bluuebunny/crossref_metadata_2025_split huggingface dataset:
A dual-function epidermal growth factor receptor pathway substrate 8 (Eps8)-derived peptide exhibits a potent cytotoxic T lymphocyte-activating effect and a specific inhibitory activity
Authors: Xie Xiaoling , Zhou Weijun , Hu Yuxing , Chen Yiran , Zhang Honghao , Li Yuhua 
Published: March 2018

AbstractThe identification and characterization of tumor-associated antigens (TAAs) that generate specific cytotoxic T lymphocytes (CTLs) are vital to the development of cancer immunotherapy. The epidermal growth factor receptor (EGFR) pathway substrate 8 gene (Eps8) is involved in regulating cancer progression and might be an ideal antigen. In this study, we searched for novel human leukocyte antigen (HLA)-A*2402-restricted epitopes derived from the Eps8 protein via the HLA-binding prediction algorithm. Among four candidates, peptides 327 (EFLDCFQKF), 534 (KYAKSKYDF) and 755 (LFSLNKDEL) induced peptide-specific CTLs to secrete higher levels of interferon-gamma (IFN-γ) and showed enhanced cytotoxic activity against malignant cancer cells. Our results demonstrated that peptide-specific CTLs showed effective antitumor responses, including upregulation of interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-α), granzyme B and perforin. Treatment with peptide-sensitized peripheral blood mononuclear cells (PBMCs) significantly reduced the tumor growth in vivo compared with the non-peptide-sensitized PBMC treatment. Importantly, our results indicated that peptide 327 may interfere with EGFR signaling by mechanistically disrupting Eps8/EGFR complex formation. We extended this observation that peptide 327 also suppressed the viability of cancer cells, blocked EGFR signal pathway and reduced the expression of downstream targets. Notably, conjugation of peptide 327 to the TAT sequence (TAT-327) resulted in potent antitumor activity and selective insertion into cancer cell membranes, where it adopted a punctate distribution. Furthermore, peptide 327 and TAT-327 displayed anticancer properties in xenograft models. Our results indicated that 327, 534 and 755 were novel HLA-A*2402-restricted epitopes from Eps8. By inhibiting the Eps8/EGFR interaction, peptide 327 and TAT-327 may serve as novel peptide inhibitors, which could provide an innovative approach for treating various cancers.
A LATS biosensor screen identifies VEGFR as a regulator of the Hippo pathway in angiogenesis
Authors: Azad T. , Janse van Rensburg H. J. , Lightbody E. D. , Neveu B. , Champagne A. , Ghaffari A. , Kay V. R. , Hao Y. , Shen H. , Yeung B. , Croy B. A. , Guan K. L. , Pouliot F. , Zhang J. , Nicol C. J. B. , Yang X. 
Published: March 2018

AbstractThe Hippo pathway is a central regulator of tissue development and homeostasis, and has been reported to have a role during vascular development. Here we develop a bioluminescence-based biosensor that monitors the activity of the Hippo core component LATS kinase. Using this biosensor and a library of small molecule kinase inhibitors, we perform a screen for kinases modulating LATS activity and identify VEGFR as an upstream regulator of the Hippo pathway. We find that VEGFR activation by VEGF triggers PI3K/MAPK signaling, which subsequently inhibits LATS and activates the Hippo effectors YAP and TAZ. We further show that the Hippo pathway is a critical mediator of VEGF-induced angiogenesis and tumor vasculogenic mimicry. Thus, our work offers a biosensor tool for the study of the Hippo pathway and suggests a role for Hippo signaling in regulating blood vessel formation in physiological and pathological settings.
Eya3 partners with PP2A to induce c-Myc stabilization and tumor progression
Authors: Zhang Lingdi , Zhou Hengbo , Li Xueni , Vartuli Rebecca L , Rowse Michael , Xing Yongna , Rudra Pratyaydipta , Ghosh Debashis , Zhao Rui , Ford Heide L 
Published: March 2018

AbstractEya genes encode a unique family of multifunctional proteins that serve as transcriptional co-activators and as haloacid dehalogenase-family Tyr phosphatases. Intriguingly, the N-terminal domain of Eyas, which does not share sequence similarity to any known phosphatases, contains a separable Ser/Thr phosphatase activity. Here, we demonstrate that the Ser/Thr phosphatase activity of Eya is not intrinsic, but arises from its direct interaction with the protein phosphatase 2A (PP2A)-B55α holoenzyme. Importantly, Eya3 alters the regulation of c-Myc by PP2A, increasing c-Myc stability by enabling PP2A-B55α to dephosphorylate pT58, in direct contrast to the previously described PP2A-B56α-mediated dephosphorylation of pS62 and c-Myc destabilization. Furthermore, Eya3 and PP2A-B55α promote metastasis in a xenograft model of breast cancer, opposing the canonical tumor suppressive function of PP2A-B56α. Our study identifies Eya3 as a regulator of PP2A, a major cellular Ser/Thr phosphatase, and uncovers a mechanism of controlling the stability of a critical oncogene, c-Myc.
miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers
Authors: Givel Anne-Marie , Kieffer Yann , Scholer-Dahirel Alix , Sirven Philemon , Cardon Melissa , Pelon Floriane , Magagna Ilaria , Gentric Géraldine , Costa Ana , Bonneau Claire , Mieulet Virginie , Vincent-Salomon Anne , Mechta-Grigoriou Fatima 
Published: March 2018

AbstractHigh-grade serous ovarian cancers (HGSOC) have been subdivided into molecular subtypes. The mesenchymal HGSOC subgroup, defined by stromal-related gene signatures, is invariably associated with poor patient survival. We demonstrate that stroma exerts a key function in mesenchymal HGSOC. We highlight stromal heterogeneity in HGSOC by identifying four subsets of carcinoma-associated fibroblasts (CAF-S1-4). Mesenchymal HGSOC show high content in CAF-S1 fibroblasts, which exhibit immunosuppressive functions by increasing attraction, survival, and differentiation of CD25+FOXP3+ T lymphocytes. The beta isoform of the CXCL12 chemokine (CXCL12β) specifically accumulates in the immunosuppressive CAF-S1 subset through a miR-141/200a dependent-mechanism. Moreover, CXCL12β expression in CAF-S1 cells plays a crucial role in CAF-S1 immunosuppressive activity and is a reliable prognosis factor in HGSOC, in contrast to CXCL12α. Thus, our data highlight the differential regulation of the CXCL12α and CXCL12β isoforms in HGSOC, and reveal a CXCL12β-associated stromal heterogeneity and immunosuppressive environment in mesenchymal HGSOC.
A meta-analysis of birth-origin effects on reproduction in diverse captive environments
Authors: Farquharson Katherine A. , Hogg Carolyn J. , Grueber Catherine E. 
Published: March 2018

AbstractSuccessfully establishing captive breeding programs is a priority across diverse industries to address food security, demand for ethical laboratory research animals, and prevent extinction. Differences in reproductive success due to birth origin may threaten the long-term sustainability of captive breeding. Our meta-analysis examining 115 effect sizes from 44 species of invertebrates, fish, birds, and mammals shows that, overall, captive-born animals have a 42% decreased odds of reproductive success in captivity compared to their wild-born counterparts. The largest effects are seen in commercial aquaculture, relative to conservation or laboratory settings, and offspring survival and offspring quality were the most sensitive traits. Although a somewhat weaker trend, reproductive success in conservation and laboratory research breeding programs is also in a negative direction for captive-born animals. Our study provides the foundation for future investigation of non-genetic and genetic drivers of change in captivity, and reveals areas for the urgent improvement of captive breeding.
The choroid plexus is an important circadian clock component
Authors: Myung Jihwan , Schmal Christoph , Hong Sungho , Tsukizawa Yoshiaki , Rose Pia , Zhang Yong , Holtzman Michael J. , De Schutter Erik , Herzel Hanspeter , Bordyugov Grigory , Takumi Toru 
Published: March 2018

AbstractMammalian circadian clocks have a hierarchical organization, governed by the suprachiasmatic nucleus (SCN) in the hypothalamus. The brain itself contains multiple loci that maintain autonomous circadian rhythmicity, but the contribution of the non-SCN clocks to this hierarchy remains unclear. We examine circadian oscillations of clock gene expression in various brain loci and discovered that in mouse, robust, higher amplitude, relatively faster oscillations occur in the choroid plexus (CP) compared to the SCN. Our computational analysis and modeling show that the CP achieves these properties by synchronization of “twist” circadian oscillators via gap-junctional connections. Using an in vitro tissue coculture model and in vivo targeted deletion of the Bmal1 gene to silence the CP circadian clock, we demonstrate that the CP clock adjusts the SCN clock likely via circulation of cerebrospinal fluid, thus finely tuning behavioral circadian rhythms.
How do environment-dependent switching rates between susceptible and persister cells affect the dynamics of biofilms faced with antibiotics?
Authors: Carvalho Gabriel , Balestrino Damien , Forestier Christiane , Mathias Jean-Denis 
Published: March 2018

AbstractPersisters form sub-populations of stress-tolerant cells that play a major role in the capacity of biofilms to survive and recover from disturbances such as antibiotic treatments. The mechanisms of persistence are diverse and influenced by environmental conditions, and persister populations are more heterogeneous than formerly suspected. We used computational modeling to assess the impact of three switching strategies between susceptible and persister cells on the capacity of bacterial biofilms to grow, survive and recover from antibiotic treatments. The strategies tested were: (1) constant switches, (2) substrate-dependent switches and (3) antibiotic-dependent switches. We implemented these strategies in an individual-based biofilm model and simulated antibiotic shocks on virtual biofilms. Because of limited available data on switching rates in the literature, nine parameter sets were assessed for each strategy. Substrate and antibiotic-dependent switches allowed high switching rates without affecting the growth of the biofilms. Compared to substrate-dependent switches, constant and antibiotic-dependent switches were associated with higher proportions of persisters in the top of the biofilms, close to the substrate source, which probably confers a competitive advantage within multi-species biofilms. The constant and substrate-dependent strategies need a compromise between limiting the wake-up and death of persisters during treatments and leaving the persister state fast enough to recover quickly after antibiotic-removal. Overall, the simulations gave new insights into the relationships between the dynamics of persister populations in biofilms and their dynamics of growth, survival and recovery when faced with disturbances.
Ultrasound-enhanced electrospinning
Authors: Nieminen Heikki J. , Laidmäe Ivo , Salmi Ari , Rauhala Timo , Paulin Tor , Heinämäki Jyrki , Hæggström Edward 
Published: March 2018

AbstractElectrospinning is commonly used to produce polymeric nanofibers. Potential applications for such fibers include novel drug delivery systems, tissue engineering scaffolds, and filters. Electrospinning, however, has shortcomings such as needle clogging and limited ability to control the fiber-properties in a non-chemical manner. This study reports on an orifice-less technique that employs high-intensity focused ultrasound,i.e. ultrasound-enhanced electrospinning. Ultrasound bursts were used to generate a liquid protrusion with a Taylor cone from the surface of a polymer solution of polyethylene oxide. When the polymer was charged with a high negative voltage, nanofibers jetted off from the tip of the protrusion landed on an electrically grounded target held at a constant distance from the tip. Controlling the ultrasound characteristics permitted physical modification of the nanofiber topography at will without using supplemental chemical intervention. Possible applications of tailor-made fibers generated by ultrasound-enhanced electrospinning include pharmaceutical controlled-release applications and biomedical scaffolds with spatial gradients in fiber thickness and mechanical properties.
Rare human Caspase-6-R65W and Caspase-6-G66R variants identify a novel regulatory region of Caspase-6 activity
Authors: Tubeleviciute-Aydin Agne , Zhou Libin , Sharma Gyanesh , Soni Ishankumar V. , Savinov Sergey N. , Hardy Jeanne A. , LeBlanc Andrea C. 
Published: March 2018

AbstractThe cysteine protease Caspase-6 (Casp6) is a potential therapeutic target of Alzheimer Disease (AD) and age-dependent cognitive impairment. To assess if Casp6 is essential to human health, we investigated the effect of CASP6 variants sequenced from healthy humans on Casp6 activity. Here, we report the effects of two rare Casp6 amino acid polymorphisms, R65W and G66R, on the catalytic function and structure of Casp6. The G66R substitution eliminated and R65W substitution significantly reduced Casp6 catalytic activity through impaired substrate binding. In contrast to wild-type Casp6, both Casp6 variants were unstable and inactive in transfected mammalian cells. In addition, Casp6-G66R acted as a dominant negative inhibitor of wild-type Casp6. The R65W and G66R substitutions caused perturbations in substrate recognition and active site organization as revealed by molecular dynamics simulations. Our results suggest that full Casp6 activity may not be essential for healthy humans and support the use of Casp6 inhibitors against Casp6-dependent neurodegeneration in age-dependent cognitive impairment and AD. Furthermore, this work illustrates that studying natural single amino acid polymorphisms of enzyme drug targets is a promising approach to uncover previously uncharacterized regulatory sites important for enzyme activity.
Unsupervised Segmentation of Greenhouse Plant Images Based on Statistical Method
Authors: Zhang Ping , Xu Lihong 
Published: March 2018

AbstractComplicated image scene of the agricultural greenhouse plant images makes it very difficult to obtain precise manual labeling, leading to the hardship of getting the accurate training set of the conditional random field (CRF). Considering this problem, this paper proposed an unsupervised conditional random field image segmentation algorithm ULCRF (Unsupervised Learning Conditional Random Field), which can perform fast unsupervised segmentation of greenhouse plant images, and further the plant organs in the image, i.e. fruits, leaves and stems, are segmented. The main idea of this algorithm is to calculate the unary potential, namely the initial label of the Dense CRF, by the unsupervised learning model LDA (Latent Dirichlet Allocation). In view of the ever-changing image features at different stages of fruit growth, a multi-resolution ULCRF is proposed to improve the accuracy of image segmentation in the middle stage and late stage of the fruit growth. An image is down-sampled twice to obtain three layers of different resolution images, and the features of each layer are interrelated with each other. Experiment results show that the proposed method can segment greenhouse plant images in an unsupervised method automatically and obtain a high segmentation accuracy together with a high extraction precision of the fruit part.
Physiological activation of mGlu5 receptors supports the ion channel function of NMDA receptors in hippocampal LTD induction in vivo
Authors: O’Riordan Kenneth J. , Hu Neng-Wei , Rowan Michael J. 
Published: March 2018

AbstractSynaptic long-term depression (LTD) is believed to underlie critical mnemonic processes in the adult hippocampus. The roles of the metabotropic and ionotropic actions of glutamate in the induction of synaptic LTD by electrical low-frequency stimulation (LFS) in the living adult animal is poorly understood. Here we examined the requirement for metabotropic glutamate (mGlu) and NMDA receptors in LTD induction in anaesthetized adult rats. LTD induction was primarily dependent on NMDA receptors and required the involvement of both the ion channel function and GluN2B subunit of the receptor. Endogenous mGlu5 receptor activation necessitated the local application of relatively high doses of either competitive or non-competitive NMDA receptor antagonists to block LTD induction. Moreover, boosting endogenous glutamate activation of mGlu5 receptors with a positive allosteric modulator lowered the threshold for NMDA receptor-dependent LTD induction by weak LFS. The present data provide support in the living animal that NMDA receptor-dependent LTD is boosted by endogenously released glutamate activation of mGlu5 receptors. Given the predominant perisynaptic location of mGlu5 receptors, the present findings emphasize the need to further evaluate the contribution and mechanisms of these receptors in NMDA receptor-dependent synaptic plasticity in the adult hippocampusin vivo.
Minor hysteresis patterns with a rounded/sharpened reversing behavior in ferromagnetic multilayer
Authors: Quach Duy-Truong , Pham Duc-Thang , Ngo Duc-The , Phan The-Long , Park Seung-Young , Lee Sang-Hyuk , Kim Dong-Hyun 
Published: March 2018

AbstractHysteresis of ferromagnetic system exhibits a fundamental stimulus-response behavior, thereby casting all the important macromagnetic system parameters such as coercivity, nucleation field, saturation magnetization, and hysteresis loss. Recently, increasing attention has been paid to exploration of relatively less understood minor loop behavior, since faster operation of magnetic devices is inevitably accompanied by minor hysteresis behavior from cycling among unsaturated ferromagnetic states. Here, we report our microscopic investigation of unusual minor hysteresis loop behavior, represented by rounded or sharpened response of minor hysteresis loop of (CoFeB/Pd)4 multilayer film. It is observed that rounded and sharpened response in the minor hysteresis response could be manifested under proper conditions. The minor loop behavior has been systematically investigated by direct microscopic magnetic domain observation using magneto-optical Kerr microscopy. The rounded response of magnetization at the reversing external field along the minor hysteresis curve, so far neglected or considered as one of ‘unusual’ behaviors, has been found to be elaborately controllable by tuning the reversing field strength and the field sweep rate for multilayers with low repeat numbers. Variable roundedness of the minor hysteresis loop is understandable based on the analysis of magnetic domain dynamics such as domain nucleation and the domain wall velocity.
Design of high‐performance bidirectional DC/DC converter applied for more electric aircraft
Authors: Liu Bo , Qiu Maohang , Jing Lei , Wang Xiaoqing , Chen Min 
Published: March 2018

Bidirectional DC/DC converter is an important part of the more electric aircraft (MEA). A high‐performance bidirectional DC/DC converter with high efficiency and power density reduces the both volume and power loss of the converter. There are mainly two kinds of basic topologies applied to bidirectional DC/DC converter. One is a dual active bridge (DAB) and the other is symmetrical CLLC resonant topology. Both topologies can realise zero‐voltage switch (ZVS). The DAB has been widely researched and applied to many fields including the MEA as DAB is easy to design and control. However the ZVS region of the DAB is limited. What is worse, the DAB always switches when the current is at the peak. Symmetrical CLLC resonant topology has also been widely researched in recent years. Compared with the DAB, the symmetrical CLLC resonant converter can reach ZVS in a wider region. In this study both the topologies are discussed and the design of the better one is demonstrated. A 3 kW symmetrical CLLC resonant converter is designed to verify the conclusion.
OH absorption in the first quadrant of the Milky Way as seen by THOR
Authors: Rugel M. R. , Beuther H. , Bihr S. , Wang Y. , Ott J. , Brunthaler A. , Walsh A. , Glover S. C. O. , Goldsmith P. F. , Anderson L. D. , Schneider N. , Menten K. M. , Ragan S. E. , Urquhart J. S. , Klessen R. S. , Soler J. D. , Roy N. , Kainulainen J. , Henning T. , Bigiel F. , Smith R. J. , Wyrowski F. , Longmore S. N. 
Published: March 2018

Context. The hydroxyl radical (OH) is present in the diffuse molecular and partially atomic phases of the interstellar medium (ISM), but its abundance relative to hydrogen is not clear.
Aims. We aim to evaluate the abundance of OH with respect to molecular hydrogen using OH absorption against cm-continuum sources over the first Galactic quadrant.
Methods. This OH study is part of the H I/OH/Recombination line survey of the inner Milky Way (THOR). THOR is a Karl G. Jansky Very Large Array (VLA) large program of atomic, molecular and ionized gas in the range 15° ≤ l ≤ 67° and |b|≤ 1°. It is the highest-resolution unbiased OH absorption survey to date towards this region. We combine the optical depths derived from these observations with literature 13CO(1–0) and H I observations to determine the OH abundance.
Results. We detect absorption in the 1665 and 1667 MHz transitions, that is, the “main” hyperfine structure lines, for continuum sources stronger than Fcont ≥ 0.1 Jy beam−1. OH absorption is found against approximately 15% of these continuum sources with increasing fractions for stronger sources. Most of the absorption occurs in molecular clouds that are associated with Galactic H II regions. We find OH and 13CO gas to have similar kinematic properties. The data indicate that the OH abundance decreases with increasing hydrogen column density. The derived OH abundance with respect to the total hydrogen nuclei column density (atomic and molecular phase) is in agreement with a constant abundance for AV < 10−20. Towards the lowest column densities, we find sources that exhibit OH absorption but no 13CO emission, indicating that OH is a well suited tracer of the low column density molecular gas. We also present spatially resolved OH absorption towards the prominent extended H II-region W43.
Conclusions. The unbiased nature of the THOR survey opens a new window onto the gas properties of the interstellar medium. The characterization of the OH abundance over a large range of hydrogen gas column densities contributes to the understanding of OH as a molecular gas tracer and provides a starting point for future investigations.