Local time penalizations with various clocks for Lévy processes

Several long-time limit theorems of one-dimensional Lévy processes weighted and normalized by functions of the local time are studied. The long-time limits are taken via certain families of random times, called clocks: exponential clock, hitting time clock, two-point hitting time clock and inverse local time clock. The limit measure can be characterized via a certain martingale expressed by an invariant function for the process killed upon hitting zero. The limit processes may differ according to the choice of the clocks when the original Lévy process is recurrent and of finite variance

The Epistatic Relationship between BRCA2 and the Other RAD51 Mediators in Homologous Recombination

RAD51 recombinase polymerizes at the site of double-strand breaks (DSBs) where it performs DSB repair. The loss of RAD51 causes extensive chromosomal breaks, leading to apoptosis. The polymerization of RAD51 is regulated by a number of RAD51 mediators, such as BRCA1, BRCA2, RAD52, SFR1, SWS1, and the five RAD51 paralogs, including XRCC3. We here show that brca2-null mutant cells were able to proliferate, indicating that RAD51 can perform DSB repair in the absence of BRCA2. We disrupted the BRCA1, RAD52, SFR1, SWS1, and XRCC3 genes in the brca2-null cells. All the resulting double-mutant cells displayed a phenotype that was very similar to that of the brca2-null cells. We suggest that BRCA2 might thus serve as a platform to recruit various RAD51 mediators at the appropriate position at the DNA–damage site.</p

Characteristic pancreatographic findings in chronic pancreatitis and their diagnostic value. …Studies on post mortem pancreas…

慢性膵炎25例および対照として正常例125例計150例の新鮮剖検膵を用いて膵管造影を行い，X線所見と同部位の組織所見とを厳密に対比させ，慢性膵炎における各X線所見の診断学的価値を検討した。その結果，主膵管像では不整拡張像，硬化＋辺縁不整像，狭窄＋辺縁不整像が，分枝像では不整拡張像および不整配列像が，positive predictive value（PPV），specificity（Sf），negative predictive value（NVP）ともに77.1～100％　の高率を示した。しかしsensitivity（St）は，2.1～18.1％　と低率であった。したがって，これらの所見は慢性膵炎を診断する上で組織予見性および特異性に優れた診断的価値のあるX線所見と言える。しかし一方では軽症の慢性膵炎の検出能はあまりよくないという限界が膵管造影法にはある。Postmortem pancreas tissue was prepared within 6 hours of death for the comparative study of pancreatographic findings and histological findings to define characteristic pancreatographic findings of chronic pancreatitis and determine their diagnostic value. Pancreas tissue was obtained from 25 patients with chronic pancreatitis and 125 with a normal pancreas. Among various pancreatographic findings, irregular dilatation and irregular arrangement of the branches of the pancreatic duct, and also irregular dilatation, rigidity with irregular margin and stenosis with irregular margin of the main pancreatic duct showed the highest sensitivity. specificity, positive predictive value and negative predictive value and conseqently had the highest diagnostic valus. However, the sensitivity was not high enough, indicating that the above pancreatographic findings could be absent at the site of positive histological findings in mild chronic pancreatitis

Moyamoya disease patient mutations in the RING domain of RNF213 reduce its ubiquitin ligase activity and enhance NFκB activation and apoptosis in an AAA+ domain-dependent manner

Moyamoya disease (MMD) is a cerebrovascular disease characterized by progressive occlusion of the internal carotid arteries. Genetic studies originally identified RNF213 as an MMD susceptibility gene that encodes a large 591 kDa protein with a functional RING domain and dual AAA+ ATPase domains. As the functions of RNF213 and its relationship to MMD onset are unknown, we set out to characterize the ubiquitin ligase activity of RNF213, and the effects of MMD patient mutations on these activities and on other cellular processes. In vitro ubiquitination assays, using the RNF213 RING domain, identified Ubc13/Uev1A as a key ubiquitin conjugating enzyme that together generate K63-linked polyubiquitin chains. However, nearly all MMD patient mutations in the RING domain greatly reduced this activity. When full-length proteins were overexpressed in HEK293T cells, patient mutations that abolished the ubiquitin ligase activities conversely enhanced nuclear factor κB (NFκB) activation and induced apoptosis accompanied with Caspase-3 activation. These induced activities were dependent on the RNF213 AAA+ domain. Our results suggest that the NFκB- and apoptosis-inducing functions of RNF213 may be negatively regulated by its ubiquitin ligase activity and that disruption of this regulation could contribute towards MMD onset

Inhibitory Effect of 1α-Hydroxyvitamin D3 on N-nitrosobis (2-oxopropyl)Amine-induced Cholangiocarcinogenesis in Syrian Hamsters

Sixty-three male 5-week-old Syrian hamsters received the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) s.c. in 5 weekly injections (the first, 70mg/kg body, and the remaining, 20mg/kg each). The hamsters that received BOP were given intragastric administration of 0.2ml of medium chain triglyceride (MCT) with or without 0.04μg of 1α-hydroxyvitamin D3 [1α(OH)D3] through a feeding tube for 12 weeks. Thus, 3 groups were assigned:Group 1;BOP alone (n＝20), Group 2;BOP＋MCT (n＝18) and Group 3;BOP＋1α(OH)D3 (n＝25). The mean body weight of Group 3 was lower than those of Groups 1 and 2 at the end of the experiment (p＜0.001,Tukey-Kramer HSD test). At the end of week 12, all surviving hamsters were put to sleep. The incidences of liver tumors were 80%, 72% and 32% in Groups 1, 2 and 3, respectively. The incidence of tumors in Group 3 was significantly lower than in Group 1 and Group 2 (p＜0.05, χ2-test). All tumors were cholangiocarcinoma. These results indicated that BOP-induced cholangiocarcinogenesis was suppressed by the supplemental administration of 1α(OH)D3

Short term effect of spa-water on gastric mucosal blood flow

臓器反射スペクトル法と内視鏡を併用して胃粘膜血流を測定し，当院温泉水飲用の消化機能に対する基礎的検討を胃粘膜血流を指標に行なった。温泉水の対照として空気と白湯を選び3群に分け検討した。その結果，温泉水は空気に比し胃粘膜血流を増加させる作用を有していることが示唆された。また温泉水は部分的ではあるが白湯にくらべても胃粘膜血流を増加させる作用があることが示唆された。よって飲泉療法の消化器疾患に対する臨床的有用性が胃粘膜血流の面からもうかがわれた。Short-term effects of spa-drink therapy on gastric mucosal blood flow were evaluated by an endoscopic organ reflex spectrophotometry, using Olympus XQ-10. Thirty-four subjects were randomly divided into three groups : 10 subjects for warm spa-water (40±C) infusion group, 10 subjects for warm tap-water infusion group, and 14 subjects for warm air infusion group. Intragastric infusion of water or air was performed through the fiberscopic infusion channel. Gastric mucosal blood flow was determined just before and 10 min after the infusion on the three points of gastric mucosa : lesser curvature of the angle, the antrum and the pylorus. Following results were obtained : 1) Spa-water exerted a beneficial effect on gastric mucosal blood flow as compared to air. The difference was statistically significant on all of the three points. 2) Spa-water tended to exert a beneficial effect on gastric mucosal blood flow as compared to tap-water. The difference, however, was significant only on the mucosa of the gastric antrum. In conclusion, it was suggested that spa-drink therapy was useful for the treatment of chronic gastritis and gastric ulcer in which impairment of gastric mucosal blood flow plays an important pathogenetic role. Studies on the long-term effects of spa-drink therapy on the gastric mucosal blood flow are now in progress

UBC13-Mediated Ubiquitin Signaling Promotes Removal of Blocking Adducts from DNA Double-Strand Breaks

Chemical modifications and adducts at DNA double-strand break (DSB) ends must be cleaned before re-joining by non-homologous end-joining (NHEJ). MRE11 nuclease is essential for efficient removal of Topoisomerase II (TOP2)-DNA adducts from TOP2 poison-induced DSBs. However, mechanisms in MRE11 recruitment to DSB sites in G1 phase remain poorly understood. Here, we report that TOP2-DNA adducts are expeditiously removed through UBC13-mediated polyubiquitination, which promotes DSB resection in G2 phase. We found that this ubiquitin signaling is required for efficient recruitment of MRE11 onto DSB sites in G1 by facilitating localization of RAP80 and BRCA1 to DSB sites and complex formation between BRCA1 and MRE11 at DSB sites. UBC13 and MRE11 are dispensable for restriction-enzyme-induced "clean" DSBs repair but responsible for over 50% and 70% of NHEJ-dependent repair of γ-ray-induced "dirty" DSBs, respectively. In conclusion, ubiquitin signaling promotes nucleolytic removal of DSB blocking adducts by MRE11 before NHEJ

Prostate cancer stromal cells and LNCaP cells coordinately activate the androgen receptor through synthesis of testosterone and dihydrotestosterone from dehydroepiandrosterone

金沢大学附属病院泌尿器科金沢大学附属病院泌尿器科One of the mechanisms through which advanced prostate cancer (PCa) usually relapses after androgen deprivation therapy (ADT) is the adaptation to residual androgens in PCa tissue. It has been observed that androgen biosynthesis in PCa tissue plays an important role in this adaptation. In the present study, we investigated how stromal cells affect adrenal androgen dehydroepiandrosterone (DHEA) metabolism in androgen-sensitive PCa LNCaP cells. DHEA alone had little effect on prostate-specific antigen (PSA) promoter activity and the proliferation of LNCaP cells. However, the addition of prostate stromal cells or PCa-derived stromal cells (PCaSC) increased DHEA-induced PSA promoter activity via androgen receptor activation in the LNCaP cells. Moreover, PCaSC stimulated the proliferation of LNCaP cells under physiological concentrations of DHEA. Biosynthesis of testosterone or dihydrotestosterone from DHEA in stromal cells and LNCaP cells was involved in this stimulation of LNCaP cell proliferation. Androgen biosynthesis from DHEA depended upon the activity of various steroidogenic enzymes present in stromal cells. Finally, the dual 5a-reductase inhibitor dutasteride appears to function not only as a 5a-reductase inhibitor but also as a 3b-hydroxysteroid dehydrogenase inhibitor in LNCaP cells. Taken together, this coculture assay system provides new insights of coordinate androgen biosynthesis under the microenvironment of PCa cells before and after ADT, and offers a model system for the identification of important steroidogenic enzymes involved in PCa progression and for the development of the corresponding inhibitors of androgen biosynthesis. © 2009 Society for Endocrinology