bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroRNA-125b reverses oxaliplatin resistance in hepatocellular carcinoma by negatively regulating EVA1A mediated autophagy
Authors: Ren Wei-Wei , Li Dan-Dan , Chen Xiaolan , Li Xiao-Long , He Ya-Ping , Guo Le-Hang , Liu Lin-Na , Sun Li-Ping , Zhang Xiao-Ping 
Published: May 2018

AbstractEVA1A (also known as transmembrane protein 166) is a transmembrane protein involved in the regulation of autophagy that acts as an adaptor protein to recruit or bind proteins in the lysosome or endoplasmic reticulum. In the present study, we identified EVA1A as a target of microRNA-125b (miR-125b), a member of a highly conserved family of miRNAs that has been proposed as a biomarker for hepatocellular carcinoma (HCC). Analysis of oxaliplatin-sensitive and oxaliplatin-resistant HCC cell lines showed that miR-125b is downregulated in resistant cells and its overexpression in sensitive cells decreased resistance to oxaliplatin by inhibiting cell proliferation, migration and epithelial–mesenchymal transition (EMT). EVA1A expression was shown to be upregulated in tissue samples from oxaliplatin-resistant HCC patients, and its ectopic expression partially induced autophagy and reversed the effect of miR-125b on inhibiting the growth of oxaliplatin-resistant cell lines and xenograft tumors. Taken together, our results suggest that miR-125b plays a role in the resistance of HCC cells to chemotherapy via a mechanism involving the downregulation of EVA1A-mediated autophagy.
CD47-ligation induced cell death in T-acute lymphoblastic leukemia
Authors: Leclair Pascal , Liu Chi-Chao , Monajemi Mahdis , Reid Gregor S. , Sly Laura M. , Lim Chinten James 
Published: May 2018

AbstractCD47 is a cell-surface marker well recognized for its anti-phagocytic functions. As such, an emerging avenue for targeted cancer therapies involves neutralizing the anti-phagocytic function using monoclonal antibodies (mAbs) to enhance tumour cell immunogenicity. A lesser known consequence of CD47 receptor ligation is the direct induction of tumour cell death. While several mAbs and their derivatives with this property have been studied, the best characterized is the commercially available mAb B6H12, which requires immobilization for induction of cell death. Here, we describe a commercially available mAb, CC2C6, which induces T-cell acute lymphoblastic leukemia (ALL) cell death in soluble form. Soluble CC2C6 induces CD47-dependent cell death in a manner consistent with immobilized B6H12, which is characterized by mitochondrial deficiencies but is independent of caspase activation. Titration studies indicated that CC2C6 shares a common CD47-epitope with B6H12. Importantly, CC2C6 retains the anti-phagocytic neutralizing function, thus possessing dual anti-tumour properties. Although CD47-ligation induced cell death occurs in a caspase-independent manner, CC2C6 was found to stimulate increases in Mcl-1 and NOXA levels, two Bcl-2 family proteins that govern the intrinsic apoptosis pathway. Further analysis revealed that the ratio of Mcl-1:NOXA were minimally altered for cells treated with CC2C6, in comparison to cells treated with agents that induced caspase-dependent apoptosis which alter this ratio in favour of NOXA. Finally, we found that CC2C6 can synergize with low dose chemotherapeutic agents that induce classical apoptosis, giving rise to the possibility of an effective combination treatment with reduced long-term sequelae associated with high-dose chemotherapies in childhood ALL.
MiR-3662 suppresses hepatocellular carcinoma growth through inhibition of HIF-1α-mediated Warburg effect
Authors: Chen Zhiqiang , Zuo Xueliang , Zhang Yao , Han Guoyong , Zhang Long , Wu Jindao , Wang Xuehao 
Published: May 2018

AbstractGlucose metabolic reprogramming from oxidative to aerobic glycolysis, referred as the Warburg effect, is a hallmark of tumor cells. Accumulating evidence suggests that a subset of microRNAs play pivotal roles in modulating such reprogramming of glucose metabolism in cancer cells. miR-3662 has been implicated previously in both pro-tumorigenic and anti-tumorigenic effects in several types of cancer. The expression level of miR-3662 is downregulated in acute myeloid leukemia, whereas increased miR-3662 expression is observed in lung adenocarcinoma. However, the roles and underlying mechanisms of miR-3662 in hepatocellular carcinoma (HCC) metabolic reprogramming remain unclear. Our present study revealed that miR-3662 was frequently downregulated in HCC tissues and cell lines. The low expression level of miR-3662 was associated with tumor size, tumor multiplicity, Edmondson grade, and tumor-node-metastasis stage. Gain-of-function and loss-of-function assays showed that miR-3662 dampened glycolysis by reducing lactate production, glucose consumption, cellular glucose-6-phosphate level, ATP generation, and extracellular acidification rate, and increasing oxygen consumption rate in HCC cells after treatment with the hypoxia mimetic CoCl2. Moreover, miR-3662 suppressed cell growth in vitro and in vivo, and induced G1/S cell cycle arrest. miR-3662 inhibited the activation of ERK and JNK signaling pathways in HCC. By combined computational and experimental approaches, hypoxia-inducible factor-1α (HIF-1α) was determined as a direct target of miR-3662. After treatment with the hypoxia mimetic CoCl2, miR-3662 regulated the Warburg effect and HCC progression via decreasing HIF-1α expression. Our findings uncover a mechanistic role for miR-3662/HIF-1α axis in HCC metabolic reprogramming, providing a potential therapeutic strategy in liver cancer.
BH4 domain peptides derived from Bcl-2/Bcl-XL as novel tools against acute pancreatitis
Authors: Vervliet Tim , Gerasimenko Julia V. , Ferdek Pawel E. , Jakubowska Monika A. , Petersen Ole H. , Gerasimenko Oleg V. , Bultynck Geert 
Published: May 2018

AbstractBiliary acute pancreatitis (AP) is a serious condition, which currently has no specific treatment. Taurolithocholic acid 3-sulfate (TLC-S) is one of the most potent bile acids causing cytosolic Ca2+ overload in pancreatic acinar cells (PACs), which results in premature activation of digestive enzymes and necrosis, hallmarks of AP. The inositol 1,4,5-trisphosphate receptor (IP3R) and the ryanodine receptor (RyR) play major roles in intracellular Ca2+ signaling. Inhibition of these endoplasmic reticulum-located channels suppresses TLC-S-induced Ca2+ release and necrosis, decreasing the severity of AP. Anti-apoptotic B-cell lymphoma (Bcl)-2-family members, such as Bcl-2 and Bcl-XL, have emerged as important modulators of IP3Rs and RyRs. These proteins contain four Bcl-2 homology (BH) domains of which the N-terminal BH4 domain exerts critical roles in regulating intracellular Ca2+ release channels. The BH4 domain of Bcl-2, but not of Bcl-XL, binds to and inhibits IP3Rs, whereas both BH4 domains inhibit RyRs. Although clear cytoprotective effects have been reported for these BH4 domains, it remains unclear whether they are capable of inhibiting pathological Ca2+-overload, associated with AP. Here we demonstrate in PACs that the BH4 domains of Bcl-2 and Bcl-XL inhibit RyR activity in response to the physiological agonist cholecystokinin. In addition, these BH4 domains inhibit pathophysiological TLC-S-induced Ca2+ overload in PACs via RyR inhibition, which in turn protects these cells from TLC-S-induced necrosis. This study shows for the first time the therapeutic potential of BH4 domain function by inhibiting pathological RyR-mediated Ca2+ release and necrosis, events that trigger AP.
Hyperglycemia potentiates a shift from apoptosis to RIP1-dependent necroptosis
Authors: McCaig William D. , Patel Payal S. , Sosunov Sergey A. , Shakerley Nicole L. , Smiraglia Tori A. , Craft Miranda M. , Walker Katharine M. , Deragon Matthew A. , Ten Vadim S. , LaRocca Timothy J. 
Published: May 2018

AbstractApoptosis and necroptosis are the primary modes of eukaryotic cell death, with apoptosis being non-inflammatory while necroptosis is highly inflammatory. We previously demonstrated that, once activated, necroptosis is enhanced by hyperglycemia in several cell types. Here, we determine if hyperglycemia affects apoptosis similarly. We show that hyperglycemia does not enhance extrinsic apoptosis but potentiates a shift to RIP1-dependent necroptosis. This is due to increased levels and activity of RIP1, RIP3, and MLKL, as well as decreased levels and activity of executioner caspases under hyperglycemic conditions following stimulation of apoptosis. Cell death under hyperglycemic conditions was classified as necroptosis via measurement of markers and involvement of RIP1, RIP3, and MLKL. The shift to necroptosis was driven by RIP1, as mutation of this gene using CRISPR–Cas9 caused cell death to revert to apoptosis under hyperglycemic conditions. The shift of apoptosis to necroptosis depended on glycolysis and production of mitochondrial ROS. Importantly, the shift in PCD was observed in primary human T cells. Levels of RIP1 and MLKL increased, while executioner caspases and PARP1 cleavage decreased, in cerebral tissue from hyperglycemic neonatal mice that underwent hypoxia-ischemia (HI) brain injury, suggesting that this cell death shift occurs in vivo. This is significant as it demonstrates a shift from non-inflammatory to inflammatory cell death which may explain the exacerbation of neonatal HI-brain injury during hyperglycemia. These results are distinct from our previous findings where hyperglycemia enhanced necroptosis under conditions where apoptosis was inhibited artificially. Here we demonstrate a shift from apoptosis to necroptosis under hyperglycemic conditions while both pathways are fully active. Therefore, while our previous work documented that intensity of necroptosis is responsive to glucose, this work sheds light on the molecular balance between apoptosis and necroptosis and identifies hyperglycemia as a condition that pushes cells to undergo necroptosis despite the initial activation of apoptosis.
Precise control of SCRaMbLE in synthetic haploid and diploid yeast
Authors: Jia Bin , Wu Yi , Li Bing-Zhi , Mitchell Leslie A. , Liu Hong , Pan Shuo , Wang Juan , Zhang Hao-Ran , Jia Nan , Li Bo , Shen Michael , Xie Ze-Xiong , Liu Duo , Cao Ying-Xiu , Li Xia , Zhou Xiao , Qi Hao , Boeke Jef D. , Yuan Ying-Jin 
Published: May 2018

AbstractCompatibility between host cells and heterologous pathways is a challenge for constructing organisms with high productivity or gain of function. Designer yeast cells incorporating the Synthetic Chromosome Rearrangement and Modification by LoxP-mediated Evolution (SCRaMbLE) system provide a platform for generating genotype diversity. Here we construct a genetic AND gate to enable precise control of the SCRaMbLE method to generate synthetic haploid and diploid yeast with desired phenotypes. The yield of carotenoids is increased to 1.5-fold by SCRaMbLEing haploid strains and we determine that the deletion of YEL013W is responsible for the increase. Based on the SCRaMbLEing in diploid strains, we develop a strategy called Multiplex SCRaMbLE Iterative Cycling (MuSIC) to increase the production of carotenoids up to 38.8-fold through 5 iterative cycles of SCRaMbLE. This strategy is potentially a powerful tool for increasing the production of bio-based chemicals and for mining deep knowledge.
Autophagy promotes the survival of dormant breast cancer cells and metastatic tumour recurrence
Authors: Vera-Ramirez Laura , Vodnala Suman K. , Nini Ryan , Hunter Kent W. , Green Jeffrey E. 
Published: May 2018

AbstractCancer recurrence after initial diagnosis and treatment is a major cause of breast cancer (BC) mortality, which results from the metastatic outbreak of dormant tumour cells. Alterations in the tumour microenvironment can trigger signalling pathways in dormant cells leading to their proliferation. However, processes involved in the initial and the long-term survival of disseminated dormant BC cells remain largely unknown. Here we show that autophagy is a critical mechanism for the survival of disseminated dormant BC cells. Pharmacologic or genetic inhibition of autophagy in dormant BC cells results in significantly decreased cell survival and metastatic burden in mouse and human 3D in vitro and in vivo preclinical models of dormancy. In vivo experiments identify autophagy gene autophagy-related 7 (ATG7) to be essential for autophagy activation. Mechanistically, inhibition of the autophagic flux in dormant BC cells leads to the accumulation of damaged mitochondria and reactive oxygen species (ROS), resulting in cell apoptosis.
Heterozygous diploid and interspecies SCRaMbLEing
Authors: Shen Michael J. , Wu Yi , Yang Kun , Li Yunxiang , Xu Hui , Zhang Haoran , Li Bing-Zhi , Li Xia , Xiao Wen-Hai , Zhou Xiao , Mitchell Leslie A. , Bader Joel S. , Yuan Yingjin , Boeke Jef D. 
Published: May 2018

AbstractSCRaMbLE (Synthetic Chromosome Rearrangement and Modification by LoxP-mediated Evolution) is a genome restructuring technique that can be used in synthetic genomes such as that of Sc2.0, the synthetic yeast genome, which contains hundreds to thousands of strategically positioned loxPsym sites. SCRaMbLE has been used to induce rearrangements in yeast strains harboring one or more synthetic chromosomes, as well as plasmid DNA in vitro and in vivo. Here we describe a collection of heterozygous diploid strains produced by mating haploid semisynthetic Sc2.0 strains to haploid native parental strains. We subsequently demonstrate that such heterozygous diploid strains are more robust to the effects of SCRaMbLE than haploid semisynthetic strains, rapidly improve rationally selected phenotypes in SCRaMbLEd heterozygous diploids, and establish that multiple sets of independent genomic rearrangements are able to lead to similar phenotype enhancements. Finally, we show that heterozygous diploid SCRaMbLE can also be carried out in interspecies hybrid strains.
Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer
Authors: Sarkar Anita , Bale Shridhar , Behrens Anna-Janina , Kumar Sonu , Sharma Shailendra Kumar , de Val Natalia , Pallesen Jesper , Irimia Adriana , Diwanji Devan C. , Stanfield Robyn L. , Ward Andrew B. , Crispin Max , Wyatt Richard T. , Wilson Ian A. 
Published: May 2018

AbstractFurin cleavage of the HIV envelope glycoprotein is an essential step for cell entry that enables formation of well-folded, native-like glycosylated trimers, releases constraints on the fusion peptide, and limits enzymatic processing of the N-glycan shield. Here, we show that a cleavage-independent, stabilized, soluble Env trimer mimic (BG505 NFL.664) exhibits a “closed-form”, native-like, prefusion conformation akin to furin-cleaved Env trimers. The crystal structure of BG505 NFL.664 at 3.39 Å resolution with two potent bNAbs also identifies the full epitopes of PGV19 and PGT122 that target the receptor binding site and N332 supersite, respectively. Quantitative site-specific analysis of the glycan shield reveals that native-like glycan processing is maintained despite furin-independent maturation in the secretory pathway. Thus, cleavage-independent NFL Env trimers exhibit quaternary protein and carbohydrate structures similar to the native viral spike that further validate their potential as vaccine immunogen candidates.
A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica
Authors: Estrada Karol , Whelan Christopher W. , Zhao Fengmei , Bronson Paola , Handsaker Robert E. , Sun Chao , Carulli John P. , Harris Tim , Ransohoff Richard M. , McCarroll Steven A. , Day-Williams Aaron G. , Greenberg Benjamin M. , MacArthur Daniel G. 
Published: May 2018

AbstractNeuromyelitis optica (NMO) is a rare autoimmune disease that affects the optic nerve and spinal cord. Most NMO patients ( > 70%) are seropositive for circulating autoantibodies against aquaporin 4 (NMO-IgG+). Here, we meta-analyze whole-genome sequences from 86 NMO cases and 460 controls with genome-wide SNP array from 129 NMO cases and 784 controls to test for association with SNPs and copy number variation (total N = 215 NMO cases, 1244 controls). We identify two independent signals in the major histocompatibility complex (MHC) region associated with NMO-IgG+, one of which may be explained by structural variation in the complement component 4 genes. Mendelian Randomization analysis reveals a significant causal effect of known systemic lupus erythematosus (SLE), but not multiple sclerosis (MS), risk variants in NMO-IgG+. Our results suggest that genetic variants in the MHC region contribute to the etiology of NMO-IgG+ and that NMO-IgG+ is genetically more similar to SLE than MS.
Optical functionalization of human Class A orphan G-protein-coupled receptors
Authors: Morri Maurizio , Sanchez-Romero Inmaculada , Tichy Alexandra-Madelaine , Kainrath Stephanie , Gerrard Elliot J. , Hirschfeld Priscila P. , Schwarz Jan , Janovjak Harald 
Published: May 2018

AbstractG-protein-coupled receptors (GPCRs) form the largest receptor family, relay environmental stimuli to changes in cell behavior and represent prime drug targets. Many GPCRs are classified as orphan receptors because of the limited knowledge on their ligands and coupling to cellular signaling machineries. Here, we engineer a library of 63 chimeric receptors that contain the signaling domains of human orphan and understudied GPCRs functionally linked to the light-sensing domain of rhodopsin. Upon stimulation with visible light, we identify activation of canonical cell signaling pathways, including cAMP-, Ca2+-, MAPK/ERK-, and Rho-dependent pathways, downstream of the engineered receptors. For the human pseudogene GPR33, we resurrect a signaling function that supports its hypothesized role as a pathogen entry site. These results demonstrate that substituting unknown chemical activators with a light switch can reveal information about protein function and provide an optically controlled protein library for exploring the physiology and therapeutic potential of understudied GPCRs.
Discretization of the total magnetic field by the nuclear spin bath in fluorine-doped ZnSe
Authors: Zhukov E. A. , Kirstein E. , Kopteva N. E. , Heisterkamp F. , Yugova I. A. , Korenev V. L. , Yakovlev D. R. , Pawlis A. , Bayer M. , Greilich A. 
Published: May 2018

AbstractThe coherent spin dynamics of fluorine donor-bound electrons in ZnSe induced by pulsed optical excitation is studied in a perpendicular applied magnetic field. The Larmor precession frequency serves as a measure for the total magnetic field exerted onto the electron spins and, surprisingly, does not increase linearly with the applied field, but shows a step-like behavior with pronounced plateaus, given by multiples of the laser repetition rate. This discretization occurs by a feedback mechanism in which the electron spins polarize the nuclear spins, which in turn generate a local Overhauser field adjusting the total magnetic field accordingly. Varying the optical excitation power, we can control the plateaus, in agreement with our theoretical model. From this model, we trace the observed discretization to the optically induced Stark field, which causes the dynamic nuclear polarization.
Methionine metabolism influences genomic architecture and gene expression through H3K4me3 peak width
Authors: Dai Ziwei , Mentch Samantha J. , Gao Xia , Nichenametla Sailendra N. , Locasale Jason W. 
Published: May 2018

AbstractNutrition and metabolism are known to influence chromatin biology and epigenetics through post-translational modifications, yet how this interaction influences genomic architecture and connects to gene expression is unknown. Here we consider, as a model, the metabolically-driven dynamics of H3K4me3, a histone methylation mark that is known to encode information about active transcription, cell identity, and tumor suppression. We analyze the genome-wide changes in H3K4me3 and gene expression in response to alterations in methionine availability in both normal mouse physiology and human cancer cells. Surprisingly, we find that the location of H3K4me3 peaks is largely preserved under methionine restriction, while the response of H3K4me3 peak width encodes almost all aspects of H3K4me3 biology including changes in expression levels, and the presence of cell identity and cancer-associated genes. These findings may reveal general principles for how nutrient availability modulates specific aspects of chromatin dynamics to mediate biological function.
Vestigial nematic order and superconductivity in the doped topological insulator Cu
x
Bi2Se3
Authors: Hecker Matthias , Schmalian Jörg 
Published: May 2018

AbstractIf the topological insulator Bi2Se3 is doped with electrons, superconductivity with Tc = 3–4 K emerges for a low density of carriers (n = 1020 cm−3) and with a small ratio of the superconducting coherence length and Fermi wave length: ξ/λ
F
= 2…4. These values make fluctuations of the superconducting order parameter increasingly important, to the extend that the Tc-value is surprisingly large. Strong spin–orbit interaction led to the proposal of an odd-parity pairing state. This begs the question of the nature of the transition in an unconventional superconductor with strong pairing fluctuations. We show that for a multi-component order parameter, these fluctuations give rise to a nematic phase at Tnem > Tc. Below Tc several experiments demonstrated a rotational symmetry breaking where the Cooper pair wave function is locked to the lattice. Our theory shows that this rotational symmetry breaking, as vestige of the superconducting state, already occurs above Tc. The nematic phase is characterized by vanishing off-diagonal long range order, yet with anisotropic superconducting fluctuations. It can be identified through direction-dependent para-conductivity, lattice softening, and an enhanced Raman response in the Eg symmetry channel. In addition, nematic order partially avoids the usual fluctuation suppression of Tc.
Systematic pan-cancer analysis of somatic allele frequency
Authors: Spurr Liam , Li Muzi , Alomran Nawaf , Zhang Qianqian , Restrepo Paula , Movassagh Mercedeh , Trenkov Chris , Tunnessen Nerissa , Apanasovich Tatiyana , Crandall Keith A. , Edwards Nathan , Horvath Anelia 
Published: May 2018

AbstractImbalanced expression of somatic alleles in cancer can suggest functional and selective features, and can therefore indicate possible driving potential of the underlying genetic variants. To explore the correlation between allele frequency of somatic variants and total gene expression of their harboring gene, we used the unique data set of matched tumor and normal RNA and DNA sequencing data of 5523 distinct single nucleotide variants in 381 individuals across 10 cancer types obtained from The Cancer Genome Atlas (TCGA). We analyzed the allele frequency in the context of the variant and gene functional features and linked it with changes in the total gene expression. We documented higher allele frequency of somatic variants in cancer-implicated genes (Cancer Gene Census, CGC). Furthermore, somatic alleles bearing premature terminating variants (PTVs), when positioned in CGC genes, appeared to be less frequently degraded via nonsense-mediated mRNA decay, indicating possible favoring of truncated proteins by the tumor transcriptome. Among the genes with multiple PTVs with high allele frequency, ARID1, TP53 and NSD1 were known key cancer genes. All together, our analyses suggest that high allele frequency of tumor somatic variants can indicate driving functionality and can serve to identify potential cancer-implicated genes.