(1) Background: The dysfunction and reduced proliferation of peripheral CD8
T cells and natural killer (NK) cells have been observed in both aging and cancer patients, thereby challenging the ...adoption of immune cell therapy in these subjects. In this study, we evaluated the growth of these lymphocytes in elderly cancer patients and the correlation of peripheral blood (PB) indices to their expansion. (2) Method: This retrospective study included 15 lung cancer patients who underwent autologous NK cell and CD8
T cell therapy between January 2016 and December 2019 and 10 healthy individuals. (3) Results: On average, CD8
T lymphocytes and NK cells were able to be expanded about 500 times from the PB of elderly lung cancer subjects. Particularly, 95% of the expanded NK cells highly expressed the CD56 marker. The expansion of CD8
T cells was inversely associated with the CD4
:CD8
ratio and the frequency of PB-CD4
T cells in PB. Likewise, the expansion of NK cells was inversely correlated with the frequency of PB-lymphocytes and the number of PB-CD8
T cells. The growth of CD8
T cells and NK cells was also inversely correlated with the percentage and number of PB-NK cells. (4) Conclusion: PB indices are intrinsically tied to immune cell health and could be leveraged to determine CD8 T and NK cell proliferation capacity for immune therapies in lung cancer patients.
The network of NF‐κB‐dependent transcription that activates both pro‐ and anti‐inflammatory genes in mammals is still unclear. As NF‐κB factors are evolutionarily conserved, we used Drosophila to ...understand this network. The NF‐κB transcription factor Relish activates effector gene expression following Gram‐negative bacterial immune challenge. Here, we show, using a genome‐wide approach, that the conserved nuclear protein Akirin is a NF‐κB co‐factor required for the activation of a subset of Relish‐dependent genes correlating with the presence of H3K4ac epigenetic marks. A large‐scale unbiased proteomic analysis revealed that Akirin orchestrates NF‐κB transcriptional selectivity through the recruitment of the Osa‐containing‐SWI/SNF‐like Brahma complex (BAP). Immune challenge in Drosophila shows that Akirin is required for the transcription of a subset of effector genes, but dispensable for the transcription of genes that are negative regulators of the innate immune response. Therefore, Akirins act as molecular selectors specifying the choice between subsets of NF‐κB target genes. The discovery of this mechanism, conserved in mammals, paves the way for the establishment of more specific and less toxic anti‐inflammatory drugs targeting pro‐inflammatory genes.
Synopsis
The nuclear factor Akirin orchestrates NF‐κB transcriptional selectivity through the recruitment of the Osa‐containing‐SWI/SNF Brahma complex (BAP), by activating a subset of NF‐κB effector genes.
In the Drosophila innate immune response, Akirin is required for NF‐κB selectivity.
Akirin interacts with the SWI/SNF Bap60 subunit upon immune challenge.
Akirin promotes SWI/SNF (BAP)‐dependent activation of a subset of immuno‐induced genes.
Relish, Akirin and Bap60 are recruited on a subset of NF‐κB‐dependent promoters.
SWI/SNF‐like (BAP) complex is required for fly defense against Gram‐negative bacteria.
The nuclear factor Akirin orchestrates NF‐κB transcriptional selectivity through the recruitment of the Osa‐containing‐SWI/SNF Brahma complex (BAP), by activating a subset of NF‐κB effector genes.
Roller burnishing is an alternative approach to enhance surface properties under plastic deformation and most investigations focused on optimizing process parameters. However, the impacts of ...operating parameters of the minimum quantity lubrication (MQL) system on the surface properties have not been considered. The roller burnishing process is widely applied to fabricate high-pressure bushings and crankshafts with superior quality, while the MQL system is extensively employed to facilitate different machining operations for saving lubricant usage, decreasing negative impacts on the environment, and protecting worker’s health. The purpose of this investigation is to select the optimal MQL system factors, including the nozzle diameter (
D
), impingement angle (
I
), flow rate (
Q
), and air pressure (
P
) for decreasing the maximum profile peak height of the roughness (MAR) and improving Vickers hardness (VH) for the roller burnishing process. The optimal artificial neural network (ANN) model was proposed to render the relations between the optimizing inputs and burnishing responses. An efficiently evolutionary technique entitled multi-objective glowworm swarm optimization (MOGSO) was utilized to produce a set of feasible solutions. The VIKOR method was employed to determine the best optimal solution. The results revealed that the 4–10–2 architecture of the developed ANN models efficiently described the burnishing performances and precisely predicted the response values. The optimal outcomes of the
D
,
I
,
Q
, and
P
were 1.5 mm, 45 deg., 130 ml/h, and 0.6 MPa, while the improvements in the MAR and VH were 17.0% and 14.0%, respectively, as compared to the common values used. The proposed approach comprising the ANN, MOGSO, and VIKOR could be considered as a powerful technique to deal with the complicated optimizing issue for the roller burnishing operation. The obtained finding could be expected as a significant contribution to enhancement in the machining quality for the roller burnishing process under the MQL condition.
Although curcumin in the form of nanoparticles has been demonstrated as a potential anti-tumor compound, the impact of curcumin and nanocurcumin in vitro on normal cells and in vivo in animal models ...is largely unknown. This study evaluated the toxicity of curcumin-loaded micelles in vitro and in vivo on several tumor cell lines, primary stromal cells, and zebrafish embryos. Breast tumor cell line (MCF7) and stromal cells (human umbilical cord vein endothelial cells, human fibroblasts, and human umbilical cord-derived mesenchymal stem cells) were used in this study. A zebrafish embryotoxicity (FET) assay was conducted following the Organisation for Economic Co-operation and Development (OECD) Test 236. Compared to free curcumin, curcumin PM showed higher cytotoxicity to MCF7 cells in both monolayer culture and multicellular tumor spheroids. The curcumin-loaded micelles efficiently penetrated the MCF7 spheroids and induced apoptosis. The nanocurcumin reduced the viability and disturbed the function of stromal cells by suppressing cell migration and tube formation. The micelles demonstrated toxicity to the development of zebrafish embryos. Curcumin-loaded micelles demonstrated toxicity to both tumor and normal primary stromal cells and zebrafish embryos, indicating that the use of nanocurcumin in cancer treatment should be carefully investigated and controlled.
Natural extracellular vesicles (EVs) are ideal drug carriers due to their remarkable biocompatibility. Their delivery specificity can be achieved by the conjugation of targeting ligands. However, ...existing methods to engineer target‐specific EVs are tedious or inefficient, having to compromise between harsh chemical treatments and transient interactions. Here, we describe a novel method for the covalent conjugation of EVs with high copy numbers of targeting moieties using protein ligases. Conjugation of EVs with either an epidermal growth factor receptor (EGFR)‐targeting peptide or anti‐EGFR nanobody facilitates their accumulation in EGFR‐positive cancer cells, both in vitro and in vivo. Systemic delivery of paclitaxel by EGFR‐targeting EVs at a low dose significantly increases drug efficacy in a xenografted mouse model of EGFR‐positive lung cancer. The method is also applicable to the conjugation of EVs with peptides and nanobodies targeting other receptors, such as HER2 and SIRP alpha, and the conjugated EVs can deliver RNA in addition to small molecules, supporting the versatile application of EVs in cancer therapies. This simple, yet efficient and versatile method for the stable surface modification of EVs bypasses the need for genetic and chemical modifications, thus facilitating safe and specific delivery of therapeutic payloads to target cells.
Narcolepsy type 1 (NT1) is an enigmatic sleep disorder characterized by the selective loss of neurons producing orexin (also named hypocretin) in the lateral hypothalamus. Although NT1 is believed to ...be an autoimmune disease, the orexinergic neuron-specific antigens targeted by the pathogenic immune response remain elusive. In this study, we evaluated the differential binding capacity of various peptides to serum immunoglobin G from patients with NT1 and other hypersomnolence complaints (OHCs). These peptides were selected using an unbiased phage display technology or based on their significant presence in the serum of NT1 patients as identified from previous studies. Although the subtractive biopanning strategy successfully enriched phage clones with high reactivity against NT1 serum IgG, the 101 randomly selected individual phage clones could not differentiate the sera from NT1 and OHC. Compared to the OHC control group, serum from several NT1 patients exhibited increased reactivity to the 12-mer peptides derived from TRBV7, BCL-6, NRXN1, RXRG, HCRT, and RTN4 proteins, although not statistically significant. Collectively, employing both unbiased and targeted methodologies, we were unable to detect the presence of specific autoantibodies in our NT1 patient cohort. This further supports the hypothesis that the autoimmune response in NT1 patients likely stems primarily from T cell-mediated immunity rather than humoral immunity.
•We investigate the tail-dependency networks of 51 financial assets.•The extreme quantile coherency is estimated using the quantile cross-spectral analysis and the tail-dependency network is built ...using the force-directed layout algorithm.•The Covid-19 pandemic asymmetrically increases the network density, with stronger effects in the left-tail dependencie of asset returns.•The cross-asset tail-dependency of equity, currency and commodity increases considerably, implying a higher degree of tail contagion effects.•Bitcoin and US Treasury bonds are disconnected from both tail-dependency networks, suggesting their safe-haven characteristics.
This study provides evidence on the frequency-based dependency networks of various financial assets in the tails of return distributions given the extreme price movements under the exceptional circumstance of the Covid-19 pandemic, qualified by the IMF as the Great Lockdown. Our results from the quantile cross-spectral analysis and tail-dependency networks show increases in the network density in both lower and upper joint distributions of asset returns. Particularly, we observe an asymmetric impact of the Covid-19 because the left-tail dependencies become stronger and more prevalent than the right-tail dependencies. The cross-asset tail-dependency of equity, currency and commodity also increases considerably, especially in the left-tail, implying a higher degree of tail contagion effects. Meanwhile, Bitcoin and US Treasury bonds are disconnected from both tail-dependency networks, which suggests their safe-haven characteristics.
Inflammation conditions are associated with autism spectrum disorder (ASD) and cerebral palsy (CP), primarily observed in the peripheral immune system. However, the extent of neuro-inflammation and ...neuro-immune dysregulation remains poorly studied. In this study, we analyzed the composition of cerebrospinal fluid (CSF) to uncover the inflammatory mediators driving the neuro-immune system in ASD and CP patients. Our findings revealed that ASD patients had elevated levels of four inflammatory cytokines (TNF-α, IL-4, IL-21, and BAFF) compared to controls, while CP patients exhibited increased levels of eight inflammatory cytokines (IFN-γ, GM-CSF, TNF-α, IL-2, IL-4, IL-6, IL-17A and IL-12), one anti-inflammatory cytokine (IL-10), and five growth factors (GFs) (NGF-β, EGF, GDF-15, G-CSF and BMP-9) compared to both controls and ASD patients. Additionally, intrathecal infusion of autologous bone marrow mononuclear cells (BMMNCs) led to a slight decrease in TGF-β and GDF-15 levels in the CSF of ASD and CP patients, respectively. Our study provides new insights into the molecular composition of CSF in ASD and CP patients, with the potential to develop more effective diagnosis methods and improved treatment for these diseases.Clinical trial registration CSF samples used in this study are from clinical trials NCT03225651, NCT05307536, NCT02569775, NCT03123562, NCT02574923, NCT05472428 and previous reports 7, 9, 17-19.
Exosomes are nano-scale and closed membrane vesicles which are promising for therapeutic applications due to exosome-enclosed therapeutic molecules such as DNA, small RNAs, proteins and lipids. ...Recently, it has been demonstrated that mesenchymal stem cell (MSC)-derived exosomes have capacity to regulate many biological events associated with wound healing process, such as cell proliferation, cell migration and blood vessel formation. This study investigated the regenerative potentials for cutaneous tissue, in regard to growth factors associated with wound healing and skin cell proliferation and migration, by exosomes released from primary MSCs originated from bone marrow (BM), adipose tissue (AD), and umbilical cord (UC) under serum- and xeno-free condition. We found crucial wound healing-mediated growth factors, such as vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2), hepatocyte growth factor (HGF), and platelet-derived growth factor BB (PDGF-BB) in exosomes derived from all three MSC sources. However, expression levels of these growth factors in exosomes were influenced by MSC origins, especially transforming growth factor beta (TGF-β) was only detected in UCMSC-derived exosomes. All exosomes released by three MSCs sources induced keratinocyte and fibroblast proliferation and migration; and, the induction of cell migration is a dependent manner with the higher dose of exosomes was used (20 μg), the faster migration rate was observed. Additionally, the influences of exosomes on cell proliferation and migration was associated with exosome origins and also target cells of exosomes that the greatest induction of primary dermal fibroblasts belongs to BMMSC-derived exosomes and keratinocytes belongs to UCMSC-derived exosomes. Data from this study indicated that BMMSCs and UCMSCs under clinical condition secreted exosomes are promising to develop into therapeutic products for wound healing treatment.
In this paper, we investigate the use of a consecutive‐interpolation for polyhedral finite element method (CIPFEM) in the analysis of three‐dimensional solid mechanics problems. A displacement‐based ...Galerkin weak form is used, in which the nodal degrees of freedom (DOF) and their derivatives are both considered for the approximation scheme. Based on arbitrary star‐convex polyhedral elements using piecewise linear shape function, the present method can have the advantage of being applicable to complicated structures. Nevertheless, the proposed interpolation technique gives higher‐order continuity, greater accuracy with the same number of DOFs. The reliability and efficiency of the CIPFEM are proved by comparing the present results with those obtained by the consecutive‐interpolation for tetrahedral element (CT4), conventional linear FEM using polyhedral elements (PFEM), and tetrahedral elements (T4) through numerical examples. Cantilever beam, concrete corbel, and complex hollow concrete revetment block are considered to show the excellent performance of the present approach.
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