bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models
Authors: Mirzamohammadi Fatemeh , Kozlova Anastasia , Papaioannou Garyfallia , Paltrinieri Elena , Ayturk Ugur M. , Kobayashi Tatsuya 
Published: April 2018

AbstractFeingold syndrome is a skeletal dysplasia caused by loss-of-function mutations of either MYCN (type 1) or MIR17HG that encodes miR-17-92 microRNAs (type 2). Since miR-17-92 expression is transcriptionally regulated by MYC transcription factors, it has been postulated that Feingold syndrome type 1 and 2 may be caused by a common molecular mechanism. Here we show that Mir17-92 deficiency upregulates TGF-β signaling, whereas Mycn-deficiency downregulates PI3K signaling in limb mesenchymal cells. Genetic or pharmacological inhibition of TGF-β signaling efficiently rescues the skeletal defects caused by Mir17-92 deficiency, suggesting that upregulation of TGF-β signaling is responsible for the skeletal defect of Feingold syndrome type 2. By contrast, the skeletal phenotype of Mycn-deficiency is partially rescued by Pten heterozygosity, but not by TGF-β inhibition. These results strongly suggest that despite the phenotypical similarity, distinct molecular mechanisms underlie the pathoetiology for Feingold syndrome type 1 and 2.
Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate
Authors: Andronesi Ovidiu C. , Arrillaga-Romany Isabel C. , Ly K. Ina , Bogner Wolfgang , Ratai Eva M. , Reitz Kara , Iafrate A. John , Dietrich Jorg , Gerstner Elizabeth R. , Chi Andrew S. , Rosen Bruce R. , Wen Patrick Y. , Cahill Daniel P. , Batchelor Tracy T. 
Published: April 2018

AbstractInhibitors of the mutant isocitrate dehydrogenase 1 (IDH1) entered recently in clinical trials for glioma treatment. Mutant IDH1 produces high levels of 2-hydroxyglurate (2HG), thought to initiate oncogenesis through epigenetic modifications of gene expression. In this study, we show the initial evidence of the pharmacodynamics of a new mutant IDH1 inhibitor in glioma patients, using non-invasive 3D MR spectroscopic imaging of 2HG. Our results from a Phase 1 clinical trial indicate a rapid decrease of 2HG levels by 70% (CI 13%, P = 0.019) after 1 week of treatment. Importantly, inhibition of mutant IDH1 may lead to the reprogramming of tumor metabolism, suggested by simultaneous changes in glutathione, glutamine, glutamate, and lactate. An inverse correlation between metabolic changes and diffusion MRI indicates an effect on the tumor-cell density. We demonstrate a feasible radiopharmacodynamics approach to support the rapid clinical translation of rationally designed drugs targeting IDH1/2 mutations for personalized and precision medicine of glioma patients.
A new failure mechanism of electromigration by surface diffusion of Sn on Ni and Cu metallization in microbumps
Authors: Chang Yuan-Wei , Hu Chia-chia , Peng Hsin-Ying , Liang Yu-Chun , Chen Chih , Chang Tao-chih , Zhan Chau-Jie , Juang Jing-Ye 
Published: April 2018

AbstractMicrobumps in three-dimensional integrated circuit now becomes essential technology to reach higher packaging density. However, the small volume of microbumps dramatically changes the characteristics from the flip-chip (FC) solder joints. For a 20 µm diameter microbump, the cross-section area and the volume are only 1/25 and 1/125 of a 100 µm diameter FC joint. The small area significantly enlarges the current density although the current crowding effect was reduced at the same time. The small volume of solder can be fully transformed into the intermetallic compounds (IMCs) very easily, and the IMCs are usually stronger under electromigration (EM). These result in the thoroughly change of the EM failure mechanism in microbumps. In this study, microbumps with two different diameter and flip-chip joints were EM tested. A new failure mechanism was found obviously in microbumps, which is the surface diffusion of Sn. Under EM testing, Sn atoms tend to migrate along the surface to the circumference of Ni and Cu metallization to form Ni3Sn4and Cu3Sn IMCs respectively. When the Sn diffuses away, necking or serious void formation occurs in the solder, which weakens the electrical and mechanical properties of the microbumps. Theoretic calculation indicates that this failure mode will become even significantly for the microbumps with smaller dimensions than the 18 µm microbumps.
Metabolomics and pathway analyses to characterize metabolic alterations in pregnant dairy cows on D 17 and D 45 after AI
Authors: Guo Y. S. , Tao J. Z. 
Published: April 2018

AbstractNutrient flow to the embryo and placenta is crucial for proper development and growth during pregnancy. In this study, a metabonomic analysis was undertaken to better understand global changes in pregnant dairy cows on D 17 and D 45 after timed artificial insemination (AI). Metabolic changes in the blood plasma of pregnant dairy cows were investigated using HPLC-MS and a multivariate statistical analysis. Changes in metabolic networks were established using the MetPA method. Alterations in six metabolic pathways were found on D 17 and D 45, including variations in the level of alpha-linolenic acid metabolism, glycerophospholipid metabolism, pentose and glucuronate interconversions, glycerolipid metabolism, folate biosynthesis, and tyrosine metabolism. In addition to these pathways, 9 metabolic pathways were markedly altered on D 45. These pathways included changes in the one-carbon pool caused by folate; phenylalanine, tyrosine and tryptophan biosynthesis; thiamine metabolism; pantothenate and CoA biosynthesis; purine metabolism; inositol phosphate metabolism; amino sugar and nucleotide sugar metabolism; pentose phosphate; and the TCA pathway. The combination of metabonomics and network methods used in this study generated rich biochemical insight into possible biological modules related to early pregnancy in dairy cows.
Beyond dose: Pulsed antibiotic treatment schedules can maintain individual benefit while reducing resistance
Authors: Baker Christopher M. , Ferrari Matthew J. , Shea Katriona 
Published: April 2018

AbstractThe emergence of treatment-resistant microbes is a key challenge for disease treatment and a leading threat to human health and wellbeing. New drugs are always in development, but microbes regularly and rapidly acquire resistance. We must consider if altering how we administer drugs at the individual level could slow development of resistance. Here we use mathematical models to show that exposing microbes to drug pulses could greatly reduce resistance without increasing individual pathogen load. Our results stem from two key factors: the presence of antibiotics creates a selection pressure for antibiotic resistant microbes, and large populations of bacteria are more likely to harbor drug resistance than small populations. Drug pulsing targets these factors simultaneously. Short duration pulses minimize the time during which there is selection for resistance, and high drug concentrations minimize pathogen abundance. Our work provides a theoretical basis for the design of in vitro and in vivo experiments to test how drug pulsing might reduce the impact of drug resistant infections.
Highly Interactive Brain–Computer Interface Based on Flicker-Free Steady-State Motion Visual Evoked Potential
Authors: Han Chengcheng , Xu Guanghua , Xie Jun , Chen Chaoyang , Zhang Sicong 
Published: April 2018

AbstractVisual evoked potential-based brain–computer interfaces (BCIs) have been widely investigated because of their easy system configuration and high information transfer rate (ITR). However, the uncomfortable flicker or brightness modulation of existing methods restricts the practical interactivity of BCI applications. In our study, a flicker-free steady-state motion visual evoked potential (FF-SSMVEP)-based BCI was proposed. Ring-shaped motion checkerboard patterns with oscillating expansion and contraction motions were presented by a high-refresh-rate display for visual stimuli, and the brightness of the stimuli was kept constant. Compared with SSVEPs, few harmonic responses were elicited by FF-SSMVEPs, and the frequency energy of SSMVEPs was concentrative. These FF-SSMVEPs evoked “single fundamental peak” responses after signal processing without harmonic and subharmonic peaks. More stimulation frequencies could thus be selected to elicit more responding fundamental peaks without overlap with harmonic peaks. A 40-target online SSMVEP-based BCI system was achieved that provided an ITR up to 1.52 bits per second (91.2 bits/min), and user training was not required to use this system. This study also demonstrated that the FF-SSMVEP-based BCI system has low contrast and low visual fatigue, offering a better alternative to conventional SSVEP-based BCIs.
Toxicity of enrofloxacin, copper and their interactions on soil microbial populations and ammonia-oxidizing archaea and bacteria
Authors: Wei Ziyan , Wang Jinhua , Zhu Lusheng , Wang Jun , Zhu Guodong 
Published: April 2018

AbstractEnrofloxacin (EFX) is one of the most frequently used broad-spectrum veterinary drugs, and copper (Cu) is a heavy metal that could easily bind to certain antibiotic molecules. Hence EFX and Cu were chosen as representatives of antibiotics and heavy metals to explore the abundance and variation of soil microbial populations with a plate-counting technique, as well as the copy numbers of amoA gene in ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) by quantitative PCR methods in Argosols samples. Treatments of applied EFX (0.05, 0.20, 0.80 mmol/kg), Cu (1.60 mmol/kg) and combined EFX and Cu (at molar ratios of 1:32,1:8,1:2) exhibited various effects on different soil microorganisms. The toxicity of combined EFX and Cu was more strongly expressed on both soil microbial populations and amoA gene (AOA and AOB) compared to the EFX treatment alone, in most cases, time and dose effects were observed. With respect to the amoA gene, the AOA-amoA gene was more abundant than the AOB-amoA gene, and the ratio ranged from ~8 to ~11. Moreover, the interaction types of EFX and Cu were more likely to be antagonistic (64.29%) than synergistic (35.71%) on soil abundance and function, which may be related to the incubation time and the ratio of EFX to Cu in the soil.
A Multi-Parameter Analysis of Cellular Coordination of Major Transcriptome Regulation Mechanisms
Authors: Jiang Wen , Guo Zhanyong , Lages Nuno , Zheng W. Jim , Feliers Denis , Zhang Fangyuan , Wang Degeng 
Published: April 2018

AbstractTo understand cellular coordination of multiple transcriptome regulation mechanisms, we simultaneously measured transcription rate (TR), mRNA abundance (RA) and translation activity (TA). This revealed multiple insights. First, the three parameters displayed systematic statistical differences. Sequentially more genes exhibited extreme (low or high) expression values from TR to RA, and then to TA; that is, cellular coordination of multiple transcriptome regulatory mechanisms leads to sequentially enhanced gene expression selectivity as the genetic information flow from the genome to the proteome. Second, contribution of the stabilization-by-translation regulatory mechanism to the cellular coordination process was assessed. The data enabled an estimation of mRNA stability, revealing a moderate but significant positive correlation between mRNA stability and translation activity. Third, the proportion of mRNA occupied by un-translated regions (UTR) exhibited a negative relationship with the level of this correlation, and was thus a major determinant of the mode of regulation of the mRNA. High-UTR-proportion mRNAs tend to defy the stabilization-by-translation regulatory mechanism, staying out of the polysome but remaining stable; mRNAs with little UTRs largely followed this regulation. In summary, we quantitatively delineated the relationship among multiple transcriptome regulation parameters, i.e., cellular coordination of corresponding regulatory mechanisms.
Antagonistic PCP Signaling Pathways in the developing Drosophila eye
Authors: Katanaev Vladimir L. , Egger-Adam Diane , Tomlinson Andrew 
Published: April 2018

AbstractIn Planar cell polarity (PCP), cells coordinately polarize their cytoskeletons within the plane of the epithelium in which they lie. In most insect epithelia this is indicated by the coordinated projections of the hairs secreted by the ectodermal cells. PCP of this form has been effectively studied in Drosophila, but it has proven difficult to achieve an integrated description of the roles played by the various proteins. In the insect eye, PCP is not evident as the polarization of individual cells, but as the asymmetric arrangements of the cells of the ommatidia. This different form of PCP allows different studies to be performed, and using this system we have detected the action of two antagonistic signaling pathways. Even though antagonistic, the two pathways synergize and cooperate to ensure that the correct arrangement of the cells is achieved. The cooperative use of antagonistic signaling pathways occurs in the polarization of chemotacting cells, and we discuss the possibility that a similar molecular principle may underlie PCP.
Inhibition of homoserine dehydrogenase by formation of a cysteine-NAD covalent complex
Authors: Ogata Kohei , Yajima Yui , Nakamura Sanenori , Kaneko Ryosuke , Goto Masaru , Ohshima Toshihisa , Yoshimune Kazuaki 
Published: April 2018

AbstractHomoserine dehydrogenase (EC 1.1.1.3, HSD) is an important regulatory enzyme in the aspartate pathway, which mediates synthesis of methionine, threonine and isoleucine from aspartate. Here, HSD from the hyperthermophilic archaeon Sulfolobus tokodaii (StHSD) was found to be inhibited by cysteine, which acted as a competitive inhibitor of homoserine with a Ki of 11 μM and uncompetitive an inhibitor of NAD and NADP with Ki’s of 0.55 and 1.2 mM, respectively. Initial velocity and product (NADH) inhibition analyses of homoserine oxidation indicated that StHSD first binds NAD and then homoserine through a sequentially ordered mechanism. This suggests that feedback inhibition of StHSD by cysteine occurs through the formation of an enzyme-NAD-cysteine complex. Structural analysis of StHSD complexed with cysteine and NAD revealed that cysteine situates within the homoserine binding site. The distance between the sulfur atom of cysteine and the C4 atom of the nicotinamide ring was approximately 1.9 Å, close enough to form a covalent bond. The UV absorption-difference spectrum of StHSD with and without cysteine in the presence of NAD, exhibited a peak at 325 nm, which also suggests formation of a covalent bond between cysteine and the nicotinamide ring.
Testing the impact of effective population size on speciation rates – a negative correlation or lack thereof in lichenized fungi
Authors: Huang Jen-Pan , Leavitt Steven D. , Lumbsch H. Thorsten 
Published: April 2018

AbstractThe effect of microevolutionary processes on macroevolutionary patterns, and vice versa, is an important but under-investigated question. Here we present an integrative population genetic and phylogenetic study using molecular sequence data from three lichen-forming fungal lineages to empirically test the potential correlation between effective population size – approximated by the parameter θ – and estimated speciation rates using a phylogenetic tree (λ). A negative association between θ and λ was supported in one lineage of lichen-forming fungi, Melanelixia (Parmeliaceae), while no significant relationships was found for two other genera within the same family, Melanohalea and Xanthoparmelia. We discuss the significance of our results and the importance of considering microevolutionary processes when studying macroevolutionary patterns.
Effects of muscle relaxants on ischaemia damage in skeletal muscle
Authors: Ledowski Thomas , Nißler Simone , Wenk Manuel , Pogatzki-Zahn Esther M. , Segelcke Daniel 
Published: April 2018

AbstractMuscle ischaemia is frequently induced intraoperatively by i.e. a surgical tourniquet or during the re-grafting phase of a free muscle transplant. The resulting muscle cell damage may impact on postoperative recovery. Neuromuscular paralysis may mitigate the effects of ischaemia. After ethics approval, 25 male Sprague-Dawley rats were anaesthetized and randomly assigned to 1 of 4 groups: Sham operation, treatment with normal saline, treatment with rocuronium (muscle relaxant) 0.6 or 1 mg kg−1, respectively. In the non-sham groups, ischaemia of one hind leg was achieved by ligation of the femoral vessels. Muscle biopsies were taken at 30 and 90 min, respectively. Cell damage was assessed in the biopsies via the expression of dystrophin, free calcium, as well as the assessment of cell viability. Pre-ischaemia muscle relaxation led to a reduction in ischaemia-induced muscle cell damage when measured by the expression of dystrophin, cell viability and the expression of free calcium even after 90 min of ischaemia (i.e. ratio control/ischaemic site for dystrophin expression after saline 0.58 ± 0.12 vs. after 1 mg/kg rocuronium 1.08 ± 0.29; P < 0.05). Muscle relaxation decreased the degree of ischaemia-induced muscle cell damage. The results may have significant clinical implications.
Quantization of geometric phase with integer and fractional topological characterization in a quantum Ising chain with long-range interaction
Authors: Sarkar Sujit 
Published: April 2018

AbstractAn attempt is made to study and understand the behavior of quantization of geometric phase of a quantum Ising chain with long range interaction. We show the existence of integer and fractional topological characterization for this model Hamiltonian with different quantization condition and also the different quantized value of geometric phase. The quantum critical lines behave differently from the perspective of topological characterization. The results of duality and its relation to the topological quantization is presented here. The symmetry study for this model Hamiltonian is also presented. Our results indicate that the Zak phase is not the proper physical parameter to describe the topological characterization of system with long range interaction. We also present quite a few exact solutions with physical explanation. Finally we present the relation between duality, symmetry and topological characterization. Our work provides a new perspective on topological quantization.
Increasing salinity drastically reduces hatching success of crustaceans from depression wetlands of the semi-arid Eastern Cape Karoo region, South Africa
Authors: Mabidi Annah , Bird Matthew S. , Perissinotto Renzo 
Published: April 2018

AbstractSalinity is an important factor affecting freshwater aquatic species distribution and diversity. The semi-arid Eastern Cape Karoo region of South Africa has been earmarked for shale gas development through hydraulic fracturing. The process uses large amounts of water and produces briny wastewater. When not managed properly, these wastewaters may lead to salinisation of surface freshwater bodies in the region. Therefore, the effect of salinity on the hatching success of crustacean resting eggs was examined using sediments from four depression wetlands found in the region. The sediments were exposed for 28 days to salinity levels of 0.5 g L−1, 2.5 g L−1, 5 g L−1 and 10 g L−1. Control aquaria in which no salt was added were also set up. There was a significant decrease in the emerged taxa richness and abundances at salinities of 2.5 g L−1 and above. Anostraca, Notostraca and Spinicaudata hatchlings were abundant at salinities of 0.5 g L−1 and below, while Copepoda, Daphniidae (Cladocera) and Ostracoda were observed in the highest salinity, but their densities were still lower with increased salinities. Given the importance of large branchiopods in the trophic balance of depression wetlands, their loss may alter the ecological balance and function of these ecosystems.
Activation of the DnaK-ClpB Complex is Regulated by the Properties of the Bound Substrate
Authors: Fernández-Higuero Jose Angel , Aguado Alejandra , Perales-Calvo Judit , Moro Fernando , Muga Arturo 
Published: April 2018

AbstractThe chaperone ClpB in bacteria is responsible for the reactivation of aggregated proteins in collaboration with the DnaK system. Association of these chaperones at the aggregate surface stimulates ATP hydrolysis, which mediates substrate remodeling. However, a question that remains unanswered is whether the bichaperone complex can be selectively activated by substrates that require remodeling. We find that large aggregates or bulky, native-like substrates activates the complex, whereas a smaller, permanently unfolded protein or extended, short peptides fail to stimulate it. Our data also indicate that ClpB interacts differently with DnaK in the presence of aggregates or small peptides, displaying a higher affinity for aggregate-bound DnaK, and that DnaK-ClpB collaboration requires the coupled ATPase-dependent remodeling activities of both chaperones. Complex stimulation is mediated by residues at the β subdomain of DnaK substrate binding domain, which become accessible to the disaggregase when the lid is allosterically detached from the β subdomain. Complex activation also requires an active NBD2 and the integrity of the M domain-ring of ClpB. Disruption of the M-domain ring allows the unproductive stimulation of the DnaK-ClpB complex in solution. The ability of the DnaK-ClpB complex to discrimínate different substrate proteins might allow its activation when client proteins require remodeling.
Satellite DNA in Vicia faba is characterized by remarkable diversity in its sequence composition, association with centromeres, and replication timing
Authors: Ávila Robledillo Laura , Koblížková Andrea , Novák Petr , Böttinger Katharina , Vrbová Iva , Neumann Pavel , Schubert Ingo , Macas Jiří 
Published: April 2018

AbstractSatellite DNA, a class of repetitive sequences forming long arrays of tandemly repeated units, represents substantial portions of many plant genomes yet remains poorly characterized due to various methodological obstacles. Here we show that the genome of the field bean (Vicia faba, 2n = 12), a long-established model for cytogenetic studies in plants, contains a diverse set of satellite repeats, most of which remained concealed until their present investigation. Using next-generation sequencing combined with novel bioinformatics tools, we reconstructed consensus sequences of 23 novel satellite repeats representing 0.008–2.700% of the genome and mapped their distribution on chromosomes. We found that in addition to typical satellites with monomers hundreds of nucleotides long, V. faba contains a large number of satellite repeats with unusually long monomers (687–2033 bp), which are predominantly localized in pericentromeric regions. Using chromatin immunoprecipitation with CenH3 antibody, we revealed an extraordinary diversity of centromeric satellites, consisting of seven repeats with chromosome-specific distribution. We also found that in spite of their different nucleotide sequences, all centromeric repeats are replicated during mid-S phase, while most other satellites are replicated in the first part of late S phase, followed by a single family of FokI repeats representing the latest replicating chromatin.