bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRIM24 is an oncogenic transcriptional co-activator of STAT3 in glioblastoma
Authors: Lv Deguan , Li Yanxin , Zhang Weiwei , Alvarez Angel A. , Song Lina , Tang Jianming , Gao Wei-Qiang , Hu Bo , Cheng Shi-Yuan , Feng Haizhong 
Published: November 2017

AbstractAberrant amplification and mutations of epidermal growth factor receptor (EGFR) are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive pathogenesis are not well understood. Here, we determine that non-canonical histone signature acetylated H3 lysine 23 (H3K23ac)-binding protein tripartite motif-containing 24 (TRIM24) is upregulated in clinical GBM specimens and required for EGFR-driven tumorigenesis. In multiple glioma cell lines and patient-derived glioma stem cells (GSCs), EGFR signaling promotes H3K23 acetylation and association with TRIM24. Consequently, TRIM24 functions as a transcriptional co-activator and recruits STAT3, leading to stabilized STAT3-chromatin interactions and subsequent activation of STAT3 downstream signaling, thereby enhancing EGFR-driven tumorigenesis. Our findings uncover a pathway in which TRIM24 functions as a signal relay for oncogenic EGFR signaling and suggest TRIM24 as a potential therapeutic target for GBM that are associated with EGFR activation.
A post-transcriptional program coordinated by CSDE1 prevents intrinsic neural differentiation of human embryonic stem cells
Authors: Ju Lee Hyun , Bartsch Deniz , Xiao Cally , Guerrero Santiago , Ahuja Gaurav , Schindler Christina , Moresco James J. , Yates John R. , Gebauer Fátima , Bazzi Hisham , Dieterich Christoph , Kurian Leo , Vilchez David 
Published: November 2017

AbstractWhile the transcriptional network of human embryonic stem cells (hESCs) has been extensively studied, relatively little is known about how post-transcriptional modulations determine hESC function. RNA-binding proteins play central roles in RNA regulation, including translation and turnover. Here we show that the RNA-binding protein CSDE1 (cold shock domain containing E1) is highly expressed in hESCs to maintain their undifferentiated state and prevent default neural fate. Notably, loss of CSDE1 accelerates neural differentiation and potentiates neurogenesis. Conversely, ectopic expression of CSDE1 impairs neural differentiation. We find that CSDE1 post-transcriptionally modulates core components of multiple regulatory nodes of hESC identity, neuroectoderm commitment and neurogenesis. Among these key pro-neural/neuronal factors, CSDE1 binds fatty acid binding protein 7 (FABP7) and vimentin (VIM) mRNAs, as well as transcripts involved in neuron projection development regulating their stability and translation. Thus, our results uncover CSDE1 as a central post-transcriptional regulator of hESC identity and neurogenesis.
Region and cell-type resolved quantitative proteomic map of the human heart
Authors: Doll Sophia , Dreßen Martina , Geyer Philipp E. , Itzhak Daniel N. , Braun Christian , Doppler Stefanie A. , Meier Florian , Deutsch Marcus-Andre , Lahm Harald , Lange Rüdiger , Krane Markus , Mann Matthias 
Published: November 2017

AbstractThe heart is a central human organ and its diseases are the leading cause of death worldwide, but an in-depth knowledge of the identity and quantity of its constituent proteins is still lacking. Here, we determine the healthy human heart proteome by measuring 16 anatomical regions and three major cardiac cell types by high-resolution mass spectrometry-based proteomics. From low microgram sample amounts, we quantify over 10,700 proteins in this high dynamic range tissue. We combine copy numbers per cell with protein organellar assignments to build a model of the heart proteome at the subcellular level. Analysis of cardiac fibroblasts identifies cellular receptors as potential cell surface markers. Application of our heart map to atrial fibrillation reveals individually distinct mitochondrial dysfunctions. The heart map is available at maxqb.biochem.mpg.de as a resource for future analyses of normal heart function and disease.
BRCA2 antagonizes classical and alternative nonhomologous end-joining to prevent gross genomic instability
Authors: Han Jinhua , Ruan Chunyan , Huen Michael S. Y. , Wang Jiadong , Xie Anyong , Fu Chun , Liu Ting , Huang Jun 
Published: November 2017

AbstractBRCA2-deficient cells exhibit gross genomic instability, but the underlying mechanisms are not fully understood. Here we report that inactivation of BRCA2 but not RAD51 destabilizes RPA-coated single-stranded DNA (ssDNA) structures at resected DNA double-strand breaks (DSBs) and greatly enhances the frequency of nuclear fragmentation following cell exposure to DNA damage. Importantly, these BRCA2-associated deficits are fueled by the aberrant activation of classical (c)- and alternative (alt)- nonhomologous end-joining (NHEJ), and rely on the well-defined DNA damage signaling pathway involving the pro-c-NHEJ factor 53BP1 and its downstream effector RIF1. We further show that the 53BP1–RIF1 axis promotes toxic end-joining events via the retention of Artemis at DNA damage sites. Accordingly, loss of 53BP1, RIF1, or Artemis prolongs the stability of RPA-coated DSB intermediates in BRCA2-deficient cells and restores nuclear integrity. We propose that BRCA2 antagonizes 53BP1, RIF1, and Artemis-dependent c-NHEJ and alt-NHEJ to prevent gross genomic instability in a RAD51-independent manner.
ER-associated degradation regulates Alzheimer’s amyloid pathology and memory function by modulating γ-secretase activity
Authors: Zhu Bing , Jiang LuLin , Huang Timothy , Zhao Yingjun , Liu Tongfei , Zhong Yongwang , Li Xiaoguang , Campos Alexandre , Pomeroy Kenneth , Masliah Eliezer , Zhang Dongxian , Xu Huaxi 
Published: November 2017

AbstractEndoplasmic-reticulum-associated degradation (ERAD) is an important protein quality control system which maintains protein homeostasis. Constituents of the ERAD complex and its role in neurodegeneration are not yet fully understood. Here, using proteomic and FRET analyses, we demonstrate that the ER protein membralin is an ERAD component, which mediates degradation of ER luminal and membrane substrates. Interestingly, we identify nicastrin, a key component of the γ-secretase complex, as a membralin binding protein and membralin-associated ERAD substrate. We demonstrate a reduction of membralin mRNA and protein levels in Alzheimer’s disease (AD) brain, the latter of which inversely correlates with nicastrin abundance. Furthermore, membralin deficiency enhances γ-secretase activity and neuronal degeneration. In a mouse AD model, downregulating membralin results in β-amyloid pathology, neuronal death, and exacerbates synaptic/memory deficits. Our results identify membralin as an ERAD component and demonstrate a critical role for ERAD in AD pathogenesis.
Food-grade cationic antimicrobial ε-polylysine transiently alters the gut microbial community and predicted metagenome function in CD-1 mice
Authors: You Xiaomeng , Einson Jonah E. , Lopez-Pena Cynthia Lyliam , Song Mingyue , Xiao Hang , McClements David Julian , Sela David A. 
Published: November 2017

AbstractDiet is an important factor influencing the composition and function of the gut microbiome, but the effect of antimicrobial agents present within foods is currently not understood. In this study, we investigated the effect of the food-grade cationic antimicrobial ε-polylysine on the gut microbiome structure and predicted metagenomic function in a mouse model. The relative abundances of predominant phyla and genera, as well as the overall community structure, were perturbed in response to the incorporation of dietary ε-polylysine. Unexpectedly, this modification to the gut microbiome was experienced transiently and resolved to the initial basal composition at the final sampling point. In addition, a differential non-random assembly was observed in the microbiomes characterized from male and female co-housed animals, although their perturbation trajectories in response to diet remain consistent. In conclusion, antimicrobial ε-polylysine incorporated into food systems transiently alters gut microbial communities in mice, as well as their predicted function. This indicates a dynamic but resilient microbiome that adapts to microbial-active dietary components.
Eph-B4 regulates adaptive venous remodeling to improve arteriovenous fistula patency
Authors: Protack Clinton D. , Foster Trenton R. , Hashimoto Takuya , Yamamoto Kota , Lee Monica Y. , Kraehling Jan R. , Bai Hualong , Hu Haidi , Isaji Toshihiko , Santana Jeans M. , Wang Mo , Sessa William C. , Dardik Alan 
Published: November 2017

AbstractLow rates of arteriovenous fistula (AVF) maturation prevent optimal fistula use for hemodialysis; however, the mechanism of venous remodeling in the fistula environment is not well understood. We hypothesized that the embryonic venous determinant Eph-B4 mediates AVF maturation. In human AVF and a mouse aortocaval fistula model, Eph-B4 protein expression increased in the fistula vein; expression of the arterial determinant Ephrin-B2 also increased. Stimulation of Eph-B-mediated signaling with Ephrin-B2/Fc showed improved fistula patency with less wall thickness. Mutagenesis studies showed that tyrosine-774 is critical for Eph-B4 signaling and administration of inactive Eph-B4-Y774F increased fistula wall thickness. Akt1 expression also increased in AVF; Akt1 knockout mice showed reduced fistula diameter and wall thickness. In Akt1 knockout mice, stimulation of Eph-B signaling with Ephrin-B2/Fc showed no effect on remodeling. These results show that AVF maturation is associated with acquisition of dual arteriovenous identity; increased Eph-B activity improves AVF patency. Inhibition of Akt1 function abolishes Eph-B-mediated venous remodeling suggesting that Eph-B4 regulates AVF venous adaptation through an Akt1-mediated mechanism.
Influence of polymerisation on the reversibility of low-energy proton exchange reactions by Para-Aminothiolphenol
Authors: Balakrishnan Divya , Lamblin Guillaume , Thomann Jean Sebastien , Guillot Jerome , Duday David , van den Berg Albert , Olthuis Wouter , Pascual-García César 
Published: November 2017

AbstractThe reversibility of redox processes is an important function for sensing and molecular electronic devices such as pH reporters or molecular switches. Here we report the electrochemical behaviour and redox reversibility of para-aminothiolphenol (PATP) after different polymerisation methods. We used electrochemical and photo-polymerisation in neutral buffers and plasma polymerisation in air to induce reversible redox states. The chemical stoichiometry and surface coverage of PATP in the polymerized layers were characterized by X-ray photoelectron spectroscopy (XPS), while cyclic voltammetry (CV) was used to measure the charge transfer, double layer capacitance and electrochemical rate of the layers during successive potential cycles. Our results show that the surface coverage of the redox active species is higher on electro-polymerised samples, however, after consecutive cycles all the methods converge to the same charge transfer, while the plasma polymerised samples achieve higher efficiency per molecule and UV polymerised samples have a higher electron transfer rate.
Structural remodeling and oligomerization of human cathelicidin on membranes suggest fibril-like structures as active species
Authors: Sancho-Vaello Enea , François Patrice , Bonetti Eve-Julie , Lilie Hauke , Finger Sebastian , Gil-Ortiz Fernando , Gil-Carton David , Zeth Kornelius 
Published: November 2017

AbstractAntimicrobial peptides as part of the mammalian innate immune system target and remove major bacterial pathogens, often through irreversible damage of their cellular membranes. To explore the mechanism by which the important cathelicidin peptide LL-37 of the human innate immune system interacts with membranes, we performed biochemical, biophysical and structural studies. The crystal structure of LL-37 displays dimers of anti-parallel helices and the formation of amphipathic surfaces. Peptide-detergent interactions introduce remodeling of this structure after occupation of defined hydrophobic sites at the dimer interface. Furthermore, hydrophobic nests are shaped between dimer structures providing another scaffold enclosing detergents. Both scaffolds underline the potential of LL-37 to form defined peptide-lipid complexes in vivo. After adopting the activated peptide conformation LL-37 can polymerize and selectively extract bacterial lipids whereby the membrane is destabilized. The supramolecular fibril-like architectures formed in crystals can be reproduced in a peptide-lipid system after nanogold-labelled LL-37 interacted with lipid vesicles as followed by electron microscopy. We suggest that these supramolecular structures represent the LL-37-membrane active state. Collectively, our study provides new insights into the fascinating plasticity of LL-37 demonstrated at atomic resolution and opens the venue for LL-37-based molecules as novel antibiotics.
Apelin conformational and binding equilibria upon micelle interaction primarily depend on membrane-mimetic headgroup
Authors: Shin Kyungsoo , Sarker Muzaddid , Huang Shuya K. , Rainey Jan K. 
Published: November 2017

AbstractApelin is one of two peptide hormones that activate the apelin receptor (AR or APJ) to regulate the cardiovascular system, central nervous system, and adipoinsular axis. Here, we apply circular dichroism (CD) spectropolarimetry and nuclear magnetic resonance (NMR) spectroscopy to characterize the potential membrane binding by the two longest bioactive apelin isoforms, apelin-55 and -36, using membrane-mimetic dodecylphosphocholine (DPC), sodium dodecyl sulfate (SDS), and 1-palmitoyl-2-hydroxy-sn-glycero-3-[phospho-rac-(1-glycerol)] (LPPG) micelles. Pulsed field gradient diffusion NMR experiments demonstrated preferential interaction of both apelin-55 and -36 with anionic SDS and LPPG micelles over zwitterionic DPC micelles. Chemical shift perturbations and changes in ps-ns scale dynamics of apelin-55 in all micelles were similarly localized along the polypeptide backbone, demonstrating clear dependence upon detergent headgroup, while comparison of chemical shifts between apelin-55 and apelin-36 showed negligible differences indicative of highly similar modes of micelle interaction. Notably, the observed behaviour was consistent with an ensemble averaged pair of free and bound states in fast exchange on the NMR timescale proportional to the fraction of micelle-bound protein, implying a similar conformational equilibrium regardless of headgroup and tailgroup. Membrane catalysis of apelin-AR binding would thus give rise to analogous behaviour in the essential C-terminal region common to all apelin isoforms.
Climate change accelerates growth of urban trees in metropolises worldwide
Authors: Pretzsch Hans , Biber Peter , Uhl Enno , Dahlhausen Jens , Schütze Gerhard , Perkins Diana , Rötzer Thomas , Caldentey Juan , Koike Takayoshi , Con Tran van , Chavanne Aurélia , Toit Ben du , Foster Keith , Lefer Barry 
Published: November 2017

AbstractDespite the importance of urban trees, their growth reaction to climate change and to the urban heat island effect has not yet been investigated with an international scope. While we are well informed about forest growth under recent conditions, it is unclear if this knowledge can be simply transferred to urban environments. Based on tree ring analyses in ten metropolises worldwide, we show that, in general, urban trees have undergone accelerated growth since the 1960s. In addition, urban trees tend to grow more quickly than their counterparts in the rural surroundings. However, our analysis shows that climate change seems to enhance the growth of rural trees more than that of urban trees. The benefits of growing in an urban environment seem to outweigh known negative effects, however, accelerated growth may also mean more rapid ageing and shortened lifetime. Thus, city planners should adapt to the changed dynamics in order to secure the ecosystem services provided by urban trees.
Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema
Authors: Egaña Isabel , Kaito Hiroshi , Nitzsche Anja , Becker Lore , Ballester-Lopez Carolina , Niaudet Colin , Petkova Milena , Liu Wei , Vanlandewijck Michael , Vernaleken Alexandra , Klopstock Thomas , Fuchs Helmut , Gailus-Durner Valerie , Hrabe de Angelis Martin , Rask-Andersen Helge , Johansson Henrik J. , Lehtiö Janne , He Liqun , Yildirim Ali Ö. , Hellström Mats ,   German Mouse Clinic Consortium, Aguilar-Pimentel Antonio , Ollert Markus , Schmidt-Weber Carsten , Amarie Oana , Graw Jochen , Beckers Johannes , Garrett Lillian , Hölter Sabine M. , Zimprich Annemarie , Wurst Wolfgang , Moreth Kristin , Bekeredjian Raffi , Neff Frauke , Calzada-Wack Julia , Rácz Ildikó , Zimmer Andreas , Rathkolb Birgit , Wolf Eckhard , Rozman Jan , Klingenspor Martin , Stoeger Tobias , Eickelberg Oliver , Treise Irina , Busch Dirk H. , Östereicher Manuela , Steinkamp Ralph , Lengger Christoph , Maier Holger , Stoeger Claudia , Leuchtenberger Stefanie 
Published: November 2017

AbstractPaladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.
Fast simultaneous assessment of renal and liver function using polymethine dyes in animal models of chronic and acute organ injury
Authors: Press A. T. , Butans M. J. , Haider T. P. , Weber C. , Neugebauer S. , Kiehntopf M. , Schubert U. S. , Clemens M. G. , Bauer M. , Kortgen A. 
Published: November 2017

AbstractSimultaneous assessment of excretory liver and kidney function is still an unmet need in experimental stress models as well as in critical care. The aim of the study was to characterize two polymethine-dyes potentially suitable for this purpose in vivo. Plasma disappearance rate and elimination measurements of simultaneously injected fluorescent dyes DY-780 (hepato-biliary elimination) and DY-654(renal elimination) were conducted using catheter techniques and intravital microscopy in animals subjected to different organ injuries, i.e. polymicrobial sepsis by peritoneal contamination and infection, ischemia-reperfusion-injury and glycerol-induced acute kidney-injury. DY-780 and DY-654 showed organ specific and determined elimination routes in both healthy and diseased animals. They can be measured simultaneously using near-infrared imaging and spectrophotometry. Plasma-disappearance rates of DY-780 and DY-654 are superior to conventional biomarkers in indicating hepatic or kidney dysfunction in different animal models. Greatest impact on liver function was found in animals with polymicrobial sepsis whereas glomerular damage due to glycerol-induced kidney-injury had strongest impact on DY-654 elimination. We therefore conclude that hepatic elimination and renal filtration can be assessed in rodents measuring plasma-disappearance rates of both dyes. Further, assessment of organ dysfunction by polymethine dyes correlates with, but outperforms conventional biomarkers regarding sensitivity and the option of spatial resolution if biophotonic strategies are applied. Polymethine-dye clearance thereby allows sensitive point-of-care assessment of both organ functions simultaneously.
Effect of short-term exposure to ambient air particulate matter on incidence of delirium in a surgical population
Authors: Che Lu , Li Yan , Gan Cheng 
Published: November 2017

AbstractDelirium remains an independent risk factor for morbidity and mortality among older surgical adults. Recent research has shed light on the relationship between pollution and dementia, yet little is known about the health impacts of particulate matter (PM) on delirium. Therefore, we aim to further explore association of PM and delirium among surgical population. We conducted a time-stratified case-crossover study. Electronic hospitalization summary reports derived from 26 major cities in China between 1 January 2014 and 31 December 2015 were used. Conditional logistic regression were applied to explore the association between perioperative PM exposure and delirium. A total of 559 surgical patients with delirium were identified. Both PM2.5 and SO2 on the day of surgery had a negative impact, with an interquartile range (IQR) increase in PM2.5 (47.5 μg/m3) and SO2 (22.2 μg/m3) significantly associated with an 8.79% (95% confidence interval [CI], 0.01–18.47%, P < 0.05) and 16.83% (95% CI, 0.10–36.35%, P < 0.05) increase in incidence of delirium, respectively. PM on other days during the perioperative period showed no significant impact. The present study showed that short-term exposure to ambient air PM on the day of surgery increased the incidence of delirium in a surgical population during hospitalization.
Essential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress
Authors: Cheng Xinlai , Peuckert Christiane , Wölfl Stefan 
Published: November 2017

AbstractStat3 is an oncogene, frequently associated with malignant transformation. A body of evidence implicates that phospho-Stat3Y705 contributes to its nucleic translocation, while phospho-Stat3S727 leads to the accumulation in mitochondria. Both are of importance for tumor cell proliferation. In comparison to well-characterized signaling pathways interplaying with Stat3Y705, little is known about Stat3S727. In this work, we studied the influence of Stat3 deficiency on the viability of cells exposed to H2O2 or hypoxia using siRNA and CRISPR/Cas9 genome-editing. We found dysregulation of mitochondrial activity, which was associated with excessive ROS formation and reduced mitochondrial membrane potential, and observed a synergistic effect for oxidative stress-mediated apoptosis in Stat3-KD cells or cells carrying Stat3Y705F, but not Stat3S727D, suggesting the importance of functional mitochondrial Stat3 in this context. We also found that ROS-mediated activation of ASK1/p38MAPK was involved and adding antioxidants, p38MAPK inhibitor, or genetic repression of ASK1 could easily rescue the cellular damage. Our finding reveals a new role of mitochondrial Stat3 in preventing ASK1/p38MAPK-mediated apoptosis, wich further support the notion that selective inhibition mitochondrial Stat3 could provide a primsing target for chemotherapy.