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Supplementary Table 1 shows the list of 4C primers applied in the Circular Chromosome Conformation Capture assay.

Supplementary Materials and Methods shows detailed descriptions of methodology or materials and methods used in this manuscript.

Supplementary Figures, including Figures S1-6, and each figure legends.

Supplementary Table 4 shows the sequences of SE fragments inserted into pGL3 vector

Supplementary Table 5 shows the results of NSD2-MASPEC in KMS11 cells.

Supplementary Table 2 shows 26 SE-associated genes commonly acquired in both t(4:14)-positive HMCLs and patient-derived MM sample.

Multiple myeloma is an incurable malignancy with marked clinical and genetic heterogeneity. The cytogenetic abnormality t(4;14) (p16.3;q32.3) confers aggressive behavior in multiple myeloma. Recently, essential oncogenic drivers in a wide range of cancers have been shown to be controlled by super-enhancers (SE). We used chromatin immunoprecipitation sequencing of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs in t(4;14)-translocated multiple myeloma. The histone chaperone HJURP was aberrantly overexpressed in t(4;14)-positive multiple myeloma due to transcriptional activation by a distal SE induced by the histone lysine methyltransferase NSD2. Silencing of HJURP with short hairpin RNA or CRISPR interference of SE function impaired cell viability and led to apoptosis. Conversely, HJURP overexpression promoted cell proliferation and abrogated apoptosis. Mechanistically, the NSD2/BRD4 complex positively coregulated HJURP transcription by binding the promoter and active elements of its SE. In summary, this study introduces SE profiling as an efficient approach to identify new targets and understand molecular pathogenesis in specific subtypes of cancer. Moreover, HJURP could be a valuable therapeutic target in patients with t(4;14)-positive myeloma.Significance:A super-enhancer screen in t(4;14) multiple myeloma serves to identify genes that promote growth and survival of myeloma cells, which may be evaluated in future studies as therapeutic targets.

Supplementary Table 3 Uni- and multivariate Cox survival analysis using HJURP and NSD2 expression in myeloma dataset

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.

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 precipitations, explained up to 90% of the functional biodiversity changes. Community-level biodiversity reliably explained freshwater ecosystem shifts whereas traditional quality indices (e.g. Trophic Diatom Index) and physicochemical parameters proved to be poor metrics for these shifts.Our study advocates the advantage 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.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor outcomes and lacks effective targeted therapies. We utilized the epigenomic landscape, TCGA database and clinical samples to show the activation of HJURP in TNBC, which is associated with poor prognosis, metastasis, and advanced stage. RNA-seq analysis of HJURP silencing induced malignant phenotypes-related transcriptional signatures of TNBC. Specifically, knock-down of HJURP suppressed cell proliferation, migration, invasion, EMT progress, and induced apoptosis of TNBC. Analysis of publicly available data sets revealed that HJURP is elevated in mutP53 vs. wtP53 breast cancer cells. Inactivation of wild type P53, by loss or mutation of wtP53, increased HJURP expression, whereas accumulation of wild-type P53 reduced HJURP promoter activity and HJURP transcription. We found the activation of HJURP in TNBC was driven by the mutant P53-regulated enhancer instead of genetic alteration. P53 positively regulated the expression of transcription factor FOXM1 and E2F1, and the FOXM1/E2F1/H3K27ac complex preferentially occupied the HJURP-enhancer and regulated HJURP transcription by binding to the active elements. CRISPR interference of enhancer structure or specific disruption of enhancer complex inhibited HJURP transcription and phenocopied HJURP silencing, leading to impaired E2F1, FOXM1 and H3K27ac binding affinity. Consistent with this result, knock-down of FOXM1 or E2F1 reduced HJURP expression in TNBC cells containing mutant alleles of P53 gene. Lastly, we uncovered marked decreases in survival of breast cancer patients expressing high HJURP levels carrying wtP53. Our findings identify enhancer-driven HJURP as a molecular bypass that suppresses the anti-proliferative and pro-apoptotic effects exerted by wtP53. Targeting HJURP allows for effective suppression of tumor invasion and attenuating metastasis in P53-mutant TNBC.

Multiple myeloma is an incurable malignancy with marked clinical and genetic heterogeneity. The cytogenetic abnormality t(4;14) (p16.3;q32.3) confers aggressive behavior in multiple myeloma. Recently, essential oncogenic drivers in a wide range of cancers have been shown to be controlled by super-enhancers (SE). We used chromatin immunoprecipitation sequencing of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs in t(4;14)-translocated multiple myeloma. The histone chaperone HJURP was aberrantly overexpressed in t(4;14)-positive multiple myeloma due to transcriptional activation by a distal SE induced by the histone lysine methyltransferase NSD2. Silencing of HJURP with short hairpin RNA or CRISPR interference of SE function impaired cell viability and led to apoptosis. Conversely, HJURP overexpression promoted cell proliferation and abrogated apoptosis. Mechanistically, the NSD2/BRD4 complex positively coregulated HJURP transcription by binding the promoter and active elements of its SE. In summary, this study introduces SE profiling as an efficient approach to identify new targets and understand molecular pathogenesis in specific subtypes of cancer. Moreover, HJURP could be a valuable therapeutic target in patients with t(4;14)-positive myeloma. SIGNIFICANCE: A super-enhancer screen in t(4;14) multiple myeloma serves to identify genes that promote growth and survival of myeloma cells, which may be evaluated in future studies as therapeutic targets. Published version The work was supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative (to W.J. Chng), the NMRC Clinician Scientist Investigator award (to W.J. Chng), the RNA Biology Center at CSI Singapore, NUS, from funding by the Singapore Ministry of Education’s Tier 3 grants, grant number MOE2014-T3–1-006 (to W.J. Chng), the National Natural Science Foundation of China (grant no. 82000212 to Y. Jia), Natural Science Foundation of Zhejiang Province (grant no. LQ21H160022 to Y. Jia), Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (grant no. 2021RC003 to Y. Jia). Y. Jia also thanks the China Scholarship Council (grant no. 201706320167) for financial support to visit National University of Singapore.

Selective inhibition of photosynthesis is a fundamental strategy to solve the global challenge caused by harmful cyanobacterial blooms. However, there is a lack of specificity of the currently used cyanocides, because most of them act on cyanobacteria by generating nontargeted oxidative stress. Here, for the first time, we find that the simplest β-diketone, acetylacetone, is a promising specific cyanocide, which acts on Microcystis aeruginosa through targeted binding on bound iron species in the photosynthetic electron transport chain, rather than by oxidizing the components of the photosynthetic apparatus. The targeted binding approach outperforms the general oxidation mechanism in terms of specificity and eco-safety. Given the essential role of photosynthesis in both natural and artificial systems, this finding not only provides a unique solution for the selective control of cyanobacteria but also sheds new light on the ways to modulate photosynthesis.

Time-resolved monitoring of microalgae agglomeration facilitates screening of coagulants/flocculants (CFs) from numerous biopolymer candidates. Herein, a filtering-flowing analysis (FFA) apparatus was developed in which dispersed microalgal cells were separated from coagulates and flocs formed by CFs and pumped into spectrophotometer for real-time quantification. Polysaccharides-based CFs for Microcystis aeruginosa and several other microalgae were tested. Cationic hydroxyethyl cellulose (CHEC), chitosan quaternary ammonium (CQA) and cationic guar gum (CGG) all triggered coagulation obeying a pseudo-second-order model. Maximal coagulation efficiencies were achieved at their respective critical dosages, i.e., 0.086 g/gM.a. CHEC, 0.022 g/gM.a. CQA, and 0.216 g/gM.a. CGG. Although not active independently, bacterial exopolysaccharides (BEPS) aided coagulation of M. aeruginosa and allowed near 100% flocculation efficiency when 0.115 g/gM.a. CQA and 1.44 g/gM.a. xanthan were applied simultaneously. The apparatus is applicable to other microalgae species including Spirulina platensis, S. maxima, Chlorella vulgaris and Isochrysis galbana. Bio-based CFs sorted out using this apparatus could help develop cleaner processes for both remediation of harmful cyanobacterial blooms and microalgae-based biorefineries.

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.

Efficient biocoagulants/bioflocculants are desired for removal of Microcystis aeruginosa, the dominant harmful bloom-forming cyanobacterium. Herein, we reported cationic hydroxyethyl cellulose (CHEC) inactivated M. aeruginosa cells after forming coagulates and floating-flocculated them with aid of Agrobacterium mucopolysaccharides (AMP) and surfactant. CHEC exhibited cyanocidal activity at 20 mg/L, coagulating 85% of M. aeruginosa biomass within 9 h and decreasing 41% of chlorophyll an after 72 h. AMP acted as an adhesive flocculation aid that accelerated and strengthened the formation of flocs, approaching a maximum in 10 min. Flocs of M. aeruginosa were floated after foaming with cocoamidopropyl betaine (CAB), which facilitated the subsequent filter harvest. 82% of M. aeruginosa biomass was suspended on water surface after treated with the coagulation/flocculation-flotation (CFF) agents containing CHEC (25 mg/L), AMP (177 mg/L) and CAB (0.1 mg/L). All components in CFF agents at the applied concentrations did not inhibit acetylcholinesterase or Vibrio fischeri. Our findings provide new insights in developing bio-based materials for sustainable control of cyanobacterial blooms.

Robust strategies to identify patients at high risk for tumor metastasis, such as those frequently observed in intrahepatic cholangiocarcinoma (ICC), remain limited. While gene/protein expression profiling holds great potential as an approach to cancer diagnosis and prognosis, previously developed protocols using multiple diagnostic signatures for expression-based metastasis prediction have not been widely applied successfully because batch effects and different data types greatly decreased the predictive performance of gene/protein expression profile-based signatures in interlaboratory and data type dependent validation. To address this problem and assist in more precise diagnosis, we performed a genome-wide integrative proteome and transcriptome analysis and developed an ensemble machine learning-based integration algorithm for metastasis prediction (EMLI-Metastasis) and risk stratification (EMLI-Prognosis) in ICC. Based on massive proteome (216) and transcriptome (244) data sets, 132 feature (biomarker) genes were selected and used to train the EMLI-Metastasis algorithm. To accurately detect the metastasis of ICC patients, we developed a weighted ensemble machine learning method based on k-Top Scoring Pairs (k-TSP) method. This approach generates a metastasis classifier for each bootstrap aggregating training data set. Ten binary expression rank-based classifiers were generated for detection of metastasis separately. To further improve the accuracy of the method, the 10 binary metastasis classifiers were combined by weighted voting based on the score from the prediction results of each classifier. The prediction accuracy of the EMLI-Metastasis algorithm achieved 97.1% and 85.0% in proteome and transcriptome datasets, respectively. Among the 132 feature genes, 21 gene-pair signatures were developed to establish a metastasis-related prognosis risk-stratification model in ICC (EMLI-Prognosis). Based on EMLI-Prognosis algorithm, patients in the high-risk group had significantly dismal overall survival relative to the low-risk group in the clinical cohort (P-value

The frequent occurrence of microcystins (MCs) has caused a series of water security issues worldwide. Although MC pollution in natural waters of China has been reported, a systematic analysis of the risk of MCs in Chinese lakes and reservoirs is still lacking. In this study, the distribution, trend, and risk of MCs in Chinese lakes and reservoirs were comprehensively revealed through meta-analysis for the first time. The results showed that MC pollution occurrence in numerous lakes and reservoirs have been reported, with MC pollution being distributed in the waters of 15 provinces in China. For lakes, the maximum mean total MC (TMC) and dissolved MC (DMC) concentrations occurred in Lake Dianchi (23.06 μg/L) and Lake Taihu (1.00 μg/L), respectively. For reservoirs, the maximum mean TMC and DMC concentrations were detected in Guanting (4.31 μg/L) and Yanghe reservoirs (0.98 μg/L), respectively. The TMC concentrations in lakes were significantly higher than those in the reservoirs (p 0.05), but no difference was observed in the DMC between the two water bodies (p 0.05). Correlation analysis showed that the total phosphorus concentrations, pH, transparency, chlorophyll a, and dissolved oxygen were significantly related to the DMC in lakes and reservoirs. The ecological risks of DMC in Chinese lakes and reservoirs were generally at low levels, but high or moderate ecological risks of TMC had occurred in several waters, which were not negligible. Direct drinking water and consumption of aquatic products in several MC-polluted lakes and reservoirs may pose human health risks. This study systematically analyzed the pollution and risk of MCs in lakes and reservoirs nationwide in China and pointed out the need for further MC research and management in waters.

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.

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.

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

Cholangiocarcinoma (CCA) is a group of malignant heterogeneous cancer arising from the biliary tree. CCA has become a global health problem with rising incidence and mortality that threatens the health of human beings. The immune microenvironment of CCA is characterized by abundant cancer-associated fibroblast and suppressive immune components. The increasing body of knowledge and recent developments in transcriptomic studies have given insight into the immune landscape of CCA, paving the way for better application of immunotherapy. Immunotherapy mainly applies in a limited subset of CCA with deficient mismatch and high microsatellite instability. With limited response rates and treatment efficacy, researchers are looking into novel strategies on combination strategies and alternatives, such as immune vaccines and adoptive cell therapy. Biomarker identification is also critical for patient selection. We present an up-to-date summary of the current research on immunotherapy for CCA patients, covering pre-clinical and clinical exploration beyond immune checkpoint inhibitors, immune vaccines, and adoptive cell therapy. In addition, we review the promising biomarkers for CCA immunotherapy and discuss recent development.

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.

In the present study, both bioanalytical and instrumental tools were employed to examine the endocrine-disruptive potentials of water samples, cyanobloom samples, and sediment samples collected from in the northern region of Taihu Lake (China) during cyanobloom season. Results from cell-based bioassays suggested the occurrence of estrogenic, anti-estrogenic, anti-androgenic, and anti-glucocorticogenic activities, while no androgenic and glucocorticogenic activities were observed in the collected samples. Using an UPLC-MS/MS system, 29 endocrine disrupting compounds including seven estrogens, seven androgens, six progestogens, and five adrenocortical hormones and four industrial pollutants were simultaneously detected. 17, 20 and 12 chemicals were detected at least in one of the water samples, cyanobloom samples and sediment samples, respectively. Since both agonistic and antagonistic endocrine-disruptive activities were detected in the present study, commonly used receptor-based in vitro bioassays resulted in net effects, suggesting that the hormone receptor agonistic potentials might be underestimated with this practice. The EDCs detected in cyanobloom samples also highlight the necessity to consider the phytoplankton matrix for understanding the mass fluxes of endocrine disruptors in eutrophic freshwaters and to consider it in monitoring strategies.

Background Growing evidence suggests that alterations in epigenetic landscape contribute to pathogenesis of multiple myeloma (MM). MM cells are highly dependent on unfolded protein response signaling pathways due to high level of endoplasmic reticulum stress. Phosphorylation of eIF2a can attenuate protein translation. The PPP1R15B(denoted as R15B hereafter) gene encodes a regulatory subunit of eIF2a-specific phosphatase complex. In this study,we identified super enhancer (SE)-driven oncogenes specific in MM with a particular focus on a candidate gene R15B, whose functional roles in MM remain largely elusive. Methods We performed H3K27Ac ChIP-seq on MM cell lines, primary MM patient samples, normal CD138+ plasma cells and memory B cells. ROSE analysis was used to annotate SEs and their associated genes. A combination of public data mining, RNAi, overexpression and CRISPR/Cas9 technologies were conducted to determine the oncogenic effects of R15B in MM. Transcriptome analysis of MM cell line H929 with R15B KD and scrambled control was performed. To further study the interactions between SE and its promoters, we are currently working on HiChIP. Results We have identified R15B as one of the SE-associated genes specific to MM patient samples and cell lines. SE activity was correlated with the expression level of R15B. Higher expression of R15B predicted poor overall survival of MM patients, suggesting its clinical relevance in MM pathogenesis. R15B KD or KO significantly reduced cell viability, clonogenicity and induced G2/M arrest. ChIP-qPCR assays showed that C/EBP-β is strongly enriched at R15B SE region. We also found that salubrinal, a selective inhibitor of eIF2a phosphorylation, inhibited MM cell proliferation in a dose-dependent manner. Conclusions Our integrative approaches identified R15B as a novel SE-driven oncogene. We propose that targeting R15B may serve as a new approach for effective anti-myeloma therapy, which warrants further clinical investigation.

Multiple myeloma is an incurable malignancy with marked clinical and genetic heterogeneity. The cytogenetic abnormality t(4;14) (p16.3;q32.3) confers aggressive behavior in multiple myeloma. Recently, essential oncogenic drivers in a wide range of cancers have been shown to be controlled by super-enhancers (SE). We used chromatin immunoprecipitation sequencing of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs in t(4;14)-translocated multiple myeloma. The histone chaperone

Background Multiple myeloma (MM) is an incurable malignancy characterized by complex heterogeneous cytogenetic abnormalities. Defined as large clusters of cis-acting enhancers, super-enhancers (SEs) could promote oncogenic transcription to which cancer cells highly addicted. Structural maintenance of chromosome 4 (SMC4) is a core subunit of condensin complexes, which contributes to chromosome condensation and segregation. Here, we identified SMC4 as a novel SE-associated oncogene of myeloma cells, whose functional roles in MM remain largely elusive. Methods We performed H3K27ac ChIP-seq and RNA-seq on primary MM patient samples, MM cell lines, normal CD138+ plasma cell and lymphoma cell lines as the controls, then the ROSE analysis was used to annotate SEs and their associated genes. THZ1 as a transcriptional CDK7 inhibitor was used to further filter THZ1-responsive genes. Combined analysis of THZ1-sensitive and SE-associated gene uncovered a number of promising MM oncogenes as SMC4. The public data mining, RNA interference, CRISPR/Cas9 gene editing system, overexpression and a variety of cellular functional assays were performed to determine the oncogenic effects of SMC4 on MM malignant. Transcriptome analysis with SMC4 silencing and overexpression, and the underlying molecular mechanism of SMC4 oncogenic role in MM are ongoing. Results We have demonstrated SMC4 as one of the SE-associated genes specific to MM patient samples and cell lines. SMC4 was related to myelomagenesis with increased expression from MGUS, SMM to MM cases, and overexpression of SMC4 predicted poor overall survival of MM patients, suggesting its clinical relevance. SMC4 silencing in MM cells suppressed cell proliferation and lead to cell apoptosis. Repression of the SMC4-SE region also led to impairment of cell viability and cell growth, consistent with an oncogenic function. Conclusion In summary, our integrative approached by combing H3H27ac ChIP-seq, RNA-seq and THZ1-sensitive transcripts identified the landscape of SEs and novel oncogenic transcripts as SMC4 in MM. Mapping these acquired SEs and their associated genes may provide novel insight into understanding MM biology, and SMC4 may serve as novel therapeutic targets in MM. Citation Format: Yunlu Jia, Jianbiao Zhou, Tze-King Tan, Tae-Hoon Chung, Yongxia Chen, Enfan Zhang, Zhen Cai, Takaomi Sanda, Wee-Joo Chng. Superenhancer-drvien SMC4 promote cell growth and proliferation in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2956.

Cyanobacteria and their toxins present potential hazard to consumers of water from lakes, reservoirs and rivers, thus their removal via water treatment or at the source, is essential. Here, we report that alkyltrimethylammonium (ATMA) surfactants, such as octadecyltrimethylammonium (ODTMA) bromide, act as cyanocides that efficiently inhibit photosynthesis and growth of cyanobacteria. Green algae were found less sensitive than cyanobacteria to ATMA compounds. Fluorescence measurements and microscopic observations demonstrated that cyanobacteria cells (Aphanizomenon or Microcystis) disintegrate and lose their metabolic activity (photosynthesis) upon exposure to ATMA bromides (estimated ED50(1hr) ranged between 1.5 and 7 μM for ODTMA-Br or hexadecyltrimethylammonium (HDTMA) bromide). Other ATMA compounds, such as tetradecyltrimethylammonium (TDTMA) or dodecyltrimethylammonium (DDTMA) bromides had similar inhibitory effect but their toxicity to cyanobacteria (measured as ED50(1hr) for photosynthetic efficiency) decreased, as the length of the alkyl chain decreased. All ATMA compounds used in this study showed lower toxicity to green algae than to cyanobacteria. A toxicity mechanism for ATMA cations is proposed, based on real time fluorescence signals and on alteration of cell ultra-structure revealed by electron microscopy. The present study sheds light on the toxic effect of ATMA surfactants on cyanobacteria and its potential application for controlling the occurrence of cyanobacterial bloom in lakes, reservoirs or rivers to secure the safety of drinking water and to mitigate and manage bloom events.

Background Adriamycin (ADM) is currently one of the most effective chemotherapeutic agents in breast cancer treatment. However, growing resistance to ADM can lead to treatment failure and poor outcome. The underlying molecular mechanisms in ADM resistance in breast cancer remains unclear. PLAC8 is reported as a novel highly-conserved protein and functions as an oncogene or tumor suppressor in various tumors. Methods Here, we analyzed the expression profile of PLAC8 in breast cancer tissues and breast cancer cell lines, and explored the correlation of PLAC8 expression levels with patients’ outcomes and ADM response. One ADM resistant MCF-7 breast cancer cell (MCF-7/ADM) and its parental cell was used as in vitro models to identify the underlying mechanism of PLAC8 and ADM resistance. Breast cancer cells were transfected with PLAC8 knockdown and overexpression vectors, and MTT and colony formation assays were performed to test the cell response to ADM. Then, we tested the effect of PLAC8 on autophagy pathway by flow cytometry and immunofluorescence analysis, and the change of main autophagy-correlated factors expressions: LC3 and p62. Next, combining treatment of autophagy inhibitor/inducer and PLAC8 downregulation/upregulation revealed the participation of PLAC8 in autophagy pathway to synergistically regulate ADM resistance in breast cancer. Results Here, higher PLAC8 expression was correlated with poorer outcome and aggressive phenotype in breast cancer, and breast cancer patients with higher PLAC8 expression showed potential ADM resistance. PLAC8 expression level was also significantly elevated in ADM resistant MCF-7 breast cancer cells (MCF-7/ADM), compared to parental MCF-7 cells. In vitro experiments further confirmed that PLAC8 inhibition by siRNA or enforced overexpression by infecting pcDNA3.1(C)-PLAC8 plasmid correspondingly decreased or increased the ADM resistance. Subsequently, we demonstrated that ectopic PLAC8 expression in MCF-7/ADM cell blocked the accumulation of the autophagy-associated protein LC3II, and resulted in cellular accumulation of p62. Rapamycin-triggered autophagy significantly increased cell response to ADM, while the autophagy inhibitor 3-MA enhanced ADM resistance. Actually, 3-MA and PLAC8 could synergistically enhance ADM resistance via blocking the autophagy process. Additionally, the downregulation of p62 by siRNA attenuated the activation of autophagy and PLAC8 expression in breast cancer cells. Conclusion Our findings suggest that PLAC8, through participation of p62, inhibits autophagy and consequently results in ADM resistance in breast cancer. PLAC8/p62/autophagy pathway may act as novel therapeutic targets in breast cancer treatment and has potential clinical application in overcoming ADM resistance.

Background The ability to use dissolved organic phosphorus (DOP) is important for survival and competition when phytoplankton are faced with scarcity of dissolved inorganic phosphorus (DIP). However, phosphorus availability to the freshwater dinoflagellate Peridinium bipes has received relatively little attention, the efficiency of glycerol phosphate use by phytoplankton has rarely been investigated, and the regulatory molecular mechanisms remain unclear. Result In the present study, cultures of the freshwater dinoflagellate Peridinium bipes were set up in 119 medium (+DIP), DIP-depleted 119 medium (P-free), and β-glycerol phosphate-replacing-DIP medium (+DOP). Gene expression was analyzed using transcriptomic sequencing. The growth rate of cells in DOP treatment group was similar to that in DIP group, but chlorophyll a fluorescence parameters RC/CS0, ABS/CS0, TR0/CS0, ET0/CS0 and RE0/CS0 markedly decreased in the DOP group. Transcriptomic analysis revealed that genes involved in photosynthesis, including psbA, psbB, psbC, psbD, psaA and psaB, were downregulated in the DOP group relative to the DIP group. Glycerol-3-phosphate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase, rather than alkaline phosphatase, were responsible for β-glycerol phosphate use. Intercellular gluconeogenesis metabolism was markedly changed in the DOP group. In addition, genes involved in ATP synthases, the TCA cycle, oxidative phosphorylation, fatty acid metabolism and amino acid metabolism in P. bipes were significantly upregulated in the DOP group compared with the DIP treatment. Conclusions These findings suggested that β-glycerol phosphate could influence the photosynthesis and metabolism of P. bipes, which provided a comprehensive understanding of the phosphorus physiology of P. bipes. The mechanisms underlying the use of β-glycerol phosphate and other DOPs are different in different species of dinoflagellates and other phytoplankton. DIP reduction may be more effective in controlling the bloom of P. bipes than DOP reduction.

Long non‑coding RNA (lncRNA) H19 and Lin28 protein have been shown to participate in various pathophysiological processes, including cellular proliferation, autophagy and epithelial‑mesenchymal transition (EMT). A number of studies have investigated lncRNAs, microRNAs and mRNAs, and their roles in the initiation and progression of cancer, in doing so identifying competitive endogenous RNA (ceRNA) networks, including the H19/let‑7/Lin28 network. However, whether the H19/let‑7/Lin28 ceRNA network is involved in autophagy and EMT in breast cancer (BC) remains unclear. The present study demonstrated that the H19/let‑7/Lin28 loop was required for the downregulation of autophagy in BC cells via western blot analysis, reverse transcription‑quantitative PCR and autophagy flux monitoring. Using wound healing, migration and invasion assays, and morphological assays, the H19/let‑7/Lin28 loop was revealed to promote EMT in BC cells. Moreover, the H19/let‑7/Lin28 network was found to contribute to autophagy by inhibiting EMT in BC cells. To the best of our knowledge, the present study is the first to suggest the important roles of the H19/let‑7/Lin28 ceRNA network in BC autophagy and EMT, thus providing insight for the use of these molecules as prognostic biomarkers and therapeutic targets in BC metastasis.

Additional file 1: Table S1. Parameters calculated using data extracted from the O-J-I-P fast fluorescence transient.

The APOE ε4 allele is associated with impaired intrinsic functional connectivity in neural networks, especially in the default mode network (DMN). However, effective connectivity (EC) reflects the direct causal effects of one brain region to another, which has rarely been investigated. Recently, Granger causality analysis (GCA) proved suitable for the study of directionality in neuronal interactions. Using GCA, we examined the differences in the EC between the anterior medial prefrontal cortex/posterior cingulate cortex (aMPFC/PCC) and the whole brain in 17 ε4 carrying and 32 non-carrying cognitively intact elderly individuals. Furthermore, correlation analyses were performed between the abnormal EC and cognition/neuropathological indices. Compared with the non-carriers, the results showed that the ε4 carriers exhibited decreased EC from the PCC to the whole brain in the middle temporal gyrus (MTG), the anterior cingulate cortex (ACC), and the precuneus (PCu). Meanwhile, the ε4 carriers demonstrated increased EC from the whole brain to the aMPFC in the inferior parietal lobe (IPL) and the postcentral gyrus (PCG). The correlation analyses suggested that the EC from the IPL/PCG to the aMPFC was related to episodic memory in non-carriers, while the decreased EC from the PCC to the ACC was associated with increased levels of t-tau in the ε4 carriers. In ε4 carriers, a negative influence can be traced from the PCC to both the anterior and posterior DMN subsystems; meanwhile, the anterior DMN subsystem receives compensatory effects from the parietal cortex. Early increases in AD-related pathologies in the PCC may act as first factors during this pathological process.

The distribution of metals in cyanobloom-forming lakes, and potential risks of these metals during irrigation with water derived from the bloom were evaluated in this study. Seven metals were monitored throughout a cyanobacterial bloom season in Lake Taihu. Cyanobloom bio-dilution of the targeted metals could be explained by the negative relationships between total phytoplankton metal contents (Cu, Fe, Zn, Pb and Cr) and Chl a concentrations (p0.05). Meanwhile, the ratios of extracellular bound to total cellular bound metals (Cu, Zn, Pb, Cr and Cd) were positively correlated with the ratios of cyanophyta to total phytoplankton (p0.01), indicating the enhanced extracellular bound of these metals during cyanobloom period. Secondly, Cd, Pb and Cr were detected in several local vegetables. In comparison to reference vegetables, vegetables (e.g., radish, soybean, and cowpea), which were irrigated with cyanobloom broth collected from Lake Taihu, presented high health risk index (HRI) and were not safe for human consumption. Collectively, the frequent dominant colonial Microcystis blooms which performed high metal affinity might mediate the distribution of heavy metals in lake and potentially transferred these pollutants into terrestrial system.

Tamoxifen resistance represents a daunting challenge to the successful treatment for breast cancer. Krüppel-like factor 4 has critical roles in the development and progression of breast cancer, but its expression, function and regulation in the efficacy of TAM therapy in breast cancer have yet to be investigated. Here, we examined the clinical significance and biologic effects of KLF4 in breast cancer. Firstly, higher expression of KLF4 correlated with increased TAM sensitivity in breast cancer cells, and analysis of GEO datasets indicated that KLF4 expression was positively correlated with ERα and enhanced expression of KLF4 sensitized breast cancer patients to endocrine therapy. Knockdown of KLF4 in MCF-7 and BCAP37 cells led to increased TAM resistance, while ectopic KLF4 expression promoted the responsiveness to TAM in T47D and TAM-resistant MCF-7/TAM cells. Secondly, ectopic KLF4 overexpression suppressed MCF-7/TAM cell growth, invasion and migration. Moreover, KLF4 expression was down-regulated in breast cancer tumor tissues and high expression of KLF4 was associated with favorable outcomes. Mechanistically, KLF4 may enhance the responsiveness of breast cancer cells to TAM through suppressing mitogen-activated protein kinase (MAPK) signaling pathway. We found that ERK and p38 were more activated in MCF-7/TAM compared with MCF-7, and treatment with MAPK-specific inhibitors significantly suppressed cell viability. Knockdown of KLF4 activated ERK and p38 and drove MCF-7 cells to become resistant to TAM. Conversely, overexpression of KLF4 in MCF-7/TAM cells suppressed ERK and p38 signaling and resulted in increased sensitivity to TAM. Therefore, our findings suggested that KLF4 contributed to TAM sensitivity in breast cancer via phosphorylation modification of ERK and p38 signaling. Collectively, this study highlighted the significance of KLF4/MAPK signal interaction in regulating TAM resistance of breast cancer, and suggested that targeting KLF4/MAPK signaling may be a potential therapeutic strategy for breast cancer treatment, especially for the TAM-resistant patients.

Background: Multiple myeloma (MM) is a hematological malignancy arising from immunoglobulin-secreting plasma cells. Despite recent progress in stem-cell transplantation, high-dose chemotherapy and novel therapies, MM remains incurable and most patients experience relapse. In addition of genetic alterations, growing evidence has suggested that alterations in epigenetic landscape contribute to pathogenesis of MM. Super enhancers (SE) are large clusters of putative enhancers with aberrantly strong binding of mediators and transcription-regulating proteins. MM cells are highly dependent on unfolded protein response (UPR) signaling pathways due to high level of endoplasmic reticulum (ER) stress. Phosphorylation of eIF2α can attenuate protein translation. The PPP1R15B (denoted as R15B hereafter) gene encodes a regulatory subunit of an eIF2α-specific phosphatase complex. In this study, we identified SE-driven oncogenes specific in MM with a particular focus on a candidate SE-associated gene R15B, whose functional roles in MM remain largely elusive. Methods: We performed H3K27Ac ChIP-seq on MM cell lines, primary MM patient samples and normal CD138+ plasma cells, memory B cells (controls). ROSE analysis was used to systematically annotate SEs and their associated genes between tumors and controls. A combination of public data mining, RNA interference (RNAi), overexpression and CRISPR/Cas9 technologies followed by functional assays were conducted to determine the oncogenic effects of R15B in MM. Transcriptome analysis of MM cell line NCI-H929 with R15B knockdown and scrambled control was performed. To further study the interactions between SE and its promoters, we are currently working on highly integrative chromatin immunoprecipitation (HiChIP) followed by sequencing. Results: We have identified R15B as one of the SE-associated genes specific to MM patient samples and MM cell lines. The expression of R15B was 6- to 50-fold higher in a panel of 8 MM cell lines than normal controls. SE activity was correlated with the expression level of R15B. Higher expression of R15B predicted poor overall survival of MM patients, suggesting its clinical relevance in MM pathogenesis. Knockdown and knockout of R15B significantly reduced cell viability, clonogenicity and induced G2/M phase cell cycle arrest. Gene Ontology (GO) enrichment and pathway analysis of downregulated genes in response to R15B knockdown indicates that these genes are significantly associated with G2/M checkpoint hallmark, oxidative phosphorylation, unfolded protein response and E2F1-related pathways. Loss of R15B may induce apoptosis via activation of UPR pro-apoptotic executors PUMA and NOXA. ChIP-qPCR assays indicates that transcription factor C/EBP-β is strongly enriched at R15B SE region. Furthermore, we examined the therapeutic effects of Salubrinal, a selective inhibitor of eIF2α phosphorylation, on MM cells. Salubrinal inhibited MM cell proliferation in a dose-dependent manner, and MM cell lines with higher R15B expression were more sensitive to Salubrinal than those with lower R15B level. Conclusions: Our integrative approaches identified R15B as a novel SE-driven oncogene, and may form a positive feedback loop with C/EBP-β. Salubrinal selectively inhibits proliferation of MM cells with high R15B expression. Hence, we propose that targeting R15B may serve as a new approach for effective anti-myeloma therapy, which warrants further clinical investigation. Disclosures Chng: Novartis: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Honoraria; Amgen: Honoraria, Research Funding.

Species of the genus Microcystis are among the most notorious cyanobacteria in eutrophic lakes worldwide, with ability present adverse effects on many aquatic organisms. In the surface sediments, Microcystis can be ingested by benthic macroinvertebrates such as Chironomus. However, the potential negative effects of Microcystis on Chironomus life history traits remain unclear. In the present study, we investigated the effect of different Microcystis diets on specific behaviors (burrowing activity, locomotion ability) and life history traits of Chironomus pallidivittatus (Diptera, Chironomidae). We also studied the interactive effects of microcystin-producing M. aeruginosa and temperature (15, 20, and 25 °C) stress on chironomid larvae. The results showed that the inhibitory effect on the cumulative emergence and burrowing activity of larvae was more severe when they were fed M. aeruginosa among the three Microcystis diets groups. Locomotion ability (i.e., locomotor distance and velocity) and adult dry weight decreased significantly in the group fed M. aeruginosa. Locomotion was significantly inhibited and mortality increased when the larvae were fed a mixture of M. aeruginosa and M. wesenbergii, which may have been the result of additive or synergistic effect of the toxins. Under the stress of lower temperature, C. pallidivittatus larvae exhibited weaker locomotion and growth ability, and the emerging adults were mostly male. At both the lower and higher temperature conditions, M. aeruginosa cause cumulative emergence decreased, and sex ratio imbalance, which inhibited the reproduction of larvae from the population perspective. The fourth-instar larvae showed better adaption to Microcystis than did the other instars. This study thus highlights the adverse effects of microcystin-producing M. aeruginosa on Chironomus. It also provides a novel perspective on how environmental factors may influence the behavior and life history traits of chironomid larvae, and how they may respond to cyanobacterial blooms and global warming.

Matrix metalloproteinase-1 (MMP1) is a member of the matrix metalloproteinases family, and its aberrant expression is implicated in tumor invasion and metastasis. However, the relationship between MMP1 abnormal expression and clinical outcome in breast cancer patients remains to be elucidated. To address this issue, we conducted immunohistochemistry in breast cancer and adjacent normal tissues, and mined the transcriptional and survival data of MMP1 in breast cancer patients through Oncomine, Kaplan-Meier Plotter, bc-GenExMiner, COSMIC and cBioPortal databases. First, we found that both protein and mRNA levels of MMP1 expression were significantly higher in breast cancer tissues. Second, high MMP1 mRNA expression correlated with worse overall survival among grade II (HR = 1.75; p = 0.011), nodal-negative (HR = 2.00; p = 0.00028), ER-positive (HR = 1.61; p = 0.00027) and HER2-negative (HR = 3.17; p = 0.029) patients with breast cancer by using Kaplan-Meier plotter database. Third, the overexpression of MMP1 was associated with unfavorable survival results including overall survival (HR = 1.6; p = 1.6e-05), relapse free survival (HR = 1.78; p < 1e-16) and distant metastasis free survival (HR = 1.65; p = 5.3e-05) in patients with breast cancer. Taken together, the expression status of MMP1 is a significant prognostic indicator and a potential drug target for breast cancer.

In this study, the distribution, transfer and fate of both polychlorinated biphenyls (PCBs) and cyanotoxins via phytoplankton routes were systematically investigated in two Chinese lakes. Results indicated that PCB adsorption/bioaccumulation dynamics has significantly positive correlations with the biomass of green alga and diatoms. Total lipid content of phytoplankton is the major factor that influences PCB adsorption/bioaccumulation. Cyanobacterial blooms with relatively lower lipid content could also absorb high amount of PCBs due to their high cell density in the water columns, and this process was proposed as major route for the transfer of PCBs in Chinese eutrophic freshwater. According to these findings, a novel route on fates of PCBs via phytoplankton and a green bioadsorption concept were proposed and confirmed. In the practice of mechanical collections of bloom biomass from Lake Taihu, cyanotoxin/cyanobacteria and PCBs were found to be removed simultaneously very efficiently followed this theory.

// Xiao Luo 1, * , Yerfan Jiaerken 1, * , Xinfeng Yu 1 , Peiyu Huang 1 , Tiantian Qiu 1 , Yunlu Jia 3 , Kaicheng Li 1 , Xiaojun Xu 1 , Zhujing Shen 1 , Xiaojun Guan 1 , Jiong Zhou 2 and Minming Zhang 1 , for The Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1 Department of Radiology, The Second Affiliated Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China 2 Department of Neurology, The Second Affiliated Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China 3 Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China * These authors have contributed equally to this work Correspondence to: Minming Zhang, email: zhangminming@zju.edu.cn Keywords: apolipoprotein E (APOE), cerebral small-vascular disease (CSVD), white matter hyperintensities (WMH), dilated perivascular space (dPVS), cognition Abbreviations: APOE: apolipoprotein E; CSVD: cerebral small-vascular disease; WMH: white matter hyperintensities; dPVS: dilated perivascular space; MBs: microbleeds Received: December 29, 2016 Accepted: April 07, 2017 Published: May 09, 2017 ABSTRACT Objective: It remains unclear if and how the interactions between APOE genotypes and cerebral small-vessel diseases (CSVD) lead to cognitive decline in the long term. Based on ADNI cohort, this longitudinal study aimed to clarify the potential relationship among APOE genotype, CSVD and cognition by integrating multi-level data. Method: There were 135 healthy elderly (including e2, e4 allele carriers and e3 homozygotes) who had completed two years’ follow-up. MRI markers of CSVD, including white matter hyperintensities (WMH), dilated perivascular space (dPVS), microbleeds and lacune, were assessed. Besides, neuropathological factors including Alzheimer’s disease-related pathology measured by CSF and PiB-PET were assessed. Repeated measurements ANOVAs were performed to test impact of different APOE genotypes on CSVD. Results: We found that APOE e4 carriers had significantly more frontal WMH burden and basal ganglia dPVS at baseline and faster progression of frontal WMH burden during follow-up. Furthermore, our results showed that APOE e4 carriers had significantly decreased Aβ 1-42 level, and its level was negatively related with baseline and progressive total WMH burden. Then, general linear modals indicated interaction between basal frontal WMH burden and e4 allele was related with declining trend of cognition. Conclusion: Our findings suggested APOE e4 allele was associated with increased Aβ deposition, which may lead to the formation and progression of WMH, especially in frontal lobe. Besides, interaction between the increased frontal WMH burden and e4 allele can exert long-term detrimental effects on individual’s trajectory of cognition.

Background Sensitivity differences to chemical pollutants in different phytoplankton species may potentially shape the community structure of phytoplankton. However, detailed information supporting the understanding of sensitivity variations between phytoplankton species is still limited. Results To investigate sensitivity differences between the cyanobacterium Microcystis aeruginosa, and the green alga Chlorella sp. to paraquat, multiple physiological parameters were measured and compared through acute and chronic toxicity assays. Early photosynthetic responses during acute toxicity assays showed that paraquat affects Photosynthesis System II energy fluxes in M. aeruginosa within 3 h of exposure, but not in Chlorella sp. After 5 h of cumulative exposure, an EC50 based on the maximum quantum yield for primary photochemistry of 0.54 mg L−1 was achieved and remained more or less constant, while the EC50 values for Chlorella fluctuated around 44.76 ± 3.13 mg L−1 after 24 h of exposure. During chronic 96 h exposure to paraquat, differences in antioxidant enzyme activities, reactive oxygen species (ROS) levels, and ultrastructure were observed in both M. aeruginosa and Chlorella sp. An increase in the intracellular levels of ROS and the number of plasma membrane damaged cells was observed in M. aeruginosa in the 0.2, 0.5, and 1.0 mg L−1 treatments (p Chlorella. In addition, at an exposure level of 1.0 mg L−1, extensive disruption of cell structure was observed in M. aeruginosa. Conversely, little disarrangement of organelle structure was found in Chlorella sp. Conclusion These results confirm that paraquat is more toxic to M. aeruginosa than to Chlorella sp. The sensitivity differences between these two species (one a prokaryote and the other a eukaryote) to paraquat might be partially explained by the differences in cell structure (cell wall and photosynthetic structure), the enzymatic antioxidant system, and the physiological vulnerability. The multiple physiological endpoint analysis approach used in the current study provides more detailed information for understanding the mechanisms of sensitivity variation between these phytoplankton species.

Extreme conditions are common in energy conversion, material processing, nuclear, airspace, and military applications. In such environments, the most hardened insertion sensors do not perform reliably for long. Ultrasonic measurements, on the other hand, can be acquired noninvasively, with sensitive components kept away from the damaging environment. We have previously developed the ultrasonic method for measuring the spatial distribution of temperatures in solid materials applicable in the cases when large thermal gradients are present. In the developed approach, we use the echogenically segmented ultrasound propagation path, structured to contain engineered or naturally occurring echogenic features, to produce a train of echoes in response to an external pulse of ultrasonic excitation. The delays between the echoes, which encode the information on the temperature distribution in the corresponding segments, is used to reconstruct unknown temperature profile. In this paper, we outline the results of pilot-scale testing of the developed approach and demonstrate its application to the measurements of the temperature distribution across the containment of a high-temperature combustion process. The validation results show that the estimated temperature profile is correctly captured, and the measurement accuracy can be comparable with traditional insertion sensors, such as thermocouples. Overall, the testing has confirmed that the developed approach has matured to become an attractive alternative to conventional sensing in solving challenging problems of long-term temperature measurements in extreme environments. Heat fluxes and thermal stresses in the structure can then be characterized noninvasively using the measured temperature distribution as the basis.

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. Electronic supplementary material The online version of this article (10.1186/s13045-019-0747-0) contains supplementary material, which is available to authorized users.

The cysteine‐rich lysosomal protein placenta‐specific 8 (PLAC8), also called onzin, has been shown to be involved in many types of cancers, and its role is highly dependent on cellular and physiological contexts. However, the precise function of PLAC8 in breast cancer (BC) progression remains unclear. In this study, we investigated both the clinical significance and biological functions of PLAC8 in BC progression. First, high PLAC8 expression was observed in primary BC tissues compared with adjacent normal tissues through immunohistochemistry analysis. The results of in vitro and in vivo assays further confirmed that PLAC8 overexpression promotes cell proliferation and suppress BC cell apoptosis, whereas PLAC8 silencing has the opposite effect. In addition, the forced expression of PLAC8 greatly induces cell migration, partially by affecting the EMT‐related genes, including down‐regulating E‐cadherin expression and facilitating vimentin expression. Further mechanistic analysis confirmed that PLAC8 contributes to cell proliferation and suppresses cell apoptosis in BC by activating the PI3K/AKT/NF‐κB pathway. The results of our study provide new insights into an oncogenic role of PLAC8 and reveal a novel PLAC8/ PI3K/AKT/NF‐κB pathway as a potential therapeutic target for BC.