scholarly journals The Nicking Step in V(D)J Recombination Is Independent of Synapsis: Implications for the Immune Repertoire

2000 ◽  
Vol 20 (21) ◽  
pp. 7914-7921 ◽  
Author(s):  
Kefei Yu ◽  
Michael R. Lieber
Keyword(s):  
Reaction Time ◽  
Genomic Instability ◽  
Strand Transfer ◽  
Immune Repertoire ◽  
Dna Transposition ◽  
Type Reaction ◽  
Time Courses

ABSTRACT In all of the transposition reactions that have been characterized thus far, synapsis of two transposon ends is required before any catalytic steps (strand nicking or strand transfer) occur. In V(D)J recombination, there have been inconclusive data concerning the role of synapsis in nicking. Synapsis between two 12-substrates or between two 23-substrates has not been ruled out in any studies thus far. Here we provide the first direct tests of this issue. We find that immobilization of signals does not affect their nicking, even though hairpinning is affected in a manner reflecting its known synaptic requirement. We also find that nicking is kinetically a unireactant enzyme-catalyzed reaction. Time courses are no different between nicking seen for a 12-substrate alone and a reaction involving both a 12- and a 23-substrate. Hence, synapsis is neither a requirement nor an effector of the rate of nicking. These results establish V(D)J recombination as the first example of a DNA transposition-type reaction in which catalytic steps begin prior to synapsis, and the results have direct implications for the order of the steps in V(D)J recombination, for the contribution of V(D)J recombination nicks to genomic instability, and for the diversification of the immune repertoire.

Chemical Availability of Bromide Dictates CsPbBr3 Nanocrystal Growth

2019 ◽  
Author(s):  
Je-Ruei Wen ◽  
Benjamin Roman ◽  
Freddy Rodriguez Ortiz ◽  
Noel Mireles Villegas ◽  
Nicholas Porcellino ◽  
...  
Keyword(s):  
Reaction Time ◽  
Growth Mechanism ◽  
Chemical Control ◽  
Critical Role ◽  
Phase Evolution ◽  
Detailed Understanding ◽  
Semiconductor Nanocrystal ◽  
Nanocrystal Growth ◽  
Chemical Availability

Lack of detailed understanding of the growth mechanism of CsPbBr3 nanocrystals has hindered sophisticated morphological and chemical control of this important emerging optoelectronic material. Here, we have elucidated the growth mechanism by slowing the reaction kinetics. When 1-bromohexane is used as an alternative halide source, bromide is slowly released into the reaction mixture, extending the reaction time from ~3 seconds to greater than 20 minutes. This enables us to monitor the phase evolution of products over the course of reaction, revealing that CsBr is the initial species formed, followed by Cs4PbBr6, and finally CsPbBr3. Further, formation of monodisperse CsBr nanocrystals is demonstrated in a bromide-deficient and lead-abundant solution. The CsBr can only be transformed into CsPbBr3 nanocubes if additional bromide is added. Our results indicate a fundamentally different growth mechanism for CsPbBr3 in comparison with more established semiconductor nanocrystal systems and reveal the critical role of the chemical availability of bromide for the growth reactions.<br>

Inflammatory Myositis Secondary to Anti-Retroviral Therapy in a Child; Case Report and Review of the Literature

2021 ◽  
pp. 1-7
Author(s):  
Marie Monaghan ◽  
Charlotte Loh ◽  
Stephen Jones ◽  
Agyepong Oware ◽  
Kathryn Urankar ◽  
...  
Keyword(s):  
Drug Regimen ◽  
Dramatic Improvement ◽  
Strand Transfer ◽  
Inflammatory Myositis ◽  
Once Daily ◽  
Immune Mediated ◽  
Show Evidence ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Here, we describe a five year old girl with congenital HIV who had a six-week onset of rapidly deteriorating mobility and progressive proximal muscle weakness, associated with a raised Creatine Kinase (CK) level of 4330 U/L [25–200 U/L], subsequently diagnosed with an inflammatory myositis. Potential causes were investigated by paediatric neurology and immunology teams. Her viral load had been undetectable over the preceding two years, excluding a primary HIV myositis. While MRI scanning did not show evidence of definite myositis, a muscle biopsy showed evidence of an inflammatory process, comprising a moderate endomysial, perimysial and perivascular mononuclear (CD8 + T cell) infiltrate with increased MHC expression. No particular features of dermatomyositis or immune-mediated necrotising myopathy were identified and there were no features of an inclusion body myositis. Given the absence of active HIV infection, the role of anti-retroviral medications was considered. She had had a recent switch in medication, from twice daily Raltegravir (an Integrase Strand Transfer Inhibitor, INSTI) to once daily Dolutegravir (an INSTI) while continuing on an established daily protocol of Abacavir and Lamivudine (Nucleoside Reverse Transcriptase Inhibitors). Changing the Dolutegravir back to Raltegravir, in combination with continuing Lamivudine and Abacavir for two months made no difference to her weakness or CK levels. Moreover, this drug regimen had been well-tolerated over the preceding 19 month period. Changing the anti-retroviral regime completely to a single drug class (Protease Inhibitors) of Ritonavir and Darunavir, resulted in a dramatic improvement in her symptomatology. Within ten days she regained the ability to stand and walk, with a reduction in her CK from 1700 U/L at time of switch to 403 U/L [25–200]. This case highlights the potential risk of developing inflammatory myositis from anti-retrovirals even 19 months into treatment.

scholarly journals Cellular Senescence in Liver Disease and Regeneration

2021 ◽  
Author(s):  
Sofia Ferreira-Gonzalez ◽  
Daniel Rodrigo-Torres ◽  
Victoria L. Gadd ◽  
Stuart J. Forbes
Keyword(s):  
Cell Cycle ◽  
Liver Disease ◽  
Cell Cycle Arrest ◽  
Genomic Instability ◽  
Cellular Senescence ◽  
Cell Populations ◽  
Cycle Arrest ◽  
Relevant Role ◽  
Extent Of Damage

AbstractCellular senescence is an irreversible cell cycle arrest implemented by the cell as a result of stressful insults. Characterized by phenotypic alterations, including secretome changes and genomic instability, senescence is capable of exerting both detrimental and beneficial processes. Accumulating evidence has shown that cellular senescence plays a relevant role in the occurrence and development of liver disease, as a mechanism to contain damage and promote regeneration, but also characterizing the onset and correlating with the extent of damage. The evidence of senescent mechanisms acting on the cell populations of the liver will be described including the role of markers to detect cellular senescence. Overall, this review intends to summarize the role of senescence in liver homeostasis, injury, disease, and regeneration.

scholarly journals The role of substance P as a neurotransmitter in the reflexes of slow time courses in the neonatal rat spinal cord

1985 ◽  
Vol 84 (3) ◽  
pp. 663-673 ◽  
Author(s):  
Hiroyuki Akagi ◽  
Shiro Konishi ◽  
Masanori Otsuka ◽  
Mitsuhiko Yanagisawa
Keyword(s):  
Spinal Cord ◽  
Substance P ◽  
Neonatal Rat ◽  
Rat Spinal Cord ◽  
Slow Time ◽  
Time Courses

scholarly journals The role of telomere dysfunction in driving genomic instability

2007 ◽  
Vol 1299 ◽  
pp. 146-149
Author(s):  
Susan M. Bailey ◽  
Eli S. Williams ◽  
Robert L. Ullrich
Keyword(s):  
Genomic Instability ◽  
Telomere Dysfunction

scholarly journals Biochemical and genetic analysis of the role of the viral polymerase in enterovirus recombination

2016 ◽  
Vol 44 (14) ◽  
pp. 6883-6895 ◽  
Author(s):  
Andrew Woodman ◽  
Jamie J. Arnold ◽  
Craig E. Cameron ◽  
David J. Evans
Keyword(s):  
Genetic Recombination ◽  
Evolutionary Process ◽  
Virus Genome ◽  
Biochemical Assay ◽  
Strand Transfer ◽  
Turnover Rates ◽  
Coding Region ◽  
Cis Acting ◽  
Polymerase Fidelity

Abstract Genetic recombination in single-strand, positive-sense RNA viruses is a poorly understand mechanism responsible for generating extensive genetic change and novel phenotypes. By moving a critical cis-acting replication element (CRE) from the polyprotein coding region to the 3′ non-coding region we have further developed a cell-based assay (the 3′CRE-REP assay) to yield recombinants throughout the non-structural coding region of poliovirus from dually transfected cells. We have additionally developed a defined biochemical assay in which the only protein present is the poliovirus RNA dependent RNA polymerase (RdRp), which recapitulates the strand transfer events of the recombination process. We have used both assays to investigate the role of the polymerase fidelity and nucleotide turnover rates in recombination. Our results, of both poliovirus intertypic and intratypic recombination in the CRE-REP assay and using a range of polymerase variants in the biochemical assay, demonstrate that RdRp fidelity is a fundamental determinant of recombination frequency. High fidelity polymerases exhibit reduced recombination and low fidelity polymerases exhibit increased recombination in both assays. These studies provide the basis for the analysis of poliovirus recombination throughout the non-structural region of the virus genome and provide a defined biochemical assay to further dissect this important evolutionary process.

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