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  • 1
    Publication Date: 2018-11-08
    Description: Cerebral cavernous malformation (CCM) is a common cerebrovascular disease that can occur sporadically or be inherited. They are major causes of stroke, cerebral hemorrhage, and neurological deficits in the younger population. Loss-of-function mutations in three genes, CCM1 , CCM2 , and CCM3 , have been identified as the cause of human CCMs. Currently, no drug is available to treat CCM disease. Hyperactive mitogen-activated protein kinase kinase Kinase 3 (MEKK3) kinase signaling as a consequence of loss of CCM genes is an underlying cause of CCM lesion development. Using a U.S. Food and Drug Administration–approved kinase inhibitor library combined with virtual modeling and biochemical and cellular assays, we have identified a clinically approved small compound, ponatinib, that is capable of inhibiting MEKK3 activity and normalizing expression of downstream kruppel-like factor (KLF) target genes. Treatment with this compound in neonatal mouse models of CCM can prevent the formation of new CCM lesions and reduce the growth of already formed lesions. At the ultracellular level, ponatinib can normalize the flattening and disorganization of the endothelium caused by CCM deficiency. Collectively, our study demonstrates ponatinib as a novel compound that may prevent CCM initiation and progression in mouse models through inhibition of MEKK3-KLF signaling.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of food science 70 (2005), S. 0 
    ISSN: 1750-3841
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Process Engineering, Biotechnology, Nutrition Technology
    Notes: : Our objective was to understand the film-forming characteristics of amylose, amylopectin, and high-amylose (55%) starch solutions at ambient environment. By using an inverted phase-contrast microscope connected to an imaging system, we were able to record and analyze the micro structural evolution of starch throughout the process of film formation. The results of image analysis suggested that the coil-to-helix transition, followed by the helices aggregation, dominated the initial stage of starch film formation from solutions, although the time when these phenomena occurred depended on the amylose content. Fresh amylose films exhibited an assembly of giant dendrites with quarternary branches. In contrast, amylopectin films showed a structure of networked clusters. Interestingly, the high-amylose (55%) starch film showed a heterogeneous structure with both amylose-rich and amylopectin-rich phases, which are integrated seamlessly by the intermolecular interaction between amylose and amylopectin.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The relative stability of and barrier to interconversion of the two possible intermediates in the electrophilic addition of iodine to ethylene have been studied by means of ab initio molecular calculations with pseudopotential approximations. The geometries of the 2-iodoethyl and ethylene iodonium cations have been optimized by the energy gradient technique with pseudopotential approximations. From the results of the calculations, it is found that the only possible intermediate is the cyclic ethylene iodonium ion, as shown by experiments.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
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  • 4
    Publication Date: 2018-08-16
    Description: Seven new cucurbitane glucosides, hemslepensides J-P ( 1 – 7 ), and two known compounds, 16,25- O -diacetyl-cucurbitane F ( 8 ) and 25- O -acetyl-23,24-dihydrocucurbitacin F ( 9 ), were isolated from the tubers of Hemsleya pengxianensis var. jinfushanensis . The structures of 1 – 7 were elucidated using infrared absorption spectroscopy, nuclear magnetic resonance spectroscopy and high-resolution electrospray ionization mass spectrometry. The treatment of HT29 cells, human colon cancer cells, with compounds 8 and 9 inhibited cell proliferation. Further study demonstrated that compounds 8 and 9 induced F-actin aggregation, G 2 /M phase cell cycle arrest and cell apoptosis in HT29 cells. In summary, the present study enriched the chemical composition research of H. pengxianensis , and suggested that the compounds 8 / 9 treatment may be a potentially useful therapeutic option for colon cancer.
    Keywords: medicinal chemistry, plant science
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 5
    Publication Date: 2018-08-17
    Description: Hepatitis delta virus (HDV) ribozyme performs the self-cleavage activity through folding to a double pseudoknot structure. The folding of functional RNA structures is often coupled with the transcription process. In this work, we developed a new approach for predicting the cotranscriptional folding kinetics of RNA secondary structures with pseudoknots. We theoretically studied the cotranscriptional folding behavior of the 99-nucleotide (nt) HDV sequence, two upstream flanking sequences, and one downstream flanking sequence. During transcription, the 99-nt HDV can effectively avoid the trap intermediates and quickly fold to the cleavage-active state. It is different from its refolding kinetics, which folds into an intermediate trap state. For all the sequences, the ribozyme regions (from 1 to 73) all fold to the same structure during transcription. However, the existence of the 30-nt upstream flanking sequence can inhibit the ribozyme region folding into the active native state through forming an alternative helix Alt1 with the segments 70–90. The longer upstream flanking sequence of 54 nt itself forms a stable hairpin structure, which sequesters the formation of the Alt1 helix and leads to rapid formation of the cleavage-active structure. Although the 55-nt downstream flanking sequence could invade the already folded active structure during transcription by forming a more stable helix with the ribozyme region, the slow transition rate could keep the structure in the cleavage-active structure to perform the activity.
    Print ISSN: 1355-8382
    Electronic ISSN: 1469-9001
    Topics: Biology , Medicine
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  • 6
    Publication Date: 2018-06-16
    Description: Mimicking subcellular compartments containing enzymes in organisms is considered a promising approach to substitute for missing or lost cellular functions. Inspired by the multicompartment structures of cellular architectures, we present a novel multienzyme system based on hollow hydrogel microcapsules with flexible enzymatic inverse opal particles. Benefiting from the precise operation capability of the microfluidic electrospray and the remarkable structural color marks in the inverse opal particles, we developed a multienzyme system with controllable number, type, and spatial arrangement of the encapsulated enzymes. The hydrogel shells also could improve enzyme stability against proteolysis in the system. The multienzyme system containing alcohol oxidase and catalase could act as a cascade biocatalyst and reduce alcohol levels in media, providing an alternative antidote and prophylactic for alcohol intoxication. These features indicated that our strategy provides an ideal enzyme cascade reaction system for complex biocatalysis and biomimetic functions of some organelles or organs.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 7
    Publication Date: 2012-06-23
    Description: The shell structure of atomic nuclei is associated with 'magic numbers' and originates in the nearly independent motion of neutrons and protons in a mean potential generated by all nucleons. During beta(+)-decay, a proton transforms into a neutron in a previously not fully occupied orbital, emitting a positron-neutrino pair with either parallel or antiparallel spins, in a Gamow-Teller or Fermi transition, respectively. The transition probability, or strength, of a Gamow-Teller transition depends sensitively on the underlying shell structure and is usually distributed among many states in the neighbouring nucleus. Here we report measurements of the half-life and decay energy for the decay of (100)Sn, the heaviest doubly magic nucleus with equal numbers of protons and neutrons. In the beta-decay of (100)Sn, a large fraction of the strength is observable because of the large decay energy. We determine the largest Gamow-Teller strength so far measured in allowed nuclear beta-decay, establishing the 'superallowed' nature of this Gamow-Teller transition. The large strength and the low-energy states in the daughter nucleus, (100)In, are well reproduced by modern, large-scale shell model calculations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hinke, C B -- Bohmer, M -- Boutachkov, P -- Faestermann, T -- Geissel, H -- Gerl, J -- Gernhauser, R -- Gorska, M -- Gottardo, A -- Grawe, H -- Grebosz, J L -- Krucken, R -- Kurz, N -- Liu, Z -- Maier, L -- Nowacki, F -- Pietri, S -- Podolyak, Zs -- Sieja, K -- Steiger, K -- Straub, K -- Weick, H -- Wollersheim, H-J -- Woods, P J -- Al-Dahan, N -- Alkhomashi, N -- Atac, A -- Blazhev, A -- Braun, N F -- Celikovic, I T -- Davinson, T -- Dillmann, I -- Domingo-Pardo, C -- Doornenbal, P C -- de France, G -- Farrelly, G F -- Farinon, F -- Goel, N -- Habermann, T C -- Hoischen, R -- Janik, R -- Karny, M -- Kaskas, A -- Kojouharov, I M -- Kroll, Th -- Litvinov, Y -- Myalski, S -- Nebel, F -- Nishimura, S -- Nociforo, C -- Nyberg, J -- Parikh, A R -- Prochazka, A -- Regan, P H -- Rigollet, C -- Schaffner, H -- Scheidenberger, C -- Schwertel, S -- Soderstrom, P-A -- Steer, S J -- Stolz, A -- Strmen, P -- England -- Nature. 2012 Jun 20;486(7403):341-5. doi: 10.1038/nature11116.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Physik Department E12, Technische Universitat Munchen, D-85748 Garching, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722192" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2013-02-08
    Description: According to the Milankovitch theory, changes in summer insolation in the high-latitude Northern Hemisphere caused glacial cycles through their impact on ice-sheet mass balance. Statistical analyses of long climate records supported this theory, but they also posed a substantial challenge by showing that changes in Southern Hemisphere climate were in phase with or led those in the north. Although an orbitally forced Northern Hemisphere signal may have been transmitted to the Southern Hemisphere, insolation forcing can also directly influence local Southern Hemisphere climate, potentially intensified by sea-ice feedback, suggesting that the hemispheres may have responded independently to different aspects of orbital forcing. Signal processing of climate records cannot distinguish between these conditions, however, because the proposed insolation forcings share essentially identical variability. Here we use transient simulations with a coupled atmosphere-ocean general circulation model to identify the impacts of forcing from changes in orbits, atmospheric CO(2) concentration, ice sheets and the Atlantic meridional overturning circulation (AMOC) on hemispheric temperatures during the first half of the last deglaciation (22-14.3 kyr BP). Although based on a single model, our transient simulation with only orbital changes supports the Milankovitch theory in showing that the last deglaciation was initiated by rising insolation during spring and summer in the mid-latitude to high-latitude Northern Hemisphere and by terrestrial snow-albedo feedback. The simulation with all forcings best reproduces the timing and magnitude of surface temperature evolution in the Southern Hemisphere in deglacial proxy records. AMOC changes associated with an orbitally induced retreat of Northern Hemisphere ice sheets is the most plausible explanation for the early Southern Hemisphere deglacial warming and its lead over Northern Hemisphere temperature; the ensuing rise in atmospheric CO(2) concentration provided the critical feedback on global deglaciation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Feng -- Shakun, Jeremy D -- Clark, Peter U -- Carlson, Anders E -- Liu, Zhengyu -- Otto-Bliesner, Bette L -- Kutzbach, John E -- England -- Nature. 2013 Feb 7;494(7435):81-5. doi: 10.1038/nature11822.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Climatic Research, Nelson Institute for Environmental Studies, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA. fenghe@wisc.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23389542" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2013-07-31
    Description: Mammalian pre-implantation development is a complex process involving dramatic changes in the transcriptional architecture. We report here a comprehensive analysis of transcriptome dynamics from oocyte to morula in both human and mouse embryos, using single-cell RNA sequencing. Based on single-nucleotide variants in human blastomere messenger RNAs and paternal-specific single-nucleotide polymorphisms, we identify novel stage-specific monoallelic expression patterns for a significant portion of polymorphic gene transcripts (25 to 53%). By weighted gene co-expression network analysis, we find that each developmental stage can be delineated concisely by a small number of functional modules of co-expressed genes. This result indicates a sequential order of transcriptional changes in pathways of cell cycle, gene regulation, translation and metabolism, acting in a step-wise fashion from cleavage to morula. Cross-species comparisons with mouse pre-implantation embryos reveal that the majority of human stage-specific modules (7 out of 9) are notably preserved, but developmental specificity and timing differ between human and mouse. Furthermore, we identify conserved key members (or hub genes) of the human and mouse networks. These genes represent novel candidates that are likely to be key in driving mammalian pre-implantation development. Together, the results provide a valuable resource to dissect gene regulatory mechanisms underlying progressive development of early mammalian embryos.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xue, Zhigang -- Huang, Kevin -- Cai, Chaochao -- Cai, Lingbo -- Jiang, Chun-yan -- Feng, Yun -- Liu, Zhenshan -- Zeng, Qiao -- Cheng, Liming -- Sun, Yi E -- Liu, Jia-yin -- Horvath, Steve -- Fan, Guoping -- P01 HD006576/HD/NICHD NIH HHS/ -- P30 HD004612/HD/NICHD NIH HHS/ -- P50 DA005010/DA/NIDA NIH HHS/ -- England -- Nature. 2013 Aug 29;500(7464):593-7. doi: 10.1038/nature12364. Epub 2013 Jul 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China. xuezhigang75@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23892778" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Blastocyst/cytology/metabolism ; Cell Cycle/genetics ; Embryo, Mammalian/cytology/*embryology/*metabolism ; Embryonic Development/*genetics ; Gene Expression Profiling ; *Gene Expression Regulation, Developmental ; Humans ; Mice ; Morula/cytology/metabolism ; Oocytes/cytology/metabolism ; *Sequence Analysis, RNA ; *Single-Cell Analysis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2013-03-15
    Description: In mammals, sex differentiation of primordial germ cells (PGCs) is determined by extrinsic cues from the environment. In mouse female PGCs, expression of stimulated by retinoic acid gene 8 (Stra8) and meiosis are induced in response to retinoic acid provided from the mesonephroi. Given the widespread role of retinoic acid signalling during development, the molecular mechanisms that enable PGCs to express Stra8 and enter meiosis in a timely manner are unknown. Here we identify gene-dosage-dependent roles in PGC development for Ring1 and Rnf2, two central components of the Polycomb repressive complex 1 (PRC1). Both paralogues are essential for PGC development between days 10.5 and 11.5 of gestation. Rnf2 is subsequently required in female PGCs to maintain high levels of Oct4 (also known as Pou5f1) and Nanog expression, and to prevent premature induction of meiotic gene expression and entry into meiotic prophase. Chemical inhibition of retinoic acid signalling partially suppresses precocious Oct4 downregulation and Stra8 activation in Rnf2-deficient female PGCs. Chromatin immunoprecipitation analyses show that Stra8 is a direct target of PRC1 and PRC2 in PGCs. These data demonstrate the importance of PRC1 gene dosage in PGC development and in coordinating the timing of sex differentiation of female PGCs by antagonizing extrinsic retinoic acid signalling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yokobayashi, Shihori -- Liang, Ching-Yeu -- Kohler, Hubertus -- Nestorov, Peter -- Liu, Zichuan -- Vidal, Miguel -- van Lohuizen, Maarten -- Roloff, Tim C -- Peters, Antoine H F M -- England -- Nature. 2013 Mar 14;495(7440):236-40. doi: 10.1038/nature11918.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23486062" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Animals ; Chromatin/genetics/metabolism ; Down-Regulation ; Female ; Gene Expression Regulation, Developmental ; Homeodomain Proteins/metabolism ; Male ; Meiosis ; Mice ; Octamer Transcription Factor-3/genetics/metabolism ; Ovum/*cytology/*metabolism ; Polycomb Repressive Complex 1/deficiency/*metabolism ; Polycomb Repressive Complex 2/metabolism ; Proteins/genetics ; Sex Characteristics ; Sex Differentiation/*physiology ; Signal Transduction ; Time Factors ; Transcription, Genetic ; Tretinoin/metabolism ; Ubiquitin-Protein Ligases/deficiency/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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