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Amber suppression

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https://www.readbyqxmd.com/read/29037038/conformationally-dynamic-radical-transfer-within-ribonucleotide-reductase
#1
Brandon L Greene, Alexander T Taguchi, JoAnne Stubbe, Daniel G Nocera
Ribonucleotide reductases (RNR) catalyze the reduction of nucleotides to deoxynucleotides through a mechanism involving an essential cysteine based thiyl radical. In the E. coli class 1a RNR the thiyl radical (C439•) is a transient species generated by radical transfer (RT) from a stable diferric-tyrosyl radical cofactor located >35 Å away across the α2:β2 subunit interface. RT is facilitated by sequential proton-coupled electron transfer (PCET) steps along a pathway of redox active amino acids (Y122β ↔ [W48β?] ↔ Y356β ↔ Y731α ↔ Y730α ↔ C439α)...
October 16, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28984438/engineering-the-genetic-code-in-cells-and-animals-biological-considerations-and-impacts
#2
Lei Wang
Expansion of the genetic code allows unnatural amino acids (Uaas) to be site-specifically incorporated into proteins in live biological systems, thus enabling novel properties selectively introduced into target proteins in vivo for basic biological studies and for engineering of novel biological functions. Orthogonal components including tRNA and aminoacyl-tRNA synthetase (aaRS) are expressed in live cells to decode a unique codon (often the amber stop codon UAG) as the desired Uaa. Initially developed in E...
October 6, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28983143/synthetic-biology-approach-for-the-development-of-conditionally-replicating-hiv-1-vaccine
#3
Nanxi Wang, Zhe Yuan, Wei Niu, Qingsheng Li, Jiantao Guo
While the combined antiretroviral therapy has resulted in a significant decrease in HIV-1 related morbidity and mortality, the HIV-1 pandemic has not been substantially averted. To curtail the 2.4 million new infections each year, a prophylactic HIV-1 vaccine is urgently needed. This review first summarizes four major completed clinical efficacy trials of prophylactic HIV-1 vaccine and their outcomes. Next, it discusses several other approaches that have not yet advanced to clinical efficacy trials, but provided valuable insights into vaccine design...
March 2017: Journal of Chemical Technology and Biotechnology
https://www.readbyqxmd.com/read/28978417/detection-and-treatment-of-fiebig-stage-i-hiv-1-infection-in-young-at-risk-women-in-south-africa-a-prospective-cohort-study
#4
Krista L Dong, Amber Moodley, Douglas S Kwon, Musie S Ghebremichael, Mary Dong, Nasreen Ismail, Zaza M Ndhlovu, Jenniffer M Mabuka, Daniel M Muema, Karyn Pretorius, Nina Lin, Bruce D Walker, Thumbi Ndung'u
BACKGROUND: HIV incidence among young women in sub-Saharan Africa remains high and their inclusion in vaccine and cure efforts is crucial. We aimed to establish a cohort of young women detected during Fiebig stage I acute HIV infection in whom treatment was initiated immediately after diagnosis to advance research in this high-risk group. METHODS: 945 women aged 18-23 years in KwaZulu-Natal, South Africa, who were HIV uninfected and sexually active consented to HIV-1 RNA testing twice a week and biological sampling and risk assessment every 3 months during participation in a 48-96 week life-skills and job-readiness programme...
September 29, 2017: Lancet HIV
https://www.readbyqxmd.com/read/28913971/chemical-functionalization-strategies-and-intracellular-applications-of-nanobodies
#5
Dominik Schumacher, Jonas Helma, Anselm F L Schneider, Heinrich Leonhardt, Christian Hackenberger
Nanobodies can be considered as next-generation life science tools for the recognition and modulation of antigens that are inaccessible to conventional antibodies. Due to their compact structure and high stability, nanobodies see frequent usage in basic research. Their chemical functionalization facilitates powerful diagnostic tools and opens the way towards promising therapeutic applications. In this review, central aspects of nanobody functionalization are given together with selected applications in molecular cell biology...
September 15, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28910072/mapping-the-binding-site-for-escitalopram-and-paroxetine-in-the-human-serotonin-transporter-using-genetically-encoded-photo-cross-linkers
#6
Hafsteinn Rannversson, Jacob Andersen, Benny Bang-Andersen, Kristian Strømgaard
In spite of the important role of the human serotonin transporter (hSERT) in depression treatment, the molecular details of how antidepressant drugs bind are still not completely understood, in particular those related to potential high- and low-affinity binding sites in hSERT. Here, we utilize amber codon suppression in hSERT to encode the photo-cross-linking unnatural amino acid p-azido-l-phenylalanine into the suggested high- and low-affinity binding sites. We then employ UV-induced cross-linking with azF to map the binding site of escitalopram and paroxetine, two prototypical selective serotonin reuptake inhibitors (SSRIs)...
September 26, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28866886/efficient-expression-of-glutathione-peroxidase-with-chimeric-trna-in-amber-less-escherichia-coli
#7
Zhenlin Fan, Jian Song, Tuchen Guan, Xiuxiu Lv, Jingyan Wei
The active center of selenium-containing glutathione peroxidase (GPx) is selenocysteine (Sec), which is is biosynthesized on its tRNA in organisms. The decoding of Sec depends on a specific elongation factor and a Sec Insertion Sequence (SECIS) to suppress the UGA codon. The expression of mammalian GPx is extremely difficult with traditional recombinant DNA technology. Recently, a chimeric tRNA (tRNA(UTu)) that is compatible with elongation factor Tu (EF-Tu) has made selenoprotein expression easier. In this study, human glutathione peroxidase (hGPx) was expressed in amber-less Escherichia coli C321...
September 12, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28817804/structural-mechanism-for-modulation-of-synaptic-neuroligin-neurexin-signaling-by-mdga-proteins
#8
Jonathan Elegheert, Vedrana Cvetkovska, Amber J Clayton, Christina Heroven, Kristel M Vennekens, Samuel N Smukowski, Michael C Regan, Wanyi Jia, Alexandra C Smith, Hiro Furukawa, Jeffrey N Savas, Joris de Wit, Jo Begbie, Ann Marie Craig, A Radu Aricescu
Neuroligin-neurexin (NL-NRX) complexes are fundamental synaptic organizers in the central nervous system. An accurate spatial and temporal control of NL-NRX signaling is crucial to balance excitatory and inhibitory neurotransmission, and perturbations are linked with neurodevelopmental and psychiatric disorders. MDGA proteins bind NLs and control their function and interaction with NRXs via unknown mechanisms. Here, we report crystal structures of MDGA1, the NL1-MDGA1 complex, and a spliced NL1 isoform. Two large, multi-domain MDGA molecules fold into rigid triangular structures, cradling a dimeric NL to prevent NRX binding...
August 16, 2017: Neuron
https://www.readbyqxmd.com/read/28758366/pyrrolysine-amber-stop-codon-suppression-development-and-applications
#9
REVIEW
Robin Brabham, Martin A Fascione
The pyrrolysine tRNA synthetase-tRNA pair is probably one of the most promiscuous tRNA-synthetase pairs found in nature, capable of genetically encoding a plethora of noncanonical amino acids through stop codon reassignment. Proteins containing reactive handles, post-translational modification mimics or both can be produced in practical quantities, allowing inter alia the probing of biological pathways, generating antibody-drug conjugates and enhancing protein function. This Minireview summarises the development of pyrrolysine amber stop-codon suppression, presents some of the considerations required to utilise this technique to its greatest potential, and showcases the creative ways in which this technique has led to a better understanding of biological systems...
July 30, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28714866/ibrutinib-treatment-improves-t-cell-number-and-function-in-cll-patients
#10
MULTICENTER STUDY
Meixiao Long, Kyle Beckwith, Priscilla Do, Bethany L Mundy, Amber Gordon, Amy M Lehman, Kami J Maddocks, Carolyn Cheney, Jeffrey A Jones, Joseph M Flynn, Leslie A Andritsos, Farrukh Awan, Joseph A Fraietta, Carl H June, Marcela V Maus, Jennifer A Woyach, Michael A Caligiuri, Amy J Johnson, Natarajan Muthusamy, John C Byrd
BACKGROUND: Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS: Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially...
August 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28611040/%C3%AE-catenin-is-a-candidate-therapeutic-target-for-myeloid-neoplasms-with-del-5q
#11
Liping Li, Yue Sheng, Wenshu Li, Chao Hu, Nupur Mittal, Kaoru Tohyama, Amber Seba, You-Yang Zhao, Howard Ozer, Tongyu Zhu, Zhijian Qian
Deletion of the chromosome 5q [del(5q)] is one of the most common cytogenetic abnormalities observed in patients with de novo myelodysplastic syndromes (MDS) and therapy-related MDS or acute myeloid leukemia (t-MDS/tAML). Emerging evidence indicates that activation of the Wnt/β-catenin pathway contributes to the development of myeloid neoplasms with del(5q). Whether β-catenin is a potential therapeutic target for myeloid neoplasms with del(5q) has yet to be evaluated. Here, we report that genetic deletion of a single allele of β-catenin rescues ineffective hematopoiesis in an Apc haploinsufficient mouse model, which recapitulates several characteristic features of the preleukemic stage of myeloid neoplasms with a -5/del(5q)...
August 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28596531/rf1-attenuation-enables-efficient-non-natural-amino-acid-incorporation-for-production-of-homogeneous-antibody-drug-conjugates
#12
Gang Yin, Heather T Stephenson, Junhao Yang, Xiaofan Li, Stephanie M Armstrong, Tyler H Heibeck, Cuong Tran, Mary Rose Masikat, Sihong Zhou, Ryan L Stafford, Alice Y Yam, John Lee, Alexander R Steiner, Avinash Gill, Kalyani Penta, Sonia Pollitt, Ramesh Baliga, Christopher J Murray, Christopher D Thanos, Leslie M McEvoy, Aaron K Sato, Trevor J Hallam
Amber codon suppression for the insertion of non-natural amino acids (nnAAs) is limited by competition with release factor 1 (RF1). Here we describe the genome engineering of a RF1 mutant strain that enhances suppression efficiency during cell-free protein synthesis, without significantly impacting cell growth during biomass production. Specifically, an out membrane protease (OmpT) cleavage site was engineered into the switch loop of RF1, which enables its conditional inactivation during cell lysis. This facilitates extract production without additional processing steps, resulting in a scaleable extract production process...
June 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28594177/a-versatile-toolbox-for-the-control-of-protein-levels-using-n-%C3%AE%C2%B5-acetyl-l-lysine-dependent-amber-suppression
#13
Wolfram Volkwein, Christopher Maier, Ralph Krafczyk, Kirsten Jung, Jürgen Lassak
The analysis of the function of essential genes in vivo depends on the ability to experimentally modulate levels of their protein products. Current methods to address this are based on transcriptional or post-transcriptional regulation of mRNAs, but approaches based on the exploitation of translation regulation have so far been neglected. Here we describe a toolbox, based on amber suppression in the presence of N(ε)-acetyl-l-lysine (AcK), for translational tuning of protein output. We chose the highly sensitive luminescence system LuxCDABE as a reporter and incorporated a UAG stop codon into the gene for the reductase subunit LuxC...
June 27, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28584229/circadian-tunable-perovskite-quantum-dot-based-down-converted-multi-package-white-led-with-a-color-fidelity-index-over-90
#14
Hee Chang Yoon, Ji Hye Oh, Soyoung Lee, Jae Byung Park, Young Rag Do
New metrics of the color and circadian performances of down-converted white light-emitting diodes (DC-WLEDs) are rapidly becoming popular in smart lighting systems. This is due to the increased desire for accurate analytical methods to measure the effects of newly developed quantum dot (QD)-based lighting on the vision, color, and circadian sensors of retina cells in the human eye. In this regard, a two-measure system known as technical memorandum TM-30-2015 (Illuminating Engineering Society of North America), encompassing the color fidelity index (CFI, R f ) and the color gamut index (CGI, R g ), has been developed as a new metrics of color to replace the currently utilized color rendering index (CRI, R a )...
June 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28468969/protein-kinase-ck2-controls-the-fate-between-th17-cell-and-regulatory-t-cell-differentiation
#15
Sara A Gibson, Wei Yang, Zhaoqi Yan, Yudong Liu, Amber L Rowse, Amy S Weinmann, Hongwei Qin, Etty N Benveniste
CK2 is a highly conserved and pleiotropic serine/threonine kinase that promotes many prosurvival and proinflammatory signaling pathways, including PI3K/Akt/mTOR and JAK/STAT. These pathways are essential for CD4(+) T cell activation and polarization, but little is known about how CK2 functions in T cells. In this article, we demonstrate that CK2 expression and kinase activity are induced upon CD4(+) T cell activation. Targeting the catalytic activity of CK2 using the next-generation small molecule inhibitor CX-4945 in vitro significantly and specifically inhibited mouse and human Th17 cell differentiation while promoting the generation of Foxp3(+) regulatory T cells (Tregs)...
June 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28422494/genetically-encoded-2-aryl-5-carboxytetrazoles-for-site-selective-protein-photo-cross-linking
#16
Yulin Tian, Marco Paolo Jacinto, Yu Zeng, Zhipeng Yu, Jun Qu, Wenshe R Liu, Qing Lin
The genetically encoded photo-cross-linkers promise to offer a temporally controlled tool to map transient and dynamic protein-protein interaction complexes in living cells. Here we report the synthesis of a panel of 2-aryl-5-carboxytetrazole-lysine analogs (ACTKs) and their site-specific incorporation into proteins via amber codon suppression in Escherichia coli and mammalian cells. Among five ACTKs investigated, N-methylpyrroletetrazole-lysine (mPyTK) was found to give robust and site-selective photo-cross-linking reactivity in E...
May 3, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28410215/cardiac-glycosides-suppress-the-maintenance-of-stemness-and-malignancy-via-inhibiting-hif-1%C3%AE-in-human-glioma-stem-cells
#17
Dae-Hee Lee, Sang Cheul Oh, Amber J Giles, Jinkyu Jung, Mark R Gilbert, Deric M Park
Tissue hypoxia contributes to solid tumor pathogenesis by activating a series of adaptive programs. We previously showed that hypoxia promotes the preferential expansion and maintenance of CD133 positive human glioma stem cells (GSC) in a hypoxia inducible factor 1 alpha (HIF-1α)-dependent mechanism. Here, we examined the activity of digitoxin (DT), a cardiac glycoside and a putative inhibitor of HIF-1α, on human GSC in vitro and in vivo. During hypoxic conditions (1% O2), we observed the effect of DT on the intracellular level of HIF-1α and the extracellular level of vascular endothelial growth factor (VEGF) in human GSC...
June 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28410196/the-p38-signaling-pathway-mediates-quiescence-of-glioma-stem-cells-by-regulating-epidermal-growth-factor-receptor-trafficking
#18
Akio Soeda, Justin Lathia, Brian J Williams, Qiulian Wu, Joseph Gallagher, Andreas Androutsellis-Theotokis, Amber J Giles, Chunzhang Yang, Zhengping Zhuang, Mark R Gilbert, Jeremy N Rich, Deric M Park
EGFR pathway is upregulated in malignant gliomas, and its downstream signaling is important for self-renewal of glioma cancer stem-like cells (GSC). p38 mitogen-activated protein kinase (MAPK) signaling, a stress-activated signaling cascade with suppressive and permissive effects on tumorigenesis, can promote internalization and ubiquitin ligase mediated degradation of EGFR. In this study, we investigated the role of p38 MAPK signaling on the self-renewal of GSCs with the hypothesis that inhibition may lead to enhanced self-renewal capacity by retention of EGFR...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28383180/two-tier-screening-platform-for-directed-evolution-of-aminoacyl-trna-synthetases-with-enhanced-stop-codon-suppression-efficiency
#19
Andrew E Owens, Katherine T Grasso, Christine A Ziegler, Rudi Fasan
Genetic code expansion through amber stop codon suppression provides a powerful tool for introducing non-proteinogenic functionalities into proteins for a broad range of applications. However, ribosomal incorporation of noncanonical amino acids (ncAAs) by means of engineered aminoacyl-tRNA synthetases (aaRSs) often proceeds with significantly reduced efficiency compared to sense codon translation. Here, we report the implementation of a versatile platform for the development of engineered aaRSs with enhanced efficiency in mediating ncAA incorporation by amber stop codon suppression...
June 19, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28320938/effectiveness-of-unaids-targets-and-hiv-vaccination-across-127-countries
#20
Jan Medlock, Abhishek Pandey, Alyssa S Parpia, Amber Tang, Laura A Skrip, Alison P Galvani
The HIV pandemic continues to impose enormous morbidity, mortality, and economic burdens across the globe. Simultaneously, innovations in antiretroviral therapy, diagnostic approaches, and vaccine development are providing novel tools for treatment-as-prevention and prophylaxis. We developed a mathematical model to evaluate the added benefit of an HIV vaccine in the context of goals to increase rates of diagnosis, treatment, and viral suppression in 127 countries. Under status quo interventions, we predict a median of 49 million [first and third quartiles 44M, 58M] incident cases globally from 2015 to 2035...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
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