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  • 1
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    Functional redundancy of histone amino-termini [Genetics] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-04-11
    Description: A large body of literature provides compelling evidence for the role of evolutionarily conserved core histone residues in various biological processes. However, site-directed mutagenesis of individual residues that are known to be sites of posttranslational modifications often does not result in clear phenotypic defects. In some cases, the combination of multiple mutations can give rise to stronger phenotypes, implying functional redundancy between distinct residues on histones. Here, we examined the “histone redundancy hypothesis” by characterizing double deletion of all pairwise combinations of amino-terminal tails (N-tails) from the four core histones encoded in budding yeast. First, we found that multiple lysine residues on the N-tails of both H2A and H4 are redundantly involved in cell viability. Second, simultaneous deletion of N-tails from H2A and H3 leads to a severe growth defect, which is correlated with perturbed gross chromatin structure in the mutant cells. Finally, by combining point mutations on H3 with deletion of the H2A N-tail, we revealed a redundant role for lysine 4 on H3 and the H2A N-tail in hydroxyurea-mediated response. Altogether, these data suggest that the N-tails of core histones share previously unrecognized, potentially redundant functions that, in some cases are different from those of the widely accepted H2A/H2B and H3/H4 dimer pairs.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-11-01
    Description: Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian-human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017780/" 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/PMC4017780/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barouch, Dan H -- Whitney, James B -- Moldt, Brian -- Klein, Florian -- Oliveira, Thiago Y -- Liu, Jinyan -- Stephenson, Kathryn E -- Chang, Hui-Wen -- Shekhar, Karthik -- Gupta, Sanjana -- Nkolola, Joseph P -- Seaman, Michael S -- Smith, Kaitlin M -- Borducchi, Erica N -- Cabral, Crystal -- Smith, Jeffrey Y -- Blackmore, Stephen -- Sanisetty, Srisowmya -- Perry, James R -- Beck, Matthew -- Lewis, Mark G -- Rinaldi, William -- Chakraborty, Arup K -- Poignard, Pascal -- Nussenzweig, Michel C -- Burton, Dennis R -- AI055332/AI/NIAID NIH HHS/ -- AI060354/AI/NIAID NIH HHS/ -- AI078526/AI/NIAID NIH HHS/ -- AI084794/AI/NIAID NIH HHS/ -- AI095985/AI/NIAID NIH HHS/ -- AI096040/AI/NIAID NIH HHS/ -- AI100148/AI/NIAID NIH HHS/ -- AI10063/AI/NIAID NIH HHS/ -- AI100663/AI/NIAID NIH HHS/ -- P01 AI100148/AI/NIAID NIH HHS/ -- P40 OD012217/OD/NIH HHS/ -- P51 RR000168/RR/NCRR NIH HHS/ -- R01 AI084794/AI/NIAID NIH HHS/ -- R37 AI055332/AI/NIAID NIH HHS/ -- R56 AI091514/AI/NIAID NIH HHS/ -- T32 AI007387/AI/NIAID NIH HHS/ -- U19 AI066305/AI/NIAID NIH HHS/ -- U19 AI078526/AI/NIAID NIH HHS/ -- U19 AI095985/AI/NIAID NIH HHS/ -- U19 AI096040/AI/NIAID NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 14;503(7475):224-8. doi: 10.1038/nature12744. Epub 2013 Oct 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24172905" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Monoclonal/*therapeutic use ; Antibodies, Neutralizing/*therapeutic use ; DNA, Viral/blood ; HIV Antibodies/immunology ; HIV-1/*immunology ; Macaca mulatta ; Simian Acquired Immunodeficiency Syndrome/*therapy ; Simian Immunodeficiency Virus/*physiology ; T-Lymphocytes/immunology ; Viremia/therapy
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-07-22
    Description: The viral reservoir represents a critical challenge for human immunodeficiency virus type 1 (HIV-1) eradication strategies. However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded rapidly after mucosal simian immunodeficiency virus (SIV) infection of rhesus monkeys and before systemic viraemia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10 and 14 after intrarectal SIVMAC251 infection. Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, after discontinuation of ART following 24 weeks of fully suppressive therapy, virus rebounded in all animals, although the monkeys that were treated on day 3 exhibited a delayed viral rebound as compared with those treated on days 7, 10 and 14. The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded rapidly after intrarectal SIV infection of rhesus monkeys, during the 'eclipse' phase, and before detectable viraemia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126858/" 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/PMC4126858/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Whitney, James B -- Hill, Alison L -- Sanisetty, Srisowmya -- Penaloza-MacMaster, Pablo -- Liu, Jinyan -- Shetty, Mayuri -- Parenteau, Lily -- Cabral, Crystal -- Shields, Jennifer -- Blackmore, Stephen -- Smith, Jeffrey Y -- Brinkman, Amanda L -- Peter, Lauren E -- Mathew, Sheeba I -- Smith, Kaitlin M -- Borducchi, Erica N -- Rosenbloom, Daniel I S -- Lewis, Mark G -- Hattersley, Jillian -- Li, Bei -- Hesselgesser, Joseph -- Geleziunas, Romas -- Robb, Merlin L -- Kim, Jerome H -- Michael, Nelson L -- Barouch, Dan H -- AI060354/AI/NIAID NIH HHS/ -- AI078526/AI/NIAID NIH HHS/ -- AI084794/AI/NIAID NIH HHS/ -- AI095985/AI/NIAID NIH HHS/ -- AI096040/AI/NIAID NIH HHS/ -- AI100645/AI/NIAID NIH HHS/ -- R01 AI084794/AI/NIAID NIH HHS/ -- R56 AI091514/AI/NIAID NIH HHS/ -- T32 AI007245/AI/NIAID NIH HHS/ -- U19 AI078526/AI/NIAID NIH HHS/ -- U19 AI095985/AI/NIAID NIH HHS/ -- U19 AI096040/AI/NIAID NIH HHS/ -- UM1 AI100645/AI/NIAID NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Aug 7;512(7512):74-7. doi: 10.1038/nature13594. Epub 2014 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA. ; Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138 USA. ; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Bioqual, Rockville, Maryland 20852, USA. ; Gilead Sciences, Foster City, California 94404, USA. ; US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25042999" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Retroviral Agents/administration & dosage/pharmacology/therapeutic use ; Carrier State/drug therapy/virology ; DNA, Viral/analysis/biosynthesis/blood ; Disease Models, Animal ; Female ; Kinetics ; Macaca mulatta/immunology/*virology ; Male ; Proviruses/genetics ; RNA, Viral/blood ; Rectum/virology ; Simian Acquired Immunodeficiency Syndrome/drug therapy/immunology/*virology ; Simian Immunodeficiency Virus/drug effects/*growth & ; development/immunology/physiology ; Time Factors ; Treatment Failure ; *Viral Load/drug effects ; Viremia/drug therapy/*virology ; Virus Replication/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    Nuclear quantum effect with pure anharmonicity and the anomalous thermal expansion of silicon [Applied Physical Sciences] (2018)
    National Academy of Sciences
    Details
    Publication Date: 2018-02-28
    Description: Despite the widespread use of silicon in modern technology, its peculiar thermal expansion is not well understood. Adapting harmonic phonons to the specific volume at temperature, the quasiharmonic approximation, has become accepted for simulating the thermal expansion, but has given ambiguous interpretations for microscopic mechanisms. To test atomistic mechanisms, we...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    Recent Advances in Thermoplastic Puncture-Healing Polymers (2009)
    In:  CASI
    Details
    Publication Date: 2019-07-13
    Description: Self-healing materials provide a route for enhanced damage tolerance in materials for aerospace applications. In particular, puncture-healing upon impact has the potential to mitigate significant damage caused by high velocity micrometeoroid impacts. This type of material also has the potential to improve damage tolerance in load bearing structures to enhance vehicle health and aircraft durability. The materials being studied are those capable of instantaneous puncture healing, providing a mechanism for mechanical property retention in lightweight structures. These systems have demonstrated healing capability following penetration of fast moving projectiles -- velocities that range from 9 mm bullets shot from a gun (approx.330 m/sec) to close to micrometeoroid debris velocities of 4800 m/sec. In this presentation, we report on a suite of polymeric materials possessing this characteristic. Figure 1 illustrates the puncture healing concept. Puncture healing in these materials is dependent upon how the combination of a polymer's viscoelastic properties responds to the energy input resulting from the puncture event. Projectile penetration increases the temperature in the vicinity of the impact. Self-healing behavior occurs following puncture, whereby energy must be transferred to the material during impact both elastically and inelastically, thus establishing two requirements for puncture healing to occur: a.) The need for the puncture event to produce a local melt state in the polymer material and b.) The molten material has to have sufficient melt elasticity to snap back and close the hole. 1,2 Previous ballistic testing studies revealed that Surlyn materials warmed up to a temperature approx.98 C during projectile puncture (3 C higher than it s melting temperature). 1,2 The temperature increase produces a localized flow state and the melt elasticity to snap back thus sealing the hole. Table 1 lists the commercially polymers studied here, together with their physical properties. The polymers were selected based on chemical structure, tensile strengths, tensile moduli, glass transition temperature, melting temperatures, and impact strength. The thermal properties of the polymers were characterized by Differential Scanning Calorimetry (DSC) and Dynamic Mechanical Analysis (DMA). Mechanical properties were assessed by a Sintech 2W instron according to ASTM D1708 or D638 at crosshead speeds of 5.08 cm/min. 7.6 cm x 7.6 cm panels of the different materials were prepared and ballistic testing was performed at various temperatures. The panels were shot with a .223 caliber semiautomatic rifle from a distance of 23 meters at various temperatures. Chronographs were used to measure initial and final bullet velocity. Temperatures at the site of impact were measured using a FLIR ThermaCAM S60 thermal camera. A Vision Research model Phantom 9 high speed video camera was used to capture high speed video footage of ballistics testing.
    Keywords: Nonmetallic Materials
    Type: LF99-8232 , 2nd International Conference on Self-Healing Materials; Jun 28, 2009 - Jul 01, 2009; Illinois; United States
    Format: application/pdf
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