bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroRNA-3619-5p suppresses bladder carcinoma progression by directly targeting β-catenin and CDK2 and activating p21
Authors: Zhang Qingsong , Miao Shuo , Han Xihong , Li Chuanchang , Zhang Mengyang , Cui Kai , Xiong Tao , Chen Zhong , Wang Chenghe , Xu Hua 
Published: September 2018

AbstractCurrent studies indicate that microRNAs (miRNAs) are widely decreased in various tumors and function as tumor suppressors by inhibiting cancer cell proliferation, survival, invasion, and migration. The potential application of using miRNAs to predict therapeutic responses to multiple types of cancer treatment holds high promise. In current study, we demonstrate that miR-3619-5p is downregulated in bladder cancer (BCa) tissues and cells. Exogenous overexpression of miR-3619-5p in BCa cells inhibits proliferation, migration, and invasion. Moreover, a nude mouse xenograft model shows that miR-3619-5p inhibits BCa cell growth. We also demonstrate that miR-3619-5p leads to the activation of p21 by targeting its promoter in BCa cells. Enforced miR-3619-5p expression consistently leads to the downregulation of β-catenin and cyclin-dependent kinase 2 (CDK2) through predicted binding sites within the β-catenin and CDK2 3′-untranslated regions (UTRs), respectively. Moreover, β-catenin and CDK2 knockdown is able to mimic BCa cells growth and metastasis effects induced by overexpressing miR-3619-5p. We further confirm that miR-3619-5p inhibits Wnt-β-catenin signal pathway and EMT progression in BCa cells. We also found that miR-3619-5p-induced growth arrest and metastasis inhibition are p21-dependent in BCa cells. Taken together, these results confirm that miR-3619-5p plays a tumor suppressive role in BCa by interfering with cell growth and metastasis and may serve as a potential therapeutic target in BCa treatment.
The role of miR-106p-5p in cervical cancer: from expression to molecular mechanism
Authors: Yi Yuexiong , Liu Yanyan , Wu Wanrong , Wu Kejia , Zhang Wei 
Published: September 2018

AbstractThis study aims to investigate the role of miR-106b-5p in cervical cancer by performing a comprehensive analysis on its expression and identifying its putative molecular targets and pathways based on The Cancer Genome Atlas (TCGA) dataset, Gene Expression Omnibus (GEO) dataset, and literature review. Significant upregulation of miR-106b-5p in cervical cancer is confirmed by meta-analysis with the data from TCGA, GEO, and literature. Moreover, the expression of miR-106b-5p is significantly correlated with the number of metastatic lymph nodes. Our bioinformatics analyses show that miR-106b could promote cervical cancer progression by modulating the expression of GSK3B, VEGFA, and PTK2 genes. Importantly, these three genes play a crucial role in PI3K-Akt signaling, focal adhesion, and cancer. Both the expression of miR-106b-5p and key genes are upregulated in cervical cancer. Several explanations could be implemented for this upregulation. However, the specific mechanism needs to be investigated further.
Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers
Authors: Kumar R. , Coronel L. , Somalanka B. , Raju A. , Aning O. A. , An O. , Ho Y. S. , Chen S. , Mak S. Y. , Hor P. Y. , Yang H. , Lakshmanan M. , Itoh H. , Tan S. Y. , Lim Y. K. , Wong A. P. C. , Chew S. H. , Huynh T. H. , Goh B. C. , Lim C. Y. , Tergaonkar V. , Cheok C. F. 
Published: September 2018

AbstractThere are considerable challenges in directly targeting the mutant p53 protein, given the large heterogeneity of p53 mutations in the clinic. An alternative approach is to exploit the altered fitness of cells imposed by loss-of-wild-type p53. Here we identify niclosamide through a HTS screen for compounds selectively killing p53-deficient cells. Niclosamide impairs the growth of p53-deficient cells and of p53 mutant patient-derived ovarian xenografts. Metabolome profiling reveals that niclosamide induces mitochondrial uncoupling, which renders mutant p53 cells susceptible to mitochondrial-dependent apoptosis through preferential accumulation of arachidonic acid (AA), and represents a first-in-class inhibitor of p53 mutant tumors. Wild-type p53 evades the cytotoxicity by promoting the transcriptional induction of two key lipid oxygenation genes, ALOX5 and ALOX12B, which catalyzes the dioxygenation and breakdown of AA. Therefore, we propose a new paradigm for targeting cancers defective in the p53 pathway, by exploiting their vulnerability to niclosamide-induced mitochondrial uncoupling.
In vivo neutralization of dendrotoxin-mediated neurotoxicity of black mamba venom by oligoclonal human IgG antibodies
Authors: Laustsen Andreas H. , Karatt-Vellatt Aneesh , Masters Edward W. , Arias Ana Silvia , Pus Urska , Knudsen Cecilie , Oscoz Saioa , Slavny Peter , Griffiths Daniel T. , Luther Alice M. , Leah Rachael A. , Lindholm Majken , Lomonte Bruno , Gutiérrez José María , McCafferty John 
Published: September 2018

AbstractThe black mamba (Dendroaspis polylepis) is one of the most feared snake species of the African savanna. It has a potent, fast-acting neurotoxic venom comprised of dendrotoxins and α-neurotoxins associated with high fatality in untreated victims. Current antivenoms are both scarce on the African continent and present a number of drawbacks as they are derived from the plasma of hyper-immunized large mammals. Here, we describe the development of an experimental recombinant antivenom by a combined toxicovenomics and phage display approach. The recombinant antivenom is based on a cocktail of fully human immunoglobulin G (IgG) monoclonal antibodies capable of neutralizing dendrotoxin-mediated neurotoxicity of black mamba whole venom in a rodent model. Our results show the potential use of fully human monoclonal IgGs against animal toxins and the first use of oligoclonal human IgG mixtures against experimental snakebite envenoming.
Chiral self-sorted multifunctional supramolecular biocoordination polymers and their applications in sensors
Authors: Shang Xiaobo , Song Inho , Jung Gwan Yeong , Choi Wanuk , Ohtsu Hiroyoshi , Lee Jeong Hyeon , Koo Jin Young , Liu Bo , Ahn Jaeyong , Kawano Masaki , Kwak Sang Kyu , Oh Joon Hak 
Published: September 2018

AbstractChiral supramolecules have great potential for use in chiral recognition, sensing, and catalysis. Particularly, chiral supramolecular biocoordination polymers (SBCPs) provide a versatile platform for characterizing biorelated processes such as chirality transcription. Here, we selectively synthesize homochiral and heterochiral SBCPs, composed of chiral naphthalene diimide ligands and Zn ions, from enantiomeric and mixed R-ligands and S-ligands, respectively. Notably, we find that the chiral self-sorted SBCPs exhibit multifunctional properties, including photochromic, photoluminescent, photoconductive, and chemiresistive characteristics, thus can be used for various sensors. Specifically, these materials can be used for detecting hazardous amine materials due to the electron transfer from the amine to the SBCP surface and for enantioselectively sensing a chiral species naproxen due to the different binding energies with regard to their chirality. These results provide guidelines for the synthesis of chiral SBCPs and demonstrate their versatility and feasibility for use in various sensors covering photoactive, chemiresistive, and chiral sensors.
Physics-based forecasting of man-made earthquake hazards in Oklahoma and Kansas
Authors: Langenbruch Cornelius , Weingarten Matthew , Zoback Mark D. 
Published: September 2018

AbstractReinjection of saltwater, co-produced with oil, triggered thousands of widely felt and several damaging earthquakes in Oklahoma and Kansas. The future seismic hazard remains uncertain. Here, we present a new methodology to forecast the probability of damaging induced earthquakes in space and time. In our hybrid physical–statistical model, seismicity is driven by the rate of injection-induced pressure increases at any given location and spatial variations in the number and stress state of preexisting basement faults affected by the pressure increase. If current injection practices continue, earthquake hazards are expected to decrease slowly. Approximately 190, 130 and 100 widely felt M ≥ 3 earthquakes are anticipated in 2018, 2019 and 2020, respectively, with corresponding probabilities of potentially damaging M ≥ 5 earthquakes of 32, 24 and 19%. We identify areas where produced-water injection is more likely to cause seismicity. Our methodology can be used to evaluate future injection scenarios intended to mitigate seismic hazards.
A bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomes
Authors: Foglizzo Martina , Middleton Adam J. , Burgess Abigail E. , Crowther Jennifer M. , Dobson Renwick C. J. , Murphy James M. , Day Catherine L. , Mace Peter D. 
Published: September 2018

AbstractAttachment of ubiquitin to lysine 119 of Histone 2A (H2AK119Ub) is an epigenetic mark characteristic of repressed developmental genes, which is removed by the Polycomb Repressive-Deubiquitinase (PR-DUB) complex. Here we report the crystal structure of the Drosophila PR-DUB, revealing that the deubiquitinase Calypso and its activating partner ASX form a 2:2 complex. The bidentate Calypso–ASX complex is generated by dimerisation of two activated Calypso proteins through their coiled-coil regions. Disrupting the Calypso dimer interface does not affect inherent catalytic activity, but inhibits removal of H2AK119Ub as a consequence of impaired recruitment to nucleosomes. Mutating the equivalent surface on the human counterpart, BAP1, also compromises activity on nucleosomes. Together, this suggests that high local concentrations drive assembly of bidentate PR-DUB complexes on chromatin—providing a mechanistic basis for enhanced PR-DUB activity at specific genomic foci, and the impact of distinct classes of PR-DUB mutations in tumorigenesis.
A distal centriolar protein network controls organelle maturation and asymmetry
Authors: Wang Lei , Failler Marion , Fu Wenxiang , Dynlacht Brian D. 
Published: September 2018

AbstractA long-standing mystery in the centrosome field pertains to the origin of asymmetry within the organelle. The removal of daughter centriole-specific/enriched proteins (DCPs) and acquisition of distal appendages on the future mother centriole are two important steps in the generation of asymmetry. We find that DCPs are recruited sequentially, and their removal is abolished in cells lacking Talpid3 or C2CD3. We show that removal of certain DCPs constitutes another level of control for distal appendage (DA) assembly. Remarkably, we also find that Talpid3 forms a distal centriolar multi-functional hub that coordinates the removal of specific DCPs, DA assembly, and recruitment of ciliary vesicles through distinct regions mutated in ciliopathies. Finally, we show that Talpid3, C2CD3, and OFD1 differentially regulate the assembly of sub-distal appendages, the CEP350/FOP/CEP19 module, centriolar satellites, and actin networks. Our work extends the spatial and functional understanding of proteins that control organelle maturation and asymmetry, ciliogenesis, and human disease.
The MinDE system is a generic spatial cue for membrane protein distribution in vitro
Authors: Ramm Beatrice , Glock Philipp , Mücksch Jonas , Blumhardt Philipp , García-Soriano Daniela A. , Heymann Michael , Schwille Petra 
Published: September 2018

AbstractThe E. coli MinCDE system has become a paradigmatic reaction–diffusion system in biology. The membrane-bound ATPase MinD and ATPase-activating protein MinE oscillate between the cell poles followed by MinC, thus positioning the main division protein FtsZ at midcell. Here we report that these energy-consuming MinDE oscillations may play a role beyond constraining MinC/FtsZ localization. Using an in vitro reconstitution assay, we show that MinDE self-organization can spatially regulate a variety of functionally completely unrelated membrane proteins into patterns and gradients. By concentration waves sweeping over the membrane, they induce a direct net transport of tightly membrane-attached molecules. That the MinDE system can spatiotemporally control a much larger set of proteins than previously known, may constitute a MinC-independent pathway to division site selection and chromosome segregation. Moreover, the here described phenomenon of active transport through a traveling diffusion barrier may point to a general mechanism of spatiotemporal regulation in cells.
Probing ultrafast spin-relaxation and precession dynamics in a cuprate Mott insulator with seven-femtosecond optical pulses
Authors: Miyamoto T. , Matsui Y. , Terashige T. , Morimoto T. , Sono N. , Yada H. , Ishihara S. , Watanabe Y. , Adachi S. , Ito T. , Oka K. , Sawa A. , Okamoto H. 
Published: September 2018

AbstractA charge excitation in a two-dimensional Mott insulator is strongly coupled with the surrounding spins, which is observed as magnetic-polaron formations of doped carriers and a magnon sideband in the Mott-gap transition spectrum. However, the dynamics related to the spin sector are difficult to measure. Here, we show that pump-probe reflection spectroscopy with seven-femtosecond laser pulses can detect the optically induced spin dynamics in Nd2CuO4, a typical cuprate Mott insulator. The bleaching signal at the Mott-gap transition is enhanced at ~18 fs. This time constant is attributable to the spin-relaxation time during magnetic-polaron formation, which is characterized by the exchange interaction. More importantly, ultrafast coherent oscillations appear in the time evolution of the reflectivity changes, and their frequencies (1400–2700 cm−1) are equal to the probe energy measured from the Mott-gap transition peak. These oscillations can be interpreted as the interference between charge excitations with two magnons originating from charge–spin coupling.
Crystal structure of the red light-activated channelrhodopsin Chrimson
Authors: Oda Kazumasa , Vierock Johannes , Oishi Satomi , Rodriguez-Rozada Silvia , Taniguchi Reiya , Yamashita Keitaro , Wiegert J. Simon , Nishizawa Tomohiro , Hegemann Peter , Nureki Osamu 
Published: September 2018

AbstractChannelrhodopsins are light-activated ion channels that mediate cation permeation across cell membranes upon light absorption. Red-light-activated channelrhodopsins are of particular interest, because red light penetrates deeper into biological tissues and also enables dual-color experiments in combination with blue-light-activated optogenetic tools. Here we report the crystal structure of the most red-shifted channelrhodopsin from the algae Chlamydomonas noctigama, Chrimson, at 2.6 Å resolution. Chrimson resembles prokaryotic proton pumps in the retinal binding pocket, while sharing similarity with other channelrhodopsins in the ion-conducting pore. Concomitant mutation analysis identified the structural features that are responsible for Chrimson’s red light sensitivity; namely, the protonation of the counterion for the retinal Schiff base, and the polar residue distribution and rigidity of the retinal binding pocket. Based on these mechanistic insights, we engineered ChrimsonSA, a mutant with a maximum activation wavelength red-shifted beyond 605 nm and accelerated closing kinetics.
Modulation of plant-mediated interactions between herbivores of different feeding guilds: Effects of parasitism and belowground interactions
Authors: Vaello Teresa , Sarde Sandeep J. , Marcos-García Mª Ángeles , de Boer Jetske G. , Pineda Ana 
Published: September 2018

AbstractHerbivory affects subsequent herbivores, mainly regulated by the phytohormones jasmonic (JA) and salicylic acid (SA). Additionally, organisms such as soil microbes belowground or parasitoids that develop inside their herbivorous hosts aboveground, can change plant responses to herbivory. However, it is not yet well known how organisms of trophic levels other than herbivores, below- and above-ground, alter the interactions between insect species sharing a host plant. Here, we investigated whether the parasitoid Aphidius colemani and different soil microbial communities (created through plant-soil feedbacks) affect the JA and SA signalling pathways in response to the aphid Myzus persicae and the thrips Frankliniella occidentalis, as well as subsequent thrips performance. Our results show that the expression of the JA-responsive gene CaPINII in sweet pepper was more suppressed by aphids than by parasitised aphids. However, parasitism did not affect the expression of CaPAL1, a biosynthetic gene of SA. Furthermore, aphid feeding enhanced thrips performance compared with uninfested plants, but this was not observed when aphids were parasitised. Soils where different plant species were previously grown, did not affect plant responses or the interaction between herbivores. Our study shows that members of the third trophic level can modify herbivore interactions by altering plant physiology.
The prognostic significance of heart-type fatty acid binding protein in patients with stable coronary heart disease
Authors: Ho Sing-Kong , Wu Yen-Wen , Tseng Wei-Kung , Leu Hsin-Bang , Yin Wei-Hsian , Lin Tsung-Hsien , Chang Kuan-Cheng , Wang Ji-Hung , Yeh Hung-I , Wu Chau-Chung , Chen Jaw-Wen 
Published: September 2018

AbstractTo investigate the prognostic value of heart-type fatty acid binding protein (H-FABP) in patients with stable coronary heart disease (SCHD). A total of 1,071 patients with SCHD were prospectively enrolled in this Taiwan multicenter registry study, followed for 24 months. The cut-off value of H-FABP, 4.143 ng/mL, was determined using receiver operating characteristic curves. The primary cardiovascular (CV) outcome was composite CV events, defined as cardiovascular or cerebrovascular death, myocardial infarction (MI), stroke, angina related-hospitalization, PAOD-related hospitalization and heart failure. Secondary outcomes included CV or cerebrovascular death, nonfatal MI, nonfatal stroke, and acute heart failure-related hospitalization. We found that the high H-FABP group had more than a two-fold higher rate of primary CV outcomes than the low H-FABP group (32.36% vs. 15.78%, p < 0.001). Eleven patients (4.82%) of the high H-FABP group died during the 24 months of follow-up, compared to only one patient (0.12%) in the low H-FABP group. The acute heart failure-related hospitalization rate was also significantly higher in the high H-FABP group (3.5% vs. 0.95%, p < 0.005). The results remained significant after adjusting for baseline covariates. In conclusion, H-FABP was an independent predictor for CV outcomes in the patients with SCHD, mainly in CV death and acute heart failure-related hospitalization.
Distribution patterns and variation analysis of simple sequence repeats in different genomic regions of bovid genomes
Authors: Qi Wen-Hua , Jiang Xue-Mei , Yan Chao-Chao , Zhang Wan-Qing , Xiao Guo-Sheng , Yue Bi-Song , Zhou Cai-Quan 
Published: September 2018

AbstractAs the first examination of distribution, guanine-cytosine (GC) pattern, and variation analysis of microsatellites (SSRs) in different genomic regions of six bovid species, SSRs displayed nonrandomly distribution in different regions. SSR abundances are much higher in the introns, transposable elements (TEs), and intergenic regions compared to the 3′-untranslated regions (3′UTRs), 5′UTRs and coding regions. Trinucleotide perfect SSRs (P-SSRs) were the most frequent in the coding regions, whereas, mononucleotide P-SSRs were the most in the introns, 3′UTRs, TEs, and intergenic regions. Trifold P-SSRs had more GC-contents in the 5′UTRs and coding regions than that in the introns, 3′UTRs, TEs, and intergenic regions, whereas mononucleotide P-SSRs had the least GC-contents in all genomic regions. The repeat copy numbers (RCN) of the same mono- to hexanucleotide P-SSRs showed significantly different distributions in different regions (P < 0.01). Except for the coding regions, mononucleotide P-SSRs had the most RCNs, followed by the pattern: di- > tri- > tetra- > penta- > hexanucleotide P-SSRs in the same regions. The analysis of coefficient of variability (CV) of SSRs showed that the CV variations of RCN of the same mono- to hexanucleotide SSRs were relative higher in the intronic and intergenic regions, followed by the CV variation of RCN in the TEs, and the relative lower was in the 5′UTRs, 3′UTRs, and coding regions. Wide SSR analysis of different genomic regions has helped to reveal biological significances of their distributions.
Transgene-free genome editing in marine algae by bacterial conjugation – comparison with biolistic CRISPR/Cas9 transformation
Authors: Sharma A. K. , Nymark M. , Sparstad T. , Bones A. M. , Winge P. 
Published: September 2018

AbstractThe CRISPR/Cas9 technology has opened the possibility for targeted genome editing in various organisms including diatom model organisms. One standard method for delivery of vectors to diatom cells is by biolistic particle bombardment. Recently delivery by conjugation was added to the tool-box. An important difference between these methods is that biolistic transformation results in transgene integration of vector DNA into the algae genome, whereas conjugative transformation allows the vector to be maintained as an episome in the recipient cells. In this study, we have used both transformation methods to deliver the CRISPR/Cas9 system to the marine diatom Phaeodactylum tricornutum aiming to induce mutations in a common target gene. This allowed us to compare the two CRISPR/Cas9 delivery systems with regard to mutation efficiency, and to assess potential problems connected to constitutive expression of Cas9. We found that the percentage of CRISPR-induced targeted biallelic mutations are similar for both methods, but an extended growth period might be needed to induce biallelic mutations when the CRISPR/Cas9 system is episomal. Independent of the CRISPR/Cas9 vector system, constitutive expression of Cas9 can cause re-editing of mutant lines with small indels. Complications associated with the biolistic transformation system like the permanent and random integration of foreign DNA into the host genome and unstable mutant lines caused by constitutive expression of Cas9 can be avoided using the episomal CRISPR/Cas9 system. The episomal vector can be eliminated from the diatom cells by removal of selection pressure, resulting in transient Cas9 expression and non-transgenic mutant lines. Depending on legislation, such lines might be considered as non-GMOs.
CDKN2A as transcriptomic marker for muscle-invasive bladder cancer risk stratification and therapy decision-making
Authors: Worst Thomas S. , Weis Cleo-Aron , Stöhr Robert , Bertz Simone , Eckstein Markus , Otto Wolfgang , Breyer Johannes , Hartmann Arndt , Bolenz Christian , Wirtz Ralph M. , Erben Philipp 
Published: September 2018

AbstractDeletions of the cell cycle control gene CDKN2A are described as progression markers of non-muscle invasive bladder cancer and to be associated with fibroblast growth factor 3 (FGFR3) mutations. The prognostic role of CDKN2A RNA expression in muscle invasive bladder cancer (MIBC) is under discussion. In 80 MIBC patients (m/f 60/20) who underwent radical cystectomy the expression of CDKN2A and FGFR3 was examined with qRT-PCR (test cohort). The MDA cohort (n = 57) and the TCGA cohort (n = 365) served for validation. The expression of drug target genes and TCGA molecular subtypes was correlated with CDKN2A expression. In the test cohort CDKN2Ahigh patients (n = 8; 10.0%) had a significantly shorter recurrence-free (p = 0.018) and disease-specific (p = 0.006) survival compared to the rest of the cohort. A similar stratification was seen in the validation cohorts (CDKN2Ahigh: n = 7, 12.3%, p = 0.001; n = 46, 12.6%, p = 0.011). In the TCGA cohort these patients had a comparably low expression of drug target genes. The expression of CDKN2A significantly differed among TGCA molecular subtypes. 71.7% of CDKN2Ahigh were TCGA basal squamous tumours but also show divergent molecular features compared to this group. In summary CDKN2A RNA expression-based risk stratification of MIBC allows the identification of a CDKN2Ahigh poor prognosis group with low expression of drug target genes.