bluuebunny/crossref_metadata_2025_split huggingface dataset:
MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer
Authors: Zhan Tianzuo , Ambrosi Giulia , Wandmacher Anna Maxi , Rauscher Benedikt , Betge Johannes , Rindtorff Niklas , Häussler Ragna S. , Hinsenkamp Isabel , Bamberg Leonhard , Hessling Bernd , Müller-Decker Karin , Erdmann Gerrit , Burgermeister Elke , Ebert Matthias P. , Boutros Michael 
Published: May 2019

AbstractIn colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of cancer stem cells. However, how other oncogenic pathways converge on Wnt signalling to modulate stem cell homeostasis in CRC currently remains poorly understood. Using large-scale compound screens in CRC, we identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling. Targeting MEK increases Wnt activity in different CRC cell lines and murine intestine in vivo. Truncating mutations of APC generated by CRISPR/Cas9 strongly synergize with MEK inhibitors in enhancing Wnt responses in isogenic CRC models. Mechanistically, we demonstrate that MEK inhibition induces a rapid downregulation of AXIN1. Using patient-derived CRC organoids, we show that MEK inhibition leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stemness and cancer relapse. Our study demonstrates that clinically used MEK inhibitors inadvertently induce stem cell plasticity, revealing an unknown side effect of RAS pathway inhibition.
Dynamic assembly of ribbon synapses and circuit maintenance in a vertebrate sensory system
Authors: Okawa Haruhisa , Yu Wan-Qing , Matti Ulf , Schwarz Karin , Odermatt Benjamin , Zhong Haining , Tsukamoto Yoshihiko , Lagnado Leon , Rieke Fred , Schmitz Frank , Wong Rachel O. L. 
Published: May 2019

AbstractRibbon synapses transmit information in sensory systems, but their development is not well understood. To test the hypothesis that ribbon assembly stabilizes nascent synapses, we performed simultaneous time-lapse imaging of fluorescently-tagged ribbons in retinal cone bipolar cells (BCs) and postsynaptic densities (PSD95-FP) of retinal ganglion cells (RGCs). Ribbons and PSD95-FP clusters were more stable when these components colocalized at synapses. However, synapse density on ON-alpha RGCs was unchanged in mice lacking ribbons (ribeye knockout). Wildtype BCs make both ribbon-containing and ribbon-free synapses with these GCs even at maturity. Ribbon assembly and cone BC-RGC synapse maintenance are thus regulated independently. Despite the absence of synaptic ribbons, RGCs continued to respond robustly to light stimuli, although quantitative examination of the responses revealed reduced frequency and contrast sensitivity.
The Pseudomonas aeruginosa lectin LecB binds to the exopolysaccharide Psl and stabilizes the biofilm matrix
Authors: Passos da Silva Daniel , Matwichuk Michael L. , Townsend Delaney O. , Reichhardt Courtney , Lamba Doriano , Wozniak Daniel J. , Parsek Matthew R. 
Published: May 2019

AbstractPseudomonas aeruginosabiofilms are composed of exopolysaccharides (EPS), exogenous DNA, and proteins that hold these communities together.P. aeruginosaproduces lectins LecA and LecB, which possess affinities towards sugars found in matrix EPS and mediate adherence ofP. aeruginosato target host cells. Here, we demonstrate that LecB binds to Psl, a key matrix EPS, and this leads to increased retention of both cells and EPS in a growing biofilm. This interaction is predicted to occur between the lectin and the branched side chains present on Psl. Finally, we show that LecB coordinates Psl localization in the biofilm. This constitutes a unique function for LecB and identifies it as a matrix protein that contributes to biofilm structure through EPS interactions.
Optimal control nodes in disease-perturbed networks as targets for combination therapy
Authors: Hu Yuxuan , Chen Chia-hui , Ding Yang-yang , Wen Xiao , Wang Bingbo , Gao Lin , Tan Kai 
Published: May 2019

AbstractMost combination therapies are developed based on targets of existing drugs, which only represent a small portion of the human proteome. We introduce a network controllability-based method, OptiCon, for de novo identification of synergistic regulators as candidates for combination therapy. These regulators jointly exert maximal control over deregulated genes but minimal control over unperturbed genes in a disease. Using data from three cancer types, we show that 68% of predicted regulators are either known drug targets or have a critical role in cancer development. Predicted regulators are depleted for known proteins associated with side effects. Predicted synergy is supported by disease-specific and clinically relevant synthetic lethal interactions and experimental validation. A significant portion of genes regulated by synergistic regulators participate in dense interactions between co-regulated subnetworks and contribute to therapy resistance. OptiCon represents a general framework for systemic and de novo identification of synergistic regulators underlying a cellular state transition.
WASH phosphorylation balances endosomal versus cortical actin network integrities during epithelial morphogenesis
Authors: Tsarouhas Vasilios , Liu Dan , Tsikala Georgia , Fedoseienko Alina , Zinn Kai , Matsuda Ryo , Billadeau Daniel D. , Samakovlis Christos 
Published: May 2019

AbstractFilamentous actin (F-actin) networks facilitate key processes like cell shape control, division, polarization and motility. The dynamic coordination of F-actin networks and its impact on cellular activities are poorly understood. We report an antagonistic relationship between endosomal F-actin assembly and cortical actin bundle integrity duringDrosophilaairway maturation. Double mutants lacking receptor tyrosine phosphatases (PTP) Ptp10D and Ptp4E, clear luminal proteins and disassemble apical actin bundles prematurely. These defects are counterbalanced by reduction of endosomal trafficking and by mutations affecting the tyrosine kinase Btk29A, and the actin nucleation factor WASH. Btk29A forms protein complexes with Ptp10D and WASH, and Btk29A phosphorylates WASH. This phosphorylation activates endosomal WASH function in flies and mice. In contrast, a phospho-mimetic WASH variant induces endosomal actin accumulation, premature luminal endocytosis and cortical F-actin disassembly. We conclude that PTPs and Btk29A regulate WASH activity to balance the endosomal and cortical F-actin networks during epithelial tube maturation.
Plant-derived virus-like particle vaccines drive cross-presentation of influenza A hemagglutinin peptides by human monocyte-derived macrophages
Authors: Makarkov Alexander I. , Golizeh Makan , Ruiz-Lancheros Elizabeth , Gopal Angelica A. , Costas-Cancelas Ian N. , Chierzi Sabrina , Pillet Stephane , Charland Nathalie , Landry Nathalie , Rouiller Isabelle , Wiseman Paul W. , Ndao Momar , Ward Brian J. 
Published: May 2019

AbstractA growing body of evidence supports the importance of T cell responses to protect against severe influenza, promote viral clearance, and ensure long-term immunity. Plant-derived virus-like particle (VLP) vaccines bearing influenza hemagglutinin (HA) have been shown to elicit strong humoral and CD4+T cell responses in both pre-clinical and clinical studies. To better understand the immunogenicity of these vaccines, we tracked the intracellular fate of a model HA (A/California/07/2009 H1N1) in human monocyte-derived macrophages (MDMs) following delivery either as VLPs (H1-VLP) or in soluble form. Compared to exposure to soluble HA, pulsing with VLPs resulted in ~3-fold greater intracellular accumulation of HA at 15 min that was driven by clathrin-mediated and clathrin-independent endocytosis as well as macropinocytosis/phagocytosis. At 45 min, soluble HA had largely disappeared suggesting its handling primarily by high-degradative endosomal pathways. Although the overall fluorescence intensity/cell had declined 25% at 45 min after H1-VLP exposure, the endosomal distribution pattern and degree of aggregation suggested that HA delivered by VLP had entered both high-degradative late and low-degradative static early and/or recycling endosomal pathways. At 45 min in the cells pulsed with VLPs, HA was strongly co-localized with Rab5, Rab7, Rab11, MHC II, and MHC I. High-resolution tandem mass spectrometry identified 115 HA-derived peptides associated with MHC I in the H1-VLP-treated MDMs. These data suggest that HA delivery to antigen-presenting cells on plant-derived VLPs facilitates antigen uptake, endosomal processing, and cross-presentation. These observations may help to explain the broad and cross-reactive immune responses generated by these vaccines.
Expression of Ice-Binding Proteins in Caenorhabditis elegans Improves the Survival Rate upon Cold Shock and during Freezing
Authors: Kuramochi Masahiro , Takanashi Chiaki , Yamauchi Akari , Doi Motomichi , Mio Kazuhiro , Tsuda Sakae , Sasaki Yuji C. 
Published: May 2019

AbstractIce-binding proteins (IBPs) are capable of binding ice crystals and inhibiting their growth at freezing temperatures. IBPs are also thought to stabilize the cell membrane at non-freezing temperatures near 0 °C. These two effects have been assumed to reduce cold- and freezing-induced damage to cells and tissues. However, knowledge regarding the effects of IBP on the living animals is limited. Here, we characterized the relationship between the IBP effects and the physiological role by using the nematode Caenorhabditis elegans. The expression of fish (NfeIBPs)- and fungus-derived IBPs (AnpIBPs and TisIBP8) in C. elegans improved its survival rate during exposure to 0 and −2 °C (cold shock) and −5 °C (freezing). The observed cold tolerance of C. elegans after cold shock is attributable to the stabilization of cell-membrane lipids with IBPs, and the freezing tolerance at −5 °C can be attributed to the inhibition of ice-crystal growth by the IBPs. Significantly, the survival rate of C. elegans at −5 °C was improved by expression of wild-type AnpIBP and maximized by that of TisIBP8, whereas it was lowered when a defective AnpIBP mutant was expressed. These results suggest that the ice-binding ability of IBP has a good correlation with the survival rate of C. elegans during freezing.
Possible activation of NRF2 by Vitamin E/Curcumin against altered thyroid hormone induced oxidative stress via NFĸB/AKT/mTOR/KEAP1 signalling in rat heart
Authors: Mishra Pallavi , Paital Biswaranjan , Jena Srikanta , Swain Shasank S. , Kumar Sunil , Yadav Manoj K. , Chainy Gagan B. N. , Samanta Luna 
Published: May 2019

AbstractOxidative stress is implicated in both hypo- and hyper-thyroid conditions. In the present study an attempt has been made to elucidate possible interaction between vitamin E or/and curcumin (two established antioxidants) with active portion (redox signaling intervening region) of nuclear factor erythroid 2-related factor 2 (NRF2) as a mechanism to alleviate oxidative stress in rat heart under altered thyroid states. Fifty Wistar strain rats were divided into two clusters (Cluster A: hypothyroidism; Cluster B: hyperthyroidism). The hypo- (0.05% (w/v) propylthiouracil in drinking water) and hyper- (0.0012% (w/v) T4 in drinking water) thyroid rats in both clusters were supplemented orally with antioxidants (vitamin E or/and curcumin) for 30 days. Interactive least count difference and principal component analyses indicated increase in lipid peroxidation, reduced glutathione level, alteration in the activities and protein expression of antioxidant enzymes like superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase under altered thyroid states. However, the expression of stress survival molecules; nuclear factor κB (NFκB) and the serine-threonine kinase B (Akt), in hyper-thyroidism only points towards different mechanisms responsible for either condition. Co-administration of vitamin E and curcumin showed better result in attenuating expression of mammalian target for rapamycin (mTOR), restoration of total protein content and biological activity of Ca2+ ATPase in hyperthyroid rats, whereas, their individual treatment showed partial restoration. Since NRF2 is responsible for activation of antioxidant response element and subsequent expression of antioxidant enzymes, possible interactions of both vitamin E or/and curcumin with the antioxidant enzymes, NRF2 and its regulator Kelch ECH associating protein (KEAP1) were studied in silico. For the first time, a modeled active portion of the zipped protein NRF2 indicated its interaction with both vitamin E and curcumin. Further, curcumin and vitamin E complex showed in silico interaction with KEAP1. Reduction of oxidative stress by curcumin and/or vitamin E may be due to modulation of NRF2 and KEAP1 function in rat heart under altered thyroid states.
Profiling the TRB and IGH repertoire of patients with H5N6 Avian Influenza Virus Infection by high-throughput sequencing
Authors: Peng Wujian , Liu Song , Meng Jingye , Huang Jiali , Huang Jianrong , Tang Donge , Dai Yong 
Published: May 2019

AbstractAvian Influenza A (H5N6) Virus causes severe influenza disease in humans and is manifested by acute respiratory distress syndrome, multi-organ failure, and high mortality rates. T cells recognize antigens specifically through a membrane protein T cell receptor (TCR). To ward off a wide variety of pathogens, the human adaptive immune system harbors a vast array of TCRs, which are collectively referred to as the TCR repertoire. The B cell receptor (BCR) is involved in inducing the humoral immune response. The generation of a diverse T cell and B cell repertoire is essential for protection against infection. In this study, multiplex PCR based on genomic DNA amplicons and Illumina high-throughput sequencing (HTS) were applied to study the characteristics and polymorphisms of the TRB and IGH repertoire in the peripheral blood mononuclear cells (PBMCs) from two H5N6 AIV patients and six healthy donors (NC). The CDR3 average length in the AIV group was different from the NC group. The TRBV12-3, TRBV12-4, and TRBV15 gene segments and TRBV30/TRBJ1-2, TRBV12-3/TRBJ1-1 and IGHV3-11/IGHJ6 gene segment pairings also exhibited a higher usage in the PBMCs of AIV donors and may provide more information for generating more effective T/B cell targeted diagnosis/protection strategies.
Degradation of D-2-hydroxyglutarate in the presence of isocitrate dehydrogenase mutations
Authors: Berger Raffaela S. , Ellmann Lisa , Reinders Joerg , Kreutz Marina , Stempfl Thomas , Oefner Peter J. , Dettmer Katja 
Published: May 2019

AbstractD-2-Hydroxyglutarate (D-2-HG) is regarded as an oncometabolite. It is found at elevated levels in certain malignancies such as acute myeloid leukaemia and glioma. It is produced by a mutated isocitrate dehydrogenase IDH1/2, a low-affinity/high-capacity enzyme. Its degradation, in contrast, is catalysed by the high-affinity/low-capacity enzyme D-2-hydroxyglutarate dehydrogenase (D2HDH). So far, it has not been proven experimentally that the accumulation of D-2-HG in IDH mutant cells is the result of its insufficient degradation by D2HDH. Therefore, we developed an LC-MS/MS-based enzyme activity assay that measures the temporal drop in substrate and compared this to the expression of D2HDH protein as measured by Western blot. Our data clearly indicate, that the maximum D-2-HG degradation rate by D2HDH is reached in vivo, as vmax is low in comparison to production of D-2-HG by mutant IDH1/2. The latter seems to be limited only by substrate availability. Further, incubation of IDH wild type cells for up to 48 hours with 5 mM D-2-HG did not result in a significant increase in either D2HDH protein abundance or enzyme activity.
Metal-free electrocatalysts for oxygen reduction reaction based on trioxotriangulene
Authors: Murata Tsuyoshi , Kotsuki Kenji , Murayama Hirotaka , Tsuji Ryotaro , Morita Yasushi 
Published: May 2019

AbstractDevelopment of a structurally well-defined small molecule with a high oxygen reduction reaction catalytic activity is a key approach for the bottom-up design of a metal-free carbon-based catalysts for metal-air batteries and fuel cells. In this paper, we characterize the oxygen reduction reaction activities of trioxotriangulene derivatives, which are stable neutral radicals with high redox abilities, via rotating disk electrode measurements in alkaline aqueous solution. Among trioxotriangulene derivatives having various substituent groups, N-piperidinyl-substituted derivative mixed with acetylene black shows a high catalytic activity with the two-electron transferring process exceeding other derivatives and quinones. To reveal the correlation between molecular structure and catalytic activity, we discuss substituent effects on the redox ability of trioxotriangulene derivatives, and demonstrate that a molecule with electron-donating groups yields relatively higher catalytic activities.
Using genetically incorporated unnatural amino acids to control protein functions in mammalian cells
Authors: Nödling Alexander R. , Spear Luke A. , Williams Thomas L. , Luk Louis Y.P. , Tsai Yu-Hsuan 
Published: May 2019

Abstract
Genetic code expansion allows unnatural (non-canonical) amino acid incorporation into proteins of interest by repurposing the cellular translation machinery. The development of this technique has enabled site-specific incorporation of many structurally and chemically diverse amino acids, facilitating a plethora of applications, including protein imaging, engineering, mechanistic and structural investigations, and functional regulation. Particularly, genetic code expansion provides great tools to study mammalian proteins, of which dysregulations often have important implications in health. In recent years, a series of methods has been developed to modulate protein function through genetically incorporated unnatural amino acids. In this review, we will first discuss the basic concept of genetic code expansion and give an up-to-date list of amino acids that can be incorporated into proteins in mammalian cells. We then focus on the use of unnatural amino acids to activate, inhibit, or reversibly modulate protein function by translational, optical or chemical control. The features of each approach will also be highlighted.
Structural biology of laminins
Authors: Hohenester Erhard 
Published: May 2019

Abstract
Laminins are large cell-adhesive glycoproteins that are required for the formation and function of basement membranes in all animals. Structural studies by electron microscopy in the early 1980s revealed a cross-shaped molecule, which subsequently was shown to consist of three distinct polypeptide chains. Crystallographic studies since the mid-1990s have added atomic detail to all parts of the laminin heterotrimer. The three short arms of the cross are made up of continuous arrays of disulphide-rich domains. The globular domains at the tips of the short arms mediate laminin polymerization; the surface regions involved in this process have been identified by structure-based mutagenesis. The long arm of the cross is an α-helical coiled coil of all three chains, terminating in a cell-adhesive globular region. The molecular basis of cell adhesion to laminins has been revealed by recent structures of heterotrimeric integrin-binding fragments and of a laminin fragment bound to the carbohydrate modification of dystroglycan. The structural characterization of the laminin molecule is essentially complete, but we still have to find ways of imaging native laminin polymers at molecular resolution.
Using Telegraphic Input With Children With Language Delays: A Survey of Speech-Language Pathologists' Practices and Perspectives
Authors: Venker Courtney E. , Yasick Megan , McDaniel Jena 
Published: May 2019

Purpose

Speech-language pathologists (SLPs) often simplify their language input when talking to young children with language delays, but there is some controversy regarding whether simplified input should be telegraphic (e.g.,
Ball under, Doggie go, More toy
) or grammatical (e.g.,
The ball went under; Go, Doggie! More toys
). The purpose of this study was to evaluate SLPs' practices and perspectives on using telegraphic input when working with children with language delays at the prelinguistic, one-word, or two-word stages of spoken language development.

Method
Practicing SLPs were recruited from a university-sponsored professional development conference focused on current best practices in speech-language pathology. Respondents completed an online survey that included questions about their own practices, as well as their overall perspectives on the usefulness of simplifying language input in different ways.

Results
The vast majority of SLPs (82%) reported using telegraphic input. SLPs reported using telegraphic input more frequently when prompting for verbal imitations than when describing play or providing a directive/request. Surprisingly, only 30% of SLPs who reported using telegraphic input felt that it was useful. SLPs reported that receptive language is the most important child characteristic to consider when deciding what kind of language input to provide.

Conclusions
These findings suggest the need for more purposeful clinical decision making in the context of providing simplified language input. In addition, in-depth, qualitative studies are needed to characterize the complex interactions among beliefs, experiences, practices, and perspectives pertaining to simplified language input.
From Cantonese Lexical Tone Awareness to Second Language English Vocabulary: Cross-Language Mediation by Segmental Phonological Awareness
Authors: Choi William , Tong Xiuli , Deacon Helene 
Published: May 2019

PurposeCantonese lexical tone awareness is closely associated with 1st language Cantonese vocabulary knowledge, but its role in 2nd language English vocabulary knowledge was unclear. We addressed this issue by investigating whether and, if so, how Cantonese lexical tone awareness contributes to English expressive vocabulary knowledge in Hong Kong Cantonese–English bilingual children.MethodA sample of 112 Hong Kong Cantonese–English bilingual 2nd graders were tested on Cantonese lexical tone awareness, English lexical stress sensitivity, Cantonese– English segmental phonological awareness, and both Cantonese and English expressive vocabulary knowledge.ResultsStructural equation modeling analyses revealed that Cantonese lexical tone awareness contributed indirectly to English expressive vocabulary knowledge through English lexical stress sensitivity and Cantonese–English segmental phonological awareness.ConclusionThese results demonstrate the role of Cantonese lexical tone awareness in Cantonese–English bilingual children's English vocabulary knowledge. This also underscores the importance of 1st language suprasegmental phonological awareness in 2nd language expressive vocabulary knowledge.