Characterization of Oxidative Guanine Damage and Repair in Mammalian Telomeres

8-oxo-7,8-dihydroguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) are among the most common oxidative DNA lesions and are substrates for 8-oxoguanine DNA glycosylase (OGG1)–initiated DNA base excision repair (BER). Mammalian telomeres consist of triple guanine repeats and are subject to oxidative guanine damage. Here, we investigated the impact of oxidative guanine damage and its repair by OGG1 on telomere integrity in mice. The mouse cells were analyzed for telomere integrity by telomere quantitative fluorescence in situ hybridization (telomere–FISH), by chromosome orientation–FISH (CO–FISH), and by indirect immunofluorescence in combination with telomere–FISH and for oxidative base lesions by Fpg-incision/Southern blot assay. In comparison to the wild type, telomere lengthening was observed in Ogg1 null (Ogg1−/−) mouse tissues and primary embryonic fibroblasts (MEFs) cultivated in hypoxia condition (3% oxygen), whereas telomere shortening was detected in Ogg1−/− mouse hematopoietic cells and primary MEFs cultivated in normoxia condition (20% oxygen) or in the presence of an oxidant. In addition, telomere length abnormalities were accompanied by altered telomere sister chromatid exchanges, increased telomere single- and double-strand breaks, and preferential telomere lagging- or G-strand losses in Ogg1−/− mouse cells. Oxidative guanine lesions were increased in telomeres in Ogg1−/− mice with aging and primary MEFs cultivated in 20% oxygen. Furthermore, oxidative guanine lesions persisted at high level in Ogg1−/− MEFs after acute exposure to hydrogen peroxide, while they rapidly returned to basal level in wild-type MEFs. These findings indicate that oxidative guanine damage can arise in telomeres where it affects length homeostasis, recombination, DNA replication, and DNA breakage repair. Our studies demonstrate that BER pathway is required in repairing oxidative guanine damage in telomeres and maintaining telomere integrity in mammals

Nitrate regulates floral induction in Arabidopsis, acting independently of light, gibberellin and autonomous pathways

The transition from vegetative growth to reproduction is a major developmental event in plants. To maximise reproductive success, its timing is determined by complex interactions between environmental cues like the photoperiod, temperature and nutrient availability and internal genetic programs. While the photoperiod- and temperature- and gibberellic acid-signalling pathways have been subjected to extensive analysis, little is known about how nutrients regulate floral induction. This is partly because nutrient supply also has large effects on vegetative growth, making it difficult to distinguish primary and secondary influences on flowering. A growth system using glutamine supplementation was established to allow nitrate to be varied without a large effect on amino acid and protein levels, or the rate of growth. Under nitrate-limiting conditions, flowering was more rapid in neutral (12/12) or short (8/16) day conditions in C24, Col-0 and Laer. Low nitrate still accelerated flowering in late-flowering mutants impaired in the photoperiod, temperature, gibberellic acid and autonomous flowering pathways, in the fca co-2 ga1-3 triple mutant and in the ft-7 soc1-1 double mutant, showing that nitrate acts downstream of other known floral induction pathways. Several other abiotic stresses did not trigger flowering in fca co-2 ga1-3, suggesting that nitrate is not acting via general stress pathways. Low nitrate did not further accelerate flowering in long days (16/8) or in 35S::CO lines, and did override the late-flowering phenotype of 35S::FLC lines. We conclude that low nitrate induces flowering via a novel signalling pathway that acts downstream of, but interacts with, the known floral induction pathways

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

New Mexico Daily Lobo, Volume 085, No 100, 2/19/1981

New Mexico Daily Lobo, Volume 085, No 100, 2/19/198