Infection of mice with sporozoites of Plasmodium berghei or Plasmodium yoelii has been used extensively to evaluate liver-stage protection by candidate preerythrocytic malaria vaccines. ...Unfortunately, repeated success of such vaccines in mice has not translated readily to effective malaria vaccines in humans. Thus, mice may be used better as models to dissect basic parameters required for immunity to Plasmodium-infection than as preclinical vaccine models. In turn, this basic information may aid in the rational design of malaria vaccines. Here, we describe a model of circumsporozoite-specific memory CD8 T cell generation that protects mice against multiple P. berghei sporozoite challenges for at least 19 months. Using this model we defined a threshold frequency of memory CD8 T cells in the blood that predicts long-term sterilizing immunity against liver-stage infection. Importantly, the number of Plasmodium-specific memory CD8 T cells required for immunity greatly exceeds the number required for resistance to other pathogens. In addition, this model allowed us to identify readily individual immunized mice that exceed or fall below the protective threshold before infection, information that should greatly facilitate studies to dissect basic mechanisms of protective CD8 T cell memory against liver-stage Plasmodium infection. Furthermore, the extremely large threshold in memory CD8 T cell frequencies required for long-term protection in mice may have important implications for development of effective malaria vaccines.
The Legionella pneumophila effector protein RalF functions as a guanine nucleotide exchange factor (GEF) that activates the host small GTPase protein ADP-ribosylation factor (Arf), and recruits this ...host protein to the vacuoles in which this pathogen resides. GEF activity is conferred by the Sec7 domain located in the N-terminal region of RalF. Structural studies indicate that the C-terminal region of RalF makes contacts with residues in the Sec7 domain important for Arf interactions. Theoretically, the C-terminal region of RalF could prevent nucleotide exchange activity by blocking the ability of Arf to interact with the Sec7 domain. For this reason, the C-terminal region of RalF has been termed a capping domain. Here, the role of the RalF capping domain was investigated by comparing biochemical and effector activities mediated by this domain in both the Legionella RalF protein (LpRalF) and in a RalF ortholog isolated from the unrelated intracellular pathogen Rickettsia prowazekii (RpRalF). These data indicate that both RalF proteins contain a functional Sec7 domain and that the capping domain regulates RalF GEF activity. The capping domain has intrinsic determinants that mediate localization of the RalF protein inside of host cells and confer distinct effector activities. Localization mediated by the capping domain of LpRalF enables the GEF to modulate membrane transport in the secretory pathway, whereas, the capping domain of RpRalF enables this bacterial GEF to modulate actin dynamics occurring near the plasma membrane. Thus, these data reveal that divergence in the function of the C-terminal capping domain alters the in vivo functions of the RalF proteins.
West Nile virus (WNV) emerged as a threat to public and veterinary health in the Midwest United States in 2001 and continues to cause significant morbidity and mortality annually. To investigate ...biotic and abiotic factors associated with disease incidence, cases of reported human disease caused by West Nile virus (WNV) in the state of Iowa were aggregated by census block groups in Iowa for the years 2002-2006. Spatially explicit data on landscape, demographic, and climatic conditions were collated and analyzed by census block groups. Statistical tests of differences between means and distributions of landscape, demographic, and climatic variables for census block groups with and without WNV disease incidence were carried out. Entomological data from Iowa were considered at the state level to add context to the potential ecological events taking place.
Numerous statistically significant differences were shown in the means and distributions of various landscape and demographic variables for census block groups with and without WNV disease incidence. Census block groups with WNV disease incidence had significantly lower population densities than those without. Landscape variables showing differences included stream density, road density, land cover compositions, presence of irrigation, and presence of animal feeding operations. Statistically significant differences in the annual means of precipitations, dew point, and minimum temperature for both the year of WNV disease incidence and the prior year, were detected in at least one year of the analysis for each parameter. However, the differences were not consistent between years.
The analysis of human WNV disease incidence by census block groups in Iowa demonstrated unique landscape, demographic, and climatic associations. Our results indicate that multiple ecological WNV transmission dynamics are most likely taking place in Iowa. In 2003 and 2006, drier conditions were associated with WNV disease incidence. In a significant novel finding, rural agricultural settings were shown to be strongly associated with human WNV disease incidence in Iowa.
OBJECTIVE To determine the proportion of yearling beef bulls classified as satisfactory potential breeders when reevaluated after failing an initial breeding soundness evaluation (BSE) and identify ...any factors at initial BSE that predicted satisfactory performance at reevaluation. DESIGN Retrospective observational study. ANIMALS 2,064 beef bulls between 11 and 14 months of age at first BSE, evaluated from 2006 to 2014. PROCEDURES For each bull, data on age (categorized by month), breed, and BSE findings were extracted from the medical records. Bulls were classified as satisfactory potential breeders if they met Society for Theriogenology standards at the initial BSE or up to 2 subsequent reevaluations. Generalized linear mixed models were generated to assess potential associations between certain variables at initial BSE and passing that evaluation or passing subsequent BSEs after initial failure. RESULTS 1,921 of 2,064 (93.1%) yearling bulls passed 1 of up to 3 BSEs. The proportion of yearling bulls that were not classified as satisfactory during initial BSE but were later classified as satisfactory was 143 of 287 (49.8%). A significant interaction was identified between bull age and breed in the probability of passing the initial evaluation. No variable, including breed, age, scrotal circumference per day of age, and spermatozoa morphology at initial BSE, significantly predicted passing subsequent reevaluations after failing an initial BSE. CONCLUSIONS AND CLINICAL RELEVANCE Age and breed information should be considered when deciding the age at which initial BSE should be scheduled for a yearling bull cohort.
To determine herd-level risk factors for bovine respiratory disease (BRD) in nursing beef calves.
Matched case-control study.
84 cow-calf operations in Nebraska, North Dakota, and South Dakota.
Case ...herds were herds that treated at least 5% of the calf crop for BRD prior to weaning. Control herds were herds that treated < 0.5% of the calf crop for BRD prior to weaning. Each case herd was matched with 2 control herds on the basis of veterinary practice and enrollment year. Herd owners or managers were interviewed by telephone, and characteristics and practices associated with case status were determined by multivariable conditional logistic regression.
30 case herds and 54 control herds were evaluated. Increasing herd size, frequent pasture movement for intensive grass management (intensive grazing), and use of estrus-synchronization programs were significantly associated with herd status. The odds of being a case herd for herds with 150 to 499 cows was 7.9 times and that for herds with ≥ 500 cows was 12 times, compared with the odds of being a case herd for herds with < 150 cows. The odds of being a case herd for herds that used intensive grazing was 3.3 times that for herds that did not use intensive grazing. The odds of being a case herd for herds that used an estrus-synchronization program was 4.5 times that for herds that did not use an estrus-synchronization program.
Management practices can be associated with an increase in the BRD incidence in nursing beef calves. Modification of management practices may decrease BRD incidence in nursing calves for herds in which it is a problem.
The potential of the eastern cottontail rabbit (CTR; Sylvilagus floridanus) to contribute to an enzootic West Nile virus (WNV) cycle was demonstrated by characterizing the WNV viremia profile of 15 ...CTRs and demonstrating that mosquitoes could become infected by feeding on these CTRs. Eight CTRs were infected with a titer of 10(5.0) cell-infectious dose 50% endpoints (CID50s) of WNV (NY99-Crow) by needle and seven CTRs by bite of one or more WNV-infected mosquitoes. There were no marked differences between the WNV viremia profiles of CTRs infected by either method. West Nile virus was detected in serums of all CTRs by 24 h p.i. The daily mean titers of all 15 CTRs on days 1-4 p.i. were 10(4.1+/-0.4), 10(4.7+/-0.3), 10(4.1+/-0.6), and 10(3.7+/-0.6) respectively, declining to 10(1.2+/-0.1) CID50s/ml of serum by day 6 p.i. No virus was detected in the blood of any CTR on day 7 p.i. The average duration of WNV titers of >or=10(4.3) and <10(5.0) CID50s/mL for all CTRs was 2.2 +/- 0.6 and 1.0 +/- 0.1 days, respectively. The minimum estimated infection rates (MEIRs) of Culex pipiens (L.) and Culex salinarius (Coq.) that fed on CTRs with titers of >or=10(4.3) and >10(5.0) were 11.5 +/- 5.5 and 21 +/- 6.0%, respectively. These rates increased to 20.5 +/- 6.4% and 25.0 +/- 3.0% when CTR serum titers were >10(5.0) CID50s/mL. Neither Aedes aegypti (L.) nor Aedes albopictus (Skuse) were infected by feeding on CTRs with titers of <10(5.0) CID50s/mL. The MEIRs of these two species were 11.5 +/- 3.5% and 1.5 +/- 0.5% after feeding on CTRs with titers of >10(5.0) CID50s/ml. None of the CTRs infected by mosquito bite or by needle showed any symptoms of WNV disease.
The West Nile virus (WNV) viremia and shedding profiles of 11 adult fox squirrels (Sciurus niger) infected by needle inoculation or mosquito bite were characterized. Daily mean titers (95% confidence ...intervals) for all squirrels on days 1 through 6 postexposure (p.e.) were: 10(1.7 (1.32.1)), 10(4.4 (4.04.8)), 10(5.3 (5.05.6)), 10(4.4 (3.94.9)), 10(2.7 (2.03.4)), and 10(1.1 (0.52.1)) plaque-forming units (PFU)/mL. The highest WNV serum titers of individual squirrels infected by needle inoculation or mosquito bite ranged from 10(4.5) to 10(6.1) and from 10(5.1) to 10(5.3) PFU/mL, respectively. Nine (82%) squirrels, including all 4 squirrels infected by mosquito bite, had WNV serum titers > or =10(5.1) PFU/mL that persisted on average for 1.6 +/- 0.3 days. Infection and dissemination rates of Culex pipiens (L.) that fed on squirrels with serum titers of 10(4.4 +/- 0.1) PFU/mL were 56% and 13%, respectively. Both of these rates increased to over 80% when fed on squirrels with a mean WNV titer of 10(5.5 +/- 0.1) PFU/mL. Infection and dissemination also occurred in Aedes triseriatus (Say) but at a much lower rate. WNV was isolated from the oral and rectal cavities of all squirrels and from urine that was opportunistically collected from 5 squirrels. The largest quantity of WNV recovered from swabs of the oral cavity and urine was 10(3.1) PFU. The longest periods after exposure that WNV was isolated from the oral cavity and urine from a squirrel were 22 and 17 days p.e., respectively. WNV RNA was also detected in kidney tissue in 1 squirrel 29 days p.e., suggesting that fox squirrels can be persistently infected. Collectively these observations provide further evidence that squirrels can contribute to the natural history and epidemiology of WNV, especially in peridomestic environments.
We use the Wide Field Camera 3 (WFC3) on the Hubble Space Telescope (HST) to reduce the uncertainty in the local value of the Hubble constant from 3.3% to 2.4%. The bulk of this improvement comes ...from new near-infrared (NIR) observations of Cepheid variables in 11 host galaxies of recent type Ia supernovae (SNe Ia), more than doubling the sample of reliable SNe Ia having a Cepheid-calibrated distance to a total of 19; these in turn leverage the magnitude-redshift relation based on ~300 SNe Ia at z< 0.15. All 19 hosts as well as the megamaser system NGC 4258 have been observed with WFC3 in the optical and NIR, thus nullifying cross-instrument zeropoint errors in the relative distance estimates from Cepheids. Other noteworthy improvements include a 33% reduction in the systematic uncertainty in the maser distance to NGC 4258, a larger sample of Cepheids in the Large Magellanic Cloud (LMC), a more robust distance to the LMC based on late-type detached eclipsing binaries (DEBs), HST observations of Cepheids in M31, and new HST-based trigonometric parallaxes for Milky Way (MW) Cepheids. We consider four geometric distance calibrations of Cepheids: (i) megamasers in NGC 4258, (ii) 8 DEBs in the LMC, (iii) 15 MW Cepheids with parallaxes measured with HST/FGS, HST/WFC3 spatial scanning and/or Hipparcos, and (iv) 2 DEBs in M31. The Hubble constant from each is 72.25 + or - 2.51, 72.04 + or - 2.67, 76.18 + or - 2.37, and 74.50 + or - 3.27 km s super(-1) Mpc super(-1), respectively. Our best estimate of H sub(0)= 73.24 + or - 1.74 km s super(-1) Mpc super(-1) combines the anchors NGC 4258, MW, and LMC, yielding a 2.4% determination (all quoted uncertainties include fully propagated statistical and systematic components). This value is 3.4sigma higher than 66.93 + or - 0.62 km s super(-1) Mpc super(-1) predicted by LambdaCDM with 3 neutrino flavors having a mass of 0.06 eV and the new Planck data, but the discrepancy reduces to 2.1sigma relative to the prediction of 69.3 + or - 0.7 km s super(-1) Mpc super(-1) based on the comparably precise combination of WMAP+ACT+SPT+BAO observations, suggesting that systematic uncertainties in CMB radiation measurements may play a role in the tension. If we take the conflict between Planck high-redshift measurements and our local determination of H sub(0) at face value, one plausible explanation could involve an additional source of dark radiation in the early universe in the range of DeltaN sub(eff)approximate 0.4-1. We anticipate further significant improvements in H sub(0) from upcoming parallax measurements of long-period MW Cepheids.
We present new measurements of the parallax of seven long-period (≥10 days) Milky Way (MW) Cepheid variables (SS CMa, XY Car, VY Car, VX Per, WZ Sgr, X Pup, and S Vul) using one-dimensional ...astrometric measurements from spatial scanning of Wide-Field Camera 3 on the Hubble Space Telescope (HST). The observations were obtained at ∼6 month intervals over 4 years. The distances are 1.7-3.6 kpc, with a mean precision of 45 as (signal-to-noise ratio (S/N) 10) and a best precision of 29 as (S/N = 14). The accuracy of the parallaxes is demonstrated through independent analyses of >100 reference stars. This raises to 10 the number of long-period Cepheids with significant parallax measurements, 8 obtained from this program. We also present high-precision mean F555W, F814W, and F160W magnitudes of these Cepheids, allowing a direct, zeropoint-independent comparison to >1800 extragalactic Cepheids in the hosts of 19 SNe Ia. This sample addresses two outstanding systematic uncertainties affecting prior comparisons of MW and extragalactic Cepheids used to calibrate the Hubble constant (H0): their dissimilarity of periods and photometric systems. Comparing the new parallaxes to their predicted values derived from reversing the distance ladder gives a ratio (or independent scale for H0) of 1.037 0.036, consistent with no change and inconsistent at the 3.5 level with a ratio of 0.91 needed to match the value predicted by Planck cosmic microwave background data in concert with ΛCDM. Using these data instead to augment the Riess et al. measurement of H0 improves the precision to 2.3%, yielding 73.48 1.66 km s−1 Mpc−1, and the tension with Planck + ΛCDM increases to 3.7 . The future combination of Gaia parallaxes and HST spatial scanning photometry of 50 MW Cepheids can support a <1% calibration of H0.
Abstract
We present detailed ultraviolet, optical, and near-infrared light curves of the Type Ia supernova (SN) 2012fr, which exploded in the Fornax cluster member NGC 1365. These precise ...high-cadence light curves provide a dense coverage of the flux evolution from −12 to +140 days with respect to the epoch of
B
-band maximum (
t
B
max
). Supplementary imaging at the earliest epochs reveals an initial slow and nearly linear rise in luminosity with a duration of ∼2.5 days, followed by a faster rising phase that is well reproduced by an explosion model with a moderate amount of
56
Ni mixing in the ejecta. From our analysis of the light curves, we conclude that: (i) the explosion occurred <22 hr before the first detection of the supernova, (ii) the rise time to peak bolometric (
λ
> 1800 Å) luminosity was 16.5 ± 0.6 days, (iii) the supernova suffered little or no host-galaxy dust reddening, (iv) the peak luminosity in both the optical and near-infrared was consistent with the bright end of normal Type Ia diversity, and (v) 0.60 ± 0.15
M
⊙
of
56
Ni was synthesized in the explosion. Despite its normal luminosity, SN 2012fr displayed unusually prevalent high-velocity Ca
ii
and Si
ii
absorption features, and a nearly constant photospheric velocity of the Si
ii
λ
6355 line at ∼12,000
km
s
−
1
that began ∼5 days before
t
B
max
. We also highlight some of the other peculiarities in the early phase photometry and the spectral evolution. SN 2012fr also adds to a growing number of Type Ia supernovae that are hosted by galaxies with direct Cepheid distance measurements.
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