Differential Regulation of Gonadotropin Synthesis and Release in Ovariectomized Ewes after Treatment with a Luteinizing Hormone-Releasing Hormone Antagonist

Our working hypothesis was that synthesis and release of LH, but not FSH, were solely dependent on LHRH. Twenty ovariectomized (OVX) ewes were randomly assigned to one of five treatments (n = 4 per group). Ewes were administered a low (10 μg/kg) or high (100 μg/kg) dose of LHRH antagonist (LHRH-Ant) at 24-h intervals for 3 or 6 days. Control ewes received vehicle (5% mannitol) at 24-h intervals for 6 days. Blood samples were collected every 15 min for 4 h before LHRH-Ant or vehicle and every 2 h during the period of treatment to determine concentrations of LH and FSH. Twenty-four hours after the last treatment with LHRH-Ant or vehicle, anterior pituitaries were collected and divided in half along the midsagittal plane; the number of receptors for LHRH, pituitary content of LH and FSH, and relative amounts of mRNA for α, LHβ, and FSHβ subunits were determined. Concentrations of LH in serum decreased (p \u3c 0.05) from 25.4 ± 4.3 ng/ml before LHRH-Ant to less than 0.5 ng/ml within 4 h after the first treatment of LHRH-Ant and remained low (\u3c 0.5 ng/ml) throughout the study. Serum concentrations of FSH declined gradually during the 3- or 6-day period of treatment with LHRH-Ant, from 37.3 ± 2.4 and 26.5 ± 4.8 ng/ml to 19.9 ± 1.8 and 13.7 ± 2.1 ng/ml, respectively. The magnitude of decline in serum concentrations of LH and FSH did not differ among ewes treated with low or high doses of LHRH-Ant. Pituitary content of LH was not different (p \u3e 0.10) from that in controls, whereas pituitary content of FSH was greater (p \u3c 0.01) in control ewes compared to ewes treated with LHRH-Ant. Receptors for LHRH were nondetectable (\u3c 0.018 x 10-16 mol receptor/μg protein) in pituitaries after 3 or 6 days of treatment with LHRH-Ant (low or high dose). Relative amounts of mRNA for α, LHβ, and FSHβ subunits were lower (p \u3c 0.01) after 6 days of treatment with LHRH-Ant (low or high dose) than after 3 days of treatment with LHRH-Ant (low or high dose). The LHRH was, therefore, required to maintain steady state amounts of mRNA for FSH and LH and to maintain pituitary stores of FSH but not LH. Our data support the hypothesis that differential regulation of LH and FSH release occurs in ewes. While synthesis and release of LH are dependent on LHRH, synthesis but not release of FSH appears to be dependent on LHRH

Mechanisms of Hearing Loss after Blast Injury to the Ear

Given the frequent use of improvised explosive devices (IEDs) around the world, the study of traumatic blast injuries is of increasing interest. The ear is the most common organ affected by blast injury because it is the bodyﾒs most sensitive pressure transducer. We fabricated a blast chamber to re-create blast profiles similar to that of IEDs and used it to develop a reproducible mouse model to study blast-induced hearing loss. The tympanic membrane was perforated in all mice after blast exposure and found to heal spontaneously. Micro-computed tomography demonstrated no evidence for middle ear or otic capsule injuries; however, the healed tympanic membrane was thickened. Auditory brainstem response and distortion product otoacoustic emission threshold shifts were found to be correlated with blast intensity. As well, these threshold shifts were larger than those found in control mice that underwent surgical perforation of their tympanic membranes, indicating cochlear trauma. Histological studies one week and three months after the blast demonstrated no disruption or damage to the intra-cochlear membranes. However, there was loss of outer hair cells (OHCs) within the basal turn of the cochlea and decreased spiral ganglion neurons (SGNs) and afferent nerve synapses. Using our mouse model that recapitulates human IED exposure, our results identify that the mechanisms underlying blast-induced hearing loss does not include gross membranous rupture as is commonly believed. Instead, there is both OHC and SGN loss that produce auditory dysfunction

The Noise Exposure Structured Interview (NESI): an instrument for the comprehensive estimation of lifetime noise exposure

Lifetime noise exposure is generally quantified by self report. The accuracy of retrospective self report is limited by respondent recall, but is also bound to be influenced by reporting procedures. Such procedures are of variable quality in current measures of lifetime noise exposure, and off-the-shelf instruments are not readily available. The Noise Exposure Structured Interview (NESI) represents an attempt to draw together some of the stronger elements of existing procedures and to provide solutions to their outstanding limitations. Reporting is not restricted to pre-specified exposure activities, and instead encompasses all activities that the respondent has experienced as noisy (defined based on sound level estimated from vocal effort). Changing exposure habits over time are reported by dividing the lifespan into discrete periods in which exposure habits were approximately stable, with life milestones used to aid recall. Exposure duration, sound level, and use of hearing protection are reported for each life period separately. Simple-to-follow methods are provided for the estimation of free-field sound level, the sound level emitted by personal listening devices, and the attenuation provided by hearing protective equipment. An energy-based means of combining the resulting data is supplied, along with a primarily energy-based method for incorporating firearm-noise exposure. Finally, the NESI acknowledges the need of some users to tailor the procedures; this flexibility is afforded and reasonable modifications are described. Competency needs of new users are addressed through detailed interview instructions (including troubleshooting tips) and a demonstration video. Limited evaluation data are available and future efforts at evaluation are proposed

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF

The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at the Fermilab Long-Baseline Neutrino Facility (LBNF) is described

Meeting Report: Validation of Toxicogenomics-Based Test Systems: ECVAM–ICCVAM/NICEATM Considerations for Regulatory Use

This is the report of the first workshop “Validation of Toxicogenomics-Based Test Systems” held 11–12 December 2003 in Ispra, Italy. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and organized jointly by ECVAM, the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). The primary aim of the workshop was for participants to discuss and define principles applicable to the validation of toxicogenomics platforms as well as validation of specific toxicologic test methods that incorporate toxicogenomics technologies. The workshop was viewed as an opportunity for initiating a dialogue between technologic experts, regulators, and the principal validation bodies and for identifying those factors to which the validation process would be applicable. It was felt that to do so now, as the technology is evolving and associated challenges are identified, would be a basis for the future validation of the technology when it reaches the appropriate stage. Because of the complexity of the issue, different aspects of the validation of toxicogenomics-based test methods were covered. The three focus areas include a) biologic validation of toxicogenomics-based test methods for regulatory decision making, b) technical and bioinformatics aspects related to validation, and c) validation issues as they relate to regulatory acceptance and use of toxicogenomics-based test methods. In this report we summarize the discussions and describe in detail the recommendations for future direction and priorities

Genome-wide survey of SNP variation uncovers the genetic structure of cattle breeds.

The imprints of domestication and breed development on the genomes of livestock likely differ from those of companion animals. A deep draft sequence assembly of shotgun reads from a single Hereford female and comparative sequences sampled from six additional breeds were used to develop probes to interrogate 37,470 single-nucleotide polymorphisms (SNPs) in 497 cattle from 19 geographically and biologically diverse breeds. These data show that cattle have undergone a rapid recent decrease in effective population size from a very large ancestral population, possibly due to bottlenecks associated with domestication, selection, and breed formation. Domestication and artificial selection appear to have left detectable signatures of selection within the cattle genome, yet the current levels of diversity within breeds are at least as great as exists within humans

The DUNE Far Detector Interim Design Report, Volume 3: Dual-Phase Module

The DUNE IDR describes the proposed physics program and technical designs of the DUNE far detector modules in preparation for the full TDR to be published in 2019. It is intended as an intermediate milestone on the path to a full TDR, justifying the technical choices that flow down from the high-level physics goals through requirements at all levels of the Project. These design choices will enable the DUNE experiment to make the ground-breaking discoveries that will help to answer fundamental physics questions. Volume 3 describes the dual-phase module's subsystems, the technical coordination required for its design, construction, installation, and integration, and its organizational structure

Long-baseline neutrino oscillation physics potential of the DUNE experiment

The sensitivity of the Deep Underground Neutrino Experiment (DUNE) to neutrino oscillation is determined, based on a full simulation, reconstruction, and event selection of the far detector and a full simulation and parameterized analysis of the near detector. Detailed uncertainties due to the flux prediction, neutrino interaction model, and detector effects are included. DUNE will resolve the neutrino mass ordering to a precision of 5σ, for all δ_(CP) values, after 2 years of running with the nominal detector design and beam configuration. It has the potential to observe charge-parity violation in the neutrino sector to a precision of 3σ (5σ) after an exposure of 5 (10) years, for 50% of all δ_(CP) values. It will also make precise measurements of other parameters governing long-baseline neutrino oscillation, and after an exposure of 15 years will achieve a similar sensitivity to sin²θ₁₃ to current reactor experiments

Long-baseline neutrino oscillation physics potential of the DUNE experiment

The sensitivity of the Deep Underground Neutrino Experiment (DUNE) to neutrino oscillation is determined, based on a full simulation, reconstruction, and event selection of the far detector and a full simulation and parameterized analysis of the near detector. Detailed uncertainties due to the flux prediction, neutrino interaction model, and detector effects are included. DUNE will resolve the neutrino mass ordering to a precision of 5σ, for all ΑCP values, after 2 years of running with the nominal detector design and beam configuration. It has the potential to observe charge-parity violation in the neutrino sector to a precision of 3σ (5σ) after an exposure of 5 (10) years, for 50% of all ΑCP values. It will also make precise measurements of other parameters governing long-baseline neutrino oscillation, and after an exposure of 15 years will achieve a similar sensitivity to sin22θ13 to current reactor experiments

Low exposure long-baseline neutrino oscillation sensitivity of the DUNE experiment

The Deep Underground Neutrino Experiment (DUNE) will produce world-leading neutrino oscillation measurements over the lifetime of the experiment. In this work, we explore DUNE's sensitivity to observe charge-parity violation (CPV) in the neutrino sector, and to resolve the mass ordering, for exposures of up to 100 kiloton-megawatt-years (kt-MW-yr). The analysis includes detailed uncertainties on the flux prediction, the neutrino interaction model, and detector effects. We demonstrate that DUNE will be able to unambiguously resolve the neutrino mass ordering at a 3$\sigma$ (5$\sigma$) level, with a 66 (100) kt-MW-yr far detector exposure, and has the ability to make strong statements at significantly shorter exposures depending on the true value of other oscillation parameters. We also show that DUNE has the potential to make a robust measurement of CPV at a 3$\sigma$ level with a 100 kt-MW-yr exposure for the maximally CP-violating values \delta_{\rm CP}} = \pm\pi/2. Additionally, the dependence of DUNE's sensitivity on the exposure taken in neutrino-enhanced and antineutrino-enhanced running is discussed. An equal fraction of exposure taken in each beam mode is found to be close to optimal when considered over the entire space of interest