and American Society of Anesthesiologists physical status classification (ASA) II-III who underwent endoscopic urological procedures. The propofol group received a dose of 1.5 mg kg⁻¹ of propofol over two minutes for induction. The sevoflurane group received 8% of sevoflurane and 100% oxygen through a plastic facemask with the fresh gas flow set at 8 L min⁻¹. The co-induction group received 4% sevoflurane through plastic facemask for two minutes, followed by a 0.75 mg kg⁻¹ dose of propofol. After ensuring full range jaw relaxation, the laryngeal mask airway (LMA) was inserted. Results: Overall, the co-induction technique had a favorable profile in terms of respiratory adverse events, while the sevoflurane group had a favorable profile in terms of hemodynamic stability. Furthermore, 24 (68.6%) patients receiving inhalational sevoflurane had episodes of transient apnea, which constitutes 77.4% of the 31 episodes of transient apnea in the studied sample (p < 0.001). Moreover, six (17.1%) patients in the sevoflurane group had an episode of partial laryngospasm (p = 0.034). Compared with the co-induction group, we found that the propofol group had significantly less systolic and diastolic blood pressures in the second minute, with p values of (0.018) and (0.015), respectively. Conclusions: The co-induction technique utilizing 4% sevoflurane at 8 L min⁻¹ flow of oxygen inhaled over two minutes followed by 0.75 mg kg⁻¹ of propofol achieved less respiratory adverse events compared with the sevoflurane group, and less hemodynamic instability compared with the propofol group. Full article

(Coinductive) natural semantics is presented as a unifying framework for the verification of total correctness of compilers in Coq (with the feature that a verified compiler can be obtained). In this way, we have a simple, easy, and intuitive framework; to carry out the verification of a compiler, using a proof assistant in which both cases are considered: terminating and non-terminating computations (total correctness). Full article

Swiprosin-1 (EFhD2) is a molecule that triggers structural adaptation of isolated adult rat cardiomyocytes to cell culture conditions by initiating a process known as cell spreading. This process mimics central aspects of cardiac remodeling, as it occurs subsequent to myocardial infarction. However, expression of swiprosin-1 in cardiac tissue and its regulation in vivo has not yet been addressed. The expression of swiprosin-1 was analyzed in mice, rat, and pig hearts undergoing myocardial infarction or ischemia/reperfusion with or without cardiac protection by ischemic pre- and postconditioning. In mouse hearts, swiprosin-1 protein expression was increased after 4 and 7 days in myocardial infarct areas specifically in cardiomyocytes as verified by immunoblotting and histology. In rat hearts, swiprosin-1 mRNA expression was induced within 7 days after ischemia/reperfusion but this induction was abrogated by conditioning. As in cultured cardiomyocytes, the expression of swiprosin-1 was associated with a coinduction of arrestin-2, suggesting a common mechanism of regulation. Rno-miR-32-3p and rno-miR-34c-3p were associated with the regulation pattern of both molecules. Moreover, induction of swiprosin-1 and ssc-miR-34c was also confirmed in the infarct zone of pigs. In summary, our data show that up-regulation of swiprosin-1 appears in the postischemic heart during cardiac remodeling and repair in different species. Full article