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Previous studies have found that activated CD8+ T cells secrete elevated levels of interferon‐gamma (IFN‐γ) to trigger ferroptosis in tumor cells. However, IFN‐γ‐mediated ferroptosis is induced at low levels in tumor cells because of the limited IFN‐γ secreted by CD8+ T cells in the immunosuppressive tumor microenvironment. Recent studies have shown that manganese ion can activate the cyclic guanosine monophosphate‐adenosine monophosphate (GMP–AMP) synthase/stimulator of interferon genes (cGAS‐STING) pathway and support adaptive immune responses against tumors, which enhances the level of tumor‐infiltrating CD8+ T cells. Therefore, tumor microenvironment‐responsive Mn‐based nanoenzymes (Mn‐based NEs) that activated the cGAS‐STING pathway are designed to amplify immune‐driven ferroptosis. The multifunctional all‐in‐one nanoplatform is simply and mildly synthesized by the coordination between Mn3+ ions and 3,3′‐dithiodipropionic acid. After intracellular delivery, each component of Mn‐based NEs exerts its function. That is, glutathione is depleted through disulfide–thiol exchange and redox pair of Mn3+/Mn2+, a hydroxyl radical (·OH) is generated via the Fenton‐like reaction to cause ferroptosis, and Mn2+ augments cGAS‐STING activity to boost immune‐driven ferroptosis. In addition, ferroptosis amplifies Mn2+‐induced immunogenic cell death and initiates the antitumor immune "closed loop" along with immune‐driven ferroptosis. Notably, this multifunctional nanoplatform is effective in killing both primary and distant tumors. [ABSTRACT FROM AUTHOR]

While a few derivatives of cinnamamides exhibited anti-inflammatory and/ or analgesic activity, in this study, we developed a highly efficient method for the synthesis of cinnamamides from methyl cinnamates and phenylethylamines catalyzed by Lipozyme® TL IM in continuous-flow microreactors. The reaction parameters and broad substrate range of the new method was studied. Maximum conversion (91.3%) was obtained under the optimal condition of substrate molar ratio of 1:2 (methyl 4-chlorocinnamate: phenylethylamine) at 45 ° C for about 40 min. The remarkable features of this work include short residence time, mild reaction conditions, easy control of the reaction process, and that the catalyst can be recycled or reused, which provide a rapid and economical strategy for the synthesis and design of cinnamamide derivatives for further research on drug activity. [ABSTRACT FROM AUTHOR]

The surge of health misinformation on social media poses a threat to public health. This qualitative study reports how users process health misinformation from the dominant strong-tie social media, WeChat, in China. We conducted ten on-site focus groups involving 76 adult participants. Drawing on the apomediation theory and the dual processing model of credibility assessment, we found the heuristic approach to processing health information was the dominant route of engagement. We identified four categories of credibility assessment cues, including (1) expertise, authority, and commercial intent of original sources, (2) expertise of apomediaries (i.e. social media information sharers) and generational bias, (3) clickbait and sensational content versus objective scientific style, and (4) disconfirmation versus confirmation bias. We highlight that apomediaries are playing an increasingly important role in informing credibility judgment. Specifically, younger adults have formed a generational bias of deeming older apomediaries as cues of lower credibility. [ABSTRACT FROM AUTHOR]

Lipase-catalyzed regioselective synthesis of neohesperidin ester derivatives was performed by Lipase TL IM from Thermomyces lanuginosus in a continuous-flow microreactor and then their antimicrobial activity was studied. It appears that neohesperidin, neohesperidin dihydrochalcone with primary OH on the sugar part is the most reactive substrate. Various reaction parameters were investigated including substrate molar ratio, reaction time and temperature. Maximum conversion (92%) was obtained under the optimal condition of substrate molar ratio of 8:1 (vinyl esters: neohesperidin) at 52 °C for about 35 min. Then, the antibacterial activity of modified neohesperidin ester derivatives was examined and showed great improvement against gram negative and gram positive bacteria. [ABSTRACT FROM AUTHOR]

Light has important effects on plant metabolism. However, the relationship between the chlorogenic acid (CGA) content and light in plants remains unclear. Here, we investigated the effects of shading treatment on gene expression and CGA content in Lonicera macranthoides Hand.-Mazz. (LM), a widely used medicinal plant. A total of 1891 differentially expressed genes (DEGs) were obtained in flower buds and 819 in leaves in response to light in shading treatment compared to the control sample by RNA-Seq. After shading treatment, the content of CGA in LM leaves decreased significantly by 1.78-fold, the carotenoid content increased, and the soluble sugar and starch contents significantly decreased. WGCNA and the expression of related genes verified by qRT‒PCR revealed that CGA synthesis pathway enzyme genes form a co-expression network with genes for carbohydrate synthesis, photosynthesis, light signalling elements, and transcription factor genes (TFs) that affect the accumulation of CGA. Through a virus-induced gene silencing (VIGS) system and CGA assay in Nicotiana benthamiana (NB), we determined that downregulation of NbHY5 expression decreased the CGA content in NB leaves. In this study, we found that light provides energy and material for the accumulation of CGA in LM, and light affects the expression of CGA accumulation-related genes. Our results show that different light intensities have multiple effects on leaves and flower buds in LM and are able to coregulate LmHY5 expression and CGA synthesis. • When ambient light intensity reduced the content of chlorogenic acid is decreased in Lonicera macranthoides Hand.-Mazz. • The transcriptional expression of chlorogenic acid synthesis pathway elements in response to changes in ambient light intensity was characterized in Lonicera macranthoides Hand.-Mazz. Was constructed. • The co-expression network of chlorogenic acid synthesis pathway genes, primary metabolic pathway genes and light signal element genes was established in Lonicera macranthoides Hand.-Mazz. • Inhibition of transcriptional expression of NbHY5 leads to a decrease in chlorogenic acid content. [ABSTRACT FROM AUTHOR]

Bcl-xL and Bcl-2 are phosphorylated in response to microtubule inhibitors, but the kinase(s) responsible and the functional significance have remained unclear. In this study, we investigated the characteristics of Bcl-xL and Bcl-2 phosphorylation in KB-3 carcinoma cells treated with vinblastine. In both asynchronous and synchronous cell cultures, Bcl-xL and Bcl-2 underwent a well-defined and coordinated cycle of phosphorylation and dephosphorylation, with a lengthy period of phosphorylation preceding apoptosis induction, and with dephosphorylation closely correlated with initiation of apoptosis. Internally, validated inhibitors of JNK, ERK, p38MAPK, or CDK1 failed to inhibit vinblastine-induced phosphorylation of Bcl-xL or Bcl-2. In vitro, Bcl-xL and Bcl-2 were poor substrates relative to c-Jun and ATF2 for active recombinant JNK1. Both Bcl-xL and Bcl-2 were localized primarily to the mitochondrial fraction in both control and vinblastine-treated cells, indicating that phosphorylation did not promote subcellular redistribution. Bcl-xL kinase activity was demonstrated in mitochondrial extracts from vinblastine-treated, but not control, cells. These findings suggest that phosphorylation of these key antiapoptotic proteins may be catalysed by a novel or unsuspected kinase that is activated or induced in response to microtubule damage. Furthermore, the same kinase and phosphatase system may be operating in tandem on both proteins, and phosphorylation appears to maintain their antiapoptotic function, whereas dephosphorylation may trigger apoptosis. These results provide evidence for a novel signaling pathway connecting microtubule damage to apoptosis induction, and help to clarify some of the controversy concerning the role of Bcl-2 phosphorylation in microtubule inhibitor-induced apoptosis.Oncogene (2005) 24, 107-117. doi:10.1038/sj.onc.1208189 Published online 8 November 2004 [ABSTRACT FROM AUTHOR]

The c-Jun NH2-terminal kinase (JNK) subgroup of mitogen-activated protein kinases has been implicated largely in stress responses, but an increasing body of evidence has suggested that JNK also plays a role in cell proliferation and survival. We examined the effect of JNK inhibition, using either SP600125 or specific antisense oligonucleotides, on cell proliferation and cell cycle progression. SP600125 was selective for JNK in vitro and in vivo versus other kinases tested including ERK, p38, cyclin-dependent protein kinase 1 (CDK1), and CDK2. SP600125 inhibited JNK activity and KB-3 cell proliferation with the same dose dependence, suggesting that inhibition of proliferation was a direct consequence of JNK inhibition. Inhibition of proliferation by SP600125 was associated with an increase in the G2-M and apoptotic fractions of cells but was not associated with p53 or p21 induction. Antisense oligonucleotides to JNK2 but not JNK1 caused highly significant inhibition of cell proliferation. Wild-type mouse fibroblasts responded similarly with proliferation inhibition and apoptosis induction, whereas c-jun-/- fibroblasts were refractory to the effects of SP600125, suggesting that JNK signaling to c-Jun is required for cell proliferation. Studies in synchronized KB-3 cells indicated that SP600125 delayed transit time through S and Ge-M phases. Correspondingly, JNK activity increased in late S phase and peaked in late G2 phase. During synchronous mitotic progression, cyclin B levels increased concomitant with phosphorylation of c-Jun, H1 histone, and Bcl-2. In the presence of SP600125, mitotic progression was prolonged, and c-Jun phosphorylation was inhibited, but neither H1 nor Bcl-2 phosphorylation was inhibited. However, the CDK inhibitor roscovitine inhibited mitotic Bcl-2 phosphorylation. These results indicate that JNK, and more specifically the JNK2 isoform, plays a key role in cell proliferation and cell cycle progression. In addition, conclusive evidence is presented that a kinase other than JNK, most likely CDK1 or a CDK1-regulated kinase, is responsible for mitotic Bcl-2 phosphorylation. [ABSTRACT FROM AUTHOR]

NaYF 4 :Er/Yb nanorods, colloidal crystal (CC) and Ag nanoparticles were obtained by solvothermal, self-assembly and hydrothermal methods, respectively. The hybrid structure of NaYF 4 :Er/Yb nanorods-colloidal crystal-Ag film (Ag-CC-NaYF 4 :Er/Yb) with low cost and large area was prepared for upconversion luminescence (UCL). The UCL enhancement was achieved by synergistic use of local reflection of incident light by colloidal crystal and reflection of incident light by Ag film. Compare with that of NaYF 4 :Er/Yb nanorods, the UCL intensity of Ag-CC-NaYF 4 :Er/Yb was increased by 33.2-folds. The UCL enhancement mechanism in Ag-CC-NaYF 4 :Er/Yb was investigated systematically. Our work has certain guiding value for promoting the application of upconversion nanocrystals in the fields of anti-counterfeiting, biological imaging, display and so on. • The hybrid of Ag-CC-NaYF 4 :Er/Yb with low cost and large area was prepared for UCL. • Compare with that of NaYF 4 :Er/Yb nanorods, the UCL intensity of Ag-CC-NaYF 4 :Er/Yb was increased by 33.2-folds. • The UCL enhancement mechanism in Ag-CC-NaYF 4 :Er/Yb was investigated systematically. [ABSTRACT FROM AUTHOR]

• Unified backstress and stress sensitivity models covering creep and viscoplasticity. • Microstructure-based constitutive model to encompass diverse deformation states. • Tensile, creep and stress-relaxation are concurrently and accurately predicted. • The model greatly improves the prediction accuracy for hybrid forming of Ti alloy. A unified model to characterize the mechanism transitions in a wide range of strain rates at elevated temperatures of titanium alloys has been developed and validated in this study. Models of microstructure-based backstress and strain rate dependent stress sensitivity covering both creep and viscoplasticity domains have been proposed, so as to predict different deformation behaviors concurrently for hot forming. Systematical experiments, including hot tensile, creep, stress-relaxation, and corresponding loading-unloading tests have been designed and performed, to get the different deformation behaviors, as well as the evolution of backstresses of titanium alloys at elevated temperatures. Microstructural observations, such as electron backscatter diffraction (EBSD), have also been performed to assist the mechanisms characterization. Based on the microstructural and macro properties results, the developed unified model has been calibrated and further implemented for typical cases of hot stamping - stress-relaxation forming (HS-SRF). The developed model achieved an excellent accuracy for all the tensile, creep, and stress-relaxation behaviors concurrently, with an error of only about 4.9 %, and a comparative 71.8 % ∼ 90.8 % reduction in springback prediction error has been reported for hot forming of typical thin-walled titanium alloy components when compared with the conventional modelling strategy where a single deformation mechanism is considered. The potential of the proposed model for process design and optimizations has also been discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Cuproptosis is a novel copper-dependent mode of cell death that has recently been discovered. The relationship between Cuproptosis-related ncRNAs and breast cancer subtypes, however, remains to be studied. Methods: The aim of this study was to construct a breast cancer subtype prediction model associated with Cuproptosis. This model could be used to determine the subtype of breast cancer patients. To achieve this aim, 21 Cuproptosis-related genes were obtained from published articles and correlation analysis was performed with ncRNAs differentially expressed in breast cancer. Random forest algorithms were subsequently utilized to select important ncRNAs and build breast cancer subtype prediction models. Results: A total of 94 ncRNAs significantly associated with Cuproptosis were obtained and the top five essential features were chosen to build a predictive model. These five biomarkers were differentially expressed in the five breast cancer subtypes and were closely associated with immune infiltration, RNA modification, and angiogenesis. Conclusion: The random forest model constructed based on Cuproptosis-related ncRNAs was able to accurately predict breast cancer subtypes, providing a new direction for the study of clinical therapeutic targets. [ABSTRACT FROM AUTHOR]

Disulfidptosis is a newly discovered mode of cell death. However, its relationship with breast cancer subtypes remains unclear. In this study, we aimed to construct a disulfidptosis-associated breast cancer subtype prediction model. We obtained 19 disulfidptosis-related genes from published articles and performed correlation analysis with lncRNAs differentially expressed in breast cancer. We then used the random forest algorithm to select important lncRNAs and establish a breast cancer subtype prediction model. We identified 132 lncRNAs significantly associated with disulfidptosis (FDR < 0.01, |R|> 0.15) and selected the first four important lncRNAs to build a prediction model (training set AUC = 0.992). The model accurately predicted breast cancer subtypes (test set AUC = 0.842). Among the key lncRNAs, LINC02188 had the highest expression in the Basal subtype, while LINC01488 and GATA3-AS1 had the lowest expression in Basal. In the Her2 subtype, LINC00511 had the highest expression level compared to other key lncRNAs. GATA3-AS1 had the highest expression in LumA and LumB subtypes, while LINC00511 had the lowest expression in these subtypes. In the Normal subtype, GATA3-AS1 had the highest expression level compared to other key lncRNAs. Our study also found that key lncRNAs were closely related to RNA methylation modification and angiogenesis (FDR < 0.05, |R|> 0.1), as well as immune infiltrating cells (P.adj < 0.01, |R|> 0.1). Our random forest model based on disulfidptosis-related lncRNAs can accurately predict breast cancer subtypes and provide a new direction for research on clinical therapeutic targets for breast cancer. [ABSTRACT FROM AUTHOR]

Disulfidptosis is a newly discovered mode of cell death. However, its relationship with breast cancer subtypes remains unclear. In this study, we aimed to construct a disulfidptosis-associated breast cancer subtype prediction model. We obtained 19 disulfidptosis-related genes from published articles and performed correlation analysis with lncRNAs differentially expressed in breast cancer. We then used the random forest algorithm to select important lncRNAs and establish a breast cancer subtype prediction model. We identified 132 lncRNAs significantly associated with disulfidptosis (FDR < 0.01, |R|> 0.15) and selected the first four important lncRNAs to build a prediction model (training set AUC = 0.992). The model accurately predicted breast cancer subtypes (test set AUC = 0.842). Among the key lncRNAs, LINC02188 had the highest expression in the Basal subtype, while LINC01488 and GATA3-AS1 had the lowest expression in Basal. In the Her2 subtype, LINC00511 had the highest expression level compared to other key lncRNAs. GATA3-AS1 had the highest expression in LumA and LumB subtypes, while LINC00511 had the lowest expression in these subtypes. In the Normal subtype, GATA3-AS1 had the highest expression level compared to other key lncRNAs. Our study also found that key lncRNAs were closely related to RNA methylation modification and angiogenesis (FDR < 0.05, |R|> 0.1), as well as immune infiltrating cells (P.adj < 0.01, |R|> 0.1). Our random forest model based on disulfidptosis-related lncRNAs can accurately predict breast cancer subtypes and provide a new direction for research on clinical therapeutic targets for breast cancer. [ABSTRACT FROM AUTHOR]

Constitutive activation of Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogenic event in certain types of human cancer and is associated with poor patient survival. Small molecule signaling inhibitors have improved the clinical outcomes of patients with various cancer types but attempts to target KRAS have been unsuccessful. Plinabulin represents a novel class of agents that inhibit tubulin polymerization with a favorable safety profile in clinical trials. In the present study, the potency of plinabulin to inhibit tubulin polymerization and growth of KRAS-driven cancer cells was characterized. In vivo efficacy of plinabulin was tested in two different mouse models; one being the RCAS/t-va gene transfer system and the other being a xenograft model. In vitro cell culture tubulin polymerization assays were used to complement the mouse models. There was improved survival in a KRAS-driven mouse gene transfer glioma model, but lack of benefit in a similar model, without constitutively active KRAS, which supports the notion of a KRAS-specific effect. This survival benefit was mediated, at least in part, by the ability of plinabulin to inhibit tubulin polymerization and disrupt endosomal recycling. It was proposed a mechanism of compromised endosomal recycling of displaced KRAS through targeting microtubules that yields inhibition of protein kinase B, but not extracellular signal regulated kinase (ERK) signaling, therefore lending rationale to combination treatments of tubulin- and ERK-targeting agents in KRAS-driven cancer. [ABSTRACT FROM AUTHOR]

Lactococcus lactis subsp. lactis is a food bacterium that has been utilized for decades in food fermentation and the development of high-value industrial goods. Among these, nisin, which is produced by several strains of L. lactis subsp. lactis, plays a crucial role as a food bio-preservative. The gene expression for nisin synthesis was evaluated using qPCR analysis. Additionally, a series of re-transformations of the strain introducing multiple copies of the nisA and nisRK genes related to nisin production were developed. The simultaneous expression of nisA and nisZ genes was used to potentiate the effective inhibition of foodborne pathogens. Furthermore, qPCR analysis indicated that the nisA and nisRK genes were expressed at low levels in wild-type L. lactis subsp. lactis. After several re-transformations of the strain with the nisA and nisRK genes, a high expression of these genes was obtained, contributing to improved nisin production. Also, co-expression of the nisA and nisZ genes resulted in extremely effective antibacterial action. Hence, this study would provide an approach to enhancing nisin production during industrial processes and antimicrobial activity. [ABSTRACT FROM AUTHOR]

Cascade reactions catalyzed by multi-enzyme systems are important in science and industry and can be used to synthesize drugs and nutrients. In this study, two types of macromolecules of bi-enzyme self-assembly clusters (BESCs) consisting of carbonyl reductase (CpCR) and glucose dehydrogenase (GDH) were examined. Stereoselective CpCR and GDH were successfully fused with SpyCatcher and SpyTag, respectively, to obtain four enzyme modules, namely: SpyCatcher-CpCR, SpyCatcher-GDH, SpyTag-CpCR, and SpyTag-GDH, which were covalently coupled in vitro to form two types of hydrogel-like BESCs: CpCR-SpyCatcher-SpyTag-GDH and GDH-SpyCatcher-SpyTag-CpCR. CpCR-SpyCatcher-SpyTag-GDH showed a better activity and efficiently converted ethyl 2-oxo-4-phenylbutyrate (OPBE) to ethyl(R)2-hydroxy-4-phenylbutanoate ((R)-HPBE), while regenerating NADPH. At 30 °C and pH 7, the conversion rate of OPBE with CpCR-SpyCatcher-SpyTag-GDH as a catalyst reached 99.9%, with the ee% of (R)-HPBE reaching above 99.9%. This conversion rate was 2.4 times higher than that obtained with the free bi-enzyme. The pH tolerance and temperature stability of the BESCs were also improved compared with those of the free enzymes. In conclusion, bi-enzyme assemblies were docked using SpyCatcher/SpyTag to produce BESCs with a special structure and excellent catalytic activity, improving the catalytic efficiency of the enzyme. [ABSTRACT FROM AUTHOR]

(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanamine, a key chiral intermediate of selective tetrodotoxin-sensitive blockers, was efficiently synthesized by a bienzyme cascade system formed by with R-ω-transaminase (ATA117) and an alcohol dehydrogenase (ADH) co-expression system. Herein, we report that the use of ATA117 as the biocatalyst for the amination of 3,5-bistrifluoromethylacetophenone led to the highest efficiency in product performance (enantiomeric excess > 99.9%). Moreover, to further improve the product yield, ADH was introduced into the reaction system to promote an equilibrium shift. Additionally, bienzyme cascade system was constructed by five different expression systems, including two tandem expression recombinant plasmids (pETDuet-ATA117-ADH and pACYCDuet-ATA117-ADH) and three co-expressed dual-plasmids (pETDuet-ATA117/pET28a-ADH, pACYCDuet-ATA117/pET28a-ADH, and pACYCDuet-ATA117/pETDuet-ADH), utilizing recombinant engineered bacteria. Subsequent studies revealed that as compared with ATA117 single enzyme, the substrate handling capacity of BL21(DE3)/pETDuet-ATA117-ADH (0.25 g wet weight) developed for bienzyme cascade system was increased by 1.50 folds under the condition of 40 °C, 180 rpm, 0.1 M pH9 Tris-HCl for 24 h. To the best of our knowledge, ours is the first report demonstrating the production of (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanamine using a bienzyme cascade system, thus providing valuable insights into the biosynthesis of chiral amines. [ABSTRACT FROM AUTHOR]

[Display omitted] As a non-invasive imaging monitoring method, molecular imaging can provide the location and expression level of disease signature biomolecules in vivo, leading to early diagnosis of relevant diseases, improved treatment strategies, and accurate assessment of treating efficacy. In recent years, a variety of nanosized imaging probes have been developed and intensively investigated in fundamental/translational research and clinical practice. Meanwhile, as an interdisciplinary discipline, this field combines many subjects of chemistry, medicine, biology, radiology, and material science, etc. The successful molecular imaging not only requires advanced imaging equipment, but also the synthesis of efficient imaging probes. However, limited summary has been reported for recent advances of nanoprobes. In this paper, we summarized the recent progress of three common and main types of nanosized molecular imaging probes, including ultrasound (US) imaging nanoprobes, magnetic resonance imaging (MRI) nanoprobes, and computed tomography (CT) imaging nanoprobes. The applications of molecular imaging nanoprobes were discussed in details. Finally, we provided an outlook on the development of next generation molecular imaging nanoprobes. [ABSTRACT FROM AUTHOR]

In nature, plants interact with a wide range of microorganisms, and most of these microorganisms could induce growth through the activation of important molecular pathways. The current study evaluated whether the endophytic bacterium Bacillus aryabhattai encourages plant growth and the transcriptional changes that might be implicated in this effect. The endophytic bacterium promotes the growth of Arabidopsis and tobacco plants. The transcriptional changes in Arabidopsis plants treated with the bacterium were also identified, and the results showed that various genes, such as cinnamyl alcohol dehydrogenase, apyrase, thioredoxin H8, benzaldehyde dehydrogenase, indoleacetaldoxime dehydratase, berberine bridge enzyme-like and gibberellin-regulated protein, were highly expressed. Also, endophytic bacterial genes, such as arginine decarboxylase, D-hydantoinase, ATP synthase gamma chain and 2-hydroxyhexa-2,4-dienoate hydratase, were activated during the interaction. These findings demonstrate that the expression of novel plant growth-related genes is induced by interaction with the endophytic bacterium B. aryabhattai and that these changes may promote plant growth in sustainable agriculture. [ABSTRACT FROM AUTHOR]

GCN1 is a highly conserved protein present widely across eukaryotes. As an upstream activator of protein kinase GCN2, GCN1 plays a pivotal role in integrated stress responses, such as amino acid starvation and oxidative stress. Through interaction with GCN2, GCN1 facilitates the activation of GCN2, thus initiating downstream signaling cascades in response to cellular stressors. In these contexts, the activation of GCN2 necessitates the presence and action of GCN1. Notably, GCN1 also operates as a ribosome collision sensor, contributing significantly to the translation quality control pathway. These discoveries offer valuable insights into cellular responses to internal stresses, vital for maintaining cellular homeostasis. Additionally, GCN1 exhibits the ability to regulate the cell cycle and suppress inflammation, among other processes, independently of GCN2. Our review outlines the structural characteristics and biological functions of GCN1, shedding light on its significant involvement in the onset and progression of various cancer and non-cancer diseases. Our work underscores the role of GCN1 in the context of drug therapeutic effects, hinting at its potential as a promising drug target. Furthermore, our work delves deep into the functional mechanisms of GCN1, promising innovative avenues for the diagnosis and treatment of diseases in the future. The exploration of GCN1's multifaceted roles not only enhances our understanding of its mechanisms but also paves the way for novel therapeutic interventions. The ongoing quest to unveil additional functions of GCN1 holds the promise of further enriching our comprehension of its mode of action. [Display omitted] • The structure of GCN1 has an essential domain RWDBD. • GCN1 activates GCN2, playing a crucial role in the stress response. • As a ribosome collision sensor, GCN1 coordinates translation control. • GCN1 is a versatile player in disease and therapeutics. [ABSTRACT FROM AUTHOR]

Assessment of specific apoptosis and survival pathways implicated in anticancer drug action is important for understanding drug mechanisms and modes of resistance in order to improve the benefits of chemotherapy. In order to better examine the role of mitogen-activated protein kinases, including JNK and ERK, as well as the tumor suppressor p53, in the response of tumor cells to chemotherapy, we compared the effects on these pathways of three structurally and functionally distinct antitumor agents. Drug concentrations equal to 50 times the concentration required to reduce cell proliferation by 50% were used. Vinblastine, doxorubicin, or etoposide (VP-16) induced apoptotic cell death in KB-3 carcinoma cells, with similar kinetic profiles of PARP cleavage, caspase 3 activation, and mitochondrial cytochrome c release. All three drugs strongly activated JNK, but only vinblastine induced c-Jun phosphorylation and AP-1 activation. Inhibition of JNK by SP600125 protected cells from drug-induced cytotoxicity. Vinblastine caused inactivation of ERK whereas ERK was unaffected in cells exposed to doxorubicin or VP-16. Inhibition of ERK signaling by the MEK inhibitor, U0126, potentiated the cytotoxic effects of vinblastine and doxorubicin, but not that of VP-16. Vinblastine induced p53 downregulation, and chemical inhibition of p53 potentiated vinblastine-induced cell death, suggesting a protective effect of p53. In contrast, doxorubicin and VP-16 induced p53, and inhibition of p53 decreased drug-induced cell death, suggesting a pro-apoptotic role for p53. These results highlight the differential roles played by several key signal transduction pathways in the mechanisms of action of key antitumor agents, and suggest ways to specifically potentiate their effects in a context-dependent manner. In addition, the novel finding that JNK activation can occur without c-Jun phosphorylation or AP-1 activation has important implications for our understanding of JNK function. [Copyright &y& Elsevier]

Stress caused by pathogens strongly damages plants. Developing products to control plant disease is an important challenge in sustainable agriculture. In this study, a heat-killed endophytic bacterium (HKEB), Bacillus aryabhattai, is used to induce plant defense against fungal and bacterial pathogens, and the main defense pathways used by the HKEB to activate plant defense are revealed. The HKEB induced high protection against different pathogens through the salicylic and jasmonic acid pathways. We report the presence of gentisic acid in the HKEB for the first time. These results show that HKEBs may be a useful tool for the management of plant diseases. [ABSTRACT FROM AUTHOR]

Abstract (TiB + La 2 O 3)/Ti composites with different initial structures were obtained through designed heat treatment. The isothermal deformation and spheroidization mechanisms of (TiB + La 2 O 3)/Ti composites with different initial structures were investigated. Initial structures were refined as the heat treatment temperature decreased. Simultaneously, the quenching and reheating resulted in finer α lamella colonies and α interlamellar spacing compared to the furnace cooling. The flow resistance of furnace cooled samples was lower than the quenched and reheated samples in terms of flow stress data. Following the deformation at 920 °C, the furnace cooled samples demonstrated lamellar α phase and partial spheroidized structure. Moreover, the spheroidization mechanism was similar to the boundary splitting model. Recrystallized grains of approximately 1 μm in diameter were obtained in the quenched and reheated sample following deformation at 920 °C. The spheroidization mechanism was attributed to the development of finer needles through quenching and reheating, as well as to subsequent dynamic recrystallization during the hot deformation. Additionally, the dislocation movement was blocked by the reinforcements on account of the composites with micron TiB and submicron La 2 O 3 during the hot deformation. Furthermore, the reinforcements could facilitate the dynamic recrystallization (DRX) of the α phase. Graphical Abstract (TiB + La 2 O 3)/Ti composites with different initial structures were obtained through designed heat treatment. The matrix was composed of lamellar α phase and acicular α phase at 920 °C, respectively. In the following deformation, the furnace cooled samples demonstrated lamellar α phase and partial spheroidized structure. Moreover, the spheroidization mechanism was similar to the boundary splitting model. The spheroidization of quenched and reheated samples occurred as complete, while high amounts of fine equiaxed grains were obtained, due to the dynamic recrystallization in the subsequent deformation. Refined lamellar microstructures could promote dynamic recrystallization. Unlabelled Image Highlights • Different initial microstructures were obtained through designed heat treatment. • Refined lamellar microstructures promoted dynamic recrystallization. • The spheroidization mechanism was attributed to dynamic recrystallization. • The micron TiB and submicron La 2 O 3 impeded dislocation movement. [ABSTRACT FROM AUTHOR]

Ti–43Al–4Nb–1Mo-0.2B (at.%) (TNM) alloy sheets were fabricated, and the corresponding microstructure developed from lamellar to duplex structure with the rolling reduction increased from 50% to 72.5%. Interestingly, a novel Z-type lamellar structure developed at 67.5% deformation strain, and the formation process was discussed by calculating the Schmid factor. Moreover, α 2 +γ→β o phase transformation occurred at the kink band boundaries. Subsequently, as the reduction increased to 72.5%, the coarse β o phase decomposed and transformed to α 2 +γ phases due to the distortion energy stored after multi-pass rolling. Finally, the room-temperature tensile properties of the TNM sheets were tested. With the comparison of the as-forged alloy, the strength and ductility increased significantly by hot rolling, and the ultimate tensile strength reached 880 MPa at 60% total reduction. The relationship between the rolling process, microstructure evolution, and corresponding properties was established. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Ti-44.5Al-3.8Nb-1Mo-0.2B alloy sheets with different initial microstructures were fabricated by the multi-pass small deformation rolling technique. • The as-rolled sheet deriving from fully lamellar structure possessed a smaller grain size than that from nearly lamellar structure. • Larger deformation was needed for fully lamellar structure to obtain complete recrystallization. Ti-44.5Al-3.8Nb-1Mo-0.2B alloy (TNM) sheets were prepared by hot rolling, and the effect of the initial microstructure on the process was discussed in this work. The as-received TNM alloy billets with nearly and fully lamellar structures were prepared by forging and casting processes (named M1 and M2), respectively. For the as-rolled sheets from M1, the fraction of recrystallization increased gradually with the decrease of reduction per pass based on GOS analysis. Compared with M1, M2 required a larger deformation to achieve complete recrystallization. Meanwhile, the as-rolled sheets from M2 possessed a smaller grain size than that from M1. In addition, the γ-DRX behavior during the multi-pass hot rolling was discussed, and the DDRX was found to play the dominant role in this process. The phase transformation of β/β 0 → α occurred in the 1200 °C rolling process. It was presumed that this transformation was promoted by increasing the rolling temperature, therefore, the volume fraction of the β 0 phase decreased. The α 2 lath decomposed gradually with the increasing of rolling temperature from 1200 °C to 1250 °C, simultaneously, the combination of the adjacent γ laths resulted in the coarsening of γ lath. [ABSTRACT FROM AUTHOR]

The preparation of thioesters through the lipase-catalysed transesterification reaction of thiols with vinyl carboxyl esters is described. The reactions were carried out by Lipase TL IM from Thermomyces lanuginosus as a catalyst and performed under a continuous flow microreactor. We first found that lipase TL IM can be used in the reaction of thioester synthesis with high efficiency. Various reaction parameters were investigated including substrate molar ratio, reaction time, and temperature. Maximum conversion (96%) was obtained under the optimal condition of a substrate molar ratio of 1:2 (4-methylbenzyl mercaptan:vinyl esters) at 50 °C for about 30 min. Compared with other methods, the salient features of this work include mild reaction conditions (50 °C), short reaction times (30 min), high yields, and environment-friendliness. [ABSTRACT FROM AUTHOR]