bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic profiling reveals p53 as a key regulator of doxorubicin-induced cardiotoxicity
Authors: McSweeney K. Melodi , Bozza William P. , Alterovitz Wei-Lun , Zhang Baolin 
Published: June 2019

AbstractDoxorubicin is an important anticancer drug in the clinic. Unfortunately, it causes cumulative and dose-dependent cardiotoxic side effects. As the population of cancer survivors who have been exposed to treatment continues to grow, there is increased interest in assessing the long-term cardiac effects of doxorubicin and understanding the underlying mechanisms at play. In this study, we investigated doxorubicin-induced transcriptomic changes using RNA-sequencing (RNAseq) and a cellular model comprised of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Analyses of predicted upstream regulators identified the p53 protein as a key regulator of transcriptomic changes induced by doxorubicin. Clustering and pathway analyses showed that increased death receptor (DR) expression and enrichment of the extrinsic apoptotic pathway are significantly associated with doxorubicin-induced cardiotoxicity. Increased expression of p53 and DRs were confirmed via immunoblotting. Our data pinpoints increased DR expression as an early transcriptomic indicator of cardiotoxicity, suggesting that DR expression might function as a predictive biomarker for cardiac damage.
LncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2/STAT3 signaling
Authors: Luo Jie , Wang Keliang , Yeh Shuyuan , Sun Yin , Liang Liang , Xiao Yao , Xu Wanhai , Niu Yuanjie , Cheng Liang , Maity Sankar N. , Jiang Runze , Chang Chawnshang 
Published: June 2019

AbstractWhile the antiandrogen enzalutamide (Enz) extends the castration resistant prostate cancer (CRPC) patients’ survival an extra 4.8 months, it might also result in some adverse effects via inducing the neuroendocrine differentiation (NED). Here we found that lncRNA-p21 is highly expressed in the NEPC patients derived xenograft tissues (NEPC-PDX). Results from cell lines and human clinical sample surveys also revealed that lncRNA-p21 expression is up-regulated in NEPC and Enz treatment could increase the lncRNA-p21 to induce the NED. Mechanism dissection revealed that Enz could promote the lncRNA-p21 transcription via altering the androgen receptor (AR) binding to different androgen-response-elements, which switch the EZH2 function from histone-methyltransferase to non-histone methyltransferase, consequently methylating the STAT3 to promote the NED. Preclinical studies using the PDX mouse model proved that EZH2 inhibitor could block the Enz-induced NED. Together, these results suggest targeting the Enz/AR/lncRNA-p21/EZH2/STAT3 signaling may help urologists to develop a treatment for better suppression of the human CRPC progression.
Feedback inhibition of cAMP effector signaling by a chaperone-assisted ubiquitin system
Authors: Rinaldi Laura , Delle Donne Rossella , Catalanotti Bruno , Torres-Quesada Omar , Enzler Florian , Moraca Federica , Nisticò Robert , Chiuso Francesco , Piccinin Sonia , Bachmann Verena , Lindner Herbert H , Garbi Corrado , Scorziello Antonella , Russo Nicola Antonino , Synofzik Matthis , Stelzl Ulrich , Annunziato Lucio , Stefan Eduard , Feliciello Antonio 
Published: June 2019

AbstractActivation of G-protein coupled receptors elevates cAMP levels promoting dissociation of protein kinase A (PKA) holoenzymes and release of catalytic subunits (PKAc). This results in PKAc-mediated phosphorylation of compartmentalized substrates that control central aspects of cell physiology. The mechanism of PKAc activation and signaling have been largely characterized. However, the modes of PKAc inactivation by regulated proteolysis were unknown. Here, we identify a regulatory mechanism that precisely tunes PKAc stability and downstream signaling. Following agonist stimulation, the recruitment of the chaperone-bound E3 ligase CHIP promotes ubiquitylation and proteolysis of PKAc, thus attenuating cAMP signaling. Genetic inactivation of CHIP or pharmacological inhibition of HSP70 enhances PKAc signaling and sustains hippocampal long-term potentiation. Interestingly, primary fibroblasts from autosomal recessive spinocerebellar ataxia 16 (SCAR16) patients carrying germline inactivating mutations of CHIP show a dramatic dysregulation of PKA signaling. This suggests the existence of a negative feedback mechanism for restricting hormonally controlled PKA activities.
Polymer-tetrodotoxin conjugates to induce prolonged duration local anesthesia with minimal toxicity
Authors: Zhao Chao , Liu Andong , Santamaria Claudia M. , Shomorony Andre , Ji Tianjiao , Wei Tuo , Gordon Akiva , Elofsson Hannes , Mehta Manisha , Yang Rong , Kohane Daniel S. 
Published: June 2019

AbstractThere is clinical and scientific interest in developing local anesthetics with prolonged durations of effect from single injections. The need for such is highlighted by the current opioid epidemic. Site 1 sodium channel blockers such as tetrodotoxin (TTX) are extremely potent, and can provide very long nerve blocks but the duration is limited by the associated systemic toxicity. Here we report a system where slow release of TTX conjugated to a biocompatible and biodegradable polymer, poly(triol dicarboxylic acid)-co-poly(ethylene glycol) (TDP), is achieved by hydrolysis of ester linkages. Nerve block by the released TTX is enhanced by administration in a carrier with chemical permeation enhancer (CPE) properties. TTX release can be adjusted by tuning the hydrophilicity of the TDP polymer backbone. In vivo, 1.0–80.0 µg of TTX released from these polymers produced a range of durations of nerve block, from several hours to 3 days, with minimal systemic or local toxicity.
Metal-organic framework crystal-glass composites
Authors: Hou Jingwei , Ashling Christopher W. , Collins Sean M. , Krajnc Andraž , Zhou Chao , Longley Louis , Johnstone Duncan N. , Chater Philip A. , Li Shichun , Coulet Marie-Vanessa , Llewellyn Philip L. , Coudert François-Xavier , Keen David A. , Midgley Paul A. , Mali Gregor , Chen Vicki , Bennett Thomas D. 
Published: June 2019

AbstractThe majority of research into metal-organic frameworks (MOFs) focuses on their crystalline nature. Recent research has revealed solid-liquid transitions within the family, which we use here to create a class of functional, stable and porous composite materials. Described herein is the design, synthesis, and characterisation of MOF crystal-glass composites, formed by dispersing crystalline MOFs within a MOF-glass matrix. The coordinative bonding and chemical structure of a MIL-53 crystalline phase are preserved within the ZIF-62 glass matrix. Whilst separated phases, the interfacial interactions between the closely contacted microdomains improve the mechanical properties of the composite glass. More significantly, the high temperature open pore phase of MIL-53, which spontaneously transforms to a narrow pore upon cooling in the presence of water, is stabilised at room temperature in the crystal-glass composite. This leads to a significant improvement of CO2 adsorption capacity.
Characteristic fast H− ion conduction in oxygen-substituted lanthanum hydride
Authors: Fukui Keiga , Iimura Soshi , Tada Tomofumi , Fujitsu Satoru , Sasase Masato , Tamatsukuri Hiromu , Honda Takashi , Ikeda Kazutaka , Otomo Toshiya , Hosono Hideo 
Published: June 2019

AbstractFast ionic conductors have considerable potential to enable technological development for energy storage and conversion. Hydride (H−) ions are a unique species because of their natural abundance, light mass, and large polarizability. Herein, we investigate characteristic H− conduction, i.e., fast ionic conduction controlled by a pre-exponential factor. Oxygen-doped LaH3 (LaH3−2xOx) has an optimum ionic conductivity of 2.6 × 10−2 S cm−1, which to the best of our knowledge is the highest H− conductivity reported to date at intermediate temperatures. With increasing oxygen content, the relatively high activation energy remains unchanged, whereas the pre-exponential factor decreases dramatically. This extraordinarily large pre-exponential factor is explained by introducing temperature-dependent enthalpy, derived from H− trapped by lanthanum ions bonded to oxygen ions. Consequently, light mass and large polarizability of H−, and the framework comprising densely packed H− in LaH3−2xOx are crucial factors that impose significant temperature dependence on the potential energy and implement characteristic fast H− conduction.
Directed propulsion of spherical particles along three dimensional helical trajectories
Authors: Lee Jin Gyun , Brooks Allan M. , Shelton William A. , Bishop Kyle J. M. , Bharti Bhuvnesh 
Published: June 2019

AbstractActive colloids are a class of microparticles that ‘swim’ through fluids by breaking the symmetry of the force distribution on their surfaces. Our ability to direct these particles along complex trajectories in three-dimensional (3D) space requires strategies to encode the desired forces and torques at the single particle level. Here, we show that spherical colloids with metal patches of low symmetry self-propel along non-linear 3D trajectories when powered remotely by an alternating current (AC) electric field. In particular, particles with triangular patches of approximate mirror symmetry trace helical paths along the axis of the field. We demonstrate that the speed and shape of the particle’s trajectory can be tuned by the applied field strength and the patch geometry. We show that helical motion can enhance particle transport through porous materials with implications for the design of microrobots that can navigate complex environments.
Duets recorded in the wild reveal that interindividually coordinated motor control enables cooperative behavior
Authors: Hoffmann Susanne , Trost Lisa , Voigt Cornelia , Leitner Stefan , Lemazina Alena , Sagunsky Hannes , Abels Markus , Kollmansperger Sandra , Maat Andries Ter , Gahr Manfred 
Published: June 2019

AbstractMany organisms coordinate rhythmic motor actions with those of a partner to generate cooperative social behavior such as duet singing. The neural mechanisms that enable rhythmic interindividual coordination of motor actions are unknown. Here we investigate the neural basis of vocal duetting behavior by using an approach that enables simultaneous recordings of individual vocalizations and multiunit vocal premotor activity in songbird pairs ranging freely in their natural habitat. We find that in the duet-initiating bird, the onset of the partner’s contribution to the duet triggers a change in rhythm in the periodic neural discharges that are exclusively locked to the initiating bird’s own vocalizations. The resulting interindividually synchronized neural activity pattern elicits vocalizations that perfectly alternate between partners in the ongoing song. We suggest that rhythmic cooperative behavior requires exact interindividual coordination of premotor neural activity, which might be achieved by integration of sensory information originating from the interacting partner.
The structural basis for release-factor activation during translation termination revealed by time-resolved cryogenic electron microscopy
Authors: Fu Ziao , Indrisiunaite Gabriele , Kaledhonkar Sandip , Shah Binita , Sun Ming , Chen Bo , Grassucci Robert A. , Ehrenberg Måns , Frank Joachim 
Published: June 2019

AbstractWhen the ribosome encounters a stop codon, it recruits a release factor (RF) to hydrolyze the ester bond between the peptide chain and tRNA. RFs have structural motifs that recognize stop codons in the decoding center and a GGQ motif for induction of hydrolysis in the peptidyl transfer center 70 Å away. Surprisingly, free RF2 is compact, with only 20 Å between its codon-reading and GGQ motifs. Cryo-EM showed that ribosome-bound RFs have extended structures, suggesting that RFs are compact when entering the ribosome and then extend their structures upon stop codon recognition. Here we use time-resolved cryo-EM to visualize transient compact forms of RF1 and RF2 at 3.5 and 4 Å resolution, respectively, in the codon-recognizing ribosome complex on the native pathway. About 25% of complexes have RFs in the compact state at 24 ms reaction time, and within 60 ms virtually all ribosome-bound RFs are transformed to their extended forms.
Transcriptomic profiles conducive to immune-mediated tumor rejection in human breast cancer skin metastases treated with Imiquimod
Authors: Rozenblit Mariya , Hendrickx Wouter , Heguy Adriana , Chiriboga Luis , Loomis Cynthia , Ray Karina , Darvishian Farbod , Egeblad Mikala , Demaria Sandra , Marincola Francesco M. , Bedognetti Davide , Adams Sylvia 
Published: June 2019

AbstractImiquimod is a topical toll-like-receptor-7 agonist currently used for treating basal cell carcinoma. Recently, imiquimod has demonstrated tumor regression in melanoma and breast cancer skin metastases. However, the molecular perturbations induced by imiquimod in breast cancer metastases have not been previously characterized. Here, we describe transcriptomic profiles associated with responsiveness to imiquimod in breast cancer skin metastases. Baseline and post-treatment tumor samples from patients treated with imiquimod in a clinical trial were profiled using Nanostring technology. Through an integrative analytic pipeline, we showed that tumors from patients who achieved a durable clinical response displayed a permissive microenvironment, substantiated by the upregulation of transcripts encoding for molecules involved in leukocyte adhesion and migration, cytotoxic functions, and antigen presentation. In responding patients, Imiquimod triggered a strong T-helper-1 (Th-1)/cytotoxic immune response, characterized by the coordinated upregulation of Th-1 chemokines, migration of Th-1 and cytotoxic T cells into the tumor, and activation of immune-effector functions, ultimately mediating tumor destruction. In conclusion, we have shown that topical imiquimod can induce a robust immune response in breast cancer metastases, and this response is more likely to occur in tumors with a pre-activated microenvironment. In this setting, imiquimod could be utilized in combination with other targeted immunotherapies to increase therapeutic efficacy.
Legume-maize rotation effect on maize productivity and soil fertility parameters under selected agronomic practices in a sandy loam soil
Authors: Uzoh Ifeyinwa Monica , Igwe Charles Arizechukwu , Okebalama Chinyere Blessing , Babalola Olubukola Olularanti 
Published: June 2019

AbstractInclusion of legumes in cropping systems is essential for sustainable management of farming systems and reducing the nitrogen (N) fertilizer requirement for maize production. The study evaluated the effect of growing legumes (soybean, cowpea and velvet bean) and maize the same year in rotation, on maize yield and soil fertility indices. The agronomic practices implemented were residue management (residue added and residue removed) and fertilizer N application (0 kg N ha−1 and 60 kg N ha−1) under four rotation systems. The result showed that growing velvet bean the same year in rotation with maize was effective in increasing maize yield and improving some soil fertility indices over growing maize after maize the same year in the same location. Compared to maize monocropping, over 100% increase in maize yield was obtained with velvet bean-maize rotation even in absence of residue incorporation. In addition, velvet bean-maize rotation increased maize yield over cowpea- and soybean- maize rotations. The rotation effect occurred as a result of improvement in soil nitrogen, avail phosphorus (P), exchangeable magnesium (exch Mg) and effective cation exchange capacity (ECEC). Grain legumes-maize rotations equally increased maize yield over sole maize. Generally legume-maize rotations increased total N, avail P, exch K, Mg and effective cation exchange capacity over sole maize. Crop residue incorporation and N fertilizer application significantly improved soil N and maize grain yield (0.18%, 2.74 tha−1 in 2008; 0.22%, 1.16 tha−1 in 2009 and 0.19%, 2.72 tha−1 in 2008; 1.35 tha−1 in 2009 respectively) over non-residue incorporation (0.16% and 1.84 tha−1 in 2008, 0.66 tha−1 in 2009) and zero N application (0.16% and 1.83 tha−1 in 2008 and 0.17% and 0.85 tha−1 in 2009). Therefore, velvet bean could be planted the same season with subsequent maize in rotation cropping for intensive sustainable maize production in sandy-loam soils without fertilizer N. For grain legumes such as soybean and cowpea to be effective in rotation cropping with maize, the grain legumes have to be planted early before the full set of rain because excess rain would affect their growth and development.
Characterization of a highly specific NQO1-activated near-infrared fluorescent probe and its application for in vivo tumor imaging
Authors: Punganuru Surendra Reddy , Madala Hanumantha Rao , Arutla Viswanath , Zhang Ruiwen , Srivenugopal Kalkunte S. 
Published: June 2019

AbstractThe Near-infrared Fluorescence (NIRF) molecular imaging of cancer is known to be superior in sensitivity, deeper penetration, and low phototoxicity compared to other imaging modalities. In view of an increased need for efficient and targeted imaging agents, we synthesized a NAD(P)H quinone oxidoreductase 1 (NQO1)-activatable NIR fluorescent probe (NIR-ASM) by conjugating dicyanoisophorone (ASM) fluorophore with the NQO1 substrate quinone propionic acid (QPA). The probe remained non-fluorescent until activation by NQO1, whose expression is largely limited to malignant tissues. With a large Stokes shift (186 nm) and a prominent near-infrared emission (646 nm) in response to NQO1, NIR-ASM was capable of monitoring NQO1 activity in vitro and in vivo with high specificity and selectivity. We successfully employed the NIR-ASM to differentiate cancer cells from normal cells based on NQO1 activity using fluorescence microscopy and flow cytometry. Chemical and genetic approaches involving the use of ES936, a specific inhibitor of NQO1 and siRNA and gene transfection procedures unambiguously demonstrated NQO1 to be the sole target activating the NIR-ASM in cell cultures. NIR-ASM was successfully used to detect and image the endogenous NQO1 in three live tumor-bearing mouse models (A549 lung cancer, Lewis lung carcinoma, and MDMAMB 231 xenografts) with a high signal-to-low noise ratiometric NIR fluorescence response. When the NQO1-proficient A549 tumors and NQO1-deficient MDA-MB-231 tumors were developed in the same animal, only the A549 malignancies activated the NIR-ASM probe with a strong signal. Because of its high sensitivity, rapid activation, tumor selectivity, and nontoxic properties, the NIR-ASM appears to be a promising agent with clinical applications.
Effectiveness of Solvent Vapor Annealing over Thermal Annealing on the Photovoltaic Performance of Non-Fullerene Acceptor Based BHJ Solar Cells
Authors: Datt Ram , Suman  , Bagui A. , Siddiqui Afzal , Sharma R. , Gupta Vinay , Yoo S. , Kumar S. , Singh Surya Prakash 
Published: June 2019

AbstractWe explore two small molecules containing arms of dicyano-n-hexylrhodanine and diathiafulvalene wings terminated with benzothiadiazole linker, denoted as BAF-4CN and BAF-2HDT, respectively, as small molecule non-fullerene acceptors (SMNFAs) in organic solar cells. The proposed materials are mixed with a low band gap polymer donor PTB7-Th having broad absorption in the range of 400–750 nm to form solution-processed bulk heterojunctions (BHJs). The photoluminescence (PL) measurements show that both donor and acceptor can quench each other’s PL effectively, implying that not only electrons are transferred from PTB7-Th → SMNFAs but also holes are transferred from SMNFAs → PTB7-Th for efficient photocurrent generation. Furthermore, solvent vapor annealing (SVA) processing is shown to yield a more balanced hole and electron mobility and thus suppresses the trap-assisted recombination significantly. With this dual charge transfer enabled via fine-tuning of end-groups and SVA treatment, power conversion efficiency of approximately 10% is achieved, demonstrating the feasibility of the proposed approach.
Brown bear attacks on humans: a worldwide perspective
Authors: Bombieri G. , Naves J. , Penteriani V. , Selva N. , Fernández-Gil A. , López-Bao J. V. , Ambarli H. , Bautista C. , Bespalova T. , Bobrov V. , Bolshakov V. , Bondarchuk S. , Camarra J. J. , Chiriac S. , Ciucci P. , Dutsov A. , Dykyy I. , Fedriani J. M. , García-Rodríguez A. , Garrote P. J. , Gashev S. , Groff C. , Gutleb B. , Haring M. , Härkönen S. , Huber D. , Kaboli M. , Kalinkin Y. , Karamanlidis A. A. , Karpin V. , Kastrikin V. , Khlyap L. , Khoetsky P. , Kojola I. , Kozlow Y. , Korolev A. , Korytin N. , Kozsheechkin V. , Krofel M. , Kurhinen J. , Kuznetsova I. , Larin E. , Levykh A. , Mamontov V. , Männil P. , Melovski D. , Mertzanis Y. , Meydus A. , Mohammadi A. , Norberg H. , Palazón S. , Pătrașcu L. M. , Pavlova K. , Pedrini P. , Quenette P. Y. , Revilla E. , Rigg R. , Rozhkov Y. , Russo L. F. , Rykov A. , Saburova L. , Sahlén V. , Saveljev A. P. , Seryodkin I. V. , Shelekhov A. , Shishikin A. , Shkvyria M. , Sidorovich V. , Sopin V. , Støen O. , Stofik J. , Swenson J. E. , Tirski D. , Vasin A. , Wabakken P. , Yarushina L. , Zwijacz-Kozica T. , Delgado M. M. 
Published: June 2019

AbstractThe increasing trend of large carnivore attacks on humans not only raises human safety concerns but may also undermine large carnivore conservation efforts. Although rare, attacks by brown bears Ursus arctos are also on the rise and, although several studies have addressed this issue at local scales, information is lacking on a worldwide scale. Here, we investigated brown bear attacks (n = 664) on humans between 2000 and 2015 across most of the range inhabited by the species: North America (n = 183), Europe (n = 291), and East (n = 190). When the attacks occurred, half of the people were engaged in leisure activities and the main scenario was an encounter with a female with cubs. Attacks have increased significantly over time and were more frequent at high bear and low human population densities. There was no significant difference in the number of attacks between continents or between countries with different hunting practices. Understanding global patterns of bear attacks can help reduce dangerous encounters and, consequently, is crucial for informing wildlife managers and the public about appropriate measures to reduce this kind of conflicts in bear country.
Incident Hepatocellular Carcinoma Risk in Patients Treated with a Sulfonylurea: A Nationwide, Nested, Case-Control Study
Authors: Lee Ji-Yeon , Jang Suk-Yong , Nam Chung Mo , Kang Eun Seok 
Published: June 2019

AbstractSeveral studies have shown that the use of sulfonylureas in patients with type 2 diabetes mellitus (T2DM) is associated with a higher risk of hepatocellular carcinoma (HCC). In this study, we investigated the effects of individual sulfonylureas on HCC development using the National Health Insurance Service-National Sample Cohort in South Korea. Among 47,738 subjects aged 40 years or older who had newly diagnosed with diabetes, 241 incident HCC cases and 1205 matched controls were identified. Adjusted odds ratios (ORs) as estimates of the relative risk of HCC were calculated using logistic regression analysis. Compared to patients never treated with a sulfonylurea, those treated with a sulfonylurea had a 1.7-fold increased risk of HCC development. Of the different types of sulfonylureas, the exclusive use of glimepiride was associated with a significantly elevated risk of HCC (OR = 1.89, 95% CI = 1.02–3.47) compared to those who were never treated with sulfonylureas. No significant associations were observed between exclusive gliclazide use and incident HCC (OR = 2.04, 95% CI = 0.75–5.52). In conclusion, the association between the use of sulfonylureas and risk of HCC was different according to the type of sulfonylurea, in patients with new-onset T2DM. Further prospective studies are warranted to confirm these results and translate them into clinical practice.