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Author: Grafiati
Published: 10 December 2022
Last updated: 28 January 2023

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1

Sono, Masanori, Roshan Perera, Shengxi Jin, Thomas M. Makris, Stephen G. Sligar, Thomas A. Bryson, and John H. Dawson. "The influence of substrate on the spectral properties of oxyferrous wild-type and T252A cytochrome P450-CAM." Archives of Biochemistry and Biophysics 436, no. 1 (April 2005): 40–49. http://dx.doi.org/10.1016/j.abb.2004.12.026.

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2

Wang, Binju, Chunsen Li, Kshatresh Dutta Dubey, and Sason Shaik. "Quantum Mechanical/Molecular Mechanical Calculated Reactivity Networks Reveal How Cytochrome P450cam and Its T252A Mutant Select Their Oxidation Pathways." Journal of the American Chemical Society 137, no. 23 (June 5, 2015): 7379–90. http://dx.doi.org/10.1021/jacs.5b02800.

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3

Hirao, Hajime, Devesh Kumar, and Sason Shaik. "On the identity and reactivity patterns of the “second oxidant” of the T252A mutant of cytochrome P450cam in the oxidation of 5-methylenenylcamphor." Journal of Inorganic Biochemistry 100, no. 12 (December 2006): 2054–68. http://dx.doi.org/10.1016/j.jinorgbio.2006.09.001.

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4

Kim, Sun Hee, Tran-Chin Yang, Roshan Perera, Shengxi Jin, Thomas A. Bryson, Masanori Sono, Roman Davydov, John H. Dawson, and Brian M. Hoffman. "Cryoreduction EPR and 13C, 19F ENDOR study of substrate-bound substates and solvent kinetic isotope effects in the catalytic cycle of cytochrome P450cam and its T252A mutant." Dalton Transactions, no. 21 (2005): 3464. http://dx.doi.org/10.1039/b506764m.

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5

Kim, Dong Keon, Jang-Seok Lee, Eun Young Lee, Hansol Jang, Suji Han, Hee Yeon Kim, In-Young Hwang, et al. "O-GlcNAcylation of Sox2 at threonine 258 regulates the self-renewal and early cell fate of embryonic stem cells." Experimental & Molecular Medicine 53, no. 11 (November 2021): 1759–68. http://dx.doi.org/10.1038/s12276-021-00707-7.

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AbstractSox2 is a core transcription factor in embryonic stem cells (ESCs), and O-GlcNAcylation is a type of post-translational modification of nuclear-cytoplasmic proteins. Although both factors play important roles in the maintenance and differentiation of ESCs and the serine 248 (S248) and threonine 258 (T258) residues of Sox2 are modified by O-GlcNAcylation, the function of Sox2 O-GlcNAcylation is unclear. Here, we show that O-GlcNAcylation of Sox2 at T258 regulates mouse ESC self-renewal and early cell fate. ESCs in which wild-type Sox2 was replaced with the Sox2 T258A mutant exhibited reduced self-renewal, whereas ESCs with the Sox2 S248A point mutation did not. ESCs with the Sox2 T258A mutation heterologously introduced using the CRISPR/Cas9 system, designated E14-Sox2TA/WT, also exhibited reduced self-renewal. RNA sequencing analysis under self-renewal conditions showed that upregulated expression of early differentiation genes, rather than a downregulated expression of self-renewal genes, was responsible for the reduced self-renewal of E14-Sox2TA/WT cells. There was a significant decrease in ectodermal tissue and a marked increase in cartilage tissue in E14-Sox2TA/WT-derived teratomas compared with normal E14 ESC-derived teratomas. RNA sequencing of teratomas revealed that genes related to brain development had generally downregulated expression in the E14-Sox2TA/WT-derived teratomas. Our findings using the Sox2 T258A mutant suggest that Sox2 T258 O-GlcNAc has a positive effect on ESC self-renewal and plays an important role in the proper development of ectodermal lineage cells. Overall, our study directly links O-GlcNAcylation and early cell fate decisions.
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6

Fan, Jun, Stephen J. Perry, Yinghong Gao, David A. Schwarz, and Richard A. Maki. "A Point Mutation in the Human Melanin Concentrating Hormone Receptor 1 Reveals an Important Domain for Cellular Trafficking." Molecular Endocrinology 19, no. 10 (October 1, 2005): 2579–90. http://dx.doi.org/10.1210/me.2004-0301.

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Abstract G protein-coupled receptors (GPCRs) are heptahelical integral membrane proteins that require cell surface expression to elicit their effects. The lack of appropriate expression of GPCRs may be the underlying cause of a number of inherited disorders. There is evidence that newly synthesized GPCRs must attain a specific conformation for their correct trafficking to the cell surface. In this study, we show that a single point mutation in human melanin-concentrating hormone receptor (hMCHR1) at position 255 (T255A), which is located at the junction of intracellular loop 3 and transmembrane domain 6, reduces the hMCHR1 cell surface expression level to 20% of that observed for the wild-type receptor. Most of these mutant receptors are located intracellularly, as opposed to the wild-type receptor, which is located primarily on the cell surface. Immunoprecipitation experiments show that hMCHR1-T255A has reduced glycosylation compared with the wild-type receptor and is associated with the chaperone protein, calnexin, and it colocalizes in the endoplasmic reticulum with KDEL-containing proteins. We also demonstrate that a cell-permeable small molecule antagonist of hMCHR1 can function as a pharmacological chaperone to restore cell surface expression of this and other MCHR1 mutants to wild-type levels. Once rescued, the T255A mutant couples to Gq proteins as efficiently as the wild-type receptor. These data suggest that this single mutation produces an hMCHR1 that folds incorrectly, resulting in its retention in the endoplasmic reticulum, but once rescued to the cell surface can still function normally.
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7

Akparov, Valery Kh, Vladimir I. Timofeev, Inna P. Kuranova, and Tatiana V. Rakitina. "Crystal structure of mutant carboxypeptidase T from Thermoactinomyces vulgaris with an implanted S1′ subsite from pancreatic carboxypeptidase B." Acta Crystallographica Section F Structural Biology Communications 74, no. 10 (September 19, 2018): 638–43. http://dx.doi.org/10.1107/s2053230x18011962.

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A site-directed mutagenesis method has been used to obtain the G215S/A251G/T257A/D260G/T262D mutant of carboxypeptidase T from Thermoactinomyces vulgaris (CPT), in which the amino-acid residues of the S1′ subsite are substituted by the corresponding residues from pancreatic carboxypeptidase B (CPB). It was shown that the mutant enzyme retained the broad, mainly hydrophobic selectivity of wild-type CPT. The mutant containing the implanted CPB S1′ subsite was crystallized and its three-dimensional structure was determined at 1.29 Å resolution by X-ray crystallography. A comparison of the three-dimensional structures of CPT, the G215S/A251G/T257A/D260G/T262D CPT mutant and CPB showed that the S1′ subsite of CPT has not been distorted by the mutagenesis and adequately reproduces the structure of the CPB S1′ subsite. The CPB-like mutant differs from CPB in substrate selectivity owing to differences between the two enzymes outside the S1′ subsite. Moreover, the difference in substrate specificity between the enzymes was shown to be affected by residues other than those that directly contact the substrate.
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8

Hasegawa, Takahiro, Ahmad Azlina, Purevjav Javkhlan, Chenjuan Yao, Tetsuya Akamatsu, and Kazuo Hosoi. "Novel phosphorylation of aquaporin-5 at its threonine 259 through cAMP signaling in salivary gland cells." American Journal of Physiology-Cell Physiology 301, no. 3 (September 2011): C667—C678. http://dx.doi.org/10.1152/ajpcell.00058.2011.

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Aquaporin-5 (AQP5), a water channel, plays key roles in salivary secretion. The novel phosphorylation of AQP5 was investigated by using human salivary gland (HSG) cells and mouse salivary glands. In the HSG cells stably transfected with a wild-type mouse AQP5 construct, a protein band immunoreactive with antibody against phosphorylated PKA substrate was detected in the AQP5 immunoprecipitated sample, and its intensity was enhanced by short-term treatment of the cells with 8-bromo-cAMP, forskolin, or phorbol 12-myristate 13-acetate, but not by that with A23187 calcium ionophore. Such enhancement was inhibited in the presence of H-89, a PKA inhibitor. An AQP5 mutant (AQP5-T259A) expressed by transfection of HSG cells was not recognized by anti-phosphorylated PKA substrate antibody, even when the cells were stimulated with the protein kinase activators. Immunoblotting and immunofluorescence studies using a specific antibody detecting AQP5 phosphorylated at its Thr259 demonstrated that AQP5 was rapidly and transiently phosphorylated at the apical membrane of acinar cells in the submandibular and parotid glands after administration of isoproterenol, but not pilocarpine. Furthermore, both AQP5 and AQP5-T259A were constitutively localized at the plasma membrane in HSG cells under the resting and forskolin-stimulated conditions. These results suggest that AQP5 is phosphorylated at its Thr259 by PKA through cAMP, but not Ca2+, signaling pathways, and that this phosphorylation does not contribute to AQP5 trafficking in the salivary gland cells.
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9

Pei, Yi, Hongyan Du, Juliet Singer, Courtney St. Amour, Selena Granitto, Stewart Shuman, and Robert P. Fisher. "Cyclin-Dependent Kinase 9 (Cdk9) of Fission Yeast Is Activated by the CDK-Activating Kinase Csk1, Overlaps Functionally with the TFIIH-Associated Kinase Mcs6, and Associates with the mRNA Cap Methyltransferase Pcm1 In Vivo." Molecular and Cellular Biology 26, no. 3 (February 1, 2006): 777–88. http://dx.doi.org/10.1128/mcb.26.3.777-788.2006.

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ABSTRACT Cyclin-dependent kinase 9 (Cdk9) of fission yeast is an essential ortholog of metazoan positive transcription elongation factor b (P-TEFb), which is proposed to coordinate capping and elongation of RNA polymerase II (Pol II) transcripts. Here we show that Cdk9 is activated to phosphorylate Pol II and the elongation factor Spt5 by Csk1, one of two fission yeast CDK-activating kinases (CAKs). Activation depends on Cdk9 T-loop residue Thr-212. The other CAK—Mcs6, the kinase component of transcription factor IIH (TFIIH)—cannot activate Cdk9. Consistent with the specificities of the two CAKs in vitro, the kinase activity of Cdk9 is reduced ∼10-fold by csk1 deletion, and Cdk9 complexes from csk1Δ but not csk1 + cells can be activated by Csk1 in vitro. A cdk9 T212A mutant is viable but phenocopies conditional growth defects of csk1Δ strains, indicating a role for Csk1-dependent activation of Cdk9 in vivo. A cdk9 T212A mcs6 S165A strain, in which neither Cdk9 nor Mcs6 can be activated by CAK, has a synthetic growth defect, implying functional overlap between the two CDKs, which have distinct but overlapping substrate specificities. Cdk9 forms complexes in vivo with the essential cyclin Pch1 and with Pcm1, the mRNA cap methyltransferase. The carboxyl-terminal region of Cdk9, through which it interacts with another capping enzyme, the RNA triphosphatase Pct1, is essential. Together, the data support a proposed model whereby Cdk9/Pch1—the third essential CDK-cyclin complex described in fission yeast—helps to target the capping apparatus to the transcriptional elongation complex.
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10

Rahman, N., B. M. Fullen, D. Canavan, and L. Stassen. "T252 DENTAL POST PROCEDURAL PAIN: IMPACT OF DEMOGRAPHIC FACTORS." European Journal of Pain Supplements 5, no. 1 (September 2011): 51. http://dx.doi.org/10.1016/s1754-3207(11)70170-5.

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11

Kapoor, Arushi, N. Rai, Partam Manalai, Maria Hipolito, and Evaristus Nwulia. "T252. Olfactory Tasks in Affective and Non Affective Disorders." Biological Psychiatry 83, no. 9 (May 2018): S227. http://dx.doi.org/10.1016/j.biopsych.2018.02.589.

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12

Chang, H., M. Azuma, B. Goldman, F. Nagashima, S. Iqbal, K. Danenberg, J. Benedetti, W. Zhang, C. Blanke, and H. Lenz. "Gene expression levels of HER2 and IL-8 and polymorphism in IL-8 associated with clinical outcome in advanced or metastatic gastric cancer treated with lapatinib in SWOG 0413 trial." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 4647. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.4647.

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4647 Background: Lapatinib (GW572016) is a dual tyrosine kinase inhibitor of EGFR and HER2. In SWOG0413 trial, advanced or metastatic gastric cancer patients were treated with lapatinib. In this study, we investigated whether gene expressions and polymorphisms of EGF and angiogenesis pathway genes were associated with clinical outcome in the patients enrolled in SWOG0413 trial. Methods: A total of 46 patients were enrolled in SWOG0413 trial and treated with lapatinib. Blood and tissue samples were available from 42 and 37 patients, respectively. RT-PCR was performed for intratumoral gene expression levels of EGFR, HER2, VEGF, IL-8, COX2 and cyclin D1 genes. We also analyzed 8 polymorphisms in the EGF, EGFR, HER2, VEGF, IL-8, COX2 and cyclin D1 genes by PCR-RFLP. Results: Patients who have lower IL-8 [median overall survival (OS), 6 vs 3 months, p=0.03] and higher HER2 (6 vs 3 months, p=0.005) gene expression levels showed better OS. According to gene polymorphisms, patients who have A allele of IL-8 T251A polymorphism showed improved OS (A/A, 10 months vs T/A, 5 months vs T/T 3 months, p=0.04). And patients with A allele of IL-8 T251A and T allele of VEGF C936T polymorphisms showed better response rates (p<0.01, p<0.01, respectively). All other polymorphisms and gene expressions did not show significant association with clinical outcome. Conclusions: Our results suggest that intratumoral gene expression levels of HER2 and IL-8 and polymorphism in IL-8 are potential molecular predictors for survival in patients with advanced or metastatic gastric cancer treated with lapatinib. And polymorphisms in IL-8 and VEGF genes may be potential markers in predicting response in this population. A larger prospective study is needed to validate and confirm these preliminary findings. [Table: see text]
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13

Kim, Donghak, Yong-Seok Heo, and Paul R. Ortiz de Montellano. "Efficient catalytic turnover of cytochrome P450cam is supported by a T252N mutation." Archives of Biochemistry and Biophysics 474, no. 1 (June 2008): 150–56. http://dx.doi.org/10.1016/j.abb.2008.02.044.

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14

Meira, Bruna, Rafael Roque, Miguel Pinto, and André Caetano. "Late-onset presentation of POLG1-associated mitochondrial disease." BMJ Case Reports 12, no. 3 (March 2019): e228482. http://dx.doi.org/10.1136/bcr-2018-228482.

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Mutations in the nuclear POLG1 gene compromise the integrity of mitochondrial DNA and show great allelic and clinical heterogeneity. Among adult POLG1-associated mitochondrial disease, the main clinical feature is chronic progressive external ophthalmoplegia. Other related clinical manifestations are sensory or cerebellar ataxia, peripheral neuropathy, myopathy or extrapyramidal symptoms. We report the case of a 72-year-old man who presented with a late onset sensory neuronopathy, chronic progressive external ophthalmoplegia, gait ataxia and parkinsonism. Genetic studies showed a compound heterozygosity of known pathogenic mutations in the POLG1 gene (variant T252I/P587 L in cis configuration in allele 1 and variant R807C in allele 2). Late life presentation highlights that mitochondrial disorders should be considered regardless of age of onset of symptoms.
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15

Ishiwata, Akira, Jun Mimuro, Hiroaki Mizukami, Yuji Kashiwakura, Atsushi Yasumoto, Asuka Sakata, Tsukasa Ohmori, et al. "Mutant Macaque Factor IX T262A: A Tool for Hemophilia B Gene Therapy Studies in Macaques." Thrombosis Research 125, no. 6 (June 2010): 533–37. http://dx.doi.org/10.1016/j.thromres.2010.01.049.

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16

Di Salvo, Martino L., J. Neel Scarsdale, Galina Kazanina, Roberto Contestabile, Verne Schirch, and H. Tonie Wright. "Structure-Based Mechanism for Early PLP-Mediated Steps of Rabbit Cytosolic Serine Hydroxymethyltransferase Reaction." BioMed Research International 2013 (2013): 1–13. http://dx.doi.org/10.1155/2013/458571.

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Serine hydroxymethyltransferase catalyzes the reversible interconversion of L-serine and glycine with transfer of one-carbon groups to and from tetrahydrofolate. Active site residue Thr254 is known to be involved in the transaldimination reaction, a crucial step in the catalytic mechanism of all pyridoxal 5′-phosphate- (PLP-) dependent enzymes, which determines binding of substrates and release of products. In order to better understand the role of Thr254, we have expressed, characterized, and determined the crystal structures of rabbit cytosolic serine hydroxymethyltransferase T254A and T254C mutant forms, in the absence and presence of substrates. These mutants accumulate a kinetically stablegem-diamine intermediate, and their crystal structures show differences in the active site with respect to wild type. The kinetic and crystallographic data acquired with mutant enzymes permit us to infer that conversion ofgem-diamine to external aldimine is significantly slowed because intermediates are trapped into an anomalous position by a misorientation of the PLP ring, and a new energy barrier hampers the transaldimination reaction. This barrier likely arises from the loss of the stabilizing hydrogen bond between the hydroxymethyl group of Thr254 and theε-amino group of active site Lys257, which stabilizes the external aldimine intermediate in wild type SHMTs.
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17

Jain, G., C. Kumar, A. Chopra, and S. Bakhshi. "T252 [LDQUO]Peripheral blood involvement by AITL: A case report and review of the literature[RDQUO]." Clinica Chimica Acta 530 (May 2022): S181—S182. http://dx.doi.org/10.1016/j.cca.2022.04.740.

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18

Liao, Yan, Chun-mei Li, Hui Chen, Qi Wu, Zhi Shan, and Xue-yi Han. "Site-Directed Mutagenesis Improves the Thermostability and Catalytic Efficiency of Aspergillus niger N25 Phytase Mutated by I44E and T252R." Applied Biochemistry and Biotechnology 171, no. 4 (August 2, 2013): 900–915. http://dx.doi.org/10.1007/s12010-013-0380-2.

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19

Davy, Clare E., Deborah J. Jackson, Kenneth Raj, Woei Ling Peh, Shirley A. Southern, Papia Das, Rina Sorathia, et al. "Human Papillomavirus Type 16 E1∧E4-Induced G2 Arrest Is Associated with Cytoplasmic Retention of Active Cdk1/Cyclin B1 Complexes." Journal of Virology 79, no. 7 (April 1, 2005): 3998–4011. http://dx.doi.org/10.1128/jvi.79.7.3998-4011.2005.

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ABSTRACT Human papillomavirus type 16 (HPV16) can cause cervical cancer. Expression of the viral E1∧E4 protein is lost during malignant progression, but in premalignant lesions, E1∧E4 is abundant in cells supporting viral DNA amplification. Expression of 16E1∧E4 in cell culture causes G2 cell cycle arrest. Here we show that unlike many other G2 arrest mechanisms, 16E1∧E4 does not inhibit the kinase activity of the Cdk1/cyclin B1 complex. Instead, 16E1∧E4 uses a novel mechanism in which it sequesters Cdk1/cyclin B1 onto the cytokeratin network. This prevents the accumulation of active Cdk1/cyclin B1 complexes in the nucleus and hence prevents mitosis. A mutant 16E1∧E4 (T22A, T23A) which does not bind cyclin B1 or alter its intracellular location fails to induce G2 arrest. The significance of these results is highlighted by the observation that in lesions induced by HPV16, there is evidence for Cdk1/cyclin B1 activity on the keratins of 16E1∧E4-expressing cells. We hypothesize that E1∧E4-induced G2 arrest may play a role in creating an environment optimal for viral DNA replication and that loss of E1∧E4 expression may contribute to malignant progression.
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20

Mao, X., B. Schwer, and S. Shuman. "Mutational analysis of the Saccharomyces cerevisiae ABD1 gene: cap methyltransferase activity is essential for cell growth." Molecular and Cellular Biology 16, no. 2 (February 1996): 475–80. http://dx.doi.org/10.1128/mcb.16.2.475.

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RNA (guanine-7-)-methyltransferase is the enzyme responsible for methylating the 5' cap structure of eukaryotic mRNA. The Saccharomyces cerevisiae enzyme is a 436-amino-acid protein encoded by the essential ABD1 gene. In this study, deletion and point mutations in ABD1 were tested for the ability to support growth of an abd1 null strain. Elimination of 109 amino acids from the N terminus had no effect on cell viability, whereas a more extensive N-terminal deletion of 155 residues was lethal, as was a C-terminal deletion of 55 amino acids. Alanine substitution mutations were introduced at eight conserved residues within a 206-amino-acid region of similarity between ABD1 and the methyltransferase domain of the vaccinia virus capping enzyme. ABD1 alleles H253A (encoding a substitution of alanine for histidine at position 253), T282A, E287A, E361A, and Y362A were viable, whereas G174A, D178A, and Y254A were either lethal or severely defective for growth. Alanine-substituted and amino-truncated ABD1 proteins were expressed in bacteria, purified, and tested for cap methyltransferase activity in vitro. Mutations that were viable in yeast cells had either no effect or only a moderate effect on the specific methyltransferase activity of the mutated ABD1 protein, whereas mutations that were deleterious in vivo yielded proteins that were catalytically defective in vitro. These findings substantiate for the first time the long-held presumption that cap methylation is an essential function in eukaryotic cells.
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21

Llabrés-Mas, A. M., A. Garrido-García, and J. M. Frade. "Regulation of the DNA damage response by E2F4 phosphorylation in its T249/T251 conserved motif and Alzheimer’s disease." IBJ Plus 1, s5 (June 3, 2022): 28. http://dx.doi.org/10.24217/2531-0151.22v1s5.00028.

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Alzheimer's disease (AD) has a multifactorial etiology that includes DNA damage in neurons. The transcription factor E2F4, which can potentially regulate DNA repair, has two conserved threonines (T249/T251 in the mouse) that can be phosphorylated by p38MAPK (p38). The expression in vivo of the T249A/T251A E2F4 mutant form (E2F4DN) has been shown to be a multifactorial therapeutic agent against AD. In this work, we have analyzed the effects of E2F4 phosphorylation in T249/T251 on the DNA repair response (DDR). To this aim, we used N2a mouse neuroblastoma cells treated with 10 µM camptothecin (CPT), a treatment known to induce Cited2 expression and subsequent cell death. In this paradigm, the repression of Cited2 by E2F4 is abolished upon CPT treatment, thus allowing its E2F1-dependent expression followed by cell death. While E2F4 can be detected in both the nucleus and cytoplasm of N2a cells, phosphoT249-E2F4-specific immunoreactivity is specifically observed in the nucleus 4 h after treatment with CPT. Therefore, the known activation of p38 in response to CPT could lead to T249 phosphorylation of E2F4, thus suppressing its inhibition on E2F1 activity and allowing Cited2 expression. This hypothesis, is being tested in CPT- treated N2a cells co-transduced with adenoviral vectors expressing E2F1 together with either wild-type E2F4 or E2F4DN, in either the presence or absence of p38 inhibitors. In summary, our work provides support for a novel mechanism used by E2F4 to regulate the response to DNA damage in pathological situations, which could participate in the therapeutic capacity of E2F4DN against AD.
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22

Vogel, Sjoerd J., Mark van der Gaag, Henderikus Knegtering, and Stynke Castelein. "Poster #T252 IS AEROBIC EXERCISE EFFECTIVE IN IMPROVING NEGATIVE SYMPTOMS IN PATIENTS WITH SCHIZOPHRENIA? THE RESULTS OF A META-ANALYSIS." Schizophrenia Research 153 (April 2014): S378—S379. http://dx.doi.org/10.1016/s0920-9964(14)71068-0.

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23

Sivaraman, G. K., K. H. Muneeb, S. Sudha, Bibek Shome, Jennifer Cole, and Mark Holmes. "Prevalence of virulent and biofilm forming ST88-IV-t2526 methicillin-resistant Staphylococcus aureus clones circulating in local retail fish markets in Assam, India." Food Control 127 (September 2021): 108098. http://dx.doi.org/10.1016/j.foodcont.2021.108098.

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24

Huber, René, Sandra Augsten, Holger Kirsten, Roland Zell, Axel Stelzner, Hansjörg Thude, Thorsten Eidner, Bruno Stuhlmüller, Peter Ahnert, and Raimund W. Kinne. "Identification of New, Functionally Relevant Mutations in the Coding Regions of the Human Fos and Jun Proto-Oncogenes in Rheumatoid Arthritis Synovial Tissue." Life 11, no. 1 (December 23, 2020): 5. http://dx.doi.org/10.3390/life11010005.

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In rheumatoid arthritis (RA), the expression of many pro-destructive/pro-inflammatory proteins depends on the transcription factor AP-1. Therefore, our aim was to analyze the presence and functional relevance of mutations in the coding regions of the AP-1 subunits of the fos and jun family in peripheral blood (PB) and synovial membranes (SM) of RA and osteoarthritis patients (OA, disease control), as well as normal controls (NC). Using the non-isotopic RNAse cleavage assay, one known polymorphism (T252C: silent; rs1046117; present in RA, OA, and NC) and three novel germline mutations of the cfos gene were detected: (i) C361G/A367G: Gln121Glu/Ile123Val, denoted as “fos121/123”; present only in one OA sample; (ii) G374A: Arg125Lys, “fos125”; and (iii) C217A/G374A: Leu73Met/Arg125Lys, “fos73/125”, the latter two exclusively present in RA. In addition, three novel somatic cjun mutations (604–606ΔCAG: ΔGln202, “jun202”; C706T: Pro236Ser, “jun236”; G750A: silent) were found exclusively in the RA SM. Tansgenic expression of fos125 and fos73/125 mutants in NIH-3T3 cells induced an activation of reporter constructs containing either the MMP-1 (matrix metalloproteinase) promoter (3- and 4-fold, respectively) or a pentameric AP-1 site (approximately 5-fold). Combined expression of these two cfos mutants with cjun wildtype or mutants (jun202, jun236) further enhanced reporter expression of the pentameric AP-1 construct. Finally, genotyping for the novel functionally relevant germline mutations in 298 RA, 288 OA, and 484 NC samples revealed no association with RA. Thus, functional cfos/cjun mutants may contribute to local joint inflammation/destruction in selected patients with RA by altering the transactivation capacity of AP-1 complexes.
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25

Mandary, Madiiha Bibi, Malihe Masomian, Seng-Kai Ong, and Chit Laa Poh. "Characterization of Plaque Variants and the Involvement of Quasi-Species in a Population of EV-A71." Viruses 12, no. 6 (June 17, 2020): 651. http://dx.doi.org/10.3390/v12060651.

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Viral plaque morphologies in human cell lines are markers for growth capability and they have been used to assess the viral fitness and selection of attenuated mutants for live-attenuated vaccine development. In this study, we investigate whether the naturally occurring plaque size variation reflects the virulence of the variants of EV-A71. Variants of two different plaque sizes (big and small) from EV-A71 sub-genotype B4 strain 41 were characterized. The plaque variants displayed different in vitro growth kinetics compared to the parental wild type. The plaque variants showed specific mutations being present in each variant strain. The big plaque variants showed four mutations I97L, N104S, S246P and N282D in the VP1 while the small plaque variants showed I97T, N237T and T292A in the VP1. No other mutations were detected in the whole genome of the two variants. The variants showed stable homogenous small plaques and big plaques, respectively, when re-infected in rhabdomyosarcoma (RD) and Vero cells. The parental strain showed faster growth kinetics and had higher viral RNA copy number than both the big and small plaque variants. Homology modelling shows that both plaque variants have differences in the structure of the VP1 protein due to the presence of unique spontaneous mutations found in each plaque variant This study suggests that the EV-A71 sub-genotype B4 strain 41 has at least two variants with different plaque morphologies. These differences were likely due to the presence of spontaneous mutations that are unique to each of the plaque variants. The ability to maintain the respective plaque morphology upon passaging indicates the presence of quasi-species in the parental population.
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Anh, Nguyễn Quỳnh, and Hà Duy Trường. "NGHIÊN CỨU ẢNH HƯỞNG CỦA GIÁ THỂ ĐẾN KHẢ NĂNG SINH TRƯỞNG CỦA GIỐNG CÀ CHUA T252 TRONG GIAI ĐOẠN VƯỜN ƯƠM." TNU Journal of Science and Technology 227, no. 10 (June 24, 2022): 120–26. http://dx.doi.org/10.34238/tnu-jst.5954.

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Cà chua (Solanum lycopersicon Mill) là một trong những loại rau phổ biến, có giá trị dinh dưỡng và giá trị kinh tế cao. Việc sử dụng cà chua trong các bữa ăn hàng ngày rất có lợi cho sức khỏe con người và được các nhà khoa học chứng minh có thể ngăn ngừa được một số loại bệnh như ung thư trực tràng, ung thư tiền liệt tuyến, phòng chống các bệnh về tim mạch. Mục đích của nghiên cứu này là tìm ra loại giá thể cho các chỉ tiêu sinh trưởng của cây cà chua T252 trong giai đoạn vườn ươm ở mức tốt nhất, phù hợp với điều kiện sản xuất trong nhà màng ở trường Đại học Nông Lâm năm 2020. Kết quả nghiên cứu cho thấy Công thức 1 (1/4 trấu hun + ¼ xơ dừa + ¼ bã dong riềng + ¼ phân lợn tinh chế) cho các chỉ tiêu sinh trưởng trong vườn ươm là tốt nhất, các chỉ tiêu lý hóa và dinh dưỡng của giá thể phân lợn ủ hoai mục cao giá trị EC thấp nhất (2,11 dS/m) tỷ lệ nảy mầm ở giai đoạn 10 ngày sau gieo đạt 96,05%. Các chỉ tiêu về chiều cao cây, số lá/cây, đường kính gốc và thể tích rễ 30 ngày sau gieo lần lượt là 6,95 cm; 3,5 lá/cây; 2,62 mm và 3,13 cm3.
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Coste, Alix T., Jérôme Crittin, Christopher Bauser, Bettina Rohde, and Dominique Sanglard. "Functional Analysis of cis- and trans-Acting Elements of the Candida albicans CDR2 Promoter with a Novel Promoter Reporter System." Eukaryotic Cell 8, no. 8 (June 26, 2009): 1250–67. http://dx.doi.org/10.1128/ec.00069-09.

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ABSTRACT Azole resistance in Candida albicans can be mediated by the upregulation of the ATP binding cassette transporter genes CDR1 and CDR2. Both genes are regulated by a cis-acting element called the drug-responsive element (DRE), with the consensus sequence 5′-CGGAWATCGGATATTTTTTT-3′, and the transcription factor Tac1p. In order to analyze in detail the DRE sequence necessary for the regulation of CDR1 and CDR2 and properties of TAC1 alleles, a one-hybrid system was designed. This system is based on a P(CDR2)-HIS3 reporter system in which complementation of histidine auxotrophy can be monitored by activation of the reporter system by CDR2-inducing drugs such as estradiol. Our results show that most of the modifications within the DRE, but especially at the level of CGG triplets, strongly reduce CDR2 expression. The CDR2 DRE was replaced by putative DREs deduced from promoters of coregulated genes (CDR1, RTA3, and IFU5). Surprisingly, even if Tac1p was able to bind these putative DREs, as shown by chromatin immunoprecipitation, those from RTA3 and IFU5 did not functionally replace the CDR2 DRE. The one-hybrid system was also used for the identification of gain-of-function (GOF) mutations either in TAC1 alleles from clinical C. albicans isolates or inserted in TAC1 wild-type alleles by random mutagenesis. In all, 17 different GOF mutations were identified at 13 distinct positions. Five of them (G980E, N972D, A736V, T225A, and N977D) have already been described in clinical isolates, and four others (G980W, A736T, N972S, and N972I) occurred at already-described positions, thus suggesting that GOF mutations can occur in a limited number of positions in Tac1p. In conclusion, the one-hybrid system developed here is rapid and powerful and can be used for characterization of cis- and trans-acting elements in C. albicans.
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Sun, Zhengrong, Gaowei Ren, Xin Cui, Weiqiang Zhou, Chao Liu, and Qiang Ruan. "Genetic Diversity of HPV-16E6,E7, andL1Genes in Women With Cervical Lesions in Liaoning Province, China." International Journal of Gynecologic Cancer 21, no. 3 (April 2011): 551–58. http://dx.doi.org/10.1097/igc.0b013e3182112023.

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IntroductionHigh-risk human papillomaviruses (HPVs) play a cardinal role in the etiology of cervical cancer. The most prevalent type, HPV-16, shows intratypic sequence variants that are known to differ in oncogenic potential and geographic distribution. Intratype variations in oncogenic E6/E7 and capsid L1 proteins of HPV-16 are associated with risk of viral persistence and progression.MethodsThis study was designed to analyze sequence variations inE6,E7, andL1genes of HPV-16 in patients with cervical lesion to identify the most prevalent and novel HPV-16 variants in northern China.ResultsOur results showed that HPV-16 variants with respect to E6 and E7 were high prevalence of the Asian lineage: 48.3% and 51.4%, respectively. Sequences of theE6gene revealed 4 amino acid changes of variants D25E and L83V, with 48.3% (69/143) and 11.2% (16/143), respectively, and variants H78Y and E113D in this study. The results also showed the prevalence of 4 hot spots of E7 nucleotide variations leading to N29H, N29S, and 2 silent variations, nucleotide G666A and nucleotide T846C, with 4.2% (6/142), 43% (61/142), 32.4% (46/142), and 43% (61/142), respectively. The following L1 variations were found in this study: L103F, P104K, P104Y, P104S, D105G, P106S, N108P, F109V, C172S, H228D, and T292A. It was also found that 448S was inserted and 465D was deleted in the L1 amino acid sequences of all the samples. No significant relationship between HPV-16 variants and high-grade lesions was found.ConclusionsThe study provides some new data on the genetic diversity of HPV-16, which may help to understand the oncogenic potential of the virus and design the diagnosis reagents and vaccine of HPV in China. Furthermore, in-depth studies are needed to determine the clinical and biological effects of these variants.
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Gunderson, Leonard L., John Milburn Jessup, Daniel J. Sargent, Frederick L. Greene, and Andrew Stewart. "Revised Tumor and Node Categorization for Rectal Cancer Based on Surveillance, Epidemiology, and End Results and Rectal Pooled Analysis Outcomes." Journal of Clinical Oncology 28, no. 2 (January 10, 2010): 256–63. http://dx.doi.org/10.1200/jco.2009.23.9194.

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Purpose The sixth edition of the American Joint Committee on Cancer (AJCC) rectal cancer staging subdivided stage II into IIA (T3N0) and IIB (T4N0) and stage III into IIIA (T1-2N1M0), IIIB (T3-4N1M0), and IIIC (anyTN2M0). Subsequent analyses supported revised substaging of stage III as a result of improved survival with T1-2N2 versus T3-4N2 and survival of T4N1 more similar to T3-4N2 than T3N1. The AJCC Hindgut Taskforce sought population-based validation that depth of invasion interacts with nodal status to affect survival. Methods Surveillance, Epidemiology, and End Results (SEER) population-based data from January 1992 to December 2004 for 35,829 patients with rectal cancer were compared with rectal pooled analysis data (3,791 patients). T4N0 cancers were stratified by tumors that perforate visceral peritoneum (T4a) versus tumors that invade or are adherent to adjacent organs or structures (T4b). N1 and N2 were stratified by number of positive nodes as follows: N1a/N1b (one v two to three nodes) and N2a/N2b (four to six v ≥ seven nodes). Five-year observed and relative survival rates were obtained for each TN category. Results SEER rectal cancer analyses confirm that T1-2N2 cancers have better prognosis than T3-4N2, T4bN1 have similar prognosis to T4N2, T1-2N1 have similar prognosis to T2N0/T3N0, and T1-2N2a have similar prognosis to T2N0/T3N0 (T1N2a) or T4aN0 (T2N2a). Prognosis for T4a lesions is better than T4b by N category. The number of positive nodes affects prognosis. Conclusion This SEER population-based rectal cancer analysis validates the rectal pooled analyses and supports the shift of T1-2N2 lesions from IIIC to IIIA or IIIB and T4bN1 from IIIB to IIIC. SEER outcomes support subdividing T4, N1, and N2 and revised substaging of stages II and III. Survival by TN category suggests a complex biologic interaction between depth of invasion and nodal status.
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Wei, Ling-ling, Wen-chan Chen, Wei-cheng Zhao, Jin Wang, Bing-ran Wang, Feng-jie Li, Meng-di Wei, et al. "Mutations and Overexpression of CYP51 Associated with DMI-Resistance in Colletotrichum gloeosporioides from Chili." Plant Disease 104, no. 3 (March 2020): 668–76. http://dx.doi.org/10.1094/pdis-08-19-1628-re.

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Chili anthracnose caused by Colletotrichum spp. is an annual production concern for growers in China. Sterol C14-demethylation inhibitors (DMIs, such as tebuconazole) have been widely used to control this disease for more than three decades. In the current study, of 48 isolates collected from commercial chili farms in Jiangsu Province of China during 2018 and 2019, 8 single-spore isolates were identified as Colletotrichum gloeosporioides and the rest were identified as C. acutatum. To determine whether the DMI resistance of isolates develops in the field, mycelial growth of the 48 isolates was measured in culture medium with and without tebuconazole. In all, 6 of the 8 C. gloeosporioides isolates were resistant to tebuconazole, but all 40 of the C. acutatum isolates were sensitive to tebuconazole. The fitness cost of resistance was low based on a comparison of fitness parameters between the sensitive and resistant isolates of C. gloeosporioides. Positive cross-resistance was observed between tebuconazole and difenconazole or propiconazole, but not prochloraz. Alignment results of the CgCYP51 amino acid sequences from the sensitive and resistant isolates indicated that mutations can be divided into three genotypes. Genotype I possessed four substitutions (V18F, L58V, S175P, and P341A) at the CgCYP51A gene but no substitutions at CgCYP51B, while genotype II had five substitutions (L58V, S175P, A340S, T379A, and N476T) at CgCYP51A, concomitant with three substitutions (D121N, T132A, and F391Y) at CgCYP51B. In addition, genotype III contained two substitutions (L58V and S175P) at CgCYP51A, concomitant with one substitution (T262A) at CgCYP51B. Molecular docking models illustrated that the affinity of tebuconazole to the binding site of the CgCYP51 protein from the resistant isolates was decreased when compared with binding site affinity of the sensitive isolates. Our findings provide not only novel insights into understanding the resistance mechanism to DMIs, but also some important references for resistance management of C. gloeosporioides on chili.
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Xu, Min-Gang, Juan Li, Xing Du, and En-Duo Wang. "Groups on the side chain of T252 in Escherichia coli leucyl-tRNA synthetase are important for discrimination of amino acids and cell viability." Biochemical and Biophysical Research Communications 318, no. 1 (May 2004): 11–16. http://dx.doi.org/10.1016/j.bbrc.2004.03.180.

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32

Bell, Richard L. "Fruit Quality of Pear Psylla-resistant Parental Germplasm." HortScience 49, no. 2 (February 2014): 138–40. http://dx.doi.org/10.21273/hortsci.49.2.138.

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Sixteen interspecific backcross hybrid selections from various breeding programs have been selected as prospective parents for breeding for resistance of European-type pears to the pear psyllids (Cacopsylla spp.). The Pyrus communis × P. pyrifolia (n = 6) backcross selections are derived mostly from NJ 1, an open-pollinated P. pyrifolia seedling, and the Pyrus communis × P. ussuriensis (n = 9) backcross selections are derived from Illinois 76, an open-pollinated P. ussuriensis seedling, and one Pyrus communis × P. ussuriensis cultivar. Ratings of psylla resistance have been based primarily on multiyear orchard observations under no-pesticide and minimal pesticide conditions. To select the best prospective parents, data on fruit quality and tree traits were analyzed. Fruit characteristics included harvest date, fruit size and shape, skin color, percentage blush, russet, overall appearance, texture (flesh fineness), texture type, juiciness, overall grittiness and grit size, flavor acceptability and type, aroma, and a quality index, which was an unweighted total of the scores for appearance, texture, grit, flavor, and aroma. For this report, comparisons were made to ‘Bartlett’, the most widely grown U.S. pear cultivar. Both the P. communis × P. pyrifolia and Pyrus communis × P. ussuriensis backcross hybrid groups had significantly lower quality indices than ‘Bartlett’, and most individual traits were similar in this respect. There were significant differences among selections for all traits as were differences between years within genotype for most traits with some exceptions. Harvest date, percentage blush, appearance, juiciness, flavor, and the quality index were relatively stable from year to year. Flesh texture type varied within each group. The P. communis × P. pyrifolia selection NJ Rock R23 T252 had the highest quality index of the selections. For eight traits, various selections ranked higher than ‘Bartlett’, although the differences were not significantly higher with the exception of the russet score. Five selections appear to have sufficient quality and are being used as parents.
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Chang, Wing Chung, Chun Ho, Chi Fai Or, Tsz Ting Liu, Fu Chun Lau, On Ki Chu, Lai Ming Hui, et al. "T252. TREATMENT DELAY AND OUTCOME COMPARISON OF EXTENDED EARLY INTERVENTION SERVICE AND STANDARD PSYCHIATRIC CARE FOR ADULTS PRESENTING WITH FIRST-EPISODE PSYCHOSIS IN HONG KONG." Schizophrenia Bulletin 44, suppl_1 (April 1, 2018): S215. http://dx.doi.org/10.1093/schbul/sby016.528.

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34

Ladner, R. D., M. A. Gordon, W. Zhang, D. Yang, F. Nagashima, H. Chang, G. Lurje, E. Borucka, and H. Lenz. "Polymorphisms in estrogen receptor beta, interleukin-8, and interleukin-8 receptor associated with clinical outcome in metastatic colorectal cancer (mCRC) patients treated with 5-fluorouracil/oxaliplatin." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 4130. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.4130.

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4130 Background: Many factors contribute to the progression of colorectal cancer and to chemoresistance. Two factors that have recently gained attention are angiogenesis and sex hormones. Interleukin-8 and its receptors play a critical role in angiogenesis, and polymorphisms in these genes have previously been reported to predict clinical outcome and resistance to therapy in a variety of cancer types. In addition, gender and the subsequent varied levels of sex hormones between males and females may also have an impact on colorectal cancer progression. Sex hormones such as estrogen exert their effects on the cell by binding to steroid receptors such as estrogen receptor beta (ER-β). It is known that ER-β is predominantly expressed in the colon, and that differential expression of this gene is predictive of clinical outcome. Therefore, functional polymorphisms within ER-β, IL-8, and the IL-8 receptors may prove to be molecular markers for predicting clinical outcome in colorectal cancer patients. Methods: 173 patients were enrolled in this phase II study. 152 patients were evaluable for genotyping and statistical analysis. There were 74 females and 78 males, and median age was 60 (range 25–87). The dose of oxaliplatin was 130mg/m2 every 3 weeks and 5-FU was 200mg/m2/day CI for 10 weeks followed by 2 weeks rest. Polymorphisms in estrogen receptor beta, IL-8, and CXCR2 (IL-8 receptor) were tested by PCR. Results: Median follow-up was 18.6 months, response rate 19%, median time to tumor progression 4.2 months and median survival 10.3 months. IL-8 T251A polymorphism was predictive of time to tumor progression (p=0.04, log-rank test). ER-β CA repeat polymorphism was predictive of tumor response as well as time to tumor progression (p=0.015, p=0.012, respectively). ER-β A730G SNP was also predictive of time to tumor progression (p=0.03). Polymorphism in CXCR2 was predictive of tumor response (p=0.034). Conclusions: Our results suggest that polymorphisms within IL-8, CXCR2, and ER-β may affect the progression of colorectal cancer and subsequent clinical outcome. These results highlight the importance of angiogenesis and hormone levels in colorectal cancer. No significant financial relationships to disclose.
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Grim, Jonathan E., Olga Sala, Nack Gyun Chung, Jerald Radich, Barbara J. Varnum-Finney, Irwin D. Bernstein, and Bruce Clurman. "Notch Regulation by the Fbw7/hcdc4/Sel-10 Ubiquitin Ligase." Blood 108, no. 11 (November 16, 2006): 1420. http://dx.doi.org/10.1182/blood.v108.11.1420.1420.

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Abstract T-cell neoplasms frequently sustain mutations in the Notch1 gene, leading to the expression of constitutively active Notch proteins. Such mutations often target the C-terminal PEST domain, which is known to be involved in protein stability. The ubiquitin ligase Fbw7/hdcd4/Sel-10 is a tumor suppressor that negatively regulates Notch function by targeting the Notch protein for ubiquitination and proteasomal degradation. Although the PEST domain is known to be important for Fbw7/Notch interactions, the specific residues that regulate binding of Notch to Fbw7 have not been defined. Based on the structural motifs (known as phosphodegrons) common to known substrates of Fbw7, we have identified two candidate peptide sequences within the Notch protein and have generated a series of mutants in these regions. Using co-immunoprecipitation assays, we show that one potential phosphodegron that is outside of the PEST domain does not appear to influence Notch binding to Fbw7. However, a second potential phosphodegron is present within the PEST domain and contains a conserved threonine residue (T2512) which is central to binding of Fbw7 to Notch. A mutant in which this residue is replaced by alanine (T2512A) shows a prolonged half life when compared to wild type Notch ICD, supporting its role in Notch stability. To evaluate the role of Fbw7 mediated Notch degradation in vitro and in vivo, we used lentiviral vectors to transfect hematopoietic cells with shRNA targeting Fbw7. These studies demonstrate that Fbw7 knockdown leads to phenotypes consistent with increased Notch activity. Because Notch is commonly mutated in human leukemias, we hypothesized that Fbw7 may also sustain mutations that lead to loss of Notch regulation. We evaluated primary human T cell leukemias for mutations in Fbw7 and found that 1 of 23 samples contains a heterozygous mutation in the Fbw7 common region (R505C). We show that this mutant is deficient in binding to Notch, suggesting that Fbw7 mutation may contribute to the deregulation of Notch that is commonly seen in T-cell neoplasms. Together, this work shows that Fbw7 is an important regulator of Notch function whose mutation may be an important step in leukemogenesis.
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Shen, Yuqiao, Galila Kitzes, Julie A. Nye, Ali Fattaey, and Terry Hermiston. "Analyses of Single-Amino-Acid Substitution Mutants of Adenovirus Type 5 E1B-55K Protein." Journal of Virology 75, no. 9 (May 1, 2001): 4297–307. http://dx.doi.org/10.1128/jvi.75.9.4297-4307.2001.

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ABSTRACT The E1B-55K protein plays an important role during human adenovirus type 5 productive infection. In the early phase of the viral infection, E1B-55K binds to and inactivates the tumor suppressor protein p53, allowing efficient replication of the virus. During the late phase of infection, E1B-55K is required for efficient nucleocytoplasmic transport and translation of late viral mRNAs, as well as for host cell shutoff. In an effort to separate the p53 binding and inactivation function and the late functions of the E1B-55K protein, we have generated 26 single-amino-acid mutations in the E1B-55K protein. These mutants were characterized for their ability to modulate the p53 level, interact with the E4orf6 protein, mediate viral late-gene expression, and support virus replication in human cancer cells. Of the 26 mutants, 24 can mediate p53 degradation as efficiently as the wild-type protein. Two mutants, R240A (ONYX-051) and H260A (ONYX-053), failed to degrade p53 in the infected cells. In vitro binding assays indicated that R240A and H260A bound p53 poorly compared to the wild-type protein. When interaction with another viral protein, E4orf6, was examined, H260A significantly lost its ability to bind E4orf6, while R240A was fully functional in this interaction. Another mutant, T255A, lost the ability to bind E4orf6, but unexpectedly, viral late-gene expression was not affected. This raised the possibility that the interaction between E1B-55K and E4orf6 was not required for efficient viral mRNA transport. Both R240A and H260A have retained, at least partially, the late functions of wild-type E1B-55K, as determined by the expression of viral late proteins, host cell shutoff, and lack of a cold-sensitive phenotype. Virus expressing R240A (ONYX-051) replicated very efficiently in human cancer cells, while virus expressing H260A (ONYX-053) was attenuated compared to wild-type virus dl309 but was more active than ONYX-015. The ability to separate the p53-inactivation activity and the late functions of E1B-55K raises the possibility of generating adenovirus variants that retain the tumor selectivity of ONYX-015 but can replicate more efficiently than ONYX-015 in a broad spectrum of cell types.
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Pawloski, John R., Brion Randolph, and Paulie Bajic. "Foundation-OneR-Heme Next Generation Sequencing of Hairy Cell Leukemia Variant Lymphocytes." Blood 128, no. 22 (December 2, 2016): 5289. http://dx.doi.org/10.1182/blood.v128.22.5289.5289.

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Abstract Hairy Cell Leukemia variant (HCL-V) is a rare disorder of small, mature, B-cell lymphocytes, and is characterized clinically by splenomegaly, an elevated white blood cell (WBC) count, and a hypercellular bone marrow. It accounts for 0.4% of chronic lymphoid and 10% of all cases of hairy cell leukemia (HCL) cases, respectively, and is now considered by the World Health Organization (WHO) to be a distinct provisional entity, biologically unrelated to classical HCL (HCL-C). The median survival is 9 years, with 42% of patients dying of unrelated causes. Transformation to large cell lymphoma is seen in 6% of patients. Whereas HCL-C patients are typically middle-aged males, who manifest lymphocytosis, splenomegaly, and cytopenias, with malignant lymphocytes that express CD103 and CD25, the median age of HCL-V patients is 71 years with no gender preference, and whose cells are characterized by expression of CD103, but lacking CD25. HCL-V also has a more aggressive clinical course, with far lower response rates to purine nucleoside analogs, but better responses to anti-CD20 and anti-CD22 immunotherapies. The BRAF-V600E mutation is considered the molecular hallmark of HCL-C, while 16% have recurrent inactivating mutations of the cell cycle inhibitor CDKN1B, making it the second most common mutation in HCL-C. In contrast, while del17p13 and mutations of the TP53 and MAP2K1 genes are frequent in HCL-V, there are no defining chromosomal or genetic abnormalities, and little is known about the genetic underpinnings of this rare condition. We evaluated a 50 year-old African-American male who was referred to us for an incidental asymptomatic lymphocytosis of 11,990/uL. Flow cytometry showed these monoclonal B lymphocytes to express CD103, CD11c (bright), CD20, CD22, and CD52, but they did not express CD5, CD10, or CD25, with a chronic lymphocytic leukemia (CLL) immunophenotypic (Matutes) score of 0, consistent with HCL-V. A CCND/IgVH translocation was seen in 5% of these cells, and the IgVH gene was mutated at a rate of 7.2%. The patient had a normal hemoglobin and platelet count, and a computed tomography (CT) scan with contrast showed no adenopathy or splenomegaly. Foundation One' Heme Next Generation Sequencing (NGS) was performed on this patient's peripheral blood lymphocytes, and revealed several variants of unknown significance (VUS) including ALK P1599H, BRD4 Q969_L9, CARD11 D764G, CBL L43_S44, CHEK2 D438Y, FANCC Q465R, FANCL S82R, FOX03 P138L, GNAS T398M, GSK3B R396Q, HDAC7 T161M, MET V919I, PIM1 E142D, SOX2 T232A, SYK Y348C, TRAF2 R372H, and YY1AP1 S47P. Notably, no abnormalities in the BRAF, TP53, MAP2K1, and CCND family of genes were observed. A search of multiple literature and genetic databases for the gene sequence variants listed above was performed to assess for their known correlations to lymphoproliferative malignancies, especially HCL-V and HCL-C. These databases included PubMed (http://www.ncbi.nlm.nih.gov/pubmed), Genetics Home Reference (https://ghr.nlm.nih.gov/) Cancer Genetics Web (http://www.cancer-genetics.org/), and Gene Cards (http://www.genecards.org/). Mutations or translocations in the genes ALK, CARD11, HDAC7, MET, leukemia, Burkitt's lymphoma and Hodgkin's disease leukemia, Burkitt's lymphoma and Hodgkin's disease leukemia, Burkitt's lymphoma and Hodgkin's diseasePIM1, SOX2, and SYK, were found to have clear associations with various lymphoid malignancies, including large B cell lymphoma (CARD11, PIM1), Burkitt lymphoma (HDAC7, MET), anaplastic large cell lymphoma (ALK, SOX2), Hodgkin lymphoma (MET), mantle cell lymphoma (SOX2), pro-B cell ALL (HDAC7), and rare peripheral T cell lymphomas (SYK). Alterations in CARD11 have also been associated with congenital B cell lymphocytosis. However, none of the specific variants/mutations identified by NGS of our patient's HCL-V cells have previously been described to be associated with either HCL-V or HCL-C. These results may thus help to elucidate the molecular pathogenesis of this rare hematologic malignancy, and emphasize the need to apply this technology to a greater number of HCL-V cases to assess for recurring genetic variations that may distinguish this unique disorder. Disclosures No relevant conflicts of interest to declare.
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Ishikawa, Masahito, Sho Yokoe, Souichiro Kato, and Katsutoshi Hori. "Efficient Counterselection forMethylococcus capsulatus(Bath) by Using a MutatedpheSGene." Applied and Environmental Microbiology 84, no. 23 (September 28, 2018). http://dx.doi.org/10.1128/aem.01875-18.

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ABSTRACTMethylococcus capsulatus(Bath) is a representative gammaproteobacterial methanotroph that has been studied extensively in diverse research fields. ThesacBgene, which encodes levansucrase, causing cell death in the presence of sucrose, is widely used as a counterselectable marker for disruption of a target gene in Gram-negative bacteria. However,sacBis not applicable to all Gram-negative bacteria, and its efficiency for the counterselection ofM. capsulatus(Bath) is low. Here, we report the construction of an alternative counterselectable marker,pheS*, by introduction of two point mutations (A306G and T252A) into thepheSgene fromM. capsulatus(Bath), which encodes the α-subunit of phenylalanyl-tRNA synthetase. The transformant harboringpheS* on an expression plasmid showed sensitivity to 10 mMp-chloro-phenylalanine, whereas the transformant harboring an empty plasmid showed no sensitivity, indicating the availability ofpheS* as a counterselectable marker inM. capsulatus(Bath). To validate the utility of thepheS* marker in counterselection, we attempted to obtain an unmarked mutant ofxoxF, a gene encoding the major subunit of Xox methanol dehydrogenase, which we failed to obtain by counterselection using thesacBmarker. PCR, immunodetection using an anti-XoxF antiserum, and a cell growth assay in the absence of calcium demonstrated successful disruption of thexoxFgene inM. capsulatus(Bath). The difference in counterselection efficiencies of the markers indicated thatpheS* is more suitable thansacBfor counterselection inM. capsulatus(Bath). This study provides a new genetic tool enabling efficient counterselection inM. capsulatus(Bath).IMPORTANCEMethanotrophs have long been considered promising strains for biologically reducing methane from the environment and converting it into valuable products, because they can oxidize methane at ambient temperatures and pressures. Although several methodologies and tools for the genetic manipulation of methanotrophs have been developed, their mutagenic efficiency remains lower than that of tractable strains such asEscherichia coli. Therefore, further improvements are still desired. The significance of our study is that we increased the efficiency of counterselection inM. capsulatus(Bath) by employingpheS*, which was newly constructed as a counterselectable marker. This will allow for the efficient production of gene-disrupted and gene-integrated mutants ofM. capsulatus(Bath). We anticipate that this counterselection system will be utilized widely by the methanotroph research community, leading to improved productivity of methane-based bioproduction and new insights into methanotrophy.
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AlAjmi, Mohamed F., Shama Khan, Arunabh Choudhury, Taj Mohammad, Saba Noor, Afzal Hussain, Wenying Lu, et al. "Impact of Deleterious Mutations on Structure, Function and Stability of Serum/Glucocorticoid Regulated Kinase 1: A Gene to Diseases Correlation." Frontiers in Molecular Biosciences 8 (November 3, 2021). http://dx.doi.org/10.3389/fmolb.2021.780284.

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Serum and glucocorticoid-regulated kinase 1 (SGK1) is a Ser/Thr protein kinase involved in regulating cell survival, growth, proliferation, and migration. Its elevated expression and dysfunction are reported in breast, prostate, hepatocellular, lung adenoma, and renal carcinomas. We have analyzed the SGK1 mutations to explore their impact at the sequence and structure level by utilizing state-of-the-art computational approaches. Several pathogenic and destabilizing mutations were identified based on their impact on SGK1 and analyzed in detail. Three amino acid substitutions, K127M, T256A, and Y298A, in the kinase domain of SGK1 were identified and incorporated structurally into original coordinates of SGK1 to explore their time evolution impact using all-atom molecular dynamic (MD) simulations for 200 ns. MD results indicate substantial conformational alterations in SGK1, thus its functional loss, particularly upon T256A mutation. This study provides meaningful insights into SGK1 dysfunction upon mutation, leading to disease progression, including cancer, and neurodegeneration.
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40

Ding, Donglin, Rongbin Zheng, Ye Tian, Rafael Jimenez, Xiaonan Hou, Saravut J. Weroha, Liguo Wang, Lei Shi, and Haojie Huang. "Retinoblastoma protein as an intrinsic BRD4 inhibitor modulates small molecule BET inhibitor sensitivity in cancer." Nature Communications 13, no. 1 (October 23, 2022). http://dx.doi.org/10.1038/s41467-022-34024-y.

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AbstractBromodomain and extraterminal (BET) proteins including BRD4 play important roles in oncogenesis and immune inflammation. Here we demonstrate that cancer cells with loss of the retinoblastoma (RB) tumor suppressor became resistant to small molecule bromodomain inhibitors of BET proteins. We find that RB binds to bromodomain-1 (BD1) of BRD4, but binding is impeded by CDK4/6-mediated RB phosphorylation at serine-249/threonine-252 (S249/T252). ChIP-seq analysis shows RB knockdown increases BRD4 occupancy at genomic loci of genes enriched in cancer-related pathways including the GPCR-GNBIL-CREB axis. S249/T252-phosphorylated RB positively correlates with GNBIL protein level in prostate cancer patient samples. BET inhibitor resistance in RB-deficient cells is abolished by co-administration of CREB inhibitor. Our study identifies RB protein as a bona fide intrinsic inhibitor of BRD4 and demonstrates that RB inactivation confers resistance to small molecule BET inhibitors, thereby revealing a regulatory hub that converges RB upstream signaling onto BRD4 functions in diseases such as cancer.
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41

Song, Hanbit, Pyung-Gang Lee, Junyeob Kim, Joonwon Kim, Sang-Hyuk Lee, Hyun Kim, Uk-Jae Lee, Jin Young Kim, Eun-Jung Kim, and Byung-Gee Kim. "Regioselective One-Pot Synthesis of Hydroxy-(S)-Equols Using Isoflavonoid Reductases and Monooxygenases and Evaluation of the Hydroxyequol Derivatives as Selective Estrogen Receptor Modulators and Antioxidants." Frontiers in Bioengineering and Biotechnology 10 (March 24, 2022). http://dx.doi.org/10.3389/fbioe.2022.830712.

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Several regiospecific enantiomers of hydroxy-(S)-equol (HE) were enzymatically synthesized from daidzein and genistein using consecutive reduction (four daidzein-to-equol–converting reductases) and oxidation (4-hydroxyphenylacetate 3-monooxygenase, HpaBC). Despite the natural occurrence of several HEs, most of them had not been studied owing to the lack of their preparation methods. Herein, the one-pot synthesis pathway of 6-hydroxyequol (6HE) was developed using HpaBC (EcHpaB) from Escherichia coli and (S)-equol-producing E. coli, previously developed by our group. Based on docking analysis of the substrate or products, a potential active site and several key residues for substrate binding were predicted to interpret the (S)-equol hydroxylation regioselectivity of EcHpaB. Through investigating mutations on the key residues, the T292A variant was verified to display specific mono-ortho-hydroxylation activity at C6 without further 3′-hydroxylation. In the consecutive oxidoreductive bioconversion using T292A, 0.95 mM 6HE could be synthesized from 1 mM daidzein, while 5HE and 3′HE were also prepared from genistein and 3′-hydroxydaidzein (3′HD or 3′-ODI), respectively. In the following efficacy tests, 3′HE and 6HE showed about 30∼200-fold higher EC50 than (S)-equol in both ERα and ERβ, and they did not have significant SERM efficacy except 6HE showing 10% lower β/α ratio response than that of 17β-estradiol. In DPPH radical scavenging assay, 3′HE showed the highest antioxidative activity among the examined isoflavone derivatives: more than 40% higher than the well-known 3′HD. In conclusion, we demonstrated that HEs could be produced efficiently and regioselectively through the one-pot bioconversion platform and evaluated estrogenic and antioxidative activities of each HE regio-isomer for the first time.
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Breitinger, Ulrike, Heinrich Sticht, and Hans-Georg Breitinger. "Modulation of recombinant human alpha 1 glycine receptor by flavonoids and gingerols." Biological Chemistry, March 22, 2021. http://dx.doi.org/10.1515/hsz-2020-0360.

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Abstract The inhibitory glycine receptor (GlyR) is a principal mediator of fast synaptic inhibition in mammalian spinal cord, brainstem, and higher brain centres. Flavonoids are secondary plant metabolites that exhibit many beneficial physiological effects, including modulatory action on neuronal receptors. Using whole-cell current recordings from recombinant human α1 GlyRs, expressed in HEK293 cells, we compared the flavonols kaempferol and quercetin, the flavanone naringenin, the flavones apigenin and nobiletin, the isoflavone genistein, and two gingerols, 6-gingerol and 8-gingerol for their modulation of receptor currents. All compounds were inhibitors of the GlyR with IC50 values ranging between 9.3 ± 2.6 µM (kaempferol) and 46.7 ± 6.5 µM (genistein), following a mixed mode of inhibition. Co-application of two inhibitors revealed distinct binding sites for flavonoids and gingerols. Pore-lining mutants T258A and T258S were strongly inhibited by quercetin and naringenin, but not by 6-gingerol, confirming the existence of distinct binding sites for flavonoids and gingerols. Apigenin, kaempferol, nobiletin, naringenin and 6-gingerol showed biphasic action, potentiating glycine-induced currents at low concentration of both, modulator and glycine, and inhibiting at higher concentrations. Identification of distinct modulatory sites for flavonoids and related compounds may present pharmacological target sites and aid the discovery of novel glycinergic drugs.
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