bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translational downregulation of Twist1 expression by antiproliferative gene, B-cell translocation gene 2, in the triple negative breast cancer cells
Authors: Devanand Preethi , Sundaramoorthy Santhoshkumar , Ryu Min Sook , Jayabalan Aravinth kumar , Ohn Takbum , Lim In Kyoung 
Published: May 2019

AbstractTwist1, a key transcription factor regulating epithelial–mesenchymal transition and cancer metastasis, is highly expressed in invasive cancers in contrast to the loss of BTG2/TIS21expression. Based on our observation that forced expression of BTG2/TIS21downregulated Twist1 protein expression without altering mRNA level, we investigated molecular mechanisms of the BTG2/TIS21-inhibited Twist1 translation in the triple negative breast cancer (TNBC) cells and in vivo BTG2/TIS21-knockout (KO) mice and human breast cancer tissues. (1) C-terminal domain of Twist1 and Box B of BTG2/TIS21interacted with each other, which abrogated Twist1 activity. (2) BTG2/TIS21inhibited translational initiation by depleting eIF4E availability via inhibiting 4EBP1 phosphorylation. (3) Expression of BTG2/TIS21maintained p-eIF2α that downregulates initiation of protein translation, confirmed by eIF2α-AA mutant expression and BTG2/TIS21knockdown in MEF cells. (4) cDNA microarray analysis revealed significantly higher expression of initiation factors-eIF2A, eIF3A, and eIF4G2-in the BTG2/TIS21-KO mouse than that in the wild type. (5) BTG2/TIS21-inhibited translation initiation lead to the collapse of polysome formation and the huge peak of 80s monomer in the BTG2/TIS21expresser, but not in the control. (6) mRNAs and protein expressions of elongation factors were also downregulated by BTG2/TIS21expression in TNBC cells, but much higher in both TIS21-KO mice and lymph node-positive human breast cancers. (7) BTG2/TIS21-mediated Twist1 loss was not due to the protein degradation by ubiquitination and autophagy activation. (8) Twist1 protein level was significantly higher in various organs of TIS21-KO mice compared with that in the control, indicating the in vivo role ofBTG2/TIS21gene in the regulation of Twist1 protein level. Altogether, the present study support our hypothesis that BTG2/TIS21is a promising target to combat with metastatic cancers with high level of Twist1 without BTG2/TIS21expression.
The appropriate frequency and function of decidual Tim-3+CTLA-4+CD8+ T cells are important in maintaining normal pregnancy
Authors: Wang Songcun , Sun Fengrun , Li Mengdie , Qian Jinfeng , Chen Chunqin , Wang Mingyan , Zang Xingxing , Li Dajin , Yu Min , Du Meirong 
Published: May 2019

AbstractMaternal decidual CD8+ T (dCD8+ T) cells must integrate the antithetical demands of maternal–fetal tolerance and anti-viral immunity to establish a successful pregnancy. T-cell immunoglobulin mucin-3 (Tim-3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are two important co-inhibitory molecules that regulating CD8+ T cells responses during infection and tumor. In the present study, we examined the co-expression of Tim-3 and CTLA-4 on CD8+ T cells during pregnancy and found the higher frequency of Tim-3+CTLA-4+dCD8+ T cells in response to trophoblasts. This Tim-3+CTLA-4+dCD8+ T cells subset showed an active status and produced more anti-inflammatory cytokines. Furthermore, the decreased number and altered function of Tim-3+CTLA-4+dCD8+ T cells correlated to miscarriage. Combined blocking Tim-3 and CTLA-4 pathways were highly effective in inhibiting the production of anti-inflammatory cytokines and were detrimental to the maintenance of pregnancy. Together, these findings supported that Tim-3 and CTLA-4 pathways might play positive roles in the establishment and/or maintenance of maternal–fetal tolerance so to promote the maintenance of normal pregnancy. So the reproductive safety must be considered, especially when anti-Tim-3/CTLA-4 antibody (and other immune checkpoint inhibitors) are used in pregnancy.
Cloxiquine, a traditional antituberculosis agent, suppresses the growth and metastasis of melanoma cells through activation of PPARγ
Authors: Zhang Wenxiang , Shao Wei , Dong Zhewen , Zhang Shiyao , Liu Chang , Chen Siyu 
Published: May 2019

AbstractMelanoma is one of the most aggressive skin cancers and 5-year survival rate is only 4.6% for metastatic melanoma patients. Current therapies, especially those involving clinical chemotherapy drugs, have achieved remarkable advances. However, their side effects, such as bone marrow suppression, limit the effectiveness of available pharmacological therapies. Therefore, exploring new antimelanoma drugs with less toxicity is critical for the treatment of melanoma. In the present study, we aimed to identify the antimelanoma drugs with ability to repress the proliferation of melanoma cells by using a high-content screening of FDA-approved drug libraries. We found that cloxiquine (CLQ), a traditional antituberculosic drug, exhibited strong inhibitory effects on the growth and metastasis of melanoma cells both in vivo and in vitro. In contrast, CLQ at the tested doses did not show any apparent toxicity in normal melanocytes and in the liver. At the metabolic level, treatment with CLQ decreased glycolysis, thus potentially inhibiting the “Warburg effect” in B16F10 cells. More importantly, combination of CLQ and 2-deoxyglucose (2-DG), a well-known glycolysis inhibitor, did not show a synergistic effect on the tumor growth and metastasis, indicating that inhibition of glycolysis is potentially involved in mediating CLQ’s antimelanoma function. Bioinformatics analyses revealed that peroxisome proliferator-activated receptor-gamma (PPARγ) served as a potential CLQ target. Mechanistically, CLQ stimulated the transcription and nuclear contents of PPARγ. Furthermore, the specific PPARγ inhibitor GW9662 or PPARγ shRNA partially abolished the effects of CLQ. Collectively, our findings demonstrate that CLQ has a great potential in the treatment of melanoma through activation of PPARγ.
The HBx–CTTN interaction promotes cell proliferation and migration of hepatocellular carcinoma via CREB1
Authors: Li Yajun , Fu Yongming , Hu Xingwang , Sun Lunquan , Tang Daolin , Li Ning , Peng Fang , Fan Xue-gong 
Published: May 2019

AbstractHepatitis B virus-encoded X protein (HBx) acts as a tumor promoter during hepatocellular carcinoma (HCC) development, probably by regulating the expression of host proteins through protein–protein interaction. A proteomics approach was used to identify HBx-interacting proteins involved in HBx-induced hepatocarcinogenesis. We validated the proteomics findings by co-immunoprecipitation and confocal microscopy. We performed cell proliferation, migration assays and cell cycle analyses in HCC cells. Finally, we confirmed the clinical significance of our findings in samples from patients. We found that cortactin (CTTN) is a novel HBx-interacting protein, and HBx regulates the expression of CTTN in the HCC cell lines MHCC-LM3 and HepG2. Mechanistically, by upregulating the expression of cAMP response element-binding protein (CREB1) and its downstream targets, such as cyclin D1 and MMP-9, the effects of the HBx-CTTN interaction on the enhancement of cellular proliferation and migration were maintained by inhibiting cell cycle arrest. In addition, we demonstrated that the levels of CTTN and CREB1 were closely correlated in clinical samples from HBV-infected patients with HCC. Overall, our data suggests that HBx contributes to cell migration and proliferation of HCC cells by interacting with CTTN and regulating the expression of CTTN and CREB1. Therefore, the HBx/CTTN/CREB1 axis is a potential novel therapeutic target in HCC.
Targeting the transcription factor receptor LXR to treat clear cell renal cell carcinoma: agonist or inverse agonist?
Authors: Wu Guangzhen , Wang Qinglian , Xu Yingkun , Li Jianyi , Zhang Hongge , Qi Guanghui , Xia Qinghua 
Published: May 2019

AbstractGrowing evidence indicates that clear cell renal cell carcinoma (ccRCC) is a metabolism-related disease. Changes in fatty acid (FA) and cholesterol metabolism play important roles in ccRCC development. As a nuclear transcription factor receptor, Liver X receptor (LXR) regulates a variety of key molecules associated with FA synthesis and cholesterol transport. Therefore, targeting LXR may provide new therapeutic targets for ccRCC. However, the potential regulatory effect and molecular mechanisms of LXR in ccRCC remain unknown. In the present study, we found that both an LXR agonist and an XLR inverse agonist could inhibit proliferation and colony formation and induce apoptosis in ccRCC cells. We observed that the LXR agonist LXR623 downregulated the expression of the low-density lipoprotein receptor (LDLR) and upregulated the expression of ABCA1, which resulted in reduced intracellular cholesterol and apoptosis. The LXR inverse agonist SR9243 downregulated the FA synthesis proteins sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthase (FASN) and stearoyl-coA desaturase 1 (SCD1), causing a decrease in intracellular FA content and inducing apoptosis in ccRCC cells. SR9243 and LXR623 induced apoptosis in ccRCC cells but had no killing effect on normal renal tubular epithelial HK2 cells. We also found that SRB1-mediated high-density lipoprotein (HDL) in cholesterol influx is the cause of high cholesterol in ccRCC cells. In conclusion, our data suggest that an LXR inverse agonist and LXR agonist decrease the intracellular FA and cholesterol contents in ccRCC to inhibit tumour cells but do not have cytotoxic effects on non-malignant cells. Thus, LXR may be a safe therapeutic target for treating ccRCC patients.
Mesostructure and orientation control of lyotropic liquid crystals in a polysiloxane matrix
Authors: Hara Mitsuo 
Published: May 2019

AbstractAs a preparation method for organic–inorganic or mesoporous inorganic materials via sol–gel condensation of a metal alkoxide, the combination of lyotropic liquid crystals (LLCs) and sol–gel chemistry is a versatile tool to fabricate various nanostructures. Despite previous investigations into such systems, no attempt has been made to utilize the dynamic switching functions of such nanostructures via the phase transition of LLCs in films. A polysiloxane containing an amine-hydrochloride group and a vinyl group was recently synthesized. By controlling the relative humidity, we achieved the phase transition of LLCs and on-demand UV-curing of LLC phases in the polysiloxane film. We further developed vertically oriented organic–inorganic nanochannels by using π−π interactions between discotic molecules and the substrate surface or the spontaneous vertical alignment of LLC containing azobenzene units.
Physically informed artificial neural networks for atomistic modeling of materials
Authors: Pun G. P. Purja , Batra R. , Ramprasad R. , Mishin Y. 
Published: May 2019

AbstractLarge-scale atomistic computer simulations of materials heavily rely on interatomic potentials predicting the energy and Newtonian forces on atoms. Traditional interatomic potentials are based on physical intuition but contain few adjustable parameters and are usually not accurate. The emerging machine-learning (ML) potentials achieve highly accurate interpolation within a large DFT database but, being purely mathematical constructions, suffer from poor transferability to unknown structures. We propose a new approach that can drastically improve the transferability of ML potentials by informing them of the physical nature of interatomic bonding. This is achieved by combining a rather general physics-based model (analytical bond-order potential) with a neural-network regression. This approach, called the physically informed neural network (PINN) potential, is demonstrated by developing a general-purpose PINN potential for Al. We suggest that the development of physics-based ML potentials is the most effective way forward in the field of atomistic simulations.
High-throughput calculations of catalytic properties of bimetallic alloy surfaces
Authors: Mamun Osman , Winther Kirsten T. , Boes Jacob R. , Bligaard Thomas 
Published: May 2019

AbstractA comprehensive database of chemical properties on a vast set of transition metal surfaces has the potential to accelerate the discovery of novel catalytic materials for energy and industrial applications. In this data descriptor, we present such an extensive study of chemisorption properties of important adsorbates - e.g., C, O, N, H, S, CHx, OH, NH, and SH - on 2,035 bimetallic alloy surfaces in 5 different stoichiometric ratios, i.e., 0%, 25%, 50%, 75%, and 100%. To our knowledge, it is the first systematic study to compile the adsorption properties of such a well-defined, large chemical space of catalytic interest. We propose that a collection of catalytic properties of this magnitude can assist with the development of machine learning enabled surrogate models in theoretical catalysis research to design robust catalysts with high activity for challenging chemical transformations. This database is made publicly available through the platform www.Catalysis-hub.org for easy retrieval of the data for further scientific analysis.
Catalysis-Hub.org, an open electronic structure database for surface reactions
Authors: Winther Kirsten T. , Hoffmann Max J. , Boes Jacob R. , Mamun Osman , Bajdich Michal , Bligaard Thomas 
Published: May 2019

AbstractWe present a new open repository for chemical reactions on catalytic surfaces, available at https://www.catalysis-hub.org. The featured database for surface reactions contains more than 100,000 chemisorption and reaction energies obtained from electronic structure calculations, and is continuously being updated with new datasets. In addition to providing quantum-mechanical results for a broad range of reactions and surfaces from different publications, the database features a systematic, large-scale study of chemical adsorption and hydrogenation on bimetallic alloy surfaces. The database contains reaction specific information, such as the surface composition and reaction energy for each reaction, as well as the surface geometries and calculational parameters, essential for data reproducibility. By providing direct access via the web-interface as well as a Python API, we seek to accelerate the discovery of catalytic materials for sustainable energy applications by enabling researchers to efficiently use the data as a basis for new calculations and model generation.
Establishment of a model of sentinel lymph node metastasis using immunodeficient swine
Authors: Kurihara Toshiaki , Matsuda Sachiko , Nakamura Yuki , Suzuki Shunichi , Fuchimoto Daiichiro , Onishi Akira , Saeki Kohei , Nakagawa Takayuki , Fujiwara Reina , Kamata Masatoshi , Kuramoto Junko , Kameyama Kaori , Sekino Masaki , Kusakabe Moriaki , Hayashida Tetsu , Jinno Hiromitsu , Kitagawa Yuko 
Published: May 2019

AbstractLymph node metastasis occurs via the migration of cancer cells through the lymphatic system. Sentinel lymph node (SLN) biopsy is a common diagnostic strategy. SLNs have been studied using healthy rodents and large animals without metastasis. Here we used immunodeficient swine to establish a model of lymph node metastasis. We used RAG2-knockout immunodeficient swine. A431 human epithelial carcinoma cells expressing green fluorescent protein were injected subcutaneously into the posterior sides of the auricle, forelimb and hindlimb of knockout swine. Indigo carmine dye was injected subcutaneously 8 weeks after tumour cell transplantation. SLNs were extracted, observed using a stereoscopic fluorescence microscope and analysed histologically using haematoxylin and eosin staining, and immunohistochemistry. Lymphoid follicles were found in wild-type swine, and a few aggregated lymphocytes and immature lymphoid follicles were observed in knockout swine. Fluorescence in the lymph nodes indicated metastasis of tumour cells to the lymph nodes. Tumour cells replaced lymph node architectures, showed high-grade nuclear atypia and formed irregular tumour nests. Our model may be useful for the preclinical validation of diagnostic methods and minimally invasive treatment of metastatic cancer.
Metabolic Characteristics of a Novel Ultrasound Quantitative Diagnostic Index for Nonalcoholic Fatty Liver Disease
Authors: Liao Yin-Yin , Yeh Chih-Kuang , Huang Kuo-Chin , Tsui Po-Hsiang , Yang Kuen-Cheh 
Published: May 2019

AbstractNonalcoholic fatty liver disease (NAFLD) is an emerging epidemic worldwide and is regarded as a hepatic manifestation of metabolic syndrome (MetS). Only a few studies have discussed the biological features associated with quantitative assessment of ultrasound for characterizing NAFLD. Our aim was to delineate relevant metabolic characteristics using a new quantitative tool, the ultrasound quantitative diagnostic index (QDI). A total of 394 ultrasound data were analyzed to extract texture-feature parameters, the signal-to-noise ratio (SNR), and the slope of the center frequency downshift (CFDS) for determining the QDI. The texture index, SNR, and CFDS slope were all negatively correlated with high-density lipoprotein and positively correlated with other anthropometric indices and metabolic factors (all P < 0.05). The SNR had the greatest contribution to anthropometric and biochemical factors, followed by the texture index and CFDS slope. An increase in 1 unit of QDI score engendered a 9% higher risk of MetS, reflecting that the tool is feasible for use in identifying MetS (area under the receiver operating characteristic curve: 0.89). The QDI was correlated with metabolic factors and an independent predictor for MetS. Thus, this QDI might be a feasible method for use in clinical surveillance, epidemiology research, and metabolic function evaluations in patients with NAFLD.
Histone demethylase KDM6B regulates human podocyte differentiation in vitro
Authors: Guo Yanyan , Xiong Zuying , Guo Xiaoqiang 
Published: May 2019

Abstract
Podocytes are terminally differentiated and highly specialized glomerular cells, which have an essential role as a filtration barrier against proteinuria. Histone methylation has been shown to influence cell development, but its role in podocyte differentiation is less understood. In this study, we first examined the expression pattern of histone demethylase KDM6B at different times of cultured human podocytes in vitro. We found that the expression of KDM6B and podocyte differentiation markers WT1 and Nephrin are increased in the podocyte differentiation process. In cultured podocytes, KDM6B knockdown with siRNA impaired podocyte differentiation and led to expression down-regulation of WT1 and Nephrin. The treatment of podocytes with GSK-J4, a specific KDM6B inhibitor, can also obtain similar results. Overexpression of WT1 can rescue differentiated phenotype impaired by disruption of KDM6B. ChIP (chromatin immunoprecipitation) assay further indicated that KDM6B can bind the promoter region of WT1 and reduce the histone H3K27 methylation. Podocytes in glomeruli from nephrotic patients exhibited increased KDM6B contents and reduced H3K27me3 levels. These data suggest a role for KDM6B as a regulator of podocyte differentiation, which is important for the understanding of podocyte function in kidney development and related diseases.
Toxins for decoding interface selectivity in nicotinic acetylcholine receptors
Authors: Kini R. Manjunatha 
Published: May 2019

Abstract
Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that play crucial roles in neurotransmission and regulate complex processes in brain functions, including anxiety, learning and memory, food intake, drug addiction, cognition and nociception. To perform these and other functions, a diverse array of nAChR subtypes are generated by homomeric or heteromeric assembly of 17 homologous nAChR subunits. Agonists, acetylcholine and nicotine, bind to the interface formed between two α subunits and between α and non-α subunits to activate the nAChR and allow cation influx. The diversity of subunit interfaces determines the channel properties, the responses to different agonists/antagonists, desensitization and downstream signaling and thus, define specialized properties and functions. Over the last several decades, snake venom neurotoxins have contributed to the purification, localization and characterization of molecular details of various nAChRs. Utkin et al. have described the purification and characterization of αδ-bungarotoxins, a novel class of neurotoxins in a recent paper published in the Biochemical Journal [Biochem. J. (2019) 476, 1285–1302]. These toxins from Bungarus candidus venom preferably bind to α–δ site with two orders of magnitude higher affinity compared with α–γ or α–ε sites. The subtle changes in the structure of αδ-bungarotoxins led to variation in interface selectivity. Such new classes of antagonists will offer us great opportunity to delineate the pharmacophores and design new highly selective antagonists. Thus, their findings provide new impetus to re-evaluate molecular details of pharmacological properties of α-neurotoxins with careful consideration towards subtype-, interface- and species-selectivity.
Loss of GCN5L1 in cardiac cells disrupts glucose metabolism and promotes cell death via reduced Akt/mTORC2 signaling
Authors: Manning Janet R. , Thapa Dharendra , Zhang Manling , Stoner Michael W. , Traba Javier , Corey Catherine , Shiva Sruti , Sack Michael N. , Scott Iain 
Published: May 2019

Abstract
GCN5L1 regulates protein acetylation and mitochondrial energy metabolism in diverse cell types. In the heart, loss of GCN5L1 sensitizes the myocardium to injury from exposure to nutritional excess and ischemia/reperfusion injury. This phenotype is associated with the reduced acetylation of metabolic enzymes and elevated mitochondrial reactive oxygen species (ROS) generation, although the direct molecular targets of GCN5L1 remain largely unknown. In this study, we sought to determine the mechanism by which GCN5L1 impacts energy substrate utilization and mitochondrial health. We find that hypoxia and reoxygenation (H/R) leads to a reduction in cell viability and Akt phosphorylation in GCN5L1 knockdown AC16 cardiomyocytes, in parallel with elevated glucose utilization and impaired fatty acid use. We demonstrate that glycolysis is uncoupled from glucose oxidation under normoxic conditions in GCN5L1-depleted cells. We show that GCN5L1 directly binds to the Akt-activating mTORC2 component Rictor, and that loss of Rictor acetylation is evident in GCN5L1 knockdown cells. Finally, we show that restoring Rictor acetylation in GCN5L1-depleted cells reduces mitochondrial ROS generation and increases cell survival in response to H/R. These studies suggest that GCN5L1 may play a central role in energy substrate metabolism and cell survival via the regulation of Akt/mTORC2 signaling.