bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conservation priorities for endangered Indian tigers through a genomic lens
Authors: Natesh Meghana , Atla Goutham , Nigam Parag , Jhala Yadvendradev V. , Zachariah Arun , Borthakur Udayan , Ramakrishnan Uma 
Published: August 2017

AbstractTigers have lost 93% of their historical range worldwide. India plays a vital role in the conservation of tigers since nearly 60% of all wild tigers are currently found here. However, as protected areas are small (<300 km2on average), with only a few individuals in each, many of them may not be independently viable. It is thus important to identify and conserve genetically connected populations, as well as to maintain connectivity within them. We collected samples from wild tigers (Panthera tigris tigris) across India and used genome-wide SNPs to infer genetic connectivity. We genotyped 10,184 SNPs from 38 individuals across 17 protected areas and identified three genetically distinct clusters (corresponding to northwest, southern and central India). The northwest cluster was isolated with low variation and high relatedness. The geographically large central cluster included tigers from central, northeastern and northern India, and had the highest variation. Most genetic diversity (62%) was shared among clusters, while unique variation was highest in the central cluster (8.5%) and lowest in the northwestern one (2%). We did not detect signatures of differential selection or local adaptation. We highlight that the northwest population requires conservation attention to ensure persistence of these tigers.
Frequency-dependent drug screening using optogenetic stimulation of human iPSC-derived cardiomyocytes
Authors: Lapp Hendrik , Bruegmann Tobias , Malan Daniela , Friedrichs Stephanie , Kilgus Carsten , Heidsieck Alexandra , Sasse Philipp 
Published: August 2017

AbstractSide effects on cardiac ion channels are one major reason for new drugs to fail during preclinical evaluation. Herein we propose a simple optogenetic screening tool measuring extracellular field potentials (FP) from paced cardiomyocytes to identify drug effects over the whole physiological heart range, which is essential given the rate-dependency of ion channel function and drug action. Human induced pluripotent stem cell-derived cardiomyocytes were transduced with an adeno-associated virus to express Channelrhodopsin2 and plated on micro-electrode arrays. Global pulsed illumination (470 nm, 1 ms, 0.9 mW/mm2) was applied at frequencies from 1 to 2.5 Hz, which evoked FP simultaneously in all cardiomyocytes. This synchronized activation allowed averaging of FP from all electrodes resulting in one robust FP signal for analysis. Field potential duration (FPD) was ~25% shorter at 2.5 Hz compared to 1 Hz. Inhibition of hERG channels prolonged FPD only at low heart rates whereas Ca2+ channel block shortened FPD at all heart rates. Optogenetic pacing also allowed analysis of the maximum downstroke velocity of the FP to detect drug effects on Na+ channel availability. In principle, the presented method is well scalable for high content cardiac toxicity screening or personalized medicine for inherited cardiac channelopathies.
Intravenous rAAV2/9 injection for murine cochlear gene delivery
Authors: Shibata Seiji B. , Yoshimura Hidekane , Ranum Paul T. , Goodwin Alexander T. , Smith Richard J. H. 
Published: August 2017

AbstractGene therapy for genetic deafness is a promising approach by which to prevent hearing loss or to restore hearing after loss has occurred. Although a variety of direct approaches to introduce viral particles into the inner ear have been described, presumed physiological barriers have heretofore precluded investigation of systemic gene delivery to the cochlea. In this study, we sought to characterize systemic delivery of a rAAV2/9 vector as a non-invasive means of cochlear transduction. In wild-type neonatal mice (postnatal day 0–1), we show that intravenous injection of rAAV2/9 carrying an eGFP-reporter gene results in binaural transduction of inner hair cells, spiral ganglion neurons and vestibular hair cells. Transduction efficiency increases in a dose-dependent manner. Inner hair cells are transduced in an apex-to-base gradient, with transduction reaching 96% in the apical turn. Hearing acuity in treated animals is unaltered at postnatal day 30. Transduction is influenced by viral serotype and age at injection, with less efficient cochlear transduction observed with systemic delivery of rAAV2/1 and in juvenile mice with rAAV2/9. Collectively, these data validate intravenous delivery of rAAV2/9 as a novel and atraumatic technique for inner ear transgene delivery in early postnatal mice.
Hypoxic Stress Decreases c-Myc Protein Stability in Cardiac Progenitor Cells Inducing Quiescence and Compromising Their Proliferative and Vasculogenic Potential
Authors: Bellio Michael A. , Pinto Mariana T. , Florea Victoria , Barrios Paola A. , Taylor Christy N. , Brown Ariel B. , Lamondin Courtney , Hare Joshua M. , Schulman Ivonne H. , Rodrigues Claudia O. 
Published: August 2017

AbstractCardiac progenitor cells (CPCs) have been shown to promote cardiac regeneration and improve heart function. However, evidence suggests that their regenerative capacity may be limited in conditions of severe hypoxia. Elucidating the mechanisms involved in CPC protection against hypoxic stress is essential to maximize their cardioprotective and therapeutic potential. We investigated the effects of hypoxic stress on CPCs and found significant reduction in proliferation and impairment of vasculogenesis, which were associated with induction of quiescence, as indicated by accumulation of cells in the G0-phase of the cell cycle and growth recovery when cells were returned to normoxia. Induction of quiescence was associated with a decrease in the expression of c-Myc through mechanisms involving protein degradation and upregulation of p21. Inhibition of c-Myc mimicked the effects of severe hypoxia on CPC proliferation, also triggering quiescence. Surprisingly, these effects did not involve changes in p21 expression, indicating that other hypoxia-activated factors may induce p21 in CPCs. Our results suggest that hypoxic stress compromises CPC function by inducing quiescence in part through downregulation of c-Myc. In addition, we found that c-Myc is required to preserve CPC growth, suggesting that modulation of pathways downstream of it may re-activate CPC regenerative potential under ischemic conditions.
Placental Dysfunction Underlies Increased Risk of Fetal Growth Restriction and Stillbirth in Advanced Maternal Age Women
Authors: Lean Samantha C. , Heazell Alexander E. P. , Dilworth Mark R. , Mills Tracey A. , Jones Rebecca L. 
Published: August 2017

AbstractPregnancies in women of advanced maternal age (AMA) are susceptible to fetal growth restriction (FGR) and stillbirth. We hypothesised that maternal ageing is associated with utero-placental dysfunction, predisposing to adverse fetal outcomes. Women of AMA (≥35 years) and young controls (20–30 years) with uncomplicated pregnancies were studied. Placentas from AMA women exhibited increased syncytial nuclear aggregates and decreased proliferation, and had increased amino acid transporter activity. Chorionic plate and myometrial artery relaxation was increased compared to controls. AMA was associated with lower maternal serum PAPP-A and sFlt and a higher PlGF:sFlt ratio. AMA mice (38–41 weeks) at E17.5 had fewer pups, more late fetal deaths, reduced fetal weight, increased placental weight and reduced fetal:placental weight ratio compared to 8–12 week controls. Maternofetal clearance of 14C-MeAIB and 3H-taurine was reduced and uterine arteries showed increased relaxation. These studies identify reduced placental efficiency and altered placental function with AMA in women, with evidence of placental adaptations in normal pregnancies. The AMA mouse model complements the human studies, demonstrating high rates of adverse fetal outcomes and commonalities in placental phenotype. These findings highlight placental dysfunction as a potential mechanism for susceptibility to FGR and stillbirth with AMA.
P53 represses pyrimidine catabolic gene dihydropyrimidine dehydrogenase (DPYD) expression in response to thymidylate synthase (TS) targeting
Authors: Gokare Prashanth , Finnberg Niklas K. , Abbosh Phillip H. , Dai Jenny , Murphy Maureen E. , El-Deiry Wafik S. 
Published: August 2017

AbstractNucleotide metabolism in cancer cells can influence malignant behavior and intrinsic resistance to therapy. Here we describe p53-dependent control of the rate-limiting enzyme in the pyrimidine catabolic pathway, dihydropyrimidine dehydrogenase (DPYD) and its effect on pharmacokinetics of and response to 5-fluorouracil (5-FU). Using in silico/chromatin-immunoprecipitation (ChIP) analysis we identify a conserved p53 DNA-binding site (p53BS) downstream of the DPYD gene with increased p53 occupancy following 5-FU treatment of cells. Consequently, decrease in Histone H3K9AC and increase in H3K27me3 marks at the DPYD promoter are observed concomitantly with reduced expression of DPYD mRNA and protein in a p53-dependent manner. Mechanistic studies reveal inhibition of DPYD expression by p53 is augmented following thymidylate synthase (TS) inhibition and DPYD repression by p53 is dependent on DNA-dependent protein kinase (DNA-PK) and Ataxia telangiectasia mutated (ATM) signaling. In-vivo, liver specific Tp53 loss increases the conversion of 5-FU to 5-FUH2 in plasma and elicits a diminished 5-FU therapeutic response in a syngeneic colorectal tumor model consistent with increased DPYD-activity. Our data suggest that p53 plays an important role in controlling pyrimidine catabolism through repression of DPYD expression, following metabolic stress imposed by nucleotide imbalance. These findings have implications for the toxicity and efficacy of the cancer therapeutic 5-FU.
Bridging the Gap: Rewritable Electronics Using Real-Time Light-Induced Dielectrophoresis on Lithium Niobate
Authors: Sperling Justin R. , Neale Steven L. , Clark Alasdair W. 
Published: August 2017

AbstractIn the context of micro-electronics, the real-time manipulation and placement of components using optics alone promises a route towards increasingly dynamic systems, where the geometry and function of the device is not fixed at the point of fabrication. Here, we demonstrate physically reconfigurable circuitry through light-induced dielectrophoresis on lithium niobate. Using virtual electrodes, patterned by light, to trap, move, and chain individual micro-solder-beads in real-time via dielectrophoresis, we demonstrate rewritable electrical contacts which can make electrical connections between surface-bound components. The completed micro-solder-bead bridges were found to have relatively low resistances that were not solely dominated by the number of interfaces, or the number of discrete beads, in the connection. Significantly, these connections are formed without any melting/fusing of the beads, a key feature of this technique that enables reconfigurability. Requiring only a low-power (~3.5 mW) laser source to activate, and without the need for external power supply or signal generation, the all-optical simplicity of virtual-electrodes may prove significant for the future development of reconfigurable electronic systems.
Nosocomial transmission of Clostridium difficile Genotype ST81 in a General Teaching Hospital in China traced by whole genome sequencing
Authors: Qin Juanxiu , Dai Yingxin , Ma Xiaowei , Wang Yanan , Gao Qianqian , Lu Huiying , Li Tianming , Meng Hongwei , Liu Qian , Li Min 
Published: August 2017

AbstractClostridium difficile infection (CDI) is increasingly recognized globally as a cause of significant morbidity and mortality. This study aimed to provide insight into the various dynamics of C. difficile transmission and infection in the hospital. We monitored the toxin and resistance profiles as well as evolutionary relationships of C. difficile strains to determine the epidemiology over time in a teaching hospital in Shanghai, China between May 2014 and August 2015. The CDI incidence of inpatients and outpatients were 67.7 cases and 0.3 cases per 100,000 patient-days, with a nosocomial patient-environment-patient transmission in May and June 2015. C. difficile genotype ST81, a clone with tcdA-negative and tcdB-positive, was not only the most common strain (30.8%, 28/91) but also had much higher resistance rates to clindamycin and moxifloxacin compared with non-ST81 genotypes. Hospitalized patients infected with ST81 genotypes were over 65 years of age and had more comorbidities, however patients infected with ST81 presented with less clinical symptoms than non-ST81 infected patients. This study provides initial epidemiological evidence that C. difficile ST81 is a successful epidemic genotype that deserves continuous surveillance in China.
Electronic properties of (Sb;Bi)2Te3 colloidal heterostructured nanoplates down to the single particle level
Authors: Mir Wasim J. , Assouline Alexandre , Livache Clément , Martinez Bertille , Goubet Nicolas , Xu Xiang Zhen , Patriarche Gilles , Ithurria Sandrine , Aubin Hervé , Lhuillier Emmanuel 
Published: August 2017

AbstractWe investigate the potential use of colloidal nanoplates of Sb2Te3 by conducting transport on single particle with in mind their potential use as 3D topological insulator material. We develop a synthetic procedure for the growth of plates with large lateral extension and probe their infrared optical and transport properties. These two properties are used as probe for the determination of the bulk carrier density and agree on a value in the 2–3 × 1019 cm−3 range. Such value is compatible with the metallic side of the Mott criterion which is also confirmed by the weak thermal dependence of the conductance. By investigating the transport at the single particle level we demonstrate that the hole mobility in this system is around 40 cm2V−1s−1. For the bulk material mixing n-type Bi2Te3 with the p-type Sb2Te3 has been a successful way to control the carrier density. Here we apply this approach to the case of colloidally obtained nanoplates by growing a core-shell heterostructure of Sb2Te3/Bi2Te3 and demonstrates a reduction of the carrier density by a factor 2.5.
Infection with the Makona variant results in a delayed and distinct host immune response compared to previous Ebola virus variants
Authors: Versteeg Krista , Menicucci Andrea R. , Woolsey Courtney , Mire Chad E. , Geisbert Joan B. , Cross Robert W. , Agans Krystle N. , Jeske Daniel , Messaoudi Ilhem , Geisbert Thomas W. 
Published: August 2017

AbstractZaire Ebolavirus (ZEBOV) continues to pose a significant threat to human health as highlighted by the recent epidemic that originated in West Africa and the ongoing outbreak in the Democratic Republic of the Congo. Although the ZEBOV variant responsible for this epidemic (Makona) shares significant genetic similarity with previously identified variants (Kikwit and Mayinga), recent reports suggest slower disease progression in nonhuman primates. However, the pathogenesis caused by the new variant is not fully understood. We present the first comprehensive approach in understanding ZEBOV-Makona pathogenesis in cynomolgus macaques by measuring changes in immune cell frequencies, plasma levels of immune mediators, and differentially expressed genes (DEGs) within whole blood (WB) and peripheral blood mononuclear cells (PBMC). Our combined approach revealed a link between: 1) increased interferon-stimulated gene expression, IFNα levels, and activated plasmacytoid dendritic cells; 2) higher proinflammatory gene expression, cytokine and chemokine levels, and non-classical monocytes; 3) gene signature of leukocyte activation and increased granulocytes; and 4) decreased expression of lymphocyte related genes and lymphopenia. In addition, our data strongly indicate delayed disease progression as well as limited overlap (~30%) in host transcriptome changes following ZEBOV-Makona infection compared to ZEBOV-Kikwit. These observations provide novel insight into the molecular mechanisms of ZEBOV-Makona pathogenesis.
Synergistic impact of mutations in Hepatitis B Virus genome contribute to its occult phenotype in chronic Hepatitis C Virus carriers
Authors: Mondal Rajiv Kumar , Khatun Mousumi , Banerjee Priyanka , Ghosh Alip , Sarkar Sumanta , Santra Amal , Das Kausik , Chowdhury Abhijit , Banerjee Soma , Datta Simanti 
Published: August 2017

AbstractWe characterized occult HBV (OHBV) from hepatitis B surface antigen (HBsAg)-negative chronic HCV carriers of Eastern India to explore the impact of genomic variability of HBV in causing undetectability of HBsAg and low viremia that define the occult phenomenon. Screening of sera samples revealed the presence of OHBV in 17.8% of HCV-infected patients. Determination of full-length OHBV sequences and comparison with that from HBsAg-positive carriers led to the detection of distinct substitutions/mutations in PreS2, S, P and X ORFs and in X-promoter and Enhancer-II of OHBV. These mutations were introduced in wild-type HBV and their effects were evaluated by transfection in Huh7 cells. In vitro assays demonstrated that S-substitutions resulted in antigenically modified HBsAg that escaped detection by immunoassays whereas those in ORF-P caused significant decline in viral replication. Impairment in Enhancer-II and X-promoter activities were noted due to occult-associated mutations that generated reduced pregenomic RNA and intracellular HBV-DNA. Additionally, Enhancer-II mutations altered the small to large surface protein ratio and diminished extracellular HBV-DNA and HBsAg secretion. Further, mutations in PreS2, X and enhancer-II increased Grp78-promoter activity, suggesting that OHBV could trigger endoplasmic reticulum stress. Thus viral mutations contribute synergistically towards the genesis of occult phenotype and disease progression.
Evidence for deficient motor planning in ADHD
Authors: Dahan Anat , Reiner Miriam 
Published: August 2017

AbstractWe compare motor planning mechanisms of ADHD and control subjects based on their effect on later observed kinematic characteristics. We monitor hand movement following planning conditions that differ in preparation time, and evaluate the differences across conditions and participants with/without ADHD. Our findings show that when there is sufficient planning time, people without ADHD seem to have a motor plan ready, and immediately initiate a planned movement after a ‘GO’ cue, with a bell shaped velocity profile. When planning time is not sufficient, they start the movement in a delayed time, possibly indicating that they needed to complete a movement plan. However, people with ADHD, did not start movement immediately after the cue, even when provided with a long preparation time, possibly indicating that even for this planning interval they did not have a motion plan ready. The movement was not only delayed, its velocity profile was not bell shaped and had several peaks. We further found differences between control and ADHD participants in the velocity profile, variability and jitter of movements. Our results suggest that ADHD motion characteristics, are associated with an immature motor plan. Based on the results we propose a paradigm to evaluate deficiencies in motor planning.
Ape1 guides DNA repair pathway choice that is associated with drug tolerance in glioblastoma
Authors: Ströbel Thomas , Madlener Sibylle , Tuna Serkan , Vose Sarah , Lagerweij Tonny , Wurdinger Thomas , Vierlinger Klemens , Wöhrer Adelheid , Price Brendan D. , Demple Bruce , Saydam Okay , Saydam Nurten 
Published: August 2017

AbstractApe1 is the major apurinic/apyrimidinic (AP) endonuclease activity in mammalian cells, and a key factor in base-excision repair of DNA. High expression or aberrant subcellular distribution of Ape1 has been detected in many cancer types, correlated with drug response, tumor prognosis, or patient survival. Here we present evidence that Ape1 facilitates BRCA1-mediated homologous recombination repair (HR), while counteracting error-prone non-homologous end joining of DNA double-strand breaks. Furthermore, Ape1, coordinated with checkpoint kinase Chk2, regulates drug response of glioblastoma cells. Suppression of Ape1/Chk2 signaling in glioblastoma cells facilitates alternative means of damage site recruitment of HR proteins as part of a genomic defense system. Through targeting “HR-addicted” temozolomide-resistant glioblastoma cells via a chemical inhibitor of Rad51, we demonstrated that targeting HR is a promising strategy for glioblastoma therapy. Our study uncovers a critical role for Ape1 in DNA repair pathway choice, and provides a mechanistic understanding of DNA repair-supported chemoresistance in glioblastoma cells.
Agile Blocker and Clock Jitter Tolerant Low-Power Frequency Selective Receiver with Energy Harvesting Capability
Authors: Hasan Abul , Helaoui Mohamed , Ghannouchi Fadhel M. 
Published: August 2017

AbstractIn this article, a novel tunable, blocker and clock jitter tolerant, low power, quadrature phase shift frequency selective (QPS-FS) receiver with energy harvesting capability is proposed. The receiver’s design embraces and integrates (i) the baseband to radio frequency (RF) impedance translation concept to improve selectivity over that of conventional homodyne receiver topologies and (ii) broadband quadrature phase shift circuitry in the RF path to remove an active multi-phase clock generation circuit in passive mixer (PM) receivers. The use of a single local oscillator clock signal with a passive clock division network improves the receiver’s robustness against clock jitter and reduces the source clock frequency by a factor of N, compared to PM receivers using N switches (N≥4). As a consequence, the frequency coverage of the QPS-FS receiver is improved by a factor of N, given a clock source of maximum frequency; and, the power consumption of the whole receiver system can eventually be reduced. The tunable QPS-FS receiver separates the wanted RF band signal from the unwanted blockers/interferers. The desired RF signal is frequency down-converted to baseband, while the undesired blocker/interferer signals are reflected by the receiver, collected and could be energy recycled using an auxiliary energy harvesting device.
Orientation anisotropy of quantitative MRI relaxation parameters in ordered tissue
Authors: Hänninen Nina , Rautiainen Jari , Rieppo Lassi , Saarakkala Simo , Nissi Mikko Johannes 
Published: August 2017

AbstractIn highly organized tissues, such as cartilage, tendons and white matter, several quantitative MRI parameters exhibit dependence on the orientation of the tissue constituents with respect to the main imaging magnetic field (B0). In this study, we investigated the dependence of multiple relaxation parameters on the orientation of articular cartilage specimens in the B0. Bovine patellar cartilage-bone samples (n = 4) were investigated ex vivo at 9.4 Tesla at seven different orientations, and the MRI results were compared with polarized light microscopy findings on specimen structure. Dependences of T2 and continuous wave (CW)-T1ρ relaxation times on cartilage orientation were confirmed. T2 (and T2*) had the highest sensitivity to orientation, followed by TRAFF2 and adiabatic T2ρ. The highest dependence was seen in the highly organized deep cartilage and the smallest in the least organized transitional layer. Increasing spin-lock amplitude decreased the orientation dependence of CW-T1ρ. T1 was found practically orientation-independent and was closely followed by adiabatic T1ρ. The results suggest that T1 and adiabatic T1ρ should be preferred for orientation-independent quantitative assessment of organized tissues such as articular cartilage. On the other hand, based on the literature, parameters with higher orientation anisotropy appear to be more sensitive to degenerative changes in cartilage.