bluuebunny/crossref_metadata_2025_split huggingface dataset:
An improved encoding of genetic variation in a Burrows-Wheeler transform
Authors: Büchler Thomas , Ohlebusch Enno 
Published: June 2019

AbstractMotivationIn resequencing experiments, a high-throughput sequencer produces DNA-fragments (called reads) and each read is then mapped to the locus in a reference genome at which it fits best. Currently dominant read mappers (Li and Durbin, 2009; Langmead and Salzberg, 2012) are based on the Burrows-Wheeler transform (BWT). A read can be mapped correctly if it is similar enough to a substring of the reference genome. However, since the reference genome does not represent all known variations, read mapping tends to be biased towards the reference and mapping errors may thus occur. To cope with this problem, Huang et al. (2013) encoded SNPs in a BWT by the IUPAC nucleotide code (Cornish-Bowden, 1985). In a different approach, Maciuca et al. (2016) provided a ‘natural encoding’ of SNPs and other genetic variations in a BWT. However, their encoding resulted in a significantly increased alphabet size (the modified alphabet can have millions of new symbols, which usually implies a loss of efficiency). Moreover, the two approaches do not handle all known kinds of variation.ResultsIn this article, we propose a method that is able to encode many kinds of genetic variation (SNPs, MNPs, indels, duplications, transpositions, inversions, and copy-number variation) in a BWT. It takes the best of both worlds: SNPs are encoded by the IUPAC nucleotide code as in (Huang et al., 2013) and the encoding of the other kinds of genetic variation relies on the idea introduced in (Maciuca et al., 2016). In contrast to Maciuca et al. (2016), however, we use only one additional symbol. This symbol marks variant sites in a chromosome and delimits multiple variants, which are added at the end of the ‘marked chromosome’. We show how the backward search algorithm, which is used in BWT-based read mappers, can be modified in such a way that it can cope with the genetic variation encoded in the BWT. We implemented our method and compared it to BWBBLE (Huang et al., 2013) and gramtools (Maciuca et al., 2016).Availabilityhttps://www.uni-ulm.de/in/theo/research/seqana/Contact:Enno.Ohlebusch@uni-ulm.de
Preadaptation of pandemic GII.4 noroviruses in hidden virus reservoirs years before emergence
Authors: Ruis Christopher , Lindesmith Lisa C. , Mallory Michael L. , Brewer-Jensen Paul D. , Bryant Josephine M. , Costantini Veronica , Monit Christopher , Vinjé Jan , Baric Ralph S. , Goldstein Richard A. , Breuer Judith 
Published: June 2019

AbstractThe control of pandemic pathogens depends on early prediction of pandemic variants and, more generally, understanding origins of such variants and factors that drive their global spread. This is especially important for GII.4 norovirus, where vaccines under development offer promise to prevent hundreds of millions of annual gastroenteritis cases. Previous studies have suggested that new GII.4 pandemic viruses evolve from previous pandemic variants through substitutions in the antigenic region of the VP1 protein that enable evasion of host population immunity, leading to global spread. In contrast, we show here that the acquisition of new genetic and antigenic characteristics is not the proximal driver of new pandemics. Instead, pandemic GII.4 viruses circulate undetected for years before causing a new pandemic, during which time they diversify and spread over wide geographical areas. Serological data demonstrate that by 2003, some nine years before it emerged as a new pandemic, the ancestral 2012 pandemic strain had already acquired the antigenic characteristics that allowed it to evade prevailing population immunity against the previous 2009 pandemic variant. These results provide strong evidence that viral genetic changes are necessary but not sufficient for GII.4 pandemic spread. Instead, we suggest that it is changes in host population immunity that enable pandemic spread of an antigenically-preadapted GII.4 variant. These results indicate that predicting future GII.4 pandemic variants will require surveillance of currently unsampled reservoir populations. Furthermore, a broadly acting GII.4 vaccine will be critical to prevent future pandemics.SignificanceNorovirus pandemics and their associated public health and economic costs could be prevented by effective vaccines. However, vaccine development and distribution will require identification of the sources and drivers of new pandemics. We here use phylogenetics and serological experiments to develop and test a new hypothesis of pandemic norovirus emergence. We find that pandemic noroviruses preadapt, diversify and spread worldwide years prior to emergence, strongly indicating that genetic changes are necessary but not sufficient to drive a new pandemic. We instead suggest that changes in population immunity enable pandemic emergence of a pre-adapted low-level variant. These findings indicate that prediction of new pandemics will require surveillance of under-sampled virus reservoirs and that norovirus vaccines will need to elicit broad immunity.
A gall-forming insect manipulates hostplant phytohormone synthesis, concentrations, and signaling
Authors: Body Mélanie J. A. , Appel Heidi M. , Edger Patrick P. , Schultz Jack C. 
Published: June 2019

AbstractInsect galls are highly specialized plant organs formed by an intimate biochemical interaction between the plant and a gall-inducing insect. Galls provide the insect enhanced nutrition and protection against natural enemies and environmental stresses. Because galls are plant organs, their development is likely to be governed by native phytohormones that function in organogenesis. We characterized concentrations of both growth and stress phytohormones in ungalled leaves and the leaf galls of Daktulosphaira vitifoliae on wild grape Vitis riparia at 4 different developmental stages. We found clear evidence of hormone manipulation by phylloxera during gall initiation and development. Phylloxera suppressed accumulation of of gibberellins, auxin, and jasmonates during the first two gall stages while absiscic acid concentrations were suppressed throughout development. Concentrations of 3 cytokinins and salicylate were greatly elevated during the earliest gall stage and declined sharply thereafter. We found no evidence of expression of cytokinin biosynthesis genes during the first gall stage, which strongly suggests that phylloxera supplied those phytohormones. High salicylate concentrations could have been caused by cytokinins, a response to microbes, or both. Our results suggest a central role for cytokinins in gall initiation and indicate the importance of the insect’s ability to manipulate other hormones.
Benefits of commitment in hierarchical inference
Authors: Qiu Cheng , Luu Long , Stocker Alan A. 
Published: June 2019

AbstractHumans have the tendency to commit to a single interpretation of what has caused some observed evidence rather than considering all possible alternatives. This tendency can explain various forms of confirmation and reference biases. However, committing to a single high-level interpretation seems short-sighted and irrational, and thus it is unclear why humans seem motivated to pursue such strategy.In a first step toward answering this question, we systematically quantified how this strategy affects estimation accuracy at the feature level in the context of two universal hierarchical inference tasks, categorical perception and causal cue combination. Using model simulations, we demonstrate that although estimation is generally impaired when conditioned on only a single high-level inter-pretation, the impairment is not uniform across the entire feature range. On the contrary, compared to a full inference strategy that considers all high-level interpretations, accuracy is actually better for feature values for which the probability of an incorrect categorical/structural commitment is relatively low. That is to say, if an observer is reasonably certain about the high-level interpretation of the feature, it is advantageous to condition subsequent feature inference only on that particular interpretation. We also show that this benefit of commitment is substantially amplified if late noise corrupts information processing (e.g., during retention in working memory). Our results suggest that top-down inference strategies that solely rely on the most likely high-level interpretation can be favorable and at least locally outperform a full inference strategy.
Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3
Authors: Huang Kerui , Miao Ting , Chang Kai , Kang Ping , Jiang Qiuhan , Simmonds Andrew J. , Cara Francesca Di , Bai Hua 
Published: June 2019

AbstractAge is a major risk factor for cardiovascular diseases. Currently, the non-autonomous regulation of age-related cardiac dysfunction is poorly understood. In the present study, we discover that age-dependent induction of cytokine unpaired 3 (Upd3) in Drosophila oenocytes (hepatocyte-like cells), due to a dampened peroxisomal import function, is the primary non-autonomous mechanism for elevated arrhythmicity in old hearts. We show that Upd3 is significantly up-regulated (52-fold) in aged oenocytes. Oenocyte-specific knockdown of Upd3 is sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent induction of Upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in aged oenocytes. Intriguingly, oenocyte-specific over-expression of Pex5, the key peroxisomal import receptor, restores peroxisomal import, blocks age-related Upd3 induction, and alleviates aging- and paraquat-induced cardiac arrhythmicity. Thus, our studies identify an important role of the evolutionarily conserved pro-inflammatory cytokine signaling and hepatocyte-specific peroxisomal import in mediating non-autonomous regulation of cardiac aging.
Suppression of store-operated calcium entry causes dilated cardiomyopathy of the Drosophila heart
Authors: Petersen Courtney E. , Wolf Matthew J. , Smyth Jeremy T. 
Published: June 2019

ABSTRACTStore-operated Ca2+ entry (SOCE) is an essential Ca2+ signaling and homeostatic mechanism present in nearly all animal cells. SOCE refers to influx of Ca2+ into cells that is activated by depletion of endoplasmic or sarcoplasmic reticulum stores (ER/SR) Ca2+ stores. In the SOCE pathway, STIM proteins function as Ca2+ sensors in the ER, and upon ER Ca2+ store depletion STIM rearranges to ER-plasma membrane junctions where it activates Orai Ca2+ influx channels. Multiple studies have implicated STIM and Orai mediated SOCE in the pathogenesis of cardiac hypertrophy. Importantly however, the functional roles of SOCE in normal heart physiology have not been well defined. We have addressed this in Drosophila melanogaster, a powerful animal model of cardiac development and physiology. We show that heart specific suppression of Drosophila Stim and Orai resulted in reduced contractility consistent with dilated cardiomyopathy, characterized by increased end diastolic and end systolic dimensions and decreased fractional shortening. Reduced contractility was apparent in larval hearts and became more pronounced in adults. Myofibers were disorganized and more widely spaced in larval and adult hearts with Stim and Orai RNAi as compared to controls, possibly reflecting decompensation or upregulated stress response signaling due to altered Ca2+ homeostasis. Lastly, we show that reduced heart function significantly affected animal health and viability, as animals with heart specific Stim and Orai suppression exhibited significant delays in post-embryonic development and adults died significantly earlier than controls. Collectively, our results demonstrate that SOCE is essential for normal heart physiology and establish Drosophila as an important model for delineation of functional SOCE roles in cardiomyocytes.
A mouse model of recurrent myocardial infarction reports diminished emergency hematopoiesis and cardiac inflammation
Authors: Cremer Sebastian , Schloss Maximilian J. , Vinegoni Claudio , Zhang Shuang , Rohde David , Feruglio Paolo Fumene , Schmidt Stephen , Wojtkiewicz Greg , Weissleder Ralph , Swirski Filip K. , Nahrendorf Matthias 
Published: June 2019

AbstractRecurrent MI is common in patients with coronary artery disease and associates with high mortality. Here we developed a surgical mouse model in which two subsequent MIs affect different left ventricular regions in the same mouse. Recurrent MI was induced by ligating the left circumflex followed by the left anterior descending branch of the coronary artery. We characterized the resulting ischemia by whole-heart fluorescent coronary angiography after optical organ clearing and by cardiac MRI. We report that a first MI induces bone marrow “memory” via a circulating signal, thereby affecting hematopoietic factor expression in bone marrow macrophages. This altered the organism’s reaction to subsequent events. Inspite at least similar extent of injury reported by blood troponin, recurrent MI caused reduced emergency hematopoiesis and less leukocytosis than a first MI. Consequently, fewer leukocytes migrated to the ischemic myocardium. The hematopoietic response to lipopolysaccharide was also mitigated after a previous MI. Our data suggest that hematopoietic and innate immune responses are shaped by a preceding MI.
Microbial community-level features linked to divergent carbon flows during early litter decomposition in a constant environment
Authors: Johansen Renee , Albright Michaeline , Lopez Deanna , Gallegos-Graves La Verne , Runde Andreas , Mueller Rebecca , Washburne Alex , Yoshida Thomas , Dunbar John 
Published: June 2019

AbstractDuring plant litter decomposition in soils, carbon has two general fates: return to the atmosphere via microbial respiration or transport into soil where long-term storage may occur. Discovering microbial community features that drive carbon fate from litter decomposition may improve modeling and management of soil carbon. This concept assumes there are features (or underlying processes) that are widespread among disparate communities, and therefore amenable to modeling. We tested this assumption using an epidemiological approach in which two contrasting patterns of carbon flow in laboratory microcosms were delineated as functional states and diverse microbial communities representing each state were compared to discover shared features linked to carbon fate. Microbial communities from 206 soil samples from the southwestern United States were inoculated on plant litter in microcosms, and carbon flow was measured as cumulative carbon dioxide (CO2) and dissolved organic carbon (DOC) after 44 days. Carbon flow varied widely among the microcosms, with a 2-fold range in cumulative CO2efflux and a 5-fold range in DOC quantity. Bacteria, not fungi, were the strongest drivers of DOC variation. The most significant community-level feature linked to DOC abundance was bacterial richness—the same feature linked to carbon fate in human-gut microbiome studies. This proof-of-principle study under controlled conditions suggests common features driving carbon flow in disparate microbial communities can be identified, motivating further exploration of underlying mechanisms that may influence carbon fate in natural ecosystems.
Distinct neural mechanisms for the prosocial and rewarding properties of MDMA
Authors: Heifets Boris D. , Salgado Juliana S. , Taylor Madison D. , Hoerbelt Paul , Cardozo Pinto Daniel F. , Steinberg Elizabeth E. , Walsh Jessica J. , Sze Ji Y. , Malenka Robert C. 
Published: June 2019

AbstractThe extensively abused recreational drug MDMA has shown promise as an adjunct to psychotherapy for treatment-resistant psychiatric disease. It is unknown, however, whether the mechanisms underlying its prosocial therapeutic effects and abuse potential are distinct. We demonstrate in mice that MDMA acting at the serotonin transporter within the nucleus accumbens is necessary and sufficient for MDMA’s prosocial effect. MDMA’s acute rewarding properties, in contrast, require dopaminergic signaling. MDMA’s prosocial effect requires 5-HT1b receptor activation and is mimicked by d-fenfluramine, a selective serotonin-releasing compound. By dissociating the mechanisms of MDMA’s prosocial effects from its addictive properties, we provide evidence for a conserved neuronal pathway, which can be leveraged to develop novel therapeutics with limited abuse liability.One Sentence SummaryMDMA, which has both therapeutic and abuse potential, engages a brain region-specific serotonergic pathway to produce its prosocial effect.
Identification of peptide coatings that enhance diffusive transport of nanoparticles through the tumor microenvironment
Authors: Mohanty Rashmi P. , Liu Xinquan , Kim Jae Y. , Peng Xiujuan , Bhandari Sahil , Leal Jasmim , Arasappan Dhivya , Wylie Dennis , Dong Tony , Ghosh Debadyuti 
Published: June 2019

In solid tumors, increasing drug penetration promotes their regression and improves the therapeutic index of compounds. However, the heterogeneous extracellular matrix (ECM) acts a steric and interaction barrier that hinders effective transport of therapeutics, including nanomedicines. Specifically, the interactions between the ECM and surface physicochemical properties of nanomedicines (e.g. charge, hydrophobicity) impedes their diffusion and penetration. To address the challenges using existing surface chemistries, we used peptide-presenting phage libraries as a high-throughput approach to screen and identify peptides as coatings with desired physicochemical properties that improve diffusive transport through the tumor microenvironment. Through iterative screening against the ECM and identification by next-generation DNA sequencing and analysis, we selected individual clones and measured their transport by diffusion assays. Here, we identified a net-neutral charge, hydrophilic peptide P4 that facilitates significantly higher diffusive transport of phage than negative control through in vitro tumor ECM. Through alanine mutagenesis, we confirmed that the hydrophilicity, charge, and their spatial ordering impact diffusive transport. P4 phage clone exhibited almost 200-fold improved uptake in ex vivo pancreatic tumor xenografts compared to the negative control. Nanoparticles coated with P4 exhibited ∼40-fold improvement in diffusivity in pancreatic tumor tissues, and P4-coated particles demonstrated less hindered diffusivity through the ECM compared to particles functionalized with gold standard poly(ethylene) glycol or iRGD peptide ligand. By leveraging the power of molecular diversity using phage display, we can greatly expand the chemical space of surface chemistries that can improve the transport of nanomedicines through the complex tumor microenvironment to ultimately improve their efficacy.Abstract Figure
M13 phage display to identify a permeating peptide against hyperconcentrated mucin
Authors: Leal Jasmim , Dong Tony , Gao Feng , Soto Melissa , Smyth Hugh D.C. , Ghosh Debadyuti 
Published: June 2019

ABSTRACTMucus is an impregnable barrier for drug delivery across the epithelia for treatment of mucosal-associated diseases. While current carriers are promising for mucus penetration, their surface chemistries do not possess chemical complexity to probe and identify optimal physicochemical properties desired for mucus penetration. As initial study, we use M13 phage display presenting random peptides to select peptides that can facilitate permeation through hyperconcentrated mucin. Here, a net-neutral charge, hydrophilic peptide was identified to facilitate transport of phage and fluorophore conjugates through mucin barrier compared to controls. This initial finding warrants further study to understand how composition and spatial distribution of physicochemical properties of peptides can be optimized to improve transport across the mucus barrier.
Divide and Conquer: Real-time maximum likelihood fitting of multiple emitters for super-resolution localization microscopy
Authors: Li Luchang , Xin Bo , Kuang Weibing , Zhou Zhiwei , Huang Zhen-Li 
Published: June 2019

AbstractMulti-emitter localization has great potential for maximizing the imaging speed of super-resolution localization microscopy. However, the slow image analysis speed of reported multi-emitter localization algorithms limits their usage in mostly off-line image processing with small image size. Here we adopt the well-known divide and conquer strategy in computer science and present a fitting-based method called QC-STORM for fast multi-emitter localization. Using simulated and experimental data, we verify that QC-STORM is capable of providing real-time full image processing on raw images with 100 µm × 100 µm field of view and 10 ms exposure time, with comparable spatial resolution as the popular fitting-based ThunderSTORM and the up-to-date non-iterative WindSTORM. This study pushes the development and practical use of super-resolution localization microscopy in high-throughput or high-content imaging of cell-to-cell differences or discovering rare events in a large cell population.
Adaptive laboratory evolution ofEscherichia coliunder acid stress
Authors: Du Bin , Olson Connor A. , Sastry Anand V. , Fang Xin , Phaneuf Patrick V. , Chen Ke , Wu Muyao , Szubin Richard , Xu Sibei , Gao Ye , Hefner Ying , Feist Adam M. , Palsson Bernhard O. 
Published: June 2019

AbstractThe ability ofEscherichia colito tolerate acid stress is important for its survival and colonization in the human digestive tract. Here, we performed adaptive laboratory evolution of the laboratory strainE. coliK-12 MG1655 at pH 5.5 in glucose minimal medium. By 800 generations, six independent populations under evolution reached 18.0% higher growth rates than their starting strain at pH 5.5, while maintaining comparable growth rates to the starting strain at pH 7. We characterized the evolved strains to find that: (1) whole genome sequencing of isolated clones from each evolved population revealed mutations inrpoCappearing in 5 of 6 sequenced clones; (2) gene expression profiles revealed different strategies to mitigate acid stress, that are related to amino acid metabolism and energy production and conversion. Thus, a combination of adaptive laboratory evolution, genome resequencing, and expression profiling reveals, on a genome-scale, the strategies thatE. colideploys to mitigate acid stress.