bluuebunny/crossref_metadata_2025 huggingface dataset:
Rosmarinic acid: modes of action, medicinal values and health benefits
Authors: Alagawany Mahmoud , Abd El-Hack Mohamed Ezzat , Farag Mayada Ragab , Gopi Marappan , Karthik Kumaragurubaran , Malik Yashpal Singh , Dhama Kuldeep
Published: November 2017

The supplementation of livestock rations with herbs containing bioactive components, such as rosmarinic acid (RA), have shown promising results as a natural feed additive in promoting growth, productive and reproductive performance, feed utilization, fertility, anti-oxidant status and immunologic indices. Furthermore, RA reportedly reduces the risks of various animal diseases and mitigates side effects of chemical and synthetic drugs. RA is a natural polyphenol present in several Lamiaceae herbs like Perilla frutescens, and RA is becoming an integral component of animal nutrition as it counters the effect of reactive oxygen species induced in the body as a consequence of different kinds of stressors. Studies have further ascertained the capability of RA to work as an anti-microbial, immunomodulatory, anti-diabetic, anti-allergic, anti-inflammatory, hepato- and renal-protectant agent, as well as to have beneficial effects during skin afflictions. Additionally, RA is favored in meat industries due to enhancing the quality of meat products by reportedly improving shelf-life and imparting desirable flavor. This review describes the beneficial applications and recent findings with RA, including its natural sources, modes of action and various useful applications in safeguarding livestock health as well as important aspects of human health.
Japan's Womenomics Diplomacy: Fighting Stigma and Constructing ODA Leadership on Gender Equality
Authors: COLEMAN LIV
Published: November 2017

Under conservative Prime Minister Abe Shinzo, Japan has embarked upon a high profile ‘Womenomics’ foreign policy agenda to highlight Japan's official development assistance (ODA) contributions to women's empowerment worldwide. This paper examines the puzzle of why such an avowedly conservative government would pursue a feminist foreign policy agenda. The paper finds that Japan's Womenomics diplomacy cannot be explained simply by materialist or domestic political explanations, but is best understood as a strategic campaign stemming from elite concern about Japan's national identity and esteem about its status in the world. Through Womenomics diplomacy, Japan's Ministry of Foreign Affairs attempts to construct Japan as a leader on women's rights and gender equality in response to the twin stigmas of Japan's treatment of wartime ‘comfort women’ and perennial low rankings on international indexes of gender equality.
ELLA FLAGG YOUNG AND THE GENDER POLITICS OFDEMOCRACY AND EDUCATION
Authors: Blount Jackie M.
Published: November 2017

Though John Dewey had considered education and democracy separately in his early career, he came to understand them as essentially linked concepts during his nearly ten-year collaboration with Ella Flagg Young at the University of Chicago. This intellectually gifted women, who eventually became superintendent of Chicago’s schools, connected education and democracy as well as theory and practice, essentially showing Dewey how democratic schools might work. This article briefly traces Dewey’s developing ideas of education and democracy in the context of his relationship with Young.
EDUCATION, EXPEDIENCY, AND DEMOCRATIC DILEMMAS IN WAR TIME: INSIDE THE DEWEY-BOURNE DEBATE
Authors: Nichols Christopher McKnight
Published: November 2017

In one of the most significant debates in U.S. intellectual history, John Dewey and Randolph Bourne attempted to redefine the relationship between democracy and war in the midst of World War I. This essay argues that the Dewey-Bourne debate is not just a vital dispute over the United States’ role in the war and the world, but that it also must be seen as a crucial moment for understanding fractures in progressive politics and debates over projects that presume to cultivate an educated citizenry. Focusing on Dewey and Bourne's developing ideas from 1914 through 1918, with an emphasis on concepts evolving in and from Dewey's Democracy and Education and Bourne's cultural criticism, the essay explores their core disagreements about the relationship between education and progressive reform, the role of intellectuals in the state, the consequences of intervention in the war and the use of force, and democratic citizenship in national and international contexts. This essay provides insights into the boundaries and pitfalls of liberal politics in the early twentieth century; it argues that this debate reveals a central ambiguity in Dewey's thought, and shows how wartime expediency and potential for progressive influence derailed aspects of the Deweyan project of democratic education.
Seed Dormancy and Seed Morphology Related to Weed Susceptibility to Biofumigation
Authors: Lefebvre Maxime , Leblanc Maryse L. , Watson Alan K.
Published: November 2017

Biofumigation is practiced to control soilborne pests and weeds in agronomic fields. The objectives of this research were to assess the dose response of weed seeds to Indian mustard biofumigation and associate responses to seed dormancy state, initial dormancy, and seed parameters. A petri dish biofumigation methodology was developed to expose seeds of common lambsquarters, bird vetch, wild carrot, common ragweed, green foxtail, velvetleaf, hairy galinsoga, and red clover to allelochemicals produced after rehydrating 0 (control), 1.94, 2.90, 5.81, 11.61, and 17.41 mg cm−2of dried mustard powder. Weed species expressed specific dose responses, estimated ED50, LD50, and maximal mortality. Hairy galinsoga and wild carrot were consistently the most affected by biofumigation, with maximal mortality reaching 97% and 95%, ED50values for germination were 1.91 and 2.68 mg cm−2, and LD50values were 3.31 and 3.69 mg cm−2of dried mustard tissue, respectively. Initial dormancy was assessed by germination and tetrazolium tests. Seed parameters such as testa thickness, relative weight of the testa, and seed size were measured directly by manual dissection, weighing seed structures, and stereomicroscopic imaging software measurements. Linear regression analyses revealed initial dormancy to be positively related to ED50and LD50values with a significant interaction with seed surface and seed width, respectively. Exposure to 5.81 mg cm−2of dried mustard powder increased common ragweed seed mortality for after-ripened seeds by 293% and by 58% for primary dormant seeds compared with untreated seeds. Mortality of common lambsquarters secondary and primary dormant seeds increased by 730% and 106%, respectively, and for wild carrot by 1,193 and 156%, respectively. Results underline the potential to incorporate biofumigation into weed management programs for repression of susceptible weed species.
Gualtieri Receives 2017 Keiiti Aki Young Scientist Award
Authors:   AGU
Published: November 2017

Lucia Gualtieri will receive the 2017 Keiiti Aki Young Scientist Award at the 2017 American Geophysical Union Fall Meeting, to be held 11–15 December in New Orleans, La. The award recognizes “scientific accomplishments of young scientists in the field of seismology.”
Experts Ponder Why Administration Released Tough Climate Report
Authors: Showstack Randy
Published: November 2017

Scientists and policy experts say the White House released the report, which differs from the administration’s stance, without political tampering to avoid potential further controversy.
Hit-and-run epigenetic editing prevents senescence entry in primary breast cells from healthy donors
Authors: Saunderson Emily A. , Stepper Peter , Gomm Jennifer J. , Hoa Lily , Morgan Adrienne , Allen Michael D. , Jones J. Louise , Gribben John G. , Jurkowski Tomasz P. , Ficz Gabriella
Published: November 2017

Aberrant promoter DNA hypermethylation is a hallmark of cancer; however, whether this is sufficient to drive cellular transformation is not clear. To investigate this question, we use a CRISPR-dCas9 epigenetic editing tool, where an inactive form of Cas9 is fused to DNA methyltransferase effectors. Using this system, here we show simultaneous de novo DNA methylation of genes commonly methylated in cancer, CDKN2A, RASSF1, HIC1 and PTEN in primary breast cells isolated from healthy human breast tissue. We find that promoter methylation is maintained in this system, even in the absence of the fusion construct, and this prevents cells from engaging senescence arrest. Our data show that the key driver of this phenotype is repression of CDKN2A transcript p16 where myoepithelial cells harbour cancer-like gene expression but do not exhibit anchorage-independent growth. This work demonstrates that hit-and-run epigenetic events can prevent senescence entry, which may facilitate tumour initiation.
The multiple antibiotic resistance operon of enteric bacteria controls DNA repair and outer membrane integrity
Authors: Sharma Prateek , Haycocks James R. J. , Middlemiss Alistair D. , Kettles Rachel A. , Sellars Laura E. , Ricci Vito , Piddock Laura J. V. , Grainger David C.
Published: November 2017

The multiple antibiotic resistance (mar) operon of Escherichia coli is a paradigm for chromosomally encoded antibiotic resistance in enteric bacteria. The locus is recognised for its ability to modulate efflux pump and porin expression via two encoded transcription factors, MarR and MarA. Here we map binding of these regulators across the E. coli genome and identify an extensive mar regulon. Most notably, MarA activates expression of genes required for DNA repair and lipid trafficking. Consequently, the mar locus reduces quinolone-induced DNA damage and the ability of tetracyclines to traverse the outer membrane. These previously unrecognised mar pathways reside within a core regulon, shared by most enteric bacteria. Hence, we provide a framework for understanding multidrug resistance, mediated by analogous systems, across the Enterobacteriaceae. Transcription factors MarR and MarA confer multidrug resistance in enteric bacteria by modulating efflux pump and porin expression. Here, Sharma et al. show that MarA also upregulates genes required for lipid trafficking and DNA repair, thus reducing antibiotic entry and quinolone-induced DNA damage.
Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology
Authors: Nuriel Tal , Angulo Sergio L. , Khan Usman , Ashok Archana , Chen Qiuying , Figueroa Helen Y. , Emrani Sheina , Liu Li , Herman Mathieu , Barrett Geoffrey , Savage Valerie , Buitrago Luna , Cepeda-Prado Efrain , Fung Christine , Goldberg Eliana , Gross Steven S. , Hussaini S. Abid , Moreno Herman , Small Scott A. , Duff Karen E.
Published: November 2017

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer’s disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4-associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques—fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics—with the most prominent hyperactivity occurring in the entorhinal cortex. Further analysis revealed that this neuronal hyperactivity is driven by decreased background inhibition caused by reduced responsiveness of excitatory neurons to GABAergic inhibitory inputs. Given the observations of neuronal hyperactivity in prodromal AD, we propose that this APOE4-driven hyperactivity may be a causative factor driving increased risk of AD among APOE4 carriers.
RNA editing by ADAR1 leads to context-dependent transcriptome-wide changes in RNA secondary structure
Authors: Solomon Oz , Di Segni Ayelet , Cesarkas Karen , Porath Hagit T. , Marcu-Malina Victoria , Mizrahi Orel , Stern-Ginossar Noam , Kol Nitzan , Farage-Barhom Sarit , Glick-Saar Efrat , Lerenthal Yaniv , Levanon Erez Y. , Amariglio Ninette , Unger Ron , Goldstein Itamar , Eyal Eran , Rechavi Gidi
Published: November 2017

Adenosine deaminase acting on RNA 1 (ADAR1) is the master RNA editor, catalyzing the deamination of adenosine to inosine. RNA editing is vital for preventing abnormal activation of cytosolic nucleic acid sensing pathways by self-double-stranded RNAs. Here we determine, by parallel analysis of RNA secondary structure sequencing (PARS-seq), the global RNA secondary structure changes in ADAR1 deficient cells. Surprisingly, ADAR1 silencing resulted in a lower global double-stranded to single-stranded RNA ratio, suggesting that A-to-I editing can stabilize a large subset of imperfect RNA duplexes. The duplexes destabilized by editing are composed of vastly complementary inverted Alus found in untranslated regions of genes performing vital biological processes, including housekeeping functions and type-I interferon responses. They are predominantly cytoplasmic and generally demonstrate higher ribosomal occupancy. Our findings imply that the editing effect on RNA secondary structure is context dependent and underline the intricate regulatory role of ADAR1 on global RNA secondary structure.
Virtual photons in the ground state of a dissipative system
Authors: De Liberato Simone
Published: November 2017

Much of the novel physics predicted to be observable in the ultrastrong light–matter coupling regime rests on the hybridisation between states with different numbers of excitations, leading to a population of virtual photons in the system’s ground state. In this article, exploiting an exact diagonalisation approach, we derive both analytical and numerical results for the population of virtual photons in presence of arbitrary losses. Specialising our results to the case of Lorentzian resonances we then show that the virtual photon population is only quantitatively affected by losses, even when those become the dominant energy scale. Our results demonstrate most of the ultrastrong-coupling phenomenology can be observed in loss-dominated systems which are not even in the standard strong coupling regime. We thus open the possibility to investigate ultrastrong-coupling physics to platforms that were previously considered unsuitable due to their large losses.
Mapping functional diversity from remotely sensed morphological and physiological forest traits
Authors: Schneider Fabian D. , Morsdorf Felix , Schmid Bernhard , Petchey Owen L. , Hueni Andreas , Schimel David S. , Schaepman Michael E.
Published: November 2017

Assessing functional diversity from space can help predict productivity and stability of forest ecosystems at global scale using biodiversity–ecosystem functioning relationships. We present a new spatially continuous method to map regional patterns of tree functional diversity using combined laser scanning and imaging spectroscopy. The method does not require prior taxonomic information and integrates variation in plant functional traits between and within plant species. We compare our method with leaf-level field measurements and species-level plot inventory data and find reasonable agreement. Morphological and physiological diversity show consistent change with topography and soil, with low functional richness at a mountain ridge under specific environmental conditions. Overall, functional richness follows a logarithmic increase with area, whereas divergence and evenness are scale invariant. By mapping diversity at scales of individual trees to whole communities we demonstrate the potential of assessing functional diversity from space, providing a pathway only limited by technological advances and not by methodology.
An unusual endo-selective C-H hydroarylationof norbornene by the Rh(I)-catalyzed reactionof benzamides
Authors: Shibata Kaname , Natsui Satoko , Tobisu Mamoru , Fukumoto Yoshiya , Chatani Naoto
Published: November 2017

Hydroarylation is an environmentally attractive strategy which incorporates all of the atoms contained in the substrates into the desired products. Almost all the hydroarylations of norbornene reported to date involve an exo-selective reaction. Here we show the endo-selective hydroarylation of norbornene in the Rh(I)-catalyzed reaction of aromatic amides. The addition of sterically bulky carboxylic acids enhances the endo-selectivity of the reaction. The results of deuterium-labeling experiments show that both the ortho-carbon and the ortho-hydrogen atoms of aromatic amides were attached to the same carbon atom of the norbornane skeleton in the hydroarylation product. These results clearly suggest that hydrometalation or carbometalation, which are commonly accepted mechanisms for the catalytic hydroarylation of C–H bonds, are not involved as the key step in the present reaction, and suggest that the reaction involves a rhodium carbene complex generated from norbornene as the key intermediate.
Highly selective nickel-catalyzed gem-difluoropropargylation of unactivated alkylzinc reagents
Authors: An Lun , Xu Chang , Zhang Xingang
Published: November 2017

In spite of the important applications of difluoroalkylated molecules in medicinal chemistry, to date, the reaction of difluoroalkylating reagents with unactivated, aliphatic substrates through a controllable manner remains challenging and has not been reported. Here we describe an efficient nickel-catalyzed cross-coupling of unactivated alkylzinc reagen\ts with gem-difluoropropargyl bromides. The reaction proceeds under mild reaction conditions with high efficiency and excellent regiochemical selectivity. Transformations of the resulting difluoroalkylated alkanes lead to a variety of biologically active molecules, providing a facile route for applications in drug discovery and development. Preliminary mechanistic studies reveal that an alkyl nickel intermediate [Ni(tpy)alkyl] (tpy, terpyridine) is involved in the catalytic cycle.
Thermostable exoshells fold and stabilize recombinant proteins
Authors: Deshpande Siddharth , Masurkar Nihar D. , Girish Vallerinteavide Mavelli , Desai Malan , Chakraborty Goutam , Chan Juliana M. , Drum Chester L.
Published: November 2017

The expression and stabilization of recombinant proteins is fundamental to basic and applied biology. Here we have engineered a thermostable protein nanoparticle (tES) to improve both expression and stabilization of recombinant proteins using this technology. tES provides steric accommodation and charge complementation to green fluorescent protein (GFPuv), horseradish peroxidase (HRPc), and Renilla luciferase (rLuc), improving the yields of functional in vitro folding by ~100-fold. Encapsulated enzymes retain the ability to metabolize small-molecule substrates, presumably via four 4.5-nm pores present in the tES shell. GFPuv exhibits no spectral shifts in fluorescence compared to a nonencapsulated control. Thermolabile proteins internalized by tES are resistant to thermal, organic, chaotropic, and proteolytic denaturation and can be released from the tES assembly with mild pH titration followed by proteolysis.
Nanopore electric snapshots of an RNA tertiary folding pathway
Authors: Zhang Xinyue , Zhang Dong , Zhao Chenhan , Tian Kai , Shi Ruicheng , Du Xiao , Burcke Andrew J. , Wang Jing , Chen Shi-Jie , Gu Li-Qun
Published: November 2017

The chemical properties and biological mechanisms of RNAs are determined by their tertiary structures. Exploring the tertiary structure folding processes of RNA enables us to understand and control its biological functions. Here, we report a nanopore snapshot approach combined with coarse-grained molecular dynamics simulation and master equation analysis to elucidate the folding of an RNA pseudoknot structure. In this approach, single RNA molecules captured by the nanopore can freely fold from the unstructured state without constraint and can be programmed to terminate their folding process at different intermediates. By identifying the nanopore signatures and measuring their time-dependent populations, we can “visualize” a series of kinetically important intermediates, track the kinetics of their inter-conversions, and derive the RNA pseudoknot folding pathway. This approach can potentially be developed into a single-molecule toolbox to investigate the biophysical mechanisms of RNA folding and unfolding, its interactions with ligands, and its functions.
Optically-controlled long-term storage and release of thermal energy in phase-change materials
Authors: Han Grace G. D. , Li Huashan , Grossman Jeffrey C.
Published: November 2017

Thermal energy storage offers enormous potential for a wide range of energy technologies. Phase-change materials offer state-of-the-art thermal storage due to high latent heat. However, spontaneous heat loss from thermally charged phase-change materials to cooler surroundings occurs due to the absence of a significant energy barrier for the liquid–solid transition. This prevents control over the thermal storage, and developing effective methods to address this problem has remained an elusive goal. Herein, we report a combination of photo-switching dopants and organic phase-change materials as a way to introduce an activation energy barrier for phase-change materials solidification and to conserve thermal energy in the materials, allowing them to be triggered optically to release their stored latent heat. This approach enables the retention of thermal energy (about 200 J g−1) in the materials for at least 10 h at temperatures lower than the original crystallization point, unlocking opportunities for portable thermal energy storage systems.
Volcanism in slab tear faults is larger than in island-arcs and back-arcs
Authors: Cocchi Luca , Passaro Salvatore , Tontini Fabio Caratori , Ventura Guido
Published: November 2017

Subduction-transform edge propagators are lithospheric tears bounding slabs and back-arc basins. The volcanism at these edges is enigmatic because it is lacking comprehensive geological and geophysical data. Here we present bathymetric, potential-field data, and direct observations of the seafloor on the 90 km long Palinuro volcanic chain overlapping the E-W striking tear of the roll-backing Ionian slab in Southern Tyrrhenian Sea. The volcanic chain includes arc-type central volcanoes and fissural, spreading-type centers emplaced along second-order shears. The volume of the volcanic chain is larger than that of the neighbor island-arc edifices and back-arc spreading center. Such large volume of magma is associated to an upwelling of the isotherms due to mantle melts upraising from the rear of the slab along the tear fault. The subduction-transform edge volcanism focuses localized spreading processes and its magnitude is underestimated. This volcanism characterizes the subduction settings associated to volcanic arcs and back-arc spreading centers.
Ist1 regulates ESCRT-III assembly and function during multivesicular endosome biogenesis in Caenorhabditis elegans embryos
Authors: Frankel E. B. , Shankar Raakhee , Moresco James J. , Yates John R. , Volkmann Niels , Audhya Anjon
Published: November 2017

Degradation of most integral membrane proteins is directed by the endosomal sorting complex required for transport (ESCRT) machinery, which selectively targets ubiquitin-modified cargoes into intralumenal vesicles (ILVs) within multivesicular endosomes (MVEs). To better understand the mechanisms underlying ESCRT-mediated formation of ILVs, we exploited the rapid, de novo biogenesis of MVEs during the oocyte-to-embryo transition in C. elegans. In contrast to previous models suggesting that ILVs form individually, we demonstrate that they remain tethered to one another subsequent to internalization, arguing that they bud continuously from stable subdomains. In addition, we show that membrane bending and ILV formation are directed specifically by the ESCRT-III complex in vivo in a manner regulated by Ist1, which promotes ESCRT-III assembly and inhibits the incorporation of upstream ESCRT components into ILVs. Our findings underscore essential actions for ESCRT-III in membrane remodeling, cargo selection, and cargo retention, which act repetitively to maximize the rate of ILV formation.
Dengue virus-reactive CD8+ T cells mediate cross-protection against subsequent Zika virus challenge
Authors: Wen Jinsheng , Elong Ngono Annie , Regla-Nava Jose Angel , Kim Kenneth , Gorman Matthew J. , Diamond Michael S. , Shresta Sujan
Published: November 2017

Zika virus (ZIKV) and dengue virus (DENV) are antigenically related flaviviruses that share cross-reactivity in antibody and T cell responses, and co-circulate in increasing numbers of countries. Whether pre-existing DENV immunity can cross-protect or enhance ZIKV infection during sequential infection of the same host is unknown. Here, we show that DENV-immuneIfnar1−/−or wild-type C57BL/6 mice infected with ZIKV have cross-reactive immunity to subsequent ZIKV infection and pathogenesis. Adoptive transfer and cell depletion studies demonstrate that DENV-immune CD8+T cells predominantly mediate cross-protective responses to ZIKV. In contrast, passive transfer studies suggest that DENV-immune serum does not protect against ZIKV infection. Thus, CD8+T cell immunity generated during primary DENV infection can confer protection against secondary ZIKV infection in mice. Further optimization of current DENV vaccines for T cell responses might confer cross-protection and prevent antibody-mediated enhancement of ZIKV infection.
Atomically-precise colloidal nanoparticles of cerium dioxide
Authors: Mitchell Kylie J. , Abboud Khalil A. , Christou George
Published: November 2017

Synthesis of truly monodisperse nanoparticles and their structural characterization to atomic precision are important challenges in nanoscience. Success has recently been achieved for metal nanoparticles, particularly Au, with diameters up to 3 nm, the size regime referred to as nanoclusters. In contrast, families of atomically precise metal oxide nanoparticles are currently lacking, but would have a major impact since metal oxides are of widespread importance for their magnetic, catalytic and other properties. One such material is colloidal CeO2 (ceria), whose applications include catalysis, new energy technologies, photochemistry, and medicine, among others. Here we report a family of atomically precise ceria nanoclusters with ultra-small dimensions up to ~1.6 nm (~100 core atoms). X-ray crystallography confirms they have the fluorite structure of bulk CeO2, and identifies surface features, H+ binding sites, Ce3+ locations, and O vacancies on (100) facets. Monodisperse ceria nanoclusters now permit investigation of their properties as a function of exact size, surface morphology, and Ce3+:Ce4+ composition.
Development of a genetic sensor that eliminates p53 deficient cells
Authors: Mircetic Jovan , Dietrich Antje , Paszkowski-Rogacz Maciej , Krause Mechthild , Buchholz Frank
Published: November 2017

The TP53 gene fulfills a central role in protecting cells from genetic insult. Given this crucial role it might be surprising that p53 itself is not essential for cell survival. Indeed, TP53 is the single most mutated gene across different cancer types. Thus, both a theoretical and a question of significant practical applicability arise: can cells be programmed to make TP53 an essential gene? Here we present a genetic p53 sensor, in which the loss of p53 is coupled to the rise of HSV-TK expression. We show that the sensor can distinguish both p53 knockout and cells expressing a common TP53 cancer mutation from otherwise isogenic TP53 wild-type cells. Importantly, the system is sensitive enough to specifically target TP53 loss-of-function cells with the HSV-TK pro-drug Ganciclovir both in vitro and in vivo. Our work opens new ways to programming cell intrinsic transformation protection systems that rely on endogenous components.
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

Aberrant 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

While 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

The 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

BRCA2-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

Endoplasmic-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

Diet 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

Low 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

The 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

Antimicrobial 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

Apelin 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

Despite 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

Paladin (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

Simultaneous 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.