Tankyrase 1 and Tankyrase 2 Are Essential but Redundant for Mouse Embryonic Development

Tankyrases are proteins with poly(ADP-ribose) polymerase activity. Human tankyrases post-translationally modify multiple proteins involved in processes including maintenance of telomere length, sister telomere association, and trafficking of glut4-containing vesicles. To date, however, little is known about in vivo functions for tankyrases. We recently reported that body size was significantly reduced in mice deficient for tankyrase 2, but that these mice otherwise appeared developmentally normal. In the present study, we report generation of tankyrase 1-deficient and tankyrase 1 and 2 double-deficient mice, and use of these mutant strains to systematically assess candidate functions of tankyrase 1 and tankyrase 2 in vivo. No defects were observed in development, telomere length maintenance, or cell cycle regulation in tankyrase 1 or tankyrase 2 knockout mice. In contrast to viability and normal development of mice singly deficient in either tankyrase, deficiency in both tankyrase 1 and tankyrase 2 results in embryonic lethality by day 10, indicating that there is substantial redundancy between tankyrase 1 and tankyrase 2, but that tankyrase function is essential for embryonic development

Ultraviolet Imaging of the Globular Cluster 47 Tucanae

We have used the Ultraviolet Imaging Telescope to obtain deep far-UV (1620 Angstrom), 40' diameter images of the prototypical metal-rich globular cluster 47 Tucanae. We find a population of about 20 hot (Teff > 9000 K) objects near or above the predicted UV luminosity of the hot horizontal branch (HB) and lying within two half-light radii of the cluster center. We believe these are normal hot HB or post-HB objects rather than interacting binaries or blue stragglers. IUE spectra of two are consistent with post-HB phases. These observations, and recent HST photometry of two other metal-rich clusters, demonstrate that populations with rich, cool HB's can nonetheless produce hot HB and post-HB stars. The cluster center also contains an unusual diffuse far-UV source which is more extended than its V-band light. It is possible that this is associated with an intracluster medium, for which there was earlier infrared and X-ray evidence, and is produced by C IV emission or scattered light from grains.Comment: 13 pages AASLaTeX including one postscript figure and one bitmapped image, JPEG format. Submitted to the Astronomical Jorunal. Full Postscript version available at http://www.astro.virginia.edu/~bd4r

UIT Detection of Hot Stars in the Globular Cluster NGC362

We used the Ultraviolet Imaging Telescope during the March 1995 Astro-2 mission to obtain a deep far-UV image of the globular cluster NGC 362, which was formerly thought to have an almost entirely red horizontal branch (HB). 84 hot (T_eff > 8500 K) stars were detected within a radius of 8'.25 of the cluster center. Of these, 43 have FUV magnitudes consistent with HB stars in NGC 362, and at least 34 are cluster members. The number of cluster members is made uncertain by background contamination from blue stars in the Small Magellanic Cloud (SMC). There are six candidate supra-HB stars which have probably evolved from the HB. We discuss the implications of these results for the production of hot blue stars in stellar populations.Comment: 10 pages AASLaTeX including one postscript figure and one compressed bitmap, .jpg format. To appear in Ap. J. Letters. Postscript version also available at http://www.astro.virginia.edu/~bd4r

Dysfunctional TRPM8 signalling in the vascular response to environmental cold in ageing.

Ageing is associated with increased vulnerability to environmental cold exposure. Previously, we identified the role of the cold-sensitive transient receptor potential (TRP) A1, M8 receptors as vascular cold sensors in mouse skin. We hypothesised that this dynamic cold-sensor system may become dysfunctional in ageing. We show that behavioural and vascular responses to skin local environmental cooling are impaired with even moderate ageing, with reduced TRPM8 gene/protein expression especially. Pharmacological blockade of the residual TRPA1/TRPM8 component substantially diminished the response in aged, compared with young mice. This implies the reliance of the already reduced cold-induced vascular response in ageing mice on remaining TRP receptor activity. Moreover, sympathetic-induced vasoconstriction was reduced with downregulation of the α2c adrenoceptor expression in ageing. The cold-induced vascular response is important for sensing cold and retaining body heat and health. These findings reveal that cold sensors, essential for this neurovascular pathway, decline as ageing onsets

Treatment with eldecalcitol positively affects mineralization, microdamage, and collagen crosslinks in primate bone

Eldecalcitol (ELD), an active form of vitamin D analog approved for the treatment of osteoporosis in Japan, increases lumbar spine bone mineral density (BMD), suppresses bone turnover markers, and reduces fracture risk in patients with osteoporosis. We have previously reported that treatment with ELD for 6months improved the mechanical properties of the lumbar spine in ovariectomized (OVX) cynomolgus monkeys. ELD treatment increased lumbar BMD, suppressed bone turnover markers, and reduced histomorphometric parameters of both bone formation and resorption in vertebral trabecular bone. In this study, we elucidated the effects of ELD on bone quality (namely, mineralization, microarchitecture, microdamage, and bone collagen crosslinks) in OVX cynomolgus monkeys in comparison with OVX-vehicle control monkeys. Density fractionation of bone powder prepared from lumbar vertebrae revealed that ELD treatment shifted the distribution profile of bone mineralization to a higher density, and backscattered electron microscopic imaging showed improved trabecular bone connectivity in the ELD-treated groups. Higher doses of ELD more significantly reduced the amount of microdamage compared to OVX-vehicle controls. The fractionated bone powder samples were divided according to their density, and analyzed for collagen crosslinks. Enzymatic crosslinks were higher in both the high-density (≥2.0mg/mL) and low-density (<2.0mg/mL) fractions from the ELD-treated groups than in the corresponding fractions in the OVX-vehicle control groups. On the other hand, non-enzymatic crosslinks were lower in both the high- and low-density fractions. These observations indicated that ELD treatment stimulated the enzymatic reaction of collagen crosslinks and bone mineralization, but prevented non-enzymatic reaction of collagen crosslinks and accumulation of bone microdamage. Bone anti-resorptive agents such as bisphosphonates slow down bone remodeling so that bone mineralization, bone microdamage, and non-enzymatic collagen crosslinks all increase. Bone anabolic agents such as parathyroid hormone decrease bone mineralization and bone microdamage by stimulating bone remodeling. ELD did not fit into either category. Histological analysis indicated that the ELD treatment strongly suppressed bone resorption by reducing the number of osteoclasts, while also stimulating focal bone formation without prior bone resorption (bone minimodeling). These bidirectional activities of ELD may account for its unique effects on bone quality.Chugai Pharmaceutical Co., Ltd

Distribution of HPV genotypes in cervical intraepithelial lesions and cervical cancer in Tanzanian women

<p>Abstract</p> <p>Background</p> <p>Infection with human papillomavirus (HPV) is associated with uterine cervical intraepithelial neoplasia (CIN) and invasive cancers (ICC). Approximately 80% of ICC cases are diagnosed in under-developed countries. Vaccine development relies on knowledge of HPV genotypes characteristic of LSIL, HSIL and cancer; however, these genotypes remain poorly characterized in many African countries. To contribute to the characterization of HPV genotypes in Northeastern Tanzania, we recruited 215 women from the Reproductive Health Clinic at Kilimanjaro Christian Medical Centre. Cervical scrapes and biopsies were obtained for cytology and HPV DNA detection.</p> <p>Results</p> <p>79 out of 215 (36.7%) enrolled participants tested positive for HPV DNA, with a large proportion being multiple infections (74%). The prevalence of HPV infection increased with lesion grade (14% in controls, 67% in CIN1 cases and 88% in CIN2-3). Among ICC cases, 89% had detectable HPV. Overall, 31 HPV genotypes were detected; the three most common HPV genotypes among ICC were HPV16, 35 and 45. In addition to these genotypes, co-infection with HPV18, 31, 33, 52, 58, 68 and 82 was found in 91% of ICC. Among women with CIN2-3, HPV53, 58 and 84/83 were the most common. HPV35, 45, 53/58/59 were the most common among CIN1 cases.</p> <p>Conclusions</p> <p>In women with no evidence of cytological abnormalities, the most prevalent genotypes were HPV58 with HPV16, 35, 52, 66 and 73 occurring equally. Although numerical constraints limit inference, findings that 91% of ICC harbor only a small number of HPV genotypes suggests that prevention efforts including vaccine development or adjuvant screening should focus on these genotypes.</p

Field Testing of Utility Robots for Lunar Surface Operations

Since 2004, NASA has been working to return to the Moon. In contrast to the Apollo missions, two key objectives of the current exploration program is to establish significant infrastructure and an outpost. Achieving these objectives will enable long-duration stays and long-distance exploration of the Moon. To do this, robotic systems will be needed to perform tasks which cannot, or should not, be performed by crew alone. In this paper, we summarize our work to develop "utility robots" for lunar surface operations, present results and lessons learned from field testing, and discuss directions for future research

Associations Between Methylation of Paternally Expressed Gene 3 (PEG3), Cervical Intraepithelial Neoplasia and Invasive Cervical Cancer.

Cytology-based screening for invasive cervical cancer (ICC) lacks sensitivity and specificity to discriminate between cervical intraepithelial neoplasia (CIN) likely to persist or progress from cases likely to resolve. Genome-wide approaches have been used to identify DNA methylation marks associated with CIN persistence or progression. However, associations between DNA methylation marks and CIN or ICC remain weak and inconsistent. Between 2008-2009, we conducted a hospital-based, case-control study among 213 Tanzania women with CIN 1/2/3 or ICC. We collected questionnaire data, biopsies, peripheral blood, cervical scrapes, Human papillomavirus (HPV) and HIV-1 infection status. We assessed PEG3 methylation status by bisulfite pyrosequencing. Multinomial logistic regression was used to estimate odds ratios (OR) and confidence intervals (CI 95%) for associations between PEG3 methylation status and CIN or ICC. After adjusting for age, gravidity, hormonal contraceptive use and HPV infection, a 5% increase in PEG3 DNA methylation was associated with increased risk for ICC (OR = 1.6; 95% CI 1.2-2.1). HPV infection was associated with a higher risk of CIN1-3 (OR = 15.7; 95% CI 5.7-48.6) and ICC (OR = 29.5, 95% CI 6.3-38.4). Infection with high risk HPV was correlated with mean PEG3 differentially methylated regions (DMRs) methylation (r = 0.34 p<0.0001), while the correlation with low risk HPV infection was weaker (r = 0.16 p = 0.047). Although small sample size limits inference, these data support that PEG3 methylation status has potential as a molecular target for inclusion in CIN screening to improve prediction of progression. Impact statement: We present the first evidence that aberrant methylation of the PEG3 DMR is an important co-factor in the development of Invasive cervical carcinoma (ICC), especially among women infected with high risk HPV. Our results show that a five percent increase in DNA methylation of PEG3 is associated with a 1.6-fold increase ICC risk. Suggesting PEG3 methylation status may be useful as a molecular marker for CIN screening to improve prediction of cases likely to progress

Causes of variation in BCG vaccine efficacy: examining evidence from the BCG REVAC cluster randomized trial to explore the masking and the blocking hypotheses.

BCG protection varies and in some places (nearest the equator) is low or absent. Understanding this variation can inform the efforts to develop new vaccines against tuberculosis. Two main hypotheses are used to explain this variation: under masking, new vaccines are unlikely to increase protection; under blocking new vaccines have a greater potential to be effective when BCG is not. We conducted a cluster randomized trial to explored the masking and blocking hypotheses by studying BCG vaccine efficacy of neonatal vaccination and when administered for the first or a second (revaccination) time at school age in two sites (Manaus close and Salvador further south from the equator). Seven hundred and sixty three state schools were matched on socio economic characteristics of the neighborhood and 239,934 children were randomized to vaccine (BCG vaccination at school age) or control group. Protection by first BCG vaccination at school age was high in Salvador (34%, 95% CI 7-53%, p=0.017) but low in Manaus (8%, 95% CI t0 39-40%, p=0.686). For revaccination at school age, protection was modest in Salvador (19%, 95% CI 3-33%, p=0.022) and absent in Manaus (1%, 95% CI to 27-23%, p=0.932). Vaccine efficacy for neonatal vaccination was similar in Salvador (40%, 95% CI 22-54%, p<0.001) and Manaus (36%, 95% CI 11-53%, p=0.008). Variation in BCG efficacy was marked when vaccine was given at school age but absent at birth, which points towards blocking as the dominant mechanism. New tuberculosis vaccines that overcome or by pass this blocking effect could confer protection in situations where BCG is not protective

Far Ultraviolet Imagery of the Edge-On Spiral Galaxy NGC 4631

Far ultraviolet FUV imagery of the edge-on, Sc/SBd galaxy, NGC 4631 reveals very strong FUV emission, resulting from active star formation, uniformly distributed along the galactic mid- plane. Multi-band imagery, HI and HII position-velocity curves and extinction considerations all imply that the emission is from the outer edges of the visible galaxy. The overall FUV morphology of this edge-on disk system is remarkably similar to those of the so-called "chain galaxies" evident at high redshift, thus suggesting a similar interpretation for at least some of those distant objects. FUV, U, B and V magnitudes, measured for 48 star forming regions, along with corresponding H-alpha and H-beta measurements are used to construct diagnostic color-color diagrams. Although there are significant exceptions, most of the star forming regions are less massive and older than 30 Doradus. Comparison with the expectations from two star formation models yields ages of 2.7 to 10 Myr for the instantaneous burst (IB) model and star formation cut-off ages of 0 to 9 Myr for the continuous star formation (CSF) model. Interpreted in terms of the IB model the photometry implies a total created mass in the 48 star forming regions of 25 million solar-masses. When viewed as resulting from constant star formation the photometry implies a star formation rate of 0.33 solar-masses/yr. These results are compared to those derived from FIR and radio observations. Corrections for FUV emission reprocessed by interstellar grains are estimated.Comment: 29 pages including 6 encapsulated Postscript figures; accepted for publication in ApJ; changed table forma