bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma redox imbalance caused by albumin oxidation promotes lung-predominant NETosis and pulmonary cancer metastasis
Authors: Inoue Minoru , Enomoto Masahiro , Koike Yuhki , Di Grappa Marco A. , Zhao Xiao , Yip Kenneth , Huang Shao Hui , Waldron John N. , Ikura Mitsuhiko , Liu Fei-Fei , Bratman Scott V. 
Published: March 2018

AbstractNeutrophil extracellular traps (NETs) entrap circulating tumor cells (CTCs) and promote metastasis within distant organs in preclinical models1,2. In these models, NETosis is triggered by exogenous massive inflammatory stimuli, and thus it remains unknown whether cancer hosts under physiologic inflammation-free conditions experience NETosis and consequent cancer metastasis. Here we show that plasma redox imbalance caused by albumin oxidation promotes inflammation-independent NETosis and cancer metastasis specifically in the lungs. Albumin is the major source of free thiol that maintains redox balance in vitro and in vivo. Oxidation of albumin-derived free thiol is sufficient to trigger NETosis via accumulation of reactive oxygen species within neutrophils. The resultant NETs are found predominantly within lungs where they contribute to the colonization of CTCs leading to pulmonary metastases in mouse models. These effects are abrogated by pharmacologic inhibition of NET formation. Moreover, albumin oxidation and the resultant decline of plasma free thiol are associated with pulmonary metastasis in a cohort of head and neck cancer patients. These results implicate plasma redox balance as an endogenous and physiologic regulator of NETosis and pulmonary cancer metastasis, providing new therapeutic and diagnostic opportunities for combatting cancer progression.
Non-canonical HIF-1 stabilization is essential for intestinal tumorigenesis
Authors: Rohwer Nadine , Jumpertz Sandra , Erdem Merve , Egners Antje , Warzecha Klaudia T. , Fragoulis Athanassios , Kühl Anja A. , Kramann Rafael , Neuss Sabine , Rudolph Ines , Endermann Tobias , Zasada Christin , Apostolova Ivayla , Gerling Marco , Kempa Stefan , Hughes Russell , Lewis Claire E. , Brenner Winfried , Malinowski Maciej B. , Stockmann Martin , Schomburg Lutz , Faller William , Sansom Owen , Tacke Frank , Morkel Markus , Cramer Thorsten 
Published: March 2018

AbstractThe hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1’s role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of wnt/β-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with nuclear HIF-1α in intestinal adenomas, pointing towards a functional importance of hypoxia-independent, i.e. non-canonical HIF-1 stabilization that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1α and suggests that hypoxia and HIF-1α stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.
Multi-hierarchical Profiling the Structure-Activity Relationships of Engineered Nanomaterials at Nano-Bio Interfaces
Authors: Cai Xiaoming , Dong Jun , Liu Jing , Zheng Huizhen , Kaweeteerawat Chitrada , Wang Fangjun , Ji Zhaoxia , Li Ruibin 
Published: March 2018

AbstractIncreasingly raised concerns (nanotoxicity, clinical translation, etc) on nanotechnology require breakthroughs in structure-activity relationship (SAR) analyses of engineered nanomaterials (ENMs) at nano-bio interfaces. However, current nano-SAR assessments failed to disclosure sufficient information to understand ENM-induced bio-effects. Here we developed a multi-hierarchical nano-SAR assessment for a representative ENM, Fe2O3 by systematically examining cellular metabolite and protein changes. This nano-SAR profile allows visualizing the contributions of 7 basal properties of Fe2O3 to their diverse bio-effects. For instance, while surface reactivity is responsible for Fe2O3-induced cell migration, the inflammatory effects of Fe2O3 nanorods and nanoplates are determined by their aspect ratio and surface reactivity, respectively. We further discovered the detailed mechanisms, including NLRP3 inflammasome pathway and monocyte chemoattractant protein-1 involved signaling. Both effects were further validated in animal lungs. Our findings provide substantial new insights at nano-bio interfaces, which may facilitate the tailored design of ENMs to endow them with desired bio-effects.
Host factors influence the sex of nematodes parasitizing roots of Arabidopsis thaliana
Authors: Anjam Muhammad Shahzad , Shah Syed Jehangir , Matera Christiane , Różańska Elżbieta , Sobczak Miroslaw , Siddique Shahid , Grundler Florian M.W. 
Published: March 2018

AbstractPlant-parasitic cyst nematodes induce hypermetabolic syncytial nurse cells in the roots of their host plants. Syncytia are their only food source. Cyst nematodes are sexually dimorphic, with their differentiation into male or female strongly influenced by host environmental conditions. Under favorable conditions with plenty of nutrients, more females develop, whereas mainly male nematodes develop under adverse conditions such as in resistant plants. Here, we developed and validated a method to predict the sex of beet cyst nematode (Heterodera schachtii) during the early stages of its parasitism in the host plant Arabidopsis thaliana. We collected root segments containing male-associated syncytia (MAS) or female-associated syncytia (FAS), isolated syncytial cells by laser microdissection, and performed a comparative transcriptome analysis. Genes belonging to categories of defense, nutrient deficiency, and nutrient starvation were overrepresented in MAS as compared to FAS. Conversely, gene categories related to metabolism, modification, and biosynthesis of cell walls were overrepresented in FAS. We used β-glucuronidase (GUS) analysis, qRT-PCR, and loss-of-function mutants to characterize FAS- and MAS-specific candidate genes. Our results demonstrated that various plant-based factors, including immune response, nutrient availability, and structural modifications, influence the sexual fate sex determination of cyst the nematodes.
Disruption in A-to-I editing levels affects C. elegans development more than a complete lack of editing
Authors: Ganem Nabeel S. , Ben-Asher Noa , Manning Aidan C. , Deffit Sarah N. , Washburn Michael C. , Wheeler Emily C. , Yeo Gene W. , Ben-Naim Zgayer Orna , Mantsur Einav , Hundley Heather A. , Lamm Ayelet T. 
Published: March 2018

SummaryA-to-I RNA editing is widespread in eukaryotic transcriptomes and plays an essential role in the creation of proteomic and phenotypic diversity. Loss of ADARs, the proteins responsible for A-to-I editing, results in lethality in mammals. In C. elegans, knocking out both ADARs, ADR-1 and ADR-2, results in aberrant behavior and abnormal development. Studies have shown that ADR-2 can actively deaminate dsRNA while ADR-1 cannot. However, as most studies of C. elegans ADARs were performed on worms mutated in both ADAR genes, the effects observed cannot be attributed to a single ADAR or to the interactions between ADAR genes. Therefore, we set to study the effects of each C. elegans ADAR on RNA editing, gene expression, protein levels and the contribution of each of ADAR to the phenotypes observed in worms mutated in both genes, in order to elucidate their distinct functions. We found significant differences in the phenotypes observed in worms mutated in a single ADAR gene. Worms harboring adr-1 mutations have a significant reduction in their lifespan, while worms harboring adr-2 mutations have extended lifespan. We also observed severe abnormalities in vulva formation in adr-1 mutants, and we suggest that these phenotypes are a result of an RNA editing independent function of ADR-1. Mutations in each ADAR resulted in expressional changes in hundreds of genes, and a significant downregulation of edited genes. However, very few changes in the protein levels were observed. In addition, we found that ADR-1 binds many edited genes and primarily promotes editing at the L4 stage of development. While editing still occurs in the absence of ADR-1, most of the editing occurs in genes that are edited in wildtype worms, suggesting that ADR-1 does not prevent editing by binding to and protecting the RNA but rather enhances or promotes editing. Our results suggest that ADR-1 plays a significant role in the RNA editing process and by altering editing levels it causes the severe phenotypes that we observed. In contrast, a complete lack of RNA editing is less harmful to the worms. Furthermore, our results indicate that the effect of RNA editing on the protein content in the cell is minor and probably the main purpose of these modifications is to antagonize or enhance other gene regulatory mechanisms that act on RNA.
Deep mutational analysis reveals functional trade-offs in the sequences of EGFR autophosphorylation sites
Authors: Cantor Aaron J. , Shah Neel H. , Kuriyan John 
Published: March 2018

AbstractUpon activation, the epidermal growth factor receptor (EGFR) phosphorylates tyrosine residues in its cytoplasmic tail, which triggers the binding of Src Homology 2 (SH2) and Phosphotyrosine Binding (PTB) domains and initiates downstream signaling. The sequences flanking the tyrosine residues (referred to as phosphosites) must be compatible with phosphorylation by the EGFR kinase domain and the recruitment of adapter proteins, while minimizing phosphorylation that would reduce the fidelity of signal transmission. In order to understand how phosphosite sequences encode these functions within a small set of residues, we carried out high-throughput mutational analysis of three phosphosite sequences in the EGFR tail. We used bacterial surface-display of peptides, coupled with deep sequencing, to monitor phosphorylation efficiency and the binding of the SH2 and PTB domains of the adapter proteins Grb2 and Shc1, respectively. We found that the sequences of phosphosites in the EGFR tail are restricted to a subset of the range of sequences that can be phosphorylated efficiently by EGFR. Although efficient phosphorylation by EGFR can occur with either acidic or large hydrophobic residues at the −1 position with respect to the tyrosine, hydrophobic residues are generally excluded from this position in tail sequences. The mutational data suggest that this restriction results in weaker binding to adapter proteins, but also disfavors phosphorylation by the cytoplasmic tyrosine kinases c-Src and c-Abl. Our results show how EGFR-family phosphosites achieve a trade-off between minimizing off-pathway phosphorylation while maintaining the ability to recruit the diverse complement of effectors required for downstream pathway activation.
Decoding neural responses with minimal information loss
Authors: Berkowitz John A. , Sharpee Tatyana O. 
Published: March 2018

AbstractCortical tissue has a circuit motif termed the cortical column, which is thought to represent its basic computational unit but whose function remains unclear. Here we propose, and show quantitative evidence, that the cortical column performs computations necessary to decode incoming neural activity with minimal information loss. The cortical decoder achieves higher accuracy compared to simpler decoders found in invertebrate and subcortical circuits by incorporating specific recurrent network dynamics. This recurrent dynamics also makes it possible to choose between alternative stimulus categories. The structure of cortical decoder predicts quadratic dependence of cortex size relative to subcortical parts of the brain. We quantitatively verify this relationship using anatomical data across mammalian species. The results offer a new perspective on the evolution and computational function of cortical columns.
Stochastic models of cell invasion with fluorescent cell cycle indicators
Authors: Simpson Matthew J , Jin Wang , Vittadello Sean T , Tambyah Tamara A , Ryan Jacob M , Gunasingh Gency , Haass Nikolas K , McCue Scott W 
Published: March 2018

AbstractFluorescent cell cycle labelling in cell biology experiments provides real time information about the location of individual cells, as well as the phase of the cell cycle of individual cells. We develop a stochastic, lattice-based random walk model of a two-dimensional scratch assay where the total population is composed of three distinct subpopulations which we visualise as red, yellow and green subpopulations. Our model mimics FUCCI technology in which cells in the G1 phase of the cell cycle fluoresce red, cells in the early S phase fluoresce yellow, and cells in the S/G2/M phase fluoresce green. The model is an exclusion process so that any potential motility or proliferation event that would place an agent on an occupied lattice site is aborted. Using experimental images and previous experimental measurements, we explain how to apply the stochastic model to simulate a scratch assay initialised with a low to moderate density monolayer of human melanoma cell line. We obtain additional mathematical insight by deriving an approximate partial differential equation (PDE) description of the stochastic model, leading to a novel system of three coupled nonlinear reaction diffusion equations. Comparing averaged simulation data with the solution of the continuum limit model confirms that the PDE description is accurate for biologically-relevant parameter combinations.
New formula and conversion factor to compute tree species basic wood density from a global wood technology database
Authors: Vieilledent Ghislain , Jörg Fischer Fabian , Chave Jérôme , Guibal Daniel , Langbour Patrick , Gérard Jean 
Published: March 2018

AbstractPremise of the studyBasic wood density is an important ecological trait for woody plants. It is used to characterize species performance and fitness in community ecology, and to compute tree and forest biomass in carbon cycle studies. While wood density has been historically measured at 12% moisture, it is convenient for ecological purposes to convert this measure to basic wood density, i.e. the ratio of dry mass over green volume. Basic wood density can then be used to compute tree dry biomass from living tree volume.MethodsHere, we derive a new, exact formula to compute the basic wood density Db from the density at moisture content w denoted Dw, the fibre saturation point S, and the volumetric shrinkage coefficient R. We estimated a new conversion factor using a global wood technology database where values to use this formula are available for 4022 trees collected in 64 countries (mostly tropical) and representing 872 species.Key resultsWe show that previous conversion factors used to convert densities at 12% moisture into basic wood densities are inconsistent. Based on theory and data, we found that basic wood density could be inferred from the density at 12% moisture using the following formula: Db = 0.828D122. This value of 0.828 provides basic wood density estimates 4-5% smaller than values inferred from previous conversion factors.ConclusionsThis new conversion factor should be used to derive basic wood densities in global wood density databases. This would prevent overestimating global forest carbon stocks and allow predicting better tree species community dynamics from wood density.
Tripartite chromatin localization of budding yeast Shugoshin involves higher-ordered architecture of mitotic chromosomes
Authors: Deng Xiexiong , Kuo Min-Hao 
Published: March 2018

ABSTRACTThe spindle assembly checkpoint (SAC) is key to faithful segregation of chromosomes. One requirement that satisfies SAC is appropriate tension between sister chromatids at the metaphase-anaphase juncture. Proper tension generated by poleward pulling of mitotic spindles signals biorientation of the underlying chromosome. In the budding yeast, the tension status is monitored by the conserved Shugoshin protein, Sgo1p, and the tension sensing motif (TSM) of histone H3. ChIP-seq reveals a unique TSM-dependent, tripartite domain of Sgo1p in each mitotic chromosome. This domain consists of one centromeric and two flanking peaks 3 – 4 kb away, and is present exclusively in mitosis. Strikingly, this trident motif coincides with cohesin localization, but only at the centromere and the two immediate adjacent loci, despite that cohesin is enriched at numerous regions throughout mitotic chromosomes. The TSM-Sgo1p-cohesin triad is at the center stage of higher-ordered chromatin architecture for error-free segregation.
Repeat-specific functions for the C-terminal domain of RNA polymerase II in budding yeast
Authors: Babokhov Michael , Mosaheb Mohammad M. , Baker Richard W. , Fuchs Stephen M. 
Published: March 2018

AbstractThe C-terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAPII) is required to regulate transcription and to integrate it with other essential cellular processes. In the budding yeastSaccharomyces cerevisiae, the CTD of Rpb1p consists of 26 conserved heptad repeats that are post-translationally modified to orchestrate protein factor binding at different stages of the transcription cycle. A long-standing question in the study of the CTD is if there are any functional differences between the 26 repeats. In this study, we present evidence that repeats of identical sequence have different functions based on their position within the CTD. We assembled plasmids expressing Rpb1p with serine to alanine substitutions in three defined regions of the CTD and measured a range of phenotypes for yeast expressing these constructs. Mutations in the beginning and middle regions of the CTD had drastic, and region-specific effects, while mutating the distal region had no observable phenotype. Further mutational analysis determined that Ser5 within the first region of repeats was solely responsible for the observed growth differences and sequencing fast-growing suppressors allowed us to further define the functional regions of the CTD. This mutational analysis is consistent with current structural models for how the RNAPII holoenzyme and the CTD specifically would reside in complex with Mediator and establishes a foundation for studying regioselective binding along the repetitive RNAPII CTD.
Electrodiffusion model of synaptic potentials in dendritic spines
Authors: Lagache Thibault , Jayant Krishna , Yuste Rafael 
Published: March 2018

ABSTRACTWhen modeling electric current flow in neurons and excitable cells, traditional cable theory ignores electrodiffusion (i.e. the interaction between electric fields and ionic diffusion) as it assumes that concentration changes associated with ionic currents are negligible. This assumption, while true for large neuronal compartments, fails when applied to femto-liter size compartments such as dendritic spines - small protrusions that form the main site of synaptic inputs in the brain. Here, we use the Poisson (P) and Nernst-Planck (NP) equations, which relate electric field to charge and couple Fick’s law of diffusion to the electric field, to model ion concentration dynamics in dendritic spines. We use experimentally measured voltage transients from spines with nanoelectrodes to explore these dynamics with realistic parameters. We find that (i) passive diffusion and electrodiffusion jointly affect the kinetics of spine excitatory post-synaptic potentials (EPSPs); (ii) spine geometry plays a key role in shaping EPSPs; and, (iii) the spine-neck resistance dynamically decreases during EPSPs, leading to short-term synaptic facilitation. Our formulation can be easily adopted to model ionic biophysics in a variety of nanoscale bio-compartments.
Atlastins mediate selective autophagy of the endoplasmic reticulum
Authors: Liang Jin Rui , Lingeman Emily , Ahmed Saba , Corn Jacob 
Published: March 2018

ABSTRACTThe selective lysosomal degradation (autophagy) of entire organelles is required for cellular homeostasis, and its dysregulation is involved in degenerative disorders such as Parkinson’s Disease. While autophagy of mitochondria (mitophagy) is becoming better understood, other forms of organelle autophagy are relatively unexplored. Here we develope multiple quantitative assays to measure organelle autophagy using flow cytometry, microscopy, and Western blotting. Focusing on autophagy of the endoplasmic reticulum (ER-phagy), we show that these assays allow facile measurement of ER-phagy, and that ER-phagy is inhibited by knockdown of either core autophagy components or the recently reported FAM134B ER-phagy receptor. Using these assays, we further identify that Atlastins, the ER-resident GTPases involved in ER membrane morphology, are key positive effectors of ER-phagy. Atlastin-depleted cells have decreased ER-phagy under starvation conditions, and Atlastin’s role in ER-phagy requires both a functional GTPase domain and proper ER localization. The three Atlastin family members functionally compensate for one another during ER-phagy and may form heteromeric complexes with one another. We also find that Atlastins act downstream of the FAM134B ER-phagy receptor. We propose that during ER-phagy, Atlastins remodel ER membrane to separate pieces of FAM134B-marked ER for efficient autophagosomal engulfment. Human mutations in Atlastins led to hereditary spastic paraplegia, and our results suggest that this disease may be linked to deficiencies in ER-phagy rather than ER morphology.
Deriving the transition probability matrix using computational mechanics
Authors: Riveros Guillermo A. , Rosario-Pérez Manuel E. 
Published: March 2018

Purpose
The combined effects of several complex phenomena cause the deterioration of elements in steel hydraulic structures (SHSs) within the US lock system: corrosion, cracking and fatigue, impact and overloads. Predicting the future condition state of these structures by the use of current condition state inspection data can be achieved through the probabilistic chain deterioration model. The purpose of this study is to derive the transition probability matrix using final elements modeling of a miter gate.

Design/methodology/approach
If predicted accurately, this information would yield benefits in determining the need for rehabilitation or replacement of SHS. However, because of the complexity and difficulties on obtaining sufficient inspection data, there is a lack of available condition states needed to formulate proper transition probability matrices for each deterioration case.

Findings
This study focuses on using a three-dimensional explicit finite element analysis (FEM) of a miter gate that has been fully validated with experimental data to derive the transition probability matrix when the loss of flexural capacity in a corroded member is simulated.

Practical implications
New methodology using computational mechanics to derive the transition probability matrices of navigation steel structures has been presented.

Originality/value
The difficulty of deriving the transition probability matrix to perform a Markovian analysis increases when limited amount of inspection data is available. The used state of practice FEM to derive the transition probability matrix is not just necessary but also essential when the need for proper maintenance is required but limited amount of the condition of the structural system is unknown.