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  • 1
    Publication Date: 2018-04-20
    Description: Diamonds have substantial hardness and durability, but attempting to deform diamonds usually results in brittle fracture. We demonstrate ultralarge, fully reversible elastic deformation of nanoscale (~300 nanometers) single-crystalline and polycrystalline diamond needles. For single-crystalline diamond, the maximum tensile strains (up to 9%) approached the theoretical elastic limit, and the corresponding maximum tensile stress reached ~89 to 98 gigapascals. After combining systematic computational simulations and characterization of pre- and postdeformation structural features, we ascribe the concurrent high strength and large elastic strain to the paucity of defects in the small-volume diamond nanoneedles and to the relatively smooth surfaces compared with those of microscale and larger specimens. The discovery offers the potential for new applications through optimized design of diamond nanostructure, geometry, elastic strains, and physical properties.
    Keywords: Engineering, Materials Science
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2018-02-03
    Description: Coagulopathy is common in patients with traumatic brain injury (TBI) and predicts poor clinical outcomes. We have shown that brain-derived extracellular microvesicles, including extracellular mitochondria, play a key role in the development of TBI-induced coagulopathy. Here, we further show in mouse models that the apoptotic cell-scavenging factor lactadherin, given at a single dose of 400 μg/kg 30 minutes before (preconditioning) or 30 minutes after cerebral fluid percussion injury, prevented coagulopathy as defined by clotting time, fibrinolysis, intravascular fibrin deposition, and microvascular bleeding of the lungs. Lactadherin also reduced cerebral edema, improved neurological function, and increased survival. It achieved these protective effects by enhancing the clearance of circulating microvesicles through phosphatidylserine-mediated phagocytosis. Together, these results identify the scavenging system for apoptotic cells as a potential therapeutic target to prevent TBI-induced coagulopathy and improve the outcome of TBI.
    Keywords: Thrombosis and Hemostasis
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 3
    Keywords: GENES ; MOUSE ; SUBGROUPS ; GLIOBLASTOMA ; INTRINSIC PONTINE GLIOMAS ; HISTONE H3.3 ; FIBRODYSPLASIA OSSIFICANS PROGRESSIVA ; BMP RECEPTOR ; I RECEPTOR ; ALK2
    Abstract: Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.
    Type of Publication: Journal article published
    PubMed ID: 24705250
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  • 4
  • 5
    ISSN: 1432-1912
    Keywords: Crotoxin ; Neurotoxin ; β-Bungarotoxin ; Neuromuscular block ; Presynaptic action ; Snake venom
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Crotoxin isolated from the venom of the Brazilian rattlesnake (Crotalus durissus terrificus) by chromatography on CM-Sephadex and Sephadex G-75 caused respiratory paralysis accompanied by peripheral neuromuscular blockade. 2. The chicken was more sensitive to crotoxin than the mouse whereas the rat was more resistant. 3. There was a slight initial facilitation and latent period before the decline of neuromuscular transmission started. In the media with low Ca2+ or high Mg2+, there was also an immediate depression before the facilitation. 4. The membrane potential, action potential and the response to high K+ of the isolated muscles were not significantly affected. 5. The response to exogenous acetylcholine and the amplitudes of m.e.p.p.s were also not affected. 6. The quantal contents of e.p.p.s were markedly depressed and the amplitudes of successive e.p.p.s elicited by a train of pulses at 100 Hz were well maintained. 7. The frequency of m.e.p.p.s in the mouse diaphragm, but not in the rat muscle, was first increased followed by a decrease when the evoked release of transmitter failed. 8. In the blocked muscle, high K+ was still able to evoke a burst of m.e.p.p.s, though less marked than in the untreated control. 9. The neuromuscular blocking activity of crotoxin was attenuated by an increase of Mg2+, Ca2+ or decrease of Ca2+ but augmented by increasing rates of stimulation. 10. The effect of crotoxin continued to progress even after washout. 11. The effects of crotoxin are very similar to those of β-bungarotoxin and most likely due to the presynaptic inhibition of the mechanism mediating the release of neurotransmitter in the nerve terminal.
    Type of Medium: Electronic Resource
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  • 6
    Publication Date: 2013-07-05
    Description: Human infection associated with a novel reassortant avian influenza H7N9 virus has recently been identified in China. A total of 132 confirmed cases and 39 deaths have been reported. Most patients presented with severe pneumonia and acute respiratory distress syndrome. Although the first epidemic has subsided, the presence of a natural reservoir and the disease severity highlight the need to evaluate its risk on human public health and to understand the possible pathogenesis mechanism. Here we show that the emerging H7N9 avian influenza virus poses a potentially high risk to humans. We discover that the H7N9 virus can bind to both avian-type (alpha2,3-linked sialic acid) and human-type (alpha2,6-linked sialic acid) receptors. It can invade epithelial cells in the human lower respiratory tract and type II pneumonocytes in alveoli, and replicated efficiently in ex vivo lung and trachea explant culture and several mammalian cell lines. In acute serum samples of H7N9-infected patients, increased levels of the chemokines and cytokines IP-10, MIG, MIP-1beta, MCP-1, IL-6, IL-8 and IFN-alpha were detected. We note that the human population is naive to the H7N9 virus, and current seasonal vaccination could not provide protection.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Jianfang -- Wang, Dayan -- Gao, Rongbao -- Zhao, Baihui -- Song, Jingdong -- Qi, Xian -- Zhang, Yanjun -- Shi, Yonglin -- Yang, Lei -- Zhu, Wenfei -- Bai, Tian -- Qin, Kun -- Lan, Yu -- Zou, Shumei -- Guo, Junfeng -- Dong, Jie -- Dong, Libo -- Zhang, Ye -- Wei, Hejiang -- Li, Xiaodan -- Lu, Jian -- Liu, Liqi -- Zhao, Xiang -- Li, Xiyan -- Huang, Weijuan -- Wen, Leying -- Bo, Hong -- Xin, Li -- Chen, Yongkun -- Xu, Cuilin -- Pei, Yuquan -- Yang, Yue -- Zhang, Xiaodong -- Wang, Shiwen -- Feng, Zijian -- Han, Jun -- Yang, Weizhong -- Gao, George F -- Wu, Guizhen -- Li, Dexin -- Wang, Yu -- Shu, Yuelong -- England -- Nature. 2013 Jul 25;499(7459):500-3. doi: 10.1038/nature12379. Epub 2013 Jul 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Institute for Viral Disease Control and Prevention, China CDC, Key Laboratory for Medical Virology, National Health and Family Planning Commission, Beijing 102206, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23823727" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Viral/immunology ; Birds/virology ; Bronchi/cytology/metabolism/virology ; Cell Line ; Chemokines/blood ; China ; Cross Reactions/immunology ; Epithelial Cells/virology ; Host Specificity ; Humans ; In Vitro Techniques ; Influenza A Virus, H5N1 Subtype/immunology/physiology ; Influenza A virus/immunology/pathogenicity/*physiology ; Influenza Vaccines/immunology ; Influenza in Birds/transmission/*virology ; Influenza, Human/blood/immunology/virology ; Lung/virology ; N-Acetylneuraminic Acid/analogs & derivatives/chemistry/metabolism ; Organ Specificity ; Pulmonary Alveoli/cytology/metabolism/virology ; Receptors, Virus/chemistry/*metabolism ; Trachea/virology ; Virus Replication ; Zoonoses/transmission/virology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    Nature Publishing Group (NPG)
    Publication Date: 2015-04-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong-Yan, Jin -- Cheung, Felix -- England -- Nature. 2015 Apr 30;520(7549):S37. doi: 10.1038/520S37a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25924200" target="_blank"〉PubMed〈/a〉
    Keywords: Bibliometrics ; China ; Hong Kong ; *Internationality ; Peer Review, Research/*methods/*standards ; *Personnel Selection ; Research Personnel/*standards ; United States ; Universities
    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: 2011-10-18
    Description: Caspase-1 activation by inflammasome scaffolds comprised of intracellular nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and the adaptor ASC is believed to be essential for production of the pro-inflammatory cytokines interleukin (IL)-1beta and IL-18 during the innate immune response. Here we show, with C57BL/6 Casp11 gene-targeted mice, that caspase-11 (also known as caspase-4) is critical for caspase-1 activation and IL-1beta production in macrophages infected with Escherichia coli, Citrobacter rodentium or Vibrio cholerae. Strain 129 mice, like Casp11(-/-) mice, exhibited defects in IL-1beta production and harboured a mutation in the Casp11 locus that attenuated caspase-11 expression. This finding is important because published targeting of the Casp1 gene was done using strain 129 embryonic stem cells. Casp1 and Casp11 are too close in the genome to be segregated by recombination; consequently, the published Casp1(-/-) mice lack both caspase-11 and caspase-1. Interestingly, Casp11(-/-) macrophages secreted IL-1beta normally in response to ATP and monosodium urate, indicating that caspase-11 is engaged by a non-canonical inflammasome. Casp1(-/-)Casp11(129mt/129mt) macrophages expressing caspase-11 from a C57BL/6 bacterial artificial chromosome transgene failed to secrete IL-1beta regardless of stimulus, confirming an essential role for caspase-1 in IL-1beta production. Caspase-11 rather than caspase-1, however, was required for non-canonical inflammasome-triggered macrophage cell death, indicating that caspase-11 orchestrates both caspase-1-dependent and -independent outputs. Caspase-1 activation by non-canonical stimuli required NLRP3 and ASC, but caspase-11 processing and cell death did not, implying that there is a distinct activator of caspase-11. Lastly, loss of caspase-11 rather than caspase-1 protected mice from a lethal dose of lipopolysaccharide. These data highlight a unique pro-inflammatory role for caspase-11 in the innate immune response to clinically significant bacterial infections.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kayagaki, Nobuhiko -- Warming, Soren -- Lamkanfi, Mohamed -- Vande Walle, Lieselotte -- Louie, Salina -- Dong, Jennifer -- Newton, Kim -- Qu, Yan -- Liu, Jinfeng -- Heldens, Sherry -- Zhang, Juan -- Lee, Wyne P -- Roose-Girma, Merone -- Dixit, Vishva M -- England -- Nature. 2011 Oct 16;479(7371):117-21. doi: 10.1038/nature10558.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiological Chemistry, Genentech Inc., South San Francisco, California 94080, USA. kayagaki@gene.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22002608" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caspase 1/metabolism ; Caspases/genetics/*metabolism ; Citrobacter rodentium/immunology ; Enzyme Activation ; Escherichia coli/immunology ; Immunity, Innate/immunology ; Inflammasomes/*metabolism ; Interleukin-1beta/biosynthesis/secretion ; Lipopolysaccharides/adverse effects/immunology ; Macrophages/immunology/secretion ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Vibrio cholerae/immunology
    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: 2015-08-27
    Description: During B-cell development, RAG endonuclease cleaves immunoglobulin heavy chain (IgH) V, D, and J gene segments and orchestrates their fusion as deletional events that assemble a V(D)J exon in the same transcriptional orientation as adjacent Cmu constant region exons. In mice, six additional sets of constant region exons (CHs) lie 100-200 kilobases downstream in the same transcriptional orientation as V(D)J and Cmu exons. Long repetitive switch (S) regions precede Cmu and downstream CHs. In mature B cells, class switch recombination (CSR) generates different antibody classes by replacing Cmu with a downstream CH (ref. 2). Activation-induced cytidine deaminase (AID) initiates CSR by promoting deamination lesions within Smu and a downstream acceptor S region; these lesions are converted into DNA double-strand breaks (DSBs) by general DNA repair factors. Productive CSR must occur in a deletional orientation by joining the upstream end of an Smu DSB to the downstream end of an acceptor S-region DSB. However, the relative frequency of deletional to inversional CSR junctions has not been measured. Thus, whether orientation-specific joining is a programmed mechanistic feature of CSR as it is for V(D)J recombination and, if so, how this is achieved is unknown. To address this question, we adapt high-throughput genome-wide translocation sequencing into a highly sensitive DSB end-joining assay and apply it to endogenous AID-initiated S-region DSBs in mouse B cells. We show that CSR is programmed to occur in a productive deletional orientation and does so via an unprecedented mechanism that involves in cis Igh organizational features in combination with frequent S-region DSBs initiated by AID. We further implicate ATM-dependent DSB-response factors in enforcing this mechanism and provide an explanation of why CSR is so reliant on the 53BP1 DSB-response factor.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592165/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592165/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong, Junchao -- Panchakshari, Rohit A -- Zhang, Tingting -- Zhang, Yu -- Hu, Jiazhi -- Volpi, Sabrina A -- Meyers, Robin M -- Ho, Yu-Jui -- Du, Zhou -- Robbiani, Davide F -- Meng, Feilong -- Gostissa, Monica -- Nussenzweig, Michel C -- Manis, John P -- Alt, Frederick W -- AI037526/AI/NIAID NIH HHS/ -- AI072529/AI/NIAID NIH HHS/ -- AI077595/AI/NIAID NIH HHS/ -- AI112602/AI/NIAID NIH HHS/ -- CA133781/CA/NCI NIH HHS/ -- R01 AI077595/AI/NIAID NIH HHS/ -- R21 AI088510/AI/NIAID NIH HHS/ -- R21 CA133781/CA/NCI NIH HHS/ -- T32HL066987/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 3;525(7567):134-9. doi: 10.1038/nature14970. Epub 2015 Aug 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Boston Children's Hospital and Joint Program in Transfusion Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Howard Hughes Medical Institute, Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26308889" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ataxia Telangiectasia Mutated Proteins/metabolism ; B-Lymphocytes/enzymology/immunology/*metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Cytidine Deaminase/*metabolism ; *DNA Breaks, Double-Stranded ; DNA Repair/*genetics ; DNA-Binding Proteins/metabolism ; Deamination ; Immunoglobulin Class Switching/*genetics ; Immunoglobulin Constant Regions/*genetics ; Immunoglobulin Heavy Chains/*genetics ; Mice ; Sequence Deletion/genetics ; VDJ Exons/genetics
    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: 2018-06-02
    Description: Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.
    Print ISSN: 0022-2275
    Electronic ISSN: 1539-7262
    Topics: Biology , Chemistry and Pharmacology , Medicine
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