bluuebunny/crossref_metadata_2025_split huggingface dataset:
A uniform survey of allele-specific binding and expression over 1000-Genomes-Project individuals
Authors: Chen Jieming , Rozowsky Joel , Galeev Timur R. , Harmanci Arif , Kitchen Robert , Bedford Jason , Abyzov Alexej , Kong Yong , Regan Lynne , Gerstein Mark 
Published: April 2016

AbstractLarge-scale sequencing in the 1000 Genomes Project has revealed multitudes of single nucleotide variants (SNVs). Here, we provide insights into the functional effect of these variants using allele-specific behaviour. This can be assessed for an individual by mapping ChIP-seq and RNA-seq reads to a personal genome, and then measuring ‘allelic imbalances’ between the numbers of reads mapped to the paternal and maternal chromosomes. We annotate variants associated with allele-specific binding and expression in 382 individuals by uniformly processing 1,263 functional genomics data sets, developing approaches to reduce the heterogeneity between data sets due to overdispersion and mapping bias. Since many allelic variants are rare, aggregation across multiple individuals is necessary to identify broadly applicable ‘allelic elements’. We also found SNVs for which we can anticipate allelic imbalance from the disruption of a binding motif. Our results serve as an allele-specific annotation for the 1000 Genomes variant catalogue and are distributed as an online resource (alleledb.gersteinlab.org).
Explanation of efficient quenching of molecular ion vibrational motion by ultracold atoms
Authors: Stoecklin Thierry , Halvick Philippe , Gannouni Mohamed Achref , Hochlaf Majdi , Kotochigova Svetlana , Hudson Eric R. 
Published: April 2016

AbstractBuffer gas cooling of molecules to cold and ultracold temperatures is a promising technique for realizing a host of scientific and technological opportunities. Unfortunately, experiments using cryogenic buffer gases have found that although the molecular motion and rotation are quickly cooled, the molecular vibration relaxes at impractically long timescales. Here, we theoretically explain the recently observed exception to this rule: efficient vibrational cooling of BaCl+ by a laser-cooled Ca buffer gas. We perform intense close-coupling calculations that agree with the experimental result, and use both quantum defect theory and a statistical capture model to provide an intuitive understanding of the system. This result establishes that, in contrast to the commonly held opinion, there exists a large class of systems that exhibit efficient vibrational cooling and therefore supports a new route to realize the long-sought opportunities offered by molecular structure.
Repulsive cues combined with physical barriers and cell–cell adhesion determine progenitor cell positioning during organogenesis
Authors: Paksa Azadeh , Bandemer Jan , Hoeckendorf Burkhard , Razin Nitzan , Tarbashevich Katsiaryna , Minina Sofia , Meyen Dana , Biundo Antonio , Leidel Sebastian A. , Peyrieras Nadine , Gov Nir S. , Keller Philipp J. , Raz Erez 
Published: April 2016

AbstractThe precise positioning of organ progenitor cells constitutes an essential, yet poorly understood step during organogenesis. Using primordial germ cells that participate in gonad formation, we present the developmental mechanisms maintaining a motile progenitor cell population at the site where the organ develops. Employing high-resolution live-cell microscopy, we find that repulsive cues coupled with physical barriers confine the cells to the correct bilateral positions. This analysis revealed that cell polarity changes on interaction with the physical barrier and that the establishment of compact clusters involves increased cell–cell interaction time. Using particle-based simulations, we demonstrate the role of reflecting barriers, from which cells turn away on contact, and the importance of proper cell–cell adhesion level for maintaining the tight cell clusters and their correct positioning at the target region. The combination of these developmental and cellular mechanisms prevents organ fusion, controls organ positioning and is thus critical for its proper function.
Induction of IL-25 secretion from tumour-associated fibroblasts suppresses mammary tumour metastasis
Authors: Yin Shu-Yi , Jian Feng-Yin , Chen Yung-Hsiang , Chien Shih-Chang , Hsieh Mao-Chih , Hsiao Pei-Wen , Lee Wen-Hwa , Kuo Yueh-Hsiung , Yang Ning-Sun 
Published: April 2016

AbstractTumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression. Here we investigate the role of IL-25, an endogenous anticancer factor secreted from TAFs, in suppression of mouse 4T1 mammary tumour metastasis. We show that a synthetic dihydrobenzofuran lignan (Q2-3), the dimerization product of plant caffeic acid methyl ester, suppresses 4T1 metastasis by increasing fibroblastic IL-25 activity. The secretion of IL-25 from treated human or mouse fibroblasts is enhanced in vitro, and this activity confers a strong suppressive effect on growth activity of test carcinoma cells. Subsequent in vivo experiments showed that the anti-metastatic effects of Q2-3 on 4T1 and human MDA-MD-231 tumour cells are additive when employed in combination with the clinically used drug, docetaxel. Altogether, our findings reveal that the release of IL-25 from TAFs may serve as a check point for control of mammary tumour metastasis and that phytochemical Q2-3 can efficiently promote such anticancer activities.
The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy
Authors: Lukey Michael J. , Greene Kai Su , Erickson Jon W. , Wilson Kristin F. , Cerione Richard A. 
Published: April 2016

AbstractMany transformed cells exhibit altered glucose metabolism and increased utilization of glutamine for anabolic and bioenergetic processes. These metabolic adaptations, which accompany tumorigenesis, are driven by oncogenic signals. Here we report that the transcription factor c-Jun, product of the proto-oncogene JUN, is a key regulator of mitochondrial glutaminase (GLS) levels. Activation of c-Jun downstream of oncogenic Rho GTPase signalling leads to elevated GLS gene expression and glutaminase activity. In human breast cancer cells, GLS protein levels and sensitivity to GLS inhibition correlate strongly with c-Jun levels. We show that c-Jun directly binds to the GLS promoter region, and is sufficient to increase gene expression. Furthermore, ectopic overexpression of c-Jun renders breast cancer cells dependent on GLS activity. These findings reveal a role for c-Jun as a driver of cancer cell metabolic reprogramming, and suggest that cancers overexpressing JUN may be especially sensitive to GLS-targeted therapies.
Structure of eukaryotic purine/H+ symporter UapA suggests a role for homodimerization in transport activity
Authors: Alguel Yilmaz , Amillis Sotiris , Leung James , Lambrinidis George , Capaldi Stefano , Scull Nicola J. , Craven Gregory , Iwata So , Armstrong Alan , Mikros Emmanuel , Diallinas George , Cameron Alexander D. , Byrne Bernadette 
Published: April 2016

AbstractThe uric acid/xanthine H+ symporter, UapA, is a high-affinity purine transporter from the filamentous fungus Aspergillus nidulans. Here we present the crystal structure of a genetically stabilized version of UapA (UapA-G411VΔ1–11) in complex with xanthine. UapA is formed from two domains, a core domain and a gate domain, similar to the previously solved uracil transporter UraA, which belongs to the same family. The structure shows UapA in an inward-facing conformation with xanthine bound to residues in the core domain. Unlike UraA, which was observed to be a monomer, UapA forms a dimer in the crystals with dimer interactions formed exclusively through the gate domain. Analysis of dominant negative mutants is consistent with dimerization playing a key role in transport. We postulate that UapA uses an elevator transport mechanism likely to be shared with other structurally homologous transporters including anion exchangers and prestin.
Structural basis for Mep2 ammonium transceptor activation by phosphorylation
Authors: van den Berg Bert , Chembath Anupama , Jefferies Damien , Basle Arnaud , Khalid Syma , Rutherford Julian C. 
Published: April 2016

AbstractMep2 proteins are fungal transceptors that play an important role as ammonium sensors in fungal development. Mep2 activity is tightly regulated by phosphorylation, but how this is achieved at the molecular level is not clear. Here we report X-ray crystal structures of the Mep2 orthologues from Saccharomyces cerevisiae and Candida albicans and show that under nitrogen-sufficient conditions the transporters are not phosphorylated and present in closed, inactive conformations. Relative to the open bacterial ammonium transporters, non-phosphorylated Mep2 exhibits shifts in cytoplasmic loops and the C-terminal region (CTR) to occlude the cytoplasmic exit of the channel and to interact with His2 of the twin-His motif. The phosphorylation site in the CTR is solvent accessible and located in a negatively charged pocket ∼30 Å away from the channel exit. The crystal structure of phosphorylation-mimicking Mep2 variants from C. albicans show large conformational changes in a conserved and functionally important region of the CTR. The results allow us to propose a model for regulation of eukaryotic ammonium transport by phosphorylation.
The complex binding mode of the peptide hormone H2 relaxin to its receptor RXFP1
Authors: Sethi Ashish , Bruell Shoni , Patil Nitin , Hossain Mohammed Akhter , Scott Daniel J. , Petrie Emma J. , Bathgate Ross A. D. , Gooley Paul R. 
Published: April 2016

AbstractH2 relaxin activates the relaxin family peptide receptor-1 (RXFP1), a class A G-protein coupled receptor, by a poorly understood mechanism. The ectodomain of RXFP1 comprises an N-terminal LDLa module, essential for activation, tethered to a leucine-rich repeat (LRR) domain by a 32-residue linker. H2 relaxin is hypothesized to bind with high affinity to the LRR domain enabling the LDLa module to bind and activate the transmembrane domain of RXFP1. Here we define a relaxin-binding site on the LDLa-LRR linker, essential for the high affinity of H2 relaxin for the ectodomain of RXFP1, and show that residues within the LDLa-LRR linker are critical for receptor activation. We propose H2 relaxin binds and stabilizes a helical conformation of the LDLa-LRR linker that positions residues of both the linker and the LDLa module to bind the transmembrane domain and activate RXFP1.
Temporal decorrelation by SK channels enables efficient neural coding and perception of natural stimuli
Authors: Huang Chengjie G. , Zhang Zhubo D. , Chacron Maurice J. 
Published: April 2016

AbstractIt is commonly assumed that neural systems efficiently process natural sensory input. However, the mechanisms by which such efficient processing is achieved, and the consequences for perception and behaviour remain poorly understood. Here we show that small conductance calcium-activated potassium (SK) channels enable efficient neural processing and perception of natural stimuli. Specifically, these channels allow for the high-pass filtering of sensory input, thereby removing temporal correlations or, equivalently, whitening frequency response power. Varying the degree of adaptation through pharmacological manipulation of SK channels reduced efficiency of coding of natural stimuli, which in turn gave rise to predictable changes in behavioural responses that were no longer matched to natural stimulus statistics. Our results thus demonstrate a novel mechanism by which the nervous system can implement efficient processing and perception of natural sensory input that is likely to be shared across systems and species.
MNK1 and MNK2 mediate adverse effects of high-fat feeding in distinct ways
Authors: Moore C. E. J. , Pickford J. , Cagampang F. R. , Stead R. L. , Tian S. , Zhao X. , Tang X. , Byrne C. D. , Proud C. G. 
Published: April 2016

AbstractThe MAP kinase-interacting kinases (MNK1 and MNK2) are non-essential enzymes which are activated by MAP kinases. They are implicated in controlling protein synthesis. Here we show that mice in which the expression of either MNK1 or MNK2 has been knocked out (KO) are protected against adverse effects of high-fat feeding, and in distinct ways. High-fat diet (HFD)-fed MNK2-KO show less weight gain than wild-type animals, and improved glucose tolerance, better insulin sensitivity and markedly diminished adipose tissue inflammation. This suggests MNK2 plays a role in adipogenesis and/or lipogenesis and in macrophage biology. MNK1-KO/HFD mice show better glucose tolerance and insulin sensitivity, but gain weight and show similar adipose inflammation to WT animals. These data suggest MNK1 participates in mediating HFD-induced insulin resistance. Our findings reveal distinct roles for the MNKs in a novel area of disease biology, metabolic dysfunction, and suggests they are potential new targets for managing metabolic disease.
Sexually Dimorphic Expression of eGFP Transgene in the Akr1A1 Locus of Mouse Liver Regulated by Sex Hormone-Related Epigenetic Remodeling
Authors: Lai Cheng-Wei , Chen Hsiao-Ling , Tsai Tung-Chou , Chu Te-Wei , Yang Shang-Hsun , Chong Kowit-Yu , Chen Chuan-Mu 
Published: April 2016

AbstractSexually dimorphic gene expression is commonly found in the liver and many of these genes are linked to different incidences of liver diseases between sexes. However, the mechanism of sexually dimorphic expression is still not fully understood. In this study, a pCAG-eGFP transgenic mouse strain with a specific transgene integration site in the Akr1A1 locus presented male-biased EGFP expression in the liver and the expression was activated by testosterone during puberty. The integration of the pCAG-eGFP transgene altered the epigenetic regulation of the adjacent chromatin, including increased binding of STAT5b, a sexually dimorphic expression regulator and the transformation of DNA methylation from hypermethylation into male-biased hypomethylation. Through this de novo sexually dimorphic expression of the transgene, the Akr1A1eGFP mouse provides a useful model to study the mechanisms and the dynamic changes of sexually dimorphic gene expression during either development or pathogenesis of the liver.
Improved emotional conflict control triggered by the processing priority of negative emotion
Authors: Yang Qian , Wang Xiangpeng , Yin Shouhang , Zhao Xiaoyue , Tan Jinfeng , Chen Antao 
Published: April 2016

AbstractThe prefrontal cortex is responsible for emotional conflict resolution and this control mechanism is affected by the emotional valence of distracting stimuli. In the present study, we investigated effects of negative and positive stimuli on emotional conflict control using a face-word Stroop task in combination with functional brain imaging. Emotional conflict was absent in the negative face context, in accordance with the null activation observed in areas regarding emotional face processing (fusiform face area, middle temporal/occipital gyrus). Importantly, these visual areas negatively coupled with the dorsolateral prefrontal cortex (DLPFC). However, the significant emotional conflict was observed in the positive face context, this effect was accompanied by activation in areas associated with emotional face processing and the default mode network (DMN), here, DLPFC mainly negatively coupled with DMN, rather than visual areas. These results suggested that the conflict control mechanism exerted differently between negative faces and positive faces, it implemented more efficiently in the negative face condition, whereas it is more devoted to inhibiting internal interference in the positive face condition. This study thus provides a plausible mechanism of emotional conflict resolution that the rapid pathway for negative emotion processing efficiently triggers control mechanisms to preventively resolve emotional conflict.
Moonlighting of Helicobacter pylori catalase protects against complement-mediated killing by utilising the host molecule vitronectin
Authors: Richter Corinna , Mukherjee Oindrilla , Ermert David , Singh Birendra , Su Yu-Ching , Agarwal Vaibhav , Blom Anna M. , Riesbeck Kristian 
Published: April 2016

AbstractHelicobacter pylori is an important human pathogen and a common cause of peptic ulcers and gastric cancer. Despite H. pylori provoking strong innate and adaptive immune responses, the bacterium is able to successfully establish long-term infections. Vitronectin (Vn), a component of both the extracellular matrix and plasma, is involved in many physiological processes, including regulation of the complement system. The aim of this study was to define a receptor in H. pylori that binds Vn and determine the significance of the interaction for virulence. Surprisingly, by using proteomics, we found that the hydrogen peroxide-neutralizing enzyme catalase KatA is a major Vn-binding protein. Deletion of the katA gene in three different strains resulted in impaired binding of Vn. Recombinant KatA was generated and shown to bind with high affinity to a region between heparin-binding domain 2 and 3 of Vn that differs from previously characterised bacterial binding sites on the molecule. In terms of function, KatA protected H. pylori from complement-mediated killing in a Vn-dependent manner. Taken together, the virulence factor KatA is a Vn-binding protein that moonlights on the surface of H. pylori to promote bacterial evasion of host innate immunity.
In situ synchrotron study of electromigration induced grain rotations in Sn solder joints
Authors: Shen Hao , Zhu Wenxin , Li Yao , Tamura Nobumichi , Chen Kai 
Published: April 2016

AbstractHere we report an in situ study of the early stage of microstructure evolution induced by electromigration in a Pb-free β-Sn based solder joint by synchrotron polychromatic X-ray microdiffraction. With this technique, crystal orientation evolution is monitored at intragranular levels with high spatial and angular resolution. During the entire experiment, no crystal growth is detected and rigid grain rotation is observed only in the two grains within the current crowding region, where high density and divergence of electric current occur. Theoretical calculation indicates that the trend of electrical resistance drop still holds under the present conditions in the grain with high electrical resistivity, while the other grain with low resistivity reorients to align its a-axis more parallel with the ones of its neighboring grains. A detailed study of dislocation densities and subgrain boundaries suggests that grain rotation in β-Sn, unlike grain rotation in high melting temperature metals which undergo displacive deformation, is accomplished via diffusional process mainly, due to the high homologous temperature.
Optical vortex knots – one photon at a time
Authors: Tempone-Wiltshire Sebastien J. , Johnstone Shaun P. , Helmerson Kristian 
Published: April 2016

AbstractFeynman described the double slit experiment as “a phenomenon which is impossible, absolutely impossible, to explain in any classical way and which has in it the heart of quantum mechanics”. The double-slit experiment, performed one photon at a time, dramatically demonstrates the particle-wave duality of quantum objects by generating a fringe pattern corresponding to the interference of light (a wave phenomenon) from two slits, even when there is only one photon (a particle) at a time passing through the apparatus. The particle-wave duality of light should also apply to complex three dimensional optical fields formed by multi-path interference, however, this has not been demonstrated. Here we observe particle-wave duality of a three dimensional field by generating a trefoil optical vortex knot – one photon at a time. This result demonstrates a fundamental physical principle, that particle-wave duality implies interference in both space (between spatially distinct modes) and time (through the complex evolution of the superposition of modes) and has implications for topologically entangled single photon states, orbital angular momentum multiplexing and topological quantum computing.
Regulatory mechanisms link phenotypic plasticity to evolvability
Authors: van Gestel Jordi , Weissing Franz J. 
Published: April 2016

AbstractOrganisms have a remarkable capacity to respond to environmental change. They can either respond directly, by means of phenotypic plasticity, or they can slowly adapt through evolution. Yet, how phenotypic plasticity links to evolutionary adaptability is largely unknown. Current studies of plasticity tend to adopt a phenomenological reaction norm (RN) approach, which neglects the mechanisms underlying plasticity. Focusing on a concrete question – the optimal timing of bacterial sporulation – we here also consider a mechanistic approach, the evolution of a gene regulatory network (GRN) underlying plasticity. Using individual-based simulations, we compare the RN and GRN approach and find a number of striking differences. Most importantly, the GRN model results in a much higher diversity of responsive strategies than the RN model. We show that each of the evolved strategies is pre-adapted to a unique set of unseen environmental conditions. The regulatory mechanisms that control plasticity therefore critically link phenotypic plasticity to the adaptive potential of biological populations.
EGFR Inhibition Blocks Palmitic Acid-induced inflammation in cardiomyocytes and Prevents Hyperlipidemia-induced Cardiac Injury in Mice
Authors: Li Weixin , Fang Qilu , Zhong Peng , Chen Lingfeng , Wang Lintao , Zhang Yali , Wang Jun , Li Xiaokun , Wang Yi , Wang Jingying , Liang Guang 
Published: April 2016

AbstractObesity is often associated with increased risk of cardiovascular diseases. Previous studies suggest that epidermal growth factor receptor (EGFR) antagonism may be effective for the treatment of angiotensin II-induced cardiac hypertrophy and diabetic cardiomyopathy. This study was performed to demonstrate if EGFR plays a role in the pathogenesis of hyperlipidemia/obesity-related cardiac injuries. The in vivo studies using both wild type (WT) and apolipoprotein E (ApoE) knockout mice fed with high fat diet (HFD) showed the beneficial effects of small-molecule EGFR inhibitors, AG1478 and 542, against obesity-induced myocardial injury. Administration of AG1478 and 542 significantly reduced myocardial inflammation, fibrosis, apoptosis and dysfunction in both two obese mouse models. In vitro, EGFR signaling was blocked by either siRNA silencing or small-molecule EGFR inhibitors in palmitic acid (PA)-stimulated cardiomyocytes. EGFR inhibition attenuated PA-induced inflammatory response and apoptosis in H9C2 cells. Furthermore, we found that PA-induced EGFR activation was mediated by the upstream TLR4 and c-Src. This study has confirmed the detrimental effect of EGFR activation in the pathogenesis of obesity-induced cardiac inflammatory injuries in experimental mice and has demonstrated the TLR4/c-Src-mediated mechanisms for PA-induced EGFR activation. Our data suggest that EGFR may be a therapeutic target for obesity-related cardiovascular diseases.