bluuebunny/crossref_metadata_2025_split huggingface dataset:
A platform of BRET-FRET hybrid biosensors for optogenetics, chemical screening, and in vivo imaging
Authors: Komatsu Naoki , Terai Kenta , Imanishi Ayako , Kamioka Yuji , Sumiyama Kenta , Jin Takashi , Okada Yasushi , Nagai Takeharu , Matsuda Michiyuki 
Published: June 2018

AbstractGenetically encoded biosensors based on the principle of Förster resonance energy transfer comprise two major classes: biosensors based on fluorescence resonance energy transfer (FRET) and those based on bioluminescence energy transfer (BRET). The FRET biosensors visualize signaling-molecule activity in cells or tissues with high resolution. Meanwhile, due to the low background signal, the BRET biosensors are primarily used in drug screening. Here, we report a protocol to transform intramolecular FRET biosensors to BRET-FRET hybrid biosensors called hyBRET biosensors. The hyBRET biosensors retain all properties of the prototype FRET biosensors and also work as BRET biosensors with dynamic ranges comparable to the prototype FRET biosensors. The hyBRET biosensors are compatible with optogenetics, luminescence microplate reader assays, and non-invasive whole-body imaging of xenograft and transgenic mice. This simple protocol will expand the use of FRET biosensors and enable visualization of the multiscale dynamics of cell signaling in live animals.
Metabolic Patterning on a Chip: Towards in vitro Liver Zonation of Primary Rat and Human Hepatocytes
Authors: Kang Young Bok , Eo Jinsu , Mert Safak , Yarmush Martin L. , Usta O. Berk 
Published: June 2018

AbstractAn important number of healthy and diseased tissues shows spatial variations in their metabolic capacities across the tissue. The liver is a prime example of such heterogeneity where the gradual changes in various metabolic activities across the liver sinusoid is termed as “zonation” of the liver. Here, we introduce the Metabolic Patterning on a Chip (MPOC) platform capable of dynamically creating metabolic patterns across the length of a microchamber of liver tissue via actively enforced gradients of various metabolic modulators such as hormones and inducers. Using this platform, we were able to create continuous liver tissues of both rat and human origin with gradually changing metabolic activities. The gradients we have created in nitrogen, carbohydrate and xenobiotic metabolisms recapitulated an in vivo like zonation and zonal toxic response. Beyond its application in recapitulation of liver zonation in vitro as we demonstrate here, the MPOC platform can be used and expanded for a variety of purposes including better understanding of heterogeneity in many different tissues during developmental and adult stages.
A System of Cytokines Encapsulated in ExtraCellular Vesicles
Authors: Fitzgerald Wendy , Freeman Michael L. , Lederman Michael M. , Vasilieva Elena , Romero Roberto , Margolis Leonid 
Published: June 2018

AbstractCytokines are soluble factors that mediate cell–cell communications in multicellular organisms. Recently, another system of cell–cell communication was discovered, which is mediated by extracellular vesicles (EVs). Here, we demonstrate that these two systems are not strictly separated, as many cytokines in vitro, ex vivo, and in vivo are released in EV-encapsulated forms and are capable of eliciting biological effects upon contact with sensitive cells. Association with EVs is not necessarily a property of a particular cytokine but rather of a biological system and can be changed upon system activation. EV-encapsulated cytokines were not detected by standard cytokine assays. Deciphering the regulatory mechanisms of EV-encapsulation will lead to a better understanding of cell–cell communications in health and disease.
Printed 5-V organic operational amplifiers for various signal processing
Authors: Matsui Hiroyuki , Hayasaka Kazuma , Takeda Yasunori , Shiwaku Rei , Kwon Jimin , Tokito Shizuo 
Published: June 2018

AbstractThe important concept of printable functional materials is about to cause a paradigm shift that we will be able to fabricate electronic devices by printing methods in air at room temperature. One of the promising applications of the printed electronics is a disposable electronic patch sensing system which can monitor the health conditions without any restraint. Operational amplifiers (OPAs) are an essential component for such sensing system, since an OPA enables a wide variety of signal processing. Here we demonstrate printed OPAs based on complementary organic semiconductor technology. They can be operated with a standard safe power source of 5 V with a minimal power consumption of 150 nW, and used as amplifiers, a variety of mathematical operators, signal converters, and oscillators. The printed micropower organic OPAs with the low voltage operation and the high versatility will open up the disposable electronic patch sensing system in near future.
Suppression of mitochondrial oxygen metabolism mediated by the transcription factor HIF-1 alleviates propofol-induced cell toxicity
Authors: Sumi Chisato , Okamoto Akihisa , Tanaka Hiromasa , Kusunoki Munenori , Shoji Tomohiro , Uba Takeo , Adachi Takehiko , Iwai Teppei , Nishi Kenichiro , Harada Hiroshi , Bono Hidemasa , Matsuo Yoshiyuki , Hirota Kiichi 
Published: June 2018

AbstractA line of studies strongly suggest that the intravenous anesthetic, propofol, suppresses mitochondrial oxygen metabolism. It is also indicated that propofol induces the cell death in a reactive oxygen species (ROS)-dependent manner. Because hypoxia-inducible factor 1 (HIF-1) is a transcription factor which is involved in cellular metabolic reprogramming by modulating gene expressions of enzymes including glycolysis pathway and oxygen utilization of mitochondria, we examined the functional role of HIF-1 activity in propofol-induced cell death. The role of HIF-1 activity on oxygen and energy metabolisms and propofol-induced cell death and caspase activity was examined in renal cell-derived RCC4 cells: RCC4-EV cells which lack von Hippel-Lindau protein (VHL) protein expression and RCC4-VHL cells, which express exogenous VHL, and in neuronal SH-SY5Y cells. It was demonstrated that HIF-1 is involved in suppressing oxygen consumption and facilitating glycolysis in cells and that the resistance to propofol-induced cell death was established in a HIF-1 activation-dependent manner. It was also demonstrated that HIF-1 activation by treatment with HIFα-hydroxylase inhibitors such as n-propyl gallate and dimethyloxaloylglycine, alleviated the toxic effects of propofol. Thus, the resistance to propofol toxicity was conferred by HIF-1 activation by not only genetic deletion of VHL but also exposure to HIFα-hydroxylase inhibitors.
The Antiviral Drug Arbidol Inhibits Zika Virus
Authors: Fink Susan L. , Vojtech Lucia , Wagoner Jessica , Slivinski Natalie S. J. , Jackson Konner J. , Wang Ruofan , Khadka Sudip , Luthra Priya , Basler Christopher F. , Polyak Stephen J. 
Published: June 2018

AbstractThere are many emerging and re-emerging globally prevalent viruses for which there are no licensed vaccines or antiviral medicines. Arbidol (ARB, umifenovir), used clinically for decades in several countries as an anti-influenza virus drug, inhibits many other viruses. In the current study, we show that ARB inhibits six different isolates of Zika virus (ZIKV), including African and Asian lineage viruses in multiple cell lines and primary human vaginal and cervical epithelial cells. ARB protects against ZIKV-induced cytopathic effects. Time of addition studies indicate that ARB is most effective at suppressing ZIKV when added to cells prior to infection. Moreover, ARB inhibits pseudoviruses expressing the ZIKV Envelope glycoprotein. Thus, ARB, a broadly acting anti-viral agent with a well-established safety profile, inhibits ZIKV, likely by blocking viral entry.
Toward a translational molecular ratchet: face-selective translation coincident with deuteration in a pseudo-rotaxane
Authors: Hashidzume Akihito , Kuse Akihiro , Oshikiri Tomoya , Adachi Seiji , Okumura Mitsutaka , Yamaguchi Hiroyasu , Harada Akira 
Published: June 2018

AbstractIn the molecular world, molecular ratchets can realize the unidirectional movement in molecular machines. However, construction of artificial molecular ratchets has been still a great challenge. In this study, we investigate the formation of pseudo-rotaxane of a newly designed two-station axis molecule with α-cyclodextrin (α-CD) and the deuteration of acidic protons in the axis in D2O by 1H NMR at varying temperatures. Using the NMR data, we roughly estimate apparent rate constants for association, dissociation, and translation of α-CD during the pseudo-rotaxane formation based on a simplified kinetic model. These rate constants are indicative of face-selective and ratchet-like translation of α-CD on the axis because of the 2-methylpyridinium residues in the axis. We also evaluate apparent first-order rate constants for the deuteration. Comparison of these rate constants indicates that the face-selective translation of α-CD somehow couples with the deuteration. On the basis of this study, it is concluded that a translational molecular ratchet can be constructed using a large energy gradient with appropriate energy barriers and an enthalpically-driven coupled reaction.
Prion-like Domains in Eukaryotic Viruses
Authors: Tetz George , Tetz Victor 
Published: June 2018

AbstractPrions are proteins that can self-propagate, leading to the misfolding of proteins. In addition to the previously demonstrated pathogenic roles of prions during the development of different mammalian diseases, including neurodegenerative diseases, they have recently been shown to represent an important functional component in many prokaryotic and eukaryotic organisms and bacteriophages, confirming the previously unexplored important regulatory and functional roles. However, an in-depth analysis of these domains in eukaryotic viruses has not been performed. Here, we examined the presence of prion-like proteins in eukaryotic viruses that play a primary role in different ecosystems and that are associated with emerging diseases in humans. We identified relevant functional associations in different viral processes and regularities in their presence at different taxonomic levels. Using the prion-like amino-acid composition computational algorithm, we detected 2679 unique putative prion-like domains within 2,742,160 publicly available viral protein sequences. Our findings indicate that viral prion-like proteins can be found in different viruses of insects, plants, mammals, and humans. The analysis performed here demonstrated common patterns in the distribution of prion-like domains across viral orders and families, and revealed probable functional associations with different steps of viral replication and interaction with host cells. These data allow the identification of the viral prion-like proteins as potential novel regulators of viral infections.
A Versatile Safeguard for Chimeric Antigen Receptor T-Cell Immunotherapies
Authors: Valton Julien , Guyot Valerie , Boldajipour Bijan , Sommer Cesar , Pertel Thomas , Juillerat Alexandre , Duclert Aymeric , Sasu Barbra Johnson , Duchateau Philippe , Poirot Laurent 
Published: June 2018

AbstractCAR T-cell therapies hold great promise for treating a range of malignancies but are however challenged by the complexity of their production and by the adverse events related to their activity. Here we report the development of the CubiCAR, a tri-functional CAR architecture that enables CAR T-cell detection, purification and on-demand depletion by the FDA-approved antibody Rituximab. This novel architecture has the potential to streamline the manufacturing of CAR T-cells, allow their tracking and improve their overall safety.
Universal response in the RKO colon cancer cell line to distinct antimitotic therapies
Authors: Lorz Alexander , Botesteanu Dana-Adriana , Levy Doron 
Published: June 2018

AbstractBoth classic and newer antimitotics commonly induce a prolonged mitotic arrest in cell culture. During arrest, cells predominantly undergo one of two fates: cell death by apoptosis, or mitotic slippage and survival. To refine this binary description, a quantitative understanding of these cell responses is needed. Herein, we propose a quantitative description of the kinetics of colon carcinoma RKO cell fates in response to different antimitotics, using data from the single cell experiments of Gascoigne and Taylor (2008). The mathematical model is calibrated using the in vitro experiments of Gascoigne and Taylor (2008). We show that the time-dependent probability of cell death or slippage is universally identical for monastrol, nocodazole and two different doses of AZ138, but significantly different for taxol. Death and slippage responses across drugs can be characterized by Gamma distributions. We demonstrate numerically that these rates increase with prolonged mitotic arrest. Our model demonstrates that RKO cells exhibit a triphasic response - first, remain in mitosis, then undergo fast and slow transition, respectively- dependent on the length of mitotic arrest and irrespective of cell fate, drug type or dose.
Opioid receptor signaling, analgesic and side effects induced by a computationally designed pH-dependent agonist
Authors: Spahn Viola , Del Vecchio Giovanna , Rodriguez-Gaztelumendi Antonio , Temp Julia , Labuz Dominika , Kloner Michael , Reidelbach Marco , Machelska Halina , Weber Marcus , Stein Christoph 
Published: June 2018

AbstractNovel pain killers without adverse effects are urgently needed. Opioids induce central and intestinal side effects such as respiratory depression, sedation, addiction, and constipation. We have recently shown that a newly designed agonist with a reduced acid dissociation constant (pKa) abolished pain by selectively activating peripheral μ-opioid receptors (MOR) in inflamed (acidic) tissues without eliciting side effects. Here, we extended this concept in that pKa reduction to 7.22 was achieved by placing a fluorine atom at the ethylidene bridge in the parental molecule fentanyl. The new compound (FF3) showed pH-sensitive MOR affinity, [35S]-GTPγS binding, and G protein dissociation by fluorescence resonance energy transfer. It produced injury-restricted analgesia in rat models of inflammatory, postoperative, abdominal, and neuropathic pain. At high dosages, FF3 induced sedation, motor disturbance, reward, constipation, and respiratory depression. These results support our hypothesis that a ligand’s pKa should be close to the pH of injured tissue to obtain analgesia without side effects.
Associations of social and economic and pregnancy exposures with blood pressure in UK White British and Pakistani children age 4/5
Authors: West Jane , Lawlor Debbie A. , Santorelli Gillian , Collings Paul , Whincup Peter H. , Sattar Naveed A. , Farrar Diane , Wright John 
Published: June 2018

AbstractSouth Asians have higher rates of coronary heart disease (CHD) than White European individuals. Blood pressure (BP) is one of the most important risk factors for CHD and ethnic differences in BP have been identified in childhood. Early life exposures could explain some of these differences. We examined associations of family social and economic and maternal pregnancy exposures and BP at age 4/5 in 1644 White British and 1824 Pakistani mother-offspring pairs from the Born in Bradford study. We found that systolic BP was similar but diastolic BP was higher, in Pakistani compared to White British children (adjusted mean differences were −0.170 mmHg 95% CI −0.884, 0.543 for systolic BP; 1.328 mmHg 95% CI 0.592, 2.064 for diastolic BP). Social and economic exposures were not associated with BP in either ethnic group. Maternal BMI was positively associated with BP in both groups but this association was mediated by child BMI. Only gestational hypertension was associated with child systolic and diastolic BP and this was only identified in Pakistani mother-offspring pairs. These findings suggest that Pakistani populations may have a different BP trajectory compared to White British groups and that this is already evident at age 4/5 years.
Ischemia-reperfusion injury and the risk of hepatocellular carcinoma recurrence after deceased donor liver transplantation
Authors: Grąt Michał , Krawczyk Marek , Wronka Karolina M. , Stypułkowski Jan , Lewandowski Zbigniew , Wasilewicz Michał , Krawczyk Piotr , Grąt Karolina , Patkowski Waldemar , Zieniewicz Krzysztof 
Published: June 2018

AbstractThis study aimed to evaluate the effects of ischemia-reperfusion injury (IRI) on the risk of hepatocellular carcinoma (HCC) recurrence after liver transplantation. Data of 195 patients were retrospectively analysed. Post-reperfusion aspartate (AST), alanine transaminase, and lactate dehydrogenase (LDH) levels were the primary measures of IRI. Tumour recurrence was the primary endpoint. Post-reperfusion AST was a continuous risk factor for tumour recurrence in patients within Milan criteria (p = 0.035), with an optimal cut-off of 1896 U/L. Recurrence-free survival of patients within Milan criteria and post-reperfusion AST of <1896 and ≥1896 U/L was 96.6% and 71.9% at 5 and 3.7 years, respectively (p = 0.006). Additionally, post-reperfusion AST and LDH exceeding the upper quartile significantly increased the risk of HCC recurrence in patients within Milan criteria (p = 0.039, hazard ratio [HR] = 5.99 and p = 0.040, HR = 6.08, respectively) and to a lesser extent, in patients within Up-to-7 criteria (p = 0.028, HR = 3.58 and p = 0.039, HR = 3.33, respectively). No other significant IRI effects were found in patients beyond the Up-to-7 criteria and in analyses stratified for independent risk factors for recurrence: tumour number and differentiation, alpha-fetoprotein, and microvascular invasion. Thus, IRI exerts major negative effects on the risk of HCC recurrence after liver transplantation in patients within standard and extended criteria.
Evidence of indiscriminate fishing effects in one of the world’s largest inland fisheries
Authors: Ngor Peng Bun , McCann Kevin S. , Grenouillet Gaël , So Nam , McMeans Bailey C. , Fraser Evan , Lek Sovan 
Published: June 2018

AbstractWhile human impacts like fishing have altered marine food web composition and body size, the status of the world’s important tropical inland fisheries remains largely unknown. Here, we look for signatures of human impacts on the indiscriminately fished Tonle Sap fish community that supports one of the world’s largest freshwater fisheries. By analyzing a 15-year time-series (2000–2015) of fish catches for 116 species obtained from an industrial-scale ‘Dai’ fishery, we find: (i) 78% of the species exhibited decreasing catches through time; (ii) downward trends in catches occurred primarily in medium to large-bodied species that tend to occupy high trophic levels; (iii) a relatively stable or increasing trend in catches of small-sized species, and; (iv) a decrease in the individual fish weights and lengths for several common species. Because total biomass of the catch has remained remarkably resilient over the last 15 years, the increase in catch of smaller species has compensated for declines in larger species. Our finding of sustained production but altered community composition is consistent with predictions from recent indiscriminate theory, and gives a warning signal to fisheries managers and conservationists that the species-rich Tonle Sap is being affected by heavy indiscriminate fishing pressure.
An immortalised mesenchymal stem cell line maintains mechano-responsive behaviour and can be used as a reporter of substrate stiffness
Authors: Galarza Torre Asier , Shaw Joshua E. , Wood Amber , Gilbert Hamish T. J. , Dobre Oana , Genever Paul , Brennan Keith , Richardson Stephen M. , Swift Joe 
Published: June 2018

AbstractThe mechanical environment can influence cell behaviour, including changes to transcriptional and proteomic regulation, morphology and, in the case of stem cells, commitment to lineage. However, current tools for characterizing substrates’ mechanical properties, such as atomic force microscopy (AFM), often do not fully recapitulate the length and time scales over which cells ‘feel’ substrates. Here, we show that an immortalised, clonal line of human mesenchymal stem cells (MSCs) maintains the responsiveness to substrate mechanics observed in primary cells, and can be used as a reporter of stiffness. MSCs were cultured on soft and stiff polyacrylamide hydrogels. In both primary and immortalised MSCs, stiffer substrates promoted increased cell spreading, expression of lamin-A/C and translocation of mechano-sensitive proteins YAP1 and MKL1 to the nucleus. Stiffness was also found to regulate transcriptional markers of lineage. A GFP-YAP/RFP-H2B reporter construct was designed and virally delivered to the immortalised MSCs for in situ detection of substrate stiffness. MSCs with stable expression of the reporter showed GFP-YAP to be colocalised with nuclear RFP-H2B on stiff substrates, enabling development of a cellular reporter of substrate stiffness. This will facilitate mechanical characterisation of new materials developed for applications in tissue engineering and regenerative medicine.
Microwave Heating-Assisted Catalytic Dry Reforming of Methane to Syngas
Authors: Hamzehlouia Sepehr , Jaffer Shaffiq A. , Chaouki Jamal 
Published: June 2018

AbstractNatural gas is a robust and environmentally friendlier alternative to oil resources for energy and chemicals production. However, gas is distributed globally within shales and hydrates, which are generally remote and difficult reserves to produce. The accessibility, transportation, and distribution, therefore, bring major capital costs. With today’s low and foreseen low price of natural gas, conversion of natural gas to higher value-added chemicals is highly sought by industry. Dry reforming of methane (DRM) is a technology pathway to convert two critical greenhouse gas components, CH4 and CO2, to syngas, a commodity chemical feedstock. To date, the challenges of carbon deposition on the catalyst and evolution of secondary gas-phase products have prevented the commercial application of the DRM process. The recent exponential growth of renewable electricity resources, wind and solar power, provides a major opportunity to activate reactions by harnessing low-cost carbon-free energy via microwave-heating. This study takes advantage of differences in dielectric properties of materials to enable selective heating by microwave to create a large thermal gradient between a catalyst surface and the gas phase. Consequently, the reaction kinetics at the higher temperature catalyst surface are promoted while the reactions of lower temperature secondary gas-phase are reduced.