614 research outputs found

    Instrumental variables estimation with flexible distribution

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    Instrumental variables are often associated with low estimator precision. This paper explores efficiency gains which might be achievable using moment conditions which are nonlinear in the disturbances and are based on flexible parametric families for error distributions. We show that these estimators can achieve the semiparametric efficiency bound when the true error distribution is a member of the parametric family. Monte Carlo simulations demonstrate low efficiency loss in the case of normal error distributions and potentially significant efficiency improvements in the case of thick-tailed and/or skewed error distributions.

    Recovery of fitness of a live attenuated simian immunodeficiency virus through compensation in both the coding and non-coding regions of the viral genome

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    We have analyzed a SIV deletion mutant that was compromised both in viral replication and RNA packaging. Serial passage of this variant in two different T-cell lines resulted in compensatory reversion and the generation of independent groups of point mutations within each cell line. Within each group, single point mutations were shown to contribute to increased viral infectivity and the rescue of wild-type replication kinetics. The complete recovery of viral fitness ultimately correlated with the restoration of viral RNA packaging. Consistent with the latter finding was the rescue of Pr55 Gag processing, also restoring proper virus core morphology in mature virions. These seemingly independently arising groups of compensatory mutations were functionally interchangeable in regard to the recovery of wild type replication in rhesus PBMCs. These findings indicate that viral reversion that overcomes a genetic bottleneck is not limited to a single pathway, and illustrates the remarkable adaptability of lentiviruses

    Calf pre-weaning traits and immunoglobulin response to bovine viral diarrhea virus vaccination

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    Calfhood vaccination for bovine viral diarrhea virus (BVDV) is a relatively new concept, and protocols are evolving. Our objective was to determine effects of BVDV type I vaccination protocol, calf behavior (chute score, and chute exit velocity), and gender on calf gain and immunoglobulin (Ig) response. Crossbred calves (n = 64) were randomly allotted to one of two vaccination protocols. In protocol 1, calves were vaccinated at 60 d of age (d 0) and at weaning (d 147). Calves assigned to protocol 2 were vaccinated against BVDV type I at 21 d prior to (d 126) and at weaning (d 147). Blood samples were collected from half of the calves in each protocol group on d 0 (60 days of age), d 21, d 126 (21 days prior to weaning), and d 147 (at weaning); serum was harvested and Ig titers were determined. Titers for BVDV type I were transformed (log base 2) and analyzed using a mixed model procedure. Calves vaccinated at d 0 and weaning had larger (P \u3c 0.0001) titers than calves vaccinated at d 126 and weaning (7.5 ± 0.36 and 5.1 ± 0.36, respectively). Mean BVDV titers were larger (P \u3c 0.0001) on d 147 when compared with d 126, d 21, and d 0 (8.3 ± 0.39, 5.1 ± 0.40, 5.9 ± 0.39 and 5.7 ± 0.39, respectively). A treatment × day interaction (P \u3c 0.0001) also affected BVDV titers. However, BVDV titers were not affected (P \u3e 0.05) by calf gender, chute score, or chute exit velocity. Weaning weight and pre-weaning average daily gain (ADG) were not related to BVDV type I titers. This study indicated that vaccinating beef calves against BVDV was effective in triggering an Ig response. Furthermore, our results suggest that calves should be vaccinated against BVDV type I at 60 d of age for greater disease resistance

    Locally advanced adenocarcinoma and adenosquamous carcinomas of the cervix compared to squamous cell carcinomas of the cervix in gynecologic oncology group trials of cisplatin-based chemoradiation

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    OBJECTIVE: Conflicting results have been reported for adeno- and adenosquamous carcinomas of the cervix with respect to their response to therapy and prognosis. The current study sought to evaluate impact of adeno- and adenosquamous histology in the randomized trials of primary cisplatin-based chemoradiation for locally advanced cervical cancer. METHODS: Patients with adeno- and adenosquamous cervical carcinomas were retrospectively studied and compared to squamous cell carcinomas in GOG trials of chemoradiation. RESULTS: Among 1671 enrolled in clinical trials of chemoradiation, 182 adeno- and adenosquamous carcinomas were identified (10.9%). A higher percentage of adeno- and adenosquamous carcinomas were stage IB2 (27.5% versus 20.0%) and fewer had stage IIIB (21.4% versus 28.6%). The mean tumor size was larger for squamous than adeno- and adenosquamous. Adeno- and adenosquamous carcinomas were more often poorly differentiated (46.2% versus 26.8%). When treated with radiation therapy alone, the 70 patients with adeno- and adenosquamous carcinoma of the cervix showed a statistically poorer overall survival (p=0.0499) compared to the 647 patients with squamous cell carcinoma of the cervix. However, when treated with radiation therapy with concurrent cisplatin-based chemotherapy, the 112 patients with adeno- and adenosquamous carcinomas had a similar overall survival (p=0.459) compared the 842 patients with squamous cell carcinoma. Adverse effects to treatment were similar across histologies. CONCLUSION: Adeno- and adenosquamous carcinomas of the cervix are associated with worse overall survival when treated with radiation alone but with similar progression-free and overall survival compared to squamous cell carcinomas of the cervix when treated with cisplatin based chemoradiation

    In Vivo Anti-HIV Activity of the Heparin-Activated Serine Protease Inhibitor Antithrombin III Encapsulated in Lymph-Targeting Immunoliposomes

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    Endogenous serine protease inhibitors (serpins) are anti-inflammatory mediators with multiple biologic functions. Several serpins have been reported to modulate HIV pathogenesis, or exhibit potent anti-HIV activity in vitro, but the efficacy of serpins as therapeutic agents for HIV in vivo has not yet been demonstrated. In the present study, we show that heparin-activated antithrombin III (hep-ATIII), a member of the serpin family, significantly inhibits lentiviral replication in a non-human primate model. We further demonstrate greater than one log10 reduction in plasma viremia in the nonhuman primate system by loading of hep-ATIII into anti-HLA-DR immunoliposomes, which target tissue reservoirs of viral replication. We also demonstrate the utility of hep-ATIIII as a potential salvage agent for HIV strains resistant to standard anti-retroviral treatment. Finally, we applied gene-expression arrays to analyze hep-ATIII-induced host cell interactomes and found that downstream of hep-ATIII, two independent gene networks were modulated by host factors prostaglandin synthetase-2, ERK1/2 and NFκB. Ultimately, understanding how serpins, such as hep-ATIII, regulate host responses during HIV infection may reveal new avenues for therapeutic intervention

    Prior exposure to an attenuated Listeria vaccine does not reduce immunogenicity: pre-clinical assessment of the efficacy of a Listeria vaccine in the induction of immune responses against HIV

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    Abstract Background We have evaluated an attenuated Listeria monocytogenes (Lm) candidate vaccine vector in nonhuman primates using a delivery regimen relying solely on oral vaccination. We sought to determine the impact of prior Lm vector exposure on the development of new immune responses against HIV antigens. Findings Two groups of rhesus macaques one Lm naive, the other having documented prior Lm vector exposures, were evaluated in response to oral inoculations of the same vector expressing recombinant HIV-1 Gag protein. The efficacy of the Lm vector was determined by ELISA to assess the generation of anti-Listerial antibodies; cellular responses were measured by HIV-Gag specific ELISpot assay. Our results show that prior Lm exposures did not diminish the generation of de novo cellular responses against HIV, as compared to Listeria-naïve monkeys. Moreover, empty vector exposures did not elicit potent antibody responses, consistent with the intracellular nature of Lm. Conclusions The present study demonstrates in a pre-clinical vaccine model, that prior oral immunization with an empty Lm vector does not diminish immunogenicity to Lm-expressed HIV genes. This work underscores the need for the continued development of attenuated Lm as an orally deliverable vaccine

    Mitochondrial Calcium Uniporter (MCU) defciency reveals an alternate path for ­Ca2+ uptake in photoreceptor mitochondria

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    Rods and cones use intracellular Ca2+ to regulate many functions, including phototransduction and neurotransmission. The Mitochondrial Calcium Uniporter (MCU) complex is thought to be the primary pathway for Ca2+ entry into mitochondria in eukaryotes. We investigate the hypothesis that mitochondrial Ca2+ uptake via MCU influences phototransduction and energy metabolism in photoreceptors using a mcu-/- zebrafish and a rod photoreceptor-specific Mcu-/- mouse. Using genetically encoded Ca2+ sensors to directly examine Ca2+ uptake in zebrafish cone mitochondria, we found that loss of MCU reduces but does not eliminate mitochondrial Ca2+ uptake. Loss of MCU does not lead to photoreceptor degeneration, mildly affects mitochondrial metabolism, and does not alter physiological responses to light, even in the absence of the Na+/Ca2+, K+ exchanger. Our results reveal that MCU is dispensable for vertebrate photoreceptor function, consistent with its low expression and the presence of an alternative pathway for Ca2+ uptake into photoreceptor mitochondria

    The BLAST Survey of the Vela Molecular Cloud: Physical Properties of the Dense Cores in Vela-D

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    The Balloon-borne Large-Aperture Submillimeter Telescope (BLAST) carried out a 250, 350 and 500 micron survey of the galactic plane encompassing the Vela Molecular Ridge, with the primary goal of identifying the coldest dense cores possibly associated with the earliest stages of star formation. Here we present the results from observations of the Vela-D region, covering about 4 square degrees, in which we find 141 BLAST cores. We exploit existing data taken with the Spitzer MIPS, IRAC and SEST-SIMBA instruments to constrain their (single-temperature) spectral energy distributions, assuming a dust emissivity index beta = 2.0. This combination of data allows us to determine the temperature, luminosity and mass of each BLAST core, and also enables us to separate starless from proto-stellar sources. We also analyze the effects that the uncertainties on the derived physical parameters of the individual sources have on the overall physical properties of starless and proto-stellar cores, and we find that there appear to be a smooth transition from the pre- to the proto-stellar phase. In particular, for proto-stellar cores we find a correlation between the MIPS24 flux, associated with the central protostar, and the temperature of the dust envelope. We also find that the core mass function of the Vela-D cores has a slope consistent with other similar (sub)millimeter surveys.Comment: Accepted for publication in the Astrophysical Journal. Data and maps are available at http://blastexperiment.info
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