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  • Elsevier  (1,429,751)
  • Wiley-Blackwell  (474,673)
  • American Institute of Physics (AIP)  (154,287)
  • Sage Publications
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  • 1
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Physics Letters B 294 (1992), S. 466-478 
    ISSN: 0370-2693
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Physics Letters B 317 (1993), S. 474-484 
    ISSN: 0370-2693
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 3
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    New York, NY : Elsevier
    Keywords: Biochemistry ; Enzymes
    Notes: This is a series title, single volumes see link below.
    ISSN: 1557-7988
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  • 4
    Call number: QZ269:203(3)
    Keywords: Radiation Oncology / methods ; Neoplasms / radiotherapy
    Pages: xxviii, 713 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128141281
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    QZ269:203(3) available
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  • 5
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    Amsterdam : Elsevier
    Call number: QZ200:575(3)/1
    Keywords: Neoplasms ; DKFZ-publications
    Notes: Contributor: Michael Baumann
    Pages: xl, 585 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128124840
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    QZ200:575(3)/1 available
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  • 6
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    Amsterdam : Elsevier
    Call number: QZ200:575(3)/3
    Keywords: Neoplasms ; DKFZ-publications
    Notes: Contributor: Michael Baumann
    Pages: xl, 605 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128124840
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    QZ200:575(3)/3 available
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  • 7
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    München : Elsevier
    Call number: QZ269:204(3)
    Keywords: Neoplasms / radiotherapy ; Radiotherapy
    Pages: xxviii, 419 p. : ill.
    Edition: 3. Aufl.
    ISBN: 9783437232923
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    QZ269:204(3) available
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  • 8
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    München : Elsevier
    Call number: WN180:10(5)
    Pages: ix, 141 p. : ill.
    Edition: 5. Aufl.
    ISBN: 9783437422973
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    WN180:10(5) available
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  • 9
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    Amsterdam : Elsevier
    Call number: QZ200:575(3)/2
    Keywords: Neoplasms ; DKFZ-publications
    Notes: Contributor: Michael Baumann
    Pages: xl, 577 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128124840
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  • 10
    Publication Date: 2018-05-26
    Description: Publication date: 7 June 2018 Source: Vaccine, Volume 36, Issue 24
    Print ISSN: 0264-410X
    Topics: Medicine
    Published by Elsevier
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  • 11
    Publication Date: 2018-06-08
    Description: Publication date: Available online 7 June 2018 Source: Urology Author(s): G Giusti, M Lucci Chiarissi, D Abate, G De Vita, S Angioni, A De Lisa Objectives To verify the feasibility and effectiveness of the correction of Vesicovaginal fistulae (VVF) through a laparoscopic transperitoneal extravesical approach and TachoSil application as interposition tissue. VVF are the most common fistulae of the urinary tract and even today there is no agreement over the preferred approach to treat this kind of pathologic condition. Methods We retrospectively analysed the data of women who, from July 2010 to July 2017, underwent early laparoscopic transperitoneal extravesical VVF repair. Patients were placed in the lithotomy position. Five operating ports were placed. After the resection of the VVF, the vesical and vaginal edges were closed in 2 layers. Finally two layers of TachoSil (4cmx4cm) were placed between the sutures. Several variables were considered in the perioperative period. Patients were re-evaluated at one and 3 months after surgery. Results 16 patients underwent VVF repair. Mean duration of the surgery was 106 minutes, mean length of stay was 3.2 days. No High grade complications according to Clavien-Dindo were reported. At 1 month all patients showed complete continence and at 3 months they reported a good quality of life. Conclusions The laparoscopic approach described enables adequate repair of VVF. The use of Tachosil is straightforward and atraumatic, and may be considered as an alternative to tissue flap interposition. Finally, we confirm that the early approach is not an hazard in such a disabling disease and can be adopted to restore as soon as possible a good quality of life for patients.
    Print ISSN: 0090-4295
    Electronic ISSN: 1527-9995
    Topics: Medicine
    Published by Elsevier
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  • 12
    Publication Date: 2018-06-08
    Description: Publication date: Available online 6 June 2018 Source: Virus Research Author(s): André Ballerini Horta, Daniel Mendes Pereira Ardisson-Araujo, Leonardo Assis da Silva, Fernando Lucas de Melo, Fabricio da Silva Morgado, Manoel Victor Franco Lemos, Zulene Antonio Ribeiro, Arlindo Leal Boiça, Carlos Frederico Wilcken, Bergmann Morais Ribeiro The eucalyptus brown looper, Thyrinteina arnobia (Stoll, 1782) (Lepidoptera: Geometridae), is the main lepidopteran defoliator of eucalyptus plantations in Brazil. Outbreaks of this insect pest are common in Brazil and can affect the productivity of planted forests severely. T. arnobia caterpillars from a laboratory colony with viral infection symptoms were analyzed by electron microscopy that revealed polyhedral occlusion bodies (OBs) with several icosahedral virus particles embedded. Analysis of its genetic material showed ten segments of dsRNA, which confirmed this virus as a possible member of the genus Cypovirus . Phylogenetic analysis of the whole genome sequence revealed its close relationship with other isolates of Cypovirus 14 species and according to these results we proposed the name Thyrinteina arnobia cypovirus 14 (TharCPV-14) for this new virus isolate. Further research will be necessary in order to analyze the potential of this virus as a biopesticide.
    Print ISSN: 0168-1702
    Electronic ISSN: 1872-7492
    Topics: Medicine
    Published by Elsevier
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  • 13
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    Elsevier
    Publication Date: 2018-06-09
    Description: Publication date: 5 June 2018 Source: Cell Reports, Volume 23, Issue 10 Author(s): Daniel C. Ellwanger, Mirko Scheibinger, Rachel A. Dumont, Peter G. Barr-Gillespie, Stefan Heller Protruding from the apical surface of inner ear sensory cells, hair bundles carry out mechanotransduction. Bundle growth involves sequential and overlapping cellular processes, which are concealed within gene expression profiles of individual cells. To dissect such processes, we developed CellTrails, a tool for uncovering, analyzing, and visualizing single-cell gene-expression dynamics. Utilizing quantitative gene-expression data for key bundle proteins from single cells of the developing chick utricle, we reconstructed de novo a bifurcating trajectory that spanned from progenitor cells to mature striolar and extrastriolar hair cells. Extraction and alignment of developmental trails and association of pseudotime with bundle length measurements linked expression dynamics of individual genes with bundle growth stages. Differential trail analysis revealed high-resolution dynamics of transcripts that control striolar and extrastriolar bundle development, including those that encode proteins that regulate [Ca 2+ ] i or mediate crosslinking and lengthening of actin filaments. Graphical abstract Teaser Ordering single cells along branching trajectories using transcriptomic data is bioinformatically challenging. Ellwanger et al. developed CellTrails and applied this tool to showcase the bifurcating sequence of gene expression as sensory hair cells develop into different subtypes that feature spatially distinct morphologies of the mechanosensitive hair bundle.
    Electronic ISSN: 2211-1247
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 14
    Publication Date: 2018-06-09
    Description: Publication date: 5 June 2018 Source: Cell Reports, Volume 23, Issue 10 Author(s): Andre M. Miranda, Mathieu Herman, Rong Cheng, Eden Nahmani, Geoffrey Barrett, Elizabeta Micevska, Gaelle Fontaine, Marie-Claude Potier, Elizabeth Head, Frederick A. Schmitt, Ira T. Lott, Ivonne Z. Jiménez-Velázquez, Stylianos E. Antonarakis, Gilbert Di Paolo, Joseph H. Lee, S. Abid Hussaini, Catherine Marquer The phosphoinositide phosphatase synaptojanin 1 (SYNJ1) is a key regulator of synaptic function. We first tested whether SYNJ1 contributes to phenotypic variations in familial Alzheimer’s disease (FAD) and show that SYNJ1 polymorphisms are associated with age of onset in both early- and late-onset human FAD cohorts. We then interrogated whether SYNJ1 levels could directly affect memory. We show that increased SYNJ1 levels in autopsy brains from adults with Down syndrome (DS/AD) are inversely correlated with synaptophysin levels, a direct readout of synaptic integrity. We further report age-dependent cognitive decline in a mouse model overexpressing murine Synj1 to the levels observed in human sporadic AD, triggered through hippocampal hyperexcitability and defects in the spatial reproducibility of place fields. Taken together, our findings suggest that SYNJ1 contributes to memory deficits in the aging hippocampus in all forms of AD. Graphical abstract Teaser Miranda et al. combine human genetics, human brain samples, and behavior and electrophysiology in a transgenic mouse model to show that synaptojanin 1 levels regulate the function of place cells in the aging hippocampus. The results have implications for memory deficits in all types of Alzheimer’s disease.
    Electronic ISSN: 2211-1247
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 15
    Publication Date: 2018-06-09
    Description: Publication date: 5 June 2018 Source: Cell Reports, Volume 23, Issue 10 Author(s): Bogdan Sieriebriennikov, Neel Prabh, Mohannad Dardiry, Hanh Witte, Waltraud Röseler, Manuela R. Kieninger, Christian Rödelsperger, Ralf J. Sommer Switching between alternative complex phenotypes is often regulated by “supergenes,” polymorphic clusters of linked genes such as in butterfly mimicry. In contrast, phenotypic plasticity results in alternative complex phenotypes controlled by environmental influences rather than polymorphisms. Here, we show that the developmental switch gene regulating predatory versus non-predatory mouth-form plasticity in the nematode Pristionchus pacificus is part of a multi-gene locus containing two sulfatases and two α-N-acetylglucosaminidases ( nag ). We provide functional characterization of all four genes, using CRISPR-Cas9-based reverse genetics, and show that nag genes and the previously identified eud-1 /sulfatase have opposing influences. Members of the multi-gene locus show non-overlapping neuronal expression and epistatic relationships. The locus architecture is conserved in the entire genus Pristionchus . Interestingly, divergence between paralogs is counteracted by gene conversion, as inferred from phylogenies and genotypes of CRISPR-Cas9-induced mutants. Thus, we found that physical linkage accompanies regulatory linkage between switch genes controlling plasticity in P. pacificus . Graphical abstract Teaser The clonally reproducing roundworm Pristionchus pacificus can develop either as a toothed predator or as a narrow-mouthed microbe feeder depending on environmental conditions. Sieriebriennikov et al. show that the switch gene controlling this developmental decision is physically linked with two other genes having opposing influence on the same phenotype.
    Electronic ISSN: 2211-1247
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 16
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    Elsevier
    Publication Date: 2018-06-09
    Description: Publication date: 5 June 2018 Source: Cell Reports, Volume 23, Issue 10 Author(s): Caiwei Guo, Hyun-Hwan Jeong, Yi-Chen Hsieh, Hans-Ulrich Klein, David A. Bennett, Philip L. De Jager, Zhandong Liu, Joshua M. Shulman Aging and neurodegenerative disease are characterized by genomic instability in neurons, including aberrant activation and mobilization of transposable elements (TEs). Integrating studies of human postmortem brain tissue and Drosophila melanogaster models, we investigate TE activation in association with Tau pathology in Alzheimer’s disease (AD). Leveraging RNA sequencing from 636 human brains, we discover differential expression for several retrotransposons in association with neurofibrillary tangle burden and highlight evidence for global TE transcriptional activation among the long interspersed nuclear element 1 and endogenous retrovirus clades. In addition, we detect Tau-associated, active chromatin signatures at multiple HERV-Fc1 genomic loci. To determine whether Tau is sufficient to induce TE activation, we profile retrotransposons in Drosophila expressing human wild-type or mutant Tau throughout the brain. We discover heterogeneous response profiles, including both age- and genotype-dependent activation of TE expression by Tau. Our results implicate TE activation and associated genomic instability in Tau-mediated AD mechanisms. Graphical abstract Teaser Integrating studies of human postmortem brain tissue and Drosophila melanogaster models, Guo et al. show that Alzheimer’s disease Tau neurofibrillary tangle pathology activates transcription of transposable element loci. An altered retrotransposon transcriptional landscape and associated genomic instability are implicated in Tau-mediated neurodegenerative mechanisms.
    Electronic ISSN: 2211-1247
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 17
    Publication Date: 2018-06-09
    Description: Publication date: 5 June 2018 Source: Cell Reports, Volume 23, Issue 10 Author(s): Mohamad-Ali Fawal, Thomas Jungas, Anthony Kischel, Christophe Audouard, Jason S. Iacovoni, Alice Davy Metabolic pathways, once seen as a mere consequence of cell states, have emerged as active players in dictating different cellular events such as proliferation, self-renewal, and differentiation. Several studies have reported a role for folate-dependent one-carbon (1C) metabolism in stem cells; however, its exact mode of action and how it interacts with other cues are largely unknown. Here, we report a link between the Eph:ephrin cell-cell communication pathway and 1C metabolism in controlling neural stem cell differentiation. Transcriptional and functional analyses following ephrin stimulation revealed alterations in folate metabolism-related genes and enzymatic activity. In vitro and in vivo data indicate that Eph-B forward signaling alters the methylation state of H3K4 by regulating 1C metabolism and locks neural stem cell in a differentiation-ready state. Our study highlights a functional link between cell-cell communication, metabolism, and epigenomic remodeling in the control of stem cell self-renewal. Graphical abstract Teaser Fawal et al. present evidence that Eph-B forward signaling inhibits 1C folate metabolism in neural stem cells, leading to differentiation and alteration of H3K4 methylation on progenitor genes. In addition, they show that these epigenomic changes are maintained long term and that NSCs are locked into a differentiation-ready state following Eph-B receptor activation.
    Electronic ISSN: 2211-1247
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 18
    Publication Date: 2018-06-09
    Description: Publication date: 5 June 2018 Source: Cell Reports, Volume 23, Issue 10 Author(s): James B. Dewey, Anping Xia, Ulrich Müller, Inna A. Belyantseva, Brian E. Applegate, John S. Oghalai The stereociliary bundles of cochlear hair cells convert mechanical vibrations into the electrical signals required for auditory sensation. While the stiffness of the bundles strongly influences mechanotransduction, its influence on the vibratory response of the cochlear partition is unclear. To assess this, we measured cochlear vibrations in mutant mice with reduced bundle stiffness or with a tectorial membrane (TM) that is detached from the sensory epithelium. We found that reducing bundle stiffness decreased the high-frequency extent and sharpened the tuning of vibratory responses obtained postmortem. Detaching the TM further reduced the high-frequency extent of the vibrations but also lowered the partition’s resonant frequency. Together, these results demonstrate that the bundle’s stiffness and attachment to the TM contribute to passive longitudinal coupling in the cochlea. We conclude that the stereociliary bundles and TM interact to facilitate passive-wave propagation to more apical locations, possibly enhancing active-wave amplification in vivo . Graphical abstract Teaser The mechanical properties of the cochlear partition determine its vibratory response to sound. Dewey et al. demonstrate that the outer hair cell stereociliary bundles’ stiffness and attachment to the tectorial membrane influence the partition’s passive vibratory response. The stereociliary bundles facilitate the propagation of cochlear waves to more apical regions.
    Electronic ISSN: 2211-1247
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 19
    Publication Date: 2018-06-09
    Description: Publication date: 5 June 2018 Source: Cell Reports, Volume 23, Issue 10 Author(s): Xuehuo Zeng, Wilnelly Hernandez-Sanchez, Mengyuan Xu, Tawna L. Whited, Diane Baus, Junran Zhang, Anthony J. Berdis, Derek J. Taylor Telomerase, the end-replication enzyme, is reactivated in malignant cancers to drive cellular immortality. While this distinction makes telomerase an attractive target for anti-cancer therapies, most approaches for inhibiting its activity have been clinically ineffective. As opposed to inhibiting telomerase, we use its activity to selectively promote cytotoxicity in cancer cells. We show that several nucleotide analogs, including 5-fluoro-2′-deoxyuridine (5-FdU) triphosphate, are effectively incorporated by telomerase into a telomere DNA product. Administration of 5-FdU results in an increased number of telomere-induced foci, impedes binding of telomere proteins, activates the ATR-related DNA-damage response, and promotes cell death in a telomerase-dependent manner. Collectively, our data indicate that telomerase activity can be exploited as a putative anti-cancer strategy. Graphical abstract Teaser Telomerase is an attractive target for anti-cancer therapies. Zeng et al. show that several nucleotide analogs, including 5-fluoro-2′-deoxyuridine (5-FdU), are effectively incorporated by telomerase to induce dysfunctional telomeres that activate the ATR-related DNA-damage response, resulting in cancer cell death in a telomerase-dependent manner.
    Electronic ISSN: 2211-1247
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 20
    Publication Date: 2018-06-09
    Description: Publication date: 5 June 2018 Source: Cell Reports, Volume 23, Issue 10 Author(s): Catherine A. Reardon, Amulya Lingaraju, Kelly Q. Schoenfelt, Guolin Zhou, Chang Cui, Hannah Jacobs-El, Ilona Babenko, Andrew Hoofnagle, Daniel Czyz, Howard Shuman, Tomas Vaisar, Lev Becker Type 2 diabetes (T2D) is associated with increased risk for atherosclerosis; however, the mechanisms underlying this relationship are poorly understood. Macrophages, which are activated in T2D and causatively linked to atherogenesis, are an attractive mechanistic link. Here, we use proteomics to show that diet-induced obesity and insulin resistance (obesity/IR) modulate a pro-atherogenic “macrophage-sterol-responsive-network” (MSRN), which, in turn, predisposes macrophages to cholesterol accumulation. We identify IFNγ as the mediator of obesity/IR-induced MSRN dysregulation and increased macrophage cholesterol accumulation and show that obesity/IR primes T cells to increase IFNγ production. Accordingly, myeloid cell-specific deletion of the IFNγ receptor ( Ifngr1−/− ) restores MSRN proteins, attenuates macrophage cholesterol accumulation and atherogenesis, and uncouples the strong relationship between hyperinsulinemia and aortic root lesion size in hypercholesterolemic Ldlr−/− mice with obesity/IR, but does not affect these parameters in Ldlr−/− mice without obesity/IR. Collectively, our findings identify an IFNγ-macrophage pathway as a mechanistic link between obesity/IR and accelerated atherogenesis. Graphical abstract Teaser Obesity and insulin resistance are major risk factors for cardiovascular disease, but the underlying mechanisms are poorly understood. Reardon et al. show that obesity and insulin resistance induce an IFNγ-macrophage pathway that exacerbates foam cell formation and aortic lesion size in atherosclerotic mice.
    Electronic ISSN: 2211-1247
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 21
    Publication Date: 2018-06-09
    Description: Publication date: 5 June 2018 Source: Cell Reports, Volume 23, Issue 10 Author(s): Nan Zhang, Xin Yang, Fengjie Yuan, Luyao Zhang, Yanan Wang, Lina Wang, Zebin Mao, Jianyuan Luo, Hongquan Zhang, Wei-Guo Zhu, Ying Zhao Autophagy is a protein degradation process by which intracellular materials are recycled for energy homeostasis. However, the metabolic status and energy source of autophagy-defective tumor cells are poorly understood. Here, our data show that amino acid uptake from the extracellular environment is increased in autophagy-deficient cells upon glutamine deprivation. This elevated amino acid uptake results from activating transcription factor 4 (ATF4)-dependent upregulation of AAT (amino acid transporter) gene expression. Furthermore, we identify SIRT6, a NAD + -dependent histone deacetylase, as a corepressor of ATF4 transcriptional activity. In autophagy-deficient cells, activated NRF2 enhances ATF4 transcriptional activity by disrupting the interaction between SIRT6 and ATF4. In this way, autophagy-deficient cells exhibit increased AAT expression and show increased amino acid uptake. Notably, inhibition of amino acid uptake reduces the viability of glutamine-deprived autophagy-deficient cells, but not significantly in wild-type cells, suggesting reliance of autophagy-deficient tumor cells on extracellular amino acid uptake. Graphical abstract Teaser Zhang et al. show that amino acid uptake from the extracellular environment is increased in autophagy-deficient cells upon glutamine deprivation, resulting from increased amino acid transporter expression. Inhibition of amino acid uptake reduces the viability of glutamine-deprived autophagy-deficient cells.
    Electronic ISSN: 2211-1247
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 22
    Publication Date: 2018-06-09
    Description: Publication date: 5 June 2018 Source: Cell Reports, Volume 23, Issue 10 Author(s): Emily J. Shields, Lihong Sheng, Amber K. Weiner, Benjamin A. Garcia, Roberto Bonasio Ants are an emerging model system for neuroepigenetics, as embryos with virtually identical genomes develop into different adult castes that display diverse physiology, morphology, and behavior. Although a number of ant genomes have been sequenced to date, their draft quality is an obstacle to sophisticated analyses of epigenetic gene regulation. We reassembled de novo high-quality genomes for two ant species, Camponotus floridanus and Harpegnathos saltator . Using long reads enabled us to span large repetitive regions and improve genome contiguity, leading to comprehensive and accurate protein-coding annotations that facilitated the identification of a Gp-9-like gene as differentially expressed in Harpegnathos castes. The new assemblies also enabled us to annotate long non-coding RNAs in ants, revealing caste-, brain-, and developmental-stage-specific long non-coding RNAs (lncRNAs) in Harpegnathos . These upgraded genomes, along with the new gene annotations, will aid future efforts to identify epigenetic mechanisms of phenotypic and behavioral plasticity in ants. Graphical abstract Teaser Using long-read sequencing, Shields et al. upgrade the genome assemblies for two ant species. Their results reveal a protein-coding gene preferentially expressed in worker ants and genes for long non-coding RNAs, several of which were expressed in the brain, in some cases at different levels in workers and reproductives.
    Electronic ISSN: 2211-1247
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 23
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    Elsevier
    Publication Date: 2018-06-09
    Description: Publication date: Available online 7 June 2018 Source: Cell Stem Cell Author(s): Shiyan Yu, Kevin Tong, Yanlin Zhao, Iyshwarya Balasubramanian, George S. Yap, Ronaldo P. Ferraris, Edward M. Bonder, Michael P. Verzi, Nan Gao Paneth cells are post-mitotic intestinal epithelial cells supporting the stem cell niche and mucosal immunity. Paneth cell pathologies are observed in various gastrointestinal diseases, but their plasticity and response to genomic and environmental challenges remain unclear. Using a knockin allele engineered at the mouse Lyz1 locus, we performed detailed Paneth cell-lineage tracing. Irradiation induced a subset of Paneth cells to proliferate and differentiate into villus epithelial cells. RNA sequencing (RNA-seq) revealed that Paneth cells sorted from irradiated mice acquired a stem cell-like transcriptome; when cultured in vitro , these individual Paneth cells formed organoids. Irradiation activated Notch signaling, and forced expression of Notch intracellular domain (NICD) in Paneth cells, but not Wnt/β-catenin pathway activation, induced their dedifferentiation. This study documents Paneth cell plasticity, particularly their ability to participate in epithelial replenishment following stem cell loss, adding to a growing body of knowledge detailing the molecular pathways controlling injury-induced regeneration. Graphical abstract Teaser Using a knockin allele engineered at the mouse Lyz1 locus, Yu et al. report that irradiation induces a subset of Paneth cells to dedifferentiate. This process can also be induced by expressing active Notch1 in this cell type. The study documents Paneth cell plasticity, expanding current understanding of intestinal regeneration.
    Print ISSN: 1934-5909
    Electronic ISSN: 1875-9777
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 24
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    Elsevier
    Publication Date: 2018-06-09
    Description: Publication date: Available online 7 June 2018 Source: Current Biology Author(s): Xinjian Jiang, Tenghai Long, Weicong Cao, Junru Li, Stanislas Dehaene, Liping Wang Understanding and producing embedded sequences in language, music, or mathematics, is a central characteristic of our species. These domains are hypothesized to involve a human-specific competence for supra-regular grammars, which can generate embedded sequences that go beyond the regular sequences engendered by finite-state automata. However, is this capacity truly unique to humans? Using a production task, we show that macaque monkeys can be trained to produce time-symmetrical embedded spatial sequences whose formal description requires supra-regular grammars or, equivalently, a push-down stack automaton. Monkeys spontaneously generalized the learned grammar to novel sequences, including longer ones, and could generate hierarchical sequences formed by an embedding of two levels of abstract rules. Compared to monkeys, however, preschool children learned the grammars much faster using a chunking strategy. While supra-regular grammars are accessible to nonhuman primates through extensive training, human uniqueness may lie in the speed and learning strategy with which they are acquired. Teaser Jiang, Long, et al. demonstrate that macaques can be trained to produce center-embedded spatial sequences. Preschool children quickly learn the grammar using chunking and geometric structure to compress the information. The human brain may possess additional computational devices to efficiently represent sequences during inductive learning.
    Print ISSN: 0960-9822
    Electronic ISSN: 1879-0445
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 25
    Publication Date: 2018-06-09
    Description: Publication date: 5 June 2018 Source: Cell Reports, Volume 23, Issue 10 Author(s): Yiming Cheng, Li Jiang, Susanne Keipert, Shuyue Zhang, Andreas Hauser, Elisabeth Graf, Tim Strom, Matthias Tschöp, Martin Jastroch, Fabiana Perocchi Activation and recruitment of thermogenic cells in human white adipose tissues (“browning”) can counteract obesity and associated metabolic disorders. However, quantifying the effects of therapeutic interventions on browning remains enigmatic. Here, we devise a computational tool, named ProFAT (profiling of fat tissue types), for quantifying the thermogenic potential of heterogeneous fat biopsies based on prediction of white and brown adipocyte content from raw gene expression datasets. ProFAT systematically integrates 103 mouse-fat-derived transcriptomes to identify unbiased and robust gene signatures of brown and white adipocytes. We validate ProFAT on 80 mouse and 97 human transcriptional profiles from 14 independent studies and correctly predict browning capacity upon various physiological and pharmacological stimuli. Our study represents the most exhaustive comparative analysis of public data on adipose biology toward quantification of browning after personalized medical intervention. ProFAT is freely available and should become increasingly powerful with the growing wealth of transcriptomics data. Graphical abstract Teaser Cheng et al. develop a computational tool named ProFAT for quantifying the thermogenic potential of mouse and human fat samples based on automated and unbiased prediction of white and brown adipocyte content from raw gene expression datasets. ProFAT is freely available and can be accessed at http://profat.genzentrum.lmu.de .
    Electronic ISSN: 2211-1247
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 26
    Publication Date: 2018-06-09
    Description: Publication date: Available online 7 June 2018 Source: Cytokine & Growth Factor Reviews Author(s): Mohammed Alasseiri, Afsar U. Ahmed, Bryan R.G. Williams Integrin-linked kinase (ILK) has emerged as a critical adaptor and mediator protein in cell signaling pathways that is commonly deregulated in acute myeloid leukemia (AML). This has led to the expectation that therapeutic targeting of ILK may be a useful option in treating leukemia. Although ILK can regulate many cellular processes, including cell differentiation, survival, migration, apoptosis and production of pro-inflammatory cytokines, its role in promoting AML is still unclear. However, its ability to mediate phosphorylation and regulate the important hematopoietic stem cell regulators protein kinase B (AKT) and glycogen synthase kinase-3β supports ILK as an attractive target for the development of novel anticancer therapeutics. In this review, we summarize the existing knowledge of ILK signaling and its impact on cytokines, paying particular attention to the relevance of ILK signaling in AML. We also discuss the rationale for targeting ILK in the treatment of AML and conclude with perspectives on the future of ILK-targeted therapy in AML. Graphical abstract
    Print ISSN: 1359-6101
    Electronic ISSN: 1359-6101
    Topics: Biology , Medicine
    Published by Elsevier
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  • 27
    Publication Date: 2018-06-09
    Description: Publication date: Available online 7 June 2018 Source: Developmental Biology Author(s): Christopher W. Williams, Jyoti Iyer, Yan Liu, Kevin F. O’Connell CDK11, a member of the cyclin-dependent kinase family, has been implicated in a diverse array of functions including transcription, RNA processing, sister chromatid cohesion, spindle assembly, centriole duplication and apoptosis. Despite its involvement in many essential functions, little is known about the requirements for CDK11 and its partner Cyclin L in a developing multicellular organism. Here we investigate the function of CDK11 and Cyclin L during development of the nematode Caenorhabditis elegans . Worms express two CDK11 proteins encoded by distinct loci: CDK-11.1 is essential for normal male and female fertility and is broadly expressed in the nuclei of somatic and germ line cells, while CDK-11.2 is nonessential and is enriched in hermaphrodite germ line nuclei beginning in mid pachytene. Hermaphrodites lacking CDK-11.1 develop normally but possess fewer mature sperm and oocytes and do not fully activate the RAS-ERK pathway that is required for oocyte production in response to environmental cues. Most of the sperm and eggs that are produced in cdk-11.1 null animals appear to complete development normally but fail to engage in sperm-oocyte signaling suggesting that CDK-11.1 is needed at multiple points in gametogenesis. Finally, we find that CDK-11.1 and CDK-11.2 function redundantly during embryonic and postembryonic development and likely do so in association with Cyclin L. Our results thus define multiple requirements for CDK-11- Cyclin L during animal development.
    Print ISSN: 0012-1606
    Electronic ISSN: 1095-564X
    Topics: Biology
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  • 28
    Publication Date: 2018-06-09
    Description: Publication date: August 2018 Source: European Journal of Cancer, Volume 99 Author(s): Stefania Gori, Fabio Puglisi, Michela Cinquini, Giovanni Pappagallo, Antonio Frassoldati, Laura Biganzoli, Laura Cortesi, Alba Fiorentino, Catia Angiolini, Corrado Tinterri, Andrea De Censi, Alessia Levaggi, Lucia Del Mastro Premenopausal women with hormone receptor-positive early breast cancer are candidates for adjuvant endocrine therapy, as recommended by the major international guidelines. To date, adjuvant endocrine options for premenopausal women include tamoxifen with or without ovarian function suppression (OFS) or an aromatase inhibitor with OFS. Multiple strategies for endocrine treatment of premenopausal women with hormone-responsive breast cancer have been assessed, and the results of randomised clinical trials have been reported over the last years. Despite this evidence, the optimal algorithm for endocrine therapy for premenopausal women with hormone receptor-positive early stage invasive breast cancer shows open questions regarding the role of OFS in addition to tamoxifen and the optimal use of hormonal agents. The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer applied the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology on three critical questions on the choice of the adjuvant hormonal therapy in premenopausal breast cancer patients to summarise available evidence and to create recommendations to help physicians in their clinical practice.
    Print ISSN: 0959-8049
    Electronic ISSN: 1879-0852
    Topics: Medicine
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  • 29
    Publication Date: 2018-05-27
    Description: Publication date: August 2018 Source: Biochemical Pharmacology, Volume 154 Author(s): Elham Khajehali, Celine Valant, Manuela Jörg, Andrew B. Tobin, P. Jeffrey Conn, Craig W. Lindsley, Patrick M. Sexton, Peter J. Scammells, Arthur Christopoulos Subtype-selective allosteric modulation of the M 1 muscarinic acetylcholine (ACh) receptor (M 1 mAChR) is an attractive approach for the treatment of numerous disorders, including cognitive deficits. The discovery of benzyl quinolone carboxylic acid, BQCA, a selective M 1 mAChR positive allosteric modulator (PAM), spurred the subsequent development of newer generation M 1 PAMs representing diverse chemical scaffolds, different pharmacodynamic properties and, in some instances, improved pharmacokinetics. Key exemplar molecules from such efforts include PF-06767832 ( N -((3 R ,4 S )-3-hydroxytetrahydro-2 H -pyran-4-yl)-5-methyl-4-(4-(thiazol-4-yl)benzyl)pyridine-2-carboxamide), VU6004256 (4,6-difluoro- N -(1 S ,2 S )-2-hydroxycyclohexyl-1-((6-(1-methyl-1 H -pyrazol-4-yl)pyridine-3-yl)methyl)-1 H -indole-3-carboxamide) and MIPS1780 (3-(2-hydroxycyclohexyl)-6-(2-((4-(1-methyl-1 H -pyrazol-4-yl)-benzyl)oxy)phenyl)pyrimidin-4(3 H )-one). Given these diverse scaffolds and pharmacodynamics, the current study combined pharmacological analysis and site-directed mutagenesis to explore the potential binding site and function of newer M 1 mAChR PAMs relative to BQCA. Interestingly, the mechanism of action of the novel PAMs was consistent with a common model of allostery, as previously described for BQCA. Key residues involved in the activity of BQCA, including Y179 in the second extracellular loop (ECL) and W400 7.35 in transmembrane domain (TM) 7, were critical for the activity of all PAMs tested. Overall, our data indicate that structurally distinct PAMs share a similar binding site with BQCA, specifically, an extracellular allosteric site defined by residues in TM2, TM7 and ECL2. These findings provide valuable insights into the structural basis underlying modulator binding, cooperativity and signaling at the M 1 mAChR, which is essential for the rational design of PAMs with tailored pharmacological properties. Graphical abstract
    Print ISSN: 0006-2952
    Electronic ISSN: 1873-2968
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 30
    Publication Date: 2018-05-27
    Description: Publication date: Available online 25 May 2018 Source: Biochimica et Biophysica Acta (BBA) - Biomembranes Author(s): Emma R. Moulton, Kelsey J. Hirsche, Monica L. Hobbs, J. Morgan Schwab, Elizabeth G. Bailey, John D. Bell At high temperature, the presence of cholesterol in phospholipid membranes alters the influence of membrane dipoles, including water molecules, on naphthalene-based fluorescent probes such as Laurdan and Patman (solvatochromism). Although both of these probes report identical changes to their emission spectra as a function of temperature in pure phosphatidylcholine bilayers, they differ in their response to cholesterol. Computer simulations of the spectra based on a simple model of solvatochromism indicated that the presence of cholesterol reduces the probability of bilayer dipole relaxation and also blunts the tendency of heat to enhance that probability. While the overall effect of cholesterol on membrane dipoles was detected identically by the two probes, Laurdan was influenced much more by the additional effect on temperature sensitivity than was Patman. A comparison of the fluorescence data with simulations using a coarse-grained bilayer model (de Meyer et al., 2010) suggested that these probes may be differentially sensitive to two closely related properties distinguishable in the presence of cholesterol. Specifically, Patman fluorescence correlated best with the average phospholipid acyl chain order. On the other hand, Laurdan fluorescence tracked more closely with the area per lipid molecule which, although affected generally by chain order, is also impacted by additional membrane-condensing effects of cholesterol. We postulate that this difference between Laurdan and Patman may be attributed to the bulkier charged headgroup of Patman which may cause the probe to preferentially locate in juxtaposition to the diminutive headgroup of cholesterol as the membrane condenses. Graphical abstract
    Print ISSN: 0005-2736
    Electronic ISSN: 1879-2642
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
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  • 31
    Publication Date: 2018-05-27
    Description: Publication date: 20 August 2018 Source: Gene, Volume 668 Author(s): Xiaodi Jiang, Xiaofeng Jiang, Zhi Yang Neurotrophin receptor-interacting melanoma antigen-encoding protein (NRAGE) is a type II melanoma-associated antigen that plays an essential role in various processes, including cell differentiation and apoptosis. NRAGE has been shown to act as a cancer-related protein, with complex and apparently contradictory functions in a variety of cancers. In the current study, we examined the expression of NRAGE protein in 169 gastric cancer samples. NRAGE upregulation was correlated with advanced TNM stage, local invasion, and poor survival. Importantly, NRAGE could serve as an independent prognostic factor in patients with gastric cancer. We also examined the expression of NRAGE protein in GES-1 normal gastric epithelial cells and in six gastric cancer cell lines. Inhibition of NRAGE expression by transfection with small interfering RNA reduced the proliferation and invasion of MGC-803 and HGC-27 cells, as demonstrated by CCK-8 and Matrigel invasion assays. NRAGE depletion also sensitized HGC-27 and MGC-803 cells to cisplatin, as shown by CCK-8 and Annexin V/propidium iodide analyses. Western blot analysis also showed that NRAGE depletion negatively regulated Bcl-2 and p-ERK and upregulated ZO-1 and p27 expression levels. In conclusion, our results suggest that NRAGE acts as a tumor promoter in gastric cancer by facilitating cancer invasion and chemoresistance, possibly through regulation of p-ERK and Bcl-2.
    Print ISSN: 0378-1119
    Electronic ISSN: 1879-0038
    Topics: Biology
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  • 32
    Publication Date: 2018-05-27
    Description: Publication date: 20 August 2018 Source: Gene, Volume 668 Author(s): Lijie Sheng, Jing Wu, Xuewu Gong, Duo Dong, Xiaoxue Sun Retinoblastoma (RB) is an intraocular malignancy for children and has a high mortality rate. Long non-coding RNAs (lncRNAs) are emerging as gene regulators and biomarkers in various malignancies. PANDAR is a novel cancer-related lncRNA that dysregulated in several types of cancers. However, its clinical value and potential effects on RB remains unclear. RT-qPCR was used to assess the relative expression of PANDAR in RB tissues and cells. Additionally, chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to investigate whether SP1 could bind to the promoter region of PANDAR and activate its transcription. Furthermore, in vitro and in vivo studies were induced to elucidate the biological functions of PANDAR. The results indicated that PANDAR was increased in RB tissues and cells, and this upregulation was associated with advanced IIRC stage, positive optic nerve invasion, and lower differentiation grade in RB patients. In addition, SP1 could bind directly to the PANDAR promoter region and activate its transcription. Furthermore, PANDAR silencing yielded tumor suppressive effects both in vitro and in vivo . Importantly, PANDAR protects against apoptosis partly by affecting Bcl-2/caspase-3 pathway. Ultimately, our work first illustrate that PANDAR plays an oncogenic role in RB and may offer a potential therapeutic target for treating this devastating disease.
    Print ISSN: 0378-1119
    Electronic ISSN: 1879-0038
    Topics: Biology
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  • 33
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    Elsevier
    Publication Date: 2018-06-09
    Description: Publication date: Available online 7 June 2018 Source: Current Biology Author(s): Ian S. Pearse, Ryan Paul, Paul J. Ode Defensive variability of crops and natural systems can alter herbivore communities and reduce herbivory [ 1, 2 ]. However, it is still unknown how defense variability translates into herbivore suppression. Nonlinear averaging and constraints in physiological tracking (also more generally called time-dependent effects) are the two mechanisms by which defense variability might impact herbivores [ 3, 4 ]. We conducted a set of experiments manipulating the mean and variability of a plant defense, showing that defense variability does suppress herbivore performance and that it does so through physiological tracking effects that cannot be explained by nonlinear averaging. While nonlinear averaging predicted higher or the same herbivore performance on a variable defense than on an invariable defense, we show that variability actually decreased herbivore performance and population growth rate. Defense variability reduces herbivore performance in a way that is more than the average of its parts. This is consistent with constraints in physiological matching of detoxification systems for herbivores experiencing variable toxin levels in their diet and represents a more generalizable way of understanding the impacts of variability on herbivory [ 5 ]. Increasing defense variability in croplands at a scale encountered by individual herbivores can suppress herbivory, even if that is not anticipated by nonlinear averaging. Teaser Pearse et al. find that defense variability reduces the performance of an herbivore. Their study suggests that constraints to physiological tracking explain the impact of variable defenses better than nonlinear averaging. These results hint at why plant communities with diverse defenses suffer less herbivore damage than agricultural monocultures.
    Print ISSN: 0960-9822
    Electronic ISSN: 1879-0445
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 34
    Publication Date: 2018-06-09
    Description: Publication date: Available online 7 June 2018 Source: Current Biology Author(s): Andrej Ondracka, Omaya Dudin, Iñaki Ruiz-Trillo Coordination of the cell division cycle with the growth of the cell is critical to achieve cell size homeostasis [ 1 ]. Mechanisms coupling the cell division cycle with cell growth have been described across diverse eukaryotic taxa [ 2–4 ], but little is known about how these processes are coordinated in organisms that undergo more complex life cycles, such as coenocytic growth. Coenocytes (multinucleate cells formed by sequential nuclear divisions without cytokinesis) are commonly found across the eukaryotic kingdom, including in animal and plant tissues and several lineages of unicellular eukaryotes [ 5 ]. Among the organisms that form coenocytes are ichthyosporeans, a lineage of unicellular holozoans that are of significant interest due to their phylogenetic placement as one of the closest relatives of animals [ 6 ]. Here, we characterize the coenocytic cell division cycle in the ichthyosporean Sphaeroforma arctica . We observe that, in laboratory conditions, S. arctica cells undergo a uniform and easily synchronizable coenocytic cell cycle, reaching up to 128 nuclei per cell before cellularization and release of daughter cells. Cycles of nuclear division occur synchronously within the coenocyte and in regular time intervals (11–12 hr). We find that the growth of cell volume is dependent on concentration of nutrients in the media; in contrast, the rate of nuclear division cycles is constant over a range of nutrient concentrations. Together, the results suggest that nuclear division cycles in the coenocytic growth of S. arctica are driven by a timer, which ensures periodic and synchronous nuclear cycles independent of the cell size and growth. Graphical abstract Teaser Ondracka et al. describe the highly regular and experimentally tractable coenocytic cell cycle of an ichthyosporean Sphaeroforma arctica , one of the closest unicellular relatives of animals. They show that the periodic nuclear division cycles are driven by a clock-like mechanism that operates independently of the cell size.
    Print ISSN: 0960-9822
    Electronic ISSN: 1879-0445
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 35
    Publication Date: 2018-06-09
    Description: Publication date: October 2018 Source: Current Opinion in Immunology, Volume 54 Author(s): William J Crisler, Laurel L Lenz Type I and type II interferons (IFNα/β and IFNγ) are cytokines that play indispensable roles in directing myeloid cell activity during inflammatory and immune responses. Each IFN type binds a distinct receptor (IFNAR or IFNGR) to transduce signals that reshape gene expression and function of myeloid and other cell types. In the context of murine models and human bacterial infections, production of IFNγ generally promotes resistance while production of IFNα/β is associated with increased host susceptibility. Here, we review mechanisms of crosstalk between type I and II IFNs in myeloid cells and their impact on myeloid cell activation and anti-microbial function.
    Print ISSN: 0952-7915
    Electronic ISSN: 1879-0372
    Topics: Biology , Medicine
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  • 36
    Publication Date: 2018-06-09
    Description: Publication date: 25 September 2018 Source: Gene, Volume 672 Author(s): Xuye Du, Huinan Wang, Jiefang He, Bin Zhu, Juan Guo, Wenqian Hou, Qingbei Weng, Xiaocun Zhang In graminaceous plants, nicotianamine (NA) is an important component of metal acquisition. NA is synthesized from S-adenosyl- l -methionine (SAM) catalyzed by nicotianamine synthase (NAS). Here, eight Triticum monococcum NAS ( TmNAS ) genes were cloned and characterized. Amino acid sequence analysis showed that TmNAS genes had high sequence identity with those from Triticum aestivum , Zea mays , Oryza sativa and Hordeum vulgare . Phylogenetic analysis showed that NAS genes were classified into two distinct groups, e.g. group I and group II. Expression analysis demonstrated that two of the TmNAS genes in group II were highly expressed in shoot tissues, and the other six TmNAS genes in group I were expressed in root tissues. Further analysis indicated that root-specific TmNAS genes were up-regulated under conditions of Fe- or Zn-deficiency growth, while shoot-specific TmNAS genes were up-regulated under conditions of Fe- or Zn-sufficiency. These results help us understand the NAS genes in T . monococcum and provide novel genetic resources for improving Fe and Zn concentrations in common wheat.
    Print ISSN: 0378-1119
    Electronic ISSN: 1879-0038
    Topics: Biology
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  • 37
    Publication Date: 2018-06-09
    Description: Publication date: Available online 8 June 2018 Source: Gynecologic Oncology Author(s): J. Michael Straughn, Teresa Boitano, Haller J. Smith, Sarah E. Dilley, Margaret I. Liang, Lea Novak A 32 year-old nulligravid woman with a uterine mass underwent exploratory laparotomy with myomectomy. Final pathology revealed a low-grade endometrial stromal sarcoma (ESS) with positive margins. She subsequently underwent definitive robotic hysterectomy and bilateral salpingectomy with ovarian preservation. She was diagnosed with a stage IB low-grade ESS. She is currently undergoing observation. Discussion of classification, surgical options, and adjuvant therapy is presented.
    Print ISSN: 0090-8258
    Electronic ISSN: 1095-6859
    Topics: Medicine
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  • 38
    Publication Date: 2018-06-09
    Description: Publication date: June 2018 Source: Heliyon, Volume 4, Issue 6 Author(s): Leandro De Lucca, Márcio da Costa Marques, Ilan Weinfeld Objectives This study aimed to evaluate the bone formation process in experimental defects created on rabbit calvarial, in which one of the bone defects was covered by the impermeable membrane before suturing the skin flap, while the other was closed only by the cutaneous flap. The experimental holes were filled only by the blood clot. Material and methods Sixteen New Zealand female rabbits weighing between 3.5 and 4 kg were used. Two experimental bone defects were made in the rabbit calvarial. The holes were filled only with the blood clot and one of them was covered with an impermeable polypropylene membrane. A histological analysis was made at 21 and 42 days following the surgery. Histological evaluation consisted of the following: 1. inflammatory process; 2. Bone repair; 3. Bone remodeling; 4. Presence of osteoid matrix and mineralization, and 5. Formation of hematopoietic tissue. Each characteristic was analyzed semi quantitatively. Results There was a statistical difference between the test and the control group at 21 days of healing in the following items: presence of cementation line (p = 0.012), presence of osteoid tissue (p = 0.012), and trabecular bone tissue development and mineralization (p = 0.012). A greater amount of lamellar bone tissue (mature) was also observed in the test group compared to the control group. Conclusion The semiquantitative analysis showed that at 21 days there was a superiority of the repair process in the test group; at 42 days there was no significant difference in bone formation between the two groups; and that the polypropylene membrane is feasible to be used in GBR. Clinical significance The impermeable polypropylene barrier is feasible for use in the guided bone regeneration technique. It can be used only on the blood clot, without the need for grafting, and can be easily removed a few days after surgery. These results are unprecedented.
    Electronic ISSN: 2405-8440
    Topics: Natural Sciences in General
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  • 39
    Publication Date: 2018-06-09
    Description: Publication date: Available online 8 June 2018 Source: Gynecologic Oncology Author(s): Pierre-Adrien Bolze, Mélodie Mathe, Touria Hajri, Benoit You, Yohann Dabi, Anne-Marie Schott, Sophie Patrier, Jérôme Massardier, François Golfier Background Low-risk gestational trophoblastic neoplasia (GTN) patients (FIGO score ≤6) are generally treated with single agent chemotherapy (methotrexate or dactinomycin) resulting in a 5-year mortality rate of 0.3%. However, despite these encouraging survival rates, chemotherapy is associated with significant adverse events in most patients. Although it is generally accepted that patients who no longer wish to conceive may be treated by hysterectomy for a hydatidiform mole, the evidence to support this strategy in low-risk GTN patients is lacking. Objectives To describe the survival, efficacy, and tolerance associated with first-line hysterectomy in low-risk non-metastatic GTN patients. Study design. Seventy-four of 1072 low-risk GTN patients treated in the French Center underwent first-line hysterectomy. Patients data with successful first-line hysterectomy were retrospectively compared to those requiring further salvage chemotherapy. Results First-line hysterectomy was followed by hCG normalization in 61 patients (82.4%, 95% confidence interval [CI] 71.8–90.3) without any further salvage chemotherapy, whereas 13 patients required salvage chemotherapy. After multivariate analysis, a FIGO score of 5–6 (exact OR 8.961, 95%CI 1.60–64.96), and the presence of choriocarcinoma (exact OR 14.295, 95%CI 1.78–138.13) were associated with the risk of requiring salvage chemotherapy. Conclusion Hysterectomy as a first-line treatment is effective without salvage chemotherapy in 82.4% of women with low-risk non-metastatic GTN and can be presented as an alternative to single-agent chemotherapy when childbearing considerations have been fulfilled. In young patients, this therapeutic option should not be considered because single-agent chemotherapies are curative in nearly 100% of patients while maintaining fertility.
    Print ISSN: 0090-8258
    Electronic ISSN: 1095-6859
    Topics: Medicine
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  • 40
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    Elsevier
    Publication Date: 2018-05-27
    Description: Publication date: July 2018 Source: Journal of Structural Biology, Volume 203, Issue 1
    Print ISSN: 1047-8477
    Electronic ISSN: 1095-8657
    Topics: Biology
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  • 41
    Publication Date: 2018-06-09
    Description: Publication date: Available online 8 June 2018 Source: International Journal of Radiation Oncology*Biology*Physics Author(s): Jared H. Hara, Ashley Wu, Javier E. Villanueva-Meyer, Gilmer Valdes, Vikas Daggubati, Sabine Mueller, Timothy D. Solberg, Steve E. Braunstein, Olivier Morin, David R. Raleigh Objectives To investigate the prognostic utility of quantitative three-dimensional (3D) magnetic resonance imaging (MRI) radiomic analysis for primary pediatric embryonal brain tumors Methods Thirty-four pediatric embryonal brain tumor patients with concurrent pre-operative T1-weighted post contrast (T1PG) and T2-weighted fluid-attenuated inversion recovery (FLAIR) MR images were identified from an institutional database. The median follow-up was 5.2 years. Radiomic features were extracted from axial T1PG and FLAIR contours using MATLAB, and 15 features were selected for analysis based on qualitative radiographic features with prognostic significance for pediatric embryonal brain tumors. Logistic regression, linear regression, receiver operating characteristic curve, Harrell’s C index and Somer’s D index were used to test the relationships between radiomic features, demographic variables and clinical outcomes. Results We found that pediatric embryonal brain tumors in older patients had increased normalized mean tumor intensity (P=0.05, T1PG), decreased tumor volume (P=0.02, T1PG) and increased markers of heterogeneity (P≤0.01, T1PG and FLAIR) relative to younger patients. We identified 10 quantitative radiomic features that delineated between medulloblastoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, including size and heterogeneity (P≤0.05, T1PG and FLAIR). Decreased markers of tumor heterogeneity were predictive of neuraxis metastases and trended towards significance (P=0.1, FLAIR). Tumors with increased size (AUC=0.7, FLAIR) and decreased heterogeneity (AUC=0.7, FLAIR) at diagnosis were more likely to recur. Conclusions Quantitative radiomic features are associated with pediatric embryonal brain tumor patient age, histology, neuraxis metastases and recurrence. These data suggest that quantitative 3D MRI radiomic analysis has the non-invasive potential to identify radiomic risk features for pediatric embryonal brain tumor patients. Teaser The relationship between clinical outcomes and imaging characteristics of pediatric embryonal brain tumors is poorly understood. Here, we analyze embryonal brain tumor magnetic resonance images to identify quantitative radiomic features associated with clinical outcomes. Our results demonstrate that features quantifying primary tumor size and heterogeneity are associated with patient age, neuraxis metastases, histology and recurrence. These data suggest that 3D MRI analysis has the non-invasive potential to identify radiomic risk features for pediatric embryonal brain tumor patients.
    Print ISSN: 0360-3016
    Electronic ISSN: 1879-355X
    Topics: Medicine
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  • 42
    Publication Date: 2018-06-09
    Description: Publication date: Available online 8 June 2018 Source: Journal of Magnetic Resonance Author(s): Pavlo Bielytskyi, Daniel Gräsing, Kaustubh R. Mote, Karthick Babu Sai Sankar Gupta, Shimon Vega, P.K. Madhu, A. Alia, Jörg Matysik In the present study, we exploit the light-induced hyperpolarization occurring on 13 C nuclei due to the solid-state photochemically induced dynamic nuclear polarization (photo-CIDNP) effect to boost the NMR signal intensity of selected protons via inverse cross-polarization. Such hyperpolarization transfer is implemented into 1 H-detected two-dimensional 13 C- 1 H correlation magic-angle-spinning (MAS) NMR experiment to study protons in frozen photosynthetic reaction centers (RCs). As a first trial, the performance of such an experiment is tested on selectively 13 C labeled RCs from the purple bacteria of Rhodobacter sphaeroides. We observed response from the protons belonging to the photochemically active cofactors in their native protein environment. Such an approach is a potential heteronuclear spin-torch experiment which could be complementary to the classical heteronuclear correlation (HETCOR) experiments for mapping proton chemical shifts of photosynthetic cofactors and to understand the role of the proton pool around the electron donors in the electron transfer process occurring during photosynthesis. Graphical abstract
    Print ISSN: 1090-7807
    Electronic ISSN: 1096-0856
    Topics: Medicine , Physics
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  • 43
    Publication Date: 2018-06-09
    Description: Publication date: Available online 8 June 2018 Source: Journal of Molecular Biology Author(s): Sarah L. Rouse, Fisentzos Stylianou, H.Y. Grace Wu, Jamie-Lee Berry, Lee Sewell, R. Marc L. Morgan, Andrea C. Sauerwein, Steve Matthews Gram-negative bacteria possess specialised biogenesis machineries that facilitate the export of amyloid subunits, the fibres of which are key components of their biofilm matrix. The secretion of bacterial functional amyloid requires a specialised outer-membrane protein channel through which unfolded amyloid substrates are translocated. We previously reported the crystal structure of the membrane-spanning domain of the amyloid subunit transporter FapF from Pseudomonas . However, the structure of the periplasmic domain, which is essential for amyloid transport, is yet to be determined. Here, we present the crystal structure of the N-terminal periplasmic domain at 1.8 Å resolution. This domain forms a novel asymmetric trimeric coiled-coil that possesses a single buried tyrosine residue as well as a extensive hydrogen-bonding network within a glutamine layer. This new structural insight allows us to understand this newly described functional amyloid secretion system in greater detail. Graphical abstract
    Print ISSN: 0022-2836
    Electronic ISSN: 1089-8638
    Topics: Biology
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  • 44
    Publication Date: 2018-06-09
    Description: Publication date: Available online 8 June 2018 Source: Journal of Molecular Biology Author(s): Jimin Pei, Lisa N. Kinch, Nick V. Grishin Abstract Genomes of metazoan organisms possess a large number of genes encoding cell surface and secreted (CSS) proteins that carry out crucial functions in cell adhesion and communication, signal transduction, extracellular matrix establishment, nutrient digestion and uptake, immunity, and developmental processes. We developed the FlyXCDB database (http://prodata.swmed.edu/FlyXCDB) that provides a comprehensive resource to investigate extracellular (XC) domains in CSS proteins of Drosophila melanogaster , the most studied insect model organism in various aspects of animal biology. More than three hundred Drosophila XC domains were discovered in Drosophila CSS proteins encoded by over 2,500 genes through analyses of computational predictions of signal peptide, transmembrane (TM) segment, and GPI-anchor signal sequence, profile-based sequence similarity searches, gene ontology, and literature. These domains were classified into six classes mainly based on their molecular functions, including protein-protein interactions (class P), signaling molecules (class S), binding of non-protein molecules or groups (class B), enzyme homologs (class E), enzyme regulation and inhibition (class R), and unknown molecular function (class U). Main cellular functions such as cell adhesion, cell signaling and extracellular matrix composition were described for the most abundant domains in each functional class. We assigned cell membrane topology categories (E - secreted; S - type I/III single-pass TM; T - type II single-pass TM; M - multi-pass TM; and G - GPI-anchored) to the products of genes with XC domains and investigated their regulation by mechanisms such as alternative splicing and stop codon readthrough. Graphical abstract
    Print ISSN: 0022-2836
    Electronic ISSN: 1089-8638
    Topics: Biology
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  • 45
    Publication Date: 2018-06-09
    Description: Publication date: Available online 8 June 2018 Source: Journal of Molecular Biology Author(s): Lina Nilsson, Annelie Pamrén, Tohidul Islam, Kristoffer Brännström, Solmaz A. Golchin, Nina Pettersson, Irina Iakovleva, Linda Sandblad, Anna L. Gharibyan, Anders Olofsson The pathological Aβ aggregates associated with Alzheimer’s disease follow a nucleation-dependent path of formation. A nucleus represents an oligomeric assembly of Aβ peptides that acts as a template for subsequent incorporation of monomers to form a fibrillar structure. Nuclei can form de novo or via surface-catalyzed secondary nucleation, and the combined rates of elongation and nucleation control the overall rate of fibril formation. Transthyretin (TTR) obstructs Aβ fibril formation in favor of alternative non-fibrillar assemblies, but the mechanism behind this activity is not fully understood. This study shows that TTR does not significantly disturb fibril elongation; rather, it effectively interferes with the formation of oligomeric nuclei. We demonstrate that this interference can be modulated by altering the relative contribution of elongation and nucleation, and we show how TTR’s effects can range from being essentially ineffective to almost complete inhibition of fibril formation without changing the concentration of TTR or monomeric Aβ. Graphical abstract
    Print ISSN: 0022-2836
    Electronic ISSN: 1089-8638
    Topics: Biology
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  • 46
    Publication Date: 2018-06-09
    Description: Publication date: Available online 7 June 2018 Source: Molecular Immunology Author(s): Chunguang Yan, Chunmin Deng, Xiufang Liu, Yutong Chen, Jiawei Ye, Rentian Cai, Yanfei Shen, Huifang Tang Although participation of IL-6 in lung inflammation has been widely elucidated, the transcriptional regulation of its generation in alveolar type II cells stimulated by TNF-α remain unclear. Here, we find that TNF-α significantly induces IL-6 production, and TNF-α induction of IL-6 is mainly regulated at transcriptional level. Upon stimulated by TNF-α, Activator Protein-1 (AP-1)-mediated transcriptional activity is apparently increased in alveolar type II epithelial cells, which might be derived from elevated phosphorylation of JNK and subsequent activation of c-Jun. Either down-regulation of c-Jun or the AP-1 site mutation leads to significant reduction of IL-6 expression. In contrast, ectopic expression of c-Jun notably increases IL-6 generation. So, c-Jun, one of the AP-1 family members, plays a pivotal role in TNF-α-induced IL-6 generation. CCAAT/enhancer binding protein δ (C/EBPδ) expression is significantly amplified by TNF-α, which may contribute to the rise of C/EBP activity in alveolar type II cells. C/EBPδ shRNA treatment results in attenuation of IL-6 expression in the cells, which is consistent with data by introduction of mutations into the C/EBP site in the promoter. However, overexpression of C/EBPδ greatly increases the IL-6 promoter activity. In addition, data regarding another transactivator in the family—C/EBPβ show that it does not affect IL-6 production. We also find that the IKK/NF-κB p65 pathway is activated in TNF-α-treated alveolar type II epithelial cells, and plays an essential role in positive regulation of IL-6 expression in TNF-α-treated alveolar type II epithelial cells via knockdown or forced expression of NF-κB p65, or elimination of κB sites in the IL-6 promoter. Notably, IL-6 promoter-driven luciferase production in primary alveolar type II epithelial cells can also be increased by the ectopic expression of c-Jun, C/EBPδ, and NF-κB p65, respectively. Collectively, our data provide insights into molecular mechanism involved in IL-6 expression in alveolar type II epithelial cells on TNF-α treatment, which provides a theoretical basis for specific inhibition of IL-6 production at the transcriptional level.
    Print ISSN: 0161-5890
    Electronic ISSN: 1872-9142
    Topics: Medicine
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  • 47
    Publication Date: 2018-06-10
    Description: Publication date: September 2018 Source: Biomaterials, Volume 177 Author(s): Ruijing Liang, Lanlan Liu, Huamei He, Zhikuan Chen, Zhiqun Han, Zhenyu Luo, Zhihao Wu, Mingbing Zheng, Yifan Ma, Lintao Cai Metastatic triple-negative breast cancer (mTNBC) is an aggressive disease among women worldwide, characterized by high mortality and poor prognosis despite systemic therapy with radiation and chemotherapies. Photodynamic therapy (PDT) is an important strategy to eliminate the primary tumor, however its therapeutic efficacy against metastases and recurrence is still limited. Here, we employed a template method to develop the core-shell gold nanocage@manganese dioxide (AuNC@MnO 2 , AM) nanoparticles as tumor microenvironment responsive oxygen producers and near-infrared (NIR)-triggered reactive oxygen species (ROS) generators for oxygen-boosted immunogenic PDT against mTNBC. In this platform, MnO 2 shell degrades in acidic tumor microenvironment pH/H 2 O 2 conditions and generates massive oxygen to boost PDT effect of AM nanoparticles under laser irradiation. Fluorescence (FL)/photoacoustic (PA)/magnetic resonance (MR) multimodal imaging confirms the effective accumulation of AM nanoparticles with sufficient oxygenation in tumor site to ameliorate local hypoxia. Moreover, the oxygen-boosted PDT effect of AM not only destroys primary tumor effectively but also elicits immunogenic cell death (ICD) with damage-associated molecular patterns (DAMPs) release, which subsequently induces DC maturation and effector cells activation, thereby robustly evoking systematic antitumor immune responses against mTNBC. Hence, this oxygen-boosted immunogenic PDT nanosystem offers a promising approach to ablate primary tumor and simultaneously prevent tumor metastases via immunogenic abscopal effects. Graphical abstract
    Print ISSN: 0142-9612
    Electronic ISSN: 1878-5905
    Topics: Biology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Medicine
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  • 48
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    Elsevier
    Publication Date: 2018-06-09
    Description: Publication date: Available online 7 June 2018 Source: Structure Author(s): Alvin Yu, Albert Y. Lau At central nervous system synapses, agonist binding to postsynaptic ionotropic glutamate receptors (iGluRs) results in signaling between neurons. N-Methyl-D-aspartic acid (NMDA) receptors are a unique family of iGluRs that activate in response to the concurrent binding of glutamate and glycine. Here, we investigate the process of agonist binding to the GluN2A (glutamate binding) and GluN1 (glycine binding) NMDA receptor subtypes using long-timescale unbiased molecular dynamics simulations. We find that positively charged residues on the surface of the GluN2A ligand-binding domain (LBD) assist glutamate binding via a “guided-diffusion” mechanism, similar in fashion to glutamate binding to the GluA2 LBD of AMPA receptors. Glutamate can also bind in an inverted orientation. Glycine, on the other hand, binds to the GluN1 LBD via an “unguided-diffusion” mechanism, whereby glycine finds its binding site primarily by random thermal fluctuations. Free energy calculations quantify the glutamate- and glycine-binding processes. Graphical abstract Teaser In the N-methyl-D-aspartic acid receptor family of ionotropic glutamate receptors, the agonist glutamate and its co-agonist glycine bind to their respective subunits by different dynamic mechanisms. Glutamate binding is assisted by structural features on the receptor surface. Glycine binding does not receive such assistance.
    Print ISSN: 0969-2126
    Electronic ISSN: 1878-4186
    Topics: Biology , Medicine
    Published by Elsevier on behalf of Cell Press.
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  • 49
    Publication Date: 2018-06-09
    Description: Publication date: Available online 7 June 2018 Source: Structure Author(s): Jose K. James, Douglas H. Pike, I. John Khan, Vikas Nanda To what extent do structural and biophysical features of food allergen proteins distinguish them from other proteins in our diet? Invertebrate tropomyosins (Tpms) as a class are considered “pan-allergens,” inducing food allergy to shellfish and respiratory allergy to dust mites. Vertebrate Tpms are not known to elicit allergy or cross-reactivity, despite their high structural similarity and sequence identity to invertebrate homologs. We expect allergens are sufficiently stable against gastrointestinal proteases to survive for immune sensitization in the intestines, and that proteolytic stability will correlate with thermodynamic stability. Thermal denaturation of shrimp Tpm shows that it is more stable than non-allergen vertebrate Tpm. Shrimp Tpm is also more resistant to digestion. Molecular dynamics uncover local dynamics that select epitopes and global differences in flexibility between shrimp and pig Tpm that discriminate allergens from non-allergens. Molecular determinants of allergenicity depend not only on sequence but on contributions of protein structure and dynamics. Graphical abstract Teaser Predictive models that anticipate new food allergens based on sequence homology to existing allergens do not perform well on the shellfish allergen tropomyosin, which shares high identity with non-allergenic vertebrate forms. Instead, allergens are discriminated from non-allergens by biophysical properties and structural dynamics.
    Print ISSN: 0969-2126
    Electronic ISSN: 1878-4186
    Topics: Biology , Medicine
    Published by Elsevier on behalf of Cell Press.
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  • 50
    Publication Date: 2018-06-10
    Description: Publication date: Available online 7 June 2018 Source: Genomics Author(s): Wai-Mun Leong, Adiratna Mat Ripen, Hoda Mirsafian, Saharuddin Bin Mohamad, Amir Feisal Merican High-depth next generation sequencing data provide valuable insights into the number and distribution of RNA editing events. Here, we report the RNA editing events at cellular level of human primary monocyte using high-depth whole genomic and transcriptomic sequencing data. We identified over a ten thousand putative RNA editing sites and 69% of the sites were A-to-I editing sites. The sites enriched in repetitive sequences and intronic regions. High-depth sequencing datasets revealed that 90% of the canonical sites were edited at lower frequencies (〈0.7). Single and multiple human monocytes and brain tissues samples were analyzed through genome sequence independent approach. The later approach was observed to identify more editing sites. Monocytes was observed to contain more C-to-U editing sites compared to brain tissues. Our results establish comparable pipeline that can address current limitations as well as demonstrate the potential for highly sensitive detection of RNA editing events in single cell type.
    Print ISSN: 0888-7543
    Electronic ISSN: 1089-8646
    Topics: Biology , Medicine
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  • 51
    Publication Date: 2018-06-10
    Description: Publication date: Available online 8 June 2018 Source: The International Journal of Biochemistry & Cell Biology Author(s): Hai-Bin Cui, Huai-E Ge, Yong-Sen Wang, Xi-Yong Bai The present studies have identified that microRNAs function as regulators in different diseases including cancers. However, the expression patterns and underlying molecular mechanisms of miR-208a involved in gastric cancer (GC) remain little known. In the study, our results demonstrated that miR-208a expression was significantly increased in GC tissues compared with adjacent normal tissues by performing qRT-PCR. Higher miR-208a expression was association with lymph node metastasis and TNM stage in GC patients. Kaplan-Meier analysis verified that patients with higher miR-208a expression were significantly associated with shorter overall survival (OS) time. Univariate and multivariate Cox analysis revealed that lymph node metastasis, TNM stage and higher miR-208a were independent risks factors of OS time. Ectopic expression of miR-208a by treatment with miR-208a mimic promoted cell proliferation and invasion abilities, but downregulation of miR-208a by treatment with miR-208a inhibitor had an opposite effects. Furthermore, we identified specific targeting sites for miR-208a in the 3’-untranslated region (3’-UTR) of the SFRP1 gene by dual-luciferase reporter assay. Upregulation of MiR-208a promoted cell proliferation and invasion by suppressing SFRP1 expression in GC cells. Moreover, dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and qRT-PCR analysis demonstrated that miR-208a targeted MEG3 and negatively regulated MEG3 expression in GC cells. Thus, these data indicated that miR-208a promoted GC progression by targeting SFRP1 and negatively regulating MEG3, which may be a potential therapeutic target of GC.
    Print ISSN: 1357-2725
    Electronic ISSN: 1878-5875
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 52
    Publication Date: 2018-06-10
    Description: Publication date: Available online 8 June 2018 Source: International Journal of Radiation Oncology*Biology*Physics Author(s): Richard Li, Ashwin Shinde, Yi-Jen Chen, Arya Amini, Stephen Lee, Thanh Dellinger, Ernest Han, Mark Wakabayashi, Rebecca Nelson, Sushil Beriwal, Scott Glaser Purpose We evaluated the utilization of brachytherapy (BT) in addition to external beam radiation therapy (EBRT) and the resulting impact on survival in patients with cervical cancer after hysterectomy with positive surgical margins. Methods and Materials Patients with cervical cancer diagnosed from 2004 to 2015 who underwent hysterectomy followed by adjuvant EBRT were identified using the National Cancer Data Base. Only patients with positive surgical margins were included for analysis. Logistic regression was used to evaluate predictors of BT utilization and for propensity score matching. Survival was compared between patients receiving EBRT alone and EBRT combined with BT for adjuvant treatment. Survival analysis using log-rank test and Cox proportional hazards modeling was performed in the overall and propensity score-matched cohorts. Results We identified 1,719 patients who received hysterectomy with positive surgical margins followed by adjuvant radiation therapy, of which 778 patients (45.3%) received additional BT. Predictors of increased receipt of BT included age > 55 years, private rather than government insurance, radiation treatment duration ≥7 weeks, external beam radiation dose ≥4500 cGy, and time between radiation and surgery ≤9 weeks. With a median follow-up of 3.8 years, 3-year overall survival was 79.4% in patients receiving BT compared to 71.9% in patients receiving EBRT alone (log-rank p〈0.001). On multivariate analysis, EBRT and BT was associated with significantly improved survival (hazard ratio 0.77; 95% confidence interval 0.64-0.92; p=0.003) compared to EBRT alone. The survival benefit of combining EBRT and BT persisted on propensity score-matched analysis (log-rank p=0.005). Conclusions In women with positive margins after hysterectomy for cervical cancer, the combination of EBRT and BT showed significantly improved overall survival compared to EBRT alone. However, only 45.3% of patients in our cohort received BT. Teaser We analyzed a cohort of patients from the National Cancer Database who underwent hysterectomy for cervical cancer with positive surgical margins followed by adjuvant radiation therapy. We found that the addition of brachytherapy to external beam radiation therapy was associated with improved overall survival compared to external beam radiation therapy alone. However, only 45% of patients in this cohort received brachytherapy.
    Print ISSN: 0360-3016
    Electronic ISSN: 1879-355X
    Topics: Medicine
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  • 53
    Publication Date: 2018-06-10
    Description: Publication date: Available online 8 June 2018 Source: The International Journal of Biochemistry & Cell Biology Author(s): Rui Jiang, Chunming Zhao, Binbin Gao, Jiawen Xu, Wei Song, Peng Shi Objective This study aimed at finding the long non-coding RNA (lncRNA), miRNA and mRNA which played critical roles in breast cancer (BrCa) by using mixOmics R package. Method The BrCa dataset were obtained from TCGA and then analyzed using "DESeq2" R package. Multivariate analyses were performed with the "mixOmics" R package and the first component of the stacked partial least-Squares discriminant analysis results were used for searching the interested lncRNA, miRNA and mRNA. qRT-PCR was applied to identify the bioinformatics results in four BrCa cell lines (MCF7, BT-20, ZR-75-1, and MX-1) and the breast epithelial cell line MCF-10 A. Then cells (MCF-1 and MX-1) were transfected with si-linc01561, miR-145-5p mimics and si- MMP11 to further investigate the effects of linc01561, miR-145-5p and MMP11 on the BrCa cells proliferation and apoptosis. Results MixOmics results showed that linc01561, miR-145-5p and MMP11 might play important roles in BrCa. qRT-PCR results identified that in BrCa cell lines, linc01561 and MMP11 were higher expressed while miR-145-5p was lower expressed compared with those in epithelial cell line. The linc01561 inhibition elevated miR-145-5p expression and then suppressed MMP11 expression. Moreover, linc01561 inhibition suppressed the BrCa cells proliferation and promoted the apoptosis, which was realized by up-regulating expression of miR-145-5p and down-regulating expression of MMP11 . Conclusion In summary, the findings of this study, based on ceRNA theory, combining the research foundation of miR-145-5p and MMP11 , and taking linc01561 as a new study point, provide new insight into molecular-level reversing proliferation and apoptosis of BrCa.
    Print ISSN: 1357-2725
    Electronic ISSN: 1878-5875
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 54
    Publication Date: 2018-06-09
    Description: Publication date: 27 June 2018 Source: Vaccine, Volume 36, Issue 28 Author(s): Hannah C. Moore, Parveen Fathima, Heather F. Gidding, Nicholas de Klerk, Bette Liu, Vicky Sheppeard, Paul V. Effler, Thomas L. Snelling, Peter McIntyre, Christopher C. Blyth Reported infant vaccination coverage at age 12 months in Australia is >90%. On-time coverage of the 2–4–6 month schedule and coverage in specific populations is rarely reported. We conducted a population-based cohort study of 1.9 million Australian births, 1996–2012, combining individual birth and perinatal records with immunisation records through probabilistic linkage. We assessed on-time coverage across 13 demographic and perinatal characteristics of diphtheria-tetanus-pertussis vaccines (DTP) defined as vaccination 14 days prior to the scheduled due date, to 30 days afterwards. On-time DTP vaccination coverage in non-Aboriginal infants was 88.1% for the 2-month dose, 82.0% for 4-month dose, and 76.7% for 6-month dose; 3-dose coverage was 91.3% when assessed at 12 months. On-time DTP coverage for Aboriginal infants was 77.0%, 66.5%, and 61.0% for the 2–4–6 month dose; 3-dose coverage at 12 months was 79.3%. Appreciable differences in on-time coverage were observed across population subgroups. On-time coverage in non-Aboriginal infants born to mothers with ≥3 previous pregnancies was 62.5% for the 6-month dose (47.9% for Aboriginal infants); up to 23.5 percentage points lower than for first-borns. Infants born to mothers who smoked during pregnancy had coverage 8.7–10.3 percentage points lower than infants born to non-smoking mothers for the 4- and 6-month dose. A linear relationship was apparent between increasing socio-economic disadvantage and decreasing on-time coverage. On-time coverage of the 2–4–6 month schedule is only 50–60% across specific population subgroups representing a significant avoidable public health risk. Aboriginal infants, multiparous mothers, and those who are socio-economically disadvantaged are key groups most likely to benefit from targeted programs addressing vaccine timeliness.
    Print ISSN: 0264-410X
    Topics: Medicine
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  • 55
    Publication Date: 2018-06-09
    Description: Publication date: 27 June 2018 Source: Vaccine, Volume 36, Issue 28 Author(s): Karen Mulligan, Julia Thornton Snider, Phyllis Arthur, Gregory Frank, Mahlet Tebeka, Amy Walker, Jason Abrevaya Background Immunization against numerous potentially life-threatening illnesses has been a great public health achievement. In the United States, the Vaccines for Children (VFC) program has provided vaccines to uninsured and underinsured children since the early 1990s, increasing vaccination rates. In recent years, some states have adopted Universal Purchase (UP) programs with the stated aim of further increasing vaccination rates. Under UP programs, states also purchase vaccines for privately-insured children at federally-contracted VFC prices and bill private health insurers for the vaccines through assessments. Methods In this study, we estimated the effect of UP adoption in a state on children’s vaccination rates using state-level and individual-level data from the 1995–2014 National Immunization Survey. For the state-level analysis, we performed ordinary least squares regression to estimate the state’s vaccination rate as a function of whether the state had UP in the given year, state demographic characteristics, other vaccination policies, state fixed effects, and a time trend. For the individual analysis, we performed logistic regression to estimate a child’s likelihood of being vaccinated as a function of whether the state had UP in the given year, the child’s demographic characteristics, state characteristics and vaccine policies, state fixed effects, and a time trend. We performed separate regressions for each of nine recommended vaccines, as well as composite measures on whether a child was up-to-date on all required vaccines. Results In the both the state-level and individual-level analyses, we found UP had no significant (p 〈 0.10) effect on any of the vaccines or composite measures in our base case specifications. Results were similar in alternative specifications. Conclusions We hypothesize that UP was ineffective in increasing vaccination rates. Policymakers seeking to increase vaccination rates would do well to consider other policies such as addressing provider practice issues and vaccine hesitancy.
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    Topics: Medicine
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  • 56
    Publication Date: 2018-06-09
    Description: Publication date: 27 June 2018 Source: Vaccine, Volume 36, Issue 28 Author(s): Jing Xia, Xiao He, Li-Jing Du, Yue-Yue Liu, Guo-Jin You, Shu-Yun Li, Ping Liu, San-Jie Cao, Xin-Feng Han, Yong Huang Avian infectious bronchitis (IB) is a highly contagious disease, and hazardous to the poultry industry. Immune failure often occurs due to the emergence of new serotypes or field strains antigenically different from the vaccine strains. To prepare a candidate vaccine against the prevalent avian infectious bronchitis virus (IBV) in China, the GI-19/QX-like field isolate Sczy3 was selected as the progenitor strain and attenuated via passaging in chicken embryo kidney (CEK) cells for 100 times. The 100th generation of CEK-adapted strain, designated SczyC100, was safe to use on one-day old specific pathogen-free (SPF) chicken as determined by pathogenicity and virulence reversion test. The efficacies of SczyC100 and two commonly used commercial vaccines (H120 and 4/91) against prevalent GI-19/QX and GI-7/TWI type virulent strains were evaluated. Sczy3C100 effectively reduced the morbidity, mortality, mean lesion scores (MLSs), and viral load of trachea of chickens challenged by GI-19/QX and GI-7/TWI strains. CEK-adapted SczyC100 is therefore a potential vaccine candidate for the control of IB in China.
    Print ISSN: 0264-410X
    Topics: Medicine
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  • 57
    Publication Date: 2018-06-09
    Description: Publication date: August 2018 Source: Virology, Volume 521 Author(s): Tian-Pei Guan, Jade L.L. Teng, Kai-Yan Yeong, Zhang-Qiang You, Hao Liu, Samson S.Y. Wong, Susanna K.P. Lau, Patrick C.Y. Woo The Sichuan takin inhabits the bamboo forests in the Eastern Himalayas and is considered as a national treasure of China with the highest legal protection and conservation status considered as vulnerable according to The IUCN Red List of Threatened Species. In this study, fecal samples of 71 Sichuan takins were pooled and deep sequenced. Among the 103,553 viral sequences, 21,961 were assigned to mammalian viruses. De novo assembly revealed genomes of an enterovirus and an astrovirus and contigs of circoviruses and genogroup I picobirnaviruses. Complete genome sequencing and phylogenetic analysis showed that Sichuan takin enterovirus is a novel serotype/genotype of the species Enterovirus G , with evidence of recombination. Sichuan takin astrovirus is a new subtype of bovine astrovirus, probably belonging to a new genogroup in the genus Mamastrovirus. Further studies will reveal whether these viruses can also be found in Mishmi takin and Shaanxi takin and their pathogenic potentials.
    Print ISSN: 0042-6822
    Electronic ISSN: 1096-0341
    Topics: Medicine
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  • 58
    Publication Date: 2018-06-09
    Description: Publication date: 27 June 2018 Source: Vaccine, Volume 36, Issue 28 Author(s): Tyler A. Garretson, Joshua G. Petrie, Emily T. Martin, Arnold S. Monto, Scott E. Hensley Human influenza viruses passaged in eggs often acquire mutations in the hemagglutinin (HA) receptor binding site (RBS). To determine if egg-adapted H1N1 vaccines commonly elicit antibodies targeting the egg-adapted RBS of HA, we completed hemagglutinin-inhibition assays with A/California/7/2009 HA and egg-adapted A/California/7/2009-X-179A HA using sera collected from 159 humans vaccinated with seasonal influenza vaccines during the 2015–16 season. We found that ∼5% of participants had ≥4-fold higher antibody titers to the egg-adapted viral strain compared to wild type viral strain. We used reverse-genetics to demonstrate that a single egg-adapted HA RBS mutation (Q226R) was responsible for this phenotype.
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    Topics: Medicine
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  • 59
    Publication Date: 2018-06-09
    Description: Publication date: 27 June 2018 Source: Vaccine, Volume 36, Issue 28 Author(s): Wei Zhang, Huiying Sun, Mohammad Atiquzzaman, Julie Sou, Aslam H. Anis, Curtis Cooper Background People with Human Immunodeficiency Virus (HIV) are highly susceptible to influenza-related morbidity and mortality. In order to assess comparative efficacy of influenza vaccine strategies among HIV-positive people, we performed a systematic review and Bayesian network meta-analysis (NMA). Methods In this systematic review, we searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL between 1946 and July 2015 for randomized controlled trials (RCTs) on influenza vaccines for HIV-positive adults reporting seroconversion or seroprotection outcomes. The NMAs were conducted within a Bayesian framework and logistic models were used for comparing the effect of the vaccine strategies on the two outcomes. Results A total of 1957 publications were identified, 143 were selected for full review, and 13 RCTs were included in our final analysis. Fourteen separate NMAs were conducted by outcomes, vaccine strain, and different outcome measurement timepoints. For example, compared with the 15 μg single vaccine strategy, the odds ratio was the highest for the adjuvant 7.5 μg booster strategy (2.99 [95% credible interval 1.18–7.66]) when comparing seroconversion for H1N1 at 14–41 days after the last dose of vaccination and for the 60 μg single strategy (2.33 [1.31–4.18]) when comparing seroconversion for strain B. Conclusions The adjuvant 7.5 μg booster and 60 μg single vaccine strategies provided better seroconversion and seroprotection outcomes. These findings have important implications for national and international guidelines for influenza vaccination for HIV-positive people and future research.
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    Topics: Medicine
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  • 60
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    Elsevier
    Publication Date: 2018-06-10
    Description: Publication date: 7 June 2018 Source: The American Journal of Human Genetics, Volume 102, Issue 6 Author(s): Sarah Ratzel, Sara B. Cullinan
    Print ISSN: 0002-9297
    Electronic ISSN: 1537-6605
    Topics: Biology , Medicine
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  • 61
    Publication Date: 2018-06-10
    Description: Publication date: Available online 8 June 2018 Source: The American Journal of Medicine Author(s): Massimo Leggio, Augusto Fusco, Paolo Severi, Massimo Armeni, Stefania D'Emidio, Elisa Caldarone, Mario Lombardi, Maria Grazia Bendini, Andrea Mazza
    Print ISSN: 0002-9343
    Electronic ISSN: 1555-7162
    Topics: Medicine
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  • 62
    Publication Date: 2018-06-11
    Description: Publication date: Available online 9 June 2018 Source: Immunology Letters Author(s): Chenlu Liu, Zhenzhen Lu, Yu Xie, Qianqian Guo, Fei Geng, Bo Sun, Hui Wu, Bin Yu, Jiaxin Wu, Haihong Zhang, Xianghui Yu, Wei Kong Soluble PD-1 (sPD1) can bind with ligands PD-L1/PD-L2 on the surface of dendritic cells (DCs). Therefore, a sPD1 vaccine fused with an immunogen can increase T cell activation against cancer. Here, we constructed a MUC1 and survivin (MS) combination gene tumor vaccine expressing MS fused with soluble PD-1 (sPD1/MS). To investigate whether the sPD1/MS fusion vaccine could enhance tumor-specific immune responses, its immunogenicity and anti-tumor activity were examined after intramuscular immunization in mice. Compared with the MS DNA vaccine, the specific cytolysis rate of the sPD1/MS fusion DNA vaccine was increased by from 21.64% to 34.77%. Moreover, the sPD1/MS vaccine increased the tumor suppression rate from 17.18% to 30.96% and prolonged survival from 6.96% to 19.44% in a murine colorectal cancer model. Combining the sPD1/MS vaccine with oxaliplatin improved the tumor suppression rate to 74.71% in the murine colorectal cancer model. The sPD1/MS vaccine could also exert a good anti-tumor effect, increasing the tumor infiltrated CD8 + T cells by 6.5-fold (from 0.10% to 0.65%) in the murine lung cancer model. In conclusion, the sPD1/MS vaccine showed good immunogenicity and anti-tumor effect by activating lymphocytes effectively.
    Print ISSN: 0165-2478
    Electronic ISSN: 1879-0542
    Topics: Medicine
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  • 63
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    Elsevier
    Publication Date: 2018-06-11
    Description: Publication date: Available online 9 June 2018 Source: Advances in Cancer Research Author(s): Clayton S. Lewis, Christina Voelkel-Johnson, Charles D. Smith Sphingosine kinases (SK1 and SK2) are key, druggable targets within the sphingolipid metabolism pathway that promote tumor growth and pathologic inflammation. A variety of isozyme-selective and dual inhibitors of SK1 and SK2 have been described in the literature, and at least one compound has reached clinical testing in cancer patients. In this chapter, we will review the rationale for targeting SKs and summarize the preclinical and emerging clinical data for ABC294640 as the first-in-class selective inhibitor of SK2.
    Electronic ISSN: 0065-230X
    Topics: Medicine
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  • 64
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    Elsevier
    Publication Date: 2018-06-10
    Description: Publication date: Available online 8 June 2018 Source: Trends in Cell Biology Author(s): Veronica Ortiz, Min Yu Whole-genome sequencing has made a significant impact on cancer research, but traditional bulk methods fail to detect information from rare cells. Recently developed single-cell sequencing methods have provided new insights and unprecedented details about cancer progression and diversity. These advancements also enable the investigation of rare cells, such as circulating tumor cells (CTCs) derived from cancer patients. In this review, we outline various single-cell sequencing techniques that can elucidate the molecular properties of CTCs. In addition, we explain the drawbacks that need to be overcome for each method.
    Print ISSN: 0962-8924
    Electronic ISSN: 1879-3088
    Topics: Biology , Medicine
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  • 65
    Publication Date: 2018-06-11
    Description: Publication date: 25 August 2018 Source: Biochemical and Biophysical Research Communications, Volume 502, Issue 4 Author(s): Amanda Tomie Ouchida, Merve Kacal, Adi Zheng, Gorbatchev Ambroise, Boxi Zhang, Erik Norberg, Helin Vakifahmetoglu-Norberg Epithelial-to-mesenchymal transition (EMT) is a fundamental mechanism governing the switch of cells from an epithelial to a motile mesenchymal-like state. This transdifferentiation is regulated by key transcription factors, including Slug. The stability and function of Slug can be regulated by multiple mechanisms, including ubiquitin-mediated post-translational modifications. Here, by using a genome wide siRNA screen for human deubiquitinating enzymes (DUBs), we identified USP10 as a deubiquitinase for Slug in cancer cells. USP10 interacts with Slug and mediates its degradation by the proteasome. Importantly, USP10 is concomitantly highly expressed with Slug in cancer biopsies. Genetic knockdown of USP10 leads to suppressed Slug levels with a decreased expression of the mesenchymal marker Vimentin. Further, it reduces the migratory capacity of cancer cells. Reversely, overexpression of USP10 elevates the level of both Slug and Vimentin. Our study identifies USP10 as a regulator of the EMT-transcription factor Slug and cell migration.
    Print ISSN: 0006-291X
    Electronic ISSN: 1090-2104
    Topics: Biology , Chemistry and Pharmacology , Physics
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  • 66
    Publication Date: 2018-06-11
    Description: Publication date: Available online 9 June 2018 Source: Advances in Cancer Research Author(s): Ahmed Elsherbini, Erhard Bieberich Exosomes are secreted extracellular vesicles (EVs) that carry micro RNAs and other factors to reprogram cancer cells and tissues affected by cancer. Exosomes are exchanged between cancer cells and other tissues, often to prepare a premetastatic niche, escape immune surveillance, or spread multidrug resistance. Only a few studies investigated the function of lipids in exosomes although their lipid composition is different from that of the secreting cells. Ceramide is one of the lipids critical for exosome formation, and it is also enriched in these EVs. New research suggests that lipids in the exosomal membrane may organize and transmit “mobile rafts” that turn exosomes into extracellular signalosomes spreading activation of cell signaling pathways in oncogenesis and metastasis. Ceramide may modulate the function of mobile rafts and their effect on these cell signaling pathways. The critical role of lipids and, in particular, ceramide for formation, secretion, and function of exosomes may lead to a radically new understanding of cancer biology and therapy.
    Electronic ISSN: 0065-230X
    Topics: Medicine
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  • 67
    Publication Date: 2018-06-11
    Description: Publication date: 25 August 2018 Source: Biochemical and Biophysical Research Communications, Volume 502, Issue 4 Author(s): Joaquín Rojas, Gabriel Castillo, Lorenzo Eugenio Leiva, Sara Elgamal, Omar Orellana, Michael Ibba, Assaf Katz It is widely believed that if a high number of genes are found for any tRNA in a rapidly replicating bacteria, then the cytoplasmic levels of that tRNA will be high and an open reading frame containing a higher frequency of the complementary codon will be translated faster. This idea is based on correlations between the number of tRNA genes, tRNA concentration and the frequency of codon usage observed in a limited number of strains as well as from the fact that artificially changing the number of tRNA genes alters translation efficiency and consequently the amount of properly folded protein synthesized. tRNA gene number may greatly vary in a genome due to duplications, deletions and lateral transfer which in turn would alter the levels and functionality of many proteins. Such changes are potentially deleterious for fitness and as a result it is expected that changes in tRNA gene numbers should be accompanied by a modification of the frequency of codon usage. In contrast to this model, when comparing the number of tRNA genes and the frequency of codon usage of several Salmonella enterica and Escherichia coli strains we found that changes in the number of tRNA genes are not correlated to changes in codon usage. Furthermore, these changes are not correlated with a change in the efficiency of codon translation. These results suggest that once a genome gains or loses tRNA genes, it responds by modulating the concentrations of tRNAs rather than modifying its frequency of codon usage.
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    Topics: Biology , Chemistry and Pharmacology , Physics
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  • 68
    Publication Date: 2018-06-11
    Description: Publication date: 25 August 2018 Source: Biochemical and Biophysical Research Communications, Volume 502, Issue 4 Author(s): Qiang Liu, Wei Hu, Yong-Li Zhang, Shou-Ping Hu, Zhuo Zhang, Xi-Jun He, Xue-Hui Cai Both the lung and the thymus are vital target organ for pathogens including viruses. The immunoproteasome (i-proteasome) enhances antigen presentation for MHC class I molecules to activate CD8+T lymphocyte. These facilitate antiviral adaptive immune response. Our previous study found that, expression of i-proteasome subunits in porcine lung was altered during normal and inflammatory conditions. To date, the expression of i-proteasome subunits in porcine thymus to viruses has not been investigated. In the present study, LMP2, LMP7, and MECL-1 were cloned, identified and their sequences encoded predicted proteins of 216, 275, and 278 amino acids, respectively. Expression of LMP2, LMP7, and MECL-1, in the cytoplasm and nucleus, was markedly altered in the porcine reproductive and respiratory syndrome virus (PRRSV)-infected lung and thymus. And dendritic cells and epithelial cells readily expressed the i-proteasome subunit LMP2 in the thymus of PRRSV-infected pigs compared to that in mock-infected pigs. Additionally, the in vitro stimulation of a PAM cell line with PolyI:C for 12 and 24 h resulted in increased LMP2, LMP7, and MECL-1 expression. These results suggest a central role for these complexes in the activation of an antiviral immune response in pigs. A better understanding of the role of the i-proteasome in different cell types, tissues, and hosts could improve vaccine design and facilitate the development of effective treatment strategies for viral infections.
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    Topics: Biology , Chemistry and Pharmacology , Physics
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  • 69
    Publication Date: 2018-06-11
    Description: Publication date: 25 August 2018 Source: Biochemical and Biophysical Research Communications, Volume 502, Issue 4 Author(s): Dongling Sun, Wei Rou, Yinghui Zhou, Tao Zhuo, Xiaojing Fan, Xun Hu, Huasong Zou Xanthomonas citri subsp. citri ( Xcc ) is the causal agent of citrus canker, a serious bacterial disease that affects citrus trees worldwide. The ectopic expression of TAL effector AvrXa7 in Xcc suppressed canker development. The Xcc strain expressing avrXa7 induced a yellow symptom around the inoculation site. Transcriptome analysis revealed 315 differentially expressed genes, which were categorized into several functional groups. The more interesting genes were those involved in the biosynthesis of terpene and ethylene. In particular, the linoleate 13 S-lipoxygenase gene CsLOX2-1 was found to possess the AvrXa7 binding sequence in the promoter region. The recognition of AvrXa7 to the CsLOX2-1 promoter was subsequently confirmed by yeast one-hybrid and electrophoretic mobility shift experiments. This demonstrated that the TALE effector AvrXa7 promotes CsLOX2-1 expression by directly binding to the promoter sequence. Our findings contribute a valuable clue to identifying the potential genes that can be used to prevent citrus canker. Graphical abstract
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  • 70
    Publication Date: 2018-06-11
    Description: Publication date: 25 August 2018 Source: Biochemical and Biophysical Research Communications, Volume 502, Issue 4 Author(s): Zhen Wu, Wangping Shi, Chendi Jiang Circular RNAs (circRNAs) are a novel class of noncoding RNAs, whose importance in cancer has been gradually acknowledged. However, the functions of circRNAs in tumorigenesis have not been fully understood. In the present study, we identified a novel circRNA hsa_circ_0002052 significantly downregulated in osteosarcoma (OS) tissues and cell lines. Moreover, we found that hsa_circ_0002052 could act as a biomarker to indicate the prognosis of OS patients. Functionally, we showed that hsa_circ_0002052 overexpression significantly suppressed OS cell proliferation, migration and invasion while promoting apoptosis in vitro . Similarly, in vivo assay indicated that ectopic expression of hsa_circ_0002052 impaired OS cell growth. In terms of mechanism, we found that hsa_circ_0002052 inhibited miR-1205 while miR1205 targeted APC2, a negative regulator of Wnt/β-catenin signaling pathway. By releasing the inhibition of miR-1205 on APC2 expression, hsa_circ_0002052 suppressed the activation of Wnt/β-catenin signaling pathway, leading to attenuated OS progression. Taken together, our study for the first time revealed a suppressive circRNA hsa_circ_0002052 involved in OS progression. Our study suggested hsa_circ_0002052/miR-1205/APC2/Wnt/β-catenin axis might be a potential target for OS therapy.
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    Topics: Biology , Chemistry and Pharmacology , Physics
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  • 71
    Publication Date: 2018-06-11
    Description: Publication date: 25 August 2018 Source: Biochemical and Biophysical Research Communications, Volume 502, Issue 4 Author(s): Jiqin Liu, Dangli Ren, Zhenhua Du, Hekong Wang, Hua Zhang, Ying Jin N 6 -Methyladenosine (m 6 A) represents the most prevalent internal modification in mammalian mRNAs. Emerging evidences suggest that m 6 A modification is profoundly implicated in many biological processes, including cancer development. However, limited knowledge is available about the functional importance of m 6 A in lung cancer. In this study, by data mining The Cancer Genome Atlas (TCGA) database, we first identified fat mass- and obesity-associated protein (FTO) as a prognostic factor for lung squamous cell carcinoma (LUSC). Then we showed that FTO, but not other m 6 A modification genes including METTL3, METTL14 and ALKBH5, was the major dysregulated factor responsible for aberrant m 6 A modification in LUSC. Loss-of-function studies suggested that FTO knockdown effectively inhibited cell proliferation and invasion, while promoted cell apoptosis of L78 and NCI-H520 cells. Furthermore, overexpression of FTO, but not its mutant form, facilitated the malignant phenotypes of CHLH-1 cells. Mechanistically, FTO enhanced MZF1 expression by reducing m 6 A levels and mRNA stability in MZF1 mRNA transcript, leading to oncogenic functions. Taken together, our study demonstrates the functional importance of FTO in the tumor progression of LUSC and provides a potential therapeutic target for LUSC treatment.
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  • 72
    Publication Date: 2018-06-11
    Description: Publication date: 25 August 2018 Source: Biochemical and Biophysical Research Communications, Volume 502, Issue 4 Author(s): Wei Wu, Juli Liu, Zhenghui Su, Zhonghao Li, Ning Ma, Ke Huang, Tiancheng Zhou, Linli Wang Neural conversion from human pluripotent cells (hPSCs) is a potential therapy to neurological disease in the future. However, this is still limited by efficiency and stability of existed protocols used for neural induction from hPSCs. To overcome this obstacle, we developed a reporter system to screen PAX6 + neural progenitor/stem cells using transcription activator like effector nuclease (TALEN). We found that knock-in 2 A-EGFP cassette into PAX6 exon of human embryonic stem cells H1 with TALEN-based homology recombination could establish PAX6 WT/EGFP H1 reporter cell line fast and efficiently. This reporter cell line could differentiate into PAX6 and EGFP double positive neural progenitor/stem cells (NPCs/NSCs) after neural induction. Those PAX6 WT/EGFP NPCs could be purified, expanded and specified to post-mitotic neurons in vitro efficiently. With this reporter cell line, we also screened out 1 NPC-specific microRNA, hsa-miR-99a-5p, and 3 ESCs-enriched miRNAs, hsa-miR-302c-5p, hsa-miR-512–3p and hsa-miR-518 b. In conclusion, the TALEN-based neural stem cell screening system is safe and efficient and could help researcher to acquire adequate and pure neural progenitor cells for further application.
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    Topics: Biology , Chemistry and Pharmacology , Physics
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  • 73
    Publication Date: 2018-06-11
    Description: Publication date: 25 August 2018 Source: Biochemical and Biophysical Research Communications, Volume 502, Issue 4 Author(s): Lei Yang, Dawei Ge, Xi Chen, Junjun Qiu, Zhaowei Yin, Shengnai Zheng, Chunzhi Jiang Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. LncRNA has been confirmed to participate in a variety of cancers. The purpose of this study was to explore the effect of FOXP4-AS1 on the development of osteosarcoma (OS) and its underlying mechanism. FOXP4-AS1 expressions in 60 OS tissues and paracancerous tissues were detected by qRT-PCR (quantitative real-time polymerase chain reaction). We confirmed that FOXP4-AS1 was overexpressed in OS tissues than that of paracancerous tissues. The disease-free survival and overall survival of OS patients were not correlated with age, gender and tumor location, but remarkably correlated with FOXP4-AS1 expression, tumor size and lung metastasis. For in vitro experiments, MG63 cells expressed a higher expression of FOXP4-AS1, whereas U2OS cells expressed a lower expression, which were selected for the following studies. Overexpressed FOXP4-AS1 led to enhanced proliferation, migration and invasion, shortened G0/G1 phase, as well as inhibited cell cycle. Knockdown of FOXP4-AS1 in MG63 cells obtained the opposite results. Furthermore, RIP assay indicated that FOXP4-AS1 could inhibit LATS1 expression by binding to LSD1 and EZH2, so as to participate in OS development. In conclusion, these results revealed that FOXP4-AS1 is overexpressed in OS, and is the independent risk factor in OS prognosis. Upregulated FOXP4-AS1 promotes the proliferation, migration and cell cycle, but inhibits apoptosis of OS cells. Furthermore, FOXP4-AS1 participates in the development and progression of OS by downregulating LATS1 via binding to LSD1 and EZH2.
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  • 74
    Publication Date: 2018-06-12
    Description: Publication date: 11 June 2018 Source: Cancer Cell, Volume 33, Issue 6 Author(s): Debanjan Dhar, Laura Antonucci, Hayato Nakagawa, Ju Youn Kim, Elisabeth Glitzner, Stefano Caruso, Shabnam Shalapour, Ling Yang, Mark A. Valasek, Sooyeon Lee, Kerstin Minnich, Ekihiro Seki, Jan Tuckermann, Maria Sibilia, Jessica Zucman-Rossi, Michael Karin How fully differentiated cells that experience carcinogenic insults become proliferative cancer progenitors that acquire multiple initiating mutations is not clear. This question is of particular relevance to hepatocellular carcinoma (HCC), which arises from differentiated hepatocytes. Here we show that one solution to this problem is provided by CD44, a hyaluronic acid receptor whose expression is rapidly induced in carcinogen-exposed hepatocytes in a STAT3-dependent manner. Once expressed, CD44 potentiates AKT activation to induce the phosphorylation and nuclear translocation of Mdm2, which terminates the p53 genomic surveillance response. This allows DNA-damaged hepatocytes to escape p53-induced death and senescence and respond to proliferative signals that promote fixation of mutations and their transmission to daughter cells that go on to become HCC progenitors. Graphical abstract Teaser Dhar et al. show that CD44 expression induced in carcinogen-exposed hepatocytes potentiates AKT signaling to activate Mdm2, which terminates the p53 genomic surveillance response. This allows DNA-damaged hepatocytes to respond to proliferative signals, leading their daughter cells to become HCC progenitors.
    Print ISSN: 1535-6108
    Electronic ISSN: 1878-3686
    Topics: Medicine
    Published by Elsevier on behalf of Cell Press.
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  • 75
    Publication Date: 2018-06-12
    Description: Publication date: Available online 11 June 2018 Source: International Journal of Radiation Oncology*Biology*Physics Author(s): M.A. Palacios, O. Bohoudi, A.M.E. Bruynzeel, J.R. van Sörnsen-de Koste, P. Cobussen, B.J. Slotman, F.J. Lagerwaard, S. Senan Purpose To study inter-fractional organ changes during MR-guided stereotactic ablative radiotherapy (SABR) for adrenal metastases and to evaluate the dosimetric advantages of online plan adaptation. Methods and Materials Seventeen patients underwent a total of 84 fractions of video-assisted, respiration-gated MR-guided adaptive radiotherapy to deliver either 50 Gy (5 fractions), 60 Gy (8 fractions) or 24 Gy (3 fractions). An MR scan was repeated prior to each fraction, followed by rigid co-registration to the GTV on the pre-treatment MR scan. Contour deformation, PTV (GTV+3mm) expansion and online plan re-optimization were then performed. Re-optimized plans were compared to baseline treatment plans recalculated on the anatomy-of-the-day (‘predicted plans’). Inter-fractional changes in OARs were quantified according to OAR volume changes within a 3 cm distance from PTV surface, centre of mass (COM) displacements and the Dice Similarity Coefficient (DSC). Plan quality evaluation was based on target coverage (GTV and PTV), and also high dose sparing of all OARs (V 36Gy , V 33Gy and V 25Gy ). Results Substantial COM displacements were observed for stomach, bowel and duodenum of 17, 27 and 36 mm, respectively. Maximum volume changes for the stomach, bowel and duodenum within 3 cm of PTV were 23.8, 20.5 and 20.9 cc, respectively. DSC values for OARs ranged from 0.0 to 0.9 for all fractions. Baseline plans recalculated on anatomy-of-the-day revealed underdosage of target volumes, and variable OAR sparing, leading to a failure to meet institutional constraints in a third of fractions. Online re-optimization improved target coverage in 63% of fractions, and reduced the number of fractions not meeting the V 95% objective for GTV and PTV. Re-optimized plans exhibited significantly better sparing of OAR. Conclusions Significant inter-fractional changes in OARs positions were observed despite breath-hold SABR delivery under MR-guidance. Online re-optimization of treatment plans led to significant improvements in target coverage and OAR sparing. Teaser Stereotactic ablative radiotherapy (SABR) delivered during shallow inspiration breath-hold under MR-guidance, was implemented for adrenal gland metastases. We studied inter-fractional changes in GTV and OARs, and also the role of online plan re-optimization in ensuring both adequate target coverage and OAR sparing. Online plan adaptation led to improved target coverage in 63% of treatment fractions, and significantly reduced OAR doses. Our results indicate that online plan adaptation is beneficial in adrenal SABR.
    Print ISSN: 0360-3016
    Electronic ISSN: 1879-355X
    Topics: Medicine
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  • 76
    Publication Date: 2018-06-12
    Description: Publication date: Available online 11 June 2018 Source: International Journal of Radiation Oncology*Biology*Physics Author(s): Robert Olson, Matthew Chan, Neelam Minhas, Gurkirat Kandola, Manpreet Tiwana, Shilo Lefresne, Ross Halperin, Devin Schellenberg, Elaine Wai, Nissar Ahmed, Scott Tyldesley Purpose There is ample evidence that single fraction radiation therapy (SFRT) is equally efficacious as more costly and morbid multi-fraction regimens. We previously demonstrated that an audit-based intervention increased the use of SFRT in all regional cancer centers the year following. However, other investigators have demonstrated interventions were only associated with a transient one-year change in prescribing practices. We sought to determine if our intervention resulted in a more lasting impact. Methods In 2012 we performed an audit of prescribing practices of individual physicians, which were then presented to leaders and oncologists as an intervention to increase SFRT. We then compared the use of SFRT from 2007-2011 (pre-intervention) and 2013-2016 (post-intervention) in all 31,192 patients treated in our provincial program. Results The use of SFRT increased from 49.2% to 58.9% post intervention (p〈0.001), with rates in 2007-2011 of 51, 51, 48, 49, and 48%, while post intervention in 2013-2016 they were 60, 62, 59, and 56%. Post intervention, half of the centers prescribed SFRT in a relatively narrow range (55-58%). However, across all centers, there was still a broad range, with the lowest and highest users at 35% and 81% respectively, though the lowest utilizing center still showed a significant increase (26% to 35%; p 〈0.001). Conclusion Our audit and educational based intervention resulted in a lasting and meaningful 10% change in practice. Our provincial rate is similar to a previously recommended benchmark rate of 60%, though we continue to see significant variation by center, suggesting further room for improvement in provincial standardization. With emerging evidence in support of ablative radiotherapy for select populations of patients with bone metastases, future benchmark rates of SFRT should be readdressed, though our data suggest programmatic comparison and dissemination of SFRT prescribing practices can achieve a population-based SFRT utilization rate near 60%. Teaser After an audit-based educational intervention in our population-based provincial radiotherapy program, we demonstrate a lasting and meaningful 10% increase in the prescription of SFRT for bone metastases. Other jurisdictions should consider using similar programmatic audit-based educational approaches in an effort to increase the use of this cost-effective treatment which has been historically used well below evidence-based benchmarks internationally. Our data suggests that the benchmark of 60% use of SFRT for bone metastases is feasible.
    Print ISSN: 0360-3016
    Electronic ISSN: 1879-355X
    Topics: Medicine
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  • 77