bluuebunny/crossref_metadata_2025_split huggingface dataset:
BCG-induced T cells shape Mycobacterium tuberculosis infection before reducing the bacterial burden
Authors: Delahaye Jared L. , Gern Benjamin H. , Cohen Sara B. , Plumlee Courtney R. , Shafiani Shahin , Gerner Michael Y. , Urdahl Kevin B. 
Published: April 2019

AbstractGrowing evidence suggests the outcome of Mycobacterium tuberculosis (Mtb) infection is established rapidly after exposure, but how the current tuberculosis vaccine, BCG, impacts early immunity is poorly understood. Here we found that murine BCG immunization promotes a dramatic shift in infected cell types. While alveolar macrophages (AM) are the major infected cell for the first two weeks in unimmunized animals, BCG promotes the accelerated recruitment and infection of lung infiltrating phagocytes. Interestingly, this shift is dependent on CD4 T cells, yet does not require intrinsic recognition of antigen presented by infected AM. Mtb-specific T cells are first activated in lung regions devoid of infected cells, and these events precede vaccine-induced reduction of the bacterial burden, which occurs only after the co-localization of T cells and infected cells. Understanding how BCG alters early immune responses to Mtb provides new avenues to improve upon the immunity it confers.
A collection of yeast cellular electron cryotomography data
Authors: Gan Lu , Ng Cai Tong , Chen Chen , Cai Shujun 
Published: April 2019

ABSTRACTBackgroundCells are powered by a large set of macromolecular complexes, which work together in a crowded environment. The in situ mechanisms of these complexes are unclear because their 3-D distribution, organization, and interactions are largely unknown. Electron cryotomography (cryo-ET) is a key tool to address these knowledge gaps because it produces cryotomograms -- 3-D images that reveal biological structure at approximately 4-nm resolution. Cryo-ET does not involve any fixation, dehydration, staining, or plastic embedment, meaning that cellular features are visualized in a life-like, frozen-hydrated state. To study chromatin and mitotic machinery in situ, we have subjected yeast cells to a variety of genetic and/or chemical perturbations, cryosectioned them, and then imaged the cells by cryo-ET.FindingsEvery study from our group has generated more cryo-ET data than needed. Only the small subset of data that contributed to figures in these studies have been publicly shared. Here we share more than 1,000 cryo-ET raw datasets of cryosectioned budding yeast S. cerevisiae. This data will be valuable to cell biologists who are interested in the nanoscale organization of yeasts and of eukaryotic cells in general. To facilitate access, all the unpublished tilt series and a subset of corresponding cryotomograms have been deposited in the EMPIAR resource for the cell-biology community to use freely. To improve tilt series discoverability, we have uploaded metadata and preliminary notes to publicly accessible google spreadsheets.ConclusionsCellular cryo-ET data can be mined to obtain new cell-biological, structural, and 3-D statistical insights in situ. Because these data capture cells in a life-like state, they contain some structures that are either absent or not visible in traditional EM data. Template matching and subtomogram averaging of known macromolecular complexes can reveal their 3-D distributions and low-resolution structures. Furthermore, these data can serve as testbeds for high-throughput image-analysis pipelines, as training sets for feature-recognition software, for feasibility analysis when planning new structural cell-biology projects, and as practice data for students who are learning cellular cryo-ET.
Identification and characterization of OmpT-like proteases in uropathogenicEscherichia coliclinical isolates
Authors: Desloges Isabelle , Taylor James A. , Leclerc Jean-Mathieu , Brannon John R. , Portt Andrea , Spencer John D. , Dewar Ken , Marczynski Gregory T , Manges Amee , Gruenheid Samantha , Le Moual Hervé , Thomassin Jenny-Lee 
Published: April 2019

AbstractBacterial colonization of the urogenital tract is limited by innate defenses, including the production of antimicrobial peptides (AMPs). UropathogenicEscherichia coli(UPEC) resist AMP-killing to cause a range of urinary tract infections (UTIs) including asymptomatic bacteriuria, cystitis, pyelonephritis, and sepsis. UPEC strains have high genomic diversity and encode numerous virulence factors that differentiate them from non-UTI causing strains, includingompT. As OmpT homologues cleave and inactivate AMPs, we hypothesized that high OmpT protease activity-levels contribute to UPEC colonization during symptomatic UTIs. Therefore, we measured OmpT activity in 58 UPEC clinical isolates. While heterogeneous OmpT activities were observed, OmpT activity was significantly greater in UPEC strains isolated from patients with symptomatic infections. Unexpectedly, UPEC strains exhibiting the greatest protease activities harboured an additionalompT-like gene calledarlC(ompTp). The presence of twoOmpT-like proteases in some UPEC isolates led us to compare the substrate specificities of OmpT-like proteases found inE. coli. While all three cleaved AMPs, cleavage efficiency varied on the basis of AMP size and secondary structure. Our findings suggest the presence ArlC and OmpT in the same UPEC isolate may confer a fitness advantage by expanding the range of target substrates.
Analysis of 19 Heliconiine Butterflies Shows Rapid TE-based Diversification and Multiple SINE Births and Deaths
Authors: Ray David A , Grimshaw Jenna R , Halsey Michaela K , Korstian Jennifer M , Osmanski Austin B , Sullivan Kevin AM , Wolf Kristen A , Reddy Harsith , Foley Nicole , Stevens Richard D , Knisbacher Binyamin , Levy Orr , Counterman Brian , Edelman Nathan B , Mallet James 
Published: April 2019

AbstractTransposable elements (TEs) play major roles in the evolution of genome structure and function. However, because of their repetitive nature, they are difficult to annotate and discovering the specific roles they may play in a lineage can be a daunting task. Heliconiine butterflies are models for the study of multiple evolutionary processes including phenotype evolution and hybridization. We attempted to determine how TEs may play a role in the diversification of genomes within this clade by performing a detailed examination of TE content and accumulation in 19 species whose genomes were recently sequenced. We found that TE content has diverged substantially and rapidly in the time since several subclades shared a common ancestor with each lineage harboring a unique TE repertoire. Several novel SINE lineages have been established that are restricted to a subset of species. Furthermore, the previously described SINE, Metulj, appears to have gone extinct in two subclades while expanding to significant numbers in others. Finally, a burst of TE origination corresponds temporally to a burst of speciation in the clade, potentially providing support to hypotheses that TEs are drivers of genotypic and phenotypic diversification. This diversity in TE content and activity has the potential to impact how heliconiine butterflies continue to evolve and diverge.
Lamina-specific neuronal properties promote robust, stable signal propagation in feedforward networks
Authors: Han Dongqi , De Schutter Erik , Hong Sungho 
Published: April 2019

AbstractFeedforward networks (FFN) are ubiquitous structures in neural systems and have been studied to understand mechanisms of reliable signal and information transmission. In many FFNs, neurons in one layer have intrinsic properties that are distinct from those in their pre-/postsynaptic layers, but how this affects network-level information processing remains unexplored. Here we show that layer-to-layer heterogeneity arising from lamina-specific cellular properties facilitates signal and information transmission in FFNs. Specifically, we found that signal transformations, made by neighboring layers of neurons on an input-driven spike signal, are complementary to each other. This mechanism boosts information transfer carried by a propagating spike signal, and thereby supports reliable spike signal and information transmission in a deep FFN. Our study suggests that distinct cell types in neural circuits have complementary computational functions and facilitate information processing on the whole.Significance StatementNeural systems have many cell types that differ in properties such as size, shape, cellular mechanisms, etc. Furthermore, neurons often propagate signals to other neurons that have properties very different from their own. We investigated what this phenomenon implies in neural information processing by using computational network models, inspired by a recent experimental study on the olfactory neural pathway of fruit flies. We found that different types of neurons can perform complementary functions in a network, which boosts information transfer on the whole and supports robust, stable signal propagation in a “deep” network with many layers. Our study demonstrates that diverse cell types with different intrinsic properties are crucial for optimal signal and information transfer in neural networks.
NAVIP: Unraveling the Influence of Neighboring Small Sequence Variants on Functional Impact Prediction
Authors: Baasner Jan-Simon , Rempel Andreas , Howard Dakota , Pucker Boas 
Published: April 2019

AbstractOnce a suitable reference sequence has been generated, intraspecific variation is often assessed by re-sequencing. Variant calling processes can reveal all differences between strains, accessions, genotypes, or individuals. These variants can be enriched with predictions about their functional implications based on available structural annotations, i.e. gene models. Although these functional impact predictions on a per-variant basis are often accurate, some challenging cases require the simultaneous incorporation of multiple adjacent variants into this prediction process. Examples include neighboring variants which modify each other’s functional impact. The Neighborhood-Aware Variant Impact Predictor (NAVIP) considers all variants within a given protein coding sequence when predicting the effect. As a proof of concept, variants between theArabidopsis thalianaaccessions Columbia-0 and Niederzenz-1 were annotated. NAVIP is freely available on GitHub (https://github.com/bpucker/NAVIP) and accessible through a web server (https://pbb-tools.de).Author SummaryIntraspecific variation gains increasing relevance as reference genome sequences are available for many investigated (plant) species. Understanding the effects of sequence variants between individuals of a population is a challenge. SnpEff (Cingolani et al., 2012) is the current standard tool for predicting the functional impact of sequence variants, but only considers one sequence variant at a time. We developed NAVIP to properly handle cases in which multiple sequence variants cluster together and influence each other’s functional impact. A comparison of twoArabidopsis thalianaaccessions demonstrates the importance of considering multiple sequence variants simultaneously for the prediction of changes in encoded proteins. NAVIP is universally applicable to any organism for which the relevant sequence information and structural annotation is available. All underlying code is freely available on GitHub and we operate a web server for users’ convenience.
Anti-HIV-1 Activity of Crocodylus mindorensis (Philippine crocodile) serum in cell-free and cell-associated virus interactions to human peripheral blood mononuclear cells
Authors: Hinay Alfredo , Mae Cadotdot Nelyn , Tablizo Marilou 
Published: April 2019

AbstractHighly-Active Antiretroviral Therapy (HAART) is the recommended treatment and management strategy for HIV infection. Although the existing antiretroviral drugs are indispensably significant in improving the quality of lives of HIV/AIDS individuals, the drugs still have many limitations including resistance, production of toxicity, and their limited availability. These limitations continue to open new opportunities in the use of ethnomedicine for the management of HIV/AIDS. With this, few researchers have made an effort to test the inhibitory activity of crocodile serum as it has a unique and diverse molecular activity in preventing HIV-1 replication. In this study, a cell culture-based assay was utilized coupled with colorimetric enzyme immunoassay to determine the HIV-1 reverse transcriptase activity. One HIV-1 seropositive serum was processed for Peripheral Blood Mononuclear Cells (PBMC) co-culture from which HIV-1 isolates were obtained. The HIV-1 reverse transcriptase activity after 21 days was 0.5928 pg/well. Moreover, a baseline Philippine crocodile serum concentration of 0.5% vol/vol was used based on the previous study conducted by Hinay and Sarol (2018) and the cell viability results showed no cell reduction of mononuclear cells after 72 hours incubation. The inhibitory activity of the Philippine crocodile serum at 0.5% and 0.25% vol/vol concentrations inhibited 65.68±2.93% and 69.92±0.45% respectively in post-infection interactions. In addition, the Philippine crocodile serum in pre-infection interaction at 0.5% and 0.25% vol/vol concentrations inhibited 68.61±1.67% and 69.95±2.24% respectively. As has been noted, the inhibitory actions of the Philippine crocodile serum effectively regulate the HIV-1 replication in both pre- and post-infection interactions.
Novel pipeline of high-frequency neoantigens heathy donor-based validation in breast cancer
Authors: Qin Lili , Huang Ying , Liang Zhaoduan , Liu Geng , Lin Xiumei , An Ting , Li Dongli , Cheng Le , Li Bo 
Published: April 2019

SummaryNeoantigen, a peptide fragment formed by genetic mutation, gives immunologist a new target for cancer therapy. Development of biotechnology has opened a new era for discovering high-frequency neoantigens. The aim of our study was to identify breast cancer neoantigens for tumor immunotherapy using an efficient way. Here, we established a computational pipeline to identify neoantigens associated with breast cancer using data from database and evaluated the immunogenicity of neoantigens using the peripheral blood of healthy donators in vitro. We identified 39,401 missense mutation sites from 285,283 single nucleotide variations (SNVs) obtained from database, and confirmed candidate epitopes by analyzing the binding affinity of mutant epitopes and human leukocyte antigen (HLA) using 6 algorithms. Peptide-binding assay was used as a complement for affinity testing. The immunogenicity of candidate peptides with high affinity were assessed through enzyme-linked immunospot (ELISPOT) assay and Cytotoxicity assay. In our study, we identified 10 candidate peptides with high binding affinity of HLA-A*0201 alleles, and seven of ten peptides showed the ability of inducing specific cytotoxic lymphocytes(CTLs) ex vivo, in healthy HLA-A2+donors. We found that the peptide derived from TWISTNB have the highest immunogenicity and cytotoxicity among those candidate peptides. Furthermore, it can trigger the immune response of specific-CTLs to destroy target cells expressing this neoantigen in vitro, and without cross-reactivity with wild-type peptides. We conclude that the effective pipeline will provide potential possibilities to rapidly identify abundant high-frequency neoantigens and create neoantigen library for immunotherapy of breast cancer and even other tumors.
Regulation of adenylyl cyclase 5 in striatal neurons confers the ability to detect coincident neuromodulatory signals
Authors: Bruce Neil J. , Narzi Daniele , Trpevski Daniel , van Keulen Siri Camee , Nair Anu G. , Röthlisberger Ursula , Wade Rebecca C. , Carloni Paolo , Kotaleski Jeanette Hellgren 
Published: April 2019

AbstractLong-term potentiation and depression of synaptic activity in response to stimuli is a key factor in reinforcement learning. Strengthening of the corticostriatal synapses depends on the second messenger cAMP, whose synthesis is catalysed by the enzyme adenylyl cyclase 5 (AC5), which is itself regulated by the stimulatory Gαolfand inhibitory Gαiproteins. AC isoforms have been suggested to act as coincidence detectors, promoting cellular responses only when convergent regulatory signals occur close in time. However, the mechanism for this is currently unclear, and seems to lie in their diverse regulation patterns. Despite attempts to isolate the ternary complex, it is not known if Gαolfand Gαican bind to AC5 simultaneously, nor what activity the complex would have. Using protein structure-based molecular dynamics simulations, we show that this complex is stable and inactive. These simulations, along with Brownian dynamics simulations to estimate protein association rates constants, constrain a kinetic model that shows that the presence of this ternary inactive complex is crucial for AC5’s ability to detect coincident signals, producing a synergistic increase in cAMP. These results reveal some of the prerequisites for corticostriatal synaptic plasticity, and explain recent experimental data on cAMP concentrations following receptor activation. Moreover, they provide insights into the regulatory mechanisms that control signal processing by different AC isoforms.Author summaryAdenylyl cyclases (ACs) are enzymes that can translate extracellular signals into the intracellular molecule cAMP, which is thus a 2ndmessenger of extracellular events. The brain expresses nine membrane-bound AC variants, and AC5 is the dominant form in the striatum. The striatum is the input stage of the basal ganglia, a brain structure involved in reward learning, i.e. the learning of behaviors that lead to rewarding stimuli (such as food, water, sugar, etc). During reward learning, cAMP production is crucial for strengthening the synapses from cortical neurons onto the striatal principal neurons, and its formation is dependent on several neuromodulatory systems such as dopamine and acetylcholine. It is, however, not understood how AC5 is activated by transient (subsecond) changes in the neuromodulatory signals. Here we combine several computational tools, from molecular dynamics and Brownian dynamics simulations to bioinformatics approaches, to inform and constrain a kinetic model of the AC5-dependent signaling system. We use this model to show how the specific molecular properties of AC5 can detect particular combinations of co-occuring transient changes in the neuromodulatory signals which thus result in a supralinear/synergistic cAMP production. Our results also provide insights into the computational capabilities of the different AC isoforms.
Single-cell transcriptomics of the naked mole-rat reveals unexpected features of mammalian immunity
Authors: Hilton HG , Rubinstein ND , Janki P , Ireland AT , Bernstein N , Wright KM , Finkle D , Martin-McNulty B , Roy M , Smith M , Imai DM , Jojic V , Buffenstein R 
Published: April 2019

AbstractUsing single-cell transcriptional profiling we mapped the immune system of the naked mole-rat (Heterocephalus glaber), a small but long-lived and cancer-resistant subterranean rodent. Both splenic and circulating immune cells were examined in healthy young animals and following an infection-mimicking lipopolysaccharide challenge. Our study revealed that the naked mole-rat immune system is characterized by a high myeloid to lymphoid cell ratio that includes a novel, lipopolysaccharide responsive, granulocyte cell subset not found in the mouse. Conversely, we find that naked mole-rats do not have a cell subset that corresponds to natural killer cells as defined in other well-characterized mammalian species. Supporting this finding, we show that the naked mole-rat genome has not expanded any of the gene families encoding diverse natural killer cell receptors, which are the genomic hallmarks of species in which natural killer cells have been described. These unusual features suggest an atypical mode of immunosurveillance and a greater reliance on myeloid-biased innate immunity.
NgAgo DNA endonuclease activity enhances homologous recombination in E. coli
Authors: Lee Kok Zhi , Mechikoff Michael A. , Kikla Archana , Liu Arren , Pandolfi Paula , Fitzgerald Kevin , Gimble Frederick S. , Solomon Kevin V. 
Published: April 2019

ABSTRACTProkaryotic Argonautes (pAgos) have been proposed as more flexible tools for gene-editing as they do not require sequence motifs adjacent to their targets for function, unlike popular CRISPR/Cas systems. One promising pAgo candidate, from the halophilic archaeon Natronobacterium gregoryi (NgAgo), however, has been the subject of intense debate regarding its potential in eukaryotic systems. Here, we revisit this enzyme and characterize its function in prokaryotes. NgAgo expresses poorly in non-halophilic hosts with the majority of protein being insoluble and inactive even after refolding. However, we report that the soluble fraction does indeed act as a DNA endonuclease. Structural homology modelling revealed that NgAgo shares canonical domains with other catalytically active pAgos but also contains a previously unrecognized single-stranded DNA binding domain (repA). Both repA and the canonical PIWI domains participate in DNA cleavage activities of NgAgo. We showed that NgAgo can be programmed with guides to cleave specific DNA in vitro and in E.coli. We also found that these endonuclease activities are essential for enhanced NgAgo-guided homologous recombination, or gene-editing, in E. coli. Collectively, our results demonstrate the potential of NgAgo for gene-editing and reconciles seemingly contradictory reports.
Dementia risk genes engage gene networks poised to tune the immune response towards chronic inflammatory states
Authors: Rexach Jessica , Swarup Vivek , Chang Timothy , Geschwind Daniel 
Published: April 2019

AbstractAn emerging challenge in neurodegenerative dementia is understanding how immune-associated genes and pathways contribute to disease. To achieve a refined view of neuroinflammatory signaling across neurodegeneration, we took an integrative functional genomics approach to consider neurodegeneration from the perspective of microglia and their interactions with other cells. Using large-scale gene expression and perturbation data, regulatory motif analysis, and gene knockout studies, we identify and characterize a microglial-centric network involving distinct gene co-expression modules associated with progressive stages of neurodegeneration. These modules, which are conserved from mouse to human, differentially incorporate specific immune sensors of cellular damage and pathways that are predicted to eventually tune the immune response toward chronic inflammation and immune suppression. Notably, common genetic risk for Alzheimer’s disease (AD), Frontotemporal dementia (FTD) and Progressive Supranuclear Palsy (PSP) resides in specific modules that distinguish between the disorders, but also show convergence on pathways related to anti-viral defense mechanisms. These results suggest a model wherein combinatorial microglial-immune signaling integrate specific immune activators and disease genes that lead to the establishment of chronic states of simultaneous inflammation and immunosuppression involving type 1 interferon in these dementias.