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Abstract Under the condition that the working face was directly covered with hard roof, the abrupt breaking of hard roof release significant amount of energy, thus prone to triggering dynamic disasters such as roadway instability or rockburst. This paper based on the engineering background of the Xieqiao Coal Mine's 11,618 working face, a numerical simulation method was put forward to study the dynamic response of roadway under the disturbance of hard roof breaking and proposed an evaluation index I C for roadway stability. Research indicates that the elastic energy released during the periodic weighting of the hard roof is higher than that released during the first weighting. Under the dynamic disturbance caused by hard roof breaking, the peak stresses of the roadway was slight decreased, accompanied by a significant increase in the range of stress concentration and plastic zone expansion. Roadway deformation patterns are significantly influenced by hard roof breaking, with noticeable increases in deformation on the roof and right side. During the period of hard roof breaking, the possibility of instability of the roadway increase significantly due to the disturbance caused by the dynamic load. The research results reveal the instability mechanism of roadway under the condition of hard roof, and provide a more reliable basis for evaluating the stability of roadway.

Abstract Background Inflammation in the eye is often associated with aggravated ocular diseases such as uveal melanoma (UM). Poor prognosis of UM is generally associated with high potential of metastatic liver dissemination. A strong driver of metastatic dissemination is the activation of the epithelial-mesenchymal transition (EMT) regulating transcription factor ZEB1, and high expression of ZEB1 is associated with aggressiveness of UM. While ZEB1 expression can be also associated with immune tolerance, the underlying drivers of ZEB1 activation remain unclear. Methods Transcriptomic, in vitro, ex vivo, and in vivo analyses were used to investigate the impact on clinical prognosis of immune infiltration in the ocular tumor microenvironment. A metastatic liver dissemination model of was developed to address the role of natural killer (NK) cells in driving the migration of UM. Results In a pan-cancer TCGA analysis, natural killer (NK) cells were associated with worse overall survival in uveal melanoma and more abundant in high-risk monosomy 3 tumors. Furthermore, uveal melanoma expressed high levels of the tumor necrosis factor superfamily member 4-1BB ligand, particularly in tumors with monosomy 3 and BAP1 mutations. Tumors expressing 4-1BB ligand induced CD73 expression on NK cells accompanied with the ability to promote tumor dissemination. Through ligation of 4-1BB, NK cells induced the expression of the ZEB1 transcription factor, leading to the formation of liver metastasis of uveal melanoma. Conclusions Taken together, the present study demonstrates a role of NK cells in the aggravation of uveal melanoma towards metastatic disease.

ABSTRACTT-cell-engaging bispecific antibodies (T-bsAbs) are promising immunotherapies for cancer treatment due to their capability of redirecting T-cells toward destroying tumor cells. Numerous T-bsAb formats have been developed, each with advantages and disadvantages in terms of developability, immunogenicity, effector functions, and pharmacokinetics. Here, we systematically compared T-bsAbs produced using eight different formats, evaluating the effect of molecular design of T-bsAbs on their manufacturability and functionality. These eight T-bsAb formats were constructed using antigen-binding fragments (Fabs) and single-chain variable fragments (scFvs) of antibodies linked to the crystallizable fragment (Fc) domain of immunoglobulin G. To ensure a fair comparison of growth and production data, we used recombinase-mediated cassette exchange technology to generate the T-bsAb-producing CHO cell lines. The produced T-bsAbs were assessed for their purification profile and recovery, binding capability, and biological activities. Our findings indicated that the manufacturability of bsAbs was adversely affected with increased number of scFv building blocks, while the functionality was affected by the combination of multiple factors, including the binding affinity and avidity of targeting moieties and the flexibility and geometry of formats. These results provide valuable insights into the impact of the format design on the optimal production and function of T-bsAbs.

Natural Killer (NK) cells are a type of innate lymphoid cells that play a crucial role in immunity by killing virally infected or tumor cells and secreting cytokines and chemokines. NK cell-mediated immunotherapy has emerged as a promising approach for cancer treatment due to its safety and effectiveness. NK cell engagers (NKCEs), such as BiKE (bispecific killer cell engager) or TriKE (trispecific killer cell engager), are a novel class of antibody-based therapeutics that exhibit several advantages over other cancer immunotherapies harnessing NK cells. By bridging NK and tumor cells, NKCEs activate NK cells and lead to tumor cell lysis. A growing number of NKCEs are currently undergoing development, with some already in clinical trials. However, there is a need for more comprehensive studies to determine how the molecular design of NKCEs affects their functionality and manufacturability, which are crucial for their development as off-the-shelf drugs for cancer treatment. In this review, we summarize current knowledge on NKCE development and discuss critical factors required for the production of effective NKCEs.

To solve the problem of poor waterproof and moisture resistance caused by the high open-cell ratio of polyacrylate foam, a special foam stabilizer (MMA-g-SI) for acrylate was synthesized with polyacrylate as the main chain and aminosiloxane as the side chain. MMA-g-SI has good foam stability in the process of acrylate foaming, and can significantly reduce the surface tension and further increase the closed-cell content. When the amount of MMA-g-SI was 1.0 wt%, the water absorption of foam decreased from 64.3% to 2.1%. The point impact energy absorption increased from 50% to 72%, and the surface impact energy absorption increased from 28% to 35%. Moreover, with the increase of density, the point impact energy absorption of the foam increased, while the surface impact energy absorption decreased. The special foam stabilizer has a good application prospect in the field of acrylate foaming. KEYWORDS energy absorption, foam stabilizer, polyacrylate, poor waterproof, surface tension, 1 | INTRODUCTION With the development of technology, electronic devices, such as mobile phones and computers, have become a part of people's life. However, the screens of these electronic devices [...]

Cell therapy encompasses an expanding spectrum of cell-based regimes for the treatment of human ailments, such as the use of immune cells, in particular T cells, for combating tumors and the modulation of inflammatory immune responses. In this review, we focus on cell therapy in the immuno-oncology space, which is largely driven by interests and demands from the clinics for better solutions to target various hard-to-treat cancers. We discuss recent advances in various types of cell therapies, including T cell receptor-T cells, chimeric antigen receptor (CAR)-T cells, tumor-infiltrating lymphocytes and natural killer cells. Particularly, the present review focuses on the strategies to improve therapeutic responses by either enhancing tumor recognition or the resilience of infused immune cells within tumor microenvironment. Finally, we discuss the potential of other innate or innate-like immune cell types currently being explored as promising CAR-cell alternatives that seek to address the limitations of conventional adoptive cell therapies.

The dysregulation of the biochemical pathways in cancer promotes oncogenic transformations and metastatic potential. Recent studies have shed light on how obesity and altered lipid metabolism could be the driving force for tumor progression. Here, in this review, we focus on liver cancer and discuss how obesity and lipid-driven metabolic reprogramming affect tumor, immune, and stroma cells in the tumor microenvironment and, in turn, how alterations in these cells synergize to influence and contribute to tumor growth and dissemination. With increasing evidence on how obesity exacerbates inflammation and immune tolerance, we also touch upon the impact of obesity and altered lipid metabolism on tumor immune escape.

Here we report a visible-light facilitated radical addition strategy for the preparation of various natural or unnatural α-amino acids from readily available glycine derivatives and alkenes. A key aspect in achieving this side carbon chain introduction reaction, while circumventing the well-documented cyclization pathway, was the employment of a radical-polar crossover strategy under redox neutral conditions. [ABSTRACT FROM AUTHOR]

Determining the advanced mining influence range of an underground working face is crucial for preventing dynamic disasters, such as coal bursts and gas outbursts. In this study, the occurrence of advanced seismicity before the working face as well as its correlation with the acoustic emission (AE) activity of coal and rocks under axial loading was analyzed. Based on the results, a novel statistical method to determine the advanced mining influence range based on advanced seismicity data was proposed and then validated with a case study. The results show that advanced seismicity is caused by the combined effects of static and dynamic stresses at the working face. This seismicity can be used to assess the mining influence degree of the working face on the advanced coal and rock mass, and determine the advanced mining influence range. Using the novel statistical method, the normalized curves for the total number and total energy of the advanced mining-induced seismicity can be plotted. Then, the advanced mining influence range can be determined using thresholds. The thresholds can be established based on the AE activities observed in coal and rock samples under axial static loading. In the case study in this research, the thresholds for the total seismic number and total seismic energy are 0.076 and 0.052, respectively. The corresponding advanced mining influence ranges are 275 m and 245 m, respectively. Field monitoring confirms an advanced mining influence range of 255 m, which validates the results obtained using the novel statistical method. [ABSTRACT FROM AUTHOR]

Abstract How pathogenesis of inflammatory bowel disease (IBD) depends on the complex interplay of host genetics, microbiome and the immune system is not fully understood. Here, we showed that Downstream of Kinase 3 (DOK3), an adapter protein involved in immune signaling, confers protection of mice from dextran sodium sulfate (DSS)-induced colitis. DOK3-deficiency promotes gut microbial dysbiosis and enhanced colitis susceptibility, which can be reversed by the transfer of normal microbiota from wild-type mice. Mechanistically, DOK3 exerts its protective effect by suppressing JAK2/STAT3 signaling in colonic neutrophils to limit their S100a8/9 production, thereby maintaining gut microbial ecology and colon homeostasis. Hence, our findings reveal that the immune system and microbiome function in a feed-forward manner, whereby DOK3 maintains colonic neutrophils in a quiescent state to establish a gut microbiome essential for intestinal homeostasis and protection from IBD.

Increased neutrophils and elevated level of circulating calprotectin are hallmarks of severe COVID-19 and they contribute to the dysregulated immune responses and cytokine storm in susceptible patients. However, the precise mechanism controlling calprotectin production during SARS-CoV-2 infection remains elusive. In this study, we showed that Dok3 adaptor restrains calprotectin production by neutrophils in response to SARS-CoV-2 spike (S) protein engagement of TLR4. Dok3 recruits SHP-2 to mediate the de-phosphorylation of MyD88 at Y257, thereby attenuating downstream JAK2-STAT3 signaling and calprotectin production. Blocking of TLR4, JAK2 and STAT3 signaling could prevent excessive production of calprotectin by Dok3-/- neutrophils, revealing new targets for potential COVID-19 therapy. As S protein from SARS-CoV-2 Delta and Omicron variants can activate TLR4-driven calprotectin production in Dok3-/- neutrophils, our study suggests that targeting calprotectin production may be an effective strategy to combat severe COVID-19 manifestations associated with these emerging variants.

Invasive fungal disease is an emerging and serious public health threat globally. The expanding population of susceptible individuals, together with the rapid emergence of multidrug-resistant fungi pathogens, call for the development of novel therapeutic strategies beyond the limited repertoire of licensed antifungal drugs. Card9 is a critical signaling molecule involved in antifungal defense; we have previously identified Dok3 to be a key negative regulator of Card9 activity in neutrophils. In this study, we identified two synthetic peptides derived from the coiled-coil domain of Card9, which can specifically block Dok3–Card9 binding. We showed that these peptides are cell-permeable, non-toxic, and can enhance antifungal cytokine production and the phagocytosis of human neutrophils upon fungal infection. Collectively, these data provide a proof of concept that disrupting the Dok3–Card9 interaction can boost the antifungal effector functions of neutrophils; they further suggest the potential utility of these peptide inhibitors as an immune-based therapeutic to fight fungal infection.

Mesenchymal stem/stromal cell (MSC) exosomes have been shown to alleviate immune dysfunction and inflammation in preclinical animal models. This therapeutic effect is attributed, in part, to their ability to promote the polarization of anti-inflammatory M2-like macrophages. One polarization mechanism has been shown to involve the activation of the MyD88-mediated toll-like receptor (TLR) signaling pathway by the presence of extra domain A-fibronectin (EDA-FN) within the MSC exosomes. Here, we uncovered an additional mechanism where MSC exosomes mediate M2-like macrophage polarization through exosomal CD73 activity. Specifically, we observed that polarization of M2-like macrophages by MSC exosomes was abolished in the presence of inhibitors of CD73 activity, adenosine receptors A2A and A2B, and AKT/ERK phosphorylation. These findings suggest that MSC exosomes promote M2-like macrophage polarization by catalyzing the production of adenosine, which then binds to adenosine receptors A2A and A2B to activate AKT/ERK-dependent signaling pathways. Thus, CD73 represents an additional critical attribute of MSC exosomes in mediating M2-like macrophage polarization. These findings have implications for predicting the immunomodulatory potency of MSC exosome preparations.