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111.
112.
A series of N-(2-aminoethyl)-alpha-amino acid thymine peptide nucleic acid (PNA) monomers bearing glycosylated side chains in the alpha-amino acid position have been synthesized. These include PNA monomers where glycine has been replaced by serine and threonine (O-glycosylated), derivatives of lysine and nor-alanine (C-glycosylated), and amide derivatives of aspartic acid (N-glycosylated). The Boc and Fmoc derivatives of these monomers were used for incorporation in PNA oligomers. Twelve PNA decamers containing the glycosylated units in one, two, or three positions were prepared, and the thermal stability (T(m)) of their complexes with a complementary RNA was determined. Incorporation of the glycosyl monomers reduced the duplex stability by 0-6 degrees C per substitution. A cysteine was attached to the amino terminus of eight of the PNA decamers (Cys-CTCATACTCT-NH(2)) for easy conjugation to a [(18)F]radiolabeled N-(4-fluorobenzyl)-2-bromoacetamide. The in vivo biodistribution of these PNA oligomers was determined in rat 2 h after intravenous administration. Most of the radioactivity was recovered in the kidneys and in the urine. However, N-acetylgalactosamine (and to a lesser extent galactose and mannose)-modified PNAs were effectively targeting the liver (40-fold over unmodified PNA). Thus, the pharmacodistribution in rats of PNA oligomers can be profoundly changed by glycosylation. These results could be of great significance for PNA drug development, as they should allow modulation and fine-tuning of the pharmacokinetic profile of a drug lead. 相似文献
113.
114.
Haruki Hasegawa Ann Hsu Christine E. Tinberg Karen E. Siegler Aaron A. Nazarian Mei-Mei Tsai 《MABS-AUSTIN》2017,9(5):854-873
Amino acid sequence differences in the variable region of immunoglobulin (Ig) cause wide variations in secretion outputs. To address how a primary sequence difference comes to modulate Ig secretion, we investigated the biosynthetic process of 2 human IgG2κ monoclonal antibodies (mAbs) that differ only by one amino acid in the light chain complementarity-determining region 1 while showing ~20-fold variance in secretion titer. Although poorly secreted, the lower-secreting mAb of the 2 was by no means defective in terms of its folding stability, antigen binding, and in vitro biologic activity. However, upon overexpression in HEK293 cells, the low-secreting mAb revealed a high propensity to aggregate into enlarged globular structures called Russell bodies (RBs) in the endoplasmic reticulum. While Golgi morphology was affected by the formation of RBs, secretory pathway membrane traffic remained operational in those cells. Importantly, cellular protein synthesis was severely suppressed in RB-positive cells through the phosphorylation of eIF2α. PERK-dependent signaling was implicated in this event, given the upregulation and nuclear accumulation of downstream effectors such as ATF4 and CHOP. These findings illustrated that the underlining process of poor Ig secretion in RB-positive cells was due to downregulation of Ig synthesis instead of a disruption or blockade of secretory pathway trafficking. Therefore, RB formation signifies an end of active Ig production at the protein translation level. Consequently, depending on how soon and how severely an antibody-expressing cell develops the RB phenotype, the productive window of Ig secretion can vary widely among the cells expressing different mAbs. 相似文献
115.
Activation of BRCA1/BRCA2-associated helicase BACH1 is required for timely progression through S phase 下载免费PDF全文
BACH1 (also known as FANCJ and BRIP1) is a DNA helicase that directly interacts with the C-terminal BRCT repeat of the breast cancer susceptibility protein BRCA1. Previous biochemical and functional analyses have suggested a role for the BACH1 homolog in Caenorhabditis elegans during DNA replication. Here, we report the association of BACH1 with a distinct BRCA1/BRCA2-containing complex during the S phase of the cell cycle. Depletion of BACH1 or BRCA1 using small interfering RNAs results in delayed entry into the S phase of the cell cycle. Such timely progression through S phase requires the helicase activity of BACH1. Importantly, cells expressing a dominant negative mutation in BACH1 that results in a defective helicase displayed increased activation of DNA damage checkpoints and genomic instability. BACH1 helicase is silenced during the G(1) phase of the cell cycle and is activated through a dephosphorylation event as cells enter S phase. These results point to a critical role for BACH1 helicase activity not only in the timely progression through the S phase but also in maintaining genomic stability. 相似文献
116.
Qiu D Zhao G Aoki Y Shi L Uyei A Nazarian S Ng JC Kao PN 《The Journal of biological chemistry》1999,274(19):13443-13450
117.
Kumar JS Prabhakaran J Arango V Parsey RV Underwood MD Simpson NR Kassir SA Majo VJ Van Heertum RL Mann JJ 《Bioorganic & medicinal chemistry letters》2004,14(10):2393-2396
Synthesis and in vitro evaluation of [O-methyl-(11)C]1-(2-chlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide ([(11)C]-1), a potential imaging agent for CB(1) receptors using PET is described. 1-(2-Chlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (5), the precursor for radiolabeling, was synthesized from 4-OTBDPS-propiophenone (2) in five steps with 30% overall yield. The reaction of alcohol 5 with [(11)C]MeOTf at 60 degrees C afforded [(11)C]-1 with an average radiochemical yield of 14.5% (EOS) and >2000 Ci/mmol specific activity. The radiotracer was found to selectively label CB(1) receptors in slide-mounted sections of postmortem human brain containing prefrontal cortex as demonstrated by in vitro autoradiography using phosphor imaging. 相似文献
118.
Jaya Prabhakaran Mark Underwood Francesca Zanderigo Norman R. Simpson Anna R. Cooper Jeffrey Matthew Harry Rubin-Falcone Ramin V. Parsey J. John Mann J.S. Dileep Kumar 《Bioorganic & medicinal chemistry letters》2018,28(14):2432-2435
Radiosynthesis and in vivo evaluation of [11C]4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (methoxy analogue of valdecoxib, [11C]MOV), a COX-2 inhibitor, was conducted in rat and baboon. Synthesis of the reference standard MOV (3), and its desmethyl precursor 2 for radiolabeling were performed using 1,2-diphenylethan-1-one as the starting material in five steps with 15% overall yield. Radiosynthesis of [11C]MOV was accomplished in 40?±?10% yield and?>99% radiochemical purity by reacting the precursor 2 in dimethyl formamide (DMF) with [11C]CH3I followed by removal of the dimethoxytrityl (DMT) protective group using trifluroacetic acid. PET studies in anesthetized baboon showed very low uptake and homogeneous distribution of [11C]MOV in brain. The radioligand underwent rapid metabolism in baboon plasma. MicroPET studies in male Sprague Dawley rats revealed [11C]MOV binding in lower thorax. The tracer binding in rats was partially blocked in heart and duodenum by the administration of 1?mg/kg oral dose of COX-2 inhibitor valdecoxib. 相似文献
119.
The achievement of consistently superior results in rhinoplasty is rendered difficult in part by a number of complex interplays between the anatomical structures of the nose and the techniques used for their alteration, such as tip sutures. The effects of sutures depend largely on the magnitude of suture tightening, the intrinsic forces on the cartilages, cartilage thickness, and the degree of soft-tissue undermining. The tip complex is perhaps the most intricate of the nasal structures, exhibiting subtle but evident responses to manipulations of the lower lateral cartilages. The three-dimensional effects of nine suture techniques that are frequently used in nasal tip surgical procedures are discussed and illustrated. (1) The medial crura suture approximates the medial crura and strengthens the support of the tip. The suture also has effects that are less conspicuous immediately. There is slight narrowing of the columella, caudal protrusion of the lobule, and minimal caudal rotation of the lateral crura. (2) The middle crura suture approximates the most anterior portion of the medial crura. There is greater strengthening of the tip and some approximation of the domes with this suture. (3) The interdomal suture approximates the domes and can equalize asymmetric domes. However, the entire tip may shift to the short side if there is a significant difference in the heights of the domes because of short lateral and medial crura. (4) Transdomal sutures narrow the domal arch while pulling the lateral crura medially. The net results are increased tip projection, alar rim concavity, and the potential need for an alar rim graft. In addition, depending on suture position, cephalic or caudal rotation of the lateral crura may be observed. (5) The lateral crura suture increases the concavity of the lateral crura, reduces the interdomal distance, and may retract the alar rims. Perhaps the most significant inadvertent results of this suture are caudal rotation of the tip and elongation of the nose. This is important because patients who undergo rhinoplasty would often benefit from cephalic, rather than caudal, rotation of the tip. (6) The medial crura-septal suture not only increases tip projection but also rotates the tip cephalically and retracts the columella. (7) The tip rotation suture shifts the tip cephalad while retracting the columella. (8) The medial crura footplate suture approximates the footplates, narrows the columella base, and improves undesirable nostril shape. (9) The lateral crura convexity control suture alters the degree of convexity of the lateral crura. The nuances of these sutures and their multiplanar effects on the nasal tip are discussed. 相似文献
120.
John A. Rennick Ara Nazarian Vahid Entezari James Kimbaris Alan Tseng Aidin Masoudi Hamid Nayeb-Hashemi Ashkan Vaziri Brian D. Snyder 《Journal of biomechanics》2013
Finite element analysis (FEA), CT based structural rigidity analysis (CTRA) and mechanical testing is performed to assess the compressive failure load of rat tibia with simulated lytic defects. 相似文献