The paper reports an analytical study of two problems of Rayleigh-Bénard convection(RBC): one in a Newtonian liquid occupying an axi-symmetric cylindrical enclosure(CE) and second in a two-dimensional rectangular enclosure(RE). Linear stability analysis is employed to obtain information on the onset of convection in terms of a critical Rayleigh number, Ra, as a function of the aspect ratio, Ro. The nature and the flow structures of the convective cells, at the onset of convection, are predicted theoretically by plotting the streamlines for different values of Ro. Not so shallow(Ro<1 or Ro≪1), and very shallow enclosures(Ro≫1) are considered. Concepts of cell-width and the wave number are respectively used in these two types of enclosures. An explicit analytical expression for the number of cells as a function of Ro is obtained theoretically. Exact prediction of the critical value of Ra, viz., Rac, as a function of Ro is also made. These are new findings in the case of both CE and RE. The fundamental differences between the problems of CE and RE are also highlighted.

In the last decade, we have witnessed an upsurge in nuclei-based studies, particularly coupled with next-generation sequencing. Such studies aim at understanding the molecular states that exist in heterogeneous cell populations by applying increasingly more affordable sequencing approaches, in addition to optimized methodologies developed to isolate and select nuclei. Although these powerful new methods promise unprecedented insights, it is important to understand and critically consider the associated challenges. Here, we provide a comprehensive overview of the rise of nuclei-based studies and elaborate on their advantages and disadvantages. Improved designs and appropriate use of the various experimental strategies will result in acquiring biologically accurate and meaningful information.

Chondroitin sulfate (CS) proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is currently under investigation as a marker of cancer malignancy, and as a potential target of anticancer drug treatment. CSPG4 acts as a driver of tumourigenesis by regulating turnover of the extracellular matrix (ECM) to promote tumour cell invasion, migration as well as inflammation and angiogenesis. While CSPG4 has been widely studied in certain malignancies, such as melanoma, evidence is emerging from global gene expression studies, which suggests a role for CSPG4 in squamous cell carcinoma (SCC). While relatively treatable, lack of widely agreed upon diagnostic markers for SCCs is problematic, especially for clinicians managing certain patients, including those who are aged or infirm, as well as those with underlying conditions such as epidermolysis bullosa (EB), for which a delayed diagnosis is likely lethal. In this review, we have discussed the structure of CSPG4, and quantitatively analysed CSPG4 expression in the tissues and pathologies where it has been identified. The aim of this review has been to collate the information available from functional studies and recent transcriptome analysis to determine the usefulness of CSPG4 expression as a diagnostic marker and therapeutic target in management of malignant SCC.

Turner syndrome (TS) is a chromosomal disorder that is caused by a missing or structurally ab-normal second sex chromosome. Subjects with TS are at an increased risk of developing intrauterine growth retardation, low birth weight, short stature, congenital heart diseases, infertility, obesity, dyslipidemia, hypertension, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular diseases (stroke and myocardial infarction). The underlying pathogenetic mechanism of TS is unknown. The assumption that X chromosome-linked gene haploinsufficiency is associated with the TS phenotype is questioned since such genes have not been identified. Thus, other pathogenic mechanisms have been suggested to explain this phenotype. Morphogenesis encompasses a series of events that includes cell division, the production of migratory precursors and their progeny, differentiation, programmed cell death, and integration into organs and systems. The precise control of the growth and differentiation of cells is essential for normal development. The cell cycle frequency and the number of proliferating cells are essential in cell growth. 45,X cells have a failure to proliferate at a normal rate, leading to a decreased cell number in a given tissue during organogenesis. A convergence of data indicates an association between a prolonged cell cycle and the phenotypical features in Turner syndrome. This review aims to examine old and new findings concerning the relationship between a prolonged cell cycle and TS phenotype. These studies reveal a diversity of phenotypic features in TS that could be explained by reduced cell proliferation. The implications of this hypothesis for our understanding of the TS phenotype and its pathogenesis are discussed. It is not surprising that 45,X monosomy leads to cellular growth pathway dysregulation with profound deleterious effects on both embryonic and later stages of development. The prolonged cell cycle could represent the beginning of the pathogenesis of TS, leading to a series of phenotypic consequences in embryonic/fetal, neonatal, pediatric, adolescence, and adulthood life.

Cost-effective and functionalized scaffolds are in high demand for stem-cell-based regenerative medicine to treat refractory bone defects in craniofacial abnormalities and injuries. One potential strategy is to utilize pharmacological and cost-effective plant polyphenols and biocompatible proteins, such as gelatin. Nevertheless, the use of chemically modified proteins with plant polyphenols in this strategy has not been standardized. Here, we demonstrated that gelatin chemically modified with epigallocatechin gallate (EGCG), the major catechin isolated from green tea, can be a useful material for dedifferentiated fat cells and adipose-derived stem cells and can induce bone regeneration in a rat congenial cleft-jaw model in vivo. Vacuum-heated gelatin sponge modified with EGCG (vhEGCG-GS) induced superior osteogenesis from these two cell types compared with vacuum-heated gelatin sponge (vhGS). The EGCG-modification converted the water wettability of vhGS to a hydrophilic property (contact angle: 110° to 3.8°) and the zeta potential to a negative surface charge; the modification enhanced the cell adhesion property and promoted calcium phosphate precipitation. These results suggest that the EGCG-modification with chemical synthesis can be a useful platform to modify the physicochemical property of gelatin. This alteration is likely to provide a preferable microenvironment for multipotent progenitor cells, inducing superior bone formation in vivo.

Aluminum (Al) toxicity is the most common factor limiting the growth of alfalfa in acidic soil conditions. Melatonin (MT), a significant pleiotropic molecule present in both plants and animals, has shown promise in mitigating Al toxicity in various plant species. This study aims to elucidate the underlying mechanism by which melatonin alleviates Al toxicity in alfalfa through a combined physiological and transcriptomic analysis. The results reveal that 5 μM MT significantly alleviates Al-induced growth inhibition and preserves the morphology of root tip cells. Moreover, MT application reduces Al accumulation in alfalfa roots and shoots by 28.6% and 27.6%, respectively. Additionally, MT plays a crucial role in scavenging Al-induced excess H2O2 by enhancing the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), consequently reducing malondialdehyde (MDA) levels. The RNA-seq results reveal that MT application significantly upregulates the expression of xyloglucan endotransglucosylase/hydrolase (XTH) and carbon metabolism-related genes, including those involved in the glycolysis process, as well as sucrose and starch metabolism, suggesting that MT application may mitigate Al toxicity by facilitating the binding of Al to the cell walls, thereby reducing intracellular Al accumulation, and by improving respiration and the content of sucrose and trehalose. Taken together, our study demonstrates that MT alleviates Al toxicity in alfalfa by restoring redox homeostasis, enhancing Al binding to the cell wall, and modulating carbon metabolism. This research advances our understanding of the mechanisms underlying MT's effectiveness in mitigating Al toxicity, offering potential strategies for reducing Al accumulation in alfalfa.

Mass cells (MCs) are tissue cells that are derived from bone marrow stem cells that contribute to allergic reactions, inflammatory diseases, innate and adaptive immunity, autoimmunity, and mental disorders. MCs located near the meninges communicate with microglia through the production of mediators such as histamine and tryptase, but also through the secretion of IL-1, IL-6 and TNF, which can create pathological effects in the brain. Preformed chemical mediators of inflammation and tumor necrosis factor (TNF) are rapidly released from the granules of MCs, the only immune cells capable of storing the cytokine TNF, although it can also be produced later through mRNA. The role of MCs in nervous system diseases has been extensively studied and reported in scientific literature and is of great clinical interest. However, many of the published articles concern studies on animals (mainly rats or mice) and not on humans. MCs are known to interact with neuropeptides that mediate endothelial cell activation, resulting in central nervous system (CNS) inflammatory disorders. In the brain, MCs interact with neurons causing neuronal excitation with the production of neuropeptides and the release of inflammatory mediators such as cytokines and chemokines. This article explores the current understanding of MC activation by neuropeptides and the role of pro-inflammatory cytokines, suggesting a therapeutic effect of the anti-inflammatory cytokines IL-37 and IL-38.

Among the different ways to reduce the secondary effects of antineoplastic drugs in cancer treatment, the use of nanoparticles has demonstrated good results due to the protection of the drug and the possibility of releasing compounds to a specific therapeutic target. The α-isoform of folate receptor (FR) is overexpressed on a significant number of human cancers; therefore, folate-targeted crosslinked nanoparticles based on BSA and alginate mixtures and loaded with paclitaxel (PTX) have been prepared to maximizing the proven antineoplastic activity of the drug against solid tumors. Nanometric-range sized particles (169 ± 28nm - 296 ± 57nm), with negative Z-potential values (between -0.12 ± 0.04 and -94.1± 0.4), were synthesized. The loaded PTX (2.63±0.19 - 3.56 ±0.13 µg PTX/mg Np) was sustainably released along 23 and 27h. Three cell lines (MCF-7, MDA-MB-231 and HeLa) were selected to test the efficacy of the folate-targeted PTX-loaded BSA/ALG nanocarriers. The presence of FR on cell membrane led to a significant larger uptake of BSA/ALG-Fol nanoparticles regarding to the equivalent nanoparticles without folic acid on its surface. The cell viability results demonstrated a cytocompatibility of unloaded nanoparticle-Fol and a gradual decrease in cell viability after treatment with PTX-loaded nanoparticles-Fol due to the sustainable PTX release.

Bacteria a Microscopic organisms are the most inexhaustible and flexible of microorganisms and constitute a huge division of the whole living earthly biomass, certain microorganisms were found to amass metallic components at a high limit Was Known as Bacterial Bio-sorption Due to their little size, capacity to become under controlled conditions, and their Accommodation to an extensive variety of ecological situations; Potent metal bio-sorbents among microorganisms, at low pH esteems, cell divider ligands are protonated and contend essentially with metals for official. With expanding pH, more ligands, such as amino and carboxyl groups, could be exposed, leading to attraction between these negative charges and the metals, and consequently increment bio-sorption onto the cell surface. Starting with Isolation and identification of heavy metal-resistant bacteria from rock Ore. Studying Factors Affecting Uranium Bio-sorption, Optimization of bacterial growth conditions and optimum for metal uptake by free and immobilized bacterial cells and Desorption ratio of uranium ions adsorbed by Coli. /alginate, All this evidence suggest that functions groups Represented in our study are responsible for metal uptake in our bacterial biomass beside change in peaks position which assigned for it's groups confirm bio-sorption of metal ions from waste due to ions charge interaction comparing with immobilized we found increase in no of binding sites indicate that immobilized bacterial have high efficiency for metal up take which also change in peaks position which assigned for its groups confirm bio-sorption of metal ions from waste due to ions charge interaction, Where the high bio-sorption yield obtained by bacteria, the Uranium & heavy metal bioremediation process expects microorganisms to be joined to a strong surface.

Passiflora cincinnata Mast is a plant popularly used in traditional medicine in northeastern Brazil. The present study aimed to evaluate the anti-lipoperoxidative and anti-α-amylase properties, and cytotoxicity of an extract and fraction of passion fruit leaves (P. cincinnata Mast), as well as the antihyperglecemiant activity of the fraction rich in glycosylated flavonoids and showing low cytotoxicity in rats with a postprandial hyperglycaemia condition. The ethyl acetate fraction (F.ACT) of the P. cincinnata leaves presented the best anti-lipoperoxide properties with TBARs 81.49%, 95.48% and 75.62% lower than AAPH, FeSO₄ and H₂O₂ induced controls, respectively, at 200 μg.mL-1. In addition, it presented an anti-α-amylase potential, with a better ability to inhibit the α-amylase enzyme in comparison to the acarbose control (IC₅₀ 6.49 ± 0.11 and 12.01 ± 0.4 μg.mL-1, respectively). The hydroalcoholic extract of P. cincinnata (ExEt) presented high content of total tannins, flavonoids and flavonols. However, F.ACT had the highest concentration of flavonoids among the fractions studied. HPLC analysis of this fraction revealed the presence of the flavonoids isovitexin, orientin and isoorientin. F.ACT showed low to no cytotoxicity below 150 μg.mL-1. Regarding the post-prandial antihyperglycaemic activity of F.ACT, it was observed at 50 and 100 mg.kg-1.

Angiotensin II (Ang II) plays a role in several inflammatory diseases and is capable of inducing the release of inflammatory mediators in several cell types. The objective was to investigate the potential of Ang II to induce mRNA expression of inflammatory mediators by cultured primary human periodontal cells. A synergistic effect of a co-treatment with Ang II and IL1β on mRNA expression of inflammatory mediators was also explored. Primary cultures of human fibroblast-like cells isolated from gingival and periodontal ligament tissues from 3 subjects were established using explant techniques. Immunophenotyping of STRO-1, Ang II type 1 receptor (AT1R) and Ang II type 2 receptor (AT2R) was performed by flow cytometry analysis. Cell cultures were challenged with Ang II (1M) for 3, 6 and 24h with or without a co-treatment with IL1β (0.1ng/mL) for 24h. mRNA expression of inflammatory mediators was performed by real time quantitative polymerase chain reaction (RT-qPCR). We present, for the first time, a precise quantification for AT1R and AT2R on human gingival and periodontal fibroblast-like cell types; the percentage of positive immunostaining compared to the total population of cells varied from 3.35% through 5.29% for AT1R and 2.97% through 4.57% for AT2R. Ang II slightly upregulated mRNA expression of IL6 and CCL2/MCP1 in gingival cells and IL8 and PTGS2/COX2 in periodontal ligament cells. IL1β induced upregulation of IL8, IL6 CCL2/MCP1, PTGS2/COX2 and IL1β mRNA in both cell types. Co-treatment with Ang II and IL1β did not show a synergistic effect under these experimental conditions. Ang II shows a low potential to induce mRNA upregulation of inflammatory mediators in cultured primary human gingival and periodontal ligament cells, most likely due to the low percentage of Ang II receptors in such cells, and no synergistic effect with the co-treatment with IL1β.

Angiotensin II (Ang II) plays a role in several inflammatory diseases and is capable of inducing the release of inflammatory mediators in several cell types. The objective was to investigate the potential of Ang II to induce mRNA expression of inflammatory mediators by cultured primary human periodontal cells. A synergistic effect of a co-treatment with Ang II and IL1β on mRNA expression of inflammatory mediators was also explored. Primary cultures of human fibroblast-like cells isolated from gingival and periodontal ligament tissues from 3 subjects were established using explant techniques. Immunophenotyping of STRO-1, AT1 and AT2 receptors was performed by flow cytometry analysis. Cell cultures were challenged with Ang II (1M) for 3, 6 and 24h with or without a co-treatment with IL1β (0.1ng/mL) for 24h. mRNA expression of inflammatory mediators was performed by real time quantitative polymerase chain reaction (RT-qPCR). We present, for the first time, a precise quantification for AT1 and AT2 receptors on human gingival and periodontal fibroblast-like cell types; the percentage of positive immunostaining compared to the total population of cells varied from 3.35% through 5.29% for AT1 and 2.97% through 4.57% for AT2. Ang II slightly upregulated mRNA expression of IL6 and CCL2/MCP1 in gingival cells and IL8 and PTGS2/COX2 in periodontal ligament cells. IL1β induced upregulation of IL8, IL6 CCL2/MCP1, PTGS2/COX2 and IL1β mRNA in both cell types. Co-treatment with Ang II and IL1β did not show a synergistic effect under these experimental conditions. Ang II shows a low potential to induce mRNA upregulation of inflammatory mediators in cultured primary human gingival and periodontal ligament cells, most likely due to the low percentage of Ang II receptors in such cells, and no synergistic effect with the co-treatment with IL1β.

Providing cellular support and modifying the glial scar around the lesion are two key strategies for promoting axonal regeneration after spinal cord injury. We showed before that over-expressing polysialic acid (PSA) on Schwann cells (SCs) by lentiviral vector (LV)-mediated expression of polysialyltransferase (PST) facilitated their integration and migration in the injured spinal cord. We also showed that PSA over-expression in the injured spinal cord modified the glial scar and promoted the growth of ascending sensory axons. In this study, we combined the PST/SC transplantation with LV/PST injection in spinal cords after dorsal column transection and found the combined treatments led to faster and more profound locomotor functional recovery compared with animals receiving combined GFP/SC transplantation with LV/GFP injection. Histological examination showed significantly more injured corticospinal axons growing close to the lesion/transplant borders and into the caudal spinal cord in the PST group than in the GFP group. We also found over-expressing PSA around the lesion site did not cause allodynia and hyperalgesia in our injury model. These results demonstrate the promising therapeutic benefit of over-expressing PSA in transplanted SCs and spinal cord in promoting axonal growth and restoring motor function.

The COVID-19 pandemic stimulated attention to the medicinal applications of messenger RNA (mRNA). mRNA is expected to be applied not only to vaccines but also to regenerative medicines. The purity of mRNA is important for its medicinal application. However, the current mRNA synthesis techniques have problems, e.g., contamination of undesired 5’-uncapped mRNA and double-stranded RNAs. Recently, our group developed a completely capped mRNA synthesis technology that contributed to the progress of mRNA research. The introduction of chemically modified nucleosides, e.g., N1-methylpseudouridine and 5-methylcytidine, have been demonstrated by Dr. Karikó and Dr. Weissman which opened the practical application of mRNA for vaccines and regenerative medicines. Dr. Yamanaka reported the production of Induced Pluripotent Stem Cells (iPSCs) by the introduction of 4 types of genes using a retrovirus vector. iPSCs are widely used for research about regenerative medicines and the preparation of disease models to screen new drug candidates. Of the Yamanaka factors, Klf4 and c-Myc are oncogenes, and there is a tumor development risk if these are integrated into genomic DNA. Therefore, regenerative medicines using mRNA, which has no risk of genome insertion, have attracted attention. In this review, we summarized the synthesis of mRNA and its application for regenerative medicine.

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by pathological processes involving autoimmunity, vasculopathy, and resultant extensive skin and organ fibrosis. Recent studies have demonstrated activation and aberrant wound healing responses in the epithelial layer of the skin in this disease, implicating the epithelial keratinocytes as a source of pro-fibrotic and inflammatory mediators. In this paper we investigated the role of Immunoglobulin G (IgG) autoantibodies directed against epithelial cells, as potential initiators and propagators of pathological keratocyte activation and the ensuing SSc fibrotic cascade. A keratinocyte cell-based ELISA is used to evaluation binding of SSc IgG. SSc skin biopsies were stained by immunofluorescence for the presence of IgG in the keratinocyte layer. Moreover, IgG purified from SSc sera is evaluated for the potential to activate keratinocytes in tissue culture and to induce signaling in TLR2 & 3 reporter cell lines. We demonstrate enhanced binding of SSc IgG to keratinocytes, and activation of these cells leading to release of IL-1α, representing a potential initiating pathway in this disease.

Progress in laser-driven proton acceleration requires increasing the proton maximum energy and laser-to-proton conversion efficiency, while reducing the divergence of the proton beam. However, achieving all these qualities simultaneously has proven challenging experimentally, the increase in beam energy often coming at the cost of beam quality. Numerical simulations suggest that coupling multi-PW laser pulses with ultrathin foils could offer a route for such simultaneous improvement. Yet experimental investigations have been limited by the scarcity of such lasers and the need for very stringent temporal contrast conditions to prevent premature target expansion before the pulse maximum. Here, combining the newly commissioned Apollon laser facility that delivers high-power ultrashort (∼24fs) pulses, with a double plasma mirror scheme to enhance its temporal contrast, we demonstrate the generation of up to 35 MeV protons with only 5 J of laser energy. This approach also achieves improved laser-to-proton energy conversion efficiency, reduced beam divergence, and optimized spatial beam profile. Therefore, despite the laser energy losses induced by the plasma mirror, the proton beams produced by this method are enhanced on all accounts compared to those obtained under standard conditions. Particle-in-cell simulations reveal that this improvement results from the intensified electrostatic field caused by a more compact hot-electron distribution.

Eurycomanone and eurycomalactone are known quassinoids present in the roots and stems of Eurycoma longifolia. These compounds had been reported to have cytotoxic effects, however, their mechanism of action in a few cancer cell lines have yet to be elucidated. This study was aimed to investigate the anti-cancer effects and mechanisms of action of eurycomanone and eurycomalactone in cervical (HeLa), colorectal (HT29) and ovarian (A2780) cancer cell lines via Sulforhodamine B assay. Their mechanism of cell death was evaluated based on Hoechst 33342 assay and in silico molecular docking toward DHFR and TNF-α as putative protein targets. Eurycomanone and eurycomalactone exhibited in vitro anti-cancer effects manifesting IC50 values of 4.58 ± 0.090 µM and 1.60 ± 0.12 µM (HeLa), 1.22 ± 0.11 µM and 2.21 ± 0.049 µM (HT-29), and 1.37 ± 0.13 µM and 2.46 ± 0.081 µM (A2780) respectively. They induced apoptotic cancer cell death in dose- and time-dependent manners. Both eurycomanone and eurycomalactone were also predicted to have good inhibitory potential as demonstrated by the docking into TNF-α with binding affinity of -8.83 and -7.51 kcal/mol, respectively, as well as into DHFR with binding affinity results of -8.05 and -8.87 kcal/mol, respectively. These results support the evidence of eurycomanone and eurycomalactone as anti-cancer agents via apoptotic cell death mechanism that could be associated with TNF-α and DHFR inhibition as among possible protein targets.

Following traumatic brain injury (TBI), secondary brain damage due to chronic inflammation is the most predominant cause of the delayed onset of mood and memory disorders. Currently no therapeutic approach is available to effectively mitigate secondary brain injury after TBI. One reason is the blood-brain barrier (BBB), which prevents passage of most therapeutic agents into the brain. Peptides have been among the leading candidates for CNS therapy due to their low immunogenicity and toxicity, bioavailability, and ease of modification. In this study, we demonstrated that non-invasive intranasal administration of KAFAK, a cell penetrating anti-inflammatory peptide, traversed the BBB in a murine model of diffuse, moderate TBI. Notably, KAFAK treatment reduced the production of pro-inflammatory cytokines that contribute to secondary injury. Furthermore, behavioral tests showed improved or restored neurological, memory, and locomotor performance in KAFAK-treated mice. This study demonstrates KAFAK's ability to cross the blood-brain barrier, to lower pro-inflammatory cytokine levels in vivo, and to restore function after a moderate TBI.

Chimeric antigen receptor (CAR) T-cell therapy has greatly improved outcomes for patients with relapsed or refractory hematological malignancies. However, challenges such as treatment resistance, relapse, and severe toxicity still hinder its widespread clinical application. Traditional transcriptome analysis has provided limited insights into the complex transcriptional landscape of both leukemia cells and engineered CAR-T cells, as well as their interactions within the tumor microenvironment. However, with the advent of single-cell sequencing techniques, a paradigm shift has occurred, providing robust tools to unravel the complexities of these factors. These techniques enable unbiased analysis of cellular heterogeneity and molecular patterns. These insights are invaluable for precise receptor design, guiding gene-based T cell modification, and optimizing manufacturing conditions. Consequently, this review utilizes modern single-cell sequencing techniques to clarify the transcriptional intricacies of leukemia cells and CAR-Ts. The aim of this manuscript is to discuss the potential mechanisms that contribute to the clinical failures of CAR-T immunotherapy. We will examine the biological characteristics of CAR-Ts, the mechanisms that govern clinical responses, and the intricacies of adverse events. By exploring these aspects, we hope to gain a deeper understanding of CAR-T therapy, which will ultimately lead to improved clinical outcomes and broader therapeutic applications.

It is important to develop new antibacterial drugs since the emergence of bacterial resistance to available antibiotics. Metal nanoparticles have the potential to combat antibiotic resistance and are effective antibacterial agents. Here, we demonstrate the biogenic production of zinc nanoparticles using Rhododendron arboreum stem bark. The biosynthesized ZnNPs were characterized through different analytical techniques such as UV-vis, FTIR, EDX, SEM, and XRD. Clinical isolates such as E. coli, S. aureus, and K. pneumonia were used to check the antibacterial efficacy of the biosynthesized zinc nanoparticles. The MIC and MBC values against K. pneumonia, S. aureu, and E. coli were found to be 34±0.21 and 11.71±0.47, 47±0.11 and 23.86±0.84 and 94±0.18 and 40.43±0.16 µg/mL, respectively. It dramatically decreased the integrity of the cell membrane and markedly increased the permeability of both inner and outer membranes. The green synthesized ZnNPs have good catalytic activity. It degraded 65% of methyl orange dye within 6h when the mixture was kept in direct sunlight, thus demonstrating good photodegradation potential and can be employed as a good photocatalyst. According to these results, biosynthesized zinc nanoparticles could be a potential therapy option for controlling bacterial pathogenesis and an effective photocatalyst for the elimination of hazardous water contaminants.

.Purpose: This paper presents a comparative analysis of state-of-the-art DIR algorithms in the context of head and neck squamous cell carcinoma (HNSCC) radiation therapy. Materials and Methods: We used a dataset of head and neck cancer patients within the Cancer Image Archive, which includes 31 patients with 3D CT image data from pre-treatment, mid-treatment, and post-treatment stages of radiotherapy. We applied DIR algorithms to two datasets, one for pre-treatment to mid-treatment registration and another for mid-treatment to post-treatment registration, by aligning one CT image to another CT image. To quantitatively analyze the patient data, we focused on the spinal cord, optic nerve, brain stem, cochlea, and PTV as the OAR datasets. To verify the DIR algorithm, we used two non-learning-based methods, SyN and NiftyReg, as well as three deep learning-based methods, Voxelmorph, Cyclemorph, and Transmorph. We trained a deep learning model by adjusting the ratio of the training dataset, validation dataset, and test dataset to 7:1:2. Results: The average DSCs of SyN and NiftyReg, the non-learning-based methods, were 0.74±0.06 and 0.70±0.12, respectively. The deep learning-based methods, Voxelmorph, Cyclemorph, and Transmorph, had average DSCs of 0.72±0.08, 0.68±0.11, and 0.69±0.13, respectively. The deep learning DIR algorithm produced transformed outputs of OAR/PTV in a shorter time than other models, including commercial and conventional mathematical algorithms (At Inference(sec/images), Voxelmorph: 0.36, Cyclemorph: 0.3, Transmorph: 5.1, SyN: 140, NiftyReg: 40.2). Conclusions: In conclusion, our study provides a comprehensive comparison of commercial DIR algorithms with traditional and deep learning-based DIR methods. Our results demonstrate that commercial DIR algorithms outperform traditional DIR methods in terms of accuracy and efficiency. However, we also show that deep learning-based DIR methods have the potential to achieve similar performance to commercial algorithms with proper training and optimization. Our findings suggest that both commercial and deep learning-based DIR methods have their respective advantages and limitations, and the choice of method should depend on the specific requirements of the clinical application. Overall, our study contributes to ongoing efforts to improve the accuracy and efficiency of DIR methods for better patient outcomes.

Lambertianic acid (LA) is a biologically active compound from the leaves of Pinus koraiensis. In the present study, apoptotic mechanisms of LA plus TNF-related apoptosis-inducing ligand (TRAIL) were elucidated in non-small cell lung cancer cells (NSCLCs). Cytotoxicity assay, flow cytometry, immunoprecipitation and Western blotting were performed. Here, combined treatment of LA and TRAIL increased cytotoxicity, sub-G1 population and cleaved poly (ADP-ribose) polymerase (PARP) and caspase3/8/9 in A549 and H1299 cells compared to LA or TRAIL alone. Furthermore, combined treatment of LA and TRAIL significantly decreased anti-apoptotic proteins such as B-cell lymphoma 2 (Bcl-2), Fas-like inhibitor protein (FLIP) and X-linked inhibitor of apoptosis protein (XIAP) and enhanced the activation of pro-apoptotic proteins Bid compared to LA or TRAIL alone. In addition, combined treatment of LA and TRAIL upregulated the expression of Death receptor 4 (DR4) and downregulated phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-B), inhibitory protein of kB family (p-IB) and FLIP in A549 and H1299 cells along with disrupted binding of XIAP with caspase3 or NF-B. Overall, these findings suggest that lambertianic acid enhances TRAIL-induced apoptosis via inhibition of XIAP/NF-B in TRAIL resistant NSCLCs.

Extracellular vesicles (EVs), a diverse group of cell-derived exocytosed particles, are pivotal in mediating intercellular communication due to their ability to selectively transfer biomolecules to specific cell types. EVs, composed of proteins, nucleic acids, and lipids, are taken up by cells to affect a variety of signaling cascades. Research in the field has primarily focused on stem-cell derived EVs, with a particular focus on mesenchymal stem cells, for their potential therapeutic benefits. Recently, tissue specific EVs or cell type specific extracellular vesicles (CTS-EVs), have garnered attention for their unique biogenesis and molecular composition because they enable highly targeted cell-specific communication. Various studies have outlined the roles that CTS-EVs play in signaling for physiological function and maintenance of homeostasis, including immune modulation, tissue regeneration, and organ development. These properties are also exploited for disease propagation, such as in cancer, neurological disorders, infectious diseases, autoimmune conditions, and more. The insights gained from analyzing CTS-EVs in different biological roles not only enhance our understanding of intercellular signaling and disease pathogenesis, but also open new avenues for innovative diagnostic biomarkers and therapeutic targets for a wide spectrum of medical conditions. This review comprehensively outlines current understanding of CTS-EV origins, function within normal physiology, and implications in diseased states.

A retrospective study including 49 women with ovarian clear cell carcinoma between January 2009 and December 2021 at Oxford cancer centre was done. The mean age was 63 years, with 78% post-menopausal. All women underwent cytoreductive surgery with no residual disease (R0) in 39 women. The follow-up time ranged between 12-144 months, with mean of 105.5 months. The 3-year OS was 73.4%, and 3-year PFS was 81.3%, with a mean of 101.7months (95%CI, 84.63-118.93). As expected, women with stage 1 disease had the best outcome. In comparing OS in respect to absence or presence of residual disease, the 3-year OS was 88.6% (95% CI 108.6-141.8), compared to 12.5% (95% CI 4.48-32.11) respectively (P<0.001). In multivariant analysis the variables included were CA 125 (< or >200 IU/ml), Hb (< or >115 g/L), albumin (< or >40 g/L), associated endometriosis, ascites, residual disease, and FIGO staging. FIGO stage was the only independent prognostic indicator of OS with (p<0.05). Surgery to achieve no residual tumour is necessary to improve the prognosis in advanced OCCC. At present, the true challenge is to predict which patients with early-stage disease are at higher risk of recurrence and would most benefit from adjuvant treatments.

CD39 is involved in adenosine metabolism through conversion of extracellular ATP to adenosine. Because extracellular adenosine plays a critical role in the immune suppression of tumor microenvironment, the inhibition of CD39 activity by monoclonal antibodies (mAbs) is one of the important strategies for tumor therapy. In this study, we developed specific and sensitive mAbs for mouse CD39 (mCD39) using the Cell-Based Immunization and Screening (CBIS) method. The established anti-mCD39 mAbs, which were established by the CBIS method including C₃₉Mab-1 (rat IgG_2a, kappa) and C₃₉Mab-2 (rat IgG_2a, lambda), reacted with not only mCD39-overexpressed Chinese hamster ovary-K1 (CHO/mCD39) but also endogenously mCD39-expressed cell lines, such as L1210 (mouse lymphocytic leukemia) and J774-1 (mouse macrophage-like) cell lines through flow cytometry. Kinetic analyses using flow cytometry indicated that the dissociation constant (K_D) of C₃₉Mab-1 and C₃₉Mab-2 for CHO/mCD39 was 7.3 × 10⁻⁹ M and 5.5 × 10⁻⁹ M, respectively. K_D of C₃₉Mab-1 and C₃₉Mab-2 for L1210 was 3.3 × 10⁻⁹ M and 3.6 × 10⁻¹⁰ M, respectively. Furthermore, C₃₉Mab-1 could detect the lysate of CHO/mCD39 by western blot analysis. These results indicate that C₃₉Mab-1 and C₃₉Mab-2 are useful for the detection of mCD39 in many functional studies.

To explore a new set of anticancer agents, a novel series of pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine derivatives 7a-l have been designed and synthesized via cyclocondensation reactions of pyrazolo-enaminone 5 with a series of arylidene malononitriles; compound 5 was obtained from 5-amino-4-cyanopyrazole (3). The structures of the target compounds 7a-l were investigated by spectral techniques and elemental analysis (IR, UV-Vis, 1H NMR, 13C NMR and ESI-MS). All compounds were evaluated for their in vitro cytotoxicity employing a panel of different human tumor cell lines, A375, HT29, MCF7, A2780, FaDu as well as non-malignant NIH 3T3 and HEK293 cells. It has been found that the conjugate 7e was the most active towards many cell lines with EC50 values ranging between 9.1 and 13.5 µM, respectively. Moreover, in silico docking studies of 7e with six anticancer drug targets, i.e. DHFR, VEGFR2, HER-2/neu, hCA-IX, CDK6 and LOX also was performed, in order to gain some insights into their putative mode of binding interaction and to estimate the free binding energy of this bioactive molecule.

Background: Oenothera biennis (evening primrose) produces bioactive substances with a diverse range of pharmacological functions. However, it is currently unknown whether extract prepared from the aerial parts of O. biennis (APOB) can protect the skin against oxidative stress. To investigate the protective effects of APOB against oxidative stress-induced damage in human skin keratinocytes (HaCaT) and elucidate the underlying mechanisms. Methods: We pretreated HaCaT cells with various concentrations of APOB or the antioxidant N-acetyl-L-cysteine before applying H2O2. We then compared the cell viability, intracellular reactive oxygen species (ROS) production, and DNA and mitochondrial damage between pretreated and untreated control cells using a range of assays, flow cytometry, and Western blot analysis and also examined the reducing power and DPPH free radical-scavenging activity of APOB. Results: APOB pretreatment significantly increased cell viability, effectively attenuated H2O2-induced comet tail formation, and inhibited H2O2-induced phosphorylation of the histone γH2AX, as well as the number of apoptotic bodies and Annexin V-positive cells. APOB was found to have a high reducing power and DPPH radical-scavenging activity and also exhibited scavenging activity against intracellular ROS accumulation and restored the loss of mitochondrial membrane potential caused by H2O2. APOB pretreatment almost totally reversed the enhanced cleavage of caspase-3, the degradation of poly (ADP-ribose)-polymerase (PARP), DNA fragmentation that usually occurs in the presence of H2O2 and increased the levels of heme oxygenase-1 (HO-1), a potent antioxidant enzyme that is associated with the induction of nuclear factor-erythroid 2-related factor 2 (Nrf2). Conclusions: APOB can protect HaCaT cells from H2O2-induced DNA damage and cell death by blocking cellular damage related to oxidative stress via a mechanism that affects ROS elimination and by activating the Nrf2/HO-1 signaling pathway.

The major stress-inducible Hsp70 (HSPA1A) is overexpressed in the cytosol of many highly aggressive tumor cells including glioblastoma multiforme and presented on their plasma membrane. Depending on its intracellular or membrane localization, Hsp70 either promotes tumor growth or serves as a target for NK cells. The kinetics of the membrane Hsp70 (mHsp70) density on human glioma cells (U87) was studied after different irradiation doses to define the optimal therapeutic window for Hsp70-targeting NK cells. To maintain the cells in the exponential growth phase during a cultivation period of 7 days different initial cell counts were seeded. Although cytosolic Hsp70 levels remained unchanged on days 4 and 7 after a sublethal irradiation with 2 Gy, 4 Gy and 6 Gy, a dose of 2 Gy resulted in an upregulated mHsp70 density in U87 cells which peaks on day 4 and starts to decline on day 7. Higher radiation doses (4 Gy, 6 Gy) resulted in an earlier and more rapid onset of the mHsp70 expression on days 2 and 1, respectively, followed by a decline on day 5. Membrane Hsp70 levels are higher in G2/M than in G1, however, an irradiation-induced cell cycle arrest on days 4 and 7, was not associated with an increase in the mHsp70 density. Extracellular Hsp70 concentrations increased significantly compared to sham (0 Gy) irradiated cells on days 4 and 7 but not on day 1. Functionally, elevated mHsp70 densities were associated with a significantly better lysis by Hsp70-targeting NK cells. In summary, the kinetics of changes in the mHsp70 density upon irradiation on tumor cells is time- and dose-dependent.

Monoclonal antibodies (mAbs) have become an increasingly important therapeutic modality in recent years, with applications in oncology, hematology, and immunology. This review discusses the production of therapeutic mAbs, including the various types of mAbs (murine, chimeric, humanized, and fully human), their key applications, and the techniques used for their production, including hybridoma technology, single B cell antibody technology, and phage display technology. The review then proposes advanced techniques to overcome them. These include microfluidic sorting, alternative expression systems (including plants, bacteria, and yeast, and cell-free production systems), and the development of complex antibody formats like bi-specific monoclonal antibodies, antibody fragments, antibody-drug conjugates, and nanobody development. These advanced techniques promise to enhance the efficiency, cost-effectiveness, and scalability of mAb production, paving the way for more effective therapeutic applications. This review highlights the theoretical significance of integrating innovative technologies to overcome existing challenges in mAb production, ultimately advancing the field of precision medicine.

Hidradenitis suppurativa and Langerhans cell histiocytosis are rare disorders that can reveal similar clinical manifestations, making differential diagnosis difficult. A definitive diagnosis requires biopsy and histological confirmation in suspicious cases. The complex pathophysiology of these diseases has still not been understood, therefore the treatment is still a challenge for physicians. It is seen with predilection in the intertriginous areas of the body, predominantly in the axillary region, rarely requiring a surgical procedure. However perineal, perianal, and gluteal HS usually necessitates some form of surgical treatment. Langerhans cell histiocytosis (histiocytosis X) is a very rare systemic disease manifested by clonal cell proliferation of histiocytic-dendritic nature, with pseudonodular manifestation that deeply infiltrates the hypodermis and ulcerates the epidermis on the surface. Langerhans cells are dendritic, antigen-presenting cells localized in the suprabasal regions of the squamous epithelium of the skin and mucous membranes, which help regulate the immune system. In this report, we present our experience with extensive gluteal, perineal, and perianal hidradenitis suppurativa and Langerhans cell histiocytosis cases, including our treatment methods and outcomes.

Glaucoma, a group of diseases characterized by progressive retinal ganglion cell loss, cupping of the optic disc and by a typical pattern of visual field defects, is a leading cause of severe visual impairment and blindness worldwide. Elevated intraocular pressure (IOP) is the leading risk factor for glaucoma development. However, glaucoma can also develop at normal pressure levels. An increased susceptibility of retinal ganglion cells to IOP, systemic vascular dysregulation, endothelial dysfunction and autoimmune imbalances have been suggested to play a role in the pathophysiology of normal tension glaucoma. Since inflammation and oxidative stress play a role in all forms of glaucoma, the goal of this review article is to resent an overview on the inflammatory and prooxidant mechanisms in the pathophysiology of glaucoma and to discuss immunomodulatory and antioxidant treatment approaches.

Nonhost disease resistance is the most common type of plant defense mechanism against potential pathogens. In this study, the metabolic enzyme formate dehydrogenase (FDH1) was identified to be involved in nonhost disease resistance in Nicotiana benthamiana and Arabidopsis thaliana. In Arabidopsis, AtFDH1 was highly upregulated in response to both host and nonhost bacterial pathogens. Arabidopsis Atfdh1 mutants were compromised in nonhost resistance, basal resistance, and gene-for-gene resistance. The expression patterns of salicylic acid (SA) and jasmonic acid (JA) marker genes after pathogen infections in Atfdh1 mutant indicated that SA is most likely involved in the FDH1-mediated plant defense response to both host and nonhost bacterial pathogens. Previous studies reported that FDH1 localizes to only mitochondria, or both mitochondria and chloroplasts. Our results showed that the AtFDH1 localized to mitochondria and the amount of FDH1 localized to mitochondria increased upon infection with host or nonhost pathogens. Interestingly, the subcellular localization of FDH1 was observed in both mitochondria and chloroplasts after infection with a nonhost pathogen in Arabidopsis. We speculate that FDH1 plays a role in cellular signaling networks between mitochondria and chloroplasts to produce coordinated defense responses such as SA-induced reactive oxygen species (ROS) generation and hypersensitive response (HR)-induced cell death against nonhost bacterial pathogens.

Traumatic brain injury represents one of the main health problems in developed countries. Growth Hormone (GH) and rehabilitation have been claimed to significantly contribute to the recovery of lost motor function after acquired brain injury, but the mechanisms by which this occurs are not well understood. In this work, we have investigated cell proliferation in the piriform cortex (PC) of adult rats with ablation of the frontal motor cortex treated with GH and rehabilitation, in order to evaluate if this region of the brain, related to the sense of smell, could be involved in benefits of GH treatment. Male rats were either ablated the frontal motor cortex in the dominant hemisphere or sham-operated and treated with GH or vehicle at 35 days post-injury (dpi) for five days. At 36 dpi, all rats received daily injections of bromodeoxyuridine (BrdU) for 4 days. We assessed motor function through the paw-reaching-for-food task. GH treatment and rehabilitation at 35 dpi significantly improved the motor deficit caused by the injury and promoted an increase of cell proliferation in the PC ipsilateral to the injury, which could be involved in the improvement observed. Cortical ablation promoted greater number of BrdU+ cells in the piriform cortex that was maintained long-term, which could be involved in the compensatory mechanisms of the brain after injury.

The production and N-glycosylation of recombinant human butyrylcholinesterase (BChE), a model highly glycosylated therapeutic protein, in a transgenic rice cell suspension culture treated with kifunensine, a strong α-mannosidase I inhibitor, was studied in a 5 L bioreactor. A media exchange was performed at day 7 of cultivation by removing spent sugar rich media (NB+S) and adding fresh sugar free (NB-S) media to induce the rice α-amylase 3D (RAmy3D) promoter to produce rice recombinant human BChE (rrBChE). Using a 1.25X concentrated sugar-free medium together with an 80% reduced working volume during the media exchange lead to a total active rrBChE production level of 79 ± 2 µg (g FW)^-1 or 7.5 ± 0.4 mg L^-1 in the presence of kifunensine, which is 1.5-times higher than our previous bioreactor runs using normal sugar free medium with no kifunensine treatment. Importantly, the amount of secreted active rrBChE in culture medium was enhanced in the presence of kifunensine, comprising 44% of the total active rrBChE at day 5 post-induction. Coomassie stained SDS-PAGE gel and Western blot analyses reveal different electrophoretic migration of purified rrBChE bands with and without kifunensine treatment, which is attributed to different N-glycoforms. N-Glycosylation analysis shows substantial increase of oligomannose glycans (Man5/6/7/8) in rrBChE treated with kifunensine compared to controls. However, mass transfer limitation of kifunensine is likely the major reason for incomplete inhibition of α-mannosidase I in this bioreactor study.

Beta adrenoblockers is a large class of drugs mainly used to manage abnormal heart rhythms. Over the last couples of decades, the anticancer effects of these compounds has been extensively studied. There is much evidence about their activity in non-small cell lung, pancreatic, breast, colorectal, prostate and ovarian cancer. However, the mechanism of beta blockers anticancer activity is still not known, and more detailed studies are needed. The aim of our study was to evaluate the anticancer activity of beta adrenoblockers in non-small cell lung cancer cell lines A549 and H1299. In order to find the relationship with their selectivity to beta adrenoreceptors, in our study we used selective (atenolol, betaxolol, esmolol, metoprolol) and non-selective (pindolol, propranolol and timolol) beta blockers. The effect on cell viability was evaluated by MTT assay and the activity on cell ability to form colonies was tested by clonogenic assay. The type of cell death was evaluated by cell double staining with Hoechst 33342 and Propidium iodide. The most active adrenoblockers against both tested cancer cell lines were propranolol and betaxolol. They completely inhibited lung cancer cell colony formation at 90% of EC50 (half maximal effective concentration) value. Most tested compounds induced cell death through apoptosis and necrosis. In A549 cell lines apoptosis was mainly induced while in H1299 cell line compounds induced both apoptosis and necrosis. There was no correlation established between beta adrenoblocker anticancer activity and their selectivity to beta adrenoreceptors.

Whole cell biosensors could serve as eco-friendly and cost-effective alternatives for detecting potentially toxic bioavailable heavy metals in aquatic environments. However, they often fail to meet practical requirements due to an insufficient limit of detection (LOD) and high background noise. In this study, we designed a synthetic genetic circuit specifically tailored for detecting ionic mercury, which we applied to environmental samples collected from artisanal gold mining sites in Peru. We developed two distinct versions of the biosensor, each utilizing a different reporter protein: a fluorescent biosensor (Mer-RFP) and a colorimetric biosensor (Mer-Blue). Mer-RFP enabled real-time monitoring of the culture’s response to mercury samples using a plate reader, whereas Mer-Blue was analysed for colour accumulation at the endpoint using a specially designed, low-cost camera set up for harvested cell pellets. Both biosensors exhibited negligible baseline expression of their respective reporter proteins and responded specifically to HgBr2 in pure water. Mer-RFP demonstrated a linear detection range from 1 nM to 1 μM, whereas Mer-Blue showed a linear range from 2 nM to 125 nM. Our biosensors successfully detected a high concentration of ionic mercury in the reaction bucket where artisanal miners produce a mercury-gold amalgam. However, they did not detect ionic mercury in the water from active mining ponds, indicating a concentration lower than 3.2 nM Hg2+ -a result consistent with chemical analysis quantitation. Furthermore, we discuss the potential of Mer-Blue as a practical and affordable monitoring tool, highlighting its stability, reliance on simple visual colorimetry, and the possibility of sensitivity expansion to organic mercury.

We propose a theoretical Photocurrent - Voltage characteristic (PC-V) model to assess the interfacial phenom-ena for a photo-electrochemical cell (PEC). The origin of voltage deficits and the distribution of the photocur-rent across the semiconductor-electrolyte interface (SEI) are reported for the cell. The model predicts the hole exchange current parameter to extract the cell polarization data at the SEI. The potential drop across the SEI across the cell is mapped for the n-type cells. The simulation results of the Pc-V model are used to differentiate the effect of the bulk and space charge region (SCR) recombination in the semiconductor cells. A deep neural network model is developed to assess the electron-hole transfer mechanism using the Pc-V characteristic curve. The applicability of the model is tested and validated with the real time data. The results show good agreement with the experimental data.

The metastatic disease is a complex and sequential process that involves the migration of tumor cells from the primary site to distant areas. This metastatic pathway is not always predictable. Therefore, this paper presents three rare cases of unusual metastases, due to their primary site: two metastases of a clear cell renal cell carcinoma, one gingival and one nasal, as well as a mandibular metastasis of a hepatocellular carcinoma. In all cases, an incisional biopsy was performed in order to sign out the diagnosis. After microscopical examination of morphological Hematoxylin and Eosin stained slides, for all cases, immunohistochemical reactions were performed to support the primary tumor site. Two cases had a previous histopathological diagnosis of a primary tumor, while for the third case, the metastatic lesion represented the first manifestation of the neoplastic disease, with an unfavorable prognosis.

Objective: The combination of docetaxel (DTX) with Laser-Activated NanoTherapy (LANT), as a treatment for head and neck cancer (HNC) may enhance the therapeutic efficacy of lower doses of DTX, thereby minimizing the effective dosage, side effects and treatment times. Material and methods: Three HNSCC cell lines, Detroit 562, FaDu, and CAL 27, were treated with four combinations of DTX + LANT to evaluate DTX dose reduction and cell viability. Results: The 1 nM DTX + 5 nM LANT combination was the most effective treatment, increasing cell death over its corresponding DTX monotreatment with approximately 86.6%, 80.7%, and 92.1% cell death for Detroit 562, FaDu, and CAL 27, respectively. In Detroit 562, the 1 nM DTX + 5 nM LANT combination treatment resulted in the highest percentage of DTX dose reduction at 84.6%; in FaDu and CAL 27, the 0.5 nM DTX + 5 nM LANT combination treatment resulted in the highest percentage of DTX dose reduction at 78.2% and 82.4%, respectively. Conclusion: LANT may increase the therapeutic efficacy of DTX at significantly lower doses, which could improve patient outcomes.

(1) Background: This study aimed to identify the recurrence and survival rates according to the mismatch repair (MMR), p53, and L1 cell adhesion molecule (L1CAM) states in patients with advanced and recurrent endometrial cancer receiving systemic chemotherapy.; (2) Methods: This single-center retrospective cohort study included chemotherapy-naïve patients (n=156) with advanced-stage (III/IV) or recurrent endometrial cancer who were administered chemotherapy as adjuvant therapy (n=112) or first-line palliative treatment (n=44) between January 2015 and June 2022. MMR and p53 states were assessed using PCR, and L1CAM was tested using immunohistochemistry in the no specific molecular profile (NSMP) group. The primary outcomes were progression-free survival (PFS) and overall survival (OS).; (3) Results: Of the 156 patients, 62 (39.7%), 53 (34.0%), and 41 (26.3%) had NSMP, abnormal p53 (p53abn), and an MMR deficiency (MMR-D), respectively. PFS and OS were longest in MMR-D, followed by NSMP, and were the least in p53abn tumors (PFS: p=0.0006, OS: p=0.0013). After NSMP was classified according to positive or negative L1CAM status, the L1CAM-negative group exhibited significantly lower survival rates than the L1CAM-positive group (PFS: p=0.0001, OS: p=0.0027); p53abn tumors were independent prognostic factors for poor PFS (p=0.039 on the multivariable analysis).; (4) Conclusions: In chemotherapy-naïve patients with advanced and recurrent endometrial cancer, the best prognosis after chemotherapy was obtained using MMR-D, followed by NSMP and p53abn tumors. The L1CAM status is a useful new marker for stratifying NSMP in advanced and recurrent patients.

Diabetes mellitus is a chronic metabolic disease that affects over 10.5 percent of the global adult population. Biochemical and hematological parameters such as albumin (ALB) and red cell dis-tribution width (RDW) have been shown to be altered in diabetic patients. This study aims to cor-relate hematological and biochemical parameters with glycated hemoglobin (HbA1c). 777 adult individuals (372 women and 405 men, aged 19-85 years) were divided into three groups: 218 par-ticipants with HbA1c < 5.7% (group A: non diabetic), 226 with HbA1c ≥ 5.7% and < 6.5% (group B: prediabetic) and 333 with HbA1c ≥ 6.4% (group C: diabetic). Biochemical and hematological parameters were compared among the 3 groups. Analysis of variance was performed to deter-mine the correlations of the parameters among groups. ALB and sodium (Na) levels were signifi-cantly decreased in group C compared to groups A (ALB: 3.8 g/dL vs. 4.1 g/dL, p < 0.0001, Na: 138.4 mmol/L vs. 139.3 mmol/L, p < 0.001), and B (ALB: 3.8 g/dL vs. 4.0 g/dL, p < 0.0001, Na: 138.4 mmol/L vs. 139.6 mmol/L, p < 0.0001), while RDW-standard deviation (RDW-SD) and urea were increased in group C compared to group A ( RDW: 45.8 vs. 43.9 fL, p < 0.0001, Urea: 55.6 mg/dL vs. 38.5 mg/dL, p < 0.0001) . Mean platelet volume (MPV) was increased in group C com-pared to group A (9.3 fL vs. 9.1 fL, p < 0.05, respectively). Τhe increase of RDW-SD from group A towards B and C demonstrates the impact of hyperglycemia on red blood cells. RDW may be re-garded as a potential innovative biomarker for improving risk assessment of developing diabetes. These results highlight the potential role of these parameters as an indication for prediabetes that would alert for measurement of HbA1c.

Neonatal disorders, particularly those resulting from prematurity, pose a major challenge to health care and have a significant impact on infant mortality and long-term child health. The limitations of current therapeutic strategies emphasize the need for innovative treatments. New cell-free technologies utilizing extracellular vesicles (EVs) offer a compelling opportunity for neonatal therapy by harnessing the inherent regenerative capabilities of EVs. These nanoscale particles, secreted by a variety of organisms including animals, bacteria, fungi and plants, contain a repertoire of bioactive molecules with therapeutic potential. This review aims to provide a comprehensive assessment of the therapeutic effects and mechanistic insights of EVs from stem cells, biological fluids and non-animal sources, with a focus on common neonatal conditions such as hypoxic-ischemic encephalopathy, respiratory distress syndrome, bronchopulmonary dysplasia and necrotizing enterocolitis. This review summarizes the evidence for the therapeutic potential of EVs, analyzes the evidence on their mechanisms of action, and discusses the challenges associated with the implementation of EV-based therapies in neonatal clinical practice.

Head and neck squamous cell carcinoma (HNSCC) is a type of cancer that arises from the epithelium lining of the oral cavity, hypopharynx, oropharynx, and larynx. Despite advancement of the current treatment to HNSCC, such as surgery, chemotherapy, and radiotherapy, the overall survival rate of HNSCC remains poor due to late diagnosis and acquired resistance to treatment. Natural products have been extensively explored as a safer and more acceptable alternative to current treatments, with numerous studies displaying their potential against HNSCC. This review highlights preclinical studies in the past 5 years involving natural products against HNSCC and explores the signalling pathways altered by these products. This review also addresses challenges and future directions of the use of natural products as chemotherapeutic and chemoprevention agents against HNSCC.

Immune checkpoints are a set of molecules dysregulated in several human and canine cancers and aberrations of the PD-1/PD-L1 axis are often correlated with a worse prognosis. To gain insight into the role of immune checkpoints in canine diffuse large B-cell lymphoma (cDLBCL), we investigated PD-L1, PD-1 and CD8A expression by RNAscope. Results were correlated with several clinico-pathological features, including treatment, Ki67 index and outcome. A total of 33 dogs treated with CHOP (n=12) or CHOP plus APAVAC (n= 21) were included. PD-L1 signal was diffusely distributed among neoplastic cells, whereas PD-1 and CD8A were localized in tumor infiltrating lymphocytes. However, PD-1 mRNA was also retrieved in tumor cells. An association between PD-L1 and PD-1 scores was identified and a higher risk of relapse and lymphoma-related death was found in dogs treated with chemotherapy alone and dogs with higher PD-L1 and PD-1 scores. The correlation between PD-L1 and PD-1 is in line with the mechanism of immune checkpoints in cancers, where neoplastic cells overexpress PD-L1 that, in turn, binds PD-1 receptors in activated TIL. We also found that Ki67 index was significantly increased in dogs with the highest PD-L1 and PD-1 scores, indirectly suggesting a role in promoting tumor proliferation. Finally, even if the biological consequence of PD-1+ tumor cells is unknown, our findings suggest that PD-1 intrinsic expression in cDLBCL might contribute to tumor growth escaping adaptive immunity.

Non-homologous end joining (NHEJ) is the main DNA repair mechanism for the repair of double strand breaks (DSBs) throughout the course of the cell cycle. DSBs are generated in developing B and T lymphocytes during V(D)J recombination to increase the repertoire of B and T cell receptors. DSBs are also generated during the class switch recombination (CSR) process in mature B lymphocytes, providing distinct effector functions of antibody heavy chain constant regions. Thus, NHEJ is important for both V(D)J recombination and CSR. NHEJ comprises core Ku70 and Ku80 subunits that form the Ku heterodimer, which binds DSBs and promotes the recruitment of accessory factors (e.g., DNA-PKcs, Artemis, PAXX, Mri) and downstream core factors (XLF, Lig4 and XRCC4). In recent decades, new NHEJ proteins have been reported, increasing complexity of this molecular pathway. Numerous in vivo mouse models have been generated and characterized to identify the interplay of NHEJ factors and their role in development of adaptive immune system. This review summarizes the currently available mouse models lacking one or several NHEJ factors, with a particular focus on early B cell development. We also underline genetic interactions and redundancy in the NHEJ pathway in mice.

Based on the key molecule of humoral adaptive immunity, the antibody, evolution of the system comprises molecular genetic, cell biologic and immunologic mechanisms, and as a network the system is likely governed and can be characterized by physical rules as well. While deep sequencing can provide vast amounts of data related primarily to clonal relationships, functional interpretation of such data is hampered by the inherent limitations of converting sequence to structure to function. In this paper a novel model of structural interaction space, termed radial adjustment of system resolution, or RADARS, is proposed. The model is based on the radial growth of resolution of structural recognition, corresponding to increasing affinity of immune reactivity, and the virtual infinity of directions of growth, corresponding to the ability to respond to almost any molecular structure. Levels of interaction strength appear as shells of the sphere representing the system. B-cell development and immune responses can be readily interpreted in the model and quantitative properties of the antibody network can be inferred from the physical properties of a quasi-spherical system growing multi-radially. The system is described by double-Pareto distribution, sampling the lognormally distributed equilibrium constants at a rate of phi square. Finally, general strategies for merging antibody sequence space into structural space are outlined.

Background: Humoral memory and specific antibodies levels depend on kind of the antigen and individual immunofactors., The presence of IgM antibodies or fourfold rise in specific IgG level, are generally accepted as diagnostic in serology of acute viral infection. This basic model is not adequate for herpesvirome especially after hematopoietic stem cell transplantation (HSCT) due to continuous, usually multifocal antigenic stimulation, various donor serostatus, immunosuppresion and individual immunoreconstitution. Methods: A  case-control study was conducted for identifying cases of Human herpesviruses (HHV) active infection (from 300 diagnosed immunocompromised patients) and evaluating historically associated humoral factors to look at outcomes. We enrolled only patients’ data with meticulous differential diagnosis to exclude other causes, thereby observe pathways and temporal relationships, not statistical ones, usually collected in cohorts. Despite the small number such data collection and analysis avoids a number of biases and indicates cause and effect.Results. In the observational study retrospective analysis of data from 300 patients with clinical diagnosis of herpes simplex (HSV) and varicella zoster virus(VZV) reactivation showed a number of biases. In two well differentiated cases (confirmed by Tzanck test) with various disease and conditioning evolution of immunoparameters showed interesting pathway. Exponential decrease of specific IgG after HSCT precedes virus replication with cytopathic effect (shingles, VZV-encephalitis and HSV-induced mucositis). Minima (smallest IgG levels) before herpes virus reactivation were 234,23 mIU/ml and 94 RU/ml for VZV and HSV, respectively. This coincides with low CD4 titer, but without other infectious process. Other immune response parameters such as Treg, cytotoxic T cells, complement and total IgG level were quite the same as before the transplant procedure. Interestingly, the second wave of immunoreconstitution with anamnestic antibody response was not always observed. It coincided with prolonged herpes viral infection. Patient with lymphocyte depletion in conditioning showed earlier second wave of immunoreconstitution (6th vs 14th month) Conclusions: Typical for infancy kinetics of IgG level is unique after HSCT (the decline phase is first). Host-microbiome factors (i.e. HHV1-3 -serostatus) should be taken into account to predict risk of non-relapse mortality and survival after HSCT. The levels of specific antibodies help to predict the prognosis and improve the management. The lack of differentiation, assessor and confusing bias are the main obstacles in statistical HHV1-3 research. Such time-lapse case studies may be first to build evidence of a pathway and association between immunoparameters and HHV disease.

Stem cell therapy in canines has increased considerably in recent years; however, there are few publications on the treatment of perianal fistulas (PF) in this species, and there is no agreed protocol for the number of cells per dose and their repetitions, nor for the in situ delivery methodology and follow-up period after cell therapy. The aim of this open-label clinical trial was to demonstrate the efficacy and safety of a new protocol for in situ administration of low-dose, expanded and cryopreserved allogeneic adipose-derived stem cells for the treatment of refractory spontaneous perianal fistula. The methodology consisted of intralesional application of 1 to 3 doses - depending on evidence of clinical signs of recurrence - of 5x106 cryopreserved allogeneic adipose-derived allogeneic stem cells in each fistula. The study was conducted in 14 dogs regardless of sex, breed or age with a clinical diagnosis of refractory PF presented between January 2019 and December 2023. Cells were diluted in 1 mL of phosphate-buffered saline and this volume was applied to five sites at the edge of the FP in an amount of 1x106 per application site. The evolution of the fistula was followed for 12 to 48 months. Efficacy was determined by complete healing as evidenced by complete closure of the fistula, which was observed in 100% of the cases studied one month after therapy, with a subsequent follow-up of 12 to 48 months after therapy. In addition, there were no local or systemic adverse effects assessed by clinical examination, complete blood count and blood biochemistry. In conclusion, the protocol used in this work demonstrates the efficacy without adverse effects of in situ application of allogeneic adipose-derived adipose stem cells in low doses and cell replicates to treat canine refractory PF, providing a simple, non-invasive, long-lasting and low-cost therapeutic option.

Protein Kinase C delta (PKCδ) has emerged as a key protective molecule against systemic lupus erythematosus (SLE or lupus), an autoimmune disease characterized by anti-double stranded (ds) DNA IgGs. Although PKCδ deficient mice and lupus patients with mutated PRKCD genes clearly demonstrate the requirement of PKCδ for preventing lupus autoimmunity, this critical tolerance mechanism remains poorly understood. We recently reported that PKCδ selectively deletes anti-dsDNA B cells in the germinal center (GC), disclosing a key B cell tolerance mechanism that prevents lupus autoimmunity. PKCδ’s tolerance function is activated by sphingomyelin synthase 2 (SMS2), a lipid enzyme whose expression is generally reduced in B cells from lupus patients. Moreover, pharmacologic strengthening of the SMS2/PKCδ tolerance pathway alleviated lupus pathogenesis in mice. Here, we review relevant publications in order to provide mechanistic insights into PKCδ’s tolerance activity, and discuss the potential significance of therapeutically targeting PKCδ’s tolerance activity in the GC for selectively inhibiting lupus autoimmunity.

The study aimed to showcase how implementing a patient blood management (PBM) program effectively cut unnecessary red blood cell (RBC) transfusions in a New York City urban community teaching hospital. Analyzing seven years from 2013 to 2019, a retrospective review of RBC transfusions was conducted. Following PBM introduction, considerable improvements were observed annually. These included a drop in mean pretransfusion hemoglobin levels from 7.26g/dL (2013) to 6.58g/dL (2019), a 34% reduction in yearly RBC unit transfusions, and fewer units given to patients with pre-Hgb levels ≥7g/dL (1210 units in 2013 to 310 units in 2019). Furthermore, the study noted a decline in two-unit RBC orders when Hgb levels were ≥7g/dL from 65 orders in 2013 to merely 3 in 2019. The estimated total cost-savings attributed to the six-year PBM program duration after full implementation in 2014 amounted to $2.1 million US dollars. Overall, PBM implementation significantly decreased RBC transfusions and enhanced transfusion practices. The findings emphasize that successful PBM strategies don't always necessitate extensive resources or increased budgets but instead rely on the application of intuitive methods, as evidenced by this study.

.Cellular senescence has emerged as an important driver of aging and age-related disease in the kidney. The activity of β-galactosidase at pH 6 (SA-β-Gal) is a classic maker of senescence in cellular biology. However the predictive role of kidney tissue SA-β-Gal on eGFR loss in chronic kidney disease (CKD) is still not understood. We retrospectively studied the expression of SA-β-Gal in kidney biopsies obtained in a cohort [n=29] of incident patients who were followed up for 3 years as for standard of care. SA-β-Gal staining was approximately 4-fold higher in the tubular compartment of patients with CKD vs. controls [26.0 ± 9 vs. 7.4 ± 6% positive tubuli in patients vs. controls; p < 0.025]. Tubular expressions of SA-β-Gal, but not proteinuria at the time of biopsy correlated with eGFR loss at follow-up; moreover, SA-β-Gal expression in more than 30% of kidney tubules was associated with fast progressive kidney disease. In summary, our study shows that SA-β-Gal is upregulated in the kidney tubular compartment of adult patients affected by CKD, and suggests that tubular SA-β-Gal is associated with accelerated loss of renal function.

Cytokinesis, as the last stage of the cell division cycle, is a tightly controlled process amongst all eukaryotes, and defective division can lead to severe cellular consequences, and is implicated in serious human diseases and conditions such as cancer. Both mammalian cells and the fission yeast Schizosaccharomyces pombe use binary fission to divide into two equal sized daughter cells. In S. pombe such cytokinetic division is driven by the assembly of an actin-myosin contractile ring (ACR) at the cell equator between the two cell tips. The ACR is composed of a complex network of membrane scaffold proteins, actin filaments, myosin motors, and other cytokinesis regulators. Contraction of the ACR leads to the formation of a cleavage furrow which is severed leading to the final cell separation during the last stage of cytokinesis, abscission. This review describes recent findings defining the three phases to establish cytokinesis in S. pombe: ACR assembly, ACR constriction, and its coordination with septation. Collectively, we provide an overview of current understanding of the mechanisms regulating the ACR-mediated cytokinesis in S. pombe.

Introduction: Bone fractures may be the result of high force impact or stress, or a minimal trauma injury as a result of certain medical conditions that weaken the bones, such as osteoporosis, osteopenia, bone cancer, or osteogenesis imperfecta, where the fracture is then properly termed a pathologic fracture. Bone cancer can be primarily or secondary to metastasis. Case presentation: We report a rare case of left humerus fracture in a 59-year-old male patient due to metastatic renal cell carcinoma. Our patient had no important past medical history. He suffered from two months of left arm pain, moderate disability and fever at night. Analgesics consumption resulted in minimal relieve. Trauma history was negative. X-ray of the left arm showed an osteolytic lesion with humerus fracture. Abdominal computed tomography with contrast showed right renal mass.Radical right nephrectomy was performed in addition to alignment nailing of the left humerus fracture with biopsy. Pathology report documented clear cell carcinoma with metastatic bone. The treatment was completed by chemotherapyDiscussion: Secondary bone tumors are metastatic lesions which have spread from other organs, most commonly carcinomas of the breast, lung, and prostate, and rarely from kidney. In some cases, bone metastasis could be the first symptoms of renal cell carcinoma. Conclusion: suspected pathological bone fractures should be investigated completely. It may hide a tumor as a cause.

Mycobacterium tuberculosis is the agent of tuberculosis, one of the most important infectious diseases in the world. This microorganism stands out from other bacteria, not only for its extremely high infection capacity, but also for its cellular characteristics that include an extremely resistant and hydrophobic cellular parade the passage of antibiotics. An incredible ability to adapt to adverse conditions inside the host as well as its vast arsenal of virulence factors that allow its survival within the inhospitable environment within the macrophage can be highlighted. This review aims to discuss several aspects of MTB microbiology, genetics, and physiology. We will address in this review details of the metabolism of MTB that allows it to replicate in the active phase and remain viable during latency, as well as the characteristics of its cell wall that contribute to the blockade of the immune response and its resistance to antibiotics.

Yttrium oxide (Y2O3) resistive random-access memory (RRAM) devices were fabricated using the sol–gel process on indium tin oxide/glass substrates. These devices exhibited conventional bipolar RRAM characteristics, without requiring a high voltage forming process. The effect of current compliance on the Y2O3 RRAM devices was investigated and revealed that as the set current compliance values increased, the resistance values gradually decreased. Consequently, intermediate resistance values were obtained, which are suitable for multi-level cell (MLC) switching. The fabricated Y2O3 RRAM devices were capable of functioning as an MLC with a capacity of 2 bits in one cell, utilizing three low resistance states and one common high resistance state. The potential of the Y2O3 RRAM for neural networks was further explored through numerical simulations. Hardware neural networks based on the Y2O3 RRAM demonstrated effective digit image classification with a high accuracy rate of approximately 88%, comparable to the ideal software-based classification (~92%). This suggests that the proposed RRAM has the potential to be utilized as a memory component in practical neuromorphic systems.

Pancreatic cancer (PC) is the seventh leading cause of cancer-related death. PC incidence has con-tinued to increase by about 1% each year in both men and women. Although the 5‐year relative survival rate of PC has increased from 3% to 12%, it is still the lowest among cancers. Hence, novel therapeutic strategies are urgently needed. Challenges in PC-targeted therapeutic strate-gies stem from the high PC heterogeneity and from the poorly understood interplay between cancer cells and the surrounding microenvironment. Signaling pathways that drive PC cell growth have been the subject of intense scrutiny and interest has been attracted by necroptosis, a distinct type of programmed cell death. In this review, we provide a historical background on necroptosis and a detailed analysis of the ongoing debate on the role of necroptosis in PC malignant progression.

The role of mesenchymal-to-endothelial transition in the angiogenic response is controversial. Toward this, the present study aimed to determine if fibroblasts contribute to angiogenesis. Endothelial differentiation of fibroblasts was induced by culturing MRC-5 cells (human fetal lung fibroblast cells) on top of Matrigel hydrogel or embedded inside the hydrogel. The formation of ca-pillary-like networks in response to angiogenic signals was observed. The tube formation occurs quickly and can be visualized us-ing a phase-contrast inverted microscope, and/or the cells can be treated with DAPI before the assay and tubes can be visualized through fluorescence or confocal microscopy. Furthermore, fibroblasts cultured in a higher concentration invaded the Matrigel hydrogel and formed stem-cell-like spheroids. These spheroids embedded in matrigel matrices of varying densities sprouted to form 3D connective-tissue networks. Collectively, our results highlight the endothelial differentiation capacity of human lung fibroblasts. The results obtained in this work may have an impact on the search for alternative cell sources for vascular tissue engineering and the overcome of obstacles to vascularization of autologous tissue-engineered constructs and the production of functional grafts for clinical use.

The influence of preoperative examination of oral squamous cell carcinoma (OSCC) mucosal surrounding by VELscope (Visually Enhanced Lesion Scope) on the radicality of surgical treatment of OSCC was the goal of this study.It is the first analysis of its kind with a total number of 122 patients suffering from OSCC with homogenous distribution of different tumor stages randomized into a study and a control group and enrolled in our study after meeting the inclusion criteria. The preoperative checkup by VELscope accompanied by the marking of the range of a loss of fluorescence in the study group was performed before the surgery. We have developed a unique mucosal tattoo marking technique for this purpose. The pathohistological results after surgical treatment, i.e. the margin status, were then compared. We achieved the pathological free margin (pFM) in 55 patients, the pathological close margin (pCM) in 6 cases and we encountered no case of the pathological positive margin (pPM) in the mucosal layer in the study group. In comparison, the control group results revealed pPM in 7 cases, pCM in 14 cases and pFM in 40 of all cases in the mucosal layer. This study proved that the preoperative autofluorescence evaluation of a tumor mucosal surrounding can enhance the ability to reach the pFM resection.

Spinal cord injury (SCI) is a condition that affects between 8.8 and 246 people in a million and, unlike many other neurological disorders, it affects mostly young people, causing deficits in sensory, motor, and autonomic functions. Promoting regrowth of axons is one of the most important goals for the neurological recovery of patients after SCI, but it is also one of the most challenging goals. A key event after SCI is the formation of a glial scar around the lesion core, which is mainly comprised of astrocytes, NG2+-glia, and microglia. Traditionally, the glial scar has been regarded as detrimental for recovery because it may act as a physical barrier for axon regrowth and release various inhibitory factors. However, more and more evidence now suggest that the glial scar is beneficial for the surrounding spared tissue after SCI. Here, we review experimental studies that used genetic and pharmacological approaches to ablate specific populations of glial cells in rodent models of SCI, in order to understand their functional role. The studies showed that ablation of either astrocytes, NG2+-glia or microglia may result in disorganization of glial scar, increased inflammation, extended tissue degeneration and impaired recovery after SCI. Hence, glial cells and glial scar appear as important beneficial players after SCI.

Atypical hemolytic uremic syndrome (aHUS) is a rare and life-threatening disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, necessitating differentiation from other thrombotic microangiopathy disorders. Definitive biomarkers for disease diagnosis and activity are currently lacking, and identifying molecular markers is essential. We conducted single-cell sequencing on peripheral blood mononuclear cells from 13 aHUS patients, 3 aHUS family members, and 4 healthy controls. Analysis included clustering, cell type annotation, pseudotime estimation, and cell-cell communication. Immune cell populations differ among aHUS, aHUS families, and healthy controls. Disease activity and treatment influence T, NK, B, and monocyte subpopulations, with increased intermediate monocyte levels distinguishing aHUS from controls and aHUS groups with varying disease activity. Subclustering revealed differential gene expression in patients compared to controls; higher expression of mitochondria-related genes suggests cell metabolism may influence clinical course. Pseudotime trajectory analysis demonstrated unique immune cell differentiation, and cell-cell interaction analysis identified distinct signaling pathways among patients, family members, and controls. This single-cell sequencing study is the first to confirm immune cell dysregulation in aHUS pathogenesis, offering valuable insights into molecular mechanisms and potential new diagnostic and disease activity markers.

Nanoparticles (NPs) are commonly used in healthcare and nano therapy, but their toxicity at high concentrations is well-known. Recent research has shown that NPs can also cause toxicity at low concentrations, disrupting various cellular functions and leading to altered mechanobiological behavior. While researchers have used different methods to investigate the effects of NPs on cells, including gene expression and cell adhesion assays, the use of mechanobiological tools in this context has been underutilized. This review emphasizes the importance of further exploring the mechanobiological effects of NPs, which could reveal valuable insights into the mechanisms behind NP toxicity. Such investigations could aid in developing new strategies to mitigate NP toxicity and improve their safety for biomedical applications. Moreover, understanding how NPs affect cell cytoskeletal functions through mechanobiology could have significant implications, including the development of innovative drug delivery systems and tissue engineering techniques. In summary, this review highlights the significance of incorporating mechanobiology into the study of NP toxicity and demonstrates the potential of this interdisciplinary field to advance our knowledge and practical use of NPs.

This concept paper gives a narrative about intelligence from insects to the human brain, showing where evolution may have been influenced by the structures in these simpler organisms. The ideas also come from the author's own cognitive model, where a number of algorithms have been developed over time and the precursor structures should be codable to some level. Through developing and trying to implement the design, ideas like separating the data from the function have become architecturally appropriate and there have been several opportunities to make the system more orthogonal. Similarly for the human brain, neural structures may work in-sync with the neural functions, or may be slightly separate from them. Each section discusses one of the neural assemblies with a potential functional result, that cover ideas such as timing or scheduling, structural intelligence and neural binding. Another aspect of self-representation or expression is interesting and may help the brain to realise higher-level functionality based on these lower-level processes.

Intramammary infections (mastitis) of dairy cows, along with other periparturient diseases, have become problematic within the dairy industry as they lead to loss of milk production. The main objective of this study was to determine whether elevated somatic cell counts (SCC) in cows prior to drying off are related to the incidence of other periparturient diseases. Additionally, we de-termined whether milk composition and milk yield are affected by a high SCC prior to drying off. Somatic cell counts of milk samples were determined prior to dry off (n = 140) and were used to classify cows in the study as high (>200,000 cells/mL) or low (<200,000 cells/mL) SCC. The com-position of milk was analyzed before drying off and at 1 and 2 weeks after calving. The results showed that an elevated SCC before drying off was related to the incidence of ketosis. Cows with a high SCC at drying off also showed an increased likelihood of retained placenta, metritis, and lameness postpartum; however, it was not statistically significant. Milk lactose was lower in cows with high SCC, while protein content was lower after parturition. Milk production was lower for cows with pre-drying elevated SCC, particularly for cows with retained placenta, keto-sis, and mastitis. In conclusion, cows with pre-drying elevated SCC were more likely to develop disease after parturition and produce less milk and with lower lactose and protein content.

Hypoxia, a condition of low oxygenation frequently found in triple-negative breast tumors (TNBC), promotes extracellular vesicle (EV) secretion and favors cell invasion, a complex process in which cell morphology is altered, dynamic focal adhesion spots are created, and ECM is re-modeled. Here, we investigated the invasive properties triggered by TNBC-derived hypoxic small EV (SEVh) in vitro in cells cultured under hypoxic and normoxic conditions, using pheno-typical and proteomic approaches. SEVh characterization demonstrated increased protein abundance and diversity over normoxic SEV (SEVn), with enrichment in pro-invasive pathways. In normoxic cells, SEVh promotes invasive behavior through pro-migratory morphology, in-vadopodia development, ECM degradation and matrix metalloprotease (MMP) secretion. Pro-teome profiling of normoxic cells exposed to SEVh determined enrichment in metabolic processes and cell cycle, modulating cell health to escape apoptotic pathways. In hypoxia, SEVh was re-sponsible for proteolytic and catabolic pathway inducement, interfering with integrin availabil-ity and gelatinase expression. Overall, our results demonstrate the importance of hypoxic signal-ing via SEV in tumors for the early establishment of metastasis.

Acute myeloid leukemia (AML) is a hematological cancer with poor outcomes due to a lack of efficacious targeted therapies. The Nuclear Factor of Activated T Cells (NFAT) family of transcription factors is well characterized as a regulator of the cell cycle and differentiation in the myeloid lineage. Recent evidence has demonstrated that NFAT family members may have roles in regulating AML leukemogenesis and resistance to targeted therapy in myeloid leukemias. Furthermore gene expression data from patient samples show that some NFATs are more highly expressed in poorly differentiated AML and after disease relapse, implying that the NFAT family may have roles in specific types of AML. This review outlines the evidence for the role of NFAT in healthy myeloid tissue and explores how NFAT might regulate AML pathogenesis, highlighting the potential to target specific NFAT proteins therapeutically in AML.

Track-structure Monte Carlo simulations are useful tools to evaluate initial DNA damage induced by irradiation. In the previous study, we have developed a Gean4-DNA-based application to estimate the cell surviving fraction of V79 cells after irradiation, bridging the gap between the initial DNA damage and the DNA-rejoining kinetics by means of the two-lesion kinetics (TLK) model. However, since the DNA repair performance depends on cell line, the same model parameters cannot be used for the different cell lines. Thus, we extended the Geant4-DNA application with an updated TLK model for the evaluation of DNA damage repair performance in HSGc-C5 carcinoma cells which are typically used for evaluating proton/carbon radiation treatment effects. For this evaluation, we also performed experimental measurements for cell surviving fractions and DNA-rejoining kinetics of the HSGc-C5s cells. Concerning fast- and slow-DNA rejoining, the TLK model parameters were adequately optimized with the simulated initial DNA damage. Using the optimized TLK model, the Geant4-DNA simulation is now able to predict cell survival and DNA-rejoining kinetics for HSGc-C5s cells.

Background: Circulating tumor cells (CTC) have relevance as prognostic markers in breast cancer. However, the functional properties of CTCs or their molecular characterization have not been well-studied. Experimental models indicate that only a few cells can survive in the circulation and eventually metastasize. Thus, it is essential to identify these surviving cells capable of forming such metastases. Methods: We isolated viable CTCs from 50 peripheral blood samples obtained from 35 patients with advanced metastatic breast cancer using RosetteSepTM for ex vivo culture. The CTCs were seeded and monitored on plates under low adherence conditions and with media supplemented with growth factors and Nanoemulsions. Phenotypic analysis was performed by immunofluorescence and gene expression analysis using RT-PCR and CTCs counting by Cellsearch® system. Results: We found that in 75% of samples the CTC cultures lasted more than 23 days, predicting a shorter Progression-Free Survival in these patients, independently of having ≥ 5 CTC by Cellsearch®. We also observed that CTCs before and after culture showed a different gene expression profile. Conclusions: the cultivability of CTCs is a predictive factor. Furthermore, the subset of cells capable of growing ex vivo show stem or mesenchymal features and may represent the CTC population with metastatic potential in vivo.

When swine flu vaccines and circulating influenza A virus (IAV) strains are poorly matched, vaccine-induced antibodies may not protect from infection. Highly conserved T cell epitopes may, however, have a disease-mitigating effect. The degree of T cell epitope conservation among circulating strains and vaccine strains can vary, which may also explain differences in vaccine efficacy. Here, we evaluate a previously developed conserved T cell epitope-based vaccine and determine the persistence of T cell epitope conservation over time. We used a pair-wise homology score to define conservation between the vaccine’s swine leukocyte antigen (SLA) class I and II-restricted epitopes and T cell epitopes found in 1,272 swine IAV strains sequenced between 2013 and 2017. Twenty-four of the 48 total T cell epitopes included in the epitope-based vaccine were highly conserved and found in >1,000 circulating swine IAV strains over the five-year period. In contrast, commercial swine IAV vaccines developed in 2013 exhibited declining conservation with the circulating IAV strains over the same five-year period. Conserved T cell epitope vaccines may be useful adjunct for commercial swine flu vaccines and to improve protection against influenza when antibodies are not cross-reactive.

The aim of this work was to evaluate the influence of various food and beverages on the viability of probiotic bacteria during passing through artificial digestion. As a model food, solutions with various concentrations of alcohol, sugar, salt, protein and acid were prepared. Different types of real foods and beverages were used as well. Viability in presence of food matrices was tested on monocultures of Lactobacillus acidophilus CCM4833 and Bifidobacterium breve CCM7825T and on mixed commercial culture with 9 different strains of probiotic microorganisms( Lactobacillus, Bifidobacterium, Streptococcus). The concentration and viability of probiotic bacteria was tested by cultivation assay and flow cytometry. In model foods, the best growth of was determined in the presence of 10% albumin and 10% ethanol. Survival of the probiotics delivered in different food matrices through a simulated gastrointestinal tract was quantitatively different. As the best food environment for probiotics complex food matrices such as pasta with cream sauce, chocolate spread and homemade beef broth were selected, followed by mixed vegetables, potato salad, salted chips, fruits and yoghurt. Among beverages the best option was milk, followed by black tea, coffee and Coca Cola. Probiotic microorganisms are more viable when consumed with meals than with beverages only. In general, the highest viability of probiotic cells has been observed in presence of foods containing high concentration of sugar and fat or their suitable combination. The increase of cell viability observed in such foods during model digestion may further contribute to the positive effect of probiotics on human health.

Single cell proteins are the dead dried cells of microorganisms or purified protein isolated from microorganism’s cell culture, used as a food supplement to humans’ food and animals feed. World suffer from malnutrition particularly developing countries, due to rapid increase in population, increased the demand for protein and nutrients requirement. Bacteria is potential microorganism for SCP production due to high protein content, fast generation time, bio-active secondary metabolites production and can grow on various substrates. Actinobacteria species and strain have capability to produce biological active compounds, produced about two-thirds of antibiotics available in the market, actively used as antibiotics, antiprotozoal, antifungal, antiviral, anticancer, anticholesterol, antihelminth and immunosuppressant. Actinomycetes can be used as probiotic as well as single cell protein that will deal with antibiotic as well as protein source.

Cancer is a leading cause of death worldwide. It is theorized that underlying genetic and epigenetic changes enable cells to proliferate out of control by escaping regulatory mechanisms. The progression of cancer is associated with increased cell proliferation, metabolic modifications, resistance to apoptosis, genetic instability, induction of angiogenesis and augmented migratory capability. Recent developments in DNA and RNA analysis have made it possible to study these genetic changes systematically. These advances have enabled us to possess a deeper knowledge of the signaling pathways and involved processes. In-depth studies of the pathways involved in carcinogenesis have led to the identification of pathways that may be targeted for therapeutic purposes. In this review, we provide an overview of the relevant mechanisms and pathways involved in the development and progression of cancer.

Cancer is a leading cause of death worldwide. It is theorized that underlying genetic and epigenetic changes enable cells to proliferate out of control by escaping regulatory mechanisms. The progression of cancer is associated with increased cell proliferation, metabolic modifications, resistance to apoptosis, genetic instability, induction of angiogenesis and augmented migratory capability. Recent developments in DNA and RNA analysis have made it possible to study these genetic changes systematically. These advances have enabled us to possess a deeper knowledge of the signaling pathways and involved processes. In-depth studies of the pathways involved in carcinogenesis have led to the identification of pathways that may be targeted for therapeutic purposes. In this review, we provide an overview of the relevant mechanisms and pathways involved in the development and progression of cancer.

Durability and performance of electrochemical energy converters such as fuel cells and electrolysers are not only dependent on the properties and the quality of the used materials. They strongly depend on operation conditions. Variations in external parameters, such as flow, pressure, temperature and, obviously, load can lead to significant local changes of current density, even local transients. The segmented cell technology was developed with the purpose to gain insight into local operation conditions in electrochemical cells, during operation. The operando measurement of the local current density and temperature distribution allows effective improvement of operation conditions, mitigation of potentially critical events and assessment of the performance of new materials. The segmented cell, which can replace a regular bipolar plate in the current state of the technology, can be used as monitoring tool and for targeted developments. This article gives an overview over the development and applications for proton exchange membrane fuel cell of this technology, such as water management or fault recognition. Recent advancements towards locally resolved monitoring of humidity and to current distributions in electrolysers are outlined.

Due to low working temperature, high energy density and low pollution, proton exchange fuel cells have been investigated under different operating conditions in different applications. Using platinum catalysts in methanol fuel cells leads to increasing the cost of this kind of fuel cell which is considered as a barrier to the commercialism of this technology. For this reason, a lot of efforts have been made to reduce the loading of the catalyst required on different supports. In this study, carbon black (CB) and carbon nanotubes (CNT) have been used as catalyst supports of the fuel cell as well as using the double-metal combination of platinum-ruthenium (PtRu) as anode electrode catalyst and platinum (Pt) as cathode electrode catalyst. The performance of these two types of electro-catalyst in the oxidation reaction of methanol has been compared based on electrochemical tests. Results showed that the carbon nanotubes increase the performance of the micro-fuel cell by 37% at maximum power density, compared to the carbon black. Based on thee-electrode tests of chronoamperometry and voltammetry, it was found that the oxidation onset potential of methanol for CNT has been around 20% less than CB, leading to the kinetic improvement of the oxidation reaction. The current density of methanol oxidation reaction increased up to 62% in CNT sample compared to CB supported one, therefore the active electrochemical surface area of the catalyst has been increased up to 90% by using CNT compared to CB which shows the significant rise of the electrocatalytic activity in CNT supported catalyst. Moreover, the resistance of the CNT supported sample to poisonous intermediate species has been found 3% more than CB supported one. According to the chronoamperometry test results, it was concluded that the performance and sustainability of the CNT electro-catalyst show remarkable improvement compared to CB electro-catalyst in the long term.

The cell’s capacity to integrate and respond to spatial information is a crucial feature of morphogenesis and development. The Planar Cell Polarity (PCP) pathway is a signaling mechanism, widely conserved across metazoans, providing spatial orientation along the plane of an epithelium in morphogenic processes ranging from insect wing patterning to mammalian cochleae. Although the core genes involved in the PCP pathway have been molecularly identified in the 1990s, the PCP signaling mechanism remains controversial. In this article I discuss the main players and previous models of PCP signaling reported in the literature, and propose a new model. According to it PCP is established through an homophobic signal by transmembrane protein Frizzled (Fz): 1) a Fz signal in one cell repeals Fz itself in the adjacent cell, thereby generating symmetry breaking; 2) the instructive PCP signal is conveyed through Fz interaction with atypical cadherin Flamingo (Fmi). More broadly, homophobic signaling may represent a novel mechanism for cell-cell signaling of spatial information through modulation of cell adhesion rather than canonical ligand-receptor binding.

Background: Sickle cell disease (SCD) is a public health problem in the Democratic Republic of Congo. While reference sickle cell centers have been implemented in capital cities of African countries and have proven to be beneficial for SCD patients, they have never been set up in rural areas for families with very low sources of income. Method: A cohort of 143 children with SCD aged 10 years old (IQR (interquartile range): 6–15 years) (sex ratio male/female = 1.3) were clinically followed for 12 months without any specific intervention aside from the management of acute events, and then for 12 months with a monthly medical visit, biological follow-up, and regular prophylaxis. Results: The median age of patients at the diagnosis of SCD was 2 years (IQR: 1–5). The implementation of standardized and regular follow-ups in a new sickle cell referral center in a remote city showed an increase in the annual mean hemoglobin level from 50 to 70 g/L (p = 0.001), and a decrease in the lymphocyte count and spleen size (p < 0.001). A significant decrease (p < 0.001) in the average annual number of hospitalizations and episodes of vaso-occlusive crises, blood transfusions, infections, and acute chest syndromes were also observed. Conclusions: Creation of a sickle cell referral center and the regular follow-up of children with SCD are possible and applicable in the context of a remote city of an African country and represent simple and accessible measures that can reduce the morbimortality of children with sickle cell disease.

Diffuse large B-cell lymphoma (DLBCL) requires a complete staging at diagnosis that may have prognostic and therapeutic implications. The role of bone marrow (BM) biopsy (BMB) is contro-versial in the era of nuclear-imaging techniques. We performed a comparative review of 25 studies focused on BM evaluation at DLBCL diagnosis, including at least two of the following techniques: BMB, flow cytometry, and positron emission tomography (PET-FDG). The report about BM involvement (BMi), diagnostic accuracy and prognostic significance was collected and compared among techniques. A concordance analysis between BMB, FCM and PET was also per-formed, and we deeply evaluated the implications of the different types of BMi: concordant by LBCL or discordant by low-grade B-cell lymphoma for both BMB and FCM, and focal or diffuse uptake pattern for PET. As main conclusion, BMB, FCM and PET are complementary tools which provide different and clinically relevant information in the assessment of BMi in newly DLBCL.

Background: After allogeneic hematopoietic stem cell transplantation (allo-HSCT), acute leukemia relapse is common, and asymmetric bone marrow recurrence hasn’t been reported. Because the anatomical distribution of acute leukemia clones in the bone marrow after allo-HSCT is presumed to be diffuse, bone marrow aspirations are performed in single site. Case presentation: We identified two acute leukemia patients, whose leukemic burden in bilateral bone marrow specimens differed significantly. The first case was a 20-year-old man who was diagnosed with acute myelomonocytic leukemia and received haploidentical allo-HSCT. He had been in complete remission for two years and off immunosuppressive medications for a year, with normal peripheral blood count. Routine bone marrow biopsy of his left posterior iliac bone marrow showed 52% leukemia blasts, while the right side had 0% blasts ten days later. Due to the discordant results, the patient refused further intervention and died of high leukocyte syndrome four months later. The second case was a 23-year-old woman who was diagnosed with acute B lymphoblastic leukemia and received HLA-identical sibling allo-HSCT. Although 62% of blasts were found in her left iliac marrow on day +122, 0 % of blasts were found on a sample obtained from the right iliac crest on day +128. Whole-body 18F-FDG PET/CT scans confirmed that the leukemic infiltration in her bone marrow was asymmetric. Considering the higher leukemic burden on the left, we chose the left posterior iliac crest aspiration for further response evaluation. After chemotherapy combined with donor lymphocyte infusion, she achieved transient hematologic complete remission. She died of septic shock with heart failure at +258 days after allo-HSCT before infusion of anti-CD19 donor chimeric antigen receptor T cells. Conclusions: To our knowledge, these are the first case reports of asymmetric bone marrow infiltration of blasts in acute leukemia patients after allo-HSCT. Bilateral posterior iliac crest aspirations or 18F-FDG-PET/CT scans may help distinguish such distribution. If discordant bone marrow specimens are observed, physicians should restrict future bone marrow studies to the more involved side.

The enhancement of human living conditions has resulted in an increase in average life expectancy, giving rise to a novel social and medical challenge: aging, which diminishes the overall quality of human life. The aging process of the body begins through the activation of effector signaling pathways of aging in cells, loss of their normal functions and deleterious effects on the microenvironment, which leads to chronic inflammation and similar transformation of neighboring cells. The cumulative retention of these senescent cells over a prolonged period results in the deterioration of tissues and organs, ultimately leading to a reduced quality of life and an elevated mortality risk. Among the most encouraging methods for addressing aging and age-related illnesses are pharmacological, genetic, and cellular therapies. Elevating the activity of aging-suppressing genes, employing specific groups of native and genetically modified cells, and utilizing senolytic medications may offer the potential to delay aging and age-related ailments over the long term. The review explores the strategies and advancements in the field of anti-aging therapies that are currently under investigation, with a particular emphasis on gene therapy involving adeno-associated vectors and cell-based therapeutic approaches.

Methanotrophic bacteria that possess a unique ability of using methane as a sole source of carbon and energy have attracted considerable attention as potential producers of a single-cell protein. So far, this biotechnology implied using freshwater methanotrophs, although many regions of the world have limited freshwater resources. This study aimed at searching for novel methanotrophs capable of fast growth in saltwater comparable in composition with seawater. A methane-oxidizing microbial consortium containing Methylomarinum- and Methylotuvimicrobium-like methanotrophs has been enriched from a sediment of the river Chernavka (water pH 7.5, total salt content 30 g L-1), a tributary river of the hypersaline Lake Elton, southern Russia. This microbial consortium, designated Ch1, demonstrated stable growth on natural gas in a bioreactor in media with a total salt content of 23 to 35.9 g L-1 at a dilution rate of 0.19-0.21 h-1. The highest biomass yield of 5.8 g CDW/L with a protein content of 63% was obtained during continuous cultivation of the consortium Ch1 in a medium with a total salt content of 29 g L-1. Isolation attempts resulted in obtaining a pure culture of methanotrophic bacteria, strain Ch1-1. The 16S rRNA gene sequence of strain Ch1-1 displayed 97.09-97.24% similarity to the corresponding gene fragments of characterized representatives of Methylomarinum vadi, methanotrophs isolated from marine habitats. The genome of strain Ch1-1 was 4.8 Mb in size and encoded 3 rRNA operons, and about 4400 proteins. The genome contained the gene cluster coding for ectoine biosynthesis, which explains the ability of strain Ch1-1 to tolerate high salt concentration.

Apoptosis, the programmed and intentional death of senescent, damaged, or otherwise superfluous cells, is the natural end-point for most cells within multicellular organisms. Apoptotic cells are not inherently damaging, but if left unattended they can lyse through secondary necrosis. The resulting release of intracellular contents drives inflammation in the surrounding tissue and can lead to autoimmunity. These negative consequences of secondary necrosis are avoided by efferocytosis—the phagocytic clearance of apoptotic cells. Efferocytosis is a product of both apoptotic cell and efferocyte mechanisms, which cooperate to ensure the rapid and complete removal of apoptotic cells. Herein, the processes used by apoptotic cells to ensure their timely removal, and the receptors, signaling, and cellular processes used by efferocytes to identify, remove, and process the apoptotic cells, are reviewed.

Different therapeutic strategies have been investigated to target and eliminate HIV-1-infected cells by using armed antibodies specific to viral proteins, with varying degrees of success. Herein, we propose a new strategy by combining photodynamic therapy (PDT) with HIV Env-targeted immunotherapy, and refer to it as HIV photoimmunotherapy (PIT). A human anti-gp41 antibody (7B2) was conjugated to two photosensitizers with different charges through different linking strategies; “Click” conjugation by using an azide-bearing porphyrin attached via a disulfide bridge linker with a drug-to-antibody ratio (DAR) of exactly 4, and “Lysine” conjugation by using phthalocyanine IRDye 700DX dye with average DARs of 2.1, 3.0 and 4.4. These photo-immunoconjugates (PICs) were compared via biochemical and immunological characterizations regarding the dosimetry, solubility, and cell targeting. Photo-induced cytotoxicity of the PICs were compared using assays for apoptosis, reactive oxygen species (ROS), photo-cytotoxicity, and confocal microscopy. Targeted phototoxicity seems to be primarily dependent on the binding of PS-antibody to the HIV antigen on the cell membrane, whilst being independent of the PS type. This is the first report of the application of PIT for HIV immunotherapy by killing HIV Env-expressing cells.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of renal cancer and its treatment is hindered by resistance to targeted and immunotherapies and combinations ob both. We have reported that knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) with chemically-modified antisense oligonucleotides induces proliferative arrest and apoptotic death in tumor cells from many human and mouse cancer types. These studies have been mostly performed in vitro and in vivo on commercially-available cancer cell lines and have shown that, in mouse models, tumor growth is stunted by the treatment. The present work was performed on cells derived from primary and metastatic ccRCC tumors. We established primary cultures fom primary and metastatic ccRCC tumors, which were subjected to knockdown of ASncmtRNAs in vitro and in vivo in an orthotopic xenograft model in NOD/SCID mice. We found that these primary ccRCC cells are affected in the same way as tumor cell lines and, in the orthotopic model, tumor growth was significantly reduced by the treatment. This study on patient-derived ccRCC tumor cells represents a model closer to actual patient ccRCC tumors and shows that knockdown of ASncmtRNAs poses a potential treatment option for these patients.

Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) have recently been grouped as lung neuroendocrine carcinomas (NECs). Because these lung NECs are clinically malignant and their treatment strategies differ from those of non-SCLC, the quality of diagnosis has a significant prognostic impact. The diagnosis of LCNEC requires positive immunohistochemical staining with chromogranin A, synaptophysin, and CD56, along with morphological diagnosis, and insulinoma-associated protein 1 (INSM1) has been proposed as an additional marker but sometimes experience difficulty in making the diagnosis. We investigated Musashi-1 as a novel immunohistochemical marker in 42 patients with SCLCs and 44 with LCNECs who underwent lung resection between 1998 and 2020 at our institution. We found Musashi-1 expression in 41 (98%) of 42 SCLCs and 40 (90%) of 44 LCNECs. These findings were similar to CD56 expression and superior to synaptophysin, chromogranin A, and INSM1. Musashi-1 also tended to show more diffuse and intense staining, especially in LCNEC, with more cases staining &gt;10% than any other existing markers (Musashi-1, 77%; INSM1, 45%; chromogranin A, 34%; synaptophysin, 41%; and CD56, 66%). In conclusion, we identified Musashi-1 as a novel immunohistochemical staining marker to aid in the diagnosis of lung NEC.

One of the most common subgroups of cutaneous T-cell lymphomas is the that of primary cutaneous CD30 positive lymphoproliferative disorders. The group includes lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (pcALCL), as well as some borderline cases. Recently, significant progress has been made in understanding the genetics and treatment of these disorders. This review article summarizes the clinical evidence supporting the current treatment options in these diseases. Recent years have seen the introduction of novel agents into clinical practice; most of these target CD30, such as anti-CD30 monoclonal antibodies and conjugated antibodies (brentuximab vedotin), bispecific antibodies and cellular therapies, particularly anti-CD30 CAR-T cells. This paper briefly reviews the biology of CD30 that makes it a good therapeutic target, and describes the anti-CD30 therapies that have emerged to date.

The peril of a 3-dimensional, robust and sustained myocardial restoration by means of Tissue Engineering is that it still remains a largely experimental approach. Prolific protocols have been developed and tested in small and large animals, but as clinical cardiac surgeons, we have not come to the privilege of utilizing any of them in our clinical practice. The question arises: why? The heart is a unique organ, anatomically and functionally. It is not an easy target to replicate with current techniques, or even to support its viability and function. Currently available therapies fail to reverse the loss of functional cardiac tissue, the fundamental pathology remains unaddressed and a heart transplantation is an ultima ratio treatment option. Owing to equivocal results of cell-based therapies, several strategies have been pursued to overcome limitations of the current treatment options. Preclinical data as well as first-in-human studies conducted to date have provided important insights into the understanding of injection-based approaches for myocardial restoration. In the light of the available data, injectable biomaterials suitable for transcatheteter delivery appear to have the highest translational potential,. This article presents a current state-of-the-art in the field of hydrogel-based myocardial restoration therapy.

Breast cancer treatment mostly revolved around radiation therapy and surgical interventions, these treatments doesn’t provide satisfactory relief to the patients and carry unmanageable side-effects. Nanomaterials show promising results in treating cancer cells and have many advantages such as high biocompatibility, bioavailability and effective therapeutic capabilities. Interestingly, fluorescent magnetic nanoparticles have been used in many biological and diagnostic applications, but there is no report of use of fluorescent magnetic submicronic polymer nanoparticles (FMSP-nanoparticles) in the treatment of human breast cancer cells. In the present study, we have tested the effect FMSP-nanoparticles on human breast cancer cells (MCF-7). We have tested different concentrations (1.25µg/1mL, 12.5µg/mL and 50µg/1mL) of FMSP-nanoparticles in MCF-7 cells and evaluated the nanoparticles response morphometrically. Our results revealed that FMSP-nanoparticles produced a concentration dependent effect on the cancer cells, dose of 1.25µg/mL produced no significant effect on the cancer cell morphology and cell death, whereas dosages of 12.5µg/mL and 50µg/mL respectively showed significant nuclear augmentation, disintegration, chromatic condensation followed by dose dependent cell death. Our results demonstrate FMSP-nanoparticles have ability to induce cell death in MCF-7 cells and may be considered as a potential anti-cancer agent for breast cancer treatments.

The genus Euonymus (L.) consists of shrubs or woody plants, distributed mainly in the Northern Hemisphere. To date, from Euonymus spp. several hundreds of different secondary metabolites have been isolated and identified. In addition, fatty oil was found in the fruits of some species of these plants, which accumulates not only in the seeds, but also in the arils. This study presents the research of unique long-term (ten-year-old) suspension cell cultures of Euonymus maximoviczianus Prokh. which were obtained from arils of unripe capsules. Suspension cells retain the ability to form oil droplets containing neutral lipids, both in the dark and in the light, the cells are able to synthesize very-long-chain fatty acids (VLCFAs), and can synthesize delphinidin-3-O-hexoside, cyanidin-3-O-hexoside, and peonidin-3-O-hexoside. Here, we research of the fatty acid, VLCFA, and anthocyanin biosynthesis dynamics in the subcultivation, as well as the influence of methyl jasmonate (MeJa) on these processes in the dark- and under-light-grown cell cultures. In the darkness, the formation of VLCFAs is more intense, and the biosynthesis of anthocyanins is significantly activated in the light. MeJA substantially enhances the biosynthesis of anthocyanins in the light and, surprisingly, the formation of VLCFAs in the darknss. In connection with the commonality of the cytosolic pool of malonyl-CoA, which is necessary both for the biosynthesis of VLCFAs and dihydroflavonols (and, ultimately, anthocyanins), the competition of these biosynthetic pathways is discussed.

In recent times, a great interest has been motivated in plant-derived compounds known as phytochemicals. The pentacyclic oleanane-, ursane-, lupane-type triterpenes are phytochemicals that exert significant activities against diseases like cancer. Lung cancer is the leading cause of cancer-related death worldwide. Although chemotherapy is the treatment of choice for lung cancer, its effectiveness is hampered by the dose‐limiting toxic effects and chemoresistance. Herein, we investigated the structure-activity relationship of six pentacyclic triterpenes: oleanolic acid (OleA), ursolic acid (UrA), asiatic acid (AsA), betulinic acid (BeA), betulin (Betu), lupeol (Lupe), on NSCLC A549 cells. From our studies, we confirmed that all these triterpenes showed cytotoxicity in the mid µM range, where BeA showed the strongest effect. Then, we determined that most of these triterpenes induced S-phase and G2/M phase cycle arrest, reactive oxygen species, mitochondrial depolarization, and caspase 3 activation. For chemoresistance markers, we elucidated that most triterpenes downregulated STAT3 and PDL1 genes. In contrast, ursane-type UrA and AsA also induced DNA damage, reactive nitrogen species and autophagy. These results showed that even slight structural changes in these triterpenes can influence the cellular response and mechanistic pathways. This study opens promising perspectives for further research on the pharmaceutical role of phytochemical triterpenoids.

Head and neck squamous cell carcinoma (HNSCC) takes the sixth place among the most common cancers in the world. Abnormal methylation can be one of the reasons for this cancer. The aim of this study was to investigate the DNA promotor methylation status of cancer-associated genes (ATM, APC, CDO1, RB1, TP53, WIF1) in patients with HNSCC. Bisulfite Conversion and Methylation-Sensitive High-Resolution Melting was used for analysis of the DNA methylation level of normal and tumor tissues in 44 patients. There were significant differences in DNA methylation level between patient’s tumor and normal tissues for CDO1 and WIF1 genes in all subjects and subgroups (p<0.05). In T3 subgroup there was significant correlation between CDO1 gene methylation and age in the normal tissue. The same correlation was detected also for the WIF1 gene methylation in tumor tissue samples in the subgroup with T3 and in normal tissue samples in the subgroup with T4 (p<0,05). In all genes no significant differences were found between the subgroups (T2, T3, T4 stage, primary/recurrent lesion, non-keratinizing/keratinizing SCC, age before/ after 50, smokers/non-smokers) of the patients. Thus, changes in the expression of the CDO1 and WIF1 genes can affect mechanisms of the occurrence and development of HNSCC.

In this study, a new approach to pesticide permeation through the apple peel into the pulp is discussed. The tested compounds can be classified, based on mode of action, as systemic (boscalid, cyprodinil, pirimicarb, propiconazole and tebuconazole) or contact (captan, cypermethrin and fludioxonil) pesticides. The barrier effect was assessed using a Franz flow-type vertical diffusion cell system. Residue analysis was performed using a modified quick, easy, cheap, efficient, rugged and safe (QuEChERS) extraction method coupled to gas chromatography with tandem mass spectrometry (GC-MS/MS). The limits of detection (LODs) ranged between 2.6 µg kg-1 (pirimicarb) and 17 µg kg-1 (captan), with the coefficient of variability (CV) lower than 6%, while recoveries ranged from 85% (boscalid) to 112% (captan) at 0.1 and 1 mg kg-1 spiked levels. The highest peel penetration was observed for pirimicarb, captan and cyprodinil, with cumulative permeation of 90, 19 and 17 µg cm-2, respectively. The total absorption was in the range from 0.32% (tebuconazole) to 32% (pirimicarb). Only cypermethrin was not quantitatively detected in the pulp and its use can be recommended in crop protection techniques. The obtained results indicate that molecular weight, octanol-water partition coefficient and water solubility are important parameters determining the process of pesticide absorption.

Abstract: (1) Background: Cancer immune escape is associated with the metabolic reprogramming of TME, and combining metabolic targets with immunotherapy has great potential to improve clinical outcomes. Among all metabolic processes, lipid metabolism, especially fatty acid (FA) metabolism, has a huge role in cancer cell survival, migration, and proliferation, but its mechanism and role in the tumor immune microenvironment remain to be investigated. (2) Methods: We comprehensively analyzed 309 fatty acid-related genes, screened 121 different genes, and used one-way COX regression to select 15 genes with prognostic impact. Systematically evaluated the correlation between FMGs modification patterns and Tumor Microenvironment Infiltration, prognosis, and Immunotherapy. The FMGs-Score was constructed to quantify the FMGs modification patterns using principal component analysis. (3) Results: Three clusters based on FMGs-related genes were demonstrated in breast cancer, with three patterns of distinct immune cell infiltration and biological behavior. An FMGsScore signature was constructed to reveal that patients with a low FMGsScore had higher immune checkpoint expression, higher immune checkpoint inhibitor (ICI) scores, increased immune microenvironment infiltration, better survival advantage, and were more sensitive to immunotherapy than those with a high FMGsScore. Finally, the expression and function of the signature key gene NDUFAB1 were examined by in vitro experiments. (4) Conclusions: This study significantly demonstrates the non-negligible role of FMGs in the immune microenvironment of breast cancer, and that FMGsScores can be used to guide the prediction of immunotherapy in breast cancer patients. In in vitro experiments, knockdown of the NDUFAB1 gene resulted in reduced proliferation and migration of MCF-7 cell lines.

Background: Three drug-combinations, ipilimumab-nivolumab (Ipi-Nivo), pembrolizumab-axitinib (Pembro-Axi) and avelumab-axitinib (Ave-Axi), have received regulatory approvals in USA and Europe for the treatment of metastatic renal cell carcinoma with clear cell component (mRCC). However, no head-to-head comparison data are available to identify the best option. Therefore, we aimed to compare these new treatments in the first-line setting. Methods: We conducted a systematic search in Pubmed, the Cochrane library and clinicaltri-al.gov website from January 2015 to October 2019, for any randomized controlled trials of treatment-naïve patients with mRCC. The process was performed according to PRISMA guide-lines. We performed a Bayesian network meta-analysis with two different approaches. The out-comes for analysis were overall survival, progression-free survival, and objective response rate. Results: Our search identified 3 published phase 3 randomized clinical trials (2835 patients). In the contrast-based model, Ave-Axi (SUCRA: 83%) and Pembro-Axi (SUCRA: 80%) exhibited the best ranking probabilities for PFS. For OS, Pembro-Axi (SUCRA: 96%) was the most pref-erable option against Ave-Axi and Ipi-Nivo. Objective response rate analysis showed Ave-Axi as the best (SUCRA= 94%) and Pembro-Axi as second best option. In the parametric models, risk of progression was comparable for Ave-Axi and Ipi-Nivo, whereas Pembro-Axi exhibited a lower risk during the first 6 months of treatment and a higher risk afterward. Furthermore, Pembro-Axi exhibited a net advantage in terms of OS over the two other regimens, while Ave-Axi was the least preferable option. Conclusions: Overall evidences suggested pembrolizumab plus axitinib may be the best option.

A pattern of NK cell heterogeneity in each individual determines proliferative and functional responses of NK cells to activating stimuli. Obtaining the progeny of a single cell by cloning original population is one of the ways to study the NK cell heterogeneity. In this work, we used single cell sorting into a plate and stimulation by IL-2 and gene-modified K562 feeder cells expressing membrane-bound IL-21 (K562-mbIL21) that led to generation of phenotypically confirmed and functionally active NK cell clones. We applied two models of clone cultivation, which differently affected their phenotype, lifespan and functional activity. The first model, which included weekly restimulation of clones with K562-mbIL21 and IL-2, resulted in the generation of relatively short-lived (5-7 weeks) clones of highly activated NK cells. HLA-DR expression in the expanded NK cells correlated strongly with IFN-γ production. The second model, in which NK cells were restimulated mainly with IL-2 alone, produced long-lived clones (8-14 weeks) that expanded up to 10⁷ cells with lower ability to produce IFN-γ. Our method is applicable for studying variability in phenotype, proliferative and functional activity of the certain NK cell progeny in response to the stimulation, which may help in selecting NK cells best suited for clinical use.

Nowadays molecular and immunological research is essential for the better understanding of tumor cells pathophysiology. The increasing number of neoplasms is taken under ‘the molecular magnifying glass’ therefore it is possible to discover complex relationships between cytophysiology and immune system action. An example could be renal cell carcinoma (RCC) which has deep interactions with immune mediators such as Interleukin 17 (IL-17) - an inflammatory cytokine reacting to tissue damage and external pathogens. RCC is one of the most fatal urological cancer because of its often late diagnosis and poor susceptibility to therapies. IL-17 and its relation with tumors is extremely complex and constitute a recent topic for numerous research. What is worth highlighting is IL-17 dual character in cancer development - it could be pro- as well as antitumorigenic. The aim of this review is to summarize the newest data considering multiple connections between IL-17 and RCC.

Organic solar cells are contributing extensively to the production of future large area and cost-effective sources of renewable energy with a compact environmental impact. Moreover, due to tunable optical properties of the active medium, the semi-transparent organic solar cell can be fabricated and become a promising nominee for building Integrated Photovoltaics (BIPV), vehicles, and mobile electronic devices. Therefore, three newly synthesized polymers used as were host materials for the active medium and blended with beetroot dye. Hence, based on BHJ structure two ternary systems have been constructed and utilized to fabricate semitransparent solar cells and characterized. The results show that the natural dye has a crucial impact on solar cell characteristic parameters. Consequently, large value of V_OC close to 1V were obtained for ternary systems and acceptor material named PINDOLE exhibits potentials for electron transport layer (ETL) and shows an improvement in both fill factor and device efficiency.

The task of conveying scientific research to individuals with varying levels of knowledge and understanding can prove to be quite challenging for a research scientist. The difficulty is further compounded when the exchange of information must be conducted within a limited timeframe. Notwithstanding, the 'elevator pitch' is a valuable tool that enables researchers to navigate these potential obstacles. An effective elevator pitch not only facilitates the communication of a researcher's scientific findings but also highlights the individual's skills and the significance of their research. Moreover, a well-crafted elevator pitch is a critical career development tool, serving as a means of networking and paving the way for future communications, scientific collaborations, and funding opportunities. This article examines the value of a scientific elevator pitch and provides step-by-step guidelines for developing and constructing an impactful pitch. Furthermore, we provide resources and an example of a successful elevator pitch delivered by a Fellow from the NIH-funded Accelerating Career Transitions (ACT) program, a professional development program established and managed by the American Society for Cell Biology (ASCB).

Background Cancer is one of the most concerning public health issues in the world. One of cancer hallmarks wildly accepted is sustaining proliferative signaling, which involved most of the cell cycle biological activities. Centromeric histone, Centromere Protein A (CENPA), a variant of canonical histone H3, plays an essential role in selective chromosome segregation in the cell cycle. However, so far, a systematic pan-cancer bioinformatic analysis has not been done yet. Methods We accessed genome, transcriptome, and clinical information from open databases. The genetic alteration, mRNA expression, functional enrichment, stemness, mutation association, expression in cell populations and cellular locations, cell cycle association, survival association of CENPA, and immune association were analyzed. A prognostic model for glioma patients was constructed as an example application of CENPA as a biomarker. Drugs targeting CENPA in cancer cells were also screened and predicted by the CENPA correlation of drug sensitivity and protein-ligand docking. Results CENPA had low gene mutation in cancers. CENPA was overexpressed in almost all cancer types in TCGA compared to their normal control. CENPA was highly expressed in the nucleus of malignant cells. CENPA was associated with the cell cycle of cancer cells. CENPA is a biomarker for the cell cycle G2 phase in cancer cells. CENPA was a diagnostic and prognostic biomarker across multiple cancer types. The prognosis of glioma with CENPA was reliable and can be applied with other prognostic factors. CENPA was associated with the immune microenvironment. Drugs CD-437, 3-Cl-AHPC, Trametinib, BI-2536, and GSK461364 were predicted to target CENPA in cancer cells. Conclusion CENPA was a cell cycle biomarker in cancers with diagnostic and prognostic value.

Quantum cell automata (QCA) is a nanotechnology that uses a transistor-free structure to design digital circuits and overcome the limitations listed for CMOS circuits. The computing circuits that make up the bulk of computers can be designed and using this technology. Subtractors are a big part of computational circuits. This research deals with the design of a subtractor that due to the innovation in the design of this circuit and the novel arrangement of quantum cells of its kind has caused the number of cells used in the design of the circuit to reach its lowest value compared to previously designed circuits. The size of the circuit as well as the loss power are minimized compared to the circuits designed by the subtractors. Another trait clears of this circuit compared to many previous designs is its single-layer design, which reduces latency and noise in the output waveform. The circuit designed by the QCADesigner simulator is tested and simulated inadition the results are displayed in the simulated waveform. Also, the results of calculations for power dissipation in each QCA cell were evaluated by QCAPro software, which is a powerful tool for estimating power loss simulation. It has less implementation and level (single layer) than Previous designs.

To investigate the effect of acidic nanoparticles on proton conductivity, permeability and fuel cell performance, a commercial Nafion® 117 membrane was impregnated with zirconium phosphates (ZrP) and sulfated zirconium (S-ZrO2) nanoparticles. The tensile test, water uptake, methanol crossover, Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Thermal gravimetric analysis (TGA) and Scanning Electron Microscopy (SEM) were used to assess the ca-pacity of nanocomposite membrane to function in a fuel cell. The modified Nafion® membrane obtained the higher water uptake and a lower water content angle than the commercial Nafion® 117 membrane, indicating that it has a greater impact on conductivity. Under strain rates of 40, 30 and 20 mm/min, the nanocomposite membranes demonstrate more stable thermal deterioration and higher mechanical strength, which offers tremendous promise for fuel cell applications. When compared to 0.113 S/cm and 0.013 S/cm, respectively, of commercial Nafion® 117 and Nafion® ZrP membranes, the modified Nafion® membrane with ammonia sulphate acid had the highest proton conductivity of 7.891 S/cm. When tested using a direct single cell methanol fuel cell, it had the highest power density of 183 m. cm-2 which is better than commercial Nafion® 117 and Nafion® ZrP membranes.