Microhomology-mediated end joining induces hypermutagenesis at breakpoint junctions

Microhomology (MH) flanking a DNA double-strand break (DSB) drives chromosomal rearrangements but its role in mutagenesis has not yet been analyzed. Here we determined the mutation frequency of a URA3 reporter gene placed at multiple locations distal to a DSB, which is flanked by different sizes (15-, 18-, or 203-bp) of direct repeat sequences for efficient repair in budding yeast. Induction of a DSB accumulates mutations in the reporter gene situated up to 14-kb distal to the 15-bp MH, but more modestly to those carrying 18- and 203-bp or no homology. Increased mutagenesis in MH-mediated end joining (MMEJ) appears coupled to its slower repair kinetics and the extensive resection occurring at flanking DNA. Chromosomal translocations via MMEJ also elevate mutagenesis of the flanking DNA sequences 7.1 kb distal to the breakpoint junction as compared to those without MH. The results suggest that MMEJ could destabilize genomes by triggering structural alterations and increasing mutation burden

Role of S5b/PSMD5 in Proteasome Inhibition Caused by TNF-α/NFκB in Higher Eukaryotes

SummaryThe ubiquitin-proteasome system is essential for maintaining protein homeostasis. However, proteasome dysregulation in chronic diseases is poorly understood. Through genome-wide cell-based screening using 5,500 cDNAs, a signaling pathway leading to NFκB activation was selected as an inhibitor of 26S proteasome. TNF-α increased S5b (HGNC symbol PSMD5; hereafter S5b/PSMD5) expression via NFκB, and the surplus S5b/PSMD5 directly inhibited 26S proteasome assembly and activity. Downregulation of S5b/PSMD5 abolished TNF-α-induced proteasome inhibition. TNF-α enhanced the interaction of S5b/PSMD5 with S7/PSMC2 in nonproteasome complexes, and interference of this interaction rescued TNF-α-induced proteasome inhibition. Transgenic mice expressing S5b/PSMD5 exhibited a reduced life span and premature onset of aging-related phenotypes, including reduced proteasome activity in their tissues. Conversely, S5b/PSMD5 deficiency in Drosophila melanogaster ameliorated the tau rough eye phenotype, enhanced proteasome activity, and extended the life span of tau flies. These results reveal the critical role of S5b/PSMD5 in negative regulation of proteasome by TNF-α/NFκB and provide insights into proteasome inhibition in human disease

Effect of preoperative statin therapy on myocardial protection and morbidity endpoints following off-pump coronary bypass surgery in patients with elevated C-reactive protein level

BACKGROUND: The aim of this study was to investigate the effects of preoperative statin therapy on myocardial protection and morbidity endpoints following off-pump coronary bypass graft surgery (OPCAB) in patients with elevated serum high-sensitivity C-reactive protein (hs-CRP) levels. METHODS: Of the 492 patients who underwent multivessel OPCAB from March 2007 to February 2009, the records of 144 patients whose baseline hs-CRP level > 2 mg/L were reviewed. According to the history of preoperative statin therapy for at least one week, patients were classified as either statin group or control group (72 subjects each). Preoperative and operative characteristics and postoperative data including troponin (Tn)-T level and major morbidity endpoints were obtained and compared. Major morbidity endpoints were defined as permanent stroke, renal dysfunction, hemostatic re-exploration, deep sternal wound infection, and the number of patients requiring prolonged ventilation. RESULTS: Preoperative and operative characteristics were similar between the two groups. There were no significant differences in the incidence of morbidity endpoints between the two groups, except for the number of patients requiring dialysis, which was significantly lower in the statin group (8 vs. 1, P = 0.033). Tn-T level at 24 h after surgery was also significantly lower in the statin group. CONCLUSIONS: In this study, we observed beneficial effects of preoperative statin therapy for at least one week in terms of less myocardial enzyme release and fewer patients requiring dialysis following OPCAB in patients whose preoperative hs-CRP was elevatedope

Volumetric Reductions of Subcortical Structures and Their Localizations in Alcohol-Dependent Patients

Changes in brain morphometry have been extensively reported in various studies examining the effects of chronic alcohol use in alcohol-dependent patients. Such studies were able to confirm the association between chronic alcohol use and volumetric reductions in subcortical structures using FSL (FMRIB software library). However, each study that utilized FSL had different sets of subcortical structures that showed significant volumetric reduction. First, we aimed to investigate the reproducibility of using FSL to assess volumetric differences of subcortical structures between alcohol-dependent patients and control subjects. Second, we aimed to use Vertex analysis, a less utilized program, to visually inspect 3D meshes of subcortical structures and observe significant shape abnormalities that occurred in each subcortical structure. Vertex analysis results from the hippocampus and thalamus were overlaid on top of their respective subregional atlases to further pinpoint the subregional locations where shape abnormalities occurred. We analyzed the volumes of 14 subcortical structures (bilateral thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens) in 21 alcohol-dependent subjects and 21 healthy controls using images acquired with 3T MRI. The images were run through various programs found in FSL, such as SIENAX, FIRST, and Vertex analysis. We found that in alcohol-dependent patients, the bilateral thalamus (left: p < 0.01, right: p = 0.01), bilateral putamen (left: p = 0.02, right: p < 0.01), right globus pallidus (p < 0.01), bilateral hippocampus (left: p = 0.05, right: p = 0.03) and bilateral nucleus accumbens (left: p = 0.05, right: p = 0.03) were significantly reduced compared to the corresponding subcortical structures of healthy controls. With vertex analysis, we observed surface reductions of the following hippocampal subfields: Presubiculum, hippocampal tail, hippocampal molecular layer, hippocampal fissure, fimbria, and CA3. We reproduced the assessment made in previous studies that reductions in subcortical volume were negatively associated with alcohol dependence by using the FMRIB Software Library. In addition, we identified the subfields of the thalamus and hippocampus that showed volumetric reduction

Antioxidant and Anti-Inflammatory Effects of Shungite against Ultraviolet B Irradiation-Induced Skin Damage in Hairless Mice

As fullerene-based compound applications have been rapidly increasing in the health industry, the need of biomedical research is urgently in demand. While shungite is regarded as a natural source of fullerene, it remains poorly documented. Here, we explored the in vivo effects of shungite against ultraviolet B- (UVB-) induced skin damage by investigating the physiological skin parameters, immune-redox profiling, and oxidative stress molecular signaling. Toward this, mice were UVB-irradiated with 0.75 mW/cm2 for two consecutive days. Consecutively, shungite was topically applied on the dorsal side of the mice for 7 days. First, we found significant improvements in the skin parameters of the shungite-treated groups revealed by the reduction in roughness, pigmentation, and wrinkle measurement. Second, the immunokine profiling in mouse serum and skin lysates showed a reduction in the proinflammatory response in the shungite-treated groups. Accordingly, the redox profile of shungite-treated groups showed counterbalance of ROS/RNS and superoxide levels in serum and skin lysates. Last, we have confirmed the involvement of Nrf2- and MAPK-mediated oxidative stress pathways in the antioxidant mechanism of shungite. Collectively, the results clearly show that shungite has an antioxidant and anti-inflammatory action against UVB-induced skin damage in hairless mice

Reversible Lansoprazole-Induced Interstitial Lung Disease Showing Improvement after Drug Cessation

Lansoprazole is an acid proton-pump inhibiting drug that is used for the treatment of duodenal or gastric ulcers, H. pylori infection, gastroesophageal reflux disease or Zollinger-Ellison syndrome. Although lansoprazole is well known for its gastrointestinal and dermatologic adverse effects, mild pulmonary symptoms are also known to develop from taking this drug. There have been no reports about lansoprazole-induced interstitial lung disease. We report here a case of lansoprazole-induced interstitial lung disease that developed in a 66-year-old man

Normal Ambulatory 24-Hour Esophageal pH Values in Koreans -A Multicenter Study-

Ambulatory 24-hr esophageal pH monitoring is considered the gold standard for diagnosing gastroesophageal reflux disease. The aim of this study was to establish normal values for gastroesophageal acid exposure in healthy Koreans. Fifty healthy volunteers (24 males and 26 females; mean age, 45 yr) without reflux symptoms and without reflux esophagitis or hiatal hernia on upper endoscopy underwent ambulatory 24-hr esophageal pH monitoring after esophageal manometry. The 95th percentiles for the reflux parameters were: the percent total time pH <4, 3.7%; the percent upright time pH <4, 5.7%; the percent supine time pH <4, 1.0%; the number of reflux episodes with pH <4, 76.5; the number of reflux episodes with pH <4 for >5 min, 1.5; the duration of the longest episode, 12.5 min; and the composite score, 14.2. Age and gender were not associated with any of the pH parameters. In conclusion, physiological gastroesophageal reflux occurs in healthy Koreans. These normal esophageal pH values will provide reference data for clinical and research studies in Korea