bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophages confer resistance to PI3K inhibitor GDC-0941 in breast cancer through the activation of NF-κB signaling
Authors: Usman Muhammad Waqas , Gao Jing , Zheng Tiezheng , Rui Chunhua , Li Ting , Bian Xing , Cheng Hailing , Liu Pixu , Luo Fuwen 
Published: July 2018

AbstractThe PI3K pathway is one of the most dysregulated signaling pathways in epithelial cancers and has become an attractive therapeutic target under active preclinical and clinical development. However, recent clinical trial studies revealed that blockade of PI3K activity in advanced cancer often leads to the development of resistance and relapse of the diseases. Intense efforts have been made to elucidate resistance mechanisms and identify rational drug combinations with PI3K inhibitors in solid tumors. In the current study, we found that PI3K inhibition by GDC-0941 increased macrophage infiltration and induced the expression of macrophage-associated cytokines and chemokines in the mouse 4T1 breast tumor model. Using the in vitro co-culture system, we showed that the presence of macrophages led to the activation of NF-κB signaling in 4T1 tumor cells, rendering tumor cells resistant to PI3K inhibition by GDC-0941. Furthermore, we found that Aspirin could block the activation of NF-κB signaling induced by PI3K inhibition, and combined use of GDC-0941 and Aspirin resulted in attenuated cell growth and enhanced apoptosis of 4T1 cells in the in vitro co-culture system with the presence of macrophages. Consistently, the combination treatment also effectively reduced tumor burden, macrophage infiltration and pulmonary metastasis in in vivo 4T1 breast tumor model. Together, our results suggested macrophages in microenvironment may contribute to the resistance of breast cancer cells to PI3K inhibition and reveal a new combination paradigm to improve the efficacy of PI3K-targeted therapy.
Oxidative stress and autophagy-related changes during retinal degeneration and development
Authors: Trachsel-Moncho Laura , Benlloch-Navarro Soledad , Fernández-Carbonell Ángel , Ramírez-Lamelas Dolores Tania , Olivar Teresa , Silvestre Dolores , Poch Enric , Miranda María 
Published: July 2018

AbstractRetinitis pigmentosa (RP) is an inherited retinopathy that leads to photoreceptor loss. RP has been related to oxidative stress, autophagy, and inflammation. This study aimed to identify changes in the levels of oxidative stress and autophagy markers in the retina of control and rd10 mice during different phases of retinal development. Changes in the retinal oxidation system were investigated by measuring the levels of oxidized and reduced glutathione (GSH/GSSG), retinal avidin-positive cells, and 4-hydroxynonenal (4-HNE) staining intensity. Autophagy characterization was explored by measuring the levels of microtubule-associated protein 1 light chain 3 (LC3), beclin, autophagy-related proteins 5 and 7 (Atg5 and Atg7), and lysosomal associated membrane protein-2A (LAMP-2A). At P28 retinal GSH concentrations decreased in rd10 mice compared to the controls. No differences were found in retinal GSSG concentrations between the control and rd10 mice. There was an increase in retinal GSSG concentrations and a decrease in the GSH/GSSG ratio in the control and rd10 mice at P21 and P28 compared to P13. We observed an increase in avidin-positive cells in rd10 retinas. 4-HNE was increased in rd10 retinas at P13, and it also increased in control mice with age. We did not observe any differences in the retinal levels of LC3II/I ratio, Beclin, Atg5, or Atg7 in the rd10 mice compared to the controls. There was an increase in the LAMP-2A concentrations in the control and rd10 mice with development age (P28 concentrations vs. P13). Although only slight differences were found in the oxidative stress and autophagy markers between the control and rd10 mice, there were increases in the GSSG, 4-HNE, and LAMP-2A with age. This increase in the oxidative stress and chaperone-mediated autophagy has not been described before and occurred just after the mice opened their eyes, potentially indicating a retinal response to light exposure.
Spontaneously opening GABAA receptors play a significant role in neuronal signal filtering and integration
Authors: O’Neill Nathanael , Sylantyev Sergiy 
Published: July 2018

AbstractContinuous (tonic) charge transfer through ionotropic receptors of γ-aminobutyric acid (GABAARs) is an important mechanism of inhibitory signalling in the brain. The conventional view has been that tonic GABA-ergic inhibitory currents are mediated by low concentrations of ambient GABA. Recently, however, it was shown that the GABA-independent, spontaneously opening GABAARs (s-GABAARs), may contribute significantly to the tonic GABAAR current. One of the common approaches to temporal lobe epilepsy (TLE) therapy is an increase of GABA concentration in the cerebrospinal fluid to augment tonic current through GABAARs. Such an increase, however, generates multiple side effects, which impose significant limitations on the use of correspondent drugs. In contrast, activation/deactivation of s-GABAARs in a GABA-independent manner may provide a mechanism of regulation of tonic conductance without modification of extracellular GABA concentration, thus avoiding connected side effects. Although s-GABAARs have been detected in our earlier work, it is unclear whether they modulate neural signalling, or, due to their independence from the neurotransmitter, they provide just a stable background effect without much impact on neural crosstalk dynamics. Here, we focused on the causal relationship between s-GABAAR activity and signal integration in the rat’s dentate gyrus granule cells to find that s-GABAARs play an important role in neural signal transduction. s-GABAARs shape the dynamics of phasic inhibitory responses, regulate the action potential generation machinery and control the coincidence detection window pertinent to excitatory input summation. Our results demonstrate that tonic inhibition delivered by s-GABAARs contributes to the key mechanisms that ensure implementation of neural signal filtering and integration, in a GABA-independent manner. This makes s-GABAAR a new and important actor in the regulation of long-term neural plasticity and a perspective target for TLE therapy.
Stability criteria for complex microbial communities
Authors: Butler Stacey , O’Dwyer James P. 
Published: July 2018

AbstractCompetition and mutualism are inevitable processes in microbial ecology, and a central question is which and how many taxa will persist in the face of these interactions. Ecological theory has demonstrated that when direct, pairwise interactions among a group of species are too numerous, or too strong, then the coexistence of these species will be unstable to any slight perturbation. Here, we refine and to some extent overturn that understanding, by considering explicitly the resources that microbes consume and produce. In contrast to more complex organisms, microbial cells consume primarily abiotic resources, and mutualistic interactions are often mediated through the mechanism of crossfeeding. We show that if microbes consume, but do not produce resources, then any positive equilibrium will always be stable to small perturbations. We go on to show that in the presence of crossfeeding, stability is no longer guaranteed. However, positive equilibria remain stable whenever mutualistic interactions are either sufficiently weak, or when all pairs of taxa reciprocate each other’s assistance.
A reliable murine model of bone metastasis by injecting cancer cells through caudal arteries
Authors: Kuchimaru Takahiro , Kataoka Naoya , Nakagawa Kenji , Isozaki Tatsuhiro , Miyabara Hitomi , Minegishi Misa , Kadonosono Tetsuya , Kizaka-Kondoh Shinae 
Published: July 2018

AbstractAlthough the current murine model of bone metastasis using intracardiac (IC) injection successfully recapitulates the process of bone metastasis, further progress in the study of bone metastasis requires a new model to circumvent some limitations of this model. Here, we present a new murine model of bone metastasis achieved by injecting cancer cells through the intra-caudal arterial (CA). This model does not require high technical proficiency, predominantly delivers cancer cells to bone marrow of hind limbs with much higher efficiency than IC injection, and greatly shortens the period of overt bone metastasis development. Moreover, CA injection barely causes acute death of mice, enabling us to inject a larger number of cancer cells to further accelerate the development of bone metastasis with a wide variety of cell lines. Our model may open a new avenue for understanding the bone metastatic processes and development of drugs preventing bone metastasis and recurrence.
Long noncoding RNA licensing of obesity-linked hepatic lipogenesis and NAFLD pathogenesis
Authors: Zhao Xu-Yun , Xiong Xuelian , Liu Tongyu , Mi Lin , Peng Xiaoling , Rui Crystal , Guo Liang , Li Siming , Li Xiaoying , Lin Jiandie D. 
Published: July 2018

AbstractHepatic lipogenesis is aberrantly induced in nonalcoholic fatty liver disease (NAFLD) via activation of the LXR-SREBP1c pathway. To date, a number of protein factors impinging on the transcriptional activity of LXR and SREBP1c have been elucidated. However, whether this regulatory axis interfaces with long noncoding RNAs (lncRNAs) remains largely unexplored. Here we show that hepatic expression of the lncRNA Blnc1 is strongly elevated in obesity and NAFLD in mice. Blnc1 is required for the induction of SREBP1c and hepatic lipogenic genes in response to LXR activation. Liver-specific inactivation of Blnc1 abrogates high-fat diet-induced hepatic steatosis and insulin resistance and protects mice from diet-induced nonalcoholic steatohepatitis. Proteomic analysis of the Blnc1 ribonucleoprotein complex identified EDF1 as a component of the LXR transcriptional complex that acts in concert with Blnc1 to activate the lipogenic gene program. These findings illustrate a lncRNA transcriptional checkpoint that licenses excess hepatic lipogenesis to exacerbate insulin resistance and NAFLD.
Controllable protein phase separation and modular recruitment to form responsive membraneless organelles
Authors: Schuster Benjamin S. , Reed Ellen H. , Parthasarathy Ranganath , Jahnke Craig N. , Caldwell Reese M. , Bermudez Jessica G. , Ramage Holly , Good Matthew C. , Hammer Daniel A. 
Published: July 2018

AbstractMany intrinsically disordered proteins self-assemble into liquid droplets that function as membraneless organelles. Because of their biological importance and ability to colocalize molecules at high concentrations, these protein compartments represent a compelling target for bio-inspired materials engineering. Here we manipulated the intrinsically disordered, arginine/glycine-rich RGG domain from the P granule protein LAF-1 to generate synthetic membraneless organelles with controllable phase separation and cargo recruitment. First, we demonstrate enzymatically triggered droplet assembly and disassembly, whereby miscibility and RGG domain valency are tuned by protease activity. Second, we control droplet composition by selectively recruiting cargo molecules via protein interaction motifs. We then demonstrate protease-triggered controlled release of cargo. Droplet assembly and cargo recruitment are robust, occurring in cytoplasmic extracts and in living mammalian cells. This versatile system, which generates dynamic membraneless organelles with programmable phase behavior and composition, has important applications for compartmentalizing collections of proteins in engineered cells and protocells.
Stabilization of three-dimensional charge order in YBa2Cu3O6+x via epitaxial growth
Authors: Bluschke M. , Frano A. , Schierle E. , Putzky D. , Ghorbani F. , Ortiz R. , Suzuki H. , Christiani G. , Logvenov G. , Weschke E. , Birgeneau R. J. , da Silva Neto E. H. , Minola M. , Blanco-Canosa S. , Keimer B. 
Published: July 2018

AbstractIncommensurate charge order (CO) has been identified as the leading competitor of high-temperature superconductivity in all major families of layered copper oxides, but the perplexing variety of CO states in different cuprates has confounded investigations of its impact on the transport and thermodynamic properties. The three-dimensional (3D) CO observed in YBa2Cu3O6+x in high magnetic fields is of particular interest, because quantum transport measurements have revealed detailed information about the corresponding Fermi surface. Here we use resonant X-ray scattering to demonstrate 3D-CO in underdoped YBa2Cu3O6+x films grown epitaxially on SrTiO3 in the absence of magnetic fields. The resonance profiles indicate that Cu sites in the charge-reservoir layers participate in the CO state, and thus efficiently transmit CO correlations between adjacent CuO2 bilayer units. The results offer fresh perspectives for experiments elucidating the influence of 3D-CO on the electronic properties of cuprates without the need to apply high magnetic fields.
Distribution-based measures of tumor heterogeneity are sensitive to mutation calling and lack strong clinical predictive power
Authors: Noorbakhsh Javad , Kim Hyunsoo , Namburi Sandeep , Chuang Jeffrey H. 
Published: July 2018

AbstractMutant allele frequency distributions in cancer samples have been used to estimate intratumoral heterogeneity and its implications for patient survival. However, mutation calls are sensitive to the calling algorithm. It remains unknown whether the relationship of heterogeneity and clinical outcome is robust to these variations. To resolve this question, we studied the robustness of allele frequency distributions to the mutation callers MuTect, SomaticSniper, and VarScan in 4722 cancer samples from The Cancer Genome Atlas. We observed discrepancies among the results, particularly a pronounced difference between allele frequency distributions called by VarScan and SomaticSniper. Survival analysis showed little robust predictive power for heterogeneity as measured by Mutant-Allele Tumor Heterogeneity (MATH) score, with the exception of uterine corpus endometrial carcinoma. However, we found that variations in mutant allele frequencies were mediated by variations in copy number. Our results indicate that the clinical predictions associated with MATH score are primarily caused by copy number aberrations that alter mutant allele frequencies. Finally, we present a mathematical model of linear tumor evolution demonstrating why MATH score is insufficient for distinguishing different scenarios of tumor growth. Our findings elucidate the importance of allele frequency distributions as a measure for tumor heterogeneity and their prognostic role.
Paleomagnetism of IODP Site U1380: Implications for the Forearc Deformation in the Costa Rican Erosive Convergent Margin
Authors: Li Yong-Xiang , Zhao Xixi , Xie Siyi , Jovane Luigi , Petronotis Katerina 
Published: July 2018

AbstractThe destructive nature of subduction erosion poses challenges to fully understanding the evolution of erosive convergent margins that are critical to understanding crustal recycling and seismogenesis. Forearc deformation holds important clues to the evolution of erosive convergent margins. Here we present detailed paleomagnetic and structural analyses of IODP Site U1380 cores from the middle slope of the forearc of the Costa Rican erosive convergent margin. The analyses reveal a strong deformation zone from ~490 to ~550 mbsf that is characterized by abundant fissility/foliations shallower than the bedding. Similar relatively strong deformation zones are recognized from the frontal prism and upper slope sites, and are broadly correlative, forming a zone of strong deformation across the forearc. This zone spans ~2.0 to 1.83 Ma and the deformation likely occurred briefly at ~1.80 Ma. The widespread, short-lived, and strong deformation is interpreted as a result of intense subhorizontal shear following the rapid forearc subsidence driven by the dramatic subduction erosion associated with the abrupt onset of the Cocos Ridge subduction. Given the typical occurrence of forearc subsidence by subduction erosion, similar styles of deformation are probably common in other erosive convergent margins as well.
Giant peak of the Inverse Faraday effect in the band gap of magnetophotonic microcavity
Authors: Kozhaev Mikhail A. , Chernov Alexander I. , Sylgacheva Daria A. , Shaposhnikov Alexander N. , Prokopov Anatoly R. , Berzhansky Vladimir N. , Zvezdin Anatoly K. , Belotelov Vladimir I. 
Published: July 2018

AbstractOptical impact on the spin system in a magnetically ordered medium provides a unique possibility for local manipulation of magnetization at subpicosecond time scales. One of the mechanisms of the optical manipulation is related to the inverse Faraday effect (IFE). Usually the IFE is observed in crystals and magnetic films on a substrate. Here we demonstrate the IFE induced by fs-laser pulses in the magnetic film inside the magnetophotonic microcavity. Spectral dependence of the IFE on the laser pulse wavelength in the band gap of the magnetophotonic microcavity has a sharp peak leading to a significant enhancement of the IFE. This phenomenon is explained by strong confinement of the electromagnetic energy within the magnetic film. Calculated near field distribution of the IFE effective magnetic field indicates its subwavelength localization within 30 nm along the film thickness. These excited volumes can be shifted along the sample depth via e.g. changing frequency of the laser pulses. The obtained results open a way for ultrafast optical control of magnetization at subwavelength scales.
Rapid Nanophotonics Assay for Head and Neck Cancer Diagnosis
Authors: Vohra P. , Strobbia P. , Ngo H. T. , Lee W. T. , Vo-Dinh T. 
Published: July 2018

AbstractEfficient and timely diagnosis of head and neck squamous cell carcinoma (HNSCC) is a critical challenge, particularly in low and middle income countries. These regions, which are expected to witness a drastic increase in HNSCC rates, are ill-prepared to handle the diagnostic burden due to limited resources, especially the low ratio of pathologists per population, resulting in delayed diagnosis and treatment. Here, we demonstrate the potential of an alternative diagnostic method as a low-cost, resource-efficient alternative to histopathological analysis. Our novel technology employs unique surface-enhanced Raman scattering (SERS) “nanorattles” targeting cytokeratin nucleic acid biomarkers specific for HNSCC. In this first study using SERS diagnostics for head and neck cancers, we tested the diagnostic accuracy of our assay using patient tissue samples. In a blinded trial, our technique demonstrated a sensitivity of 100% and specificity of 89%, supporting its use as a useful alternative to histopathological diagnosis. The implications of our method are vast and significant in the setting of global health. Our method can provide a rapid diagnosis, allowing for earlier treatment before the onset of distant metastases. In comparison to histopathology, which can take several months in remote limited-resources regions, our method provides a diagnosis within a few hours.
Fc-apelin fusion protein attenuates lipopolysaccharide-induced liver injury in mice
Authors: Zhou Huifen , Yang Rongze , Wang Weimin , Xu Feng , Xi Yue , Brown Robert A. , Zhang Hong , Shi Lin , Zhu Dalong , Gong Da-Wei 
Published: July 2018

AbstractApelin is a peptide hormone with anti-oxidative and anti-inflammatory activities and is proposed to be a potential therapeutic for many disease conditions, including sepsis. However, short in vivo half-life of the apelin peptide would limit its potential clinical applications. This study aims to investigate the effects of Fc-apelin, a novel long-acting apelin fusion protein, on lipopolysaccharide (LPS)-induced liver injury. Liver injury was induced by systemic injection of LPS in mice. Hepatoprotective activities of Fc-apelin against inflammation were evaluated in LPS mice and/or hepatoma Huh-7 cells with respect to serum ALT, apoptosis, oxidative stress, macrophage infiltration and gene expression. We found that LPS induced systemic inflammation and liver damage. Co-administration of Fc-apelin significantly attenuated serum ALT elevation, diminished LPS-induced apoptosis and ROS production in the liver and in Huh-7 cells, mitigated hepatic macrophage infiltration, and reduced TNFα and IL-6 gene expression. Collectively, Fc-apelin fusion protein exerts protective effects against LPS-induced liver damage and may serve as a potential therapeutic for endotoxin-induced liver injury.
Neutralization of Junín virus by single domain antibodies targeted against the nucleoprotein
Authors: Linero Florencia , Sepúlveda Claudia , Christopoulou Ioanna , Hulpiau Paco , Scolaro Luis , Saelens Xavier 
Published: July 2018

AbstractThe syndrome viral haemorrhagic fever (VHF) designates a broad range of diseases that are caused by different viruses including members of the family Arenaviridae. Prophylaxis for Argentine Haemorrhagic Fever (AHF), caused by the arenavirus Junín (JUNV), has been achieved by the use of a live attenuated vaccine, named Candid#1. The standard treatment of AHF is transfusion of convalescent human plasma. Our aim was to develop an alternative and safer treatment for AHF based on the use of virus-neutralizing single domain antibodies (VHHs). We describe the first reported VHHs directed against an arenavirus. These VHHs could neutralize Candid#1 by altering virion binding/fusion. Surprisingly, the neutralizing VHHs appeared to be specific for the viral nucleoprotein (N) that is not known to be involved in arenavirus entry. Candid#1 VHH-escape viruses had acquired a predicted N-glycosylation site in the surface glycoprotein GP1 that is present in highly pathogenic JUNV strains. Accordingly, the Candid#1-neutralizing VHHs could not neutralize pathogenic JUNV strains, but they could still bind to cells infected with a pathogenic strain or the escape mutant viruses. These results show that the attenuated strains of JUNV can be potently neutralized by nucleoprotein-specific VHHs.
LRP1 is required for novobiocin-mediated fibronectin turnover
Authors: Boel Natasha Marie-Eraine , Hunter Morgan Campbell , Edkins Adrienne Lesley 
Published: July 2018

AbstractFibronectin (FN) plays a major role in the stability and organization of the extracellular matrix (ECM). We have previously demonstrated that FN interacts directly with Hsp90, as well as showing that the Hsp90 inhibitor novobiocin results in FN turnover via a receptor mediated process. However, the receptor involved has not been previously identified. LRP1 is a ubiquitous receptor responsible for the internalisation of numerous ligands that binds both Hsp90 and FN, and therefore we investigated whether LRP1 was involved in novobiocin-mediated FN turnover. FN, LRP1 and Hsp90 could be isolated in a common complex, and inhibition of Hsp90 by novobiocin increased the colocalisation of FN and LRP1. Novobiocin induced an increase (at low concentrations) followed by a loss of FN that was primarily derived from extracellular matrix-associated FN and led to a concomitant increase in intracellular FN. The effect of novobiocin was specific to LRP1-expressing cells and could be recapitulated by an LRP1 blocking antibody and the allosteric C-terminal Hsp90 inhibitor SM253, but not the N-terminal inhibitor geldanamycin. Together these data suggest that LRP1 is required for FN turnover in response to Hsp90 inhibition by novobiocin, which may have unintended physiological consequences in contexts where C-terminal Hsp90 inhibition is to be used therapeutically.