On the nucleolus of neighbor games

Assignment problems are well-known problems in practice. We mention house markets, job markets, and production planning. The games of interest in this paper, the neighbor games, arise from a special class of assignment problems. We focus on the nucleolus [d. Schmeidler, siam j. Appl. Math. 17 (1969) 1163–1170], one of the most prominent core solutions. A core solution is interesting with respect to neighbor games because it divides the profit of an optimal matching in a stable manner. This paper establishes a polynomial bounded algorithm of quadratic order in the number of players for calculating the nucleolus of neighbor games

Novel role of neuronal Ca2+ sensor-1 as a survival factor up-regulated in injured neurons

A molecular basis of survival from neuronal injury is essential for the development of therapeutic strategy to remedy neurodegenerative disorders. In this study, we demonstrate that an EF-hand Ca2+-binding protein neuronal Ca2+ sensor-1 (NCS-1), one of the key proteins for various neuronal functions, also acts as an important survival factor. Overexpression of NCS-1 rendered cultured neurons more tolerant to cell death caused by several kinds of stressors, whereas the dominant-negative mutant (E120Q) accelerated it. In addition, NCS-1 proteins increased upon treatment with glial cell line–derived neurotrophic factor (GDNF) and mediated GDNF survival signal in an Akt (but not MAPK)-dependent manner. Furthermore, NCS-1 is significantly up-regulated in response to axotomy-induced injury in the dorsal motor nucleus of the vagus neurons of adult rats in vivo, and adenoviral overexpression of E120Q resulted in a significant loss of surviving neurons, suggesting that NCS-1 is involved in an antiapoptotic mechanism in adult motor neurons. We propose that NCS-1 is a novel survival-promoting factor up-regulated in injured neurons that mediates the GDNF survival signal via the phosphatidylinositol 3-kinase–Akt pathway

Electron transport through 8-oxoG: NEGF/DFT study

We present a first-principles study of the conductance of Guanine and 8-Oxoguanine (8-oxoG) attached to Au(111) electrodes. Cellular levels of 8-oxoG have been found in larger concentrations in cancer patients. The current through the structure was calculated using a DFT–NEGF formalism. We have compared flat and pyramidal electrode geometries and show that there is a measurable difference between the I–V characteristics of the pristine molecule and the 8-oxoG. For a flat electrode geometry, 8-oxoG produces a 2.57 (18.3) times increase in current than the corresponding counterpart at 3 V with a bond separation of 1.2 Å (2.4 Å). This can be attributed to molecular orbital energies shifting at the junction. Overall the flat geometry produces larger currents. We have also investigated the sensitivity of the current to the electrode molecule separation. For the flat geometry, the current dropped approximately 80% (97%) for 8-oxoG (pristine Guanine) with the doubling of the electrode separation

Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2

Deregulated redox metabolism in cancer leads to oxidative damage to cellular components including deoxyribonucleoside triphosphates (dNTPs). Targeting dNTP pool sanitizing enzymes, such as MTH1, is a highly promising anticancer strategy. The MTH2 protein, known as NUDT15, is described as the second human homologue of bacterial MutT with 8-oxo-dGTPase activity. We present the first NUDT15 crystal structure and demonstrate that NUDT15 prefers other nucleotide substrates over 8-oxo-dGTP. Key structural features are identified that explain different substrate preferences for NUDT15 and MTH1. We find that depletion of NUDT15 has no effect on incorporation of 8-oxo-dGTP into DNA and does not impact cancer cell survival in cell lines tested. NUDT17 and NUDT18 were also profiled and found to have far less activity than MTH1 against oxidized nucleotides. We show that NUDT15 is not a biologically relevant 8-oxo-dGTPase, and that MTH1 is the most prominent sanitizer of the cellular dNTP pool known to date

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

Role of Operon aaoSo-mutT in Antioxidant Defense in Streptococcus oligofermentans

Previously, we have found that an insertional inactivation of aaoSo, a gene encoding L-amino acid oxidase (LAAO), causes marked repression of the growth of Streptococcus oligofermentans. Here, we found that aaoSo and mutT, a homolog of pyrophosphohydrolase gene of Escherichia coli, constituted an operon. Deletion of either gene did not impair the growth of S. oligofermentans, but double deletion of both aaoSo and mutT was lethal. Quantitative PCR showed that the transcript abundance of mutT was reduced for 13-fold in the aaoSo insertional mutant, indicating that gene polarity derived from the inactivation of aaoSo attenuated the expression of mutT. Enzymatic assays were conducted to determine the biochemical functions of LAAO and MutT of S. oligofermentans. The results indicated that LAAO functioned as an aminoacetone oxidase [47.75 nmol H2O2 (min·mg protein)–1]; and MutT showed the pyrophosphohydrolase activity, which removed mutagens such as 8-oxo-dGTP. Like paraquat, aaoSo mutations increased the expression of SOD, and addition of aminoacetone (final concentration, 5 mM) decreased the mutant’s growth by 11%, indicating that the aaoSo mutants are under ROS stress. HPLC did reveal elevated levels of cytoplasmic aminoacetone in both the deletion and insertional gene mutants of aaoSo. Electron spin resonance spectroscopy showed increased hydroxyl radicals in both types of aaoSo mutant. This demonstrated that inactivation of aaoSo caused the elevation of the prooxidant aminoacetone, resulting the cellular ROS stress. Our study indicates that the presence of both LAAO and MutT can prevent endogenous metabolites-generated ROS and mutagens. In this way, we were able to determine the role of the aaoSo-mutT operon in antioxidant defense in S. oligofermentans

A haplotype variation affecting the mitochondrial transportation of hMYH protein could be a risk factor for colorectal cancer in Chinese

<p>Abstract</p> <p>Background</p> <p>The human MutY homolog (<it>hMYH</it>), a DNA glycolsylase involved in the excision repair of oxidative DNA damage, is currently studied in colorectal cancer (CRC). We previously demonstrated a haplotype variant c.53C>T/c.74G>A of <it>hMYH </it>(T/A) increasing the risk for gastric cancer in Chinese. However, most investigations on correlation between <it>hMYH </it>and CRC are conducted in Western countries and the underlying mechanism has been poorly understood.</p> <p>Methods</p> <p>To determine whether the haplotype T/A variant of <it>hMYH </it>was related to colorectal carcinogenesis, we performed a case-control study in 138 colorectal cancer (CRC) patients and 343 healthy controls in a Chinese population. Furthermore, the C/G for wild-type, C/A or T/G for single base variant and T/A for haplotype variant <it>hMYH </it>cDNAs with a flag epitope tag were cloned into pcDNA3.1+ vector and transfected into cos-7 cell line. Their subcellular localizations were determined by immunofluorescence assay.</p> <p>Results</p> <p>It was found that the frequency of haplotype variant allele was statistically higher in CRC patients than that in controls (<it>P </it>= 0.02, odds ratio = 5.06, 95% confidence interval = 1.26 – 20.4). Similarly, significant difference of heterozygote frequency was indicated between the two groups (<it>P </it>= 0.019), while no homozygote was found. In addition, immunofluorescence analysis showed that hMYH protein with haplotype T/A variation presented in both nucleus and mitochondria, in contrast to the wild-type protein only converging in mitochondria. However, neither of the single missense mutations alone changed the protein subcelluar localization.</p> <p>Conclusion</p> <p>Although preliminarily, these results suggest that: the haplotype variant allele of <it>hMYH </it>leads to a missense protein, which partly affects the protein mitochondrial transportation and results as nuclear localization. This observation might be responsible for the increased susceptibility to cancers, including CRC, in Chinese.</p