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101.
Said Aoufouchi Annie De Smet Frédéric Delbos Camille Gelot Ida Chiara Guerrera Jean-Claude Weill Claude-Agnès Reynaud 《Molecular and cellular biology》2015,35(17):3059-3070
Mice derived from the 129 strain have a nonsense codon mutation in exon 2 of the polymerase iota (Polι) gene and are therefore considered Polι deficient. When we amplified Polι mRNA from 129/SvJ or 129/Ola testes, only a small fraction of the full-length cDNA contained the nonsense mutation; the major fraction corresponded to a variant Polι isoform lacking exon 2. Polι mRNA lacking exon 2 contains an open reading frame, and the corresponding protein was detected using a polyclonal antibody raised against the C terminus of the murine Polι protein. The identity of the corresponding protein was further confirmed by mass spectrometry. Although the variant protein was expressed at only 5 to 10% of the level of wild-type Polι, it retained de novo DNA synthesis activity, the capacity to form replication foci following UV irradiation, and the ability to rescue UV light sensitivity in Polι−/− embryonic fibroblasts derived from a new, fully deficient Polι knockout (KO) mouse line. Furthermore, in vivo treatment of 129-derived male mice with Velcade, a drug that inhibits proteasome function, stabilized and restored a substantial amount of the variant Polι in these animals, indicating that its turnover is controlled by the proteasome. An analysis of two xeroderma pigmentosum-variant (XPV) cases corresponding to missense mutants of Polη, a related translesion synthesis (TLS) polymerase in the same family, similarly showed a destabilization of the catalytically active mutant protein by the proteasome. Collectively, these data challenge the prevailing hypothesis that 129-derived strains of mice are completely deficient in Polι activity. The data also document, both for 129-derived mouse strains and for some XPV patients, new cases of genetic defects corresponding to the destabilization of an otherwise functional protein, the phenotype of which is reversible by proteasome inhibition. 相似文献
102.
103.
Huang C Moree WJ Zamani-Kord S Li BF Tucci FC Malany S Wen J Wang H Hoare SR Yang C Madan A Crowe PD Beaton G 《Bioorganic & medicinal chemistry letters》2011,21(3):947-951
Structure-activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H1-antihistamines. Reductions in pKa via incorporation of a β-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6. 相似文献
104.
Scott LM Chen L Daniel KG Brooks WH Guida WC Lawrence HR Sebti SM Lawrence NJ Wu J 《Bioorganic & medicinal chemistry letters》2011,21(2):730-733
Shp2 protein tyrosine phosphate (PTP) is a novel target for anticancer drug discovery. We identified estramustine phosphate as a Shp2 PTP inhibitor from the National Cancer Institute Approved Oncology Drug set. A focused structure-activity relationship study indicated that the 17-phosphate group is required for the Shp2 PTP inhibitor activity of estramustine phosphate. A search for estramustine phosphate analogs led to identification of two triterpenoids, enoxolone, and celastrol, having Shp2 PTP inhibitor activity. With the previously reported PTP1B inhibitor trodusquemine, our study reveals steroids and triterpenoids with negatively charged phosphate, carboxylate, or sulfonate groups as novel pharmacophores of selective PTP inhibitors. 相似文献
105.
In this study, effects of different starches (tapioca (TS), wheat (WS), corn (CS), potato (PS), modified corn (MCS) and modified
potato (MPS)) and gums (xanthan gum (XG), guar gum (GG), alginate (A), salep (S), locust bean gum (LBG) and carrageen (C))
on the rheological properties of model hot chocolate beverage were studied. Swelling power (SP) of the starches and water
absorption capacity (WAC) of the gums were determined. Hot chocolate beverages showed pseudoplastic behaviour. Ostwald de
Waele model accurately described flow behaviour of each beverage sample. K, n, R
2 values for Ostwald model were in the range of 4.8–160.3 mPa.sn, 0.5117–0.9745, 0.9972–0.9998, respectively. The highest synergic effect in the model was observed between the interaction
of MCS and XG. The XG-PS, XG-TS, XG-CS combinations showed the highest K and viscosity values, respectively. 相似文献
106.
Aim
To highlight gender-related differences in octogenarians with a congenital coronary artery fistula (CAF).Materials and methods
We present two elderly female patients with a congenital fistula, a septuagenarian and a nonagenarian, and review the world literature between 1954–2010.Results
The septuagenarian patient presented with easy fatigability and the nonagenarian patient with acute myocardial infarction contralaterally to the fistula. Coronary angiography (CAG) demonstrated a coronary-pulmonary artery fistula (CPF). The nonagenarian patient underwent percutaneous coronary intervention of the right coronary artery. CAG revealed a CPF associated with a huge multiple aneurysmal formation. Data from 57 mainly symptomatic patients with a mean age of 75.3 years (range 70–87 years) were collected. The cohort was subdivided into female (mean age 84.3 years) and male (mean age 75.2 years) subgroups and compared with each other. Multi-origin (bilateral and multilateral) was prevalent in females, 40% versus 12% in males. Aneurysmal formation was found in females and males in 40% and 18%, respectively. Ethnicity was 65% Caucasian and 35% Asian. Multi-origin fistulas were prevalent in the Asian (45%) compared with the Caucasian (11%) subset.Conclusions
A septuagenarian and a nonagenarian female patient with congenital CAF are presented. On reviewing the literature, important differences were found between elderly females and males with congenital CAF. 相似文献107.
108.
Temfemo A Carling C Ahmaidi S 《Journal of strength and conditioning research / National Strength & Conditioning Association》2011,25(4):915-921
The aim of this study was to assess the relationship between power output, lactate, skin temperature, and quadriceps muscle activity during brief repeated exercise with increasing intensity. Eighteen regional level soccer players (age 24.5 ± 3.8 years) were selected after a test of maximal exercise capacity to participate in 2 force velocity (Fv) exercise tests separated by 3 days. The tests were done to examine the reliability of variables measured in the selected subjects during this type of task. During each Fv exercise test, data on power output, heart rate (HR), skin temperature, blood lactate accumulation, the root mean square (RMS), and the mean power frequency (MPF) of the surface electromyography of the superficial quadriceps muscle were collected. Results showed a significant correlation between power output and HR, skin temperature, blood lactate accumulation, and RMS. However, no association was observed with MPF that informs on the level of fatigue and power output. Thus, the result of this study may suggest that the Fv exercise test is not a fatigability test. 相似文献
109.
Sayyed A Hamidi Richard Z Lin Anthony M Szema Sergey Lyubsky Ya Ping Jiang Sami I Said 《Respiratory research》2011,12(1):141
Background
Pulmonary Arterial Hypertension (PAH) remains a therapeutic challenge, and the search continues for more effective drugs and drug combinations. We recently reported that deletion of the vasoactive intestinal peptide (VIP) gene caused the spontaneous expression of a PH phenotype that was fully corrected by VIP. The objectives of this investigation were to answer the questions: 1) Can VIP protect against PH in other experimental models? and 2) Does combining VIP with an endothelin (ET) receptor antagonist bosentan enhance its efficacy?Methods
Within 3 weeks of a single injection of monocrotaline (MCT, s.c.) in Sprague Dawley rats, PAH developed, manifested by pulmonary vascular remodeling, lung inflammation, RV hypertrophy, and death within the next 2 weeks. MCT-injected animals were either untreated, treated with bosentan (p.o.) alone, with VIP (i.p.) alone, or with both together. We selected this particular combination upon finding that VIP down-regulates endothelin receptor expression which is further suppressed by bosentan. Therapeutic outcomes were compared as to hemodynamics, pulmonary vascular pathology, and survival.Results
Treatment with VIP, every other day for 3 weeks, begun on the same day as MCT, almost totally prevented PAH pathology, and eliminated mortality for 45 days. Begun 3 weeks after MCT, however, VIP only partially reversed PAH pathology, though more effectively than bosentan. Combined therapy with both drugs fully reversed the pathology, while preventing mortality for at least 45 days.Conclusions
1) VIP completely prevented and significantly reversed MCT-induced PAH; 2) VIP was more effective than bosentan, probably because it targets a wider range of pro-remodeling pathways; and 3) combination therapy with VIP plus bosentan was more effective than either drug alone, probably because both drugs synergistically suppressed ET-ET receptor pathway. 相似文献110.