bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer
Authors: Arechederra Maria , Daian Fabrice , Yim Annie , Bazai Sehrish K. , Richelme Sylvie , Dono Rosanna , Saurin Andrew J. , Habermann Bianca H. , Maina Flavio 
Published: August 2018

AbstractEpigenetic modifications such as aberrant DNA methylation reshape the gene expression repertoire in cancer. Here, we used a clinically relevant hepatocellular carcinoma (HCC) mouse model (Alb-R26Met) to explore the impact of DNA methylation on transcriptional switches associated with tumorigenesis. We identified a striking enrichment in genes simultaneously hypermethylated in CpG islands (CGIs) and overexpressed. These hypermethylated CGIs are located either in the 5′-UTR or in the gene body region. Remarkably, such CGI hypermethylation accompanied by gene upregulation also occurs in 56% of HCC patients, which belong to the “HCC proliferative-progenitor” subclass. Most of the genes upregulated and with hypermethylated CGIs in the Alb-R26Met HCC model undergo the same change in a large proportion of HCC patients. Among reprogrammed genes, several are well-known oncogenes. For others not previously linked to cancer, we demonstrate here their action together as an “oncogene module”. Thus, hypermethylation of gene body CGIs is predictive of elevated oncogene levels in cancer, offering a novel stratification strategy and perspectives to normalise cancer gene dosages.
Crystalline polymeric carbon dioxide stable at megabar pressures
Authors: Dziubek Kamil F. , Ende Martin , Scelta Demetrio , Bini Roberto , Mezouar Mohamed , Garbarino Gaston , Miletich Ronald 
Published: August 2018

AbstractCarbon dioxide is a widespread simple molecule in the Universe. In spite of its simplicity it has a very complex phase diagram, forming both amorphous and crystalline extended phases above 40 GPa. The stability range and nature of these phases are still debated, especially in view of their possible role within the deep carbon cycle. Here, we report static synchrotron X-ray diffraction and Raman high-pressure experiments in the megabar range providing evidence for the stability of the polymeric phase V at pressure-temperature conditions relevant to the Earth’s lowermost mantle. The equation of state has been extended to 120 GPa and, contrary to earlier experimental findings, neither dissociation into diamond andε-oxygen nor ionization was observed. Severe deviatoric stress and lattice deformation along with preferred orientation are removed on progressive annealing, thus suggesting CO2-V as the stable structure also above one megabar.
Coherence in carotenoid-to-chlorophyll energy transfer
Authors: Meneghin Elena , Volpato Andrea , Cupellini Lorenzo , Bolzonello Luca , Jurinovich Sandro , Mascoli Vincenzo , Carbonera Donatella , Mennucci Benedetta , Collini Elisabetta 
Published: August 2018

AbstractThe subtle details of the mechanism of energy flow from carotenoids to chlorophylls in biological light-harvesting complexes are still not fully understood, especially in the ultrafast regime. Here we focus on the antenna complex peridinin–chlorophyll a–protein (PCP), known for its remarkable efficiency of excitation energy transfer from carotenoids—peridinins—to chlorophylls. PCP solutions are studied by means of 2D electronic spectroscopy in different experimental conditions. Together with a global kinetic analysis and multiscale quantum chemical calculations, these data allow us to comprehensively address the contribution of the potential pathways of energy flow in PCP. These data support dominant energy transfer from peridinin S2 to chlorophyll Qy state via an ultrafast coherent mechanism. The coherent superposition of the two states is functional to drive population to the final acceptor state, adding an important piece of information in the quest for connections between coherent phenomena and biological functions.
Interphase human chromosome exhibits out of equilibrium glassy dynamics
Authors: Shi Guang , Liu Lei , Hyeon Changbong , Thirumalai D. 
Published: August 2018

AbstractFingerprints of the three-dimensional organization of genomes have emerged using advances in Hi-C and imaging techniques. However, genome dynamics is poorly understood. Here, we create the chromosome copolymer model (CCM) by representing chromosomes as a copolymer with two epigenetic loci types corresponding to euchromatin and heterochromatin. Using novel clustering techniques, we establish quantitatively that the simulated contact maps and topologically associating domains (TADs) for chromosomes 5 and 10 and those inferred from Hi-C experiments are in good agreement. Chromatin exhibits glassy dynamics with coherent motion on micron scale. The broad distribution of the diffusion exponents of the individual loci, which quantitatively agrees with experiments, is suggestive of highly heterogeneous dynamics. This is reflected in the cell-to-cell variations in the contact maps. Chromosome organization is hierarchical, involving the formation of chromosome droplets (CDs) on genomic scale, coinciding with the TAD size, followed by coalescence of the CDs, reminiscent of Ostwald ripening.
Palladium prompted on-demand cysteine chemistry for the synthesis of challenging and uniquely modified proteins
Authors: Jbara Muhammad , Laps Shay , Morgan Michael , Kamnesky Guy , Mann Guy , Wolberger Cynthia , Brik Ashraf 
Published: August 2018

AbstractOrganic chemistry allows for the modification and chemical preparation of protein analogues for various studies. The thiolate side chain of the Cys residue has been a key functionality in these ventures. In order to generate complex molecular targets, there is a particular need to incorporate orthogonal protecting groups of the thiolated amino acids to control the directionality of synthesis and modification site. Here, we demonstrate the tuning of palladium chemoselectivity in aqueous medium for on-demand deprotection of several Cys-protecting groups that are useful in protein synthesis and modification. These tools allow the preparation of highly complex analogues as we demonstrate in the synthesis of the copper storage protein and selectively modified peptides with multiple Cys residues. We also report the synthesis of an activity-based probe comprising ubiquitinated histone H2A and its incorporation into nucleosomes and demonstrate its reactivity with deubiquitinating enzyme to generate a covalent nucleosome–enzyme complex.
Molecular architecture of the multifunctional collagen lysyl hydroxylase and glycosyltransferase LH3
Authors: Scietti Luigi , Chiapparino Antonella , De Giorgi Francesca , Fumagalli Marco , Khoriauli Lela , Nergadze Solomon , Basu Shibom , Olieric Vincent , Cucca Lucia , Banushi Blerida , Profumo Antonella , Giulotto Elena , Gissen Paul , Forneris Federico 
Published: August 2018

AbstractLysyl hydroxylases catalyze hydroxylation of collagen lysines, and sustain essential roles in extracellular matrix (ECM) maturation and remodeling. Malfunctions in these enzymes cause severe connective tissue disorders. Human lysyl hydroxylase 3 (LH3/PLOD3) bears multiple enzymatic activities, as it catalyzes collagen lysine hydroxylation and also their subsequent glycosylation. Our understanding of LH3 functions is currently hampered by lack of molecular structure information. Here, we present high resolution crystal structures of full-length human LH3 in complex with cofactors and donor substrates. The elongated homodimeric LH3 architecture shows two distinct catalytic sites at the N- and C-terminal boundaries of each monomer, separated by an accessory domain. The glycosyltransferase domain displays distinguishing features compared to other known glycosyltransferases. Known disease-related mutations map in close proximity to the catalytic sites. Collectively, our results provide a structural framework characterizing the multiple functions of LH3, and the molecular mechanisms of collagen-related diseases involving human lysyl hydroxylases.
SENP3 maintains the stability and function of regulatory T cells via BACH2 deSUMOylation
Authors: Yu Xiaoyan , Lao Yimin , Teng Xiao-Lu , Li Song , Zhou Yan , Wang Feixiang , Guo Xinwei , Deng Siyu , Chang Yuzhou , Wu Xuefeng , Liu Zhiduo , Chen Lei , Lu Li-Ming , Cheng Jinke , Li Bin , Su Bing , Jiang Jin , Li Hua-Bing , Huang Chuanxin , Yi Jing , Zou Qiang 
Published: August 2018

AbstractRegulatory T (Treg) cells are essential for maintaining immune homeostasis and tolerance, but the mechanisms regulating the stability and function of Treg cells have not been fully elucidated. Here we show SUMO-specific protease 3 (SENP3) is a pivotal regulator of Treg cells that functions by controlling the SUMOylation and nuclear localization of BACH2. Treg cell-specific deletion of Senp3 results in T cell activation, autoimmune symptoms and enhanced antitumor T cell responses. SENP3-mediated BACH2 deSUMOylation prevents the nuclear export of BACH2, thereby repressing the genes associated with CD4+ T effector cell differentiation and stabilizing Treg cell-specific gene signatures. Notably, SENP3 accumulation triggered by reactive oxygen species (ROS) is involved in Treg cell-mediated tumor immunosuppression. Our results not only establish the role of SENP3 in the maintenance of Treg cell stability and function via BACH2 deSUMOylation but also clarify the function of SENP3 in the regulation of ROS-induced immune tolerance.
Discrete time information diffusion in online social networks: micro and macro perspectives
Authors: Qi Jinshan , Liang Xun , Wang Yi , Cheng Hengchao 
Published: August 2018

AbstractOpinions shared publicly in online social networks spread broadly and at an extremely high speed. However, modelling information diffusion in online social networks is still a challenge that is intriguing to many researchers. To monitor public opinions online, it is necessary to model the process of information dissemination. In this paper, we first study information diffusion based on the network structure and time occupation. By taking into consideration the availability of a user, e.g., his online or offline state, we present the discrete-time bi-probability independent cascade model. We next analyse the information diffusion from a macro perspective. A diffusion model is established by merging the interferences from other events and the cumulative effect that occurs over time. Finally, we observe the factors in online social networks that impact a message’s diffusion from a micro perspective and discuss more complex user behaviour and various types of interferences with their effects from a macro perspective. Experiments are conducted with real world data, and the experimental results justify our models.
Dynamics of fault motion and the origin of contrasting tectonic style between Earth and Venus
Authors: Karato Shun-ichiro , Barbot Sylvain 
Published: August 2018

AbstractPlate tectonics is one mode of mantle convection that occurs when the surface layer (the lithosphere) is relatively weak. When plate tectonics operates on a terrestrial planet, substantial exchange of materials occurs between planetary interior and its surface. This is likely a key in maintaining the habitable environment on a planet. Therefore it is essential to understand under which conditions plate tectonics operates on a terrestrial planet. One of the puzzling observations in this context is the fact that plate tectonics occurs on Earth but not on Venus despite their similar size and composition. Factors such as the difference in water content or in grain-size have been invoked, but these models cannot easily explain the contrasting tectonic styles between Earth and Venus. We propose that strong dynamic weakening in friction is a key factor. Fast unstable fault motion is found in cool Earth, while slow and stable fault motion characterizes hot Venus, leading to substantial dynamic weakening on Earth but not on Venus. Consequently, the tectonic plates are weak on Earth allowing for their subduction, while the strong plates on Venus promote the stagnant lid regime of mantle convection.
Effects of polymorphic variation on the thermostability of heterogenous populations of CYP3A4 and CYP2C9 enzymes in solution
Authors: Arendse Lauren B. , Blackburn Jonathan M. 
Published: August 2018

AbstractThe effect of non-synonymous single nucleotide polymorphisms (SNPs) on cytochrome P450 (CYP450) drug metabolism is currently poorly understood due to the large number of polymorphisms, the diversity of potential substrates and the complexity of CYP450 function. Previously we carried out in silico studies to explore the effect of SNPs on CYP450 function, using in silico calculations to predict the effect of mutations on protein stability. Here we have determined the effect of eight CYP3A4 and seven CYP2C9 SNPs on the thermostability of proteins in solution to test these predictions. Thermostability assays revealed distinct CYP450 sub-populations with only 65–70% of wild-type CYP3A4 and CYP2C9 susceptible to rapid heat-induced P450 to P420 conversion. CYP3A4 mutations G56D, P218R, S222P, I223R, L373F and M445T and CYP2C9 mutations V76M, I359L and I359T were destabilising, increasing the proportion of protein sensitive to the rapid heat-induced P450 to P420 conversion and/or reducing the half-life of this conversion. CYP2C9 Q214L was the only stabilising mutation. These results corresponded well with the in silico protein stability calculations, confirming the value of these predictions and together suggest that the changes in thermostability result from destabilisation/stabilisation of the protein fold, changes in the haem-binding environment or effects on oligomer formation/conformation.
Selective targeting of KRAS oncogenic alleles by CRISPR/Cas9 inhibits proliferation of cancer cells
Authors: Lee Wookjae , Lee Joon Ho , Jun Soyeong , Lee Ji Hyun , Bang Duhee 
Published: August 2018

AbstractMutations within the KRAS oncogene are associated with the proliferation of various cancers. Therapeutic approaches for treating cancers with such mutations have focused on targeting the downstream protein effectors of KRAS. However, to date, no approved treatment has targeted the mutated KRAS oncogene directly. Presently, we used the selectivity of the CRISPR/Cas9 system to directly target mutated KRAS alleles. We designed single-guide RNAs (sgRNAs) to target two specific single-nucleotide missense mutations on KRAS codon-12 located in the seed region adjacent to a protospacer adjacent motif (PAM). Lentiviral transduction of Cas9 and the sgRNAs into cancer cells with respective KRAS mutations resulted in high frequency of indels in the seed region. Indel-associated disruption of the mutant KRAS alleles correlated with reduced viability of the cancer cells. The results indicate that CRISPR-Cas9-mediated genome editing can potentially be used for the treatment of cancer patients, specifically those with oncogenic KRAS mutations.
Biochemical analyses reveal amino acid residues critical for cell cycle-dependent phosphorylation of human Cdc14A phosphatase by cyclin-dependent kinase 1
Authors: Ovejero Sara , Ayala Patricia , Malumbres Marcos , Pimentel-Muiños Felipe X. , Bueno Avelino , Sacristán María P. 
Published: August 2018

AbstractCdc14 enzymes compose a family of highly conserved phosphatases that are present in a wide range of organisms, including yeast and humans, and that preferentially reverse the phosphorylation of Cyclin-Dependent Kinase (Cdk) substrates. The budding yeast Cdc14 orthologue has essential functions in the control of late mitosis and cytokinesis. In mammals, however, the two Cdc14 homologues, Cdc14A and Cdc14B, do not play a prominent role in controlling late mitotic events, suggesting that some Cdc14 functions are not conserved across species. Moreover, in yeast, Cdc14 is regulated by changes in its subcellular location and by phosphorylation events. In contrast, little is known about the regulation of human Cdc14 phosphatases. Here, we have studied how the human Cdc14A orthologue is regulated during the cell cycle. We found that Cdc14A is phosphorylated on Ser411, Ser453 and Ser549 by Cdk1 early in mitosis and becomes dephosphorylated during late mitotic stages. Interestingly, in vivo and in vitro experiments revealed that, unlike in yeast, Cdk1-mediated phosphorylation of human Cdc14A did not control its catalytic activity but likely modulated its interaction with other proteins in early mitosis. These findings point to differences in Cdk1-mediated mechanisms of regulation between human and yeast Cdc14 orthologues.
Assessment of the physicochemical properties and bacterial composition of Lactobacillus plantarum and Enterococcus faecium-fermented Astragalus membranaceus using single molecule, real-time sequencing technology
Authors: Qiao Hongxing , Zhang Xiaojing , Shi Hongtao , Song Yuzhen , Bian Chuanzhou , Guo Aizhen 
Published: August 2018

AbstractWe investigated if fermentation with probiotic cultures could improve the production of health-promoting biological compounds in Astragalus membranaceus. We tested the probiotics Enterococcus faecium, Lactobacillus plantarum and Enterococcus faecium + Lactobacillus plantarum and applied PacBio single molecule, real-time sequencing technology (SMRT) to evaluate the quality of Astragalus fermentation. We found that the production rates of acetic acid, methylacetic acid, aethyl acetic acid and lactic acid using E. faecium + L. plantarum were 1866.24 mg/kg on day 15, 203.80 mg/kg on day 30, 996.04 mg/kg on day 15, and 3081.99 mg/kg on day 20, respectively. Other production rates were: polysaccharides, 9.43%, 8.51%, and 7.59% on day 10; saponins, 19.6912 mg/g, 21.6630 mg/g and 20.2084 mg/g on day 15; and flavonoids, 1.9032 mg/g, 2.0835 mg/g, and 1.7086 mg/g on day 20 using E. faecium, L. plantarum and E. faecium + L. plantarum, respectively. SMRT was used to analyze microbial composition, and we found that E. faecium and L. plantarum were the most prevalent species after fermentation for 3 days. E. faecium + L. plantarum gave more positive effects than single strains in the Astragalus solid state fermentation process. Our data demonstrated that the SMRT sequencing platform is applicable to quality assessment of Astragalus fermentation.
Monthly and annual temperature extremes and their changes on the Tibetan Plateau and its surroundings during 1963–2015
Authors: Ding Jin , Cuo Lan , Zhang Yongxin , Zhu Fuxin 
Published: August 2018

AbstractIn this study, the spatiotemporal distributions of monthly and annual temperature minima (Tmin) and maxima (Tmax), extreme Tmin and Tmax, the highest (lowest) Tmin (Tmax), frost day (FD), icing day (ID), summer day (SD) and tropical night (TR) at 112 stations and over the ten large river basins on the Tibetan Plateau and its surroundings (TPS) during 1963–2015 are examined. Mann-Kendall test is applied for the trends. The analyses show: the northwest experiences the hottest summer while the central TPS has the coldest winter and most frequent frost and icing days. The northwest (southeast) features the highest (lowest) monthly extreme temperature ranges. The northwest has the most frequent hot summer days, whereas the southeast has the least frequent frost and icing days. The entire TPS displays few tropical nights. Most stations show positive trends for all monthly and annual Tmin and Tmax variables. February displays the most positive trends for both monthly Tmin and Tmax variables while April shows the highest number of stations with decreasing trends in monthly Tmax. The trends of FD and ID are negative, whereas the trends of SU and TR are positive. Over river basins, the trends of monthly Tmin are all positive and statistically significant and the trends of monthly Tmax are all positive except for one negative trend and around 1/3 of the positive trends are statistically significant. Relatively larger increases in monthly Tmin and Tmax are noted for the cold season than the warm. The monthly and annual Tmin variables increase more than Tmax variables.
Ursodeoxycholic acid improves liver function via phenylalanine/tyrosine pathway and microbiome remodelling in patients with liver dysfunction
Authors: Kim Da Jung , Yoon Seonghae , Ji Sang Chun , Yang Jinho , Kim Yoon-Keun , Lee SeungHwan , Yu Kyung-Sang , Jang In-Jin , Chung Jae-Yong , Cho Joo-Youn 
Published: August 2018

AbstractUrsodeoxycholic acid (UDCA) is a metabolic by-product of intestinal bacteria, showing hepatoprotective effects. However, its underlying molecular mechanisms remain unclear. The purpose of this study was to elucidate the action mechanisms underlying the protective effects of UDCA and vitamin E against liver dysfunction using metabolomics and metagenomic analysis. In this study, we analysed blood and urine samples from patients with obesity and liver dysfunction. Nine patients were randomly assigned to receive UDCA (300 mg twice daily), and 10 subjects received vitamin E (400 IU twice daily) for 8 weeks. UDCA significantly improved the liver function scores after 4 weeks of treatment and effectively reduced hepatic deoxycholic acid and serum microRNA-122 levels. To better understand its protective mechanism, a global metabolomics study was conducted, and we found that UDCA regulated uremic toxins (hippuric acid, p-cresol sulphate, and indole-derived metabolites), antioxidants (ascorbate sulphate and N-acetyl-L-cysteine), and the phenylalanine/tyrosine pathway. Furthermore, microbiome involvement, particularly of Lactobacillus and Bifidobacterium, was demonstrated through metagenomic analysis of bacteria-derived extracellular vesicles. Meanwhile, vitamin E treatment did not result in such alterations, except that it reduced uremic toxins and liver dysfunction. Our findings suggested that both treatments were effective in improving liver function, albeit via different mechanisms.
Improving sample classification by harnessing the potential of 1H-NMR signal chemical shifts
Authors: Cañueto Daniel , Salek Reza M. , Correig Xavier , Cañellas Nicolau 
Published: August 2018

AbstractNMR spectroscopy is a technology that is widely used in metabolomic studies. The information that these studies most commonly use from NMR spectra is the metabolite concentration. However, as well as concentration, pH and ionic strength information are also made available by the chemical shift of metabolite signals. This information is typically not used even though it can enhance sample discrimination, since many conditions show pH or ionic imbalance. Here, we demonstrate how chemical shift information can be used to improve the quality of the discrimination between case and control samples in three public datasets of different human matrices. In two of these datasets, chemical shift information helped to provide an AUROC value higher than 0.9 during sample classification. In the other dataset, the chemical shift also showed discriminant potential (AUROC 0.831). These results are consistent with the pH imbalance characteristic of the condition studied in the datasets. In addition, we show that this signal misalignment dependent on sample class can alter the results of fingerprinting approaches in the three datasets. Our results show that it is possible to use chemical shift information to enhance the diagnostic and predictive properties of NMR.