bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating dispensable content in the human interactome
Authors: Ghadie Mohamed , Xia Yu 
Published: July 2019

AbstractProtein-protein interaction (PPI) networks (interactome networks) have successfully advanced our knowledge of molecular function, disease and evolution. While much progress has been made in quantifying errors and biases in experimental PPI datasets, it remains unknown what fraction of the error-free PPIs in the cell are completely dispensable, i.e., effectively neutral upon disruption. Here, we estimate dispensable content in the human interactome by calculating the fractions of PPIs disrupted by neutral and non-neutral mutations. Starting with the human reference interactome determined by experiments, we construct a human structural interactome by building homology-based three-dimensional structural models for PPIs. Next, we map common mutations from healthy individuals as well as Mendelian disease-causing mutations onto the human structural interactome, and perform structure-based calculations of how these mutations perturb the interactome. Using our predicted as well as experimentally-determined interactome perturbation patterns by common and disease mutations, we estimate that <~20% of the human interactome is completely dispensable.
Effects of changing population or density on urban carbon dioxide emissions
Authors: Ribeiro Haroldo V. , Rybski Diego , Kropp Jürgen P. 
Published: July 2019

AbstractThe question of whether urbanization contributes to increasing carbon dioxide emissions has been mainly investigated via scaling relationships with population or population density. However, these approaches overlook the correlations between population and area, and ignore possible interactions between these quantities. Here, we propose a generalized framework that simultaneously considers the effects of population and area along with possible interactions between these urban metrics. Our results significantly improve the description of emissions and reveal the coupled role between population and density on emissions. These models show that variations in emissions associated with proportionate changes in population or density may not only depend on the magnitude of these changes but also on the initial values of these quantities. For US areas, the larger the city, the higher is the impact of changing its population or density on its emissions; but population changes always have a greater effect on emissions than population density.
Global evidence of positive biodiversity effects on spatial ecosystem stability in natural grasslands
Authors: Wang Yongfan , Cadotte Marc W. , Chen Yuxin , Fraser Lauchlan H. , Zhang Yuhua , Huang Fengmin , Luo Shan , Shi Nayun , Loreau Michel 
Published: July 2019

AbstractThe effect of biodiversity on primary productivity has been a hot topic in ecology for over 20 years. Biodiversity–productivity relationships in natural ecosystems are highly variable, although positive relationships are most common. Understanding the conditions under which different relationships emerge is still a major challenge. Here, by analyzing HerbDivNet data, a global survey of natural grasslands, we show that biodiversity stabilizes rather than increases plant productivity in natural grasslands at the global scale. Our results suggest that the effect of species richness on productivity shifts from strongly positive in low-productivity communities to strongly negative in high-productivity communities. Thus, plant richness maintains community productivity at intermediate levels. As a result, it stabilizes plant productivity against environmental heterogeneity across space. Unifying biodiversity–productivity and biodiversity–spatial stability relationships at the global scale provides a new perspective on the functioning of natural ecosystems.
TurboID-based proximity labeling reveals that UBR7 is a regulator of N NLR immune receptor-mediated immunity
Authors: Zhang Yongliang , Song Gaoyuan , Lal Neeraj K. , Nagalakshmi Ugrappa , Li Yuanyuan , Zheng Wenjie , Huang Pin-jui , Branon Tess C. , Ting Alice Y. , Walley Justin W. , Dinesh-Kumar Savithramma P. 
Published: July 2019

AbstractNucleotide-binding leucine-rich repeat (NLR) immune receptors play a critical role in defence against pathogens in plants and animals. However, we know very little about NLR-interacting proteins and the mechanisms that regulate NLR levels. Here, we used proximity labeling (PL) to identify the proteome proximal to N, which is an NLR that confers resistance to Tobacco mosaic virus (TMV). Evaluation of different PL methods indicated that TurboID-based PL provides more efficient levels of biotinylation than BioID and BioID2 in plants. TurboID-based PL of N followed by quantitative proteomic analysis and genetic screening revealed multiple regulators of N-mediated immunity. Interestingly, a putative E3 ubiquitin ligase, UBR7, directly interacts with the TIR domain of N. UBR7 downregulation leads to an increased amount of N protein and enhanced TMV resistance. TMV-p50 effector disrupts the N-UBR7 interaction and relieves negative regulation of N. These findings demonstrate the utility of TurboID-based PL in plants and the N-interacting proteins we identified enhance our understanding of the mechanisms underlying NLR regulation.
Trade-off in membrane distillation with monolithic omniphobic membranes
Authors: Wang Wei , Du Xuewei , Vahabi Hamed , Zhao Song , Yin Yiming , Kota Arun K. , Tong Tiezheng 
Published: July 2019

AbstractOmniphobic membranes are attractive for membrane distillation (MD) because of their superior wetting resistance. However, a design framework for MD membrane remains incomplete, due to the complexity of omniphobic membrane fabrication and the lack of fundamental relationship between wetting resistance and water vapor permeability. Here we present a particle-free approach that enables rapid fabrication of monolithic omniphobic membranes for MD desalination. Our monolithic omniphobic membranes display excellent wetting resistance and water purification performance in MD desalination of hypersaline feedwater containing surfactants. We identify that a trade-off exists between wetting resistance and water vapor permeability of our monolithic MD membranes. Utilizing membranes with tunable wetting resistance and permeability, we elucidate the underlying mechanism of such trade-off. We envision that our fabrication method as well as the mechanistic insight into the wetting resistance-vapor permeability trade-off will pave the way for smart design of MD membranes in diverse water purification applications.
NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance
Authors: Li Xiaoguang , Liu Zhida , Zhang Anli , Han Chuanhui , Shen Aijun , Jiang Lingxiang , Boothman David A. , Qiao Jian , Wang Yang , Huang Xiumei , Fu Yang-Xin 
Published: July 2019

AbstractLack of proper innate sensing inside tumor microenvironment (TME) limits T cell-targeted immunotherapy. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly enriched in multiple tumor types and has emerged as a promising target for direct tumor-killing. Here, we demonstrate that NQO1-targeting prodrug β-lapachone triggers tumor-selective innate sensing leading to T cell-dependent tumor control. β-Lapachone is catalyzed and bioactivated by NQO1 to generate ROS in NQO1high tumor cells triggering oxidative stress and release of the damage signals for innate sensing. β-Lapachone-induced high mobility group box 1 (HMGB1) release activates the host TLR4/MyD88/type I interferon pathway and Batf3 dendritic cell-dependent cross-priming to bridge innate and adaptive immune responses against the tumor. Furthermore, targeting NQO1 is very potent to trigger innate sensing for T cell re-activation to overcome checkpoint blockade resistance in well-established tumors. Our study reveals that targeting NQO1 potently triggers innate sensing within TME that synergizes with immunotherapy to overcome adaptive resistance.
Epitope targeting with self-assembled peptide vaccines
Authors: Zeigler David F. , Gage Emily , Roque Richard , Clegg Christopher H. 
Published: July 2019

AbstractNanoparticle-based delivery systems are being used to simplify and accelerate new vaccine development. Previously, we described the solid-phase synthesis of a 61-amino acid conjugate vaccine carrier comprising a α-helical domain followed by two universal T cell epitopes. Circular dichroism, analytical centrifugation, and dynamic light scattering indicate that this carrier forms coiled-coil nanoparticles. Here we expand the potential of this carrier by appending B cell epitopes to its amino acid sequence, thereby eliminating the need for traditional conjugation reactions. Peptides containing Tau or amyloid-β epitopes at either terminus assemble into ~20 nm particles and induce antibody responses in outbred mice. Vaccine function was verified in three experiments. The first targeted gonadotropin-releasing hormone, a 10-amino acid neuropeptide that regulates sexual development. Induction of peak antibody titers in male mice stimulated a dramatic loss in fertility and marked testis degeneration. The second experiment generated antibodies to an epitope on the murine IgE heavy chain analogous to human IgE sequence recognized by omalizumab, the first monoclonal antibody approved for the treatment of allergic asthma. Like omalizumab, the anti-IgE antibodies in immunized mice reduced the concentrations of circulating free IgE and prevented IgE-induced anaphylaxis. Finally, a peptide containing the highly conserved Helix A epitope within the influenza hemagglutinin stem domain induced antibodies that successfully protected mice against a lethal H1N1 challenge. These results establish the utility of a new vaccine platform for eliciting prophylactic and therapeutic antibodies to linear and helical B cell epitopes.
Ex vivo metabolite profiling of paediatric central nervous system tumours reveals prognostic markers
Authors: Bennett Christopher D. , Gill Simrandip K. , Kohe Sarah E. , Wilson Martin P. , Davies Nigel P. , Arvanitis Theodoros N. , Tennant Daniel A. , Peet Andrew C. 
Published: July 2019

AbstractBrain tumours are the most common cause of cancer death in children. Molecular studies have greatly improved our understanding of these tumours but tumour metabolism is underexplored. Metabolites measured in vivo have been reported as prognostic biomarkers of these tumours but analysis of surgically resected tumour tissue allows a more extensive set of metabolites to be measured aiding biomarker discovery and providing validation of in vivo findings. In this study, metabolites were quantified across a range of paediatric brain tumours using 1H-High-Resolution Magic Angle Spinning nuclear magnetic resonance spectroscopy (HR-MAS) and their prognostic potential investigated. HR-MAS was performed on pre-treatment frozen tumour tissue from a single centre. Univariate and multivariate Cox regression was used to examine the ability of metabolites to predict survival. The models were cross validated using C-indices and further validated by splitting the cohort into two. Higher concentrations of glutamine were predictive of a longer overall survival, whilst higher concentrations of lipids were predictive of a shorter overall survival. These metabolites were predictive independent of diagnosis, as demonstrated in multivariate Cox regression models. Whilst accurate quantification of metabolites such as glutamine in vivo is challenging, metabolites show promise as prognostic markers due to development of optimised detection methods and increasing use of 3 T clinical scanners.
Large-scale Discovery of Substrates of the Human Kinome
Authors: Sugiyama Naoyuki , Imamura Haruna , Ishihama Yasushi 
Published: July 2019

AbstractKinase networks are important for cellular signal transduction. Despite tremendous efforts to uncover these signaling pathways, huge numbers of uncharacterized phosphosites still remain in the human proteome. Because of the transient nature of kinase-substrate interactions in vivo, it is almost impossible to identify direct substrates. Here, we present a strategy for the rapid, accurate and high-throughput discovery of in vitro kinase substrates using quantitative proteomics. Using 385 purified kinases (354 wild-type protein kinases, 21 mutants and 10 lipid kinases), we identified a total of 175,574 potential direct kinase substrates. In addition, we identified novel kinase groups, such as one group containing 30 threonine-directed kinases and another containing 15 serine/threonine/tyrosine kinases. Surprisingly, we observed that the diversity of substrates for tyrosine kinases was much higher than that for serine-threonine kinases.
Adiabatic Quantum-Flux-Parametron: Towards Building Extremely Energy-Efficient Circuits and Systems
Authors: Chen Olivia , Cai Ruizhe , Wang Yanzhi , Ke Fei , Yamae Taiki , Saito Ro , Takeuchi Naoki , Yoshikawa Nobuyuki 
Published: July 2019

AbstractAdiabatic Quantum-Flux-Parametron (AQFP) logic is an adiabatic superconductor logic family that has been proposed as a future technology towards building extremely energy-efficient computing systems. In AQFP logic, dynamic energy dissipation can be drastically reduced due to the adiabatic switching operations using AC excitation currents, which serve as both clock signals and power supplies. As a result, AQFP could overcome the power/energy dissipation limitation in conventional superconductor logic families such as rapid-single-flux-quantum (RSFQ). Simulation and experimental results show that AQFP logic can achieve an energy-delay-product (EDP) near quantum limit using practical circuit parameters and available fabrication processes. To shed some light on the design automation and guidelines of AQFP circuits, in this paper we present an automatic synthesis framework for AQFP and perform synthesis on 18 circuits, including 11 ISCAS-85 circuit benchmarks, 6 deep-learning accelerator components, and a 32-bit RISC-V ALU, based on our developed standard cell library of AQFP technology. Synthesis results demonstrate the significant advantage of AQFP technology. We forecast 9,313×, 25,242× and 48,466× energy-per-operation advantage, compared to the synthesis results of TSMC (Taiwan Semiconductor Manufacturing Company) 12 nm fin field-effect transistor (FinFET), 28 nm and 40 nm complementary metal-oxide-semiconductor (CMOS) technology nodes, respectively.
Large-scale viral genome analysis identifies novel clinical associations between hepatitis B virus and chronically infected patients
Authors: Podlaha Ondrej , Gane Edward , Brunetto Maurizia , Fung Scott , Chuang Wan-Long , Pan Calvin Q. , Jiang Zhaoshi , Liu Yang , Bhardwaj Neeru , Mukherjee Prasenjit , Flaherty John , Gaggar Anuj , Subramanian Mani , Izumi Namiki , Shalimar  , Lim Young-Suk , Marcellin Patrick , Buti Maria , Chan Henry L. Y. , Agarwal Kosh 
Published: July 2019

AbstractDespite the high global prevalence of chronic hepatitis B (CHB) infection, datasets covering the whole hepatitis B viral genome from large patient cohorts are lacking, greatly limiting our understanding of the viral genetic factors involved in this deadly disease. We performed deep sequencing of viral samples from patients chronically infected with HBV to investigate the association between viral genome variation and patients’ clinical characteristics. We discovered novel viral variants strongly associated with viral load and HBeAg status. Patients with viral variants C1817T and A1838G had viral loads nearly three orders of magnitude lower than patients without those variants. These patients consequently experienced earlier viral suppression while on treatment. Furthermore, we identified novel variants that either independently or in combination with precore mutation G1896A were associated with the transition from HBeAg positive to the negative phase of infection. These observations are consistent with the hypothesis that mutation of the HBeAg open reading frame is an important factor driving CHB patient’s HBeAg status. This analysis provides a detailed picture of HBV genetic variation in the largest patient cohort to date and highlights the diversity of plausible molecular mechanisms through which viral variation affects clinical phenotype.
Crystallized but not soluble uric acid elicits pro-inflammatory response in short-term whole blood cultures from healthy men
Authors: Brovold Henrik , Lund Trine , Svistounov Dmitri , Solbu Marit D. , Jenssen Trond G. , Ytrehus Kirsti , Zykova Svetlana N. 
Published: July 2019

AbstractSeveral epidemiological studies have pointed at serum uric acid (SUA) as an independent risk factor for mortality, diabetes, hypertension, cardiovascular and kidney disease; however, no clear pathogenic pathway is established. Uric acid (UA) crystals show pro-inflammatory properties and can thus create or contribute to the state of chronic low-grade inflammation, a widely accepted pathogenic mechanism in several of the above-mentioned pathologies. On the other hand, soluble uric acid possesses antioxidant properties that might attenuate inflammatory responses. We aimed to explore the net effects of experimentally rising SUA in human whole blood cultures on several mediators of inflammation. Production of TNF-α, IL-1ß, IL-1RA, MCP-1 and IL-8 was assessed upon addition of 200 µM UA, 500 µM UA or monosodium urate (MSU) crystals in the presence or absence of 5 ng/ml lipopolysaccharide (LPS). RT-qPCR and multiplex bead based immunoassay were used to measure mRNA expression and cytokine release at 2 and 4 h of culture, respectively. 14C labeled UA was used to assess intracellular uptake of UA. We show that crystallized, but not soluble, UA induces production of pro-inflammatory mediators in human whole blood. Soluble UA is internalized in blood cells but does not potentiate or reduce LPS-induced release of cytokines.
Excitation spectra in fluids: How to analyze them properly
Authors: Kryuchkov Nikita P. , Mistryukova Lukiya A. , Brazhkin Vadim V. , Yurchenko Stanislav O. 
Published: July 2019

AbstractAlthough the understanding of excitation spectra in fluids is of great importance, it is still unclear how different methods of spectral analysis agree with each other and which of them is suitable in a wide range of parameters. Here, we show that the problem can be solved using a two-oscillator model to analyze total velocity current spectra, while other considered methods, including analysis of the spectral maxima and single mode analysis, yield rough results and become unsuitable at high temperatures and wavenumbers. To prove this, we perform molecular dynamics (MD) simulations and calculate excitation spectra in Lennard-Jones and inverse-power-law fluids at different temperatures, both in 3D and 2D cases. Then, we analyze relations between thermodynamic and dynamic features of fluids at (Frenkel) crossover from a liquid- to gas-like state and find that they agree with each other in the 3D case and strongly disagree in 2D systems due to enhanced anharmonicity effects. The results provide a significant advance in methods for detail analysis of collective fluid dynamics spanning fields from soft condensed matter to strongly coupled plasmas.
The Role of Conformational Dynamics in Abacavir-Induced Hypersensitivity Syndrome
Authors: Fodor James , Riley Blake T. , Kass Itamar , Buckle Ashley M. , Borg Natalie A. 
Published: July 2019

AbstractAbacavir is an antiretroviral drug used to reduce human immunodeficiency virus (HIV) replication and decrease the risk of developing acquired immune deficiency syndrome (AIDS). However, its therapeutic value is diminished by the fact that it is associated with drug hypersensitivity reactions in up to 8% of treated patients. This hypersensitivity is strongly associated with patients carrying human leukocyte antigen (HLA)-B*57:01, but not patients carrying closely related alleles. Abacavir’s specificity to HLA-B*57:01 is attributed to its binding site within the peptide-binding cleft and subsequent influence of the repertoire of peptides that can bind HLA-B*57:01. To further our understanding of abacavir-induced hypersensitivity we used molecular dynamics (MD) to analyze the dynamics of three different peptides bound to HLA-B*57:01 in the presence and absence of abacavir or abacavir analogues. We found that abacavir and associated peptides bind to HLA-B*57:01 in a highly diverse range of conformations that are not apparent from static crystallographic snapshots, but observed no difference in either the conformations, nor degree of flexibility when compared to abacavir-unbound systems. Our results support hypersensitivity models in which abacavir-binding alters the conformational ensemble of neopeptides, so as to favour exposed peptide surfaces that are no longer recognized as self by circulating CD8+ T cells, and are conducive to TCR binding. Our findings highlight the need to also consider the role of dynamics in understanding drug-induced hypersensitivities at the molecular and mechanistic level. This additional insight can help inform the chemical modification of abacavir to prevent hypersensitivity reactions in HLA-B*57:01+ HIV patients whilst retaining potent antiretroviral activity.
The anti-aflatoxigenic mechanism of cinnamaldehyde in Aspergillus flavus
Authors: Wang Ping , Ma Longxue , Jin Jing , Zheng Mumin , Pan Lin , Zhao Yueju , Sun Xiulan , Liu Yang , Xing Fuguo 
Published: July 2019

AbstractAflatoxin B1 (AFB1), the predominant and most carcinogenic naturally polyketide, is mainly produced by Aspergillus flavus and Aspergillus parasiticus. Cinnamaldehyde has been reported for inhibiting the growth and aflatoxin biosynthesis in A. flavus. But its molecular mechanism of action still remains largely ambiguous. Here, the anti-aflatoxigenic mechanism of cinnamaldehyde in A. flavus was investigated via a comparative transcriptomic analysis. The results indicated that twenty five of thirty genes in aflatoxin cluster showed down-regulation by cinnamaldehyde although the cluster regulators aflR and aflS were slightly up-regulated. This may be due to the up-regulation of the oxidative stress-related genes srrA, msnA and atfB being caused by the significant down-regulation of the diffusible factor FluG. Cinnamaldehyde also inhibited aflatoxin formation by perturbing GPCRs and oxylipins normal function, cell wall biosynthesis and redox equilibrium. In addition, accumulation of NADPH due to up-regulation of pentose phosphate pathway drove acetyl-CoA to lipids synthesis rather than polyketides. Both GO and KEGG analysis suggested that pyruvate and phenylalanine metabolism, post-transcriptional modification and key enzymes biosynthesis might be involved in the suppression of AFB1 production by cinnamaldehyde. This study served to decipher the anti-aflatoxigenic properties of cinnamaldehyde in A. flavus and provided powerful evidence for its use in practice.
Categorical processing of fast temporal sequences in the guinea pig auditory brainstem
Authors: Burghard Alice , Voigt Mathias Benjamin , Kral Andrej , Hubka Peter 
Published: July 2019

AbstractDiscrimination of temporal sequences is crucial for auditory object recognition, phoneme categorization and speech understanding. The present study shows that auditory brainstem responses (ABR) to pairs of noise bursts separated by a short gap can be classified into two distinct groups based on the ratio of gap duration to initial noise burst duration in guinea pigs. If this ratio was smaller than 0.5, the ABR to the trailing noise burst was strongly suppressed. On the other hand, if the initial noise burst duration was short compared to the gap duration (a ratio greater than 0.5), a release from suppression and/or enhancement of the trailing ABR was observed. Consequently, initial noise bursts of shorter duration caused a faster transition between response classes than initial noise bursts of longer duration. We propose that the described findings represent a neural correlate of subcortical categorical preprocessing of temporal sequences in the auditory system.