bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling alcoholic liver disease in a human Liver-Chip
Authors: Nawroth Janna C. , Petropolis Debora B. , Manatakis Dimitris V. , Maulana Tengku Ibrahim , Burchett Gabriel , Schlünder Katharina , Witt Anke , Shukla Abhishek , Hamilton Geraldine , Seki Ekihiro , Lu Shelley , Karalis Katia 
Published: July 2020

AbstractFatty liver disease (FLD), is a major public health burden that affects up to 30% of people in Western countries and leads to progressive liver injury, comorbidities, and increased mortality. Key risk factors for developing FLD are obesity and alcohol consumption, both of which are growing in prevalence worldwide. There is an urgent need for human-relevant preclinical models to improve our understanding of FLD progression to steatohepatitis and for the development of sensitive noninvasive diagnostics and therapies. Alcohol-induced liver disease (ALD) represents an ideal case for modeling FDL as ethanol exposure is a comparatively simpler trigger for experimental induction of the pathology, as opposed to the complexity of modeling the diet- and life-style induced FLD. Further, despite their different root causes, the two pathologies share several common characteristics in disease progression and deterioration of liver function, highlighting the potential of an ALD microphysiological model for broad application in translational research. Here, we leverage our recently reported human Liver-Chip for toxicity applications, to expand the capabilities of the platform for broad application in translational research. We report the firstin vitromodeling of ALD that uses human relevant blood alcohol concentrations (BAC) and affords multimodal profiling of clinically relevant endpoints. Our ALD Liver-Chip recapitulates established FLD markers in response to ethanol in a concentration-dependent manner, including lipid accumulation and oxidative stress. Importantly, we show that the ALD Liver-Chip supports the study of secondary insults common in patients with advanced ALD, such as high blood endotoxin levels due to alcohol-associated increased intestinal permeability and barrier dysfunction. Moreover, owing to new developments in the design, the ALD Liver-Chip enables the measurement of structural changes of the bile canaliculi (BC) network as a novelin vitroquantitative readout of alcoholic liver toxicity. In summary, we report the development of a human ALD Liver-Chip as a new platform for modeling the progression of alcohol-induced liver injury with direct translation to clinical research.
Metastatic Site Prediction in Breast Cancer using Omics Knowledge Graph and Pattern Mining with Kirchhoff’s Law Traversal
Authors: Jha Alokkumar , Khan Yasar , Sahay Ratnesh , d’Aquin Mathieu 
Published: July 2020

AbstractPrediction of metastatic sites from the primary site of origin is a impugn task in breast cancer (BRCA). Multi-dimensionality of such metastatic sites - bone, lung, kidney, and brain, using large-scale multi-dimensional Poly-Omics (Transcriptomics, Proteomics and Metabolomics) data of various type, for example, CNV (Copy number variation), GE (Gene expression), DNA methylation, path-ways, and drugs with clinical associations makes classification of metastasis a multi-faceted challenge. In this paper, we have approached the above problem in three steps; 1) Applied Linked data and semantic web to build Poly-Omics data as knowledge graphs and termed them as cancer decision network; 2) Reduced the dimensionality of data using Graph Pattern Mining and explained gene rewiring in cancer decision network by first time using Kirchhoff’s law for knowledge or any graph traversal; 3) Established ruled based modeling to understand the essential -Omics data from poly-Omics for breast cancer progression 4) Predicted the disease’s metastatic site using Kirchhoff’s knowledge graphs as a hidden layer in the graph convolution neural network(GCNN). The features (genes) extracted by applying Kirchhoff’s law on knowledge graphs are used to predict disease relapse site with 91.9% AUC (Area Under Curve) and performed detailed evaluation against the state-of-the-art approaches. The novelty of our approach is in the creation of RDF knowledge graphs from the poly-omics, such as the drug, disease, target(gene/protein), pathways and application of Kirchhoff’s law on knowledge graph to and the first approach to predict metastatic site from the primary tumor. Further, we have applied the rule-based knowledge graph using graph convolution neural network for metastasis site prediction makes the even classification novel.
Antibody Escape by Polyomavirus Capsid Mutation Facilitates Neurovirulence
Authors: Lauver Matthew D. , Goetschius Daniel J. , Netherby-Winslow Colleen S. , Ayers Katelyn N. , Jin Ge , Haas Daniel G. , Frost Elizabeth L. , Cho Sung Hyun , Bator Carol M. , Bywaters Stephanie M. , Christensen Neil D. , Hafenstein Susan L. , Lukacher Aron E. 
Published: July 2020

SUMMARYJCPyV polyomavirus, a member of the human virome, causes Progressive Multifocal Leukoencephalopathy (PML), an oft-fatal demyelinating brain disease in individuals receiving immunomodulatory therapies. Mutations in the major viral capsid protein, VP1, are common in JCPyV from PML patients (JCPyV-PML) but whether they confer neurovirulence or escape from virus-neutralizing antibody (nAb)in vivois unknown. A mouse polyomavirus (MuPyV) with a sequence-equivalent JCPyV-PML VP1 mutation replicated poorly in the kidney, a major reservoir for JCPyV persistence, but retained the CNS infectivity, cell tropism, and neuropathology of the parental virus. This mutation rendered MuPyV resistant to a monoclonal Ab (mAb), whose specificity overlapped the endogenous anti-VP1 response. Using cryo EM and a custom subvolume refinement approach, we resolved an MuPyV:Fab complex map to 3.1 Å resolution. The structure revealed the mechanism of mAb evasion. Our findings demonstrate convergence between nAb evasion and CNS neurovirulencein vivoby a frequent JCPyV-PML VP1 mutation.
The FlgN chaperone activates the Na+-driven engine of the flagellar protein export apparatus
Authors: Minamino Tohru , Kinoshita Miki , Morimoto Yusuke V. , Namba Keiichi 
Published: July 2020

AbstractThe bacterial flagellar protein export machinery promotes H+-coupled translocation of flagellar proteins to the cell exterior. When the cytoplasmic ATPase complex does not function, the transmembrane export gate complex opens its Na+channel and continues protein transport. However, it remains unknown how. Here we report that the FlgN chaperone acts as a switch to activate a backup export mechanism for the ATPase complex by activating the Na+-driven engine. Impaired interaction of FlhA with the FliJ subunit of the ATPase complex increased Na+-dependence of flagellar protein export. Deletion of FlgN inhibited protein export in the absence of the ATPase complex but not in its presence. Gain-of-function mutations in FlhA restored not only the FlgN defect but also the FliJ defect. We propose that the interaction of FlgN with FlhA opens the Na+channel in the export engine, thereby maintaining the protein export activity in the absence of the active ATPase complex.
Binding of guide piRNA triggers methylation of the unstructured N-terminal region of Aub leading to assembly of the piRNA amplification complex
Authors: Huang Xiawei , Hu Hongmiao , Webster Alexandre , Zou Fan , Du Jiamu , Toth Katalin Fejes , Aravin Alexei A. , Li Sisi 
Published: July 2020

SummaryPiwi proteins use guide piRNAs to repress selfish genomic elements, protecting the genomic integrity of gametes and ensuring the fertility of animal species. Efficient transposon repression depends on amplification of piRNA guides in the ping-pong cycle, which in Drosophila entails tight cooperation between two Piwi proteins, Aub and Ago3. Here we show that post-translational modification, symmetric dimethylarginine (sDMA), of Aub is essential for piRNA biogenesis, transposon silencing and fertility. Methylation is triggered by loading of a piRNA guide into Aub, which exposes its unstructured N-terminal region to the PRMT5 methylosome complex. Thus, sDMA modification is a signal that Aub is loaded with piRNA guide. Amplification of piRNA in the ping-pong cycle requires assembly of a tertiary complex scaffolded by Krimper, which simultaneously binds the N-terminal regions of Aub and Ago3. To promote generation of new piRNA, Krimp uses its two Tudor domains to bind Aub and Ago3 in opposite modification and piRNA-loading states. Our results reveal that post-translational modifications in unstructured regions of Piwi proteins and their binding by Tudor domains that are capable of discriminating between modification states is essential for piRNA biogenesis and silencing.HighlightssDMA modification of Aub is essential for ping-pong cycle, transposon silencing and fertility.piRNA loading triggers Aub sDMA modification by exposing its unstructured N terminal region to the methylosome complex.A single molecule of Krimp simultaneously binds piRNA-bound Aub and empty Ago3 to assemble ping-pong complex.The distinct structure of two Tudor domains of Krimp ensures binding of Ago3 and Aub in opposite modification and piRNA-loading states.
Genetic basis of offspring number and body weight variation inDrosophila melanogaster
Authors: Akhund-Zade Jamilla , Lall Shraddha , Gajda Erika , Yoon Denise , de Bivort Benjamin 
Published: July 2020

AbstractDrosophila melanogasteregg production, a proxy for fecundity, is an extensively studied life-history trait with a strong genetic basis. As eggs develop into larvae and adults, space and resource constraints can put pressure on the developing offspring, leading to a decrease in viability, body size, and lifespan. Our goal was to map the genetic basis of offspring number and weight under the restriction of a standard laboratory vial. We screened 143 lines from theDrosophilaGenetic Reference Panel for offspring numbers and weights to create an ‘offspring index’ that captured the number vs. weight trade-off. We found 30 associated variants in 18 genes. Validation ofhid,Sox21b,CG8312, andmubcandidate genes using gene disruption mutants demonstrated a role in adult stage viability, while mutations inIhandRbpincreased offspring number and increased weight, respectively. The polygenic basis of offspring number and weight, with many variants of small effect, as well as the involvement of genes with varied functional roles, support the notion of Fisher’s “infinitesimal model” for this life-history trait.
Stator remodeling mechanism ofBacillus subtilisflagellar motor during biofilm development
Authors: Terahara Naoya , Namba Keiichi , Minamino Tohru 
Published: July 2020

AbstractBacillus subtilispossesses two distinct types of stator protein complexes for the flagellar motor: H+-type MotAB and Na+-type MotPS. The MotPS complex is used when both the external Na+concentration and viscosity are high. Because deletion of themotPSgenes does not affect swimming motility of cells, a physiological role of MotPS-dependent motility remains unclear. Here, we report that the MotPS stator complex is required for efficient biofilm maturation. Depletion of the MotPS complex did not cause a significant delay in the initiation of biofilm formation but reduced the number of viable cells in the biofilm. The MotAB stator units were efficiently replaced by the MotPS complexes with an increase in the viscosity of the environments. Therefore, we propose that MotPS-dependent motility of motile cells in the biofilm structure is required to efficiently keep the bacterial society in the biofilm healthy.
Molecular insight into Nickel(II) binding by Her2-specific IgE: a possible mechanistic insight into the pathogenesis of Type I nickel hypersensitivity
Authors: Su Chinh Tran-To , Lua Wai-Heng , Poh Jun-Jie , Ling Wei-Li , Yeo Joshua Yi , Gan Samuel Ken-En 
Published: July 2020

SUMMARYNickel (Ni) allergy has been reported in contact dermatitis Type IV (Ni-specific T cells mediated) and asthmatic Type I (IgE-mediated) hypersensitivities. Associations between the two hypersensitivities have been found in some patients, but the underlying mechanisms remain enigmatic. Using Her2-specific IgEs as models, we found additional binding to Ni-NTA without observable changes in binding to Her2 and that glutamine, together with the canonical Ni2+-binding histidine, could form Ni2+binding signatures. This mechanism may underlie Type I hypersensitivity in the selection of anti-Ni2+IgEs. This mechanism may also underlie Type IV hypersensitivity and the interaction of immunoglobulin proteins with other heavy metal ions. Our findings shed light to how Ni hypersensitivities can occur and how they can be avoided in therapeutics design, or even incorporated for biotechnological purification purposes.
The molecular basis of socially-mediated phenotypic plasticity in a eusocial paper wasp
Authors: Taylor Benjamin A. , Cini Alessandro , Wyatt Christopher D. R. , Reuter Max , Sumner Seirian 
Published: July 2020

AbstractPhenotypic plasticity, the ability to produce multiple phenotypes from a single genotype, represents an excellent model with which to examine the relationship between gene expression and phenotypes. Despite this, analyses of the molecular bases of plasticity have been limited by the challenges of linking individual phenotypes with individual-level gene expression profiles, especially in the case of complex social phenotypes. Here, we tackle this challenge by analysing the individual-level gene expression profiles ofPolistes dominulapaper wasps following the loss of a queen, a perturbation that induces some individuals to undergo a significant phenotypic shift and become replacement reproductives. Using a machine learning approach, we find a strong response of caste-associated gene expression to queen loss, wherein individuals’ expression profiles become intermediate between queen and worker states. Importantly, this change occurs even in individuals that appear phenotypically unaffected. Part of this response is explained by individual attributes, most prominently age. These results demonstrate that large changes in gene expression may occur in the absence of detectable phenotypic changes, resulting here in a socially mediated de-differentiation of individuals at the transcriptomic but not the phenotypic level. Our findings also highlight the complexity of the relationship between gene expression and phenotype, where transcriptomes are neither a direct reflection of the genotype nor a proxy for the molecular underpinnings of the external phenotype.
AGC kinase members phosphorylate ubiquitin
Authors: Kolbe Carl-Christian , Latz Eicke 
Published: July 2020

AbstractThe posttranslational modification of proteins with ubiquitin controls most cellular processes, such as protein degradation or transport, cell signaling, or transcription1–5. Ubiquitin can be phosphorylated at multiple sites, which likely further modulates the function of protein ubiquitination6,7. However, except for PINK18–10, the kinases involved in ubiquitin phosphorylation remain unknown, which hampers our understanding of phospho-ubiquitin signaling. In this study, we performed genome-wide in vitro kinase screenings and discovered that AGC kinases phosphorylate ubiquitin. Ubiquitin phosphorylation by members of the PKA, PKC, PKG and RSK families as well as by less well-characterized kinases, such as SGK2, was not solely dependent on peptide specificity but required additional kinase recruitment to ubiquitin. The stabilization of the kinase interaction with ubiquitin resulted in phosphorylation of suboptimal kinase motifs on ubiquitin, suggesting that ubiquitin phosphorylation is dictated primarily through the recruitment of kinases to the ubiquitinated proteins. Hence, we identify AGC kinase members as enzymes that can phosphorylate ubiquitin in a mechanism regulated by protein interactions outside of the catalytic kinase domain and are only applicable to specific subsets of ubiquitinated proteins.
Myeloid deletion and therapeutic activation of AMP-activated protein kinase (AMPK) do not alter atherosclerosis in male or female mice
Authors: LeBlond Nicholas D. , Ghorbani Peyman , O’Dwyer Conor , Ambursley Nia , Nunes Julia R. C. , Smith Tyler K.T. , Trzaskalski Natasha A. , Mulvihill Erin E. , Viollet Benoit , Foretz Marc , Fullerton Morgan D. 
Published: July 2020

AbstractObjectiveThe dysregulation of myeloid-derived cell metabolism can drive atherosclerosis. AMP-activated protein kinase (AMPK) controls various aspects of macrophage dynamics and lipid homeostasis, which are important during atherogenesis.Approach and ResultsWe aimed to clarify the role of myeloid-specific AMPK signaling by using LysM-Cre to drive the deletion of both the α1 and α2 catalytic subunits (MacKO), in male and female mice made acutely atherosclerotic by PCSK9-AAV and Western diet-feeding. After 6 weeks of Western diet feeding, half received daily injection of either the AMPK activator, A-769662 or a vehicle control for a further 6 weeks. After 12 weeks, myeloid cell populations were not different between genotype or sex. Similarly, aortic sinus plaque size, lipid staining and necrotic area were not different in male and female MacKO mice compared to their littermate floxed controls. Moreover, therapeutic intervention with A-769662 had no effect. There were no differences in the amount of circulating total cholesterol or triglyceride, and only minor differences in the levels of inflammatory cytokines between groups. Finally, CD68+ area or markers of autophagy showed no effect of either lacking AMPK signaling or systemic AMPK activation.ConclusionsOur data suggest that while defined roles for each catalytic AMPK subunit have been identified, global deletion of myeloid AMPK signaling does not significantly impact atherosclerosis. Moreover, we show that intervention with the first-generation AMPK activator, A-769662, was not able to stem the progression of atherosclerosis.Highlights- The deletion of both catalytic subunits of AMPK in myeloid cells has no significant effect on the progression of atherosclerosis in either male or female mice- Therapeutic delivery of a first-generation AMPK activator (A-769662) for the last 6 weeks of 12-week study had no beneficial effect in either male or female mice- Studying total AMPK deletion may mask specific effects of each isoform and highlights the need for targeted disruption of AMPK phosphorylation sites via knock-in mutations, rather than the traditional “sledgehammer” knockout approach
NATURAL ENEMIES OF HERBIVORES MAINTAIN THEIR BIOLOGICAL CONTROL POTENTIAL UNDER FUTURE CO2, TEMPERATURE AND PRECIPITATION PATTERNS
Authors: Van Doan Cong , Pfander Marc , Guyer Anouk , Zhang Xi , Maurer Corina , Robert Christelle A.M. 
Published: July 2020

ABSTRACTClimate change will profoundly alter the physiology and ecology of plants, insect herbivores and their natural enemies, resulting in strong effects on multitrophic interactions. Yet, manipulative studies that investigate the direct combined impacts of changes in CO2, temperature, and precipitation on this group of organisms remain rare. Here, we assessed how three day exposure to elevated CO2, increased temperature, and decreased precipitation affect the performance and predation success on species from four major groups of natural enemies of insect herbivores: an entomopathogenic nematode, a wolf spider, a ladybug and a parasitoid wasp. Future climatic conditions (RCP 8.5), entailing a 28% decrease in precipitation, a 3.4°C raise in temperature and a 400 ppm increase in CO2levels, slightly reduced the survival of entomopathogenic nematodes, but had no effect on the survival of other species. Predation success was not negatively affected in any of the tested species, but was even increased for wolf spiders and entomopathogenic nematodes. Factorial manipulation of climate variables revealed a positive effect of reduced soil moisture on nematode infectivity, but not of increased temperature or elevated CO2. These results suggest that natural enemies of herbivores are well adapted to short term changes in climatic conditions and may not suffer from direct negative effects of future climates. These findings provide mechanistic insights that will inform future efforts to disentangle the complex interplay of biotic and abiotic factors that drive climate-dependent changes in multitrophic interaction networks.
Electrical properties of graphite-glass thick-film resistors
Authors: Matusiak Tomasz , Dabrowski Arkadiusz , Golonka Leszek 
Published: July 2020

Purpose
The purpose of this paper is to present the properties of thick-film resistors made of novel pastes prepared from glass and graphite.

Design/methodology/approach
Graphite-based resistors were made of thick-film pastes with different graphite-to-glass mass fraction were prepared and examined. Sheet resistance, temperature coefficient of resistance, impact of humidity and short-term overload were investigated. The properties of the layers fired in atmospheres of air at 550°C and nitrogen at 875°C were compared.

Findings
Graphite-based resistors with various graphite-to-glass ratios made possible to obtain a wide range of sheet resistance from single O/square to few kO/square. These values were dependent on firing atmosphere, paste composition and the number of screen-printed layers. The samples made of paste with 1:1 graphite-to-glass ratio exhibited the temperature coefficient of resistance of about −1,000 ppm/°C, almost independently on the firing atmosphere and presence of a top coating. The resistors fired in the air after coating with overglaze, exhibited significantly lower sheet resistance, reduced impact of humidity and improved power capabilities.

Originality/value
In this paper, graphite-based resistors for applications in typical high-temperature cermet thick-film circuits were presented, whereas typical graphite-based resistors were fabricated in polymer thick-film technology. Owing to very low cost of the graphite, the material is suitable for low-power passive circuits, where components are not subjected into high temperature, above the typical temperature of operation of standard electronic components.
FPGA-based experiments for demonstrating bi-stability in tabu learning neuron model
Authors: Zhu Dong , Hou Liping , Chen Mo , Bao Bocheng 
Published: July 2020

Purpose
The purpose of this paper is to develop an field programmable gate array (FPGA)-based neuron circuit to mimic dynamical behaviors of tabu learning neuron model.

Design/methodology/approach
Numerical investigations for the tabu learning neuron model show the coexisting behaviors of bi-stability. To reproduce the numerical results by hardware experiments, a digitally FPGA-based neuron circuit is constructed by pure floating-point operations to guarantee high computational accuracy. Based on the common floating-point operators provided by Xilinx Vivado software, the specific functions used in the neuron model are designed in hardware description language programs. Thus, by using the fourth-order Runge-Kutta algorithm and loading the specific functions orderly, the tabu learning neuron model is implemented on the Xilinx FPGA board.

Findings
With the variation of the activation gradient, the initial-related coexisting attractors with bi-stability are found in the tabu learning neuron model, which are experimentally demonstrated by a digitally FPGA-based neuron circuit.

Originality/value
Without any piecewise linear approximations, a digitally FPGA-based neuron circuit is implemented using pure floating-point operations, from which the initial conditions-related coexisting behaviors are experimentally demonstrated in the tabu learning neuron model.