bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic epidemiology supports multiple introductions and cryptic transmission of Zika virus in Colombia
Authors: Black Allison , Moncla Louise H. , Laiton-Donato Katherine , Potter Barney , Pardo Lissethe , Rico Angelica , Tovar Catalina , Rojas Diana P. , Longini Ira M. , Halloran M. Elizabeth , Peláez-Carvajal Dioselina , Ramírez Juan D. , Mercado-Reyes Marcela , Bedford Trevor 
Published: October 2018

AbstractBackgroundColombia was the second most affected country during the American Zika virus (ZIKV) epidemic, with over 109,000 reported cases. Despite the scale of the outbreak, limited genomic sequence data were available from Colombia. We sought to sequence additional samples and use genomic epidemiology to describe ZIKV dynamics in Colombia.MethodsWe sequenced ZIKV genomes directly from clinical diagnostic specimens and infected Aedes ae-gypti samples selected to cover the temporal and geographic breadth of the Colombian outbreak. We performed phylogeographic analysis of these genomes, along with other publicly-available ZIKV genomes from the Americas, to estimate the frequency and timing of ZIKV introductions to Colombia.ResultsWe attempted PCR amplification on 184 samples; 19 samples amplified sufficiently to perform sequencing. Of these, 8 samples yielded sequences with at least 50% coverage. Our phylogeo-graphic reconstruction indicates two separate introductions of ZIKV to Colombia, one of which was previously unrecognized. We find that ZIKV was first introduced to Colombia in February 2015 (95%CI: Jan 2015 - Apr 2015), corresponding to 5 to 8 months of cryptic ZIKV transmission prior to confirmation in September 2015. Despite the presence of multiple introductions, we find that the majority of Colombian ZIKV diversity descends from a single introduction. We find evidence for movement of ZIKV from Colombia into bordering countries, including Peru, Ecuador, Panama, and Venezuela.ConclusionsSimilarly to genomic epidemiologic studies of ZIKV dynamics in other countries, we find that ZIKV circulated cryptically in Colombia. This more accurate dating of when ZIKV was circulating refines our definition of the population at risk. Additionally, our finding that the majority of ZIKV transmission within Colombia was attributable to transmission between individuals, rather than repeated travel-related importations, indicates that improved detection and control might have succeeded in limiting the scale of the outbreak within Colombia.
Interpretable classification of Alzheimer’s disease pathologies with a convolutional neural network pipeline
Authors: Tang Ziqi , Chuang Kangway V. , DeCarli Charles , Jin Lee-Way , Beckett Laurel , Keiser Michael J. , Dugger Brittany N. 
Published: October 2018

AbstractNeuropathologists assess vast brain areas to identify diverse and subtly-differentiated morphologies. Standard semi-quantitative scoring approaches, however, are coarse-grained and lack precise neuroanatomic localization. We report a proof-of-concept deep learning pipeline identifying specific neuropathologies—amyloid plaques and cerebral amyloid angiopathy—in immunohistochemically-stained archival slides. Using automated segmentation of stained objects and a cloud-based interface, we annotated >70,000 plaque candidates from 43 whole slide images (WSIs) to train and evaluate convolutional neural networks. Networks achieved strong plaque classification on a 10-WSI hold-out set (0.993 and 0.743 areas under the receiver operating characteristic and precision recall curve, respectively). Prediction confidence maps visualized morphology distributions for WSIs at high resolution. Resulting plaque-burden scores correlated well with established semi-quantitative scores on a 30-WSI blinded hold-out. Finally, saliency mapping demonstrated that networks learned patterns agreeing with accepted pathologic features. This scalable means to augment a neuropathologist’s ability may suggest a route to neuropathologic deep phenotyping.
Wood modification by furfuryl alcohol caused delayed decomposition response inRhodonia (Postia) placenta
Authors: Skrede Inger , Solbakken Monica Hongrø , Hess Jaqueline , Fossdal Carl Gunnar , Hegnar Olav , Alfredsen Gry 
Published: October 2018

ABSTRACTThe aim of this study was to investigate differential expression profiles of the brown rot fungusRhodonia placenta(previouslyPostia placenta) harvested at several time points when grown onPinus radiata(radiata pine) andP. radiatawith three different levels of modification by furfuryl alcohol, an environmentally benign commercial wood protection system. For the first time the entire gene expression pattern of a decay fungus is followed in untreated and modified wood from initial to advanced stages of decay. Results support the current model of a two-step decay mechanism, with an initial oxidative depolymerization followed by hydrolysis of cell-wall polysaccharides. The wood decay process is finished, and the fungus goes into starvation mode after five weeks when grown on unmodifiedP. radiatawood. The pattern of repression of oxidative processes and oxalate synthesis found inP. radiataat later stages of decay is not mirrored for the high furfurylation treatment. The high treatment level provided a more unpredictable expression pattern throughout the entire incubation period. Furfurylation does not seem to directly influence the expression of core plant cell wall hydrolyzing enzymes, as a delayed and prolonged, but similar pattern was observed in theP. radiataand the modified experiments. This indicates that the fungus starts a common decay process in the modified wood, but proceeds at a slower pace as access to the plant cell wall polysaccharides is restricted. This is further supported by the downregulation of hydrolytic enzymes for the high treatment level at the last harvest point (mass loss 14%). Moreover, the mass loss does not increase the last weeks. Collectively, this indicates a potential threshold for lower mass loss for highly modified wood.IMPORTANCEFungi are important decomposers of woody biomass in natural habitats. Investigation of the mechanisms employed by decay fungi in their attempt to degrade wood is important for both the basic scientific understanding of ecology and carbon cycling in nature, and for applied uses of woody materials. For wooden building materials long service life and carbon storage is essential, but decay fungi are responsible for massive losses of wood in service. Thus, optimizing durable wood products for the future are of major importance. In this study we have investigated the fungal genetic response to furfurylated wood, a commercial environmentally benign wood modification approach, that improves service life of wood in outdoor applications. Our results show that there is a delayed wood decay by the fungus as a response to furfurylated wood and new knowledge about the mechanisms behind the delay is provided.
Soil microbial communities with greater investment in resource acquisition have lower growth yield
Authors: Malik Ashish A. , Puissant Jeremy , Goodall Tim , Allison Steven D. , Griffiths Robert I. 
Published: October 2018

AbstractResource acquisition and growth yield are fundamental traits of microorganisms that have consequences for ecosystem functioning. However, there is a lack of empirical observations linking these traits. Using a landscape-scale survey of temperate near-neutral pH soils, we show tradeoffs in key community-level parameters linked to these traits. Increased investment into extracellular enzymes was associated with reduced growth yield; this reduction was linked more to carbon than nitrogen acquisition enzymes suggesting smaller stoichiometric constraints on community metabolism in examined soils.
Tuning of ventral tenia tecta neurons of the olfactory cortex to distinct scenes of feeding behavior
Authors: Shiotani Kazuki , Manabe Hiroyuki , Tanisumi Yuta , Murata Koshi , Hirokawa Junya , Sakurai Yoshio , Mori Kensaku 
Published: October 2018

AbstractVentral tenia tecta (vTT) is a part of the olfactory cortex that receives both olfactory sensory signals from the olfactory bulb and top-down signals from the prefrontal cortex. To address the question whether and how the neuronal activity of the vTT is modulated by prefrontal cognitive processes such as attention, expectation and working memory that occurs during goal-directed behaviors, we recorded individual neuronal responses in the vTT of freely moving awake mice that performed learned odor-guided feeding and drinking behaviors. We found that the firing pattern of individual vTT cells had repeatable behavioral correlates such that the environmental and behavioral scene the mouse encountered during the learned behavior was the major determinant of when individual vTT neurons fired maximally. Furthermore, spiking activity of these scene cells was modulated not only by the present scene but also by the future scene that the mouse predicted. We show that vTT receives afferent input from the olfactory bulb and top-down inputs from the medial prefrontal cortex and piriform cortex.These results indicate that different groups of vTT cells are activated at different scenes and suggest that processing of olfactory sensory information is handled by different scene cells during distinct scenes of learned feeding and drinking behaviors. In other words, during the feeding and drinking behavior, vTT changes its working mode moment by moment in accord with the scene change by selectively biasing specific scene cells. The scene effect on olfactory sensory processing in the vTT has implications for the neuronal circuit mechanisms of top-down attention and scene-dependent encoding and recall of olfactory memory.
Cryo-EM structures and functional characterization of the lipid scramblase TMEM16F
Authors: Alvadia Carolina , Lim Novandy K. , Mosina Vanessa Clerico , Oostergetel Gert T. , Dutzler Raimund , Paulino Cristina 
Published: October 2018

SUMMARYThe lipid scramblase TMEM16F initiates blood coagulation by catalyzing the exposure of phosphatidylserine in platelets. The protein is part of a family of membrane proteins, which encompasses calcium-activated channels for ions and lipids. Here, we reveal features of TMEM16F that underlie its function as lipid scramblase and ion channel. The cryo-EM structures of TMEM16F in Ca2+-bound and Ca2+-free states display a striking similarity to the scrambling-incompetent anion channel TMEM16A, yet with distinct differences in the catalytic site and in the conformational changes upon activation. In conjunction with functional data, we demonstrate the relationship between ion conduction and lipid scrambling. Although activated by a common mechanism, which likely resembles an equivalent process defined in the homologue nhTMEM16, both functions appear to be mediated by alternate protein conformations, which are at equilibrium in the ligand-bound state.
Knock-in rat lines with Cre recombinase at the dopamine D1 and adenosine 2a receptor loci
Authors: Pettibone Jeffrey R. , Yu Jai Y. , Derman Rifka C. , Faust Thomas W. , Hughes Elizabeth D. , Filipiak Wanda E. , Saunders Thomas L. , Ferrario Carrie R. , Berke Joshua D. 
Published: October 2018

ABSTRACTGenetically-modified mice have become standard tools in neuroscience research. Our understanding of the basal ganglia in particular has been greatly assisted by BAC mutants with selective transgene expression in striatal neurons forming the direct or indirect pathways. However, for more sophisticated behavioral tasks and larger intracranial implants, rat models are preferred. Furthermore, BAC lines can show variable expression patterns depending upon genomic insertion site. We therefore used CRISPR/Cas9 to generate two novel knock-in rat lines specifically encoding Cre recombinase immediately after the dopamine D1 receptor (Drd1a) or adenosine 2a receptor (Adora2a) loci. Here we validate these lines usingin situhybridization and viral vector mediated transfection to demonstrate selective, functional Cre expression in the striatal direct and indirect pathways respectively. We used whole-genome sequencing to confirm the lack of off-target effects, and established that both rat lines have normal locomotor activity and learning in simple instrumental and Pavlovian tasks. We expect these new D1-Cre and A2a-Cre rat lines will be widely used to study both normal brain functions and neurological and psychiatric pathophysiology.
Mendelian Randomization analysis reveals a causal influence of circulating sclerostin levels on bone mineral density and fractures
Authors: Zheng Jie , Maerz Winfried , Gergei Ingrid , Kleber Marcus , Drechsler Christiane , Wanner Christoph , Brandenburg Vincent , Reppe Sjur , Gautvik Kaare M , Medina-Gomez Carolina , Shevroja Enisa , Gilly Arthur , Park Young-Chan , Dedoussis George , Zeggini Eleftheria , Lorentzon Mattias , Henning Petra , Lerner Ulf H. , Nilsson Karin , Movérare-Skrtic Sofia , Baird Denis , Elsworth Benjamin , Falk Louise , Groom Alix , Capellini Terence D. , Grundberg Elin , Nethander Maria , Ohlsson Claes , Smith George Davey , Tobias Jonathan H. 
Published: October 2018

ABSTRACTIn bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two sample Mendelian Randomisation (MR). A genetic instrument for circulating sclerostin, derived from a genome wide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n= 32,744) in GEFOS, and estimated BMD by heel ultrasound (eBMD; n=426,824), and fracture risk (n=426,795), in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation (SD)) change in sclerostin per A allele (β=0.20, P=4.6×10−49), and GALNT1 (β=0.11 per G allele, P=4.4×10−11). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two SNPs as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β= −0.12, 95%CI= −0.20 to −0.05) and eBMD (β= −0.12, 95%CI= −0.14 to −0.10), and a positive relationship with fracture risk (β= 0.11, 95%CI= 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (Probability>99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis.
Definitive demonstration by synthesis of genome annotation completeness
Authors: Jaschke Paul R. , Dotson Gabrielle A , Hung Kay , Liu Diane , Endy Drew 
Published: October 2018

AbstractBacteriophage øX174 was the first DNA genome to be sequenced. The genome is well studied by classical methods and is known to encode 11 essential genes. At least 23 closely-relatedBullavirinaegenome sequences are now available. We identified 315 potential open reading frames (ORFs) within the genome via bioinformatic analysis, and a subset of 82 highly-conserved ORFs that have no known gene products or functions. Using genome scale design and synthesis we made a mutant genome in which all 11 essential genes are simultaneously disrupted, leaving intact only the 82 conserved-but-cryptic ORFs. The resulting genome is not viable, as expected. Cell-free gene expression followed by mass spectrometry revealed only a single peptide expressed from both the cryptic-ORF and wild-type genomes, suggesting a potential new gene. A second synthetic genome in which 71 conserved cryptic ORFs were simultaneously disrupted is viable but with ~50% reduced fitness relative to the wild type. However, rather than finding any new genes, repeated evolutionary adaptation revealed a single point mutation modulating translation of gene H, a known essential gene, that fully suppressed the fitness defect. Taken together, we conclude that the annotation of ORFs for the øX174 genome is formally complete. Sequencing and bioinformatics followed by synthesis-enabled reverse genomics, proteomics, and evolutionary adaptation can definitely establish the sufficiency and completeness of natural genome annotations.
Embedding single-cell experimental conditions to reveal manifold structure of cancer drug perturbation effects
Authors: Chen William S. , Zivanovic Nevena , van Dijk David , Wolf Guy , Bodenmiller Bernd , Krishnaswamy Smita 
Published: October 2018

AbstractPreviously, the effect of a drug on a cell population was measured based on simple metrics such as cell viability. However, as single-cell technologies are becoming more advanced, drug screen experiments can now be conducted with more complex readouts such as gene expression profiles of individual cells. The increasing complexity of measurements from these multi-sample experiments calls for more sophisticated analytical approaches than are currently available. We developed a novel method called PhEMD (Phenotypic Earth Mover’s Distance) and show that it can be used to embed the space of drug perturbations on the basis of the drugs’ effects on cell populations. When testing PhEMD on a newly-generated, 300-sample CyTOF kinase inhibition screen experiment, we find that the state space of the perturbation conditions is surprisingly low-dimensional and that the network of drugs demonstrates manifold structure. We show that because of the fairly simple manifold geometry of the 300 samples, we can accurately capture the full range of drug effects using a dictionary of only 30 experimental conditions. We also show that new drugs can be added to our PhEMD embedding using similarities inferred from other characterizations of drugs using a technique called Nystrom extension. Our findings suggest that large-scale drug screens can be conducted by measuring only a small fraction of the drugs using the most expensive high-throughput single-cell technologies—the effects of other drugs may be inferred by mapping and extending the perturbation space. We additionally show that PhEMD can be useful for analyzing other types of single-cell samples, such as patient tumor biopsies, by mapping the patient state space in a similar way as the drug state space. We demonstrate that PhEMD is scalable, compatible with leading batch effect correction techniques, and generalizable to multiple experimental designs. Altogether, our analyses suggest that PhEMD may facilitate drug discovery efforts and help uncover the network geometry of a collection of single-cell samples.
Proximity proteomics identifies cancer cell membrane cis-molecular complex as a potential cancer target
Authors: Kotani Norihiro , Yamaguchi Arisa , Ohnishi Tomoko , Kuwahara Ryusuke , Nakano Takanari , Nakano Yuka , Ida Yui , Murakoshi Takayuki , Honke Koichi 
Published: October 2018

ABSTRACTCancer-specific antigens expressed in the cell membrane have been used as targets for several molecular targeted strategies in recent years with remarkable success. To develop more effective cancer treatments, novel targets and strategies for targeted therapies are needed. Here, we examined the cancer cell membrane-resident “cis-bimolecular complex” as a possible cancer target (cis-bimolecular cancer target: BiCAT) using proximity proteomics, a technique that has attracted attention in recent years. BiCATs were detected using a previously developed method, termed the enzyme-mediated activation of radical source (EMARS), to label the components proximal to a given cell membrane molecule. EMARS analysis identified some BiCATs, such as close homolog of L1 (CHL1), fibroblast growth factor 3 (FGFR3) and α2 integrin, which are commonly expressed in mouse primary lung cancer cells and human lung squamous cell carcinoma cells. Analysis of cancer specimens from 55 lung cancer patients revealed that approximately half of patients were positive for these BiCATs. In vitro simulation of effective drug combinations used for multiple drug treatment strategy was performed using reagents targeted to BiCAT molecules. The combination treatment based on BiCAT information moderately suppressed cancer cell proliferation compared with single administration, suggesting that the information about BiCATs in cancer cells is profitable for the appropriate selection of the combination among molecular targeted reagents. Thus, BiCAT has the possibility to make a contribution to several molecular targeted strategies in future.
A multi-modal proteomics strategy for characterizing posttranslational modifications of tumor suppressor p53 reveals many sites but few modified forms
Authors: DeHart Caroline J. , Fornelli Luca , Anderson Lissa C. , Fellers Ryan T. , Lu Dan , Hendrickson Christopher L. , Lahav Galit , Gunawardena Jeremy , Kelleher Neil L. 
Published: October 2018

SummaryPost-translational modifications (PTMs) are found on most proteins, particularly on “hub” proteins like the tumor suppressor p53, which has over 100 possible PTM sites. Substantial crosstalk between PTM sites underlies the ability of such proteins to integrate diverse signals and coordinate downstream responses. However, disentangling the combinatorial explosion in global PTM patterns across an entire protein (“modforms”) has been challenging, as conventional peptide-based mass spectrometry strategies (so-called “bottom-up” MS) destroy such global correlations. Alternatively, direct analysis of intact and modified proteins using “top-down” MS retains global information. Here, we applied both strategies to recombinant p53 phosphorylatedin vitrowith Chk1 kinase, which exhibited 41 modified sites by bottom-up MS, but no more than 8 modified sites per molecule detected by top-down MS. This observation that many low-abundance modifications comprise relatively few modforms above a 1% threshold indicates that endogenous p53 PTM complexity may be more definable than previously thought.
Does closing the eyes enhance auditory attention? Eye closure increases attentional alpha-power modulation but not listening performance
Authors: Wöstmann Malte , Schmitt Lea-Maria , Obleser Jonas 
Published: October 2018

AbstractIn challenging listening conditions, closing the eyes is a strategy with intuitive appeal to improve auditory attention and perception. On the neural level, closing the eyes increases the power of alpha oscillations (∼10 Hz), which are a prime signature of auditory attention. Here, we test whether eye closure benefits neural and behavioural signatures of auditory attention and perception. Participants (N = 22) attended to one of two alternating streams of spoken numbers with open or closed eyes in a darkened chamber. After each trial, participants indicated whether probes had been among the to-be-attended or to-be-ignored numbers. In the electroencephalogram, states of relative high versus low alpha power accompanied the presentation of attended versus ignored numbers. Importantly, eye closure did not only increase the overall level of absolute alpha power but also the attentional modulation thereof. Behaviourally, however, neither perceptual sensitivity nor response criterion was affected by eye closure. To further examine whether this behavioural null-result would conceptually replicate in a simple auditory detection task, a follow-up experiment was conducted that required participants (N = 19) to detect a near-threshold target tone in noise. As in the main experiment, our results provide evidence for the absence of any difference in perceptual sensitivity and criterion for open versus closed eyes. In sum, we demonstrate here that the modulation of the human alpha rhythm by auditory attention is increased when participants close their eyes. However, our results speak against the widely held belief that eye closure per se improves listening behaviour.