Translesion DNA synthesis, a process orchestrated by monoubiquitinated PCNA, is critical for DNA damage tolerance. While the ubiquitin-conjugating enzyme RAD6 and ubiquitin ligase RAD18 are known to monoubiquitinate PCNA, how they are regulated by DNA damage is not fully understood. We show that NBS1 (mutated in Nijmegen breakage syndrome) binds to RAD18 after UV irradiation and mediates the recruitment of RAD18 to sites of DNA damage. Disruption of NBS1 abolished RAD18-dependent PCNA ubiquitination and Polη focus formation, leading to elevated UV sensitivity and mutation. Unexpectedly, the RAD18-interacting domain of NBS1, which was mapped to its C terminus, shares structural and functional similarity with the RAD18-interacting domain of RAD6. These domains of NBS1 and RAD6 allow the two proteins to interact with RAD18 homodimers simultaneously and are crucial for Polη-dependent UV tolerance. Thus, in addition to chromosomal break repair, NBS1 plays a key role in translesion DNA synthesis.
We measured the single-breath diffusing capacity for carbon monoxide (DLCO), total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV) in anesthetized male hamsters, rats, guinea pigs, and rabbits whose weights varied from 40 to 3,500 g. TLC (defined as an airway pressure of 25 cmH2O) was calculated by neon dilution. The DLCO was estimated by a modification of the single-breath method. There was a high correlation between body weight and our measurement of both the diffusing capacity and the lung volumes. No significant difference in DLCO was observed in rats when measured in different body positions, at airway pressures of 10 or 20 cmH2O, from FRC or RV, in male or female rats, or following hyperventilation.
Although hyperlactemia is known to accompany hepatic failure and metabolic acidosis, few reports examined the relationships between lactate concentrations and outcome after liver resection. We examined the ability of arterial plasma lactate concentration to predict the patient outcome after hepatectomy. The relationships of arterial lactate and base excess (BE) measured on admission to the intensive care unit (ICU) after hepatectomy to postoperative outcome were investigated in 151 consecutive patients. Lactate level was significantly higher in nonsurvivors than in survivors (P < 0.001), and in patients with postoperative complications than in those without complications (P < 0.001). Base excess was significantly reduced in nonsurvivors (P < 0.001) and in patients with postoperative complications (P = 0.004). The area under the receiver-operator curve of lactate to mortality was 0.86, whereas that of BE to the mortality was 0.82. Moderate correlation was observed between the lactate level at ICU admission and the highest total bilirubin concentration measured within 14 days after the surgery (r = 0.61), whereas the correlation between BE and bilirubin levels was lower (r = 0.35). Using multivariate analysis, the lactate level independently predicted mortality (P = 0.008) and morbidity (P = 0.013). Lactate (P < 0.001) and BE (P = 0.0068) levels both independently predicted the highest bilirubin concentration. The arterial plasma lactate concentration measured on admission to ICU seemed an excellent predictor of patient outcome after liver resection.
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