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Abstract Multiple myeloma is a hematological malignancy arising from immunoglobulin-secreting plasma cells. It remains poorly understood how chromatin rewiring of regulatory elements contributes to tumorigenesis and therapy resistance in myeloma. Here we generate a high-resolution contact map of myeloma-associated super-enhancers by integrating H3K27ac ChIP-seq and HiChIP from myeloma cell lines, patient-derived myeloma cells and normal plasma cells. Our comprehensive transcriptomic and phenomic analyses prioritize candidate genes with biological and clinical implications in myeloma. We show that myeloma cells frequently acquire SE that transcriptionally activate an oncogene PPP1R15B, which encodes a regulatory subunit of the holophosphatase complex that dephosphorylates translation initiation factor eIF2α. Epigenetic silencing or knockdown of PPP1R15B activates pro-apoptotic eIF2α-ATF4-CHOP pathway, while inhibiting protein synthesis and immunoglobulin production. Pharmacological inhibition of PPP1R15B using Raphin1 potentiates the anti-myeloma effect of bortezomib. Our study reveals that myeloma cells are vulnerable to perturbation of PPP1R15B-dependent protein homeostasis, highlighting a promising therapeutic strategy.

Summary: Stress granules (SGs), membrane-less cellular organelles formed via liquid-liquid phase separation, are central to how cells adapt to various stress conditions, including endoplasmic reticulum stress, nutrient scarcity, and hypoxia. Recent studies have underscored a significant link between SGs and the process of tumorigenesis, highlighting that proteins, associated components, and signaling pathways that facilitate SG formation are often upregulated in cancer. SGs play a key role in enhancing tumor cell proliferation, invasion, and migration, while also inhibiting apoptosis, facilitating immune evasion, and driving metabolic reprogramming through multiple mechanisms. Furthermore, SGs have been identified as crucial elements in the development of resistance against chemotherapy, immunotherapy, and radiotherapy across a variety of cancer types. This review delves into the complex role of SGs in cancer development and resistance, bringing together the latest progress in the field and exploring new avenues for therapeutic intervention.

Abstract Background Extranodal natural killer/T-cell lymphoma (NKTL) is an aggressive type of non-Hodgkin lymphoma with dismal outcome. A better understanding of disease biology and key oncogenic process is necessary for the development of targeted therapy. Super-enhancers (SEs) have been shown to drive pivotal oncogenes in various malignancies. However, the landscape of SEs and SE-associated oncogenes remain elusive in NKTL. Methods We used Nano-ChIP-seq of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs NKTL primary tumor samples. Integrative analysis of RNA-seq and survival data further pinned down high value, novel SE oncogenes. We utilized shRNA knockdown, CRISPR-dCas9, luciferase reporter assay, ChIP-PCR to investigate the regulation of transcription factor (TF) on SE oncogenes. Multi-color immunofluorescence (mIF) staining was performed on an independent cohort of clinical samples. Various function experiments were performed to evaluate the effects of TOX2 on the malignancy of NKTL in vitro and in vivo. Results SE landscape was substantially different in NKTL samples in comparison with normal tonsils. Several SEs at key transcriptional factor (TF) genes, including TOX2, TBX21(T-bet), EOMES, RUNX2, and ID2, were identified. We confirmed that TOX2 was aberrantly overexpressed in NKTL relative to normal NK cells and high expression of TOX2 was associated with worse survival. Modulation of TOX2 expression by shRNA, CRISPR-dCas9 interference of SE function impacted on cell proliferation, survival and colony formation ability of NKTL cells. Mechanistically, we found that RUNX3 regulates TOX2 transcription by binding to the active elements of its SE. Silencing TOX2 also impaired tumor formation of NKTL cells in vivo. Metastasis-associated phosphatase PRL-3 has been identified and validated as a key downstream effector of TOX2-mediated oncogenesis. Conclusions Our integrative SE profiling strategy revealed the landscape of SEs, novel targets and insights into molecular pathogenesis of NKTL. The RUNX3-TOX2-SE-TOX2-PRL-3 regulatory pathway may represent a hallmark of NKTL biology. Targeting TOX2 could be a valuable therapeutic intervene for NKTL patients and warrants further study in clinic.

IntroductionSmall cell lung cancer (SCLC) transformation serves as a significant mechanism of resistance to tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. To address this clinical challenge, we conducted a retrospective analysis at Zhejiang University School of Medicine, the First Affiliated Hospital, focusing on patients with EGFR sensitizing mutations.MethodsA total of 1012 cases were included in this retrospective analysis. The cohort primarily consisted of patients with EGFR sensitizing mutations. Biopsy-confirmed small cell transformation was observed in seven patients, accounting for 0.7% of the cases. All patients in this subset were initially diagnosed with stage IV adenocarcinoma (ADC), with four cases classified as poorly differentiated and three as moderately to poorly differentiated ADC. EGFR exon 19 deletions were identified in five of these cases. Next-generation sequencing (NGS) was performed on seven cases, revealing mutations in the tumor protein p53 (TP53) gene in four cases and loss of the retinoblastoma1 (RB1) gene in three cases.ResultsThe median duration from the initial diagnosis to small cell transformation was 35.9 months (interquartile range: 12.1–84 months). Following small cell transformation during EGFR inhibition, all patients received etoposide/platinum-based treatment, leading to a median progression-free survival (PFS) of 4.7 months (interquartile range: 2.7–10.1 months). Notably, most patients in this series had poorly differentiated adenocarcinomas at the outset. TP53 mutations and RB1 loss were common genetic alterations observed in patients with small cell transformation in this cohort.DiscussionThe findings underscore the clinical significance of SCLC transformation as a resistance mechanism to EGFR TKIs in NSCLC with EGFR mutations. The observed genetic alterations, including TP53 mutations and RB1 loss, suggest potential associations with the transformation process and warrant further investigation. Understanding the genetic landscape and clinical outcomes in patients experiencing small cell transformation can contribute to improved strategies for managing resistance in EGFR-mutant NSCLC.

Despite efforts from scientists and regulators, biodiversity is declining at an alarming rate. Unless we find transformative solutions to preserve biodiversity, future generations may not be able to enjoy nature’s services. We have developed a conceptual framework that establishes the links between biodiversity dynamics and abiotic change through time and space using artificial intelligence. Here, we apply this framework to a freshwater ecosystem with a known history of human impact and study 100 years of community-level biodiversity, climate change and chemical pollution trends. We apply explainable network models with multimodal learning to community-level functional biodiversity measured with multilocus metabarcoding, to establish correlations with biocides and climate change records. We observed that the freshwater community assemblage and functionality changed over time without returning to its original state, even if the lake partially recovered in recent times. Insecticides and fungicides, combined with extreme temperature events and precipitation, explained up to 90% of the functional biodiversity changes. The community-level biodiversity approach used here reliably explained freshwater ecosystem shifts. These shifts were not observed when using traditional quality indices (e.g. Trophic Diatom Index). Our study advocates the use of high-throughput systemic approaches on long-term trends over species-focused ecological surveys to identify the environmental factors that cause loss of biodiversity and disrupt ecosystem functions.

Abstract Triple-negative breast cancer is still a difficult point in clinical treatment at present, and a deep study of its pathogenesis has great clinical value. Therefore, our research mainly focuses on exploring the progression of triple-negative breast cancer and determines the important role of the HJURP/YAP1/NDRG1 transcriptional regulation axis in triple-negative breast cancer. We observed significantly increased HJURP expression levels in triple-negative breast cancer compared to other subtypes. HJURP could affect the level of ubiquitination modification of YAP1 protein and then regulate its downstream transcriptional activity. Mechanistically, we found that YAP1 positively regulates NDRG1 transcription by binding the promoter region of the NDRG1 gene. And HJURP/YAP1/NDRG1 axis could affect cell proliferation and chemotherapy sensitivity in triple-negative breast cancer. Taken together, these findings provide insights into the transcriptional regulation axis of HJURP/YAP1/NDRG1 in triple-negative breast cancer progression and therapeutic response.

Summary: Despite the epidemiological association between intrahepatic cholangiocarcinoma (ICC) and hepatitis B virus (HBV) infection, little is known about the relevant oncogenic effects. A cohort of 32 HBV-infected ICC and 89 non-HBV-ICC patients were characterized using whole-exome sequencing, proteomic analysis, and single-cell RNA sequencing. Proteomic analysis revealed decreased cell-cell junction levels in HBV-ICC patients. The cell-cell junction level had an inverse relationship with the epithelial-mesenchymal transition (EMT) program in ICC patients. Analysis of the immune landscape found that more CD8 T cells and Th2 cells were present in HBV-ICC patients. Single-cell analysis indicated that transforming growth factor beta signaling–related EMT program changes increased in tumor cells of HBV-ICC patients. Moreover, ICAM1+ tumor-associated macrophages are correlated with a poor prognosis and contributed to the EMT in HBV-ICC patients. Our findings provide new insights into the behavior of HBV-infected ICC driven by various pathogenic mechanisms involving decreased cell junction levels and increased progression of the EMT program.

Although programmed cell death (PCD) has been reported in phytoplankton, knowledge of the characterization of the PCD pathway and cascade process in different phytoplankton species is still limited. In this study, PCD progression in cyanobacterium Microcystis aeruginosa and green algae Chlorella luteoviridis by paraquat-induced oxidative stress was monitored. The results showed that paraquat-induced PCD in the two species belonged to the caspase-dependent pathway. Dose- and time-dependent PCD characteristics in the two strains under paraquat included the increase in caspase-like activity, DNA fragmentation, and chromatin condensation. However, the signaling pathway and cascade events of PCD in M. aeruginosa and C. luteoviridis differed. In M. aeruginosa, the free Ca2+ concentration was rapidly increased at 8 h, followed by a significant elevation of the reactive oxygen species (ROS) level at 24 h, and eventual cell death. In C. luteoviridis, the mitochondrial apoptosis pathway, revealed by the depolarization of the mitochondrial membrane potential at 1 h and increase in the ROS level and caspase-like activity at 8 h, might contribute to cell death. In addition, the dynamics of ROS levels and metacaspase activity were synchronized, suggesting that paraquat-triggered PCD was ROS-mediated in both M. aeruginosa and C. luteoviridis. These results provide insights into PCD patterns in prokaryotic cyanobacteria and eukaryotic green algae under similar stress.

BackgroundAs the forefront of nanomedicine, bionic nanotechnology has been widely used for drug delivery in order to obtain better efficacy but less toxicity for cancer treatments. With the rise of immunotherapy, the combination of nanotechnology and immunotherapy will play a greater potential of anti-tumor therapy. Due to its advantage of homologous targeting and antigen library from source cells, cancer cell membrane (CCM)-wrapped nanoparticles (CCNPs) has become an emerging topic in the field of immunotherapy.Key scientific concepts of reviewCCNP strategies include targeting or modulating the tumor immune microenvironment and combination therapy with immune checkpoint inhibitors and cancer vaccines. This review summarizes the current developments in CCNPs for cancer immunotherapy and provides insight into the challenges of transferring this technology from the laboratory to the clinic as well as the potential future of this technology.ConclusionThis review described CCNPs have enormous potential in cancer immunotherapy, but there are still challenges in terms of translating their effects in vitro to the clinical setting. We believe that these challenges can be addressed in the future with a focus on individualized treatment with CCNPs as well as CCNPs combined with other effective treatments.

Abstract Multiple myeloma (MM) is an aggressive plasma cell neoplasm characterized by genomic heterogeneity. Superenhancers (SEs) are defined as large clusters of enhancers in close genomic proximity, which regulate genes for maintaining cellular identity and promote oncogenic transcription to which cancer cells highly addicted. Here, we analyzed cis-regulatory elements in MM samples with H3K27ac ChIP-seq, to identify novel SE-associated genes involved in the myeloma pathogenesis. SEs and their associated genes in cancerous tissue were compared with the control samples, and we found SE analysis alone uncovered cell-lineage-specific transcription factors and well-known oncogenes ST3GAL6 and ADM. Using a transcriptional CDK7 inhibitor, THZ1, coupled with H3K27ac ChlP-seq, we identified MAGI2 as a novel SE-associated gene of myeloma cells. Elevated MAGI2 was related to myelomagenesis with gradual increased expression from MGUS, SMM to newly diagnosed and relapsed MM. High prevalence of MAGI2 was also associated with poor survival of MM patients. Importantly, inhibition of the SE activity associated with MAGI2 decreased MAGI2 expression, inhibited cell growth and induced cell apoptosis. Mechanistically, we revealed that the oncogenic transcription factor, MAF, directly bound to the SE region and activated gene transcription. In summary, the discoveries of these acquired SEs-associated genes and the novel mechanism by which they are regulated provide new insights into MM biology and MAGI2-MAF-SE regulatory circuit offer potential novel targets for disease treatment.

Although platinum-based chemotherapeutics such as cisplatin are the cornerstone of treatment for ovarian cancer, their clinical application is profoundly limited due to chemoresistance and severe adverse effects. Sporoderm-broken spores of Ganoderma lucidum (SBSGL) have been reported to possess antitumor effects. However, the function and mechanism of SBSGL and its essential composition, ganoderic acid D (GAD), in the cisplatin therapy on ovarian cancer have yet to be investigated. Here, we investigated the combined effect of SBSGL and cisplatin in an ovarian tumor xenograft model. The results showed that combining SBSGL with cisplatin reduced tumor growth and ameliorated cisplatin-induced intestinal injury and myelosuppression. We also confirmed that GAD could enhance the therapeutic effect of cisplatin in SKOV3 and cisplatin-resistant SKOV3/DDP cells by increasing the intracellular reactive oxygen species (ROS). Mechanistically, we proved that ROS-mediated ERK signaling inhibition played an important role in the chemo-sensitization effect of GAD on cisplatin in ovarian cancer. Taken together, combining SBSGL with cisplatin provides a novel therapeutic strategy against ovarian cancer.

NRF2 is an important regulatory transcription factor involved in tumor immunity and tumorigenesis. In this study, we firstly identified that FKBP4/NR3C1 axis was a novel negative regulator of NRF2 in human breast cancer (BC) cells. The effect of FKBP4 appeared to be at protein level of NRF2 since it could not suppress the expression of NRF2 at mRNA level. Bioinformatics analysis and in vitro experiments further demonstrated that FKBP4 regulated NRF2 via regulating nuclear translocation of NR3C1. We then reported that naringenin, a flavonoid, widely distributed in citrus and tomato, could suppress autophagy and proliferation of BC cells through FKBP4/NR3C1/NRF2 signaling pathway in vitro and in vivo. Naringenin was also found to promote dendritic cell (DC) differentiation and maturation through FKBP4/NR3C1/NRF2 axis. Therefore, our study found that naringenin could induce inhibition of autophagy and cell proliferation in BC cells and enhance DC differentiation and maturation, at least in part, though regulation of FKBP4/NR3C1/NRF2 signaling pathway. Identification of FKBP4/NR3C1/NRF2 axis would provide insights for novel anti-tumor strategy against BC among tumor microenvironment.

Chemoresistance is a daunting challenge to the prognosis of patients with breast cancer. Signal transducer and activator of transcription (STAT) 5a plays vital roles in the development of various cancers, but its function in breast cancer is controversial, and its role in chemoresistance in breast cancer remains unexplored. Here we identified STAT5a as a chemoresistance inducer that regulates the expression of ABCB1 in breast cancer and can be targeted by pimozide, an FDA-approved psychotropic drug. First, we found that STAT5a and ABCB1 were expressed at higher levels in doxorubicin-resistant cell lines and chemoresistant patients, and their expression was positively correlated. Then, we confirmed the essential roles of STAT5a and ABCB1 in doxorubicin resistance in breast cancer cells and the regulation of ABCB1 transcription by STAT5a. Subsequently, the efficacy of pimozide in inhibiting STAT5a and sensitizing doxorubicin-resistant breast cancer cells was tested. Finally, we verified the role of STAT5a in doxorubicin resistance in breast cancer and the efficacy of pimozide in reversing this resistance in vivo. Our study demonstrated the vital role of STAT5a in doxorubicin resistance in breast cancer. Targeting STAT5a might be a promising strategy for treating doxorubicin-resistant breast cancer. Moreover, repurposing pimozide for doxorubicin resensitization is attractive due to the safety profile of pimozide.

Abstract Background Tamoxifen resistance remains a clinical challenge for hormone receptor-positive breast cancer. Recently, dysregulations in autophagy have been suggested as a potential mechanism for tamoxifen resistance. Although the long noncoding RNA H19 is involved in various stages of tumorigenesis, its role in tamoxifen resistance remains unknown. Here, we assessed the role of H19 in the development of tamoxifen-resistant breast cancer. Methods Quantitative real-time PCR analyzed expression of H19 in tamoxifen-resistant breast cancer tissues. Knockdown of H19 was used to assess the sensitivity to tamoxifen in vitro and in vivo. Both knockdown and overexpression of H19 were used to analyze the status of autophagy. Real-time quantitative methylation-specific polymerase chain reaction, chromatin immunoprecipitation, immunofluorescence, and Western blot were used to explore the tamoxifen resistance mechanism of H19. Results In this study, we observed that the expression of H19 was substantially upregulated in tamoxifen-resistant breast cancer cell line and tumor tissues, and knockdown of H19 enhanced the sensitivity to tamoxifen both in vitro and in vivo. Furthermore, knockdown of H19 significantly inhibited autophagy in MCF7 tamoxifen-resistant (MCF7/TAMR) cells. Conversely, overexpression of H19 promoted autophagy. Interestingly, overexpression of H19 in MCF7 tamoxifen-sensitive cells could recapitulate tamoxifen resistance. Moreover, an increase in methylation in the promoter region of Beclin1 was observed in MCF7/TAMR-shH19 cells. In the double knockdown groups, both shH19+shSAHH and shH19+shDNMT3B rescued the Beclin1 promoter region methylation levels and reactivated autophagy functions. A chromatin immunoprecipitation assay further validated that DNMT3B binds to the Beclin1 promoter region and the knockdown of H19 increases this binding. Conclusions Our findings demonstrate that H19 induces autophagy activation via the H19/SAHH/DNMT3B axis, which could contribute to tamoxifen resistance in breast cancer.

Abstract Super-enhancers (SEs) in a broad range of human cell types are large clusters of enhancers with aberrant high levels of transcription factor binding, which are central to drive expression of genes in controlling cell identity and stimulating oncogenic transcription. Cancer cells acquire super-enhancers at oncogene and cancerous phenotype relies on these abnormal transcription propelled by SEs. Furthermore, specific inhibitors targeting SEs assembly and activation have offered potential targets for treating various tumors including hematological malignancies. Here, we first review the identification, functional significance of SEs. Next, we summarize recent findings of SEs and SE-driven gene regulation in normal hematopoiesis and hematologic malignancies. The importance and various modes of SE-mediated MYC oncogene amplification are illustrated. Finally, we highlight the progress of SEs as selective therapeutic targets in basic research and clinical trials. Some open questions regarding functional significance and future directions of targeting SEs in the clinic will be discussed too.

Mitigation of harmful cyanobacterial blooms that constitute a serious threat to water quality, particularly in eutrophic water, such as in aquaculture, is essential. Thus, in this study, we tested the efficacy of selected cyanocides towards bloom control in laboratory and outdoor mesocosm experiments. Specifically, we focused on the applicability of a group of cationic disinfectants, alkyltrimethyl ammonium (ATMA) compounds and H2O2. The biocidal effect of four ATMA cations with different alkyl chain lengths was evaluated ex situ using Microcystis colonies collected from a fish pond. The most effective compound, octadecyl trimethyl ammonium (ODTMA), was further evaluated for its selectivity towards 24 cyanobacteria and eukaryotic algae species, including Cyanobacteria, Chlorophyta, Bacillariophyta, Euglenozoa and Cryptophyta. The results indicated selective inhibition of cyanobacteria by ODTMA-Br (C18) on both Chroccocales and Nostocales, but a minor effect on Chlorophytes and Bacillariophytes. The efficacy of ODTMA-Br (C18) (6.4 μM) in mitigating the Microcystis population was compared with that of a single low dose of H2O2 treatments (117.6 μM). ODTMA-Br (C18) suppressed the regrowth of Microcystis for a longer duration than did H2O2. The results suggested that ODTMA-Br (C18) may be used as an effective cyanocide and that it is worth further evaluating this group of cationic compounds as a treatment to mitigate cyanobacterial blooms in aquaculture.

Through a meticulous analysis of ancient Chinese literature, this study comprehensively documents the geographical distribution of Fuling, a traditional Chinese medicinal material, during the Tang, Song, Ming, and Qing dynasties spanning from the seventh to the twentieth century in China. Based on the contemporary distribution information of Fuling, we utilized the maximum entropy (MaxEnt) model to simulate the suitable distribution areas of Fuling under both present-day conditions and in the future (2081~2100). The findings reveal that climate change has influenced the distribution of Fuling production areas. The shifts in Fuling’s origin during different periods in ancient and modern times align with climate fluctuations and concurrent societal development. During the Tang and Song dynasties, Fuling primarily originated in northern China. However, it migrated southward during the Little Ice Age (LIA) and has recently shown a slight northward shift, in line with the climate fluctuations of the LIA and contemporary global warming trends. This study offers a comprehensive analysis of the changes in the distribution and production areas of Fuling over a 1500-year period, encompassing ancient, modern, and future periods. The results provide critical insights for adjusting Fuling cultivation areas in response to climate change and for further exploration of the mechanisms through which climate impacts the growth of Fuling.

Finite mixture of linear regression (FMLR) models are among the most exemplary statistical tools to deal with various heterogeneous data. In this paper, we introduce a new procedure to simultaneously determine the number of components and perform variable selection for the different regressions for FMLR models via an exponential power error distribution, which includes normal distributions and Laplace distributions as special cases. Under some regularity conditions, the consistency of order selection and the consistency of variable selection are established, and the asymptotic normality for the estimators of non-zero parameters is investigated. In addition, an efficient modified expectation-maximization (EM) algorithm and a majorization-maximization (MM) algorithm are proposed to implement the proposed optimization problem. Furthermore, we use the numerical simulations to demonstrate the finite sample performance of the proposed methodology. Finally, we apply the proposed approach to analyze a baseball salary data set. Results indicate that our proposed method obtains a smaller BIC value than the existing method.

Abstract G protein-coupled receptor (GPCR) heterodimers are new targets for the treatment of depression. Increasing evidence supports the importance of serotonergic and orexin-producing neurons in numerous physiological processes, possibly via a crucial interaction between 5-hydroxytryptamine 1A receptor (5-HT1AR) and orexin receptor 1 (OX1R). However, little is known about the function of 5-HT1AR/OX1R heterodimers. It is unclear how the transmembrane domains (TMs) of the dimer affect its function and whether its modulation mediates antidepressant-like effects. Here, we examined the mechanism of 5-HT1AR/OX1R dimerization and downstream G protein-dependent signaling. We found that 5-HT1AR and OX1R form constitutive heterodimers that induce novel G protein-dependent signaling, and that this heterodimerization does not affect recruitment of β-arrestins to the complex. In addition, we found that the structural interface of the active 5-HT1AR/OX1R dimer transforms from TM4/TM5 in the basal state to TM6 in the active conformation. We also used mutation analyses to identify key residues at the interface (5-HT1AR R1514.40, 5-HT1AR Y1985.41, and OX1R L2305.54). Injection of chronic unpredictable mild stress (CUMS) rats with TM4/TM5 peptides improved their depression-like emotional status and decreased the number of endogenous 5-HT1AR/OX1R heterodimers in the rat brain. These antidepressant effects may be mediated by upregulation of BDNF levels and enhanced phosphorylation and activation of CREB in the hippocampus and medial prefrontal cortex. This study provides evidence that 5-HT1AR/OX1R heterodimers are involved in the pathological process of depression. Peptides including TMs of the 5-HT1AR/OX1R heterodimer interface are candidates for the development of compounds with fast-acting antidepressant-like effects.

In order to reveal the effect of irradiation damage caused by high-level liquid radioactive wastes on the welded joint of the container, the irradiation-induced microstructure evolution and mechanical properties degradation of the 310S stainless steel welded joints were investigated in this study. For this purpose, the 1.3 MeV 60Co and 2 MeV accelerators were used to simulate irradiation experiments on 310S welded joints. The uniaxial tensile tests characterized the specimens' mechanical properties and fracture morphology. The results revealed that elongation was reduced by about 5% of irradiation damage by 60Co, and the fracture morphology shows a large number of secondary cracks. In contrast, the elongation was recovered irradiated by the accelerator, and the fracture morphology showed a large number of dimples. Following the interrupted creep deformation, creep fracture tests were conducted for irradiation specimens. The 60Co irradiation damage significantly decreases the creep resistance, leading to deformation of creep, which is increased to 1.5 times that of those unirradiated specimens. At the same time, the ductility is seriously degraded for the irradiated creep fracture specimens. As a result, the creep fracture strain of 60Co specimens is reduced to 70% of that of unirradiated specimens. Further, ductility reduction was related to the irradiated hardening by 60Co, while Nano-indenter hardness was 5.9 GPa, higher by 44% than the unirradiated specimens. The results are shown in an enrichment of Cr, C and P elements at phase boundaries for 60Co irradiation specimens, while the magnitude of element segregation increased by the accelerator combination irradiation. Finally, the creep cracking analysis results show intergranular cracking was observed on the surfaces of the irradiated specimens, while the M23C6 has a primary relationship with the intergranular cracks. The synergic effect of irradiation promoted damage, and element segregation was the primary cause of the intergranular cracking of the 310S welded joints.

In nonlinear time series analysis, the mixture autoregressive model (MAR) is an effective statistical tool to capture the multimodality of data. However, the traditional methods usually need to assume that the error follows a specific distribution that is not adaptive to the dataset. This paper proposes a mixture autoregressive model via an asymmetric exponential power distribution, which includes normal distribution, skew-normal distribution, generalized error distribution, Laplace distribution, asymmetric Laplace distribution, and uniform distribution as special cases. Therefore, the proposed method can be seen as a generalization of some existing model, which can adapt to unknown error structures to improve prediction accuracy, even in the case of fat tail and asymmetry. In addition, an expectation-maximization algorithm is applied to implement the proposed optimization problem. The finite sample performance of the proposed approach is illustrated via some numerical simulations. Finally, we apply the proposed methodology to analyze the daily return series of the Hong Kong Hang Seng Index. The results indicate that the proposed method is more robust and adaptive to the error distributions than other existing methods.

In order to reveal the effects of the glass solidification bottling process of high-level liquid radioactive wastes on the welded joints of containers, the microstructure evolution and mechanical properties of 310S stainless steel welded joints were investigated. For this purpose, samples were heat-treated in a resistance furnace at 1100 °C, with two groups of samples being thermally shocked and heat-treated in the furnace. The results indicated that the grain-size distribution changed from unimodal to bimodal for the thermally shocked samples, which was caused by abnormal growth due to the grain growth driving force during recrystallization. Spinel oxide ((Fe, Cr, Ni)3O4) and Cr2O3 were the main oxides at 1100 °C. The dislocations almost disappeared and needle-like structures that were rich in N and Cr formed in the welded joints after being thermally shocked. The tensile properties of the thermally shocked welded joints showed decreases in yield strength and plasticity. The fracture morphologies of the samples heated in the furnace and the as-welded samples presented with dimples. However, the morphologies of the fracture surfaces of the thermally shocked samples presented large numbers of secondary cracks and smooth characteristics.

Apelin and Elabela are endogenous peptide ligands for Apelin receptor (APJ), a widely expressed G protein-coupled receptor. They constitute a spatiotemporal dual ligand system to control APJ signal transduction and function. We investigated the effects of Apelin-13, pGlu1-apelin-13, Apelin-17, Apelin-36, Elabela-21 and Elabela-32 peptides on APJ signal transduction. Whether different ligands are biased to different APJ mediated signal transduction pathways was studied. We observed the different changes of G protein dependent and β-arrestin dependent signaling pathways after APJ was activated by six peptide ligands. We demonstrated that stimulation with APJ ligands resulted in dose-dependent increases in both G protein dependent [cyclic AMP (cAMP), Ca2+ mobilization, and the early phase extracellular related kinase (ERK) activation] and β-arrestin dependent [GRKs, β-arrestin 1, β-arrestin 2, and β2 subunit of the clathrin adaptor AP2] signaling pathways. However, the ligands exhibited distinct signaling profiles. Elabela-32 showed a >1000-fold bias to the β-statin-dependent signaling pathway. These data provide that Apelin-17 was biased toward β-arrestin dependent signaling. Eabela-21 and pGlu1-Apelin-13 exhibited very distinct activities on the G protein dependent pathway. The activity profiles of these ligands could be valuable for the development of drugs with high selectivity for specific APJ downstream signaling pathways.

The apelin and Elabela proteins constitute a spatiotemporal double-ligand system that controls apelin receptor (APJ) signal transduction. Phosphorylation of multiple sites within the C-terminus of APJ is essential for the recruitment of β-arrestins. We sought to determine the precise mechanisms by which apelin and Elabela promote APJ phosphorylation, and to elucidate the influence of β-arrestin phosphorylation on G-protein-coupled receptor (GPCR)/β-arrestin-dependent signaling. We used techniques including mass spectrometry (MS), mutation analysis, and bioluminescence resonance energy transfer (BRET) to evaluate the role of phosphorylation sites in APJ-mediated G-protein-dependent and β-dependent signaling. Phosphorylation of APJ occurred at five serine residues in the C-terminal region (Ser335, Ser339, Ser345, Ser348 and Ser369). We also identified two phosphorylation sites in β-arrestin1 and three in β-arrestin2, including three previously identified residues (Ser412, Ser361, and Thr383) and two new sites, Tyr47 in β-arrestin1 and Tyr48 in β-arrestin2. APJ mutations did not affect the phosphorylation of β-arrestins, but it affects the β-arrestin signaling pathway, specifically Ser335 and Ser339. Mutation of Ser335 decreased the ability of the receptor to interact with β-arrestin1/2 and AP2, indicating that APJ affects the β-arrestin signaling pathway by stimulating Elabela. Mutation of Ser339 abolished the capability of the receptor to interact with GRK2 and β-arrestin1/2 upon stimulation with apelin-36, and disrupted receptor internalization and β-arrestin-dependent ERK1/2 activation. Five peptides act on distinct phosphorylation sites at the APJ C-terminus, differentially regulating APJ signal transduction and causing different biological effects. These findings may facilitate screening for drugs to treat cardiovascular and metabolic diseases.

The orphan receptor APJ and its endogenous ligand apelin, which are expressed in the brain, are the major components of the apelin/APJ system. Growing evidence shows that the apelin/APJ system plays a vital role in the pathophysiology of cerebral ischemic injury. Targeting the apelin/APJ system may have protective effects on cerebral ischemic injury. In this review, we sum up the latest research progress relating to the actions and therapeutic potential of the apelin/APJ system in ischemic stroke. An in-depth knowledge of the pathophysiological effects of the apelin/APJ system and the underlying mechanisms will help to develop novel therapeutic interventions for ischemic stroke.

In order to reveal the creep failure behavior of novel modified 310S austenite steel welded joints, the creep life and microstructure evolution of the 310S austenite steel welded joints were investigated in this study. The rupture life was assessed to estimate the damage of the welded joint based on creep rupture tests performed at 600 °C in the stress range of 170–238 MPa. Compared with WM, HAZ facilitated the occurrence of creep failure in long term creep due to the combination of a smaller hardness value, a more heterogenous microstructure accompanied by coarsened M23C6, a larger grain size, higher KAM and Schmid factor. Discontinuous Laves phases appeared near the boundaries between the δ-ferrite and γ-austenite grains in the WM, and dislocation strengthening and precipitation strengthening were observed near the boundary in the BM. Furthermore, segregation elements were detected by APT and EDS adjacent to the boundary. Cr and C segregation near grain boundaries weaken the creep resistance in long term creep service.

Growth hormone secretagogue receptor 1α (GHSR1a) and Orexin 1 receptor (OX1R) are involved in various important physiological processes, and have many similar characteristics in function and distribution in peripheral tissues and the central nervous system. We explored the possibility of heterodimerization between GHSR1a and OX1R and revealed a signal transduction pathway mechanism. In this study, bioluminescence and fluorescence resonance energy transfer and co-immunoprecipitation (Co-IP) analyses were performed to demonstrate the formation of functional GHSR1a/OX1R heterodimers. This showed that a peptide corresponding to the 5-transmembrane domain of OX1R impaired heterodimer construction. We found that ghrelin stimulated GHSR1a/OX1R heterodimer cells to increase the activation of Gαs protein, compared to the cells that express GHSR1a. Stimulation of GHSR1a/OX1R heterodimers with orexin-A did not alter GPCR interactions with Gα protein subunits. GHSR1a/OX1R heterodimers induced Gαs and downstream signaling pathway activity, including increase of cAMP-response element luciferase reporter activity and cAMP levels. In addition, ghrelin induced a higher proliferation rate in SH-SY5Y cells than in controls. This suggests that ghrelin GHSR1a/OX1R heterodimers promotes an upregulation of a Gαs-cAMP-cAMP-responsive element signaling pathway in vitro and an increase in neuroblastoma cell proliferation.