bluuebunny/crossref_metadata_2025_split huggingface dataset:
SmartGraph: A Network Pharmacology Investigation Platform
Authors: Zahoránszky-Kőhalmi Gergely , Sheils Timothy , Oprea Tudor I. 
Published: July 2019

AbstractMotivationDrug discovery investigations need to incorporate network pharmacology concepts while navigating the complex landscape of drug-target and target-target interactions. This task requires solutions that integrate high-quality biomedical data, combined with analytic and predictive workflows as well as efficient visualization. SmartGraph is an innovative platform that utilizes state-of-the-art technologies such as a Neo4j graph-database, Angular web framework, RxJS asynchronous event library and D3 visualization to accomplish these goals.ResultsThe SmartGraph framework integrates high quality bioactivity data and biological pathway information resulting in a knowledgebase comprised of 420,526 unique compound-target interactions defined between 271,098 unique compounds and 2,018 targets. SmartGraph then performs bioactivity predictions based on the 63,783 Bemis-Murcko scaffolds extracted from these compounds. Through several use-cases, we illustrate the use of SmartGraph to generate hypotheses for elucidating mechanism-of-action, drug-repurposing and off-target prediction.Availabilityhttps://smartgraph.ncats.io/
Designed Nanoparticles Elicit Cross-Reactive Antibody Responses To Conserved Influenza Virus Hemagglutinin Stem Epitopes
Authors: McCraw Dustin M. , Myers Mallory L. , Gulati Neetu M. , Gallagher John R. , Kim Alexander J. , Torian Udana , Harris Audray K. 
Published: July 2019

AbstractDespite the availability of seasonal vaccines and antiviral medications, influenza virus continues to be a major health concern and pandemic threat due to the continually changing antigenic regions of the major surface glycoprotein, hemagglutinin (HA). One emerging strategy for the development of more efficacious seasonal and universal influenza vaccines is structure-guided design of nanoparticles that display conserved regions of HA, such as the stem. Using the H1 HA subtype to establish proof of concept, we found that an alpha-helical fragment (helix-A) from the conserved stem region can be displayed on nanoparticles. The stem region of HA on these nanoparticles is immunogenic and the nanoparticles are biochemically robust in that heat exposure did not destroy the particles and immunogenicity was retained. Furthermore, H1-nanoparticles protected mice from lethal challenge with H1N1 influenza virus. Importantly, antibodies elicited by these nanoparticles demonstrated homosubtypic and heterosubtypic cross-reactivity. The helix-A stem nanoparticle design represents a novel approach to display several hundred copies of non-trimeric conserved HA stem epitopes on vaccine nanoparticles. This design concept provides a new approach to universal influenza vaccine development strategies and opens up opportunities for the development of nanoparticles with broad coverage over many antigenically diverse influenza HA subtypes.SignificanceInfluenza virus is a public health issue that affects millions of people globally each year. Commercial influenza vaccines are based on the hemagglutinin (HA) surface glycoprotein, which can change antigenically every year, demanding the manufacture of newly matched vaccines annually. HA stem epitopes have a higher degree of conservation than HA molecules contained in conventional vaccine formulations and we demonstrate that we are able to design nanoparticles that display hundreds of HA stem fragments on nanoparticles. These designed nanoparticles are heat-stable, elicit antibodies to the HA stem, confer protection in mouse challenge models, and show cross-reactivity between HA subtypes. This technology provides promising opportunities to improve seasonal vaccines, develop pandemic preparedness vaccines, and facilitate the development of a universal influenza vaccine.
Versatile multi-transgene expression using improved BAC TG-EMBED toolkit, novel BAC episomes, and BAC-MAGIC
Authors: Zhao Binhui , Chaturvedi Pankaj , Zimmerman David L. , Belmont Andrew S. 
Published: July 2019

ABSTRACTAchieving reproducible, stable, and high-level transgene expression in mammalian cells remains problematic. Previously, we attained copy-number-dependent, chromosome-position-independent expression of reporter minigenes by embedding them within a BAC containing the mouseMsh3-Dhfrlocus (DHFR BAC). Here we extend this “BAC TG-EMBED” approach. First, we report a toolkit of endogenous promoters capable of driving transgene expression over a 0.01-5 fold expression range relative to the CMV promoter, allowing fine-tuning of relative expression levels of multiple reporter genes expressed on a single BAC. Second, we show small variability in both the expression level and long-term expression stability of a reporter gene embedded in BACs containing either transcriptionally active or inactive genomic regions, making choice of BACs more flexible. Third, we describe an intriguing phenomenon in which BAC transgenes are maintained as episomes in a large fraction of stably selected clones. Finally, we demonstrate the utility of BAC TG-EMBED by simultaneously labeling three nuclear compartments in 94% of stable clones using a multi-reporter DHFR BAC, constructed with a combination of synthetic biology and BAC recombineering tools. Our extended BAC TG-EMBED method provides a versatile platform for achieving reproducible, stable simultaneous expression of multiple transgenes maintained either as episomes or stably integrated copies.
Atrial fibrillation associated common risk variants in SYNE2 lead to lower expression of nesprin-2α1 and increased nuclear stiffness
Authors: Liu Nana , Hsu Jeffrey , Mahajan Gautam , Sun Han , Barnard John , Van Wagoner David R. , Kothapalli Chandrasekhar R. , Chung Mina K. , Smith Jonathan D. 
Published: July 2019

ABSTRACTRationaleAtrial fibrillation (AF) genome-wide association studies (GWAS) identified significant associations for rs1152591 and linked variants in the SYNE2 gene encoding the nesprin-2 protein that connects the nuclear membrane with the cytoskeletonObjectiveDetermine the effects of the AF-associated rs1152591 and rs1152595, two linked intronic single nucleotide polymorphisms (SNPs), on SYNE2 expression and investigate the mechanisms for their association with AF.Methods and ResultsRNA sequencing of human left atrial appendage (LAA) tissues indicated that rs1152591 and rs1152595 were significantly associated with the expressions of SYNE2α1, a short mRNA isoform, without an effect on the expression of the full-length SYNE2 mRNA. SYNE2α1 mRNA uses an alternative transcription start site and encodes an N-terminal deleted 62 kDa nesprin-2α1 isoform, which can act as a dominant-negative on nuclear-cytoskeleton connectivity. Western blot and qPCR assays confirmed that AF risk alleles of both SNPs were associated with lower expression of nesprin-2α1 in human LAA tissues. Reporter gene transfections demonstrated that the risk vs. reference alleles of rs1152591 and rs1152595 had decreased enhancer activity. SYNE2 siRNA knockdown (KD) or nesprin-2α1 overexpression studies in human stem cell-derived induced cardiomyocytes (iCMs) resulted in ~12.5 % increases in the nuclear area compared to controls (p<0.001). Atomic force microscopy demonstrated that SYNE2 KD or nesprin-2α1 overexpression led to 57.5% or 33.2% decreases, respectively, in nuclear stiffness compared to controls (p< 0.0001).ConclusionsAF-associated SNPs rs1152591 and rs1152595 downregulate the expression of SYNE2α1, increasing nuclear-cytoskeletal connectivity and nuclear stiffness. The resulting increase in mechanical stress may play a role in the development of AF.
α-carboxysome formation is mediated by the multivalent and disordered protein CsoS2
Authors: Oltrogge Luke M. , Chaijarasphong Thawatchai , Chen Allen W. , Bolin Eric R. , Marqusee Susan , Savage David F. 
Published: July 2019

AbstractCarboxysomes are bacterial microcompartments that function as the centerpiece of the bacterial CO2-concentrating mechanism, feeding high concentrations of CO2 to the enzyme Rubisco for fixation. The carboxysome self-assembles from thousands of individual proteins into icosahedral-like particles with a dense enzyme cargo encapsulated within a proteinaceous shell. In the case of the α-carboxysome, there is little molecular insight into protein-protein interactions which drive the assembly process. Here we show that the N-terminus of CsoS2, an intrinsically disordered protein found in the α-carboxysome, possesses a repeated peptide sequence that binds Rubisco. X-ray structural analysis of the peptide bound to Rubisco reveals a series of conserved electrostatic interactions that are only made with properly assembled hexadecameric Rubisco. Although biophysical measurements indicate this single interaction is weak, its implicit multivalency induces high-affinity binding through avidity. Taken together, our results indicate CsoS2 acts as an interaction hub to condense Rubisco and enable efficient α-carboxysome formation.
Selection against archaic hominin genetic variation in regulatory regions
Authors: Telis Natalie , Aguilar Robin , Harris Kelley 
Published: July 2019

AbstractTraces of archaic hominin DNA persist in the human gene pool, but are systematically depleted around genes and other functionally important genomic regions. This suggests that many Neandertal and Denisovan alleles had harmful effects on hybrid fitness. We hypothesized that if some harmful effects were mediated by gene dysregulation in specific tissues, alleles previously flagged as archaic using a conditional random field (CRF) should be depleted from those tissues’ regulatory enhancers compared to “control” alleles matched for allele frequency and the strength of background selection. By this metric, both Neandertal and Denisovan variation appear depleted from enhancers, particularly enhancers that show pleiotropic activity across tissues. This depletion is driven by young archaic SNPs that the CRF confidently identifies as private to Neandertals or Denisovans; older variants that were likely present in both archaic species are not depleted from enhancers. We found that enhancer pleiotropy is not only a predictor of archaic SNP depletion, but also a predictor of intolerance to new mutations as measured by both phastCons scores and the frequency spectrum of African variation. In other respects, however, the landscape of selection against young archaic alleles appears qualitatively different from the landscape of ordinary purifying selection, suggesting that archaic alleles had a different distribution of fitness effects from ordinary new mutations. Most strikingly, fetal brain and muscle are the tissues most depleted of young archaic variation in their regulatory regions, but only brain enhancers appear commensurately intolerant to new mutations. In contrast, fetal muscle enhancers show no evidence of elevated purifying selection relative to other enhancers. This suggests that epistatic incompatibility between human and archaic alleles is needed to explain the degree of archaic variant depletion from fetal muscle enhancers, perhaps due to divergent selection for higher muscle mass in archaic hominins compared to humans.
Computational modeling of the photon transport, tissue heating, and cytochrome C oxidase absorption during transcranial near-infrared stimulation
Authors: Bhattacharya Mahasweta , Dutta Anirban 
Published: July 2019

AbstractTranscranial near-infrared stimulation (tNIRS) has been proposed as a tool to modulate cortical excitability. However, the underlying mechanisms are not clear where the heating effects on the brain tissue needs investigation due to increased near-infrared (NIR) absorption by water and fat. Moreover, the risk of localized heating of tissues (including the skin) during optical stimulation of the brain tissue is a concern. The challenge in estimating localized tissue heating is due to the light interaction with the tissues’ constituents, which is dependent on the combination ratio of the scattering and absorption properties of the constituent. Here, apart from tissue heating that can modulate the cortical excitability (“photothermal effects”); the other mechanism reported in the literature is the stimulation of the mitochondria in the cells which are active in the adenosine triphosphate (ATP) synthesis. In the mitochondrial respiratory chain, the complex IV, also named as the cytochrome c oxidase(CCO), is the unit four with three copper atoms. The absorption peaks of CCO are in the visible (420-450nm and 600-700nm) and the near-infrared (760-980nm) spectral region which have been shown to be promising for low level light therapy (LLLT), also known as “photobiomodulation”. While much higher CCO absorption peaks in the visible spectrum can be used for the photobiomodulation of the skin, 810nm has been proposed for the non-invasive brain stimulation (using tNIRS) due to the optical window in the NIR spectral region. In this article, we applied a computational approach to delineate the “photothermal effects” from the “photobiomodulation,” i.e., to estimate the amount of light absorbed individually by each chromophore in the brain tissue (with constant scattering) and the related tissue heating. Photon migration simulations were performed for motor cortex tNIRS based on a prior work that used a 500mW cm−2light source placed on the scalp. We simulated photon migration at 630nm and 700nm (red spectral region) and 810nm (near-infrared spectral region). We found a temperature increase in the scalp below 0.25 ° C and a minimal temperature increase in the gray matter less than 0.04 ° C at 810nm. Similar heating was found for 630nm and 700nm used for LLLT, so photothermal effects are postulated to be unlikely in the brain tissue.
Developing a primary Paralichthys olivaceus gill epithelial cells as an in vitro model for propagation of VHSV show a corresponding increase in cell viability with increase in protein concentration in growth media
Authors: Han Sori , Hong Jimin , Seo Jong-pyo , Munang’andu Hetron Mweemba , Yeo In-kyu , Kim Sung-hyun 
Published: July 2019

AbstractBackgroundViral Hemorrhagic Septicemia Virus (VHSV) is a rhabdovirus that causes high mortalities linked to high economic losses in aquaculture. It has been grouped in four genotypes of which some do not easily propagate on continuous cell lines. As an alternative, the objectives of this study was to develop a primary gill epithelial cell (GEC) model from olive flounder (Paralichthys olivaceus) as an in vitro model for the propagation of VHSV.ResultsOur findings show that the primary GECs developed herein are highly permissive to replication of the JF-09 genotype IVa strain leading to high cytopathic effect observed within 96 hours post virus inoculation. Our findings also show that the viability GECs produced herein corresponded with increase in the concentration fetal bovine serum in growth medium. We envision that GECs produced herein will heighten our understanding of immune mechanisms associated with virus entry on gill mucosal surfaces in flounder.
Identifying the essential genes ofMycobacterium aviumsubsp.hominissuiswith Tn-Seq using a rank-based filter procedure
Authors: Matern William M. , Jenquin Robert L. , Bader Joel S. , Karakousis Petros C. 
Published: July 2019

AbstractMycobacterium avium(Mav) is increasingly recognized as a significant cause of morbidity, particularly in elderly patients or those with immune deficiency or underlying structural lung disease. Generally, Mav infection is treated with 2-3 antimicrobial drugs for at least 12 months. Identification of genes essential for Mav growth may yield novel strategies for improving curative therapy. We have generated saturating genome-wide transposon mutant pools in a commonly used laboratory strain ofMycobacterium aviumsubsp.hominissuis(MAC109) and developed a computational technique for classifying annotated genomic features as essential (ES), growth defect (GD), growth advantage (GA), or no-effect (NE) based on thein vitroeffect of disruption by transposon. We identified 270 features as ES with 230 of these overlapping with ES features inMycobacterium tuberculosis. These results may be useful for identifying drug targets or for informing studies requiring genetic manipulation ofMycobacterium avium, which should seek to avoid disrupting ES features to ensure bacterial viability.ImportanceMycobacterium avium subsp. hominissuisis an emerging cause of morbidity in vulnerable populations in many countries. It is known to be particularly difficult to treat, often requiring years of antibiotic therapy. In this study we report the genes ofMycobacterium aviumsubsp.hominissuisthat are required for the organism to growin vitro. Our findings may help guide future research into identifying new drugs to improve the treatment of this serious infection.
kCSD-python, reliable current source density estimation with quality control
Authors: Chintaluri Chaitanya , Bejtka Marta , Średniawa Władysław , Czerwiński Michał , Dzik Jakub M. , Jędrzejewska-Szmek Joanna , Wójcik Daniel K. 
Published: July 2019

AbstractInterpretation of the extracellular recordings can be difficult due to the long range of electric field but can be facilitated by estimating the density of current sources (CSD). Here we introducekCSD-python, an open Python package implementing Kernel Current Source Density (kCSD) method, and introduce several new techniques to facilitate CSD analysis of experimental data and interpretation of the results. We investigate the limitations imposed by noise and assumptions in the method itself.kCSD-pythonallows CSD estimation for arbitrary distribution of electrodes in 1D, 2D, and 3D, assuming distributions of sources in tissue, a slice, or in a single cell, and includes a range of diagnostic aids. We demonstrate its features in a Jupyter notebook tutorial to facilitate uptake by the community.
Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta
Authors: Teo Emelyne , Ravi Sudharshan , Barardo Diogo , Kim Hyung-Seok , Fong Sheng , Cazenave-Gassiot Amaury , Tan Tsze Yin , Ching Jianhong , Kovalik Jean-Paul , Wenk Markus R , Gunawan Rudiyanto , Moore Philip K , Halliwell Barry , Tolwinski Nicholas , Gruber Jan 
Published: July 2019

AbstractAlzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on a deeper analysis of these metabolic changes associated with Aβ-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics, biochemical studies and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Aβ expression. In particular, GRU102 show reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects are associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurs before any significant increase in global protein aggregate is detectable. Treatment with an antidiabetes drug, Metformin, reverses Aβ-induced metabolic defects, reduces protein aggregation and normalizes the lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in AD pathology and a promising target for intervention.
How Sampling-Based Overdispersion Undermines India’s Tiger Monitoring Orthodoxy
Authors: Gopalaswamy Arjun M. , Karanth K. Ullas , Delampady Mohan , Stenseth Nils Chr. 
Published: July 2019

AbstractConservation agencies entrusted with recovery of iconic mammals may exaggerate population trends without adequate scientific evidence. Recently, such populations were termed as ‘political populations’ in the conservation literature. We surmise that political populations emerge when agencies are pressured to report abundances at large spatial scales for species that are difficult to survey. Indian tiger conservation agencies use an experimental approach called double-sampling using index-calibration models. A recent, mathematical, study demonstrated the unreliability of this approach in the context of India’s tigers. Yet, this approach continues to be applied and even promoted by global tiger conservation agencies in other tiger range countries. In this article, we aim to: (1) discuss the ecological oddities emerging from results of India’s national tiger surveys, (2) demystify the mathematics underlying the problems of this survey methodology and (3) confront these findings with results from India’s recent national tiger survey of 2014. Our analyses show that the predictions of tiger abundance using sign-based indices reported in the 2014 survey in fact vary greatly and can be severely misleading and confirming the presence of high sampling-based overdispersion and parameter covariance. We call for species conservation initiatives to implement monitoring methods that are designed to clearly answer, a priori, scientific or management objectives instead of potentially implementing them as reactions to extraneous, social or fund raising pressures.
Neural ensemble activity depends on stimulus type in mouse primary visual cortex
Authors: Tolkiehn Marie , Schultz Simon R. 
Published: July 2019

ABSTRACTEarly cortical processing of visual information has long been investigated by describing the response properties such as receptive fields or orientation selectivity of individual neurons to moving gratings. However, thanks to recent technological advances, it has been become easier to record from larger neuronal populations which allow us to analyse the population responses to probe visual information processing at the population level. In the end, it is unlikely that sensory processing is a single-neuron effort but that of an entire population. Here we show how different stimulus types evoke distinct binary activity patterns (words) of simultaneous events on different sites in the anaesthetised mouse. Spontaneous activity and natural scenes indicated lower word distribution divergences than each to drifting gratings. Accounting for firing rate differences, spontaneous activity was linked to more unique patterns than stimulus-driven responses. Multidimensional scaling conveyed that pattern probability distributions clustered for spatial frequencies but not for directions. Further, drifting gratings modulated the Shannon entropy estimated on spatial patterns in a similar fashion as classical directional and spatial frequency tuning functions of neurons. This was supported by a distinct sublinear relationship between Shannon entropy and mean population firing rate.