bluuebunny/crossref_metadata_2025_split huggingface dataset:
An exhaustive analysis of single amino acid variants in helical transmembrane proteins
Authors: Llorian-Salvador Oscar , Bernhofer Michael , Mahlich Yannick , Rost Burkhard 
Published: December 2019

AbstractSingle nucleotide variants (SNVs) have been widely studied in the past due to being the main source of human genetic variation. Less is known about the effect of single amino acid variants (SAVs) due to the immense resources required for comprehensive experimental studies. In contrast, in silico methods predicting the effects of sequence variants upon molecular function and upon the organism are readily available and have contributed unexpected suggestions, e.g. that SAVs common to a human population (shared by >5% of the population) have, on average, more significant impact on the molecular function of proteins than do rare SAVs (shared by <1% of the population). Here, we investigated the impact of variants in a human population upon helical transmembrane proteins (TMPs). Three main results stood out. Firstly, common SAVs, on average, have stronger effects than rare SAVs for TMPs, and are enriched, in particular, in the membrane helices. Secondly, proteins with seven transmembrane helices (7TM, including GPCRs, i.e. G protein-coupled receptors) are depleted of SAVs in comparison to other proteins, possibly due to increased evolutionary constraints in these important proteins. Thirdly, rare SAVs with strong effect are significantly absent (over common SAVs) in signal peptide regions.
Lost and found: re-searching and re-scoring proteomics data aids the discovery of bacterial proteins and improves proteome coverage
Authors: Willems Patrick , Fijalkowski Igor , Van Damme Petra 
Published: December 2019

ABSTRACTProkaryotic genome annotation is heavily dependent on automated gene annotation pipelines that are prone to propagate errors and underestimate genome complexity. We describe an optimized proteogenomic workflow that uses ribo-seq and proteomic data ofSalmonella Typhiumuriumto identify unannotated proteins or alternative protein forms raised upon alternative translation initiation (i.e. N-terminal proteoforms). This data analysis encompasses the searching of co-fragmenting peptides and post-processing with extended peptide-to-spectrum quality features including comparison to predicted fragment ion intensities. When applying this strategy, an enhanced proteome-depth is achieved as well as greater confidence for unannotated peptide hits. We demonstrate the general applicability of our pipeline by re-analyzing publicDeinococcus radioduransdatasets. Taken together, systematic re-analysis using available prokaryotic (proteome) datasets holds great promise to assist in experimentally-based genome annotation.
Methods for combining multiple correlated biomarkers with application to the study of low-grade inflammation and muscle mass in senior horses
Authors: Vsevolozhskaya Olga A. , Herbst Alisa C. , Adams Amanda A. , Burns Cailey , Cantu Bertsie , Barker Virginia D. , Zaykin Dmitri V. 
Published: December 2019

AbstractThe simplest analysis of biomarker data is based on a series of single biomarker hypothesis tests, followed by correction for multiple testing. However, it is intuitively plausible that a joint analysis of multiple biomarkers will have higher statistical power and promise improved discrimination over tests based on single markers. In this article, we study analytical properties of the approach for joint analysis of correlated summary statistics based on the test for quadratic forms (TQ). Based on the derivation of the TQ-distribution, we proposed a scale-location approximation of the TQ statistic, which we call approximate TQ. We show that the approximate TQ has very similar power to the traditional TQ test under varying correlation structures among biomarkers. Our application of both the TQ and the approximate TQ test to data on biomarkers for inflamm-aging – an age-related low-grade chronic inflammation – reveals an association between the percentage of IFNγ positive lymphocytes and overall muscle condition in senior horses.
Tuning Extracellular Electron Transfer byShewanella oneidensisUsing Transcriptional Logic Gates
Authors: Dundas Christopher M. , Keitz Benjamin K. 
Published: December 2019

AbstractExtracellular electron transfer pathways, such as those in the bacteriumShewanella oneidensis, interface cellular metabolism with a variety of redox-driven applications. However, designer control over EET flux inS. oneidensishas proven challenging since a functional understanding of its EET pathway proteins and their effect on engineering parameterizations (e.g., response curves, dynamic range) is generally lacking. To address this, we systematically altered transcription and translation of single genes encoding parts of the primary EET pathway ofS. oneidensis, CymA/MtrCAB, and examined how expression differences affected model-fitted parameters for Fe(III) reduction kinetics. Using a suite of plasmid-based inducible circuits maintained by appropriateS. oneidensisknockout strains, we pinpointed construct/strain pairings that expressedcymA, mtrA, andmtrCwith maximal dynamic range of Fe(III) reduction rate. These optimized EET gene constructs were employed to create Buffer and NOT gate architectures, that predictably turn on and turn off EET flux, respectively, in response to IPTG. Furthermore, we found that response functions generated by these logic gates (i.e., EET activity vs. inducer concentration) were comparable to those generated by conventional synthetic biology circuits, where fluorescent reporters are the output. Our results provide insight on programming EET activity with transcriptional logic gates and suggest that previously developed transcriptional circuitry can be adapted to predictably control EET flux.
Resolving the spatial profile of figure enhancement in human V1 through population receptive field modeling
Authors: Poltoratski Sonia , Tong Frank 
Published: December 2019

AbstractThe detection and segmentation of meaningful figures from their background is a core function of vision. While work in non-human primates has implicated early visual mechanisms in this figure-ground modulation, neuroimaging in humans has instead largely ascribed the processing of figures and objects to higher stages of the visual hierarchy. Here, we used high-field fMRI at 7Tesla to measure BOLD responses to task-irrelevant orientation-defined figures in human early visual cortex, and employed a novel population receptive field (pRF) mapping-based approach to resolve the spatial profiles of two constituent mechanisms of figure-ground modulation: a local boundary response, and a further enhancement spanning the full extent of the figure region that is driven by global differences in features. Reconstructing the distinct spatial profiles of these effects reveals that figure enhancement modulates responses in human early visual cortex in a manner consistent with a mechanism of automatic, contextually-driven feedback from higher visual areas.Significance StatementA core function of the visual system is to parse complex 2D input into meaningful figures. We do so constantly and seamlessly, both by processing information about visible edges and by analyzing large-scale differences between figures and background. While influential neurophysiology work has characterized an intriguing mechanism that enhances V1 responses to perceptual figures, we have a poor understanding of how the early visual system contributes to figure-ground processing in humans. Here, we use advanced computational analysis methods and high-field human fMRI data to resolve the distinct spatial profiles of local edge and global figure enhancement in the early visual system (V1 and LGN); the latter is distinct and consistent a mechanism of automatic, stimulus-driven feedback from higher-level visual areas.
Visualizing the metazoan proliferation-terminal differentiation decisionin vivo
Authors: Adikes Rebecca C. , Kohrman Abraham Q. , Martinez Michael A. Q. , Palmisano Nicholas J. , Smith Jayson J. , Medwig-Kinney Taylor N. , Min Mingwei , Sallee Maria D. , Ahmed Ononnah B. , Kim Nuri , Liu Simeiyun , Morabito Robert D. , Weeks Nicholas , Zhao Qinyun , Zhang Wan , Feldman Jessica L. , Barkoulas Michalis , Pani Ariel M. , Spencer Sabrina L. , Martin Benjamin L. , Matus David Q. 
Published: December 2019

SummaryCell proliferation and terminal differentiation are intimately coordinated during metazoan development. Here, we adapt a cyclin-dependent kinase (CDK) sensor to uncouple these cell cycle-associated events live inC. elegansand zebrafish. The CDK sensor consists of a fluorescently tagged CDK substrate that steadily translocates from the nucleus to the cytoplasm in response to increasing CDK activity and consequent sensor phosphorylation. We show that the CDK sensor can distinguish cycling cells in G1 from terminally differentiated cells in G0, revealing a commitment point and a cryptic stochasticity in an otherwise invariantC. eleganscell lineage. We also derive a predictive model of future proliferation behavior inC. elegansand zebrafish based on a snapshot of CDK activity in newly born cells. Thus, we introduce a live-cell imaging tool to facilitatein vivostudies of cell cycle control in a wide-range of developmental contexts.
Fully Human Monoclonal Antibodies Effectively Neutralizing Botulinum Neurotoxin Serotype B
Authors: Matsumura Takuhiro , Amatsu Sho , Misaki Ryo , Yutani Masahiro , Du Anariwa , Kohda Tomoko , Fujiyama Kazuhito , Ikuta Kazuyoshi , Fujinaga Yukako 
Published: December 2019

ABSTRACTBotulinum neurotoxin (BoNT) is the most potent natural toxin known. Of the seven BoNT serotypes (A to G), types A, B, E, and F cause human botulism. Treatment of human botulism requires the development of effective toxin-neutralizing antibodies without side effects such as serum sickness and anaphylaxis. In this study, we generated fully human monoclonal antibodies (HuMAbs) against serotype B BoNT (BoNT/B1) using a murine–human chimera fusion partner cell line named SPYMEG. Of these HuMAbs, M2, which specifically binds to the light chain of BoNT/B1, showed neutralization activity in a mouse bioassay (approximately ≥ 100 i.p. LD50/mg of antibody), and M4, which binds to the C-terminal of heavy chain, showed partial protection. The combination of M2 and M4 was able to completely neutralize BoNT/B1 with a potency greater than 10,000 i.p. LD50/mg of antibodies, and was effective both prophylactically and therapeutically in the mouse model of botulism. Moreover, this combination showed broad neutralization activity against three type B subtypes, namely BoNT/B1, BoNT/B2, and BoNT/B6. These data demonstrate that the combination of M2 and M4 is promising in terms of a foundation for new human therapeutics for BoNT/B intoxication.IMPORTANCEBotulinum neurotoxins (BoNTs) produced byClostridium botulinumand related species cause human botulism. Immunotherapy is the most effective treatment for botulism and equine immune serum formulations are used in cases of human botulism. However, these antisera may cause serum sickness or anaphylaxis. Additionally, the production of immune sera involves complicated and time-consuming manufacturing processes and quality management. Therefore, the development of safe, effective, and higher productive antibodies is required. Here we generated fully human monoclonal antibodies against serotype B BoNT (BoNT/B). We found that the combination of these antibodies (M2+M4) had potent and broad neutralization activity against BoNT/B, and showed therapeutic and preventive effects against botulism in mouse models. These data indicate that M2+M4 are promising candidates for the development of human therapeutics and prophylactics for BoNT/B intoxication.
A clinically and genomically annotated nerve sheath tumor biospecimen repository
Authors: Pollard Kai , Banerjee Jineta , Doan Xengie , Wang Jiawan , Guo Xindi , Allaway Robert , Langmead Shannon , Slobogean Bronwyn , Meyer Christian F. , Loeb David M. , Morris Carol D. , Belzberg Allan J. , Blakeley Jaishri O. , Rodriguez Fausto J. , Guinney Justin , Gosline Sara J.C. , Pratilas Christine A. 
Published: December 2019

AbstractNerve sheath tumors occur as a heterogeneous group of neoplasms in patients with neurofibromatosis type 1 (NF1). The malignant form represents the most common cause of death in people with NF1, and even when benign, these tumors can result in significant disfigurement, neurologic dysfunction, and a range of profound symptoms. Lack of human tissue across the peripheral nerve tumors common in NF1 has been a major limitation in the development of new therapies. To address this unmet need, we have created an annotated collection of patient tumor samples, patient-derived cell lines, and patient-derived xenografts, and carried out high-throughput genomic and transcriptomic characterization to serve as a resource for further biologic and preclinical therapeutic studies. In this work, we release genomic and transcriptomic datasets comprised of 55 tumor samples derived from 23 individuals, complete with clinical annotation. All data are publicly available through the NF Data Portal and athttp://synapse.org/jhubiobank.
Neural evidence of cognitive conflict during binocular rivalry
Authors: Drew Alice , Torralba Mireia , Ruzzoli Manuela , Fernández Luis Morís , Sabaté Alba , Pápai Márta Szabina , Soto-Faraco Salvador 
Published: December 2019

AbstractTo make sense of ambiguous and, at times, incomplete sensory input, the brain relies on a process of active interpretation. At any given moment, only one of several possible perceptual outcomes prevails in our conscious experience. Our hypothesis is that the competition between alternative representations induces cognitive conflict, eventually leading to fluctuations between different perceptual interpretations. We used binocular rivalry, a popular protocol to probe changes in perceptual awareness [1–3] and drew on the conflict monitoring theory, which holds that cognitive control is invoked by the detection of conflict during information processing. We looked for an increase in power of fronto-medial theta oscillations (5-7 Hz), an established EEG marker of conflict detection [4–7]. Our results show that fm-theta power increases right before perceptual alternations and decreases thereafter, suggesting that conflict monitoring is related to perceptual competition. Furthermore, to investigate conflict resolution via attentional engagement, as held by the conflict monitoring theory [8], we also looked for changes in parieto-occipital alpha oscillations (8-12 Hz) associated to perceptual switches. These oscillations have been associated to attention allocation via functional inhibition in sensory cortices [9–12]. The power of parieto-occipital alpha was inversely related to that of fm-theta, reflecting periods of high inter-ocular inhibition during stable perception, and low inhibition around moments of perceptual change. Our findings validate a prediction made 20 years ago in the seminal paper formulating the conflict monitoring theory, and establish a previously unknown link between conflict mechanisms and the processes leading to perceptual awareness.HighlightsBinocular rivalry induces conflict between competing perceptual representationsMid-frontal theta power increases around the resolution of perceptual conflictPosterior alpha decreases reflect neural excitability around perceptual switchesThe results link cognitive conflict theory with perceptual inference
Genomic analysis of carbapenemase-encoding plasmids fromKlebsiella pneumoniaeacross Europe highlights three major patterns of dissemination
Authors: David Sophia , Cohen Victoria , Reuter Sandra , Sheppard Anna E. , Giani Tommaso , Parkhill Julian ,   the European Survey of Carbapenemase-Producing Enterobacteriaceae (EuSCAPE) Working Group,   the ESCMID Study Group for Epidemiological Markers (ESGEM), Rossolini Gian Maria , Feil Edward J. , Grundmann Hajo , Aanensen David M. 
Published: December 2019

AbstractThe incidence ofKlebsiella pneumoniaeinfections that are resistant to carbapenems, a last-line class of antibiotics, has been rapidly increasing. The primary mechanism of carbapenem resistance is production of carbapenemase enzymes, which are most frequently encoded on plasmids byblaOXA-48-like,blaVIM,blaNDMandblaKPCgenes. Using short-read sequence data, we previously analysed genomes of 1717 isolates from theK. pneumoniaespecies complex submitted during the European survey of carbapenemase-producingEnterobacteriaceae(EuSCAPE). Here, we investigated the diversity, prevalence and transmission dynamics of carbapenemase-encoding plasmids using long-read sequencing of representative isolates (n=79) from this collection in combination with short-read data from all isolates. We highlight three major patterns by which carbapenemase genes have disseminated via plasmids. First,blaOXA-48-likegenes have spread across diverse lineages primarily via a highly conserved, epidemic pOXA-48-like plasmid. Second,blaVIMandblaNDMgenes have spread via transient associations of diverse plasmids with numerous lineages. Third,blaKPCgenes have transmitted predominantly by stable association with one clonal lineage (ST258/512) despite frequent mobilisation between pre-existing yet diverse plasmids within the lineage. Despite contrasts in these three modes of carbapenemase gene spread, which can be summarised as using one plasmid/multiple lineages, multiple plasmids/multiple lineages, and multiple plasmids/one lineage, all are underpinned by significant propagation along high-risk clonal lineages.
UMAP does not preserve global structure any better than t-SNE when using the same initialization
Authors: Kobak Dmitry , Linderman George C. 
Published: December 2019

AbstractOne of the most ubiquitous analysis tools employed in single-cell transcriptomics and cytometry is t-distributed stochastic neighbor embedding (t-SNE) [1], used to visualize individual cells as points on a 2D scatter plot such that similar cells are positioned close together. Recently, a related algorithm, called uniform manifold approximation and projection (UMAP) [2] has attracted substantial attention in the single-cell community. InNature Biotechnology, Becht et al. [3] argued that UMAP is preferable to t-SNE because it better preserves the global structure of the data and is more consistent across runs. Here we show that this alleged superiority of UMAP can be entirely attributed to different choices of initialization in the implementations used by Becht et al.: t-SNE implementations by default used random initialization, while the UMAP implementation used a technique called Laplacian eigenmaps [4] to initialize the embedding. We show that UMAP with random initialization preserves global structure as poorly as t-SNE with random initialization, while t-SNE with informative initialization performs as well as UMAP with informative initialization. Hence, contrary to the claims of Becht et al., their experiments do not demonstrate any advantage of the UMAP algorithmper se, but rather warn against using random initialization.
Identification of a Novel Retrieval-Dependent Memory Process in the CrabNeohelice granulata
Authors: Merlo Santiago A. , Santos Maria J. , Pedreira Maria E. , Merlo Emiliano 
Published: December 2019

AbstractFully consolidated associative memories may be altered by alternative retrieval dependent memory processes. While a brief exposure to the conditioned stimulus (CS) can trigger reconsolidation of the original memory, a prolonged CS exposure will trigger memory extinction. The conditioned response is maintained after reconsolidation, but is inhibited after extinction, presumably by the formation of a new inhibitory memory trace. In rats and humans, it has been shown that CS exposure of intermediate duration leave the memory in an insensitive or limbo state. Limbo is characterised by the absence of reconsolidation or extinction. Here we investigated the evolutionary conserved nature of limbo using a contextual Pavlovian conditioning (CPC) memory paradigm in the crabNeohelice granulata. In animals with fully consolidated CPC memory, systemic administration of the protein synthesis inhibitor cycloheximide after 1 CS presentation disrupted the memory, presumably by interfering with memory reconsolidation. The same intervention given after 320 CSs prevented CPC memory extinction. Cycloheximide had no behavioural effect when administered after 80 CS presentations, a protocol that failed to extinguish CPC memory. Also, we observed that a stronger CPC memory engaged reconsolidation after 80 CS instead of limbo, indicating that memory strength affects the parametrical conditions to engage either reconsolidation or limbo. Altogether, these results indicate that limbo is an evolutionary conserved memory process segregating reconsolidation from extinction in the number of CSs space. Limbo appears as an intrinsic component of retrieval dependent memory processing, with a key function in the transition from memory maintenance to inhibition.Author statement (CRediT Roles)Santiago A. Merlo:Conceptualization, Data curation, Formal Analysis, Investigation, Software, Validation, Visualization, Writing – original draft, Writing – review & editing.Jimena Santos:Investigation, Writing – review & editing.Maria Eugenia Pedreira:Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing.Emiliano Merlo:Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing.
Vitamin D-binding protein is required for the maintenance of α-cell function and glucagon secretion
Authors: Viloria Katrina , Nasteska Daniela , Briant Linford J.B. , Heising Silke , Larner Dean , Fine Nicholas H.F. , Ashford Fiona B. , Silva Xavier Gabriela da , Ramos Maria Jiménez , Manning Fox Jocelyn E. , MacDonald Patrick E. , Akerman Ildem , Lavery Gareth G. , Flaxman Christine , Morgan Noel G. , Richardson Sarah J. , Hewison Martin , Hodson David J. 
Published: December 2019

ABSTRACTVitamin D-binding protein (DBP) or GC-globulin carries vitamin D metabolites from the circulation to target tissues. DBP expression is highly-localized to the liver and pancreatic α-cells. While DBP serum levels, gene polymorphisms and autoantigens have all been associated with diabetes risk, the underlying mechanisms remain unknown. Here, we show that DBP regulates α-cell morphology, α-cell function and glucagon secretion. Deletion of DBP led to smaller and hyperplastic α-cells, altered Na+channel conductance, impaired α-cell activation by low glucose, and reduced rates of glucagon secretion. Mechanistically, this involved reversible changes in islet microfilament abundance and density, as well as changes in glucagon granule distribution. Defects were also seen in β-cell and δ-cell function. Immunostaining of human pancreata revealed generalized loss of DBP expression as a feature of late-onset and longstanding, but not early-onset type 1 diabetes. Thus, DBP is a critical regulator of α-cell phenotype, with implications for diabetes pathogenesis.HIGHLIGHTSDBP expression is highly-localized to mouse and human α-cellsLoss of DBP increases α-cell number, but decreases α-cell sizeα-cells in DBP knockout islets are dysfunctional and secrete less glucagonDBP expression is decreased in α-cells of donors with late-onset or longstanding type 1 diabetes