bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death
Authors: Liu Rui , Liu Jing , Wang Shuqing , Wang Yinsong , Zhang Tao , liu Yang , Geng Xin , Wang Feng 
Published: July 2019

AbstractG-quadruplex telomeric secondary structures represent natural replication fork barriers and must be resolved to permit efficient replication. Stabilization of telomeric G4 leads to telomere dysfunctions demonstrated by telomere shortening or damage, resulting in genome instability and apoptosis. Chemical compounds targeting G4 structures have been reported to induce telomere disturbance and tumor suppression. Here, virtual screening was performed in a natural compound library using PyRx to identify novel G4 ligands. Emodin was identified as one of the best candidates, showing a great G4-binding potential. Subsequently, we confirmed that emodin could stabilize G4 structures in vitro and trigger telomere dysfunctions including fragile telomeres, telomere loss, and telomeric DNA damage. However, this telomere disturbance could be rescued by subsequent elevation of telomerase activity; in contrast, when we treated the cells with the telomerase inhibitor BIBR1532 upon emodin treatment, permanent telomere disturbance and obvious growth inhibition of 4T1-cell xenograft tumors were observed in mice. Taken together, our results show for the first time that emodin-induced telomeric DNA damage can upregulate telomerase activity, which may weaken its anticancer effect. The combined use of emodin and the telomerase inhibitor synergistically induced telomere dysfunction and inhibited tumor generation.
A novel mutation in gelatinous drop-like corneal dystrophy and functional analysis
Authors: Nagahara Yukiko , Tsujikawa Motokazu , Takigawa Toru , Xu Peng , Kai Chifune , Kawasaki Satoshi , Nakatsukasa Mina , Inatomi Tsutomu , Kinoshita Shigeru , Nishida Kohji 
Published: July 2019

AbstractWe identified a novel mutation of the tumor-associated calcium signal transducer 2 (TACSTD2) gene in a Japanese patient with gelatinous drop-like corneal dystrophy (GDLD). Genetic analysis revealed a novel homozygous mutation (c.798delG, which may result in frameshift mutation p.Lys267SerfsTer4) in the TACSTD2 gene. This mutated gene was devoid of its original function in helping the claudin (CLDN) 1 and 7 proteins transfer from the cytoplasm to the plasma membrane.
NHC-catalyzed atropoenantioselective synthesis of axially chiral biaryl amino alcohols via a cooperative strategy
Authors: Yang Gongming , Guo Donghui , Meng Di , Wang Jian 
Published: July 2019

AbstractAxially chiral biaryl amino-alcohols play a pivotal role in organic synthesis and drug discovery. However, only a very few enantioselective methods have been reported to synthesize chiral biaryl amino-alcohols. Therefore, the rapid enantioselective construction of optically active biaryl amino-alcohols still remains a formidable challenge. Here we report an N-heterocyclic carbene (NHC)-catalyzed atropoenantioselective acylation of biphenols triggered by a cooperative strategy consisting of desymmetrization followed by kinetic resolution. This protocol features broad substrate scope and good functional group tolerance, and allows for a rapid construction of axially chiral biaryl amino-alcohols in good to high yields and with excellent enantioselectivities. Furthermore, the structurally diverse axially chiral biaryl amino-alcohol derivatives provide multiple possibilities for chemists to develop catalysts or ligands for different chemical transformations.
Retention of paternal DNA methylome in the developing zebrafish germline
Authors: Skvortsova Ksenia , Tarbashevich Katsiaryna , Stehling Martin , Lister Ryan , Irimia Manuel , Raz Erez , Bogdanovic Ozren 
Published: July 2019

AbstractTwo waves of DNA methylation reprogramming occur during mammalian embryogenesis; during preimplantation development and during primordial germ cell (PGC) formation. However, it is currently unclear how evolutionarily conserved these processes are. Here we characterise the DNA methylomes of zebrafish PGCs at four developmental stages and identify retention of paternal epigenetic memory, in stark contrast to the findings in mammals. Gene expression profiling of zebrafish PGCs at the same developmental stages revealed that the embryonic germline is defined by a small number of markers that display strong developmental stage-specificity and that are independent of DNA methylation-mediated regulation. We identified promoters that are specifically targeted by DNA methylation in somatic and germline tissues during vertebrate embryogenesis and that are frequently misregulated in human cancers. Together, these detailed methylome and transcriptome maps of the zebrafish germline provide insight into vertebrate DNA methylation reprogramming and enhance our understanding of the relationships between germline fate acquisition and oncogenesis.
Zinc-binding to the cytoplasmic PAS domain regulates the essential WalK histidine kinase of Staphylococcus aureus
Authors: Monk Ian R. , Shaikh Nausad , Begg Stephanie L. , Gajdiss Mike , Sharkey Liam K. R. , Lee Jean Y. H. , Pidot Sacha J. , Seemann Torsten , Kuiper Michael , Winnen Brit , Hvorup Rikki , Collins Brett M. , Bierbaum Gabriele , Udagedara Saumya R. , Morey Jacqueline R. , Pulyani Neha , Howden Benjamin P. , Maher Megan J. , McDevitt Christopher A. , King Glenn F. , Stinear Timothy P. 
Published: July 2019

AbstractWalKR (YycFG) is the only essential two-component regulator in the human pathogen Staphylococcus aureus. WalKR regulates peptidoglycan synthesis, but this function alone does not explain its essentiality. Here, to further understand WalKR function, we investigate a suppressor mutant that arose when WalKR activity was impaired; a histidine to tyrosine substitution (H271Y) in the cytoplasmic Per-Arnt-Sim (PASCYT) domain of the histidine kinase WalK. Introducing the WalKH271Y mutation into wild-type S. aureus activates the WalKR regulon. Structural analyses of the WalK PASCYT domain reveal a metal-binding site, in which a zinc ion (Zn2+) is tetrahedrally-coordinated by four amino acids including H271. The WalKH271Y mutation abrogates metal binding, increasing WalK kinase activity and WalR phosphorylation. Thus, Zn2+-binding negatively regulates WalKR. Promoter-reporter experiments using S. aureus confirm Zn2+ sensing by this system. Identification of a metal ligand recognized by the WalKR system broadens our understanding of this critical S. aureus regulon.
Structural basis for transcription antitermination at bacterial intrinsic terminator
Authors: You Linlin , Shi Jing , Shen Liqiang , Li Lingting , Fang Chengli , Yu Chengzhi , Cheng Wenbo , Feng Yu , Zhang Yu 
Published: July 2019

AbstractBacteriophages typically hijack the host bacterial transcriptional machinery to regulate their own gene expression and that of the host bacteria. The structural basis for bacteriophage protein-mediated transcription regulation—in particular transcription antitermination—is largely unknown. Here we report the 3.4 Å and 4.0 Å cryo-EM structures of two bacterial transcription elongation complexes (P7-NusA-TEC and P7-TEC) comprising the bacteriophage protein P7, a master host-transcription regulator encoded by bacteriophage Xp10 of the rice pathogen Xanthomonas oryzae pv. Oryzae (Xoo) and discuss the mechanisms by which P7 modulates the host bacterial RNAP. The structures together with biochemical evidence demonstrate that P7 prevents transcription termination by plugging up the RNAP RNA-exit channel and impeding RNA-hairpin formation at the intrinsic terminator. Moreover, P7 inhibits transcription initiation by restraining RNAP-clamp motions. Our study reveals the structural basis for transcription antitermination by phage proteins and provides insights into bacterial transcription regulation.
Molecular bilayer graphene
Authors: Zhao Xin-Jing , Hou Hao , Fan Xue-Ting , Wang Yu , Liu Yu-Min , Tang Chun , Liu Shun-He , Ding Peng-Peng , Cheng Jun , Lin Dong-Hai , Wang Cheng , Yang Ye , Tan Yuan-Zhi 
Published: July 2019

AbstractBilayer graphene consists of two stacked graphene layers bound together by van der Waals interaction. As the molecular analog of bilayer graphene, molecular bilayer graphene (MBLG) can offer useful insights into the structural and functional properties of bilayer graphene. However, synthesis of MBLG, which requires discrete assembly of two graphene fragments, has proved to be challenging. Here, we show the synthesis and characterization of two structurally well-defined MBLGs, both consisting of two π−π stacked nanographene sheets. We find they have excellent stability against variation of concentration, temperature and solvents. The MBLGs show sharp absorption and emission peaks, and further time-resolved spectroscopic studies reveal drastically different lifetimes for the bright and dark Davydov states in these MBLGs.
Building egg-tray-shaped graphenes that have superior mechanical strength and band gap
Authors: Liu Wei , Zhao Lei , Zurek Eva , Xia Jing , Zheng Yong-hao , Lin Hai-qing , Liu Jing-yao , Miao Mao-sheng 
Published: July 2019

AbstractThe major hindrances of implementing graphene in two-dimensional (2D) electronics are both mechanical (the tendency to crumble and form ripples) and electrical (the lack of a band gap). Moreover, the inevitable structural defects in graphene have a profound influence on its physical and chemical properties. Here, we propose a family of 2D egg-tray graphenes constructed by arranging pentagon and heptagon defects in the graphene lattice based on a careful analysis of the topological distribution of minima, maxima, and saddle points. First-principles calculations show that the egg-tray graphenes are dynamically stable, and their energies, which depend on the concentration of pentagons and heptagons, are the lowest among carbon allotropes. These 2D carbon allotropes exhibit a large variation in their electronic properties, ranging from semimetallic to semiconducting, including some allotropes that have Dirac cones in their band structures. Furthermore, some egg-tray graphenes are predicted to have negative Poisson’s ratios. The adsorption of Li atoms on the egg-tray graphenes is considerably stronger than the adsorption on perfect graphene, therefore they may absorb Li more effectively than graphene, which is important for improving the performance of rechargeable Li batteries.
Real-life prescribing of asthmatic treatments in UK general practice over time using 2014 BTS/SIGN steps
Authors: Gayle Alicia , Tebboth Abigail , Pang Marie , Guelfucci Florent , Argoubi Ramzi , Sherman Steven , Mak Vincent 
Published: July 2019

AbstractThe 2014 British Thoracic Society (BTS) and Scottish Intercollegiate Guideline Network (SIGN) guidelines recommend a stepwise approach to asthma management. We investigated the management of asthma in primary care in the UK to understand how real-world practice compares with BTS/SIGN guidelines. Asthma patients were identified from the UK Clinical Practice Research Datalink from September 2006 to August 2016. Aims were to classify patients according to BTS/SIGN steps, describe the proportion of patients transitioning between steps and describe patient demographics and clinical characteristics per group. Overall, 647,308 patients with asthma were identified (40,096 aged 5–11 years; 607,212 aged 12–80 years). Most treated patients were in step 1 or 2 (88.3% of children/67.5% of adults in December 2007; 83.0% of children/67.0% of adults in June 2016). Most patients remained within their treatment step within a 6-month interval (>78% of children and adults throughout the study duration). The proportion of patients stepping up and down reduced from the beginning of the study, although stepping down to step 1 was relatively common in both adults and children. Few patients had a recorded asthma review in the year before reference date (18.8% of children and 14.8% of adults). Although prescribing patterns meant that most patients remained within their treatment step throughout the study, we cannot be sure that this was because their disease was truly stable. The small proportion of patients stepping up/down and the lack of recorded asthma review suggest that patients may not be treated in accordance with BTS/SIGN guidelines.
XPNPEP2 is associated with lymph node metastasis in prostate cancer patients
Authors: Li Fei , Dai Yun , Xu Hao , Huang Kecheng , Zhou Ying , Luo Danfeng , Ma Ding , Xi Ling , Lv Mengqin , Ma Xiangyi 
Published: July 2019

AbstractAs we reported in our previous studies, TMTP1, a tumor-homing peptide, selectively targets highly metastatic tumors and their metastatic foci. Aminopeptidase P2 (XPNPEP2) is a receptor for TMTP1 tumor-homing peptide. However, the biological and clinical significance of Aminopeptidase P2 in human cancers remains unknown. In this study, the high-density multiple organ tumor tissue array was employed for the analysis of XPNPEP2 expression profiles in human specimens. The results showed that XPNPEP2 was moderately expressed in the normal prostate tissues, but significantly decreased in the prostate cancer. Hence we used TCGA, IHC, and ELISA to further analyze the expression of XPNPEP2 in tissues and serum of prostate cancer patients. In general, XPNPEP2 expression was lower in prostate cancer tissue than in normal prostate tissue, but was higher in prostate cancer tissues with local invasion and LN metastasis than in tissues with localized Pca. Western blot clarified XPNPEP2 had a secreted form in the serum. Then the serums of 128 Pca patients, 70 healthy males and 40 prostate hyperplasia patients were obtained for detecting serum XPNPEP2 levels.The results indicated that the concentration of XPNPEP2 in serums of Pca patients with LN metastasis (142.7 ± 14.40 ng/mL) were significantly higher than levels in Pca patients without LN metastasis (61.63 ± 5.50 ng/mL) (p < 0.01). An ROC analysis revealed that the combination of PSA and XPNPEP2 was more efficient than PSA or XPNPEP2 alone for predicting LN metastasis, especially for Pca patients with low serum PSA levels. In summary, serum XPNPEP2 levels when combined with PSA levels may result in increased sensitivity for predicting LN metastasis in Pca patients, especially for patients with low serum PSA levels.
The effects of magnetic treatment on nitrogen absorption and distribution in seedlings of Populus × euramericana ‘Neva’ under NaCl stress
Authors: Liu Xiumei , Zhu Hong , Wang Lu , Bi Sisheng , Zhang Zhihao , Meng Shiyuan , Zhang Ying , Wang Huatian , Song Chengdong , Ma Fengyun 
Published: July 2019

AbstractA potted experiment with Populus × euramericana ‘Neva’ was carried out to assess whether there are positive effects of magnetic treatment of saline water (MTSW) on nitrogen metabolism under controlled conditions in a greenhouse. Growth properties, nitrogen contents, enzyme activities and metabolite concentrations were determined based on field experiments and laboratory analysis after a 30-day treatment. The results were as follows: (1) Biomass accumulation, root morphological properties and total nitrogen content were improved by MTSW. (2) Magnetization led to a greater increase in nitrate-nitrogen (NO3−-N) content in roots than in leaves, accompanied by greater NO3− efflux and activated nitrate reductase. (3) MTSW led to a higher ammonium-nitrogen (NH4+-N) content and greater uptake of net NH4+ in the leaves than that in the roots. (4) Magnetization stimulated glutamine synthase, glutamate dehydrogenase and glutamate synthase activities, whereas the concentrations of glutathione and oxidized glutathione were increased in leaves but decreased in roots, and the total glutathione content was increased. Overall, these results indicated some beneficial impacts of MTSW on nitrogen translocation under field conditions, especially for equilibrating the distribution of NO3−-N and NH4+-N. Moreover, these findings confirmed the potential of using low-quality water for agriculture.
Probing the role of perception in fear generalization
Authors: Zaman J. , Struyf D. , Ceulemans E. , Beckers T. , Vervliet B. 
Published: July 2019

AbstractBehavior in novel situations is guided by similarities to previous experiences, a phenomenon known as generalization. Despite the widespread influence of generalization on healthy and pathological behavior, insight into the underlying mechanisms is lacking. It remains unclear whether a failure to notice situational changes contributes to the generalization of learned behavior. We combined a fear conditioning and generalization procedure with a perceptual decision task in humans and found that a failure to perceive a novel stimulus as different from the initial fear-evoking stimulus was associated with increased conditioned responding. These findings demonstrate the potential of a perception-centered approach to better understand (pathological) behavior and its underlying mechanism and are a promising avenue for the development of refined generalization protocols.
PadR-type repressors controlling production of a non-canonical FtsW/RodA homologue and other trans-membrane proteins
Authors: Hauf Samuel , Möller Lars , Fuchs Stephan , Halbedel Sven 
Published: July 2019

AbstractThe Gram-positive bacterium Listeria monocytogenes occurs ubiquitously in the environment and infects humans upon ingestion. It encodes four PadR-like repressors, out of which LftR has been characterized previously and was shown to control gene expression in response to the antibiotic aurantimycin produced by other environmental bacteria. To better understand the PadR regulons of L. monocytogenes, we performed RNA-sequencing with mutants of the other three repressors LadR, LstR and Lmo0599. We show that LadR is primarily responsible for the regulation of the mdrL gene, encoding an efflux pump, while LstR and Lmo0599 mainly regulate their own operons. The lstR operon contains the lmo0421 gene, encoding a homolog of the RodA/FtsW protein family. However, this protein does not possess such functionality, as we demonstrate here. The lmo0599 operon contains two additional genes coding for the hypothetical trans-membrane proteins lmo0600 and lmo0601. A striking phenotype of the lmo0599 mutant is its impaired growth at refrigeration temperature. In light of these and other results we suggest that Lmo0599 should be renamed and propose LltR (listerial low temperature regulator) as its new designation. Based on the nature of the PadR target genes we assume that these repressors collectively respond to compounds acting on the cellular envelope.
Metabolomics Analysis of Skeletal Muscles from FKRP-Deficient Mice Indicates Improvement After Gene Replacement Therapy
Authors: Vannoy Charles Harvey , Leroy Victoria , Broniowska Katarzyna , Lu Qi Long 
Published: July 2019

AbstractMuscular dystrophy-dystroglycanopathies comprise a heterogeneous and complex group of disorders caused by loss-of-function mutations in a multitude of genes that disrupt the glycobiology of α-dystroglycan, thereby affecting its ability to function as a receptor for extracellular matrix proteins. Of the various genes involved, FKRP codes for a protein that plays a critical role in the maturation of a novel glycan found only on α-dystroglycan. Yet despite knowing the genetic cause of FKRP-related dystroglycanopathies, the molecular pathogenesis of disease and metabolic response to therapeutic intervention has not been fully elucidated. To address these challenges, we utilized mass spectrometry-based metabolomics to generate comprehensive metabolite profiles of skeletal muscle across diseased, treated, and normal states. Notably, FKRP-deficient mice elicit diverse metabolic abnormalities in biomarkers of extracellular matrix remodeling and/or aging, pentoses/pentitols, glycolytic intermediates, and lipid metabolism. More importantly, the restoration of FKRP protein activity following AAV-mediated gene therapy induced a substantial correction of these metabolic impairments. While interconnections of the affected molecular mechanisms remain unclear, our datasets support the notion that global metabolic profiling can be valuable for determining the involvement of previously unsuspected regulatory or pathological pathways as well as identifying potential targets for drug discovery and diagnostics.
Fibrogenesis in Chronic DSS Colitis is Not Influenced by Neutralisation of Regulatory T Cells, of Major T Helper Cytokines or Absence of IL-13
Authors: Creyns Brecht , Cremer Jonathan , Hoshino Tomoaki , Geboes Karel , de Hertogh Gert , Ferrante Marc , Vermeire Séverine , Ceuppens Jan L. , Van Assche Gert , Breynaert Christine 
Published: July 2019

AbstractMechanisms underlying fibrogenesis in chronic colitis are largely unknown. There is an urgent need for clinical markers and identification of targets to prevent, treat and limit intestinal fibrosis. This study investigated the contribution of major T cell cytokines and T regulatory cells (Tregs) to inflammation and fibrosis induced in a model of experimental colitis by oral intake of dextran sodium sulphate (DSS) in wild type and IL-13 knock-out C57Bl/6 mice. Inflammation and fibrosis were scored by macroscopic and histological examination and fibrosis was quantified by hydroxyproline. Numbers of Tregs and IFN-γ+, IL-13+ and IL-17A+ CD4+ T helper (Th) cells in mesenteric lymph nodes increased during chronic DSS administration and mRNA for IFN-γ and IL-17 in the inflamed colon tissue was upregulated. However, antibody-mediated neutralisation of IFN-γ or IL-17A/F in a therapeutic setting had no effect on chronic intestinal inflammation and fibrosis. Antibody-mediated depletion of Tregs did not enhance fibrosis, nor did IL-13 deficiency have an effect on the fibrotic disease. These data argue against an important contribution of Tregs and of the cytokines IFN-γ, IL-13, IL-17A, IL-17F in the induction and/or control of fibrosis in this Crohn’s disease like murine model.
Characterization of two putative Dichelobacter nodosus footrot vaccine antigens identifies the first lysozyme inhibitor in the genus
Authors: Humbert Maria Victoria , Jackson Alexandra , Orr Christian M. , Tews Ivo , Christodoulides Myron 
Published: July 2019

AbstractThe Gram-negative anaerobic bacterium Dichelobacter nodosus (Dn) causes footrot in ruminants, a debilitating and highly contagious disease that results in necrotic hooves and significant economic losses in agriculture. Vaccination with crude whole-cell vaccine mixed with multiple recombinant fimbrial proteins can provide protection during species-specific outbreaks, but subunit vaccines containing broadly cross-protective antigens are desirable. We have investigated two D. nodosus candidate vaccine antigens. Macrophage Infectivity Potentiator Dn-MIP (DNO_0012, DNO_RS00050) and Adhesin Complex Protein Dn-ACP (DNO_0725, DNO_RS06795) are highly conserved amongst ~170 D. nodosus isolates in the https://pubmlst.org/dnodosus/ database. We describe the presence of two homologous ACP domains in Dn-ACP with potent C-type lysozyme inhibitor function, and homology of Dn-MIP to other putative cell-surface and membrane-anchored MIP virulence factors. Immunization of mice with recombinant proteins with a variety of adjuvants induced antibodies that recognised both proteins in D. nodosus. Notably, immunization with fimbrial-whole-cell Footvax vaccine induced anti-Dn-ACP and anti-Dn-MIP antibodies. Although all adjuvants induced high titre antibody responses, only antisera to rDn-ACP-QuilA and rDn-ACP-Al(OH)3 significantly prevented rDn-ACP protein from inhibiting lysozyme activity in vitro. Therefore, a vaccine incorporating rDn-ACP in particular could contribute to protection by enabling normal innate immune lysozyme function to aid bacterial clearance.