bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma
Authors: Hasan Tanwir , Caragher Seamus P. , Shireman Jack M. , Park Cheol H. , Atashi Fatemeh , Baisiwala Shivani , Lee Gina , Guo Donna , Wang Jennifer Y. , Dey Mahua , Wu Meijing , Lesniak Maciej S. , Horbinski Craig M. , James C. David , Ahmed Atique U. 
Published: March 2019

AbstractEmerging evidence reveals enrichment of glioma-initiating cells (GICs) following therapeutic intervention. One factor known to contribute to this enrichment is cellular plasticity—the ability of glioma cells to attain multiple phenotypes. To elucidate the molecular mechanisms governing therapy-induced cellular plasticity, we performed genome-wide chromatin immunoprecipitation sequencing (ChIP-Seq) and gene expression analysis (gene microarray analysis) during treatment with standard of care temozolomide (TMZ) chemotherapy. Analysis revealed significant enhancement of open-chromatin marks in known astrocytic enhancers for interleukin-8 (IL-8) loci as well as elevated expression during anti-glioma chemotherapy. The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project data demonstrated that IL-8 transcript expression is negatively correlated with GBM patient survival (p = 0.001) and positively correlated with that of genes associated with the GIC phenotypes, such as KLF4, c-Myc, and HIF2α (p < 0.001). Immunohistochemical analysis of patient samples demonstrated elevated IL-8 expression in about 60% of recurrent GBM tumors relative to matched primary tumors and this expression also positively correlates with time to recurrence. Exposure to IL-8 significantly enhanced the self-renewing capacity of PDX GBM (average threefold,p < 0.0005), as well as increasing the expression of GIC markers in the CXCR2 population. Furthermore, IL-8 knockdown significantly delayed PDX GBM tumor growth in vivo (p < 0.0005). Finally, guided by in silico analysis of TCGA data, we examined the effect of therapy-induced IL-8 expression on the epigenomic landscape of GBM cells and observed increased trimethylation of H3K9 and H3K27. Our results show that autocrine IL-8 alters cellular plasticity and mediates alterations in histone status. These findings suggest that IL-8 signaling participates in regulating GBM adaptation to therapeutic stress and therefore represents a promising target for combination with conventional chemotherapy in order to limit GBM recurrence.
Bone marrow-derived Ly6C− macrophages promote ischemia-induced chronic kidney disease
Authors: Yang Qian , Wang Yuxi , Pei Guangchang , Deng Xuan , Jiang Hongyang , Wu Jianliang , Zhou Cheng , Guo Yi , Yao Ying , Zeng Rui , Xu Gang 
Published: March 2019

AbstractMacrophages play an important role in renal injury and repair after acute kidney injury (AKI) and the subsequent chronic kidney disease (CKD) that often results. However, as macrophages have a high degree of plasticity and heterogeneity, the function(s) of macrophage subtypes in AKI-to-CKD progression are not fully understood. Here, we focused on Ly6C− macrophages, which are derived from the embryonic yolk sac and post-development become resident in the kidneys. We found that C–C chemokine receptor type 2 (CCR2) deficiency, which blocks the migration of Ly6C+ macrophages from the bone marrow to the sites of injury, alleviated ischemia-induced AKI in mice. Unexpectedly, though, CCR2 deficiency worsened the subsequent renal fibrosis, which was marked by notable intra-renal infiltration of Ly6C− macrophages. These Ly6C− macrophages were greater in number in both the acute and chronic phases after ischemia reperfusion (I/R) in kidneys of wild type (WT) mice, and we showed them to be derived from the bone marrow by bone marrow chimerism. Clodronate Liposomes (CLs)-mediated depletion of renal Ly6C− macrophages in CCR2−/− mice or in WT mice after I/R alleviated the renal injury and fibrosis. On the contrary, adoptive transfer of Ly6C− macrophages from injured kidneys of WT mice into immune-deficient mice was sufficient to induce renal injury and fibrosis. Transcriptome sequencing of Ly6C− macrophages from injured kidneys revealed that they secreted various cytokines and growth factors, which were associated with the transdifferentiation of fibroblasts into myofibroblasts. This transdifferentiation effect was further supported by in vitro studies showing that Ly6C− macrophages induced the secretion of extracellular matrix proteins from co-cultured fibroblasts. In conclusion, the presence of bone marrow-derived Ly6C− macrophages after ischemia induces AKI and worsens subsequent CKD.
Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma
Authors: López Cristina , Kleinheinz Kortine , Aukema Sietse M. , Rohde Marius , Bernhart Stephan H. , Hübschmann Daniel , Wagener Rabea , Toprak Umut H. , Raimondi Francesco , Kreuz Markus , Waszak Sebastian M. , Huang Zhiqin , Sieverling Lina , Paramasivam Nagarajan , Seufert Julian , Sungalee Stephanie , Russell Robert B. , Bausinger Julia , Kretzmer Helene , Ammerpohl Ole , Bergmann Anke K. , Binder Hans , Borkhardt Arndt , Brors Benedikt , Claviez Alexander , Doose Gero , Feuerbach Lars , Haake Andrea , Hansmann Martin-Leo , Hoell Jessica , Hummel Michael , Korbel Jan O. , Lawerenz Chris , Lenze Dido , Radlwimmer Bernhard , Richter Julia , Rosenstiel Philip , Rosenwald Andreas , Schilhabel Markus B. , Stein Harald , Stilgenbauer Stephan , Stadler Peter F. , Szczepanowski Monika , Weniger Marc A. , Zapatka Marc , Eils Roland , Lichter Peter , Loeffler Markus , Möller Peter , Trümper Lorenz , Klapper Wolfram ,   ICGC MMML-Seq Consortium, Wagner Susanne , Richter Gesine , Eils Jürgen , Kerssemakers Jules , Jaeger-Schmidt Christina , Scholz Ingrid , Borst Christoph , Braulke Friederike , Dreyling Martin , Eberth Sonja , Einsele Hermann , Frickhofen Norbert , Haas Siegfried , Karsch Dennis , Klepl Nicole , Kneba Michael , Lisfeld Jasmin , Mantovani-Löffler Luisa , Ott German , Stadler Christina , Staib Peter , Zenz Thorsten , Kube Dieter , Kostezka Ulrike , Binder Vera , Leich Ellen , Nagel Inga , Pischimariov Jordan , Schreiber Stefan , Vater Inga , Hopp Lydia , Langenberger David , Rosolowski Maciej , Hoffmann Steve , Küppers Ralf , Burkhardt Birgit , Schlesner Matthias , Siebert Reiner 
Published: March 2019

AbstractBurkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.
Nucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma
Authors: Bachmaier Sabine , Volpato Santos Yuri , Kramer Susanne , Githure George Boniface , Klöckner Thomas , Pepperl Julia , Baums Cordula , Schenk Robin , Schwede Frank , Genieser Hans-Gottfried , Dupuy Jean-William , Forné Ignasi , Imhof Axel , Basquin Jerôme , Lorentzen Esben , Boshart Michael 
Published: March 2019

AbstractProtein kinase A (PKA), the main effector of cAMP in eukaryotes, is a paradigm for the mechanisms of ligand-dependent and allosteric regulation in signalling. Here we report the orthologous but cAMP-independent PKA of the protozoan Trypanosoma and identify 7-deaza-nucleosides as potent activators (EC50 ≥ 6.5 nM) and high affinity ligands (KD ≥ 8 nM). A co-crystal structure of trypanosome PKA with 7-cyano-7-deazainosine and molecular docking show how substitution of key amino acids in both CNB domains of the regulatory subunit and its unique C-terminal αD helix account for this ligand swap between trypanosome PKA and canonical cAMP-dependent PKAs. We propose nucleoside-related endogenous activators of Trypanosoma brucei PKA (TbPKA). The existence of eukaryotic CNB domains not associated with binding of cyclic nucleotides suggests that orphan CNB domains in other eukaryotes may bind undiscovered signalling molecules. Phosphoproteome analysis validates 7-cyano-7-deazainosine as powerful cell-permeable inducer to explore cAMP-independent PKA signalling in medically important neglected pathogens.
Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction
Authors: Simonetta Kyle R. , Taygerly Joshua , Boyle Kathleen , Basham Stephen E. , Padovani Chris , Lou Yan , Cummins Thomas J. , Yung Stephanie L. , von Soly Szerenke Kiss , Kayser Frank , Kuriyan John , Rape Michael , Cardozo Mario , Gallop Mark A. , Bence Neil F. , Barsanti Paul A. , Saha Anjanabha 
Published: March 2019

AbstractProtein–protein interactions (PPIs) governing the recognition of substrates by E3 ubiquitin ligases are critical to cellular function. There is significant therapeutic potential in the development of small molecules that modulate these interactions; however, rational design of small molecule enhancers of PPIs remains elusive. Herein, we report the prospective identification and rational design of potent small molecules that enhance the interaction between an oncogenic transcription factor, β-Catenin, and its cognate E3 ligase, SCFβ-TrCP. These enhancers potentiate the ubiquitylation of mutant β-Catenin by β-TrCP in vitro and induce the degradation of an engineered mutant β-Catenin in a cellular system. Distinct from PROTACs, these drug-like small molecules insert into a naturally occurring PPI interface, with contacts optimized for both the substrate and ligase within the same small molecule entity. The prospective discovery of ‘molecular glue’ presented here provides a paradigm for the development of small molecule degraders targeting hard-to-drug proteins.
USP32 regulates late endosomal transport and recycling through deubiquitylation of Rab7
Authors: Sapmaz Aysegul , Berlin Ilana , Bos Erik , Wijdeven Ruud H. , Janssen Hans , Konietzny Rebecca , Akkermans Jimmy J. , Erson-Bensan Ayse E. , Koning Roman I. , Kessler Benedikt M. , Neefjes Jacques , Ovaa Huib 
Published: March 2019

AbstractThe endosomal system is a highly dynamic multifunctional organelle, whose complexity is regulated in part by reversible ubiquitylation. Despite the wide-ranging influence of ubiquitin in endosomal processes, relatively few enzymes utilizing ubiquitin have been described to control endosome integrity and function. Here we reveal the deubiquitylating enzyme (DUB) ubiquitin-specific protease 32 (USP32) as a powerful player in this context. Loss of USP32 inhibits late endosome (LE) transport and recycling of LE cargos, resulting in dispersion and swelling of the late compartment. Using SILAC-based ubiquitome profiling we identify the small GTPase Rab7—the logistical centerpiece of LE biology—as a substrate of USP32. Mechanistic studies reveal that LE transport effector RILP prefers ubiquitylation-deficient Rab7, while retromer-mediated LE recycling benefits from an intact cycle of Rab7 ubiquitylation. Collectively, our observations suggest that reversible ubiquitylation helps switch Rab7 between its various functions, thereby maintaining global spatiotemporal order in the endosomal system.
Multiple plant diversity components drive consumer communities across ecosystems
Authors: Schuldt Andreas , Ebeling Anne , Kunz Matthias , Staab Michael , Guimarães-Steinicke Claudia , Bachmann Dörte , Buchmann Nina , Durka Walter , Fichtner Andreas , Fornoff Felix , Härdtle Werner , Hertzog Lionel R. , Klein Alexandra-Maria , Roscher Christiane , Schaller Jörg , von Oheimb Goddert , Weigelt Alexandra , Weisser Wolfgang , Wirth Christian , Zhang Jiayong , Bruelheide Helge , Eisenhauer Nico 
Published: March 2019

AbstractHumans modify ecosystems and biodiversity worldwide, with negative consequences for ecosystem functioning. Promoting plant diversity is increasingly suggested as a mitigation strategy. However, our mechanistic understanding of how plant diversity affects the diversity of heterotrophic consumer communities remains limited. Here, we disentangle the relative importance of key components of plant diversity as drivers of herbivore, predator, and parasitoid species richness in experimental forests and grasslands. We find that plant species richness effects on consumer species richness are consistently positive and mediated by elevated structural and functional diversity of the plant communities. The importance of these diversity components differs across trophic levels and ecosystems, cautioning against ignoring the fundamental ecological complexity of biodiversity effects. Importantly, plant diversity effects on higher trophic-level species richness are in many cases mediated by modifications of consumer abundances. In light of recently reported drastic declines in insect abundances, our study identifies important pathways connecting plant diversity and consumer diversity across ecosystems.
Two recipes for repelling hot water
Authors: Mouterde Timothée , Lecointre Pierre , Lehoucq Gaëlle , Checco Antonio , Clanet Christophe , Quéré David 
Published: March 2019

AbstractAlthough a hydrophobic microtexture at a solid surface most often reflects rain owing to the presence of entrapped air within the texture, it is much more challenging to repel hot water. As it contacts a colder material, hot water generates condensation within the cavities at the solid surface, which eventually builds bridges between the substrate and the water, and thus destroys repellency. Here we show that both “small” (~100 nm) and “large” (~10 µm) model features do reflect hot drops at any drop temperature and in the whole range of explored impact velocities. Hence, we can define two structural recipes for repelling hot water: drops on nanometric features hardly stick owing to the miniaturization of water bridges, whereas kinetics of condensation in large features is too slow to connect the liquid to the solid at impact.
The anti-cancer drugs curaxins target spatial genome organization
Authors: Kantidze Omar L. , Luzhin Artem V. , Nizovtseva Ekaterina V. , Safina Alfiya , Valieva Maria E. , Golov Arkadiy K. , Velichko Artem K. , Lyubitelev Alexander V. , Feofanov Alexey V. , Gurova Katerina V. , Studitsky Vasily M. , Razin Sergey V. 
Published: March 2019

AbstractRecently we characterized a class of anti-cancer agents (curaxins) that disturbs DNA/histone interactions within nucleosomes. Here, using a combination of genomic and in vitro approaches, we demonstrate that curaxins strongly affect spatial genome organization and compromise enhancer-promoter communication, which is necessary for the expression of several oncogenes, including MYC. We further show that curaxins selectively inhibit enhancer-regulated transcription of chromatinized templates in cell-free conditions. Genomic studies also suggest that curaxins induce partial depletion of CTCF from its binding sites, which contributes to the observed changes in genome topology. Thus, curaxins can be classified as epigenetic drugs that target the 3D genome organization.
Cancer risk in relation to body fat distribution, evaluated by DXA-scans, in postmenopausal women – the Prospective Epidemiological Risk Factor (PERF) study
Authors: Staunstrup Line Mærsk , Nielsen Henning Bay , Pedersen Bente Klarlund , Karsdal Morten , Blair Joseph Patrick Michele , Christensen Jesper Frank , Bager Cecilie Liv 
Published: March 2019

AbstractStudies with direct measures of body fat distribution are required to explore the association between central and general obesity to cancer risk in postmenopausal women. This study investigates the association between central obesity and general obesity to overall/site-specific cancer risk in postmenopausal women. The analysis included 4,679 Danish postmenopausal women. Body fat distribution was evaluated by whole-body dual-energy X-ray absorptiometry scanners. Cancer diagnoses were extracted from the Danish Cancer Registry and multivariable Cox regression models explored the association between cancer risk and central obesity after adjusting for BMI. Our results showed that high central obese women had a 50% increased risk of overall cancer relative to low central obese women (Q1vs.Q4: [HR:1.50, CI:1.20–1.88]). For site-specific cancers, central obesity was significantly associated with Respiratory (Q1vs.Q4: [HR:2.01, CI:1.17–3.47]), Gastrointestinal (Q1vs.Q4: [HR:1.55, CI:0.99–2.41]) and Female genital organs (Q1vs.Q4: [HR:1.95, CI:1.00–3.78]) cancer diagnoses. Sub-analyses stratified by smoking-habits found a significant association between central obesity and a cancer diagnosis for current (Q1vs.Q4: [HR:1.93, CI:1.25–2.99]) and former smokers (Q1vs.Q4: [HR:1.90, CI:1.23–2.94]). These analyses suggest that central obesity is associated with some cancers in postmenopausal women independent of BMI.
The formin Drosophila homologue of Diaphanous2 (Diaph2) controls microtubule dynamics in colorectal cancer cells independent of its FH2-domain
Authors: Grueb Saskia S. , Muhs Stefanie , Popp Yannes , Schmitt Sebastian , Geyer Matthias , Lin Yuan-Na , Windhorst Sabine 
Published: March 2019

AbstractIn this study, we analyzed the functional role of the formin Drosophila Homologue of Diaphanous2 (Diaph2) in colorectal cancer cells. We show that stable down-regulation of Diaph2 expression in HT29 cells decreased chromosome alignment and the velocity of chromosome movement during M-phase, thus reducing the proliferation rate and colony formation. In interphase cells, Diaph2 was diffusely distributed in the cytosol, while in metaphase cells the protein was located to spindle microtubules (MTs). Diaph2-depletion increased the concentration of stable spindle MTs, showing that the formin is required to control spindle MT-dynamics. Our cellular data indicate that Diaph2-controls spindle MT-dynamics independent of Cdc42 activity and ourin vitroresults reveal that bacterially produced full-length (FL) Diaph2 strongly altered MT-dynamics in absence of Cdc42, where its actin-nucleating activity is auto-inhibited. FL-Diaph2 mediates a 10-fold increase in MT-polymerization compared to the Diaph2-FH2-domain. Interestingly, a Diaph2-mutant lacking the FH2-domain (ΔFH2) increased MT-polymerization to a similar extent as the FH2-domain, indicating the existence of a second MT-binding domain. However, in contrast to FL-Diaph2 and the FH2-domain, ΔFH2 did not alter the density of taxol-stabilized MTs. Thus, the FH2-domain and the second Diaph2-binding domain appear to control MT-dynamics by different mechanisms. In summary, our data indicate that Diaph2 controls M-phase progression under basal conditions by regulating spindle MT-dynamics. In addition, a region outside of the canonical MT-regulating FH2-domain is involved in Diaph2-mediated control of MT-dynamics.
Acoustic and Perceptual Consequences of Speech Cues for Mandarin Speakers With Parkinson's Disease
Authors: Hsu Sih-Chiao , McAuliffe Megan J. , Lin Peiyi , Wu Ruey-Meei , Levy Erika S. 
Published: March 2019

Purpose
This study investigated the effects of cueing for increased loudness and reduced speech rate on scaled intelligibility and acoustics of speech produced by Mandarin speakers with hypokinetic dysarthria due to Parkinson's disease (PD).

Method
Eleven speakers with PD read passages in habitual, loud, and slow speaking conditions. Fifteen listeners rated ease of understanding (EOU) of the speech samples on a visual analog scale. Effects of the cues on EOU, vocal loudness, pitch range, pause duration and frequency, articulation rate, and vowel space, as well as relationships between EOU gains and acoustic features, were analyzed.

Results
EOU increased significantly in the loud condition only. The loud cue resulted in increased intensity, and the slow cue resulted both in reduced articulation rate and increased pause frequency. In the loud condition, EOU increased significantly as intensity increased and vowel centralization decreased. In the slow condition, EOU tended to increase as intensity increased and vowel centralization decreased but did not reach statistical significance.

Conclusion
Cueing for loud speech may yield greater EOU gains than cueing for slow speech in Mandarin speakers with PD. Theoretical and clinical implications are discussed, although further investigations with more participants and a larger range of dysarthria severity are warranted.
The Impact of a Novel Gaming Reinforcement System on Oral Intake Outcomes in Pediatric Feeding Therapy: A Single Case Study
Authors: Budhan Jamie , Scarborough Donna , Kuren Michael Bailey-Van 
Published: March 2019

PurposeThe aim of this study was to implement a novel reinforcement strategy into traditional dysphagia therapy with a school-age child diagnosed with a rare genetic syndrome, anxiety, and a hypersensitive gag reflex response. This clinical focus article evaluated the impact of a computer-based straw-drinking game on total liquid volume intake and the relationship between motivation and its role in feeding therapy.MethodA longitudinal pilot study was used and required the development and implementation of a computer-based straw-drinking game as a novel reinforcement strategy. The gaming system was implemented to supplement ongoing dysphagia treatment in a single-subject case study design utilizing a client with pediatric dysphagia.ResultsThe participant exhibited a trend of increased endurance during therapy sessions, allowing for increased volume per sip, increased trials per session, and decreased time between sequential trials. Average daily volume of oral intake remained less than 30 ml.ConclusionsThe gaming system maximized opportunities for orosensory desensitization of tactile input, resulting in increased comfort and endurance during therapy sessions, leading to more opportunities to practice the swallow. A novelty effect was observed as motivation and interest in the gaming system appeared greatest at the onset of the study. Generalized fatigue and anxiety continue to serve as barriers to more significant progress.
On lifetime evaluation of medium‐voltage drives based on modular multilevel converter
Authors: Júnior Paulo R.M. , Cupertino Allan F. , Mendonça Gabriel A. , Pereira Heverton A. 
Published: March 2019

Reliability is an important issue related to the modular multilevel converter (MMC)‐based medium voltage (MV) drives. The design for reliability (DFR) approach has been discussed in many power electronic systems in recent years. MMC‐based MV drives power losses and thermal cycling are strongly affected by start‐up and low‐speed operation, since zero‐sequence current injection must be applied. In order to implement fast thermal simulations, the traditional DFR approach does not consider the heat sink thermal capacitance, which can significantly affect the MMC lifetime prediction. This article discusses how the heat sink realisations (material, thickness) affect the MMC‐predicted lifetime and evaluates how the drive start‐up time affects the damage in the power converter. The case study is based on a 1.4 MW slurry pump system driven by a three‐phase induction motor. The lifetime evaluation of the MMC is realised through the Monte–Carlo simulation. The results show that the traditional approach results in an underestimation of up to 42.5% of the converter lifetime. In addition, long start‐up times lead to a longer lifetime when compared to the shorter start‐up times, due to the reduced thermal stresses in the semiconductors.