Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease

Prion diseases are fatal, transmissible, neurodegenerative diseases caused by the misfolding of the prion protein (PrP). At present, the molecular pathways underlying prion-mediated neurotoxicity are largely unknown. We hypothesized that the transcriptional regulator of the stress response, heat shock factor 1 (HSF1), would play an important role in prion disease. Uninoculated HSF1 knockout (KO) mice used in our study do not show signs of neurodegeneration as assessed by survival, motor performance, or histopathology. When inoculated with Rocky Mountain Laboratory (RML) prions HSF1 KO mice had a dramatically shortened lifespan, succumbing to disease ≈20% faster than controls. Surprisingly, both the onset of home-cage behavioral symptoms and pathological alterations occurred at a similar time in HSF1 KO and control mice. The accumulation of proteinase K (PK)-resistant PrP also occurred with similar kinetics and prion infectivity accrued at an equal or slower rate. Thus, HSF1 provides an important protective function that is specifically manifest after the onset of behavioral symptoms of prion disease

Cephalosporin-3’-diazeniumdiolate NO-donor prodrug PYRRO-C3D enhances azithromycin susceptibility of non-typeable Haemophilus influenzae biofilms

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Objectives: PYRRO-C3D is a cephalosporin-3-diazeniumdiolate nitric oxide (NO)-donor prodrug designed to selectively deliver NO to bacterial infection sites. The objective of this study was to assess the activity of PYRRO-C3D against non-typeable Haemophilus influenzae (NTHi) biofilms and examine the role of NO in reducing biofilm-associated antibiotic tolerance. Methods: The activity of PYRRO-C3D on in vitro NTHi biofilms was assessed through CFU enumeration and confocal microscopy. NO release measurements were performed using an ISO-NO probe. NTHi biofilms grown on primary ciliated respiratory epithelia at an air-liquid interface were used to investigate the effects of PYRRO-C3D in the presence of host tissue. Label-free LC/MS proteomic analyses were performed to identify differentially expressed proteins following NO treatment. Results: PYRRO-C3D specifically released NO in the presence of NTHi, while no evidence of spontaneous NO release was observed when the compound was exposed to primary epithelial cells. NTHi lacking β-lactamase activity failed to trigger NO release. Treatment significantly increased the susceptibility of in vitro NTHi biofilms to azithromycin, causing a log-fold reduction in viability (p<0.05) relative to azithromycin alone. The response was more pronounced for biofilms grown on primary respiratory epithelia, where a 2-log reduction was observed (p<0.01). Label-free proteomics showed that NO increased expression of sixteen proteins involved in metabolic and transcriptional/translational functions. Conclusions: NO release from PYRRO-C3D enhances the efficacy of azithromycin against NTHi biofilms, putatively via modulation of NTHi metabolic activity. Adjunctive therapy with NO mediated through PYRRO-C3D represents a promising approach for reducing biofilm associated antibiotic tolerance

Characterizing Multi-planet Systems with Classical Secular Theory

Classical secular theory can be a powerful tool to describe the qualitative character of multi-planet systems and offer insight into their histories. The eigenmodes of the secular behavior, rather than current orbital elements, can help identify tidal effects, early planet-planet scattering, and dynamical coupling among the planets, for systems in which mean-motion resonances do not play a role. Although tidal damping can result in aligned major axes after all but one eigenmode have damped away, such alignment may simply be fortuitous. An example of this is 55 Cancri (orbital solution of Fischer et al., 2008) where multiple eigenmodes remain undamped. Various solutions for 55 Cancri are compared, showing differing dynamical groupings, with implications for the coupling of eccentricities and for the partitioning of damping among the planets. Solutions for orbits that include expectations of past tidal evolution with observational data, must take into account which eigenmodes should be damped, rather than expecting particular eccentricities to be near zero. Classical secular theory is only accurate for low eccentricity values, but comparison with other results suggests that it can yield useful qualitative descriptions of behavior even for moderately large eccentricity values, and may have advantages for revealing underlying physical processes and, as large numbers of new systems are discovered, for triage to identify where more comprehensive dynamical studies should have priority.Comment: Published in Celestial Mechanics and Dynamical Astronomy, 25 pages, 10 figure

Electroreflectance spectroscopy in self-assembled quantum dots: lens symmetry

Modulated electroreflectance spectroscopy $\Delta R/R$ of semiconductor self-assembled quantum dots is investigated. The structure is modeled as dots with lens shape geometry and circular cross section. A microscopic description of the electroreflectance spectrum and optical response in terms of an external electric field (${\bf F}$) and lens geometry have been considered. The field and lens symmetry dependence of all experimental parameters involved in the $\Delta R/R$ spectrum have been considered. Using the effective mass formalism the energies and the electronic states as a function of ${\bf F}$ and dot parameters are calculated. Also, in the framework of the strongly confined regime general expressions for the excitonic binding energies are reported. Optical selection rules are derived in the cases of the light wave vector perpendicular and parallel to $$. Detailed calculation of the Seraphin coefficients and electroreflectance spectrum are performed for the InAs and CdSe nanostructures. Calculations show good agreement with measurements recently performed on CdSe/ZnSe when statistical distribution on size is considered, explaining the main observed characteristic in the electroreflectance spectra

Plasma Total Glutathione in Humans and its Association with Demographic and Health-Related Factors

The tripeptide glutathione is proposed to be protective against a number of chronic diseases including cardiovascular disease and cancer. However, there have been few studies of plasma glutathione levels in humans and in those studies the numbers of participants have been very small. In an exploratory analysis the determinants of plasma total glutathione (GSHt) were investigated in a group of 100 volunteers aged 18–61 years in Atlanta, Georgia, USA during June and July 1989. Data on demographic and health-related factors were collected by interview and plasma GSHt was measured using a recently modified laboratory method. The mean concentration of plasma GSHt for all 100 participants was 761 pg/1, with a standard deviation of 451 pg/1, a range of 86–2889 pg/1 and a median of 649 pg/1. Men had significantly higher levels of plasma GSHt than women (924 v. 692 pg/1; P = 0.006). Seventh-day Adventists participating in the present study had higher plasma GSHt levels than other subgroups defined by race and/or religion. Among Seventh-day Adventists consumption of a vegetarian diet was associated with increased plasma GSHt concentration (P = 0.002). Plasma GSHt levels also appeared to vary by race, but relationships with race could not be clearly disassociated from relationships with religion. Among white participants plasma GSHt concentration decreased with age in women but increased with age in men (P = 0.05). Few other factors were associated with plasma GSHt concentration, although use of oral contraceptives (P=0.10) was somewhat associated with decreased plasma GSHt levels. These findings suggest that plasma GSHt levels may vary with several demographic and health-related attributes and support the need for further research on this potentially important disease-preventive compound. © 1993, The Nutrition Society. All rights reserved

Optical Imaging and Spectroscopic Observation of the Galactic Supernova Remnant G85.9-0.6

Optical CCD imaging with H$\alpha$ and [SII] filters and spectroscopic observations of the galactic supernova remnant G85.9-0.6 have been performed for the first time. The CCD image data are taken with the 1.5m Russian-Turkish Telescope (RTT150) at TUBITAK National Observatory (TUG) and spectral data are taken with the Bok 2.3 m telescope on Kitt Peak, AZ. The images are taken with narrow-band interference filters H$\alpha$, [SII] and their continuum. [SII]/H$\alpha$ ratio image is performed. The ratio obtained from [SII]/H$\alpha$ is found to be $\sim$0.42, indicating that the remnant interacts with HII regions. G85.9-0.6 shows diffuse-shell morphology. [SII]$\lambda\lambda 6716/6731$ average flux ratio is calculated from the spectra, and the electron density $N_{e}$ is obtained to be 395 $cm^{-3}$. From [OIII]/H$\beta$ ratio, shock velocity has been estimated, pre-shock density of $n_{c}=14$ $cm^{-3}$, explosion energy of $E=9.2\times10^{50}$ ergs, interstellar extinction of $E(B-V)=0.28$, and neutral hydrogen column density of $N(HI)=1.53\times10^{21}$ $cm^{-2}$ are reported.Comment: 20 pages, 4 tables, 4 figures. Accepted for publication in Astrophysics & Space Scienc

Effect of the stellar spin history on the tidal evolution of close-in planets

We investigate how the evolution of the stellar spin rate affects, and is affected by, planets in close orbits, via star-planet tidal interactions. To do this, we used a standard equilibrium tidal model to compute the orbital evolution of single planets orbiting both Sun-like stars and 0.1 M\odot M-dwarfs. We tested two stellar spin evolution profiles, one with fast initial rotation (P=1.2 day) and one with slow initial rotation (P=8 day). We tested the effect of varying the stellar and planetary dissipation and the planet's mass and initial orbital radius. Conclusions: Tidal evolution allows to differentiate the early behaviors of extremely close-in planets orbiting either a rapidly rotating star or a slowly rotating star. The early spin-up of the star allows the close-in planets around fast rotators to survive the early evolution. For planets around M-dwarfs, surviving the early evolution means surviving on Gyr timescales whereas for Sun-like stars the spin-down brings about late mergers of Jupiter planets. In light of this study, we can say that differentiating between one spin evolution from another given the present position of planets can be very tricky. Unless we can observe some markers of former evolution it is nearly impossible to distinguish the two very different spin profiles, let alone intermediate spin profiles. Though some conclusions can still be drawn from statistical distributions of planets around fully convective M-dwarfs. However, if the tidal evolution brings about a merger late in its history it can also entail a noticeable acceleration of the star in late ages, so that it is possible to have old stars that spin rapidly. This raises the question of better constraining the age of stars

A One Health Framework for the Evaluation of Rabies Control Programmes: A Case Study from Colombo City, Sri Lanka

<div><p>Background</p><p>One Health addresses complex challenges to promote the health of all species and the environment by integrating relevant sciences at systems level. Its application to zoonotic diseases is recommended, but few coherent frameworks exist that combine approaches from multiple disciplines. Rabies requires an interdisciplinary approach for effective and efficient management.</p><p>Methodology/Principal Findings</p><p>A framework is proposed to assess the value of rabies interventions holistically. The economic assessment compares additional monetary and non-monetary costs and benefits of an intervention taking into account epidemiological, animal welfare, societal impact and cost data. It is complemented by an ethical assessment. The framework is applied to Colombo City, Sri Lanka, where modified dog rabies intervention measures were implemented in 2007. The two options included for analysis were the control measures in place until 2006 (“baseline scenario”) and the new comprehensive intervention measures (“intervention”) for a four-year duration. Differences in control cost; monetary human health costs after exposure; Disability-Adjusted Life Years (DALYs) lost due to human rabies deaths and the psychological burden following a bite; negative impact on animal welfare; epidemiological indicators; social acceptance of dogs; and ethical considerations were estimated using a mixed method approach including primary and secondary data. Over the four years analysed, the intervention cost US $1.03 million more than the baseline scenario in 2011 prices (adjusted for inflation) and caused a reduction in dog rabies cases; 738 DALYs averted; an increase in acceptability among non-dog owners; a perception of positive changes in society including a decrease in the number of roaming dogs; and a net reduction in the impact on animal welfare from intermediate-high to low-intermediate.</p><p>Conclusions</p><p>The findings illustrate the multiple outcomes relevant to stakeholders and allow greater understanding of the value of the implemented rabies control measures, thereby providing a solid foundation for informed decision-making and sustainable control.</p></div

Visual onset expands subjective time

We report a distortion of subjective time perception in which the duration of a first interval is perceived to be longer than the succeeding interval of the same duration. The amount of time expansion depends on the onset type defining the first interval. When a stimulus appears abruptly, its duration is perceived to be longer than when it appears following a stationary array. The difference in the processing time for the stimulus onset and motion onset, measured as reaction times, agrees with the difference in time expansion. Our results suggest that initial transient responses for a visual onset serve as a temporal marker for time estimation, and a systematic change in the processing time for onsets affects perceived time