bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic plasticity and rapid host switching can promote the evolution of generalism: a case study in the zoonotic pathogen Campylobacter
Authors: Woodcock Dan J. , Krusche Peter , Strachan Norval J. C. , Forbes Ken J. , Cohan Frederick M. , Méric Guillaume , Sheppard Samuel K.
Published: August 2017

Horizontal gene transfer accelerates bacterial adaptation to novel environments, allowing selection to act on genes that have evolved in multiple genetic backgrounds. This can lead to ecological specialization. However, little is known about how zoonotic bacteria maintain the ability to colonize multiple hosts whilst competing with specialists in the same niche. Here we develop a stochastic evolutionary model and show how genetic transfer of host segregating alleles, distributed as predicted for niche specifying genes, and the opportunity for host transition could interact to promote the emergence of host generalist lineages of the zoonotic bacterium Campylobacter. Using a modelling approach we show that increasing levels of homologous recombination enhance the efficiency with which selection can fix combinations of beneficial alleles, speeding adaptation. We then show how these predictions change in a multi-host system, with low levels of recombination, consistent with real r/m estimates, increasing the standing variation in the population, allowing a more effective response to changes in the selective landscape. Our analysis explains how observed gradients of host specialism and generalism can evolve in a multihost system through the transfer of ecologically important loci among coexisting strains.
Embodiment in a Child-Like Talking Virtual Body Influences Object Size Perception, Self-Identification, and Subsequent Real Speaking
Authors: Tajadura-Jiménez Ana , Banakou Domna , Bianchi-Berthouze Nadia , Slater Mel
Published: August 2017

People’s mental representations of their own body are malleable and continuously updated through sensory cues. Altering one’s body-representation can lead to changes in object perception and implicit attitudes. Virtual reality has been used to embody adults in the body of a 4-year-old child or a scaled-down adult body. Child embodiment was found to cause an overestimation of object sizes, approximately double that during adult embodiment, and identification of the self with child-like attributes. Here we tested the contribution of auditory cues related to one’s own voice to these visually-driven effects. In a 2 × 2 factorial design, visual and auditory feedback on one’s own body were varied across conditions, which included embodiment in a child or scaled-down adult body, and real (undistorted) or child-like voice feedback. The results replicated, in an older population, previous findings regarding size estimations and implicit attitudes. Further, although auditory cues were not found to enhance these effects, we show that the strength of the embodiment illusion depends on the child-like voice feedback being congruent or incongruent with the age of the virtual body. Results also showed the positive emotional impact of the illusion of owning a child’s body, opening up possibilities for health applications.
Hypertension Susceptibility Loci are Associated with Anthracycline-related Cardiotoxicity in Long-term Childhood Cancer Survivors
Authors: Hildebrandt Michelle A. T. , Reyes Monica , Wu Xifeng , Pu Xia , Thompson Kara A. , Ma Jianzhong , Landstrom Andrew P. , Morrison Alanna C. , Ater Joann L.
Published: August 2017

Anthracycline-based chemotherapy is associated with dose-dependent, irreversible damage to the heart. Childhood cancer survivors with hypertension after anthracycline exposure are at increased risk of cardiotoxicity, leading to the hypothesis that genetic susceptibility loci for hypertension may serve as predictors for development of late cardiotoxicity. Therefore, we determined the association between 12 GWAS-identified hypertension-susceptibility loci and cardiotoxicity in a cohort of long-term childhood cancer survivors (N = 108) who received anthracyclines and were screened for cardiac function via echocardiograms. Hypertension-susceptibility alleles of PLCE1:rs9327264 and ATP2B1:rs17249754 were significantly associated with cardiotoxicity risk conferring a protective effect with a 64% (95% CI: 0.18–0.76, P = 0.0068) and 74% (95% CI: 0.07–0.96, P = 0.040) reduction in risk, respectively. In RNAseq experiments of human induced pluripotent stem cell (iPSC) derived cardiomyocytes treated with doxorubicin, both PLCE1 and ATP2B1 displayed anthracycline-dependent gene expression profiles. In silico functional assessment further supported this relationship - rs9327264 in PLCE1 (P = 0.0080) and ATP2B1 expression (P = 0.0079) were both significantly associated with daunorubicin IC50 values in a panel of lymphoblastoid cell lines. Our findings demonstrate that the hypertension-susceptibility variants in PLCE1 and ATP2B1 confer a protective effect on risk of developing anthracycline-related cardiotoxicity, and functional analyses suggest that these genes are influenced by exposure to anthracyclines.
Evaluating the role of coherent delocalized phonon-like modes in DNA cyclization
Authors: Alexandrov Ludmil B. , Rasmussen Kim Ø. , Bishop Alan R. , Alexandrov Boian S.
Published: August 2017

The innate flexibility of a DNA sequence is quantified by the Jacobson-Stockmayer’s J-factor, which measures the propensity for DNA loop formation. Recent studies of ultra-short DNA sequences revealed a discrepancy of up to six orders of magnitude between experimentally measured and theoretically predicted J-factors. These large differences suggest that, in addition to the elastic moduli of the double helix, other factors contribute to loop formation. Here, we develop a new theoretical model that explores how coherent delocalized phonon-like modes in DNA provide single-stranded ”flexible hinges” to assist in loop formation. We combine the Czapla-Swigon-Olson structural model of DNA with our extended Peyrard-Bishop-Dauxois model and, without changing any of the parameters of the two models, apply this new computational framework to 86 experimentally characterized DNA sequences. Our results demonstrate that the new computational framework can predict J-factors within an order of magnitude of experimental measurements for most ultra-short DNA sequences, while continuing to accurately describe the J-factors of longer sequences. Further, we demonstrate that our computational framework can be used to describe the cyclization of DNA sequences that contain a base pair mismatch. Overall, our results support the conclusion that coherent delocalized phonon-like modes play an important role in DNA cyclization.
One-reactor plasma assisted fabrication of ZnO@TiO
2
multishell nanotubes: assessing the impact of a full coverage on the photovoltaic performance
Authors: Filippin Alejandro Nicolas , Macias-Montero Manuel , Saghi Zineb , Idígoras Jesús , Burdet Pierre , Sanchez-Valencia Juan R. , Barranco Angel , Migdley Paul A. , Anta Juan A. , Borras Ana
Published: August 2017

This paper addresses the fabrication of vertically aligned ZnO@TiO2 multishell nanotubes by a combined full vacuum-plasma approach at mild temperatures. The growth is carried out within the premises of a one-reactor approach, i.e. minimizing the number of vacuum chambers and sample transferences. In this way, the interface between ZnO and TiO2 is fully preserved from humidity thus increasing ZnO durability and stability. These nanostructures are studied by scanning electron microscopy (SEM), scanning transmission electron microscopy (STEM) and energy dispersive X-ray spectroscopy in STEM (EDX-STEM). High density one-dimensional arrays of these nanotubes formed on FTO substrates are applied as photoanode in a dye-sensitized solar cell (DSC). The evolution of the dye adsorption capacity and solar cells parameters are explored as a function of the crystallinity and thickness of the TiO2 shell. The results show the critical effect of a full coverage by TiO2 of ZnO core to explain the mixed results found in the literature.
A heart-coronary arteries structure of carbon nanofibers/graphene/silicon composite anode for high performance lithium ion batteries
Authors: Ma Xiaoxin , Hou Guangmei , Ai Qing , Zhang Lin , Si Pengchao , Feng Jinkui , Ci Lijie
Published: August 2017

In an animal body, coronary arteries cover around the whole heart and supply the necessary oxygen and nutrition so that the heart muscle can survive as well as can pump blood in and out very efficiently. Inspired by this, we have designed a novel heart-coronary arteries structured electrode by electrospinning carbon nanofibers to cover active anode graphene/silicon particles. Electrospun high conductive nanofibers serve as veins and arteries to enhance the electron transportation and improve the electrochemical properties of the active “heart” particles. This flexible binder free carbon nanofibers/graphene/silicon electrode consists of millions of heart-coronary arteries cells. Besides, in the graphene/silicon “hearts”, graphene network improves the electrical conductivity of silicon nanopaticles, buffers the volume change of silicon, and prevents them from directly contacting with electrolyte. As expected, this novel composite electrode demonstrates excellent lithium storage performance with a 86.5% capacity retention after 200 cycles, along with a high rate performance with a 543 mAh g−1 capacity at the rate of 1000 mA g−1.
A new route to enhance the ferromagnetic transition temperature in diluted magnetic semiconductors
Authors: Pradhan Kalpataru , Das Subrat K.
Published: August 2017

We investigate the magnetic and the transport properties of diluted magnetic semiconductors using a spin-fermion Monte-Carlo method on a simple cubic lattice in the intermediate coupling regime. The ferromagnetic transition temperature Tc shows an optimization behavior with respect to the absolute carrier density pabs and the magnetic impurity concentration x as seen in the experiments. Our calculations also show an insulator-metal-insulator transition across the optimum pabs where the Tc is maximum. Remarkably, the optimum pabs values lie in a narrow range around 0.11 (holes/site) for all x values and the ferromagnetic Tc increases with x. We explain our results using the polaron percolation mechanism and outline a new route to enhance the ferromagnetic transition temperature in experiments.
Anosmia impairs homing orientation but not foraging behaviour in free-ranging shearwaters
Authors: Padget O. , Dell’Ariccia G. , Gagliardo A. , González-Solís J. , Guilford T.
Published: August 2017

Shearwaters deprived of their olfactory sense before being displaced to distant sites have impaired homing ability but it is unknown what the role of olfaction is when birds navigate freely without their sense of smell. Furthermore, treatments used to induce anosmia and to disrupt magneto-reception in displacement experiments might influence non-specific factors not directly related to navigation and, as a consequence, the results of displacement experiments can have multiple interpretations. To address this, we GPS-tracked the free-ranging foraging trips of incubating Scopoli’s shearwaters within the Mediterranean Sea. As in previous experiments, shearwaters were either made anosmic with 4% zinc sulphate solution, magnetically impaired by attachment of a strong neodymium magnet or were controls. We found that birds from all three treatments embarked on foraging trips, had indistinguishable at-sea schedules of behaviour and returned to the colony having gained mass. However, we found that in the pelagic return stage of their foraging trips, anosmic birds were not oriented towards the colony though coastal navigation was unaffected. These results support the case for zinc sulphate having a specific effect on the navigational ability of shearwaters and thus the view that seabirds consult an olfactory map to guide them across seascapes.
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

Tigers 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

Side 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

Gene 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

Cardiac 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

Pregnancies 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

Nucleotide 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

In 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

Clostridium 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

We 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

Zaire 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

We 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

We 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

Ape1 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

In 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

In 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.
Investigation of beam splitter in a zero-refractive-index photonic crystal at the frequency of Dirac-like point
Authors: Qiu Pingping , Qiu Weibin , Lin Zhili , Chen Houbo , Ren Junbo , Wang Jia-Xian , Kan Qiang , Pan Jiao-Qing
Published: August 2017

The Dirac-like cone dispersion of the photonic crystal induced by the three-fold accidental degeneracy at the Brillouin center is calculated in this paper. Such photonic crystals can be mapped to zero-refractive-index materials at the vicinity of the Dirac-like point frequency, and utilized to construct beam splitter of high transmission efficiency. The splitting ratio is studied as a function of the position of the input/output waveguides. Furthermore, variant beam splitters with asymmetric structures, bulk defects, and some certain bending angles are numerically simulated. Finally, we show that 1 × 2 to 1 × N beam splitting can be realized with high transmission efficiency in such a zero-refractive-index photonic crystal at the frequency of Dirac-like point. The proposed structure could be a fundamental component of the high density photonic integrated circuit technique.
Connecting individual to collective cell migration
Authors: George Mishel , Bullo Francesco , Campàs Otger
Published: August 2017

Collective cell migration plays a pivotal role in the formation of organs, tissue regeneration, wound healing and many disease processes, including cancer. Despite the considerable existing knowledge on the molecular control of cell movements, it is unclear how the different observed modes of collective migration, especially for small groups of cells, emerge from the known behaviors of individual cells. Here we derive a physical description of collective cellular movements from first principles, while accounting for known phenomenological cell behaviors, such as contact inhibition of locomotion and force-induced cell repolarization. We show that this theoretical description successfully describes the motion of groups of cells of arbitrary numbers, connecting single cell behaviors and parameters (e.g., adhesion and traction forces) to the collective migration of small groups of cells and the expansion of large cell colonies. Specifically, using a common framework, we explain how cells characterized by contact inhibition of locomotion can display coherent collective behavior when in groups, even in the absence of biochemical signaling. We find an optimal group size leading to maximal group persistence and show that cell proliferation prevents the buildup of intercellular forces within cell colonies, enabling their expansion.
Development of an Affimer-antibody combined immunological diagnosis kit for glypican-3
Authors: Xie Chunmei , Tiede Christian , Zhang Xuanyi , Wang Congrong , Li Zhixiong , Xu Xiao , McPherson Michael J. , Tomlinson Darren C. , Xu Weiwen
Published: August 2017

Glypican-3 (GPC3) is a promising new marker for hepatocellular carcinoma, but the reported values for serum GPC3 differ markedly between currently available kits. Here we isolated Affimer non-antibody binding proteins against GPC3 by phage display and developed a new sandwich chemiluminescence immunoassay (CLIA) combining an Affimer with a monoclonal antibody (Affimer-MAb CLIA). The proposed CLIA assay demonstrated a wide linear range  0.03–600 ng/mL) with a good linear correlation coefficient (0.9999), a high detection limitation (0.03 ng/mL) and specificity (0–0.002%) for detection of GPC3. The accuracy, hook effect and stability were demonstrated to be satisfactory. The mean level of GPC3 in serum was higher (>8.5 fold, P < 0.001) in hepatocellular carcinoma patients compared to healthy and other liver disease individuals. A poor correlation (correlation coefficients ranged from −0.286 to 0.478) was observed through pairwise comparison within different kits. However, only this newly developed CLIA test showed high specificity and correlated with the “gold standard” GPC3-immunohistochemistry. This study indicates that Affimer-MAb CLIA can be used to generate a sensitive immunodiagnostic kit, which offers the potential for a highly specific clinically-relevant detection system.
External validation of the NUn score for predicting anastomotic leakage after oesophageal resection
Authors: Paireder Matthias , Jomrich Gerd , Asari Reza , Kristo Ivan , Gleiss Andreas , Preusser Matthias , Schoppmann Sebastian F.
Published: August 2017

Early detection of anastomotic leakage (AL) after oesophageal resection for malignancy is crucial. This retrospective study validates a risk score, predicting AL, which includes C-reactive protein, albumin and white cell count in patients undergoing oesophageal resection between 2003 and 2014. For validation of the NUn score a receiver operating characteristic (ROC) curve is estimated. Area under the ROC curve (AUC) is reported with 95% confidence interval (CI). Among 258 patients (79.5% male) 32 patients showed signs of anastomotic leakage (12.4%). NUn score in our data has a median of 9.3 (range 6.2–17.6). The odds ratio for AL was 1.31 (CI 1.03–1.67; p = 0.028). AUC for AL was 0.59 (CI 0.47–0.72). Using the original cutoff value of 10, the sensitivity was 45.2% an the specificity was 73.8%. This results in a positive predictive value of 19.4% and a negative predictive value of 90.6%. The proportion of variation in AL occurrence, which is explained by the NUn score, was 2.5% (PEV = 0.025). This study provides evidence for an external validation of a simple risk score for AL after oesophageal resection. In this cohort, the NUn score is not useful due to its poor discrimination.
Association between selected antimicrobial resistance genes and antimicrobial exposure in Danish pig farms
Authors: Birkegård Anna Camilla , Halasa Tariq , Græsbøll Kaare , Clasen Julie , Folkesson Anders , Toft Nils
Published: August 2017

Bacterial antimicrobial resistance (AMR) in pigs is an important public health concern due to its possible transfer to humans. We aimed at quantifying the relationship between the lifetime exposure of antimicrobials and seven antimicrobial resistance genes in Danish slaughter pig farms. AMR gene levels were quantified by qPCR of total-community DNA in faecal samples obtained from 681 batches of slaughter pigs. The lifetime exposure to antimicrobials was estimated at batch level for the piglet, weaner, and finisher periods individually for the sampled batches. We showed that the effect of antimicrobial exposure on the levels of AMR genes was complex and unique for each individual gene. Several antimicrobial classes had both negative and positive correlations with the AMR genes. From 10–42% of the variation in AMR gene levels could be explained in the final regression models, indicating that antimicrobial exposure is not the only important determinant of the AMR gene levels.
TCA cycle rewiring fosters metabolic adaptation to oxygen restriction in skeletal muscle from rodents and humans
Authors: Capitanio Daniele , Fania Chiara , Torretta Enrica , Viganò Agnese , Moriggi Manuela , Bravatà Valentina , Caretti Anna , Levett Denny Z. H. , Grocott Michael P. W. , Samaja Michele , Cerretelli Paolo , Gelfi Cecilia
Published: August 2017

In mammals, hypoxic stress management is under the control of the Hypoxia Inducible Factors, whose activity depends on the stabilization of their labile α subunit. In particular, the skeletal muscle appears to be able to react to changes in substrates and O2 delivery by tuning its metabolism. The present study provides a comprehensive overview of skeletal muscle metabolic adaptation to hypoxia in mice and in human subjects exposed for 7/9 and 19 days to high altitude levels. The investigation was carried out combining proteomics, qRT-PCR mRNA transcripts analysis, and enzyme activities assessment in rodents, and protein detection by antigen antibody reactions in humans and rodents. Results indicate that the skeletal muscle react to a decreased O2 delivery by rewiring the TCA cycle. The first TCA rewiring occurs in mice in 2-day hypoxia and is mediated by cytosolic malate whereas in 10-day hypoxia the rewiring is mediated by Idh1 and Fasn, supported by glutamine and HIF-2α increments. The combination of these specific anaplerotic steps can support energy demand despite HIFs degradation. These results were confirmed in human subjects, demonstrating that the TCA double rewiring represents an essential factor for the maintenance of muscle homeostasis during adaptation to hypoxia.
The MC4R genotype is associated with postpartum weight reduction and glycemic changes among women with prior gestational diabetes: longitudinal analysis
Authors: de Carvalho Aline Martins , Shao Ping , Liu Huikun , Cheng Han-Ling , Zheng Yan , Leng Junhong , Li Weiqin , Huang Tao , Wang Tiange , Wang Leishen , Zhang Shuang , Hu Gang , Qi Lu
Published: August 2017

The genetic variants near the Melanocortin-4 receptor gene (MC4R), a key protein regulating energy balance and adiposity, have been related to obesity and glucose metabolism. We aimed to assess whether the MC4R genotype affected longitudinal changes in body weight and glucose metabolism biomarkers among women with prior gestational diabetes mellitus (GDM). The MC4R genotype, postpartum weight reduction, and glycemic changes between after delivery and pregnancy were assessed in a cohort of 1208 Chinese women who had experienced GDM. The adiposity-increasing allele (C) of the MC4R variant rs6567160 was associated with greater postpartum increase of HbA1c (β = 0.08%; P = 0.03) and 2-hour OGTT glucose concentrations (β = 0.25 mmol/L; P = 0.02). In addition, we found an interaction between the MC4R genotype and postpartum weight reduction on changes in fasting plasma glucose (P-interaction = 0.03). We found that the MC4R genotype was associated with postpartum glycemic changes; and the association with fasting glucose were significantly modified by postpartum weight reduction in women who had experienced GDM.
Prognosis of HIV Patients Receiving Antiretroviral Therapy According to CD4 Counts: A Long-term Follow-up study in Yunnan, China
Authors: Ren Li , Li Juan , Zhou Shiyi , Xia Xueshan , Xie Zhenrong , Liu Pan , Xu Yu , Qian Yuan , Zhang Huifeng , Ma Litang , Pan Qiuwei , Wang Kunhua
Published: August 2017

We aim to evaluate the overall survival and associated risk factors for HIV-infected Chinese patients on antiretroviral therapy (ART). 2517 patients receiving ART between 2006 and 2016 were prospectively enrolled in Yunnan province. Kaplan-Meier analyses and Cox proportional hazard regression analyses were performed. 216/2517 patients died during a median 17.5 (interquartile range [IQR] 6.8–33.2) months of follow-up. 82/216 occurred within 6 months of starting ART. Adjusted hazard ratios were10.69 (95%CI 2.38–48.02, p = 0.002) for old age, 1.94 (95%CI 1.40–2.69, p < 0.0001) for advanced WHO stage, and 0.42 (95%CI 0.27–0.63, p < 0.0001) for heterosexual transmission compared to injecting drug users. Surprisingly, adjusted hazard ratios comparing low CD4 counts group (<50 cells/µl) with high CD4 counts group (≥500 cells/µl) within six months after starting ART was 20.17 (95%CI 4.62–87.95, p < 0.0001) and it declined to 3.57 (95%CI 1.10–11.58, p = 0.034) afterwards. Age, WHO stage, transmission route are significantly independent risk factors for ART treated HIV patients. Importantly, baseline CD4 counts is strongly inversely associated with survival in the first six months; whereas it becomes a weak prognostic factor after six months of starting ART.