Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/- mice

INTRODUCTION Treatment with estrogen and progesterone (E+P) mimics the protective effect of parity on mammary tumors in rodents and depends upon the activity of p53. The following experiments tested whether exogenous E+P primes p53 to be more responsive to DNA damage and whether these pathways confer resistance to mammary tumors in a mouse model of Li-Fraumeni syndrome. METHODS Mice that differ in p53 status (Trp53+/+, Trp53+/-, Trp53-/-) were treated with E+P for 14 days and then were tested for p53-dependent responses to ionizing radiation. Responses were also examined in parous and age-matched virgins. The effects of hormonal exposures on tumor incidence were examined in BALB/c-Trp53+/- mammary tissues. RESULTS Nuclear accumulation of p53 and apoptotic responses were increased similarly in the mammary epithelium from E+P-treated and parous mice compared with placebo and age-matched virgins. This effect was sustained for at least 7 weeks after E+P treatment and did not depend on the continued presence of ovarian hormones. Hormone stimulation also enhanced apoptotic responses to ionizing radiation in BALB/c-Trp53+/- mice but these responses were intermediate compared with Trp53+/+ and Trp-/- tissues, indicating haploinsufficiency. The appearance of spontaneous mammary tumors was delayed by parity in BALB/c-Trp53+/- mice. The majority of tumors lacked estrogen receptor (ER), but ER+ tumors were observed in both nulliparous and parous mice. However, apoptotic responses to ionizing radiation and tumor incidence did not differ among outgrowths of epithelial transplants from E+P-treated donors and nulliparous donors. CONCLUSION Therefore, E+P and parity confer a sustained increase in p53-mediated apoptosis within the mammary epithelium and suppress mammary tumorigenesis, but this effect was not retained in epithelial outgrowths.This work was supported by grants from the US Army Medical Research and Materiel Command (W81XWH0410385 to KAD and DAMD17-01-1-0315 to ACB) and the National Institutes of Health (RO1-CA095164 to DJJ)

Architecture and Selectivity in Aquaporins: 2.5 Å X-Ray Structure of Aquaporin Z

Aquaporins are a family of water and small molecule channels found in organisms ranging from bacteria to animals. One of these channels, the E. coli protein aquaporin Z (AqpZ), has been shown to selectively conduct only water at high rates. We have expressed, purified, crystallized, and solved the X-ray structure of AqpZ. The 2.5 Å resolution structure of AqpZ suggests aquaporin selectivity results both from a steric mechanism due to pore size and from specific amino acid substitutions that regulate the preference for a hydrophobic or hydrophilic substrate. This structure provides direct evidence on the molecular mechanisms of specificity between water and glycerol in this family of channels from a single species. It is to our knowledge the first atomic resolution structure of a recombinant aquaporin and so provides a platform for combined genetic, mutational, functional, and structural determinations of the mechanisms of aquaporins and, more generally, the assembly of multimeric membrane proteins

Data report : spectral reflectance observations from recovered sediments

Sediment spectral reflectance measurements were generated aboard the JOIDES Resolution during Ocean Drilling Program Leg 162 shipboard operations. The large size of the raw data set (over 1.3 gigabytes) and limited computer hard disk storage space precluded detailed analysis of the data at sea, although broad band averages were used as aids in developing splices and determining lithologic boundaries. This data report describes the methods used to collect these data and their shipboard and postcruise processing. These initial results provide the basis for further postcruise research

Diffuse spectral reflectance as a proxy for percent carbonate content in North Atlantic sediments

Diffuse reflectance records from Feni Drift in the North Atlantic faithfully record sediment percent carbonate. A high-resolu­tion, reflectance-based age model for these sediments derived from an orbitally tuned age model for western equatorial Atlantic, Ceara Rise sediments was generated by spectral frequency mapping. Power spectra of the Feni Drift record indicate statistically significant sub­Milankovitch cyclicity at 7.6-8.4 and 4.8-6.1 kyr. We infer that these ∼8 and ∼5 kyr cycles document a linkage between North and equa­torial Atlantic climate given our ability to correlate these records. These climate cycles influence Atlantic basin carbonate prior to the intensification of Northern Hemisphere glaciation and thus must arise from some portion of the climate system other than the dynamics of large ice sheets. The presence of these peaks, which could be related to equatorial clipped precession, implies a possible non-linear response to Milankovitch forcing

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism

Enhanced Virulence of Chlamydia muridarum Respiratory Infections in the Absence of TLR2 Activation

Chlamydia trachomatis is a common sexually transmitted pathogen and is associated with infant pneumonia. Data from the female mouse model of genital tract chlamydia infection suggests a requirement for TLR2-dependent signaling in the induction of inflammation and oviduct pathology. We hypothesized that the role of TLR2 in moderating mucosal inflammation is site specific. In order to investigate this, we infected mice via the intranasal route with C. muridarum and observed that in the absence of TLR2 activation, mice had more severe disease, higher lung cytokine levels, and an exaggerated influx of neutrophils and T-cells into the lungs. This could not be explained by impaired bacterial clearance as TLR2-deficient mice cleared the infection similar to controls. These data suggest that TLR2 has an anti-inflammatory function in the lung during Chlamydia infection, and that the role of TLR2 in mucosal inflammation varies at different mucosal surfaces

Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes

<p>Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.</p> <p>Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.</p> <p>Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.</p&gt

Hubble Space Telescope Imaging of Lyman Alpha Emission at z=4.4

We present the highest redshift detections of resolved Lyman alpha emission, using Hubble Space Telescope/ACS F658N narrowband-imaging data taken in parallel with the Wide Field Camera 3 Early Release Science program in the GOODS CDF-S. We detect Lyman alpha emission from three spectroscopically confirmed z = 4.4 Lyman alpha emitting galaxies (LAEs), more than doubling the sample of LAEs with resolved Lyman alpha emission. Comparing the light distribution between the rest-frame ultraviolet continuum and narrowband images, we investigate the escape of Lyman alpha photons at high redshift. While our data do not support a positional offset between the Lyman alpha and rest-frame ultraviolet (UV) continuum emission, the half-light radii in two out of the three galaxies are significantly larger in Lyman alpha than in the rest-frame UV continuum. This result is confirmed when comparing object sizes in a stack of all objects in both bands. Additionally, the narrowband flux detected with HST is significantly less than observed in similar filters from the ground. These results together imply that the Lyman alpha emission is not strictly confined to its indigenous star-forming regions. Rather, the Lyman alpha emission is more extended, with the missing HST flux likely existing in a diffuse outer halo. This suggests that the radiative transfer of Lyman alpha photons in high-redshift LAEs is complicated, with the interstellar-medium geometry and/or outflows playing a significant role in galaxies at these redshifts.Comment: Submitted to the Astrophysical Journal. 11 pages, 10 figure

Wetland Management Strategies that Maximize Marsh Bird Use in the Midwest: Final Performance Report: F14AP00485

We sought to investigate marsh bird occupancy and abundance across a wide range of representative wetlands types, hydrologic regimes, management practices, and former disturbance regimes in Illinois. We hypothesized that characteristics of wetlands that were actively and passively managed for waterfowl would be positively correlated with marsh bird occupancy and abundance in Illinois during the migration and breeding seasons. Our specific objectives were to: 1) compare marsh bird use of wetland impoundments managed for waterfowl across a continuum of management intensities and strategies to predict how impoundment management actions can increase use by both groups; 2) compare marsh bird use of restored and natural wetlands; and 3) determine characteristics of wetlands and the surrounding landscape that influence marsh bird use of restored wetlands. Our results are important to understanding spatiotemporal, hydrological, and vegetative conditions suitable for multi-species management of wetlands. Moreover, our research provided information regarding the effectiveness of conservation actions, particularly wetland restoration in meeting conservation priorities for migrating birds.U.S. Fish & Wildlife Service Wildlife and Sport Fish Restoration Programsunpublishednot peer reviewedOpe