| 1. |
- Indukuri, Rajitha, et al.
(author)
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Genome-wide estrogen receptor β chromatin binding in humancolon cancer cells reveals its tumor suppressor activity
- 2021
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215.
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Journal article (peer-reviewed)abstract
- Colorectal cancer (CRC) is the third leading cause of cancer death in the western world. In women, menopausal hormone therapy has been shown to reduce CRC incidence by 20%. Studies demonstrate that estrogen activating estrogen receptor beta (ERβ) protects against CRC. ERβ is a nuclear receptor that regulates gene expression through interactions with the chromatin. This molecular mechanism is, however, not well characterized in colon. Here, we present for the first time, the cistrome of ERβ in different colon cancer cell lines. We use cell lines engineered to express ERβ, optimize and validate an ERβ antibody for chromatin-immunoprecipitation (ChIP), and perform ChIP-Seq. We identify key binding motifs, including ERE, AP-1, and TCF sites, and we determine enrichment of binding to cis-regulatory chromatin sites of genes involved in tumor development, cell migration, cell adhesion, apoptosis, and Wnt signaling pathways. We compare the corresponding cistromes of colon and breast cancer and find that they are conserved for about a third of genes, including GREB1, but that ERβ tethering to TCF and KLF family motifs is characteristic for colon. We exemplify upregulation of putative CRC tumor suppressor gene CST5 where ERβ in colon cells binds to cis-regulatory regions nearby (−351 bp) the transcriptional start site. Our work provides a foundation for understanding the mechanism of action of ERβ in CRC prevention.
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| 2. |
- Lu, Yehu, et al.
(author)
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A novel personal cooling system (PCS) incorporated with phase change materials (PCMs) and ventilation fans: An investigation on its cooling efficiency
- 2015
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In: Journal of Thermal Biology. - : Elsevier BV. - 0306-4565. ; 52, s. 137-146
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Journal article (peer-reviewed)abstract
- Personal cooling systems (PCS) have been developed to mitigate the impact of severe heat stress for humans working in hot environments. It is still a great challenge to develop PCSs that are portable, inexpensive, and effective. We studied the performance of a new hybrid PCS incorporating both ventilation fans and phase change materials (PCMs). The cooling efficiency of the newly developed PCS was investigated on a sweating manikin in two hot conditions: hot humid (HH, 34 °C, 75% RH) and hot dry (HD, 34 °C, 28% RH). Four test scenarios were selected: fans off with no PCMs (i.e., Fan-off, the CONTROL), fans on with no PCMs (i.e., Fan-on), fans off with fully solidified PCMs (i.e., PCM+Fan-off), and fans on with fully solidified PCMs (i.e., PCM+Fan-on). It was found that the addition of PCMs provided a 54∼78 min cooling in HH condition. In contrast, the PCMs only offered a 19–39 min cooling in HD condition. In both conditions, the ventilation fans greatly enhanced the evaporative heat loss compared with Fan-off. The hybrid PCS (i.e., PCM+Fan-on) provided a continuous cooling effect during the three-hour test and the average cooling rate for the whole body was around 111 and 315 W in HH and HD conditions, respectively. Overall, the new hybrid PCS may be an effective means of ameliorating symptoms of heat stress in both hot-humid and hot-dry environments.
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| 3. |
- Sha, Chao, et al.
(author)
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A Periodic and Distributed Energy Supplement Method based on Maximum Recharging Benefit in Sensor Networks
- 2021
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In: IEEE Internet of Things Journal. - : IEEE. - 2327-4662. ; 8:4, s. 2649-2669
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Journal article (peer-reviewed)abstract
- The issue of using vehicles to wirelessly recharge nodes for energy supplement in Wireless Sensor Networks has become a research hotspot in recent works. Unfortunately, most of the researches did not consider the rationality of the recharging request threshold and also overlooked the difference of node’s power consumption, which may lead to premature death of nodes as well as low efficiency of Wireless Charging Vehicles(WCVs). In order to solve the above problems, a Periodic and Distributed Energy Supplement Method based on maximum recharging benefit (PDESM) is proposed in this paper. Firstly, to avoid frequent recharging requests from nodes, we put forward an annuluses based cost-balanced data uploading strategy under deterministic deployment. Then, one WCV in each annulus periodically selects and recharges nodes located in this region which send the energy supplement requests. In addition, the predicted value of power consumption of nodes are calculated out according to the real-time energy consumption rate, and thus the most appropriate recharging request threshold is obtained. Finally, a moving path optimization scheme based on Minimum Spanning Tree is constructed for distributed recharging. Simulation results show that, PDESM performs well on enhancing the proportion of the alive nodes as well as the wireless recharging efficiency compared with NFAOC and FCFS. Moreover, it also has advantage in balancing the energy consumption of WCVs.
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| 4. |
- Song, Dandan
(author)
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A multi-omics approach to reveal critical mechanisms of activator protein 1 (AP-1) in cancer
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Activator protein-1 (AP-1) is a transcriptional factor complex that mainly consists of Fos and Jun family members. Jun proteins can form both homodimers and heterodimers, whereas Fos family members only form heterodimers with the Jun family. Fra-1 is a member of the Fos family proteins and plays a vital role in breast cancer progression. It is overexpressed in triplenegative breast cancer (TNBC) and related to poor clinical outcome [1]. Fra-1 is a potential therapeutic target for TNBC. As Fra-1/AP-1 is a transcriptional factor, and its transcriptional activity is controlled by coregulators, I investigated its interactome, cistrome and transcriptome with multi-omics methods in this thesis, in order to provide a comprehensive understanding of its activity. In Paper I, we reported the Fra-1 associated interactome, and identified 118 endogenous proteins that interacted with Fra-1. The most enriched one was DDX5. We investigated the cistrome and transcriptome data of both Fra-1 and DDX5 and found an extensive overlap, indicating a high degree of association between them. Further, we described that DDX5 promoted cell growth in TNBC cells, and enhanced Fra-1-related cell proliferation through enhancing the transcriptional activity of Fra-1/AP-1. Using immunohistochemistry on a breast cancer tissue microarray, we determined that DDX5 was overexpressed in basal-like breast cancer samples compared to non-basal-like tumors, similar to Fra-1. Also DDX5 was associated with poor clinical outcome of breast cancer patients. We suggested that DDX5 is a coactivator of Fra-1 and may be of interest for theraputical targeting. Besides DDX5, we found that PARP1 was among the 118 endogenous proteins that interacted with chromatin-bound Fra-1 in TNBC cells. The PARP1 inhibitor olaparib is used in the clinic for BRCA-mutated TNBC breast cancer patients. In Paper II, we explored the interaction between Fra-1 and PARP1, and demonstrated that PARP1 downregulated Fra-1 expression, and reduced Fra-1/AP-1 transcriptional activity. We found that Fra-1 can mediate resistance towards olaparib treatment, and that silencing or inhibiting Fra-1 sensitized cells towards olaparib treatment. Additionally, we determined gene expressions modified by PARP1 and that a significant fraction of these were dependent on Fra-1 expression. Next, we described that also PARP1 was overexpressed in basal-like breast cancer compared to non-basal-like patients, and that high PARP1 expression indicated a poor clinical outcome in breast cancer patients. All in all, we suggested that Fra-1 inhibition may overcome olaparib resistance in TNBC patients. Coregulators can modulate AP-1 transcriptional activity, and there is a well known but incompletely understood crosstalk between AP-1 and nuclear receptors, including estrogen receptors (ERs). A majority of breast tumors express ERα and estrogen drives the growth of these tumors. They are successfully treated with the ERα modulator tamoxifen. However, many develop resistance to this treatment, and the crosstalk between ERα and AP-1 has been reported to play a vital role in this resistance. On the contrary, estrogen signaling protects against colorectal cancer development. In the colon, ERβ is the predominant ER. We explored the transcriptional regulation, genome-wide binding activity of ERβ, and its impact on AP-1 transcription in presence and absence of tamoxifen, in Paper III. De novo motif analysis of ChIP-seq data generated with validated ERβ antibody in colon cancer cell lines with exogenous expression of ERβ revealed that ERE was the most enriched motif, followed by AP-1, indicating significant tethering by ERβ to AP-1 in colon cells. The TCF and KLF motifs were specific for colon and have not been described before in relation to ERβ cistromes (mostly performed in breast cancer cells). We demonstrated that ERβ bound and regulated tumor suppressors and oncogenes, exemplified by CST5 and LRP6, which indicated the molecular underpinnings of its anti-tumorigenic role in colon cancer. As ER/AP-1 crosstalk plays an important role in the function of both ERα and ERβ. The two receptors appear to have reverse effects in cancer development, but also significant cell- and tissue-specific effects. To better understand the differencies and similarities between the homologues ERα and ERβ, and the respective role of AP-1 crosstalk, a model where the two receptors can be studied individually in the exact same estrogen responsive cell context is needed. No suitable cell line with endogenous expression of both receptors exist, and ERβ is rarely or never expressed in cell lines. Thus, in order to provide a suitable model, in Paper IV, we used CRISPR/Cas9 to establish a estrogen-responsive MCF7 cell model which had ERβ (only) expression. In presence of Tet, these cells express no ER, and in absence of Tet, they express ERβ (only). We based this model on previously generated MCF7 Tet-Off ERβ inducible cells. Cultured with Tet, these MCF7 Tet-Off Mock cells express only ERα, similar to the parental MCF7 cells, which was our control in this study. MCF7 cells with no ER did not grow. Inducing ERβ the cells grew at a low rate, but ERα (only)-expressing cells grew faster than ERβ (only)-expressing cells. Upon E2 stimulation, ERα and ERβ showed opposite responses. Estrogen increased proliferation of ERα (only) expressing cells while decreasing proliferation of ERβ (only) expressing cells. However, ERβ (only)-expressing cells migrated faster than ERα (only)-expressing cells, but E2 treatment reduced migration of ERβ (only) cells. The transcriptome data further indicated that ERα and ERβ to some extent both regulated a proportion of genes. But that ERβ also uniquely modulated the gene expression profiles, especially genes related to ‘negative regulation of cell proliferation’, whereas ERα mediated ‘positive regulation of cell proliferation’. Combined with cistrome data, we detailed this regulation, and exemplified how ERβ uniquely binds chromatin and regulates ANXA9 which is related to migration. In conclusion, this thesis demonstrated the mechanism of Fra-1/AP-1 with multi-omics methods. We further characterized two proteins, DDX5 and PARP1, in TNBC, suggested that they played important roles in the Fra-1 signaling pathway, and their interaction provided novel strategies for TNBC therapy. Furthermore, we explored the interaction between ERβ and AP- 1, through analysis of genome-wide binding sites of ERβ in colon cancer cells, and elucidated the specific roles of ERα and ERβ in the same cellular context.
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| 5. |
- Song, Dandan, et al.
(author)
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Blocking Fra-1 sensitizes triple-negative breast cancer to PARP inhibitor
- 2021
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In: Cancer Letters. - : Elsevier BV. - 0304-3835 .- 1872-7980. ; 506, s. 23-34
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Journal article (peer-reviewed)abstract
- The AP-1 member Fra-1 is overexpressed in TNBC and plays crucial roles in tumor progression and treatment resistance. In a previous large-scale screen, we identified PARP1 to be among 118 proteins that interact with endogenous chromatin-bound Fra-1 in TNBC cells. PARP1 inhibitor (olaparib) is currently in clinical use for treatment of BRCA-mutated TNBC breast cancer. Here, we demonstrate that the Fra-1-PARP1 interaction impacts the efficacy of olaparib treatment. We show that PARP1 interacts with and downregulates Fra-1, thereby reducing AP-1 transcriptional activity. Olaparib treatment, or silencing of PARP1, consequently, increases Fra-1 levels and enhances its transcriptional activity. Increased Fra-1 can have adverse effect, including treatment resistance. We also found that a large fraction of PARP1-regulated genes was dependent on Fra-1. We show that by inhibiting Fra-1/AP-1, non-BRCA-mutated TNBC cells can become sensitized to olaparib treatment. We identify that high PARP1 expression is indicative of a poor clinical outcome in breast cancer patients overall (P = 0.01), but not for HER-2 positive patients. In conclusion, by exploring the functionality of the Fra-1 and PARP1 interaction, we propose that targeting Fra-1 could serve as a combinatory therapeutic approach to improve olaparib treatment outcome for TNBC patients.
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| 6. |
- Song, Dandan, et al.
(author)
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ER alpha and ER beta Homodimers in the Same Cellular Context Regulate Distinct Transcriptomes and Functions
- 2022
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In: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 13
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Journal article (peer-reviewed)abstract
- The two estrogen receptors ER alpha and ER beta are nuclear receptors that bind estrogen (E2) and function as ligand-inducible transcription factors. They are homologues and can form dimers with each other and bind to the same estrogen-response element motifs in the DNA. ER alpha drives breast cancer growth whereas ER beta has been reported to be anti-proliferative. However, they are rarely expressed in the same cells, and it is not fully investigated to which extent their functions are different because of inherent differences or because of different cellular context. To dissect their similarities and differences, we here generated a novel estrogen-dependent cell model where ER alpha homodimers can be directly compared to ER beta homodimers within the identical cellular context. By using CRISPR-cas9 to delete ER alpha in breast cancer MCF7 cells with Tet-Off-inducible ER beta expression, we generated MCF7 cells that express ER beta but not ER alpha. MCF7 (ER beta only) cells exhibited regulation of estrogen-responsive targets in a ligand-dependent manner. We demonstrated that either ER was required for MCF7 proliferation, but while E2 increased proliferation via ER alpha, it reduced proliferation through a G2/M arrest via ER beta. The two ERs also impacted migration differently. In absence of ligand, ER beta increased migration, but upon E2 treatment, ER beta reduced migration. E2 via ER alpha, on the other hand, had no significant impact on migration. RNA sequencing revealed that E2 regulated a transcriptome of around 800 genes via each receptor, but over half were specific for either ER alpha or ER beta (417 and 503 genes, respectively). Functional gene ontology enrichment analysis reinforced that E2 regulated cell proliferation in opposite directions depending on the ER, and that ER beta specifically impacted extracellular matrix organization. We corroborated that ER beta bound to cis-regulatory chromatin of its unique proposed migration-related direct targets ANXA9 and TFAP2C. In conclusion, we demonstrate that within the same cellular context, the two ERs regulate cell proliferation in the opposite manner, impact migration differently, and each receptor also regulates a distinct set of target genes in response to E2. The developed cell model provides a novel and valuable resource to further complement the mechanistic understanding of the two different ER isoforms.
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| 7. |
- Wang, Kui, et al.
(author)
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Efficient electro-demulsification of O/W emulsions and simultaneous oil removal enabled by a multiscale porous biocarbon electrode
- 2024
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In: Chemical Engineering Journal. - : Elsevier BV. - 1385-8947 .- 1873-3212. ; 481
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Journal article (peer-reviewed)abstract
- Emulsion wastewater contain substantial amounts of oil and various additives, which pose threats to the environment and human health. Demulsification is a crucial pretreatment stage for wastewater. This study aims to identify a novel electro-demulsification method with high oil removal efficiency and low energy consumption. Modified carbonized birch wood with a unique isotropic multiscale pore structure is used as a self-standing electrode to treat a toluene oil-in-water (O/W) emulsion. The electrode must have a highly porous structure to facilitate efficient water diffusion and oil adsorption. It must also have high electronic conductivity to expedite polarized molecular electrophoresis to realize penetration into the pores and, subsequently, demulsification. Guided by an applied electric field force, polarized O/W droplets are drawn toward the electrode, revealing electrical characteristics distinct from those of polarized organic molecules. This electric field force augments the capture and adhesion of droplets by the electric double layer at the electrode interface. Consequently, adsorbed droplets in close proximity to the electrode rupture due to the combined influence of the electric field force and the electrostatic effects stemming from the electrode's multiscale porous structure. This synergistic action enables demulsification to occur efficiently at low energy consumption levels. This study has revealed that electro-demulsification can effectively treat toluene emulsions stabilized by various surfactants and microemulsion containing toluene. Therefore, this electro-demulsification technology can be further developed for various types of water pollution.
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