bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ancient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket
Authors: Manville Rían W. , Abbott Geoffrey W. 
Published: September 2018

AbstractEpilepsy has been treated for centuries with herbal remedies, including leaves of the African shrub Mallotus oppositifolius, yet the underlying molecular mechanisms have remained unclear. Voltage-gated potassium channel isoforms KCNQ2–5, predominantly KCNQ2/3 heteromers, underlie the neuronal M-current, which suppresses neuronal excitability, protecting against seizures. Here, in silico docking, mutagenesis and cellular electrophysiology reveal that two components of M. oppositifolius leaf extract, mallotoxin (MTX) and isovaleric acid (IVA), act synergistically to open neuronal KCNQs, including KCNQ2/3 channels. Correspondingly, MTX and IVA combine to suppress pentylene tetrazole-induced tonic seizures in mice, whereas individually they are ineffective. Co-administering MTX and IVA with the modern, synthetic anticonvulsant retigabine creates a further synergy that voltage independently locks KCNQ2/3 open. Leveraging this synergy, which harnesses ancient and modern medicines to exploit differential KCNQ isoform preferences, presents an approach to developing safe yet effective anticonvulsants.
Robust single-cell DNA methylome profiling with snmC-seq2
Authors: Luo Chongyuan , Rivkin Angeline , Zhou Jingtian , Sandoval Justin P. , Kurihara Laurie , Lucero Jacinta , Castanon Rosa , Nery Joseph R. , Pinto-Duarte António , Bui Brian , Fitzpatrick Conor , O’Connor Carolyn , Ruga Seth , Van Eden Marc E. , Davis David A. , Mash Deborah C. , Behrens M. Margarita , Ecker Joseph R. 
Published: September 2018

AbstractSingle-cell DNA methylome profiling has enabled the study of epigenomic heterogeneity in complex tissues and during cellular reprogramming. However, broader applications of the method have been impeded by the modest quality of sequencing libraries. Here we report snmC-seq2, which provides improved read mapping, reduced artifactual reads, enhanced throughput, as well as increased library complexity and coverage uniformity compared to snmC-seq. snmC-seq2 is an efficient strategy suited for large-scale single-cell epigenomic studies.
Transcriptional profiling of Zygosaccharomyces bailii early response to acetic acid or copper stress mediated by ZbHaa1
Authors: Antunes Miguel , Palma Margarida , Sá-Correia Isabel 
Published: September 2018

AbstractThe non-conventional yeast species Zygosaccharomyces bailii is remarkably tolerant to acetic acid, a highly important microbial inhibitory compound in Food Industry and Biotechnology. ZbHaa1 is the functional homologue of S. cerevisiae Haa1 and a bifunctional transcription factor able to modulate Z. bailii adaptive response to acetic acid and copper stress. In this study, RNA-Seq was used to investigate genomic transcription changes in Z. bailii during early response to sublethal concentrations of acetic acid (140 mM, pH 4.0) or copper (0.08 mM) and uncover the regulatory network activated by these stresses under ZbHaa1 control. Differentially expressed genes in response to acetic acid exposure (297) are mainly related with the tricarboxylic acid cycle, protein folding and stabilization and modulation of plasma membrane composition and cell wall architecture, 17 of which, directly or indirectly, ZbHaa1-dependent. Copper stress induced the differential expression of 190 genes mainly involved in the response to oxidative stress, 15 ZbHaa1-dependent. This study provides valuable mechanistic insights regarding Z. bailii adaptation to acetic acid or copper stress, as well as useful information on transcription regulatory networks in pre-whole genome duplication (WGD) (Z. bailii) and post-WGD (S. cerevisiae) yeast species, contributing to the understanding of transcriptional networks’ evolution in yeasts.
Separation of blood microsamples by exploiting sedimentation at the microscale
Authors: Forchelet D. , Béguin S. , Sajic T. , Bararpour N. , Pataky Z. , Frias M. , Grabherr S. , Augsburger M. , Liu Y. , Charnley M. , Déglon J. , Aebersold R. , Thomas A. , Renaud P. 
Published: September 2018

AbstractMicrosample analysis is highly beneficial in blood-based testing where cutting-edge bioanalytical technologies enable the analysis of volumes down to a few tens of microliters. Despite the availability of analytical methods, the difficulty in obtaining high-quality and standardized microsamples at the point of collection remains a major limitation of the process. Here, we detail and model a blood separation principle which exploits discrete viscosity differences caused by blood particle sedimentation in a laminar flow. Based on this phenomenon, we developed a portable capillary-driven microfluidic device that separates blood microsamples collected from finger-pricks and delivers 2 µL of metered serum for bench-top analysis. Flow cytometric analysis demonstrated the high purity of generated microsamples. Proteomic and metabolomic analyses of the microsamples of 283 proteins and 1351 metabolite features was consistent with samples generated via a conventional centrifugation method. These results were confirmed by a clinical study scrutinising 8 blood markers in obese patients.
Enhanced antibacterial effect of the novel T4-like bacteriophage KARL-1 in combination with antibiotics against multi-drug resistant Acinetobacter baumannii
Authors: Jansen Mathias , Wahida Adam , Latz Simone , Krüttgen Alex , Häfner Helga , Buhl Eva Miriam , Ritter Klaus , Horz Hans-Peter 
Published: September 2018

AbstractThe continuing rise of infections caused by multi-drug resistant bacteria has led to a renewed interest in bacteriophage therapy. Here we characterize phage vB_AbaM-KARL-1 with lytic activity against multi-drug resistant clinical isolates of Acinetobacter baumannii (AB). Besides genomic and phenotypic phage analysis, the objective of our study was to investigate the antibacterial outcome when the phage acts in concert with distinct antibiotics. KARL-1 belongs to the family of Myoviridae and is able to lyse 8 of 20 (40%) tested clinical isolates. Its double-stranded DNA genome consists of 166,560 bp encoding for 253 open reading frames. Genome wide comparison suggests that KARL-1 is a novel species within the subfamily Tevenvirinae, sharing 77% nucleotide identity (coverage 58%) with phage ZZ1. The antibacterial efficacy at various multiplicities of infection (MOI) was monitored either alone or in combination with meropenem, ciprofloxacin, and colistin. A complete clearance of liquid cultures was achieved with KARL-1 at an MOI of 10−1 and meropenem (>128 mg/l). KARL-1 was still effective at an MOI of 10−7, but antibacterial activity was significantly augmented with meropenem. While ciprofloxacin did generally not support phage activity, the application of KARL-1 at an MOI of 10−7 and therapeutic doses of colistin significantly elevated bacterial suppression. Hence, KARL-1 represents a novel candidate for use against multi-drug resistant AB and the therapeutic outcome may be positively influenced by the addition of traditional antibiotics.
Cryptic population structure reveals low dispersal in Iberian wolves
Authors: Silva Pedro , López-Bao José Vicente , Llaneza Luis , Álvares Francisco , Lopes Susana , Blanco Juan Carlos , Cortés Yolanda , García Emilio , Palacios Vicente , Rio-Maior Helena , Ferrand Nuno , Godinho Raquel 
Published: September 2018

AbstractHighly mobile mammalian carnivores are expected to have the capability to maintain high levels of gene flow across large geographic scales. Nonetheless, surprising levels of genetic structure have been found in many such populations. We combined genetic and spatial behavioural information from wolves (Canis lupus) in the Iberian Peninsula (Western Europe) during the last two decades to present a particular case of low dispersal levels in a large carnivore population persisting in human-dominated landscapes. We found an exceptionally reticulated pattern of cryptic population structure emerging at two hierarchical levels, in which four or eleven meaningful genetic clusters can be recognized, respectively. These clusters were characterized by moderate-high levels of differentiation (average pairwise FST = 0.09–0.19), low levels of admixture and varying degrees of genetic diversity. The number of dispersers identified among the 11 clusters was very low (<4% out of 218 wolves). Spatial information of tracked wolves further confirmed the geographical genetic patterns (only 2 out of 85 collared wolves overlapped with more than one genetic cluster). The high levels of genetic structure in this population may be determined by the recent demographic history of this population, among other factors. The identification of meaningful genetic clusters has implications for the delineation of conservation units and, consequently, on the conservation and management actions for Iberian wolves.
HP1 cooperates with CAF-1 to compact heterochromatic transgene repeats in mammalian cells
Authors: Yan Haiyan , Xiang Xingfeng , Chen Qinfu , Pan Xuan , Cheng Hankun , Wang Fangwei 
Published: September 2018

AbstractThe nuclear organization of tightly condensed heterochromatin plays important roles in regulating gene transcription and genome integrity. Heterochromatic domains are usually present at chromosomal regions containing a large array of repeated DNA sequences. We previously showed that integration of a 1,000-copy tandem array of an inducible reporter gene into the genome of mammalian cells induces the formation of a highly compact heterochromatic domain enriched in heterochromatin protein 1 (HP1). It remains to be determined how these DNA repeats are packaged into a heterochromatic form and are silenced. Here, we show that HP1-mediated transgene condensation and silencing require the interaction with PxVxL motif-containing proteins. The chromatin assembly factor 1 (CAF-1) complex concentrates at the transgenic locus through the interaction of its PxVxL motif-containing p150 subunit with HP1. Knockdown of p150 relieves HP1-mediated transgene compaction and repression. When targeted to the transgenic locus, p150 mutants defective in binding HP1 cause transgene decondensation and activation. Taken together, these results suggest that HP1 cooperates with CAF-1 to compact transgene repeats. This study provides important insight into how heterochromatin is maintained at chromosomal regions with abundant DNA repeats.
Vps34/PI3KC3 deletion in kidney proximal tubules impairs apical trafficking and blocks autophagic flux, causing a Fanconi-like syndrome and renal insufficiency
Authors: Grieco Giuseppina , Janssens Virginie , Gaide Chevronnay Héloïse P. , N’Kuli Francisca , Van Der Smissen Patrick , Wang Tongsong , Shan Jingdong , Vainio Seppo , Bilanges Benoit , Jouret François , Vanhaesebroeck Bart , Pierreux Christophe E. , Courtoy Pierre J. 
Published: September 2018

AbstractKidney proximal tubular cells (PTCs) are highly specialized for ultrafiltrate reabsorption and serve as paradigm of apical epithelial differentiation. Vps34/PI3-kinase type III (PI3KC3) regulates endosomal dynamics, macroautophagy and lysosomal function. However, its in vivo role in PTCs has not been evaluated. Conditional deletion of Vps34/PI3KC3 in PTCs by Pax8-Cre resulted in early (P7) PTC dysfunction, manifested by Fanconi-like syndrome, followed by kidney failure (P14) and death. By confocal microscopy, Vps34∆/∆ PTCs showed preserved apico-basal specification (brush border, NHERF-1 versus Na+/K+-ATPase, ankyrin-G) but basal redistribution of late-endosomes/lysosomes (LAMP-1) and mis-localization to lysosomes of apical recycling endocytic receptors (megalin, cubilin) and apical non-recycling solute carriers (NaPi-IIa, SGLT-2). Defective endocytosis was confirmed by Texas-red-ovalbumin tracing and reduced albumin content. Disruption of Rab-11 and perinuclear galectin-3 compartments suggested mechanistic clues for defective receptor recycling and apical biosynthetic trafficking. p62-dependent autophagy was triggered yet abortive (p62 co-localization with LC3 but not LAMP-1) and PTCs became vacuolated. Impaired lysosomal positioning and blocked autophagy are known causes of cell stress. Thus, early trafficking defects show that Vps34 is a key in vivo component of molecular machineries governing apical vesicular trafficking, thus absorptive function in PTCs. Functional defects underline the essential role of Vps34 for PTC homeostasis and kidney survival.
A novel mechanism of plasminogen activation in epithelial and mesenchymal cells
Authors: Bydoun Moamen , Sterea Andra , Weaver Ian C. G. , Bharadwaj Alamelu G. , Waisman David M. 
Published: September 2018

AbstractCancer dissemination is initiated by the movement of cells into the vasculature which has been reported to be triggered by EMT (epithelial to mesenchymal transition). Cellular dissemination also requires proteases that remodel the extracellular matrix. The protease, plasmin is a prominent player in matrix remodeling and invasion. Despite the contribution of both EMT and the plasminogen activation (PA) system to cell dissemination, these processes have never been functionally linked. We reveal that canonical Smad-dependent TGFβ1 signaling and FOXC2-mediated PI3K signaling in cells undergoing EMT reciprocally modulate plasminogen activation partly by regulating the plasminogen receptor, S100A10 and the plasminogen activation inhibitor, PAI-1. Plasminogen activation and plasminogen-dependent invasion were more prominent in epithelial-like cells and were partly dictated by the expression of S100A10 and PAI-1.
Nitrite producing bacteria inhibit reinforcement bar corrosion in cementitious materials
Authors: Erşan Yusuf Çağatay , Van Tittelboom Kim , Boon Nico , De Belie Nele 
Published: September 2018

AbstractChemicals and synthetic coatings are widely used to protect steel against corrosion. Bio-based corrosion inhibition strategies can be an alternative in the arising bioeconomy era. To maintain the good state of steel reinforcement in cracked concrete, microbe-based self-healing cementitious composites (MSCC) have been developed. Yet, proposed strategies involve reasonably slow crack filling by biomineralization and thus risk the possible rebar corrosion during crack healing. Here we upgrade the rebar protection to a higher level by combining MSCC with microbial induced corrosion inhibition. Presented NO3− reducing bacterial granules inhibit rebar corrosion by producing the anodic corrosion inhibitor NO2− and meanwhile heal a 300-µm-wide crack in 28 days. During 120 days exposure to 0.5 M Cl− solution, the rebars in cracked MSCC keep showing open circuit potentials above the critical value of −250 mV and they lose less than 2% of the total rebar material which corresponds to half the material loss in cracked plain mortar. Overall, the obtained rebar protection performance is comparable with that of uncracked mortar and mortar containing chemical inhibitor, hence the microbe-based system becomes an alternative to the traditional methods.
Tooth oxygen isotopes reveal Late Bronze Age origin of Mediterranean fish aquaculture and trade
Authors: Guy Sisma-Ventura , Thomas Tütken , Irit Zohar , Andreas Pack , Dorit Sivan , Omri Lernau , Ayelet Gilboa , Guy Bar-Oz 
Published: September 2018

AbstractPast fish provenance, exploitation and trade patterns were studied by analyzing phosphate oxygen isotope compositions (δ18OPO4) of gilthead seabream (Sparus aurata) tooth enameloid from archaeological sites across the southern Levant, spanning the entire Holocene. We report the earliest evidence for extensive fish exploitation from the hypersaline Bardawil lagoon on Egypt’s northern Sinai coast, as indicated by distinctively high δ18OPO4 values, which became abundant in the southern Levant, both along the coast and further inland, at least from the Late Bronze Age (3,550–3,200 BP). A period of global, postglacial sea-level stabilization triggered the formation of the Bardawil lagoon, which was intensively exploited and supported a widespread fish trade. This represents the earliest roots of marine proto-aquaculture in Late Holocene coastal domains of the Mediterranean. We demonstrate the potential of large-scale δ18OPO4 analysis of fish teeth to reveal cultural phenomena in antiquity, providing unprecedented insights into past trade patterns.
Words affect visual perception by activating object shape representations
Authors: Noorman Samuel , Neville David A. , Simanova Irina 
Published: September 2018

AbstractLinguistic labels are known to facilitate object recognition, yet the mechanism of this facilitation is not well understood. Previous psychophysical studies have suggested that words guide visual perception by activating information about visual object shape. Here we aimed to test this hypothesis at the neural level, and to tease apart the visual and semantic contribution of words to visual object recognition. We created a set of object pictures from two semantic categories with varying shapes, and obtained subjective ratings of their shape and category similarity. We then conducted a word-picture matching experiment, while recording participants’ EEG, and tested if the shape or the category similarity between the word’s referent and target picture explained the spatiotemporal pattern of the picture-evoked responses. The results show that hearing a word activates representations of its referent’s shape, which interacts with the visual processing of a subsequent picture within 100 ms from its onset. Furthermore, non-visual categorical information, carried by the word, affects the visual processing at later stages. These findings advance our understanding of the interaction between language and visual perception and provide insights into how the meanings of words are represented in the brain.
Astaxanthin alleviated ethanol-induced liver injury by inhibition of oxidative stress and inflammatory responses via blocking of STAT3 activity
Authors: Han Ji Hye , Ju Jung Heun , Lee Yong Sun , Park Ju Ho , Yeo In Jun , Park Mi Hee , Roh Yoon Seok , Han Sang Bae , Hong Jin Tae 
Published: September 2018

AbstractAstaxanthin (AXT) is classified as a xanthophyll carotenoid compound which have broader functions including potent antioxidant, anti-inflammatory and neuroprotective properties. Considerable researches have demonstrated that AXT shows preventive and therapeutic properties against for Diabetes, Osteoarthritis and Rheumatoid Arthritis. However, the protective effect of AXT on liver disease has not yet been reported. In this study, we investigated effects of AXT on ethanol-induced liver injury in chronic plus binge alcohol feeding model. The hepatic steatosis and inflammation induced by ethanol administration were alleviated by AXT. Serum levels of aspartate transaminase and alanine transaminase were decreased in the livers of AXT administrated group. The ethanol-induced expression of cytochrome P450 2E1 (CYP2E1), pro-inflammatory proteins, cytokines, chemokines and reactive oxygen species (ROS) levels were also reduced in the livers of AXT administrated group. Moreover, ethanol-induced infiltration of neutrophils was decreased in the livers of AXT administrated group. Docking model and pull-down assay showed that AXT directly binds to the DNA binding site of STAT3. Moreover, AXT decreased STAT3 phosphorylation in the liver of AXT administration group. Therefore, these results suggest that AXT could prevent ethanol-induced hepatic injury via inhibition of oxidant and inflammatory responses via blocking of STAT3 activity.
First- and second-order contributions to depth perception in anti-correlated random dot stereograms
Authors: Asher Jordi M. , Hibbard Paul B. 
Published: September 2018

AbstractThe binocular energy model of neural responses predicts that depth from binocular disparity might be perceived in the reversed direction when the contrast of dots presented to one eye is reversed. While reversed-depth has been found using anti-correlated random-dot stereograms (ACRDS) the findings are inconsistent across studies. The mixed findings may be accounted for by the presence of a gap between the target and surround, or as a result of overlap of dots around the vertical edges of the stimuli. To test this, we assessed whether (1) the gap size (0, 19.2 or 38.4 arc min) (2) the correlation of dots or (3) the border orientation (circular target, or horizontal or vertical edge) affected the perception of depth. Reversed-depth from ACRDS (circular no-gap condition) was seen by a minority of participants, but this effect reduced as the gap size increased. Depth was mostly perceived in the correct direction for ACRDS edge stimuli, with the effect increasing with the gap size. The inconsistency across conditions can be accounted for by the relative reliability of first- and second-order depth detection mechanisms, and the coarse spatial resolution of the latter.
Menisci protect chondrocytes from load-induced injury
Authors: Abusara Z. , Andrews S. H. J. , Von Kossel M. , Herzog W. 
Published: September 2018

AbstractMenisci in the knee joint are thought to provide stability, increased contact area, decreased contact pressures, and offer protection to the underlying articular cartilage and bone during joint loading. Meniscal loss or injury is typically accompanied by degenerative changes in the knee, leading to an increased risk for osteoarthritis in animals including humans. However, the detailed mechanisms underlying joint degeneration and the development of osteoarthritis remain largely unknown, and the acute effects of meniscal loss have not been studied systematically. We developed a microscopy-based system to study microscale joint mechanics in living mice loaded by controlled muscular contractions. Here, we show how meniscal loss is associated with rapid chondrocyte death (necrosis) in articular cartilage within hours of injury, and how intact menisci protect chondrocytes in vivo in the presence of intense muscle-based joint loading and/or injury to the articular cartilage. Our findings suggest that loading the knee after meniscal loss is associated with extensive cell death in intact and injured knees, and that early treatment interventions should be aimed at preventing chondrocyte death.
Adaptive Gaze Strategies to Reduce Environmental Uncertainty During a Sequential Visuomotor Behaviour
Authors: Domínguez-Zamora F. Javier , Gunn Shaila M. , Marigold Daniel S. 
Published: September 2018

AbstractPeople must decide where, when, and for how long to allocate gaze to perform different motor behaviours. However, the factors guiding gaze during these ongoing, natural behaviours are poorly understood. Gaze shifts help acquire information, suggesting that people should direct gaze to locations where environmental details most relevant to the task are uncertain. To explore this, human subjects stepped on a series of targets as they walked. We used different levels of target uncertainty, and through instruction, altered the importance of (or subjective value assigned to) foot-placement accuracy. Gaze time on targets increased with greater target uncertainty when precise foot placement was more important, and these longer gaze times associated with reduced foot-placement error. Gaze times as well as the gaze shifts to and from targets relative to stepping differed depending on the target’s position in the sequence and uncertainty level. Overall, we show that gaze is allocated to reduce uncertainty about target locations, and this depends on the value of this information gain for successful task performance. Furthermore, we show that the spatial-temporal pattern of gaze to resolve uncertainty changes with the evolution of the motor behaviour, indicating a flexible strategy to plan and control movement.