bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nanotopography enhances dynamic remodeling of tight junction proteins through cytosolic complexes
Authors: Huang Xiao , Shi Xiaoyu , Hansen Mollie Eva , Nemeth Cameron L. , Ceili Anna , Huang Bo , Mauro Theodora , Koval Michael , Desai Tejal A. 
Published: November 2019

AbstractThe epithelial tight junction regulates barrier function and is responsive to extracellular stimuli. Here we demonstrated that contact of synthetic surfaces with defined nanotopography at the apical surface of epithelial monolayers increased paracellular permeability of macromolecules. To monitor changes in tight junction morphology in live cells, we fluorescently tagged the scaffold protein zonula occludens-1 (ZO-1) through CRISPR/Cas9-based gene editing. Contact between cells and nanostructured surfaces destabilized junction-associated ZO-1 and promoted its arrangement into highly dynamic non-junctional cytosolic complexes that averaged ∼2 μm in diameter. Junction-associated ZO-1 rapidly remodeled, and we also observed the direct transformation of cytosolic complexes into junction-like structures. Claudin-family tight junction transmembrane proteins and F-actin also were associated with these ZO-1 containing cytosolic complexes. These data suggest that the cytosolic structures are novel intermediates formed in response to nanotopographic cues that facilitate rapid tight junction remodeling in order to regulate paracellular permeability.
Multiple roles for laccase2 in butterfly wing pigmentation, scale development, and cuticle tanning
Authors: Peng Ceili L. , Mazo-Vargas Anyi , Brack Benjamin J. , Reed Robert D. 
Published: November 2019

ABSTRACTLepidopteran wing scales play important roles in a number of functions including color patterning and thermoregulation. Despite the importance of wing scales, however, we still have a limited understanding of the genetic mechanisms that underlie scale patterning, development, and coloration. Here we explore the function of the phenoloxidase-encoding gene laccase2 in wing and scale development in the nymphalid butterfly Vanessa cardui. Somatic deletion mosaics of laccase2 generated by CRISPR/Cas9 genome editing presented several distinct mutant phenotypes. Consistent with work in other non-lepidopteran insect groups, we observed reductions in melanin pigmentation and defects in cuticle formation. We were also surprised, however, to see distinct effects on scale development including complete loss of wing scales. This work highlights laccase2 as a gene that plays multiple roles in wing and scale development and provides new insight into the evolution of lepidopteran wing coloration.
TAT-Cx43266-283impairs metabolic plasticity in glioma stem cells in vitro and in vivo
Authors: Pelaz Sara G. , Jaraíz-Rodríguez Myriam , Talaverón Rocío , García-Vicente Laura , de Cedrón Marta Gómez , Tabernero María , de Molina Ana Ramírez , Lillo Concepción , Medina José M. , Tabernero Arantxa 
Published: November 2019

AbstractGlioblastoma is the most aggressive primary brain cancer, with a median survival of 1 to 2 years1. These tumours contain glioma stem cells (GSCs), which are highly tumorigenic, resistant to conventional therapies2, 3, and exhibit metabolic plasticity to adapt to challenging environments4, 5. GSCs can be specifically targeted by a short cell-penetrating peptide based on connexin43 (Cx43) (TAT-Cx43266-283) that reduces tumour growth and increases survival in preclinical models6via c-Src inhibition7. Because several reports revealed poor clinical efficacy of various antitumoral drugs due to metabolic rewiring in cancer cells8–10, we investigated the effect of TAT-Cx43266-283on GSC metabolism and metabolic plasticity. Here we show that TAT-Cx43266-283decreases GSC glucose uptake and oxidative phosphorylation without a compensatory increase in glycolysis, with no effect on neuron or astrocyte metabolism. GSC changes were mediated by decreased hexokinase (HK) activity and aberrant mitochondrial localization, ultrastructure and function. Moreover, TAT-Cx43266-283reduced GSC growth and survival under different nutrient availability conditions by impairing the metabolic plasticity needed to exploit glucose as an energy source in the absence of other nutrients. Finally, GSCs intracranially implanted into mice together with TAT-Cx43266-283showed decreased levels of important targets for cancer therapy, such as HK-211, 12and glucose transporter 3 (GLUT-3)13, evidencing the reduced ability of treated GSCs to survive in challenging environments. Our results confirm the value of TAT-Cx43266-283for glioma therapy alone or in combination with therapies whose resistance relies on metabolic adaptation. More importantly, these results allow us to conclude that the advantageous metabolic plasticity of GSCs is a targetable vulnerability in malignant gliomas.
A male infertility mutation reverts NANOS1 activity from anti-apoptotic to pro-apoptotic by disrupting repression ofGADD45A,GADD45B,GADD45GandRHOBgenes
Authors: Janecki Damian M. , Ilaslan Erkut , Smialek Maciej J. , Sajek Marcin P. , Kotecki Maciej , Ginter-Matuszewska Barbara , Spik Anna , Krainski Patryk , Jaruzelska Jadwiga , Kusz-Zamelczyk Kamila 
Published: November 2019

AbstractBackgroundWhile Nanos-mediated maintenance of germ cells inDrosophilaand mice has been related to regulation of apoptosis, the relevance of these findings to human physiology is uncertain. Previously we have described the p.[(Pro34Thr);(Ser83del)] doubleNANOS1mutation as associated with an absence of germ cells in the testes of infertile patients. The aim of this study was to identify the mechanism underlying infertility phenotype of patients bearing theNANOS1mutation.MethodsConstructs encoding a wild-type or mutated NANOS1 protein were used for transfection of TCam-2 cell line, representing male germ cells in culture. Influence of this mutation on cell proliferation was performed using MTS assay while apoptosis and cell cycle were measured by flow cytometry. RNA-Seq analysis including quantitative RT-PCR was conducted for selecting pro-apoptotic genes, repressed by the wild-type NANOS1. Influence of the p.[(Pro34Thr);(Ser83del)] NANOS1 mutation on that repression was investigated by quantitative RT-PCR.ResultsWe show here that the p.[(Pro34Thr);(Ser83del)] doubleNANOS1mutation causes NANOS1 to functionally switch from being anti-apoptotic to pro-apoptotic in the human male germ cell line TCam-2. This mutation disrupts repression of mRNAs encoding pro-apoptotic GADG45A, GADD45B, GADD45G and RHOB factors, which could contribute to an increase in apoptosis.ConclusionsThis report underscores the conservation of Nanos from flies to humans as a repressor of pro-apoptotic mRNAs in germ cells, and provides a basis for understanding NANOS1 functions in human reproductive health.
FLIP(L) determines p53 induced life or death
Authors: Lees Andrea , McIntyre Alexander J. , Falcone Fiammetta , Crawford Nyree T. , McCann Christopher , Quinn Gerard P. , Roberts Jamie Z. , Sessler Tamas , Gallagher Peter F. , Gregg Gemma M.A. , McAllister Katherine , McLaughlin Kirsty M. , Allen Wendy L. , Holohan Caitriona , Egan Laurence J. , Ryan Aideen E. , Labonte-Wilson Melissa , Dunne Phillip D. , Wappett Mark , Coyle Vicky M. , Johnston Patrick G. , Kerr Emma M. , Longley Daniel B. , McDade Simon S. 
Published: November 2019

AbstractHow p53 differentially activates cell cycle arrest versus cell death remains poorly understood. Here, we demonstrate that upregulation of canonical pro-apoptotic p53 target genes in colon cancer cells imposes a critical dependence on the long splice form of the caspase-8 regulator FLIP (FLIP(L)), which we identify as a direct p53 transcriptional target. Inhibiting FLIP(L) expression with siRNA or Class-I HDAC inhibitors promotes apoptosis in response to p53 activation by the MDM2 inhibitor Nutlin-3A, which otherwise predominantly induces cell-cycle arrest. When FLIP(L) upregulation is inhibited, apoptosis is induced in response to p53 activation via a novel ligand-independent TRAIL-R2/caspase-8 complex, which, by activating BID, induces mitochondrial-mediated apoptosis. Notably, FLIP(L) depletion inhibits p53-induced expression of the cell cycle regulator p21 and enhances p53-mediated upregulation of PUMA, with the latter activating mitochondrial-mediated apoptosis in FLIP(L)-depleted, Nutlin-3A-treated cells lacking TRAIL-R2/caspase-8. Thus, we report two previously undescribed, novel FLIP(L)-dependent mechanisms that determine cell fate following p53 activation.
GCNCDA: A New Method for Predicting CircRNA-Disease Associations Based on Graph Convolutional Network Algorithm
Authors: Wang Lei , You Zhu-Hong , Li Yang-Ming , Zheng Kai , Huang Yu-An 
Published: November 2019

AbstractNumerous evidences indicate that Circular RNAs (circRNAs) are widely involved in the occurrence and development of diseases. Identifying the association between circRNAs and diseases plays a crucial role in exploring the pathogenesis of complex diseases and improving the diagnosis and treatment of diseases. However, due to the complex mechanisms between circRNAs and diseases, it is expensive and time-consuming to discover the new circRNA-disease associations by biological experiment. Therefore, there is increasingly urgent need for utilizing the computational methods to predict novel circRNA-disease associations. In this study, we propose a computational method called GCNCDA based on the deep learning Fast learning with Graph Convolutional Networks (FastGCN) algorithm to predict the potential disease-associated circRNAs. Specifically, the method first forms the unified descriptor by fusing disease semantic similarity information, disease and circRNA Gaussian Interaction Profile (GIP) kernel similarity information based on known circRNA-disease associations. The FastGCN algorithm is then used to objectively extract the high-level features contained in the fusion descriptor. Finally, the new circRNA-disease associations are accurately predicted by the Forest by Penalizing Attributes (Forest PA) classifier. The 5-fold cross-validation experiment of GCNCDA achieved 91.2% accuracy with 92.78% sensitivity at the AUC of 90.90% on circR2Disease benchmark dataset. In comparison with different classifier models, feature extraction models and other state-of-the-art methods, GCNCDA shows strong competitiveness. Furthermore, 10 of the top 15 circRNA-disease association candidates with the highest prediction scores were confirmed by recently published literature. These results suggest that GCNCDA can effectively predict potential circRNA-disease associations and provide highly credible candidates for biological experiments.Author SummaryThe recognition of circRNA-disease association is the key of disease diagnosis and treatment, and it is of great significance for exploring the pathogenesis of complex diseases. Computational methods can predicte the potential disease-related circRNAs quickly and accurately. Based on the hypothesis that circRNA with similar function tends to associate with similar disease, GCNCDA model is proposed to effectively predict the potential association between circRNAs and diseases by combining FastGCN algorithm. The performance of the model was verified by cross-validation experiments, different feature extraction algorithm and classifier models comparison experiments. Furthermore, 10 of the top 15 disease-associated circRNAs with the highest prediction scores were confirmed by recently published literature. It is anticipated that GCNCDA model can give priority to the most promising circRNA-disease associations on a large scale to provide reliable candidates for further biological experiment.
Large Ankyrin repeat proteins are formed with similar and energetically favorable units
Authors: Galpern Ezequiel A. , Freiberger María I. , Ferreiro Diego U. 
Published: November 2019

AbstractAnkyrin containing proteins are one of the most abundant repeat protein families present in all extant organisms. They are made with tandem copies of similar amino acid stretches that fold into elongated architectures. Here, we build and curated a dataset of 200 thousand proteins that contain 1,2 million Ankyrin regions and characterize the abundance, structure and energetics of the repetitive regions in natural proteins. We found that there is a continuous roughly exponential variety of array lengths with an exceptional frequency at 24 repeats. We describe that individual repeats are seldom interrupted with long insertions and accept few deletions, consistently with the know tertiary structures. We found that longer arrays are made up of repeats that are more similar to each other than shorter arrays, and display more favourable folding energy, hinting at their evolutionary origin. The array distributions show that there is a physical upper limit to the size of an array of Ankyrin repeats of about 120 copies, consistent with the limit found in nature. Analysis of the identity patterns within the arrays suggest that they may have originated by sequential copies of more than one Ankyrin unit.Author summaryRepeat proteins are coded in tandem copies of similar amino acid stretches. We built and curated a large dataset of Ankyrin containing proteins, one of the most abundant families of repeat proteins, and characterized the structure of the arrays formed by the repetitions. We found that large arrays are constructed with repetitions that are more similar to each other than shorter arrays. Also, the largest the array, the more energetically favourable its folding energy is. We speculate about the mechanistic origin of large arrays and hint into their evolutionary dynamics.
Temporal and spatial modulation of the immune response of the murine Gl261 glioma tumor microenvironment
Authors: McKelvey Kelly J , Hudson Amanda L , Kumar Ramyashree Prasanna , Wilmott James S , Attrill Grace H , Long Georgina V , Scolyer Richard A , Clarke Stephen J , Wheeler Helen R , Diakos Connie I , Howell Viive M 
Published: November 2019

AbstractGlioblastoma, the most aggressive form of glioma, has a 5-year survival rate of <5%. While radiation and immunotherapies are routinely studied in the murine Gl261 glioma model, little is known about its inherent immune response. This study quantifies the temporal and spatial localization of immune cell populations and mediators during glioma development.Eight-week old male C57Bl/6 mice were orthotopically inoculated with 1×106Gl261 cells and tumor morphology, local and systemic immune cell populations, and plasma cytokines/chemokines assessed at Day-0, 1, 3, 7, 14, and 21 post-inoculation by magnetic resonance imaging, chromogenic immunohistochemistry, multiplex immunofluorescent immunohistochemistry, flow cytometry and multiplex immunoassay respectively.From Day-3 tumors were distinguishable with >30% Ki67 and increased tissue vascularization (p<0.05). Increasing tumor proliferation/malignancy and vascularization were associated with significant temporal changes in immune cell populations within the tumor (p<0.05) and systemic compartments (p=0.02 to p<0.0001). Of note, at Day-14 16/24 plasma cytokine/chemokines levels decreased coinciding with an increase in tumor cytotoxic T cells, natural killer and natural killer/T cells. Data derived provide baseline characterization of the local and systemic immune response during glioma development. They reveal that type II macrophages and myeloid-derived suppressor cells are more prevalent in tumors than regulatory T cells, highlighting these cell types for further therapeutic exploration.
Pathogenicity of urinary tract infectionEscherichia coliinCaenorhabditis elegans
Authors: Hashimoto Masayuki , Ma Yi-Fen , Wang Sin-Tian , Chen Chang-Shi , Teng Ching-Hao 
Published: November 2019

AbstractUropathogenicEscherichia coli(UPEC) is a major bacterial pathogen that causes urinary tract infections (UTIs). Several virulence factors (VFs) in the bacteria have been associated with the pathogenicity. The mouse is an available UTI model for studying the pathogenicity; however,Caenorhabditis elegansrepresents as an alternative surrogate host for studying UPEC with the capacity for high-throughput analysis. Therefore, we established a simple assay for a UPEC infection model withC. elegansfor large-scale screening. AnE. coliculture to be tested and synchronizedC. eleganswere mixed in 96-well plates, and the pathogenicity was determined by comparison of the turbidity before and after incubation. A total of 133 clinically isolatedE. colistrains, which included UTI-associated and fecal isolates, were applied to demonstrate the liquid pathogenicity assay. TheE. coliisolates associated with UTIs showed higher pathogenicity inC. elegansthan the fecal isolates, suggesting that the simple assay withC. elegansis useful as a UPEC infectious model. From the screening, VFs involved with iron acquisition (chuA, fyuA, andirp2) were significantly associated with high pathogenicity.C. elegansis a heme auxotroph, and iron homeostasis also serves innate immunity inC. elegans. We then evaluated whether the VFs in UPEC were involved in the pathogenicity. Mutants ofE. coliUTI89 with defective iron acquisition systems were applied to a solid killing assay withC. elegans. As a result, the survival rate ofC. elegansfed with the mutants significantly increased compared to when fed with the parent strain. To our knowledge, this is the first report of the involvement of iron acquisition in the pathogenicity of UPEC in aC. elegansmodel.
Theoretical investigation of a genetic switch for metabolic adaptation
Authors: Laxhuber Kathrin S. , Morrison Muir J. , Phillips Rob 
Published: November 2019

AbstractMembrane transporters carry key metabolites through the cell membrane and, from a resource standpoint, are hypothesized to be produced when necessary. The expression of membrane transporters in metabolic pathways is often upregulated by the transporter substrate. InE. coli, such systems include for example thelacY, araFGH, andxylFGHgenes, which encode for lactose, arabinose, and xylose transporters, respectively. As a case study of a minimal system, we build a generalizable physical model of thexapABRgenetic circuit, which features a regulatory feedback loop through membrane transport (positive feedback) and enzymatic degradation (negative feedback) of an inducer. Dynamical systems analysis and stochastic simulations show that the membrane transport makes the model system bistable in certain parameter regimes. Thus, it serves as a genetic “on-off” switch, enabling the cell to only produce a set of metabolic enzymes when the corresponding metabolite is present in large amounts. We find that the negative feedback from the degradation enzyme does not significantly disturb the positive feedback from the membrane transporter. We investigate hysteresis in the switching and discuss the role of cooperativity and multiple binding sites in the model circuit. Fundamentally, this work explores how a stable genetic switch for a set of enzymes is obtained from transcriptional auto-activation of a membrane transporter through its substrate.
Cell-based simulations of Notch-dependent cell differentiation on growing domains
Authors: Stopka Anna , Boareto Marcelo , Iber Dagmar 
Published: November 2019

AbstractNotch signalling controls cell differentiation and proliferation in many tissues. The Notch signal is generated by the interaction between the Notch receptor of one cell with the Notch ligand (Delta or Jagged) of a neighbouring cell. Therefore, the pathway requires cell-cell contact in order to be active. During organ development, cell differentiation occurs concurrently with tissue growth and changes in cell morphology. How growth impacts on Notch signalling and cell differentiation remains poorly understood. Here, we developed a modelling environment to simulate Notch signalling in a growing tissue. We use our model to simulate the differentiation process of pancreatic progenitor cells. Our results suggest that Notch-mediated differentiation in the developing pancreas is first mediated by geometric effects that result in loss of Notch signalling on the tissue boundary, leading to the differentiation of tip versus trunk cells. A second wave of differentiation further happens in the trunk cells due to a reduction in the expression of the ligandJagged, which has been shown to be controlled by signalling factors secreted from the surrounding mesenchyme. Our results bring new insights into how cells coordinate tissue growth with cell fate specification during organ development.
Identification of Duhem-type piezoelectric hysteresis using a modified bee colony algorithm
Authors: Chen Qun , Yang Zong-Xiao 
Published: November 2019

Purpose
The determination of parameters of Duhem model that can describe piezoelectric hysteresis is usually a great challenge. The purpose of this paper is to find a way to identify the parameters of Duhem model by using a modified bee colony algorithm.

Design/methodology/approach
The promising bee colony algorithm has great potential to identify hysteresis nonlinearity, but has not yet been used to identify the Duhem-type hysteresis in the literatures. To explore this possibility, the classical bee colony algorithm is modified to enhance its performance regarding both searching capability and convergence speed. In the modification, the current optimal solution is used to guide the search direction, which can balance the local and global searching ability. Moreover, a new searching formula for scout bees is proposed to enhance the convergence ability of the algorithm.

Findings
Through a series of experiments, the modified algorithm can attain the optimal parameters with a 0.61 µm peak valley error and a 0.12 µm root-mean-square error. Compared to the particle swarm optimization and classical bee colony algorithms, the modified bee colony algorithm can reach higher parameter identification accuracy. Based on 50 trials, the robustness of the posed algorithm was also proved.

Originality/value
The well-performed modified bee colony algorithm is a good candidate in parameter identification of Duhem-type hysteresis nonlinear systems. As there is no work studying the parameter identification of Duhem model using a bee colony algorithm in the literatures, this work closed this gap and explored the ability of bee colony algorithm to identify piezoelectric hysteresis with superb accuracy and robustness.
Hierarchical shape optimization of one-sided transverse flux heating induction coil
Authors: Schulze Martin , Nikanorov Alexander , Nacke Bernard 
Published: November 2019

Purpose
The transverse flux heating (TFH) concept offers very high electrical efficiency in combination with unique technological flexibility. Numerous advantages make this method beyond competition to be applied in e.g. processing lines. However, all potential advantages of TFH can be realized in practice only by optimal design of the inductor shape using numerical modelling and optimization techniques. This paper aims to describe a hierarchical approach to the optimal design of a one-sided induction coil, which will be used for one-sided TFH of continuous moving thin metal strip to achieve a homogeneous temperature distribution along the strip width.

Design/methodology/approach
Depending on the design step, 2D or 3D FEM simulations using ANSYS® Mechanical including the electromagnetics package are used. The harmonic electromagnetic solution is coupled to a transient thermal model which takes the strip movement into account. All models use the symmetries of the inductor workpiece arrangement to keep the calculation times as low as possible.

Findings
Due to the geometry of a TFH coil, the models can image a quarter or half of the arrangement. Preliminary investigations of different inductor head shapes can be carried out quickly and then further improved on more complex models in combination with the use of optimization algorithms.

Practical implications
Using hierarchical structure for designing a one-sided TFH coil, offers an efficient and quick way to create a coil which is adapted to the application.

Originality/value
The one-sided inductor design is considered, and the results are generally valid.