During meiosis, repair of programmed DNA double-strand breaks (DSBs) by recombination promotes pairing of homologous chromosomes and their connection by crossovers. Two DNA strand-exchange proteins, Rad51 and Dmc1, are required for meiotic recombination in many organisms. Studies in budding yeast imply that Rad51 acts to regulate Dmc1's strand exchange activity, while its own exchange activity is inhibited. However, in a dmc1 mutant, elimination of inhibitory factor, Hed1, activates Rad51's strand exchange activity and results in high levels of recombination without participation of Dmc1. Here we show that Rad51-mediated meiotic recombination is not subject to regulatory processes associated with high-fidelity chromosome segregation. These include homolog bias, a process that directs strand exchange between homologs rather than sister chromatids. Furthermore, activation of Rad51 does not effectively substitute for Dmc1's chromosome pairing activity, nor does it ensure formation of the obligate crossovers required for accurate homolog segregation. We further show that Dmc1's dominance in promoting strand exchange between homologs involves repression of Rad51's strand-exchange activity. This function of Dmc1 is independent of Hed1, but requires the meiotic kinase, Mek1. Hed1 makes a relatively minor contribution to homolog bias, but nonetheless this is important for normal morphogenesis of synaptonemal complexes and efficient crossing-over especially when DSB numbers are decreased. Super-resolution microscopy shows that Dmc1 also acts to organize discrete complexes of a Mek1 partner protein, Red1, into clusters along lateral elements of synaptonemal complexes; this activity may also contribute to homolog bias. Finally, we show that when interhomolog bias is defective, recombination is buffered by two feedback processes, one that increases the fraction of events that yields crossovers, and a second that we propose involves additional DSB formation in response to defective homolog interactions. Thus, robust crossover homeostasis is conferred by integrated regulation at initiation, strand-exchange and maturation steps of meiotic recombination.

Human papillomavirus (HPV), a small, nonenveloped, double-stranded DNA virus, is established as the key etiological factor in cervical neoplasms (24,29,30). More than 90% of cervical neoplasms are attributed to HPV infection. Persistence of high-risk HPV types is a major risk factor for the development of high-risk cervical intraepithelial neoplasia (CIN) (9). Although the regression of HPV infection commonly takes place within 3 years, compelling evidence indicated that a small but definite fraction of the infected population is at risk for developing invasive cervical cancer after many years or decades of a long latency period of primary infection (3,10,14).Currently, HPV DNA testing has played a triage role for atypical squamous cells of undetermined significance (ASCUS), primary screening in conjunction with cytology for the detection of cervical cancer and CIN, and follow-up in a variety of clinical settings (4,15,16,18,25).HPV DNA detection by the FDA-approved Hybrid Capture II HPV DNA test (HCII) (Digene Corporation, Gaithersburg, MD) is the most widely used method. The HCII system, a commercial liquid hybridization kit using RNA probes against HPV DNA genomic targets followed by signal amplification, has been validated for its reproducibility in HPV DNA detection (18,26,29). Thirteen carcinogenic types implicated in the pathogenesis of high-grade squamous intraepithelial lesions (HSILs) and invasive cancer, such as HPV type 16 (HPV

The aim of this study was to determine the effect of male gender on the clinical presentation of symptomatic cholelithiasis. Laparoscopic cholecystectomy (LC) has been accepted as standard procedure for the management of symptomatic cholelithiasis even when the gallbladder is acutely inflamed. With the accumulated experience in the management of acute cholecystitis, some factors including male gender were recognized to influence the clinical presentation of symptomatic cholelithiasis and increase the conversion rate during LC. This retrospective study tried to clarify the correlation between male gender and the clinical presentation of symptomatic cholelithiasis. The medical records of all patients presenting with symptomatic cholelithiasis from January 1994 to August 1999 were evaluated. These cases were divided into four groups as follows: (1) elective LC group: patients with a history of biliary colic or acute attack of cholecystitis but whose LC was performed electively without any inflammatory change in the gallbladder during operation; (2) acute LC group: patients presenting with acute cholecystitis, and LC was performed successfully without conversion; (3) acute conversion group: patients who underwent LC during the course of acute cholecystitis but the procedure were disturbed by severe inflammatory change so they were converted to open surgery; (4) acute open group: patients whose acute cholecystitis was managed by direct open surgery due to the preoperative prediction that LC would not succeed. The correlation of gender, age, and operating time were assessed among these four groups. We found that: (1) the male/female ratio increased (in the patient group sequence of simple LC, acute LC, acute open, and acute conversion group); (2) in the acute LC group male patients had significantly (p = 0.04, t-test) longer operating time than females; (3) although there was no significant difference between the mean age of male (55.7 +/- 13.4) and female (56.3 +/- 15.7) patients in the acute cholecystitis groups (i.e., all patients in the acute LC, acute conversion, and acute open groups), the distribution curve by age in male patients showed a significantly shift to a younger age compared with female patients (p = 0.009, Fisher's exact test).

Human papillomavirus (HPV) persistence is essential for cervical cancer development. We accrued nested-cohort subjects from a population-based study to investigate the host and viral factors related to outcome of HPV infection. Women (age ≥ 30 years old) with HPV-positive but normal cytology and negative colposcopy were invited to participate. After signing informed consent, every participant completed a structured questionnaire and had 6-monthly follow-ups of Pap smear, HPV testing and colposcopy. Total and type-specific HPV clearance rates as well as host and viral factors associated with clearance in 3-year longitudinal followup were analyzed. Adjusted hazard ratios (HRs) of progression to ≥ cervical intraepithelial neoplasia (CIN) 2 according to baseline HPV of the women with normal cytology were calculated from national registry database. Among the 626 eligible women, 526 (median age 47, 29-75) were enrolled and 412 returned for followup at least once. The median follow-up of enrolled subjects was 23 months (range 6.8-39). The 3-year cumulative total HPV clearance rate was 49.0% (95% confidence interval [CI]: 43.3-54.7%). The median 3-year cumulative type-specific HPV clearance rate was 50.0% (range 0-100.0%) with a median time to clearance of 12.4 months (6.4-24.5). Older age was associated with significantly decreased total HPV clearance and decreased type-specific clearance in HPV-18 and -53, while high viral load was associated with decreased total and type-specific clearance. After adjusting confounding variables, the HR of developing CIN2 in baseline HPVpositive women was 34.0-fold (95% CI: 15.5-74.7) as compared to HPV-negative women. ' 2008 Wiley-Liss, Inc.Key words: human papillomavirus; genotype; viral load; clearance Cervical cancer is one of the leading cancers in female worldwide. 1 There is strong epidemiological and molecular biological evidence indicating that human papillomavirus (HPV) plays a central role in the etiology of cervical cancer. 2,3 Over 90% of cervical cancers and their precursor lesions are attributable to HPV infection. 4,5 However, the prevalence of genital-tract HPV infections has been reported to range from 1.4 to 25.6% in cytologically normal population. 6 It is widely believed that persistent HPV infection is necessary for the development of cervical cancer. 3,7,8 Incorporation of HPV testing into cervical cancer screening has been advocated, although specificity is decreased with expected increase in sensitivity in early detection of high-grade cervical neoplasms. 9-11 However, identifying infection of high-risk HPV causes anxiety in the individual woman. Because of lack of adequate knowledge in predicting outcome, the appropriate management is unclear except periodical follow-up.Several 8,13 HPV variants 17 have been reported associated with HPV persistence/decreased clearance, whereas ever users of oral contraceptives were associated with faster clearance. 15 Multiple infections, viral load 15 and smoking 8 were unrelated to clearance in other longitudinal follow-u...

The histone H3 variant Cse4 specifies centromere identity in Saccharomyces cerevisiae by its incorporation into a special nucleosome positioned at CEN DNA and promotes the assembly of the kinetochore complex, which is required for faithful chromosome segregation. Our previous work showed that Cse4 is also associated with the partitioning locus STB of the 2m circle-a multicopy plasmid that resides in the yeast nucleus and propagates itself stably. Cse4 is essential for the functional assembly of the plasmid partitioning complex, including the recruitment of the yeast cohesin complex at STB. We have located Cse4 association strictly at the origin-proximal subregion of STB. Three of the five directly repeated tandem copies of a 62-bp consensus sequence element constituting this region are necessary and sufficient for the recruitment of Cse4. The association of Cse4 with STB is dependent on Scm3, the loading factor responsible for the incorporation of Cse4 into the CEN nucleosome. A chromosomally integrated copy of STB confers on the integration site the capacity for Cse4 association as well as cohesin assembly. The localization of Cse4 in chromatin digested by micrococcal nuclease is consistent with the potential assembly of one Cse4-containing nucleosome, but not more than two, at STB. The remarkable ability of STB to acquire a very specialized, and strictly regulated, chromosome segregation factor suggests its plausible evolutionary kinship with CEN.The 2m plasmid of Saccharomyces cerevisiae is an example of a highly optimized, circular, multicopy extrachromosomal selfish DNA element (25,27,49). The plasmid does not seem to contribute to the host's fitness under standard laboratory growth conditions. However, at its steady-state copy number of 40 to 60 molecules per cell, any growth disadvantage imposed by the plasmid is rather small (16,30). The most remarkable attribute of this selectively almost neutral entity is its ability to propagate with nearly chromosome-like stability at its steadystate copy number. The entire genetic makeup of the 2m circle is devoted to three functions: efficient replication by the host machinery, equal segregation, and maintenance of the copy number. The plasmid accomplishes these goals with minimal metabolic encumbrance to its host.Direct visualization of fluorescence-tagged reporter plasmids in live cells suggests that 2m circle molecules are organized in the nucleus as 3 to 5 dynamic foci that form a closeknit cluster (47). The plasmid also segregates as a clustered entity; sister clusters part from each other and move away at the anaphase stage of the cell cycle. Population analysis and time lapse assays have revealed close similarities between the 2m circle and the yeast chromosomes or a centromere plasmid (minichromosome) in their dynamics and kinetics of segregation (17, 47). The relevant inference from a variety of experiments is that plasmid segregation is tightly coupled to chromosome segregation, perhaps by attachment of duplicated plasmid clusters to a pair of sister chro...

This analysis was undertaken to compare the clinicopathological features of infants with choledochal cysts to those of older children with these entities and to evaluate the surgical outcomes for both subject groups. The medical records of all children admitted to the Cathay General Hospital with choledochal cysts over a 20-year period were retrospectively reviewed. Twenty-five subjects were included and divided into the infant (<1 year at presentation; 8 subjects) and classical pediatric (1-18 years at presentation; 17 subjects) groups. Anatomical subtypes were: IA (16), IC (6), and IVA (3). The median biliary amylase value was markedly elevated for the pediatric group but not for the infant group. Most (82.4%) patients in the pediatric group, but none in the infant group, presented with abdominal pain. Jaundice and clay-colored stool were present in all patients in the infant group but only 35% of those in the pediatric group. All patients underwent choledochocystectomy and Roux-en-Y hepaticojejunostomy with good outcomes. Neonates/infants with choledochal cysts present differently from older children with these entities. Amylase measurements may serve to distinguish biliary atresia with cystic dilatation from choledochal cyst in neonates/infants. Prognosis following radical cyst excision and reconstruction with Roux-en-Y hepaticojejunostomy is excellent.

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The tolerability of intravaginal self-administered imiquimod is confirmed. Its efficacy in the treatment of women with persistent HPV infection and normal cytology warrants further randomized, controlled trials to determine appropriate dosages and scheduling.