bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide association study results for educational attainment aid in identifying genetic heterogeneity of schizophrenia
Authors: Bansal V. , Mitjans M. , Burik C. A. P. , Linnér R. K. , Okbay A. , Rietveld C. A. , Begemann M. , Bonn S. , Ripke S. , de Vlaming R. , Nivard M. G. , Ehrenreich H. , Koellinger P. D.
Published: July 2018

Higher educational attainment (EA) is negatively associated with schizophrenia (SZ). However, recent studies found a positive genetic correlation between EA and SZ. We investigate possible causes of this counterintuitive finding using genome-wide association study results for EA and SZ (N = 443,581) and a replication cohort (1169 controls; 1067 cases) with deeply phenotyped SZ patients. We find strong genetic dependence between EA and SZ that cannot be explained by chance, linkage disequilibrium, or assortative mating. Instead, several genes seem to have pleiotropic effects on EA and SZ, but without a clear pattern of sign concordance. Using EA as a proxy phenotype, we isolateFOXO6andSLITRK1as novel candidate genes for SZ. Our results reveal that current SZ diagnoses aggregate over at least two disease subtypes: one part resembles high intelligence and bipolar disorder (BIP), while the other part is a cognitive disorder that is independent of BIP.
Sleep-dependent reconsolidation after memory destabilization in starlings
Authors: Brawn Timothy P. , Nusbaum Howard C. , Margoliash Daniel
Published: July 2018

Reconsolidation theory describes memory formation as an ongoing process that cycles between labile and stable states. Though sleep is critical for the initial consolidation of a memory, there has been little evidence that sleep facilitates reconsolidation. We now demonstrate in two experiments that a sleep-consolidated memory can be destabilized if the memory is reactivated by retrieval. The destabilized memory, which can be impaired if an interference task is encountered after, but not before, the memory is reactivated, is then reconsolidated after sleep. In two additional experiments, we provide evidence suggesting that the learning of the interference task promotes the subsequent sleep-dependent enhancement of the original memory. These results provide novel insight into the complex mechanisms of memory processing, as well as critical evidence supporting the view that long-term memory formation involves a dynamic process of sleep-dependent consolidation, use-dependent destabilization, and sleep-dependent reconsolidation.
Social interactions impact on the dopaminergic system and drive individuality
Authors: Torquet N. , Marti F. , Campart C. , Tolu S. , Nguyen C. , Oberto V. , Benallaoua M. , Naudé J. , Didienne S. , Debray N. , Jezequel S. , Le Gouestre L. , Hannesse B. , Mariani J. , Mourot A. , Faure P.
Published: July 2018

Individuality is a striking feature of animal behavior. Individual animals differ in traits and preferences which shape their interactions and their prospects for survival. However, the mechanisms underlying behavioral individuation are poorly understood and are generally considered to be genetic-based. Here, we devised a large environment, Souris City, in which mice live continuously in large groups. We observed the emergence of individual differences in social behavior, activity levels, and cognitive traits, even though the animals had low genetic diversity (inbred C57BL/6J strain). We further show that the phenotypic divergence in individual behaviors was mirrored by developing differences in midbrain dopamine neuron firing properties. Strikingly, modifying the social environment resulted in a fast re-adaptation of both the animal’s traits and its dopamine firing pattern. Individuality can rapidly change upon social challenges, and does not just depend on the genetic status or the accumulation of small differences throughout development.
Potential-induced nanoclustering of metallic catalysts during electrochemical CO2 reduction
Authors: Huang Jianfeng , Hörmann Nicolas , Oveisi Emad , Loiudice Anna , De Gregorio Gian Luca , Andreussi Oliviero , Marzari Nicola , Buonsanti Raffaella
Published: July 2018

In catalysis science stability is as crucial as activity and selectivity. Understanding the degradation pathways occurring during operation and developing mitigation strategies will eventually improve catalyst design, thus facilitating the translation of basic science to technological applications. Herein, we reveal the unique and general degradation mechanism of metallic nanocatalysts during electrochemical CO2 reduction, exemplified by different sized copper nanocubes. We follow their morphological evolution during operation and correlate it with the electrocatalytic performance. In contrast with the most common coalescence and dissolution/precipitation mechanisms, we find a potential-driven nanoclustering to be the predominant degradation pathway. Grand-potential density functional theory calculations confirm the role of the negative potential applied to reduce CO2 as the main driving force for the clustering. This study offers a novel outlook on future investigations of stability and degradation reaction mechanisms of nanocatalysts in electrochemical CO2 reduction and, more generally, in electroreduction reactions.
Molecular insights into antibiotic resistance - how a binding protein traps albicidin
Authors: Rostock Lida , Driller Ronja , Grätz Stefan , Kerwat Dennis , von Eckardstein Leonard , Petras Daniel , Kunert Maria , Alings Claudia , Schmitt Franz-Josef , Friedrich Thomas , Wahl Markus C. , Loll Bernhard , Mainz Andi , Süssmuth Roderich D.
Published: July 2018

The worldwide emergence of antibiotic resistance poses a serious threat to human health. A molecular understanding of resistance strategies employed by bacteria is obligatory to generate less-susceptible antibiotics. Albicidin is a highly potent antibacterial compound synthesized by the plant-pathogenic bacterium Xanthomonas albilineans. The drug-binding protein AlbA confers albicidin resistance to Klebsiella oxytoca. Here we show that AlbA binds albicidin with low nanomolar affinity resulting in full inhibition of its antibacterial activity. We report on the crystal structure of the drug-binding domain of AlbA (AlbAS) in complex with albicidin. Both α-helical repeat domains of AlbAS are required to cooperatively clamp albicidin, which is unusual for drug-binding proteins of the MerR family. Structure-guided NMR binding studies employing synthetic albicidin derivatives give valuable information about ligand promiscuity of AlbAS. Our findings thus expand the general understanding of antibiotic resistance mechanisms and support current drug-design efforts directed at more effective albicidin analogs.
Synthetic microbe communities provide internal reference standards for metagenome sequencing and analysis
Authors: Hardwick Simon A. , Chen Wendy Y. , Wong Ted , Kanakamedala Bindu S. , Deveson Ira W. , Ongley Sarah E. , Santini Nadia S. , Marcellin Esteban , Smith Martin A. , Nielsen Lars K. , Lovelock Catherine E. , Neilan Brett A. , Mercer Tim R.
Published: July 2018

The complexity of microbial communities, combined with technical biases in next-generation sequencing, pose a challenge to metagenomic analysis. Here, we develop a set of internal DNA standards, termed “sequins” (sequencing spike-ins), that together constitute a synthetic community of artificial microbial genomes. Sequins are added to environmental DNA samples prior to library preparation, and undergo concurrent sequencing with the accompanying sample. We validate the performance of sequins by comparison to mock microbial communities, and demonstrate their use in the analysis of real metagenome samples. We show how sequins can be used to measure fold change differences in the size and structure of accompanying microbial communities, and perform quantitative normalization between samples. We further illustrate how sequins can be used to benchmark and optimize new methods, including nanopore long-read sequencing technology. We provide metagenome sequins, along with associated data sets, protocols, and an accompanying software toolkit, as reference standards to aid in metagenomic studies.
An atmospheric chronology for the glacial-deglacial Eastern Equatorial Pacific
Authors: Zhao Ning , Keigwin Lloyd D.
Published: July 2018

Paleoclimate reconstructions are only as good as their chronology. In particular, different chronological assumptions for marine sediment cores can lead to different reconstructions of ocean ventilation age and atmosphere−ocean carbon exchange history. Here we build the first high-resolution chronology that is free of the dating uncertainties common in marine sediment records, based on radiocarbon dating twigs found with computed tomography scans in two cores from the Eastern Equatorial Pacific (EEP). With this accurate chronology, we show that the ventilation ages of the EEP thermocline and intermediate waters were similar to today during the Last Glacial Maximum and deglaciation, in contradiction with previous studies. Our results suggest that the glacial respired carbon pool in the EEP was not significantly older than today, and that the deglacial strengthening of the equatorial Pacific carbon source was probably driven by low-latitude processes rather than an increased subsurface supply of upwelled carbon from high-latitude oceans.
NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer
Authors: Ludlow Andrew T. , Wong Mandy Sze , Robin Jerome D. , Batten Kimberly , Yuan Laura , Lai Tsung-Po , Dahlson Nicole , Zhang Lu , Mender Ilgen , Tedone Enzo , Sayed Mohammed E. , Wright Woodring E. , Shay Jerry W.
Published: July 2018

Alternative splicing is dysregulated in cancer and the reactivation of telomerase involves the splicing of TERT transcripts to produce full-length (FL) TERT. Knowledge about the splicing factors that enhance or silence FL hTERT is lacking. We identified splicing factors that reduced telomerase activity and shortened telomeres using a siRNA minigene reporter screen and a lung cancer cell bioinformatics approach. A lead candidate, NOVA1, when knocked down resulted in a shift in hTERT splicing to non-catalytic isoforms, reduced telomerase activity, and progressive telomere shortening. NOVA1 knockdown also significantly altered cancer cell growth in vitro and in xenografts. Genome engineering experiments reveal that NOVA1 promotes the inclusion of exons in the reverse transcriptase domain of hTERT resulting in the production of FL hTERT transcripts. Utilizing hTERT splicing as a model splicing event in cancer may provide new insights into potentially targetable dysregulated splicing factors in cancer.
Breast cancer diagnosed during pregnancy is associated with enrichment of non-silent mutations, mismatch repair deficiency signature and mucin mutations
Authors: Nguyen Bastien , Venet David , Azim Hatem A. , Brown David , Desmedt Christine , Lambertini Matteo , Majjaj Samira , Pruneri Giancarlo , Peccatori Fedro , Piccart Martine , Rothé Françoise , Sotiriou Christos
Published: July 2018

Breast cancer diagnosed during pregnancy (BCP) is a rare and highly challenging disease. To investigate the impact of pregnancy on the biology of breast cancer, we conducted a comparative analysis of a cohort of BCP patients and non-pregnant control patients by integrating gene expression, copy number alterations and whole genome sequencing data. We showed that BCP exhibit unique molecular characteristics including an enrichment of non-silent mutations, a higher frequency of mutations in mucin gene family and an enrichment of mismatch repair deficiency mutational signature. This provides important insights into the biology of BCP and suggests that these features may be implicated in promoting tumor progression during pregnancy. In addition, it provides an unprecedented resource for further understanding the biology of breast cancer in young women and how pregnancy could modulate tumor biology.
Unsupervised phase mapping of X-ray diffraction data by nonnegative matrix factorization integrated with custom clustering
Authors: Stanev Valentin , Vesselinov Velimir V. , Kusne A. Gilad , Antoszewski Graham , Takeuchi Ichiro , Alexandrov Boian S.
Published: July 2018

Analyzing large X-ray diffraction (XRD) datasets is a key step in high-throughput mapping of the compositional phase diagrams of combinatorial materials libraries. Optimizing and automating this task can help accelerate the process of discovery of materials with novel and desirable properties. Here, we report a new method for pattern analysis and phase extraction of XRD datasets. The method expands the Nonnegative Matrix Factorization method, which has been used previously to analyze such datasets, by combining it with custom clustering and cross-correlation algorithms. This new method is capable of robust determination of the number of basis patterns present in the data which, in turn, enables straightforward identification of any possible peak-shifted patterns. Peak-shifting arises due to continuous change in the lattice constants as a function of composition and is ubiquitous in XRD datasets from composition spread libraries. Successful identification of the peak-shifted patterns allows proper quantification and classification of the basis XRD patterns, which is necessary in order to decipher the contribution of each unique single-phase structure to the multi-phase regions. The process can be utilized to determine accurately the compositional phase diagram of a system under study. The presented method is applied to one synthetic and one experimental dataset and demonstrates robust accuracy and identification abilities.
Study on the Aging Mechanism of Boron Potassium Nitrate (BKNO3) for Sustainable Efficiency in Pyrotechnic Mechanical Devices
Authors: Lee Junwoo , Kim Taewan , Ryu Seung Un , Choi Kyoungwon , Ahn Gil Hwan , Paik Jong Gyu , Ryu Byungtae , Park Taiho , Won Yong Sun
Published: July 2018

The aging of propellants in PMDs is considered to be one of the primary factors affecting the performance of PMDs. Thus, studies on the aging mechanism of propellants, which have not yet been addressed extensively, pose a solution to securing the sustainable operation of PMDs. We characterized one of the most commonly used commercial propellants (boron potassium nitrate (BKNO3)) and investigated its aging mechanism rigorously. Based on thermal analyses, we demonstrate that the decomposition of laminac, a polymer binder, is the fastest spontaneous reaction. However, it will not self-initiate at a storage temperature as high as 120 °C. The effect of the humidity level was examined by characterizing BKNO3 samples prepared. The heat of reaction and the reaction rate decreased by 18% and 67% over 16 weeks of aging, respectively. This is attributed to the oxide shells on the surface of boron particles. The formation of oxide shells could be confirmed using X-ray photoelectron spectroscopy and transmission electron microscopy–energy dispersive spectroscopy. In conclusion, surface oxide formation with the aging of BKNO3 will decrease its propulsive efficiency; oxidation reduces the potential energy of the system and the resulting oxide decreases the reaction rate.
Enhanced Defluoridation Using Novel Millisphere Nanocomposite of La-Doped Li-Al Layered Double Hydroxides Supported by Polymeric Anion Exchanger
Authors: Cai Jianguo , Zhang Yanyang , Qian Yue , Shan Chao , Pan Bingcai
Published: July 2018

A novel nanocomposite bead LaLiAl-LDH@201 was fabricated by doping a small amount of La into nanocrystalline Li/Al layered double hydroxides (LDHs) pre-confined inside polystyrene anion exchanger D201 (LiAl-LDH@201). A systematic characterisation of the resultant LaLiAl-LDH@201 (XRD, SEM-EDS, TEM-EDS, and XPS) evidenced the successful incorporation of La into the Li/Al LDHs, with their interlayer distance expanded to allow more exchangeable sites for fluoride uptake. The resultant LaLiAl-LDH@201 showed high and stable defluoridation performance over a wide range of pH from 4 to 9. The superior uptake capacity and affinity for fluoride of LaLiAl-LDH@201 over LiAl-LDH@201 were driven by both the increased anion exchange capacity of the embedded LDHs and the specific La-F interaction evidenced via XPS and TEM-EDS characterisation. Fixed-bed column test confirmed that the working capacity of LaLiAl-LDH@201 for defluoridation of authentic fluoride-rich groundwater was nearly twice that of LiAl-LDH@201. The fluoride-loaded LaLiAl-LDH@201 could be conveniently regenerated in situ by using NaOH + NaCl binary solution, achieving desorption efficiency above 98%. Moreover, negligible capacity loss, La leaching, or structure alteration was observed after five adsorption-regeneration cycles, indicating the high stability of LaLiAl-LDH@201. Therefore, the novel millisphere nanocomposite LaLiAl-LDH@201 was promising for efficient defluoridation from water and wastewater.
Confronting species aesthetics with ecological functions in coral reef fish
Authors: Tribot Anne-Sophie , Carabeux Quentin , Deter Julie , Claverie Thomas , Villéger Sébastien , Mouquet Nicolas
Published: July 2018

The biodiversity crisis has spurred scientists to assess all facets of biodiversity so that stakeholders can establish protection programs. However, species that are perceived as beautiful receive more attention than less attractive species. This dynamic could have tremendous consequences on people’s willingness to preserve biodiversity. Coral reefs might be particularly affected by this issue as they are key ecosystems that provide many services, such as aesthetic and cultural benefits attracting millions of tourists each year. Here we show the results of an online photographic questionnaire completed by 8,000 participants whereby preferences were assessed for a set of 116 reef fishes. Based on these preferences, we compared the functional richness, i.e. the amount of functional space filled, by groups of fishes based on their perceived attractiveness. We present evidence indicating that the least attractive coral reef fishes have a much higher functional richness than the most attractive species. Our results highlight the extent to which species aesthetic values’ may be disconnected from their ecological values and could be misleading for conservation purposes. There is thus an urgent need to increase the attention of scientists and the general public towards less attractive species to better appreciate and protect the species that crucially support functional diversity in endangered ecosystems.
Development of an inducible anti-VEGF rAAV gene therapy strategy for the treatment of wet AMD
Authors: Reid Christopher A. , Nettesheim Emily R. , Connor Thomas B. , Lipinski Daniel M.
Published: July 2018

Vascular endothelial growth factor (VEGF) is a key mediator in the development and progression of choroidal neovascularization (CNV) in patients with wet age-related macular degeneration (AMD). As a consequence, current treatment strategies typically focus on the administration of anti-VEGF agents, such as Aflibercept (Eylea), that inhibit VEGF function. While this approach is largely successful at counteracting CNV progression, the treatment can require repetitive (i.e. monthly) intravitreal injections of the anti-VEGF agent throughout the patient’s lifetime, imposing a substantial financial and medical burden on the patient. Moreover, repetitive injection of anti-VEGF agents over a period of years may encourage progression of retinal and choroidal atrophy in patients with AMD, leading to a decrease in visual acuity. Herein, we have developed a single-injection recombinant adeno-associated virus (rAAV)-based gene therapy treatment for wet AMD that prevents CNV formation through inducible over-expression of Eylea. First, we demonstrate that by incorporating riboswitch elements into the rAAV expression cassette allows protein expression levels to be modulated in vivo through oral supplementation on an activating ligand (e.g. tetracycline). We subsequently utilized this technology to modulate the intraocular concentration of Eylea following rAAV delivery, leading to nearly complete (p = 0.0008) inhibition of clinically significant CNV lesions in an established mouse model of wet AMD. The results shown in this study pave the way for the development of a personalized gene therapy strategy for the treatment of wet AMD that is substantially less invasive and more clinically adaptable than the current treatment paradigm of repetitive bolus injections of anti-VEGF agents.
Author Correction: Electrical Conductivity Distribution in Detonating Benzotrifuroxane
Authors: Satonkina Nataliya , Ershov Alexander , Kashkarov Alexey , Mikhaylov Anatoly , Pruuel Eduard , Rubtsov Ivan , Spirin Ivan , Titova Victoria
Published: July 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Publisher Correction: Deletion of DDB1- and CUL4- associated factor-17 (Dcaf17) gene causes spermatogenesis defects and male infertility in mice
Authors: Ali Asmaa , Mistry Bhavesh V. , Ahmed Hala A. , Abdulla Razan , Amer Hassan A. , Prince Abdelbary , Alazami Anas M. , Alkuraya Fowzan S. , Assiri Abdullah
Published: July 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Spatial segregation of home ranges between neighbouring colonies in a diurnal raptor
Authors: Cecere Jacopo G. , Bondì Salvatore , Podofillini Stefano , Imperio Simona , Griggio Matteo , Fulco Egidio , Curcio Andrea , Ménard Delphine , Mellone Ugo , Saino Nicola , Serra Lorenzo , Sarà Maurizio , Rubolini Diego
Published: July 2018

Enhancement of information transfer has been proposed as a key driver of the evolution of coloniality. Transfer of information on location of food resources implies that individuals from the same colony share foraging areas and that each colony can be associated to a specific foraging area. In colonial breeding vertebrates, colony-specific foraging areas are often spatially segregated, mitigating intercolony intraspecific competition. By means of simultaneous GPS tracking of lesser kestrels (Falco naumanni) from neighbouring colonies, we showed a clear segregation of space use between individuals from different colonies. Foraging birds from different neighbouring colonies had home ranges that were significantly more segregated in space than expected by chance. This was the case both between large and between small neighbouring colonies. To our knowledge, the lesser kestrel is the only terrestrial species where evidence of spatial segregation of home ranges between conspecifics from neighbouring colonies has been demonstrated. The observed spatial segregation pattern is consistent with the occurrence of public information transfer about foraging areas and with the avoidance of overexploited areas located between neighbouring colonies. Our findings support the idea that spatial segregation of exploited areas may be widespread among colonial avian taxa, irrespective of colony size.
Tigecycline as a dual inhibitor of retinoblastoma and angiogenesis via inducing mitochondrial dysfunctions and oxidative damage
Authors: Xiong Ying , Liu Wei , Huang Qian , Wang Jierong , Wang Yanjun , Li Huijuan , Fu Xuedong
Published: July 2018

Retinoblastoma is the most common intraocular malignancy in children with poor prognosis. The progression of retinoblastoma is dependent on a robust angiogenic response. Targeting both retinoblastoma cells and angiogenesis may therefore provide an alternative therapeutic strategy in retinoblastoma. Here, we demonstrated the inhibitory effects of tigecycline, a FDA-approved antibiotic, in retinoblastoma and angiogenesis in vitro and in vivo. We showed that tigecycline significantly inhibited growth and induced caspase-dependent apoptosis of multiple retinoblastoma cell lines. Tigecycline also effectively inhibited angiogenesis through suppressing capillary network formation, migration, proliferation and survival of human retinal microvascular endothelial cell (HREC). Mechanistically, tigecycline acts on both retinoblastoma cells and HREC via inhibiting mitochondrial protein translation, resulting in mitochondrial dysfunction, energy crisis, and oxidative damage. Importantly, we demonstrated the in vivo efficacy of tigecycline in inhibiting retinoblastoma and angiogenesis, and inducing oxidative stress on xenograft mouse model. In addition, ATP levels and growth rates were largely affected in retinoblastoma ρ0 cells that lacked mitochondrial respiration. Our work provides systematic pre-clinical evidence for repurposing tigecycline from its traditional use for retinoblastoma treatment. Our work demonstrates the essential roles of mitochondrial metabolism in both retinoblastoma and its angiogenesis.
Estimation of the cancer risk induced by therapies targeting stem cell replication and treatment recommendations
Authors: Meyer-Hermann Michael
Published: July 2018

Rejuvenation of stem cell activity might increase life expectancy by prolonging functionality of organs. Higher stem cell replication rates also bear the risk of cancer. The extent of this risk is not known. While it is difficult to evaluate this cancer risk in experiments, it can be estimated using a mathematical model for tissue homeostasis by stem cell replication and associated cancer risk. The model recapitulates the observation that treatments targeting stem cell replication can induce a substantial delay of organ failure. The model predicts that the cancer risk is minor under particular conditions. It depends on the assumed implications for cell damage repair during treatment. The benefit of rejuvenation therapy and its impact on cancer risk depend on the biological age at the time of treatment and on the overall cell turnover rate of the organs. Different organs have to be considered separately in the planning of systemic treatments. In recent years, the transfer of blood from young to old individuals was shown to bear the potential of rejuvenation of stem cell activity. In this context, the model predicts that the treatment schedule is critical for success and that schedules successful in animal experiments are not transferable to humans. Guidelines for successful protocols are proposed. The model presented here may be used as a guidance for the development of stem cell rejuvenation treatment protocols and the identification of critical parameters for cancer risk.
Developmental auditory exposure shapes responses of catecholaminergic neurons to socially-modulated song
Authors: Barr Helena J. , Woolley Sarah C.
Published: July 2018

Developmental sensory experience is critical to the tuning of sensory systems and can shape perceptual abilities and their neural substrates. Neuromodulators, including catecholamines, contribute to sensory plasticity in both older and younger individuals and provide a mechanism for translating sensory experience into changes in brain and behavior. Less well known, however, is whether developmental sensory experience has lasting effects on the neuromodulatory neurons themselves. Here, we used female zebra finches to investigate the degree to which developmental auditory experience can have lasting effects on the density and sensory responsiveness of catecholamine-synthesizing neuron populations. We found that hearing courtship, but not non-courtship, song increased expression of the activity-dependent immediate early gene cFOS in dopamine neurons of the caudal ventral tegmental area (VTA) and this increase was dependent on whether females heard adult song during development. Developmental song exposure also affected the density of dopamine producing neurons in the rostral VTA. In contrast, song-evoked responses in noradrenergic neurons of the Locus Coeruleus were not affected by either developmental song exposure or the social context of the stimulus. These data highlight the lasting effects that developmental auditory experience can have in shaping both the density and sensory responsiveness of dopamine neuron populations.
PLVAP and GKN3 Are Two Critical Host Cell Receptors Which Facilitate Japanese Encephalitis Virus Entry Into Neurons
Authors: Mukherjee Sriparna , Sengupta Nabonita , Chaudhuri Ankur , Akbar Irshad , Singh Noopur , Chakraborty Sibani , Suryawanshi Amol Ratnakar , Bhattacharyya Arindam , Basu Anirban
Published: July 2018

Japanese Encephalitis Virus (JEV), a globally important pathogen, belongs to the family Flaviviridae, is transmitted between vertebrate hosts by mosquitoes, principally by Culex tritaeniorhynchus. The E-glycoprotein of the virus mediates its attachment to the host cell receptors. In this study, we cloned and purified JEV E-glycoprotein in pET28a vector using E. coli BL21 (DE3) cells. A pull down assay was performed using plasma membrane fraction of BALB/c mouse brain and E-glycoprotein as a bait protein. 2-Dimensional Gel Electrophoresis based separation of the interacting proteins was analyzed by mass spectrometry. Among all the identified partners of E-glycoprotein, PLVAP (Plasmalemma vesicle associated protein) and GKN3 (Gastrokine3) showed significant up-regulation in both JEV infected mouse brain and neuro2a cells. In-silico studies also predicted significant interaction of these receptors with E-glycoprotein. Additionally, overexperssion and silencing of these receptors resulted in increase and reduction in viral load respectively, suggesting them as two critical cellular receptors governing JEV entry and propagation in neurons. In support, we observed significant expression of PLVAP but not GKN3 in post-mortem autopsied human brain tissue. Our results establish two novel receptor proteins in neurons in case of JEV infection, thus providing potential targets for antiviral research.
Metabolic enhancers supporting 1-carbon cycle affect sperm functionality: an in vitro comparative study
Authors: Gallo A. , Menezo Y. , Dale B. , Coppola G. , Dattilo M. , Tosti E. , Boni R.
Published: July 2018

The sperm plasma membrane is a sensitive target to oxidative stress. The most representative reactive oxygen species (ROS) scavengers in the genital tract, hypotaurine and glutathione, require, for their synthesis, cysteine whose availability is associated with the 1-carbon cycle (1-CC). Human, bovine and ascidian spermatozoa were incubated with compounds supporting the 1-CC (Vitamin B6, Methylcobalamin, 5 Methyl Tetrahydrofolate, Zinc Bisglycinate and N-acetyl-cysteine) (TRT) and compared to the effects induced solely by N-acetyl-cysteine (NAC). In control groups (CNTRL), spermatozoa were incubated with medium alone. After 90 and 180 minutes of incubation, the mitochondrial membrane potential (ΔΨM) in TRT and NAC was significantly (P < 0.01) higher than in CNTRL. At H2DCFDA evaluation, ROS production differed between species whereas, at 2-OH Ethidium, it significantly decreased in bovine TRT group. Intracellular pH (pHi) did not significantly vary in relation to treatment. In ascidian spermatozoa, the NAC supplementation decreased external pH, which in turn brought to a pHilowering. Buffering seawater with NaHCO3reversed the beneficial effects of N-acetyl-cysteine supplementation. In conclusion, both fully supporting the 1-CC and treatment with N-acetyl-cysteine alone improved kinetics, ΔΨM and ROS production in mammalian sperm demonstrating for the first time the directin vitroeffects of these compounds on sperm functionality.
Inverse-response Ca2+ indicators for optogenetic visualization of neuronal inhibition
Authors: Zhao Yufeng , Bushey Daniel , Zhao Yongxin , Schreiter Eric R. , Harrison D. Jed , Wong Allan M. , Campbell Robert E.
Published: July 2018

We have developed a series of yellow genetically encoded Ca2+ indicators for optical imaging (Y-GECOs) with inverted responses to Ca2+ and apparent dissociation constants (Kd′) ranging from 25 to 2400 nM. To demonstrate the utility of this affinity series of Ca2+ indicators, we expressed the four highest affinity variants (Kd′s = 25, 63, 121, and 190 nM) in the Drosophila medulla intrinsic neuron Mi1. Hyperpolarization of Mi1 by optogenetic stimulation of the laminar monopolar neuron L1 produced a decrease in intracellular Ca2+ in layers 8–10, and a corresponding increase in Y-GECO fluorescence. These experiments revealed that lower Kd′ was associated with greater increases in fluorescence, but longer delays to reach the maximum signal change due to slower off-rate kinetics.
All optical dual stage laser wakefield acceleration driven by two-color laser pulses
Authors: Pathak Vishwa Bandhu , Kim Hyung Taek , Vieira J. , Silva L. O. , Nam Chang Hee
Published: July 2018

We propose an all-optical dual-stage laser wakefield acceleration (LWFA), staged with co-propagating two-color laser pulses in a plasma medium, to enhance the electron bunch energy. After the depletion of the leading fundamental laser pulse that initiates self-injection and sets up the first stage particle acceleration, the subsequent second-harmonic laser pulse takes over the acceleration process and accelerates the electron bunch in the second stage over a significantly longer distance than in the first stage. In this all optical dual-stage LWFA, the electrons can gain 3 times higher energy as compared to the energy gain from the single stage LWFA driven by a single-color laser pulse with equivalent energy. Our multi-dimensional particle-in-cell simulations demonstrate that a 10-GeV electron bunch with 20-pC charge can be obtained by the two-color dual-stage LWFA using total input laser power of 0.6 PW.
Novel Nanosized Chitosan-Betulinic Acid Against Resistant Leishmania Major and First Clinical Observation of such parasite in Kidney
Authors: Zadeh Mehrizi Tahereh , Shafiee Ardestani Mehdi , Haji Molla Hoseini Mostafa , Khamesipour Ali , Mosaffa Nariman , Ramezani Amitis
Published: July 2018

Regarding the antiparasitic effects of Betulinic acid (B) against Leishmaniasis, it was loaded into nanochitosan (K) for the first time in order to improve its therapeutic effects and decrease its side effects for the treatment of Leishmania major-infected Balb/c mice. Improvement the therapeutic efficacy of Bas an anti-leishmania agent through increasing the effective dose was achieved by using a novel solvent and phase separation method for K synthesis. The synthesized K with the size of 102 nm and Betulinic acid-nanochitosan (BK) with the size of 124 nm and drug loading efficiency of 93%, cellular uptake of 97.5% with the slow drug release pattern was prepared. To increase the therapeutic dose, a modified 10% acetic acid solvent was used. Thein vitroandin vivoresults showed that the nanodrug of BK was non toxic by 100% and BK20 mg/kg could completely performed the wound healing and inhibit the parasite in a large extent (P ˂ 0.001) compared to other groups. Therefore, BK could be considered as an alternative regimen for treatment of L. major.
Co-expression of Cancer Stem Cell Markers OCT4 and NANOG Predicts Poor Prognosis in Renal Cell Carcinomas
Authors: Rasti Arezoo , Mehrazma Mitra , Madjd Zahra , Abolhasani Maryam , Saeednejad Zanjani Leili , Asgari Mojgan
Published: July 2018

Many renal cancer patients experience disease recurrence after combined treatments or immunotherapy due to permanence of cancer stem cells (CSCs). This study was conducted to evaluate the expression patterns and clinical significance of octamer-binding transcription factor 4 (OCT4) and NANOG as the key stem cell factors in renal cell carcinoma (RCC). A total of 186 RCC tissues were immunostained on a tissue microarray (TMA) for the putative CSC markers OCT4 and NANOG. Subsequently, the correlation among the expression of these markers, the clinicopathological variables and survival outcomes were determined. OCT4 and NANOG were expressed in both the nucleus and the cytoplasm of RCC cells. Coexpression of OCT4 and NANOG in renal cancer was significantly associated with RCC subtypes. A significant association was found among nuclear coexpression of OCT4 and NANOG, worse PFS in RCC, and the clear cell renal cell carcinomas (ccRCC) subtype. The OCT4-nuclear high/NANOG-nuclear high phenotype in RCC and ccRCC subtype indicated aggressive tumor behavior and predicted a worse clinical outcome, which may be a useful biomarker to identify patients at high risk of postoperative recurrence and metastasis. Cytoplasmic expression of NANOG could be considered as a novel independent prognostic predictor in patients with renal cancer.
Ectopic overexpression of Kir6.1 in the mouse heart impacts on the life expectancy
Authors: Watanabe Yasuhiro , Kishimoto Takashi , Miki Takashi , Seino Susumu , Nakaya Haruaki , Matsumoto Akio
Published: July 2018

We recently reported the reduced ATP-sensitive potassium (KATP) channel activities in the transgenic mouse heart overexpressing the vascular type KATP channel pore-forming subunit (Kir6.1). Although dysfunction of cardiac KATP channel has been nominated as a cause of cardiomyopathy in human, these transgenic mice looked normal as wild-type (WT) during the experiment period (~20 weeks). Extended observation period revealed unexpected deaths beginning from 30 weeks and about 50% of the transgenic mice died by 55 weeks. Surface ECG recordings from the transgenic mice at rest demonstrated the normal sinus rhythm and the regular ECG complex as well as the control WT mice except for prolonged QT interval. However, the stress ECG test with noradrenaline revealed abnormal intraventricular conduction delay and arrhythmogeneity in the transgenic mouse. Fibrotic changes in the heart tissue were remarkable in aged transgenic mice, and the cardiac fibrosis developed progressively at least from the age of 30 weeks. Gene expression analyses revealed the differentiation of cardiac fibroblasts to myofibroblasts with elevated cytokine expressions was initiated way in advance before the fibrotic changes and the upregulation of BNP in the ventricle. In sum, Kir6.1TG mice provide an electro-pathological disease concept originated from KATP channel dysfunction.
Sample size effects on the assessment of eukaryotic diversity and community structure in aquatic sediments using high-throughput sequencing
Authors: Nascimento Francisco J. A. , Lallias Delphine , Bik Holly M. , Creer Simon
Published: July 2018

Understanding how biodiversity changes in time and space is vital to assess the effects of environmental change on benthic ecosystems. Due to the limitations of morphological methods, there has been a rapid expansion in the application of high-throughput sequencing methods to study benthic eukaryotic communities. However, the effect of sample size and small-scale spatial variation on the assessment of benthic eukaryotic diversity is still not well understood. Here, we investigate the effect of different sample volumes in the genetic assessment of benthic metazoan and non-metazoan eukaryotic community composition. Accordingly, DNA was extracted from five different cumulative sediment volumes comprising 100% of the top 2 cm of five benthic sampling cores, and used as template for Ilumina MiSeq sequencing of 18 S rRNA amplicons. Sample volumes strongly impacted diversity metrics for both metazoans and non-metazoan eukaryotes. Beta-diversity of treatments using smaller sample volumes was significantly different from the beta-diversity of the 100% sampled area. Overall our findings indicate that sample volumes of 0.2 g (1% of the sampled area) are insufficient to account for spatial heterogeneity at small spatial scales, and that relatively large percentages of sediment core samples are needed for obtaining robust diversity measurement of both metazoan and non-metazoan eukaryotes.
Control of swarming of molecular robots
Authors: Keya Jakia Jannat , Kabir Arif Md. Rashedul , Inoue Daisuke , Sada Kazuki , Hess Henry , Kuzuya Akinori , Kakugo Akira
Published: July 2018

Recently we demonstrated swarming of a self-propelled biomolecular motor system microtubule (MT)-kinesin where interactions among thousands of motile MTs were regulated in a highly programmable fashion by using DNA as a processor. However, precise control of this potential system is yet to be achieved to optimize the swarm behavior. In this work, we systematically controlled swarming of MTs on kinesin adhered surface by different physicochemical parameters of MT-kinesin and DNA. Tuning the length of DNA sequences swarming was precisely controlled with thermodynamic and kinetic feasibility. In addition, swarming was regulated using different concentration of DNA crosslinkers. Reversibility of swarming was further controlled by changing the concentration of strand displacement DNA signal allowing dissociation of swarm. The control over the swarm was accompanied by variable stiffness of MTs successfully, providing translational and circular motion. Moreover, the morphology of swarm was also found to be changed not only depending on the stiffness but also body length of MTs. Such detail study of precise control of swarming would provide new insights in developing a promising molecular swarm robotic system with desired functions.
Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners
Authors: Vallet Sylvain D. , Miele Adriana E. , Uciechowska-Kaczmarzyk Urszula , Liwo Adam , Duclos Bertrand , Samsonov Sergey A. , Ricard-Blum Sylvie
Published: July 2018

Lysyl oxidase (LOX) catalyzes the oxidative deamination of lysine and hydroxylysine residues in collagens and elastin, which is the first step of the cross-linking of these extracellular matrix proteins. It is secreted as a proenzyme activated by bone morphogenetic protein-1, which releases the LOX catalytic domain and its bioactive N-terminal propeptide. We characterized the recombinant human propeptide by circular dichroism, dynamic light scattering, and small-angle X-ray scattering (SAXS), and showed that it is elongated, monomeric, disordered and flexible (Dmax: 11.7 nm, Rg: 3.7 nm). We generated 3D models of the propeptide by coarse-grained molecular dynamics simulations restrained by SAXS data, which were used for docking experiments. Furthermore, we have identified 17 new binding partners of the propeptide by label-free assays. They include four glycosaminoglycans (hyaluronan, chondroitin, dermatan and heparan sulfate), collagen I, cross-linking and proteolytic enzymes (lysyl oxidase-like 2, transglutaminase-2, matrix metalloproteinase-2), a proteoglycan (fibromodulin), one growth factor (Epidermal Growth Factor, EGF), and one membrane protein (tumor endothelial marker-8). This suggests new roles for the propeptide in EGF signaling pathway.
Conflict and adaptation signals in the anterior cingulate cortex and ventral tegmental area
Authors: Elston Thomas W. , Kalhan Shivam , Bilkey David K.
Published: July 2018

The integration and utilization of feedback in order to determine which decision strategy to use in different contexts is the core of executive function. The anterior cingulate cortex (ACC) is central to these processes but how feedback is made available to the ACC is unclear. To address this question, we trained rats with implants in the ACC and the ventral tegmental area (VTA), a dopaminergic brain region implicated in feedback processing, in a spatial decision reversal task with rule switching occurring approximately every 12 trials. Following a rule switch, the rats had to shift and sustain responses to the alternative side in order to obtain reward. Partial directed coherence (PDC) models of signal directionality between the ACC and VTA indicated that VTA → ACC communication (near 4 Hz) increased immediately prior to incorrect choices and during post-error decisions. This increase did not occur during correct choices. These data indicate that the VTA provides a feedback-driven, bottom-up modulating signal to the ACC which may be involved in assessing, and correcting for, decision conflict.
Hybrid cell reactor system from Escherichia coli protoplast cells and arrayed lipid bilayer chamber device
Authors: Moriizumi Yoshiki , Tabata Kazuhito V. , Watanabe Rikiya , Doura Tomohiro , Kamiya Mako , Urano Yasuteru , Noji Hiroyuki
Published: July 2018

We developed a novel hybrid cell reactor system via functional fusion of single Escherichia coli protoplast cells, that are deficient in cell wall and expose plasma membrane, with arrayed lipid bilayer chambers on a device in order to incorporate the full set of cytosolic and membrane constituents into the artificial chambers. We investigated gene expression activity to represent the viability of the hybrid cell reactors: over 20% of hybrid cells showed gene expression activity from plasmid or mRNA. This suggests that the hybrid cell reactors retained fundamental activity of genetic information transduction. To expand the applicability of the hybrid cell reactors, we also developed the E. coli-in-E. coli cytoplasm system as an artificial parasitism system. Over 30% of encapsulated E. coli cells exhibited normal cell division, showing that hybrid cells can accommodate and cultivate living cells. This novel artificial cell reactor technology would enable unique approaches for synthetic cell researches such as reconstruction of living cell, artificial parasitism/symbiosis system, or physical simulation to test functionality of synthetic genome.
On the use of functional responses to quantify emergent multiple predator effects
Authors: Sentis Arnaud , Boukal David S.
Published: July 2018

Non-independent interactions among predators can have important consequences for the structure and dynamics of ecological communities by enhancing or reducing prey mortality rate through, e.g., predator facilitation or interference. The multiplicative risk model, traditionally used to detect these emergent multiple predator effects (MPEs), is biased because it assumes linear functional response (FR) and no prey depletion. To rectify these biases, two approaches based on FR modelling have recently been proposed: the direct FR approach and the population-dynamic approach. Here we compare the strengths, limitations and predictions of the three approaches using simulated data sets. We found that the predictions of the direct FR and the multiplicative risk models are very similar and underestimate predation rates when prey density is high or prey depletion is substantial. As a consequence, these two approaches often fail in detecting risk reduction. Finally, parameters estimated with the direct FR approach lack mechanistic interpretation, which limits the understanding of the mechanisms driving multiple predator interactions and potential extension of this approach to more complex food webs. We thus strongly recommend using the population-dynamic approach because it is robust, precise, and provides a scalable mechanistic framework to detect and quantify MPEs.
Chitin promotes antigen-specific Th2 cell-mediated murine asthma through induction of IL-33-mediated IL-1β production by DCs
Authors: Arae Ken , Morita Hideaki , Unno Hirotoshi , Motomura Kenichiro , Toyama Sumika , Okada Naoko , Ohno Tatsukuni , Tamari Masato , Orimo Keisuke , Mishima Yuko , Suto Hajime , Okumura Ko , Sudo Katsuko , Miyazawa Hiroshi , Taguchi Haruhiko , Saito Hirohisa , Matsumoto Kenji , Nakae Susumu
Published: July 2018

Chitin, which is a major component of house dust mites (HDM), fungi, crustaceans, etc., can activate immune cells, suggesting that it contributes to development of allergic disorders such as asthma. Although the pathophysiological sensitization route of asthmatic patients to allergens is considered via the respiratory tract, the roles of intranasally-administered chitin in development of asthma remain unclear. After ovalbumin (OVA) challenge, development of airway inflammation was profoundly exacerbated in mice sensitized with OVA in the presence of chitin. The exacerbation was dependent on IL-33, but not IL-25, thymic stromal lymphopoietin or IL-17A. Chitin enhanced IL-33-dependent IL-1β production by dendritic cells (DCs). Furthermore, chitin- and IL-33-stimulated DC-derived IL-1β promoted OVA-specific Th2 cell activation, resulting in aggravation of OVA-induced airway inflammation. These findings indicate the adjuvant activity of chitin via a new mechanism and provide important clues for development of therapeutics for allergic disorders caused by HDM, fungi and crustaceans.